Modular Synthesis of Chiral -Aminophosphine PN Ligands and ... · Modular Synthesis of Chiral...

Modular Synthesis of Chiral -Aminophosphine P,N-Ligands and Their Applications in Asymmetric

Catalysis

by

Yixiong Song

A thesis submitted in conformity with the requirements for the degree of Master of Science

Graduate Department of Chemistry University of Toronto

© Copyright by Yixiong Song 2015

ii

Modular Synthesis of Chiral -Aminophosphine P,N-Ligands and Their

Applications in Asymmetric Catalysis

Yixiong Song

Master of Science

Graduate Department of Chemistry

University of Toronto

2015

Abstract

A series of chiral -aminophosphine ligands bearing different carbon backbones and

electronically differentiated diarylphosphino groups were prepared using a modular approach.

These P,N-ligands were found to induce a modest level of enantioselectivities in the Pd-

catalyzed asymmetric decarboxylative allylation reaction. Thiourea-phosphine bifunctional

catalysts derived from the chiral -aminophosphine building blocks were prepared and applied to

the asymmetric Morita-Baylis-Hillman (MBH) reaction of methyl acrylate and 4-

nitrobenzaldehyde. The electronically unmodified diarylphosphino-thiourea was found to be

optimal for achieving high activity and enantioselectivity in this particular MBH reaction. We

also reported the synthesis of a P-chiral C2-symmetric bisphosphine ligand. However, the utility

of this Trost-type ligand remains to be explored in the future.

iii

Acknowledgments

iv

Table of Contents

Chapter 1. Modular Synthesis of -Aminophosphine P,N-Ligands and Their Applications in

the Pd-Catalyzed Asymmetric Decarboxylative Allylation Reaction ..................................... 1

1 Introduction ..................................................................................................................... 1

1.1 Overview of P,N-ligands in Asymmetric Catalysis .............................................. 1

1.2 Decarboxylative Allylation Reaction .................................................................10

2 Objectives .......................................................................................................................18

3 Results and Discussion ....................................................................................................19

3.1 Synthesis of -Substituted -Aminophosphines and Their appplications in the

Pd-Catalyzed Asymmetric Decarboxylative Allylation Reaction ........................19

3.2 Attempted Synthesis of -Disubstituted -Aminophosphines ...........................26

3.3 Attempted C–H Activation of (R)-2-Phenylglycinol ............................................31

4 Experimental ...................................................................................................................36

4.1 Procedures and Compounds................................................................................36

4.1 1H NMR,

13C NMR and

31P NMR Spectra ..........................................................53

Chapter 2. Synthesis of Bifunctional Thiourea-Phosphine Organocatalysts and Their

Applications in the Asymmetric Morita-Baylis-Hillman (MBH) Reaction ............................83

1 Introduction ....................................................................................................................83

1.1 Mechanism of the MBH Reaction ......................................................................83

1.2 The Asymmetric MBH Reaction........................................................................87

1.3 The Asymmetric aza-MBH Reaction ..................................................................91

1.4 Asymmetric Transformations Related to the MBH Reaction ................................95

2 Objectives .......................................................................................................................98

3 Results and Discussion ....................................................................................................98

4 Conclusion and Future Work ......................................................................................... 105

v

5 Experimental ................................................................................................................. 106

5.1 Procedures and Compounds.............................................................................. 106

5.2 1H NMR,

13C NMR and

31P NMR Spectra ........................................................ 116

5.3 X-Ray Crystallography Data ............................................................................ 139

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List of Abbreviations

(m) Medium

(s) Strong (w) Weak

°C Degrees Celsius

Ac Acetate

acac Acetylacetone

Ar Aryl

Boc tert-Butyloxycarbonyl

Bn Benzyl

Bz Benzoyl

cod 1,5-Cyclooctadiene

DART Direct Analysis in Real Time dba Dibenzylideneacetone

DCC Dicyclohexylcarbodiimide

DMAP 4-Dimethylaminopyridine

DMF Diastereomeric ratio

ee Enantiomeric excess

er Enantiomeric ratio

eq. Equivalent

ESI Electro-spray ionisation

Et Ethyl

EWG Electron withdrawing group

g Grams HRMS High resolution mass spectrometry

i-Pr iso-Propyl

IR Infra red

L Ligand

Leu Leucine

M Molar

m- meta m/z Mass/charge ratio

Me Methyl

MeCN Acetonitrile mg Milligrams

MHz Mega hertz

min. Minutes

mL Milliliters

n-Bu normal-Butyl

nbd Norbornadiene

NMR Nuclear magnetic resonance

Nu Nucleophile

o- ortho p- para PMP para-methoxyphenyl

vii

TBAB Tetrabutylammonium bromide

TBAB Tetrabutylammonium chloride

TBS tert-Butyldimethylsilyl

t-Bu tert-Butyl

Tf Triflate

THF Tetrahydrofuran Ts Tosyl

v/v Volume per volume

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List of Tables

Table 1. Scope for secondary phosphine oxides .......................................................................24

Table 2. Scope for -substituted--aminophosphine oxides .....................................................24

Table 3. Scope for -substituted--aminophosphines...............................................................25

Table 4. Screening of P,N-ligands for decarboxylative allylic alkylation ..................................26

Table 5. Decomposition products isolated in the reduction of aminophosphine oxide ...............30

Table 6. Scope for thiourea-phosphine catalysts ......................................................................98

Table 7. Screening of bifunctional catalysts in the MBH reaction ............................................98

Table 8. Screening of P-chiral bifunctional catalysts in the MBH reaction ............................. 102

Table 9. Screening of P-chiral C2-symmetrical bisphosphine ligand in Pd-catalyzed AAA

reaction ................................................................................................................................ 103

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List of Figures

Figure 1. X-ray crystal data Pd -allyl complex ....................................................................... 2

Figure 2. The exo-endo equilibrium of the Pd-allyl complex ..................................................... 3

Figure 3. 31

P NMR spectra of ring-opening reaction using KOtBu and NaOtBu .......................23

Figure 4. X-ray crystal structure of thiourea-phosphine-borane 2.28a .................................... 100

x

List of Schemes

Scheme 1. Asymmetric allylic substitution reactions of 1,3-dialkylallyl acetates using PHOX

ligand ...................................................................................................................................... 2

Scheme 2. Asymmetric allylic substitution of 1,3-dimethylallyl acetate with dimethyl malonate 4

Scheme 3. Asymmetric allylic substitution of cyclic substrates with dimethyl malonate............. 4

Scheme 4. Intermolecular asymmetric Heck reaction using PHOX and BINAP ligands ............. 5

Scheme 5. Ir-catalyzed asymmetric hydrogenation of non-functionalized olefins ....................... 5

Scheme 6. Asymmetric hydroboration-oxidation of arylalkenes using Rh-QUINAP .................. 5

Scheme 7. Asymmetric diboration-oxidation of olefins using Rh-QUINAP ............................... 6

Scheme 8. Asymmetric three component condensation employing QUINAP and its analog ....... 6

Scheme 9. Asymmetric Kumada coupling reaction using -aminophosphine ............................. 7

Scheme 10. Cu-catalyzed conjugated addition of diethylzinc to enones using iminophosphine ... 8

Scheme 11. Ru-catalyzed asymmetric tandem Michael addition/hydrogenation of cyclic enone . 8

Scheme 12. Fe-catalyzed hydrogenation of esters and N-heterocycles ....................................... 9

Scheme 13. Fe-catalyzed asymmetric hydrogenation of ketones and activated imines ................ 9

Scheme 14. The Tsuji reaction ................................................................................................10

Scheme 15. Proposed catalytic cycle of the decarboxylative allylic alkylation of allyl enol

carbonates and allyl β-keto esters ............................................................................................11

Scheme 16. The initial report of enantioselective Tsuji reaction using Trost P,P-ligand and

PHOX P,N-ligand ...................................................................................................................11

Scheme 17. Asymmetric decarboxylative allylic alkylation using Trost ligands ........................12

Scheme 18. Asymmetric decarboxylative allylic alkylation using PHOX 1.4 and 1.16 ..............13

xi

Scheme 19. Synthesis of chiral -fluoroketones through decarboxylative allylic alkylation ......14

Scheme 20. Enantioselective decarboxylative enolate alkylation cascade .................................14

Scheme 21. Ir-catalyzed allylic alkylation of -substituted β-ketoesters ...................................15

Scheme 22. Sequential allylic alkylation catalyzed by Ir and Pd complexes ..............................16

Scheme 23. Proposed mechanism by Stoltz and Goddard for asymmetric decarboxylative allylic

alkylation using PHOX ..........................................................................................................17

Scheme 24. Proposed mechanism by Trost for asymmetric decarboxylative allylic alkylation

using Trost ligand ...................................................................................................................17

Scheme 25. Asymmetric decarboxylative allylic alkylation of cis-1.18 using Trost ligand ........18

Scheme 26. Asymmetric decarboxylative allylic alkylation using -aminophosphin .................18

Scheme 27. Modular synthesis of -aminophosphines .............................................................18

Scheme 28. Conventional synthesis of chiral -aminophosphines ............................................19

Scheme 29. Previous literature reports on synthesis of chiral -aminophosphines via tosyl

displacement...........................................................................................................................20

Scheme 30. Synthesis of chiral -aminophosphines via cyclic sulfamidates..............................21

Scheme 31. The first successful ring-opening of cyclic sulfamidate with secondary phosphine

oxide ......................................................................................................................................22

Scheme 32. Tautomerism of secondary phosphine oxides ........................................................22

Scheme 33. Competing reaction pathways in the ring-opening of cyclic sulfamidate with

secondary phosphine oxide......................................................................................................23

Scheme 34. Reductive amination of P,N-ligand .......................................................................26

xii

Scheme 35. Attempted ring-opening of 1,2-disubstituted cyclic sulfamidate with secondary

phosphine oxide ......................................................................................................................27

Scheme 36. Decomposition pathway of benzylic tosylate ........................................................27

Scheme 37. Ring-opening of cyclic sulfamidates with fluoride ................................................28

Scheme 38. Ring-opening and P-alkylation of cyclic sulfamidates ...........................................29

Scheme 39. Attempted synthesis of -disubstituted -aminophosphine derived from 1-amino-

2-indanol 1.42.........................................................................................................................31

Scheme 40. -C−H arylation of alanine ..................................................................................32

Scheme 41. Hypothetical divergent synthesis of -substituted -aminophosphines via C–H

activation ................................................................................................................................33

Scheme 42. Known C–H activation of primary benzylamines .................................................34

Scheme 43. Synthesis of starting materials for C–H activation .................................................34

Scheme 44. Attempted C–H iodination using I2 .......................................................................35

Scheme 45. Regeneration of Pd(OAc)2 from PdI2 ....................................................................35

Scheme 46. Attempted C–H iodination using IOAc .................................................................36

Scheme 47. The Morita-Baylis-Hillman reaction .....................................................................83

Scheme 48. Mechanism of MBH reaction proposed in 1980s ...................................................84

Scheme 49. Kinetic study of MBH reaction by Hill and Issac ..................................................84

Scheme 50. Kinetic study performed by McQuade et al. ..........................................................85

Scheme 51. Mechanism of MBH reaction revised by McQuade and Aggarwal .........................85

Scheme 52. Asymmetric MBH reaction using a quinidine derivative as a bifunctional catalyst .87

xiii

Scheme 53. Asymmetric MBH reaction using quinidine binaphthyl thiourea-tertiary amine 2.2 88

Scheme 54. Asymmetric MBH reaction using cyclohexyl thiourea-phosphine 2.3 ....................88

Scheme 55. Asymmetric MBH reaction using threonine derived thiourea-phosphine 2.4 ..........89

Scheme 56. Asymmetric MBH reaction using acid-base co-catalyst systems ...........................90

Scheme 57. Asymmetric aza-MBH reaction using quinidine derivatives ..................................91

Scheme 58. Asymmetric aza-MBH reaction using BINOL derived bifunctional catalyst ...........92

Scheme 59. Asymmetric aza-MBH reaction using thiourea/DABCO cocatalyst system ............93

Scheme 60. Asymmetric aza-MBH reaction using phosphine-sulfonamide catalyst 2.12 ...........93

Scheme 61. Enantioselective [3+2] annulation of allenoate with acrylate..................................94

Scheme 62. Mechanism of [3+2] annulation of allenoate with acrylate .....................................95

Scheme 63. Asymmetric Michael addition of oxindoles catalyzed by chiral phosphine .............95

Scheme 64. Mechanism of asymmetric Michael addition catalyzed by chiral phosphine ...........96

Scheme 65. Asymmetric Michael addition reaction and aza-Henry reaction catalyzed by chiral

phosphines..............................................................................................................................96

Scheme 66. Asymmetric MBH reaction catalyzed by amino acid based thiourea-phosphines ....97

Scheme 67. P-chiral phosphino-thiourea catalysts ..................................................................99

Scheme 68. Synthesis of unsymmetrical secondary phosphine oxide ........................................99

Scheme 69. Synthesis of P-chiral phosphine-thiourea catalysts .............................................. 101

Scheme 70. Synthesis of P-chiral C2-symmetrical bisphosphine ligands ................................. 102

Scheme 71. AAA reactions using Trost ligand ...................................................................... 102

xiv

Scheme 72. Rh-catalyzed asymmetric hydrosilylation of ketones ........................................... 105

1

Chapter 1

Modular Synthesis of -Aminophosphine P,N-Ligands and Their Applications in the Pd-Catalyzed

Asymmetric Decarboxylative Allylation Reaction

1 Introduction

1.1 Overview of P,N-Ligands in Asymmetric Catalysis

P,N-ligands are an important class of ligands for asymmetric catalysis. P,N-ligands are highly

effective in promoting a variety of metal-catalyzed enantioseletive transformations, including

asymmetric allylic alkylation, asymmetric hydrogenation, and enantioselective diboration of

alkenes.1 P,N-ligands contain two electronically distinct donor atoms: a “hard” nitrogen atom

with -donor property and a “soft” phosphorus atom that can act as botha -donor and a -

acceptor. This combination of mixed donors exerts regiocontrol when applied to the context of

-allyl metal complexes where the allylic terminus trans to the phosphorus donor is

preferentially attacked by the incoming nucleophile.1c

The thermodynamic trans effect of P,N-

ligands is reflected by the different Pd–C distances in the X-ray crystal structure (Figure 1).1a

PHOX ligands developed independently by the groups of Helmchen, Pfaltz and Williams,2 give

rise to reactive palladium complexes in the asymmetric allylic substitution reactions of

symmetric allylic acetates, providing up to 99% ee for 1,3-diphenylallyl acetate with dimethyl

1 a) Pfaltz, A.; Drury, W. J. Proc. Natl. Acad. Sci. USA. 2004, 101, 5723–5726. b) ern nde , E.; Guiry, P.

2 a) Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure Appl. Chem. 1997, 69, 513−518. b)

Pfaltz, A. Acta Chem. Scand. B 1996, 50, 189−194. c) Williams, J. M. J. Synlett 1996, 705−710.

2

malonate. However, diminishing enantioselectivities were observed for smaller alkyl groups.

Interestingly, there was no selectivity for cyclohexene-2-yl acetate using this ligand (Scheme 1).3

Figure 1. X-ray crystal data Pd -allyl complex

3 Helmchen, G.; Pfaltz, A. Acc. Chem. Res.2000, 33, 336−345.

3

Scheme 1. Asymmetric allylic substitution reactions of 1,3-dialkylallyl acetates using PHOX

ligand

Figure 2. The exo-endo equilibrium of the Pd-allyl complex

Mechanistic investigations using NMR spectroscopy revealed a rapid equilibrium between

two conformers of the -allyl intermediates in a ratio of 9:1 in favor of the exo conformation

(Figure 2).3 Assuming subsequent nucleophilic attack only occurs at the allylic terminus trans to

the P-donor, the enantiomeric ratio of the product is determined by the exo/endo ratio. The X-ray

crystal structure of the more stable exo conformer of the Pd -allyl complex suggested that the

endo diastereomer is destabilized by the steric clash between the equatorial P-aryl group of the

4

PHOX ligand and the phenyl group of the allyl substrate.5 The energy difference between the

two diastereomers diminishes as the steric demand of the allyl substituent decreases and thus

results in the erosion of exo/endo ratio and the enantioselectivity. The modified ligand 1.2 gave

90% ee for 1,3-dimethylallyl acetate (Scheme 2), while 1.3 provided excellent ee for cyclic

substrates (Scheme 3).3

Scheme 2. Asymmetric allylic substitution of 1,3-dimethylallyl acetate with dimethyl malonate

Scheme 3. Asymmetric allylic substitution of cyclic substrates with dimethyl malonate

In addition to their application in the asymmetric allylic substitution reactions, PHOX ligands

have shown great potential in intermolecular asymmetric Heck reaction, providing significant

improvement in yields and/or enantioselectivities compared to bisphosphine ligands (Scheme

4).4 Lastly, the Ir-PHOX system is uniquely effective in the asymmetric hydrogenation of non-

functionalized olefins. Ir-PHOX system can be complementary to Rh- and Ru-bisphosphine

catalyst systems that are selective toward functionalized olefins containing coordinating groups

such as amides and carboxylic acids in close proximity to the double bond (Scheme 5).5

4 McCartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122−5150.

5 a) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402−1411. b) erendel mies

i gue , M.; Andersson, P. G. Chem. Rev. 2014, 114, 2130−2169.

5

Scheme 4. Intermolecular asymmetric Heck reaction using PHOX and BINAP ligands

Scheme 5. Ir-catalyzed asymmetric hydrogenation of non-functionalized olefins

The axially chiral P,N-ligand, QUINAP, that was introduced concurrently with the PHOX

ligands in 1993, was successfully employed in the asymmetric hydroboration-oxidation of

styrene derivatives using catecholborane, achieving good to excellent enantioselectivity for a

wider range of alkenes compared to the initial Rh-BINAP system (Scheme 6).1a

Scheme 6. Asymmetric hydroboration-oxidation of arylalkenes using Rh-QUINAP

In 2003, Morken’s group reported a highly enantioselective syn-addition of

bis(catecholato)diboron across trans-disubstituted alkenes.6 However, the enantioselectivity was

6 Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003, 125, 8702−8703.

6

less satisfactory for other classes of alkene substrates (Scheme 7). In the same year, Knochel’s

group developed a powerful three-component coupling reaction between an aldehyde, a

secondary amine, and an alkyne using Cu-QUINAP as the catalyst system, giving good yields

and ees when dibenzylamines were coupled with a wide range of aliphatic aldehydes and alkynes

(Scheme 8). More recently, another variant of QUINAP 1.8 was developed to address some of

the challenging aldehyde substrates reported previously (Scheme 8). 7

Scheme 7. Asymmetric diboration-oxidation of olefins using Rh-QUINAP

Scheme 8. Asymmetric three component condensation employing QUINAP and its analog 1.8

7 a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed. 2003, 42, 5763−

5766. b) Gommermann, N.; Knochel, P. Chem. Eur. J. 2006, 12, 4380−4392. c) Cardoso, F. S. P.;

Abboud, K. A.; Aponick, A. J. Am. Chem. Soc. 2013, 135, 14548−14551.

7

-Aminophosphines, which can be readily prepared from chiral amino acids, were first used by

Hayashi and Kumada in the asymmetric Kumada coupling reaction (Scheme 9). The hemilabile

property of the amine group proved to be critical for obtaining high enantioselectivity. During

the enantio-discriminatig step, the dimethylamino group on the ligand is believed to dissociate

from the nickel centre and bind preferentially with one of the enantiomers of Grignard reagent.

Subsequent transmetallation and reductive elimination give enantio-enriched products in up to

94% ee (Scheme 9).8

Scheme 9. Asymmetric Kumada coupling reaction using -aminophosphine ligand 1.9

Iminophosphine 1.10 was shown to be a competent chiral ligand for the Cu-catalyzed conjugated

addition of diethylzinc to enones (Scheme 10).9

8 a) Hayashi, T.; Fukushima, M.; Konishi, M.; Kumada, M. Tetrahedron Lett. 1980, 21, 79−82. b)

Grushin, V. V. Chem. Rev. 2004, 104, 1629−1662.

9 Saitoh, A.; Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry 1997, 8, 3567.

8

Scheme 10. Cu-catalyzed conjugated addition of diethylzinc to enones using iminophosphine

1.10

Morris and coworkers developed a ruthenium hydride borohydride complex 1.11 containing -

aminophosphine ligand and demonstrated its utility in the highly enantioselective tandem

Michael addition /H2-hydrogenation of the cyclic enone (Scheme 11).10

Scheme 11. Ru-catalyzed asymmetric tandem Michael addition/hydrogenation of cyclic enone

More recently, Guan et al. and Jones et al. reported the use of an earth-abundant and nontoxic

iron-based catalyst bearing a PNP-pincer ligand in the hydrogenation of esters and N-

heterocycles (Scheme 12). 11

10 a) Guo, R.; Morris, R. H.; Song, D. J. Am. Chem. Soc. 2005, 127, 516−517. b) Guo, R.; Lough, A. J.;

Morris, R. H.; Song, D. Organometallics 2004, 23, 5524−5529. c) Abdur-Rashid, K.; Guo, R.; Lough, A.

J.; Morris, R. H.; Song. Adv. Synth. Catal. 2005, 347, 571−579.

11 Chakraborty, S.; Dai, H.; Bhattacharya, P.; Fairweather, N. T.; Gibson, M. S.; Krause, J. A.; Guan, H. J.

Am. Chem. Soc. 2014, 136, 7869−7872. b) Chakraborty, S.; Brennessel, W. W.; Jones, W. D. J. Am.

Chem. Soc. 2014, 136, 8564−8567.

9

Scheme 12. Fe-catalyzed hydrogenation of esters and N-heterocycles

Morris et al. achieved good to excellent enantioselectivities in the asymmetric hydrogenation of

ketones and activated imines employing an iron precatalyst 1.13 containing unsymmetrical N ’

pincer ligand (Scheme 13).12

Scheme 13. Fe-catalyzed asymmetric hydrogenation of ketones and activated imines

12 a) Lagaditis, P. O.; Sues, P. E.; Sonnenberg, J. F.; Wan, K. Y.; Lough, A. J.; Morris, R. H. J. Am.

Chem. Soc. 2014, 136, 1367−1380. b) Sonnenberg, J. F.; Lough, A. J.; Morris, R. H. Organometallics

2014, 33, 6452−6465.

10

In addition to their role as ligands for transition metals, -aminophosphines are receiving new

attention as the building blocks for chiral bifunctional catalysts in the field of organocatalysis,

which will be discussed in Chapter 2.

1.2 Decarboxylative Allylation Reaction

The decarboxylative allylic alkylation reaction, discovered by Tsuji and co-workers in the 1980s,

allows the construction of all-carbon quaternary centres from allyl enol carbonates or allyl β-keto

esters precursors under mild and neutral conditions (Scheme 14).13

The preparation of these α-

quaternary ketones would otherwise have been difficult under basic conditions, due to the

regioselectivity issue caused by two enolizable protons with very similar pKa values.

Scheme 14. The Tsuji reaction

The proposed mechanism is shown in Scheme 15. The coordination and ionization of the allyl

moiety by the Pd(0) complex takes place to generate a palladium carbonate intermediate, and

subsequent decarboxylation of the carbonate leads to the palladium enolate intermediate. This in

13 a) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793–1796. b) Shimizu, I.; Yamada, T.;

Tsuji, J. Tetrahedron Lett. 1980, 21, 3199–3202.

11

situ generated enolate nucleophile then recombines with the palladium -allyl electrophile to

give the product and regenerates the catalyst.14

Scheme 15. Proposed catalytic cycle of the decarboxylative allylic alkylation of allyl enol

carbonates and allyl β-keto esters

The first enantioselective variant of the Tsuji reaction was reported independently by the Trost

group and the Stoltz group employing different ligands (Scheme 16).15,16

Scheme 16. The initial report of enantioselective Tsuji reaction using Trost P,P-ligand and

PHOX P,N-ligand

14 a) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381–6384. b)

Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140–145. 15

Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044–15045.

16 Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846–2847.

12

Trost was able to obtain excellent enantioselectivities for mostly benzannulated substrates using

the bisphosphine ligand 1.14. The substrate scope was further expanded by the same group and

the group of Murakami to include vinylogous esters and thioesters, acyclic carbonates and allyl

-acetamido--keto carboxylates (Scheme 17).17

Scheme 17. Asymmetric decarboxylative allylic alkylation using Trost ligands

Stoltz et al. discovered that PHOX ligands provided excellent reactivity and high

enantioselectivity for carbocyclic and heterocyclic substrates with tolerance to a wide array of

17 a) Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem. Int. Ed. 2006, 45, 3109–3112. b) Trost, B. M.; Xu,

J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343–18357. c) Kuwano, R.; Ishida, N.; Murakami, M.

Chem. Commun. 2005, 31, 3951–3952.

13

substituents and functionalities.18

The electron-deficient variant of the original PHOX ligand

PHOX 1.16 was identified to significantly enhance the rate, ee or dr of the reaction and thus is

key for achieving a broad substrate scope (Scheme 18).19

Scheme 18. Asymmetric decarboxylative allylic alkylation using PHOX 1.4 and 1.16

A notable expansion of the reaction scope was made by Nakamura to prepare enantio-enriched

α-fluoroketones (Scheme 19).20

18 a) Hong, A.Y.; Stoltz, B. M. Eur. J. Org. Chem. 2013, 14, 2745–2759. b) Liu, Y.; Han, S. J.; Liu, W. -B.;

Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740–751.

19 Craig II, R. A.; Stoltz, B. M. Tetrahedron Lett. 2015, 56, 4670–4673.

20 Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem. Int. Ed. 2005, 44, 7248–7251.

14

Scheme 19. Synthesis of chiral -fluoroketones through decarboxylative allylic alkylation

Interestingly, Stoltz et al. showed that the enolate nucleophile can be trapped with a Michael

acceptor before allylic alkylation, giving rise to cyclic ketones bearing adjacent quaternary and

tertiary stereocenters (Scheme 20). However, excellent diastereoselectivity was achieved only for

a limited number of substrates.21

Scheme 20. Enantioselective decarboxylative enolate alkylation cascade

Alternatively, ketones bearing adjacent quaternary and tertiary stereocenters can be obtained by

Ir-catalyzed allylic alkylation of -substituted β-ketoesters employing phosphoramide as the

21 Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2010, 2 192−196

15

chiral ligand (Scheme 21). Excellent regio‑, diastereo‑, and enantioselectivities were achieved

for both the cyclic and acyclic substrates using different lithium salt additives.22

Scheme 21. Ir-catalyzed allylic alkylation of -substituted β-ketoesters

To add another level of sophistication to the system, Stoltz demonstrated that using a cleverly

devised 2-(trimethylsilyl)ethyl -ketoester can lead to sequential double allylic alkylation using

the Ir-phosphoramide/Pd-PHOX dual catalyst system. Treatment with fluoride triggered a

cascade degradation of the 2-(trimethylsilyl)ethyl group and exposed the prochiral enolate to Pd-

allyl electrophile. The consecutive allylic alkylation reaction furnished the products with

excellent diastereo‑ and enantioselectivities (Scheme 22).19b

22 a) Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 17298–17301. b) Liu, W.-B.;

Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 10626–10629.

16

Scheme 22. Sequential allylic alkylation catalyzed by Ir and Pd complexes

The mechanism of the Pd-catalyzed decarboxylative allylic alkylation reaction of enol

carbonates has been investigated by both the Stoltz and the Trost groups. Based on theoretical

calculations, Stoltz and Goddard proposed that a relatively stable pentacoordinated-

allylpalladium enolate complex exo-5 is formed following the decarboxylation (Scheme 23).

This pentacoordinate species rearranges to the tetracoordinate -allylpalladium enolate complex

(Re/Si)-8. Furthermore, the Re/Si faces of the enolate interact differently with PHOX ligand

during the transition state. Therefore, the formation of (Re/Si)-8 could be the enantio-

determining step, provided that the rotation barrier (currently unknown) about Pd-O bond is large

enough to prevent racemization of (Re/Si)-8. (Re/Si)-8 then undergoes an uncommon pericyclic

reductive rearrangement transition state that is different from the traditional three-centered

reductive elimination. Hence, the final product is believed to be generated via an “inner sphere”

mechanism.23

23 a) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.;

Goddard, W. A. J. Am. Chem. Soc. 2007, 129, 11876–11877. b) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R. J.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc.

2012, 131, 19050–19060.

17

Scheme 23. Proposed mechanism by Stoltz and Goddard for asymmetric decarboxylative allylic

alkylation using PHOX

Trost and coworkers argued that covalently bonded palladium enolate, even if it exists, would

equilibrate with the tight enolate/-allylpalladium ion-pair and an “outer sphere” SN2 attack of

the enolate on the -allylpalladium complex should mostly likely be the operating mechanism

(Scheme 24). To support their argument, they carried out an enantioselective Tsuiji reaction

using enol carbonate cis-1.18 in the presence of a bisphosphine ligand (Scheme 25).14b

The cis

configuration from the starting material is preserved in the product. This result provides strong

evidence for a double inversion “outer sphere” mechanism that is common for allylic alkylation

of “soft” nucleophiles.

Scheme 24. Proposed mechanism by Trost for asymmetric decarboxylative allylic alkylation

using Trost ligand

18

Scheme 25. Asymmetric decarboxylative allylic alkylation of cis-1.18 using Trost ligand

2 Objectives

Previous research in our group showed that electron-deficient -aminophosphine 1.20 displayed

excellent reactivity and induced good enantioselectivity in the decarboxylative allylation of enol

carbonate (Scheme 26).

Scheme 26. Asymmetric decarboxylative allylic alkylation using -aminophosphine

In order to further improve the enantioselectivity of the reaction, we aimed to generate a ligand

library using a novel modular approach recently developed in our lab (Scheme 27).

Scheme 27. Modular synthesis of -aminophosphines

3 Results and Discussion

19

3.1 Synthesis of -Substituted -Aminophosphines and Their

Applications in Decarboxylative Allylation Reaction

Traditionally, chiral -aminophosphines are prepared from chiral 1,2-aminoalcohols in four

synthetic steps: Boc-protection of the primary amine, tosylation of the alcohol followed by

displacement of the tosyl group with potassium diphenylphosphide, and, finally, deprotection of

the Boc group (Scheme 28).24

Scheme 28. Conventional synthesis of chiral -aminophosphines

There are reports in the literature that describe the successful syntheses of these -

aminophosphines from the corresponding tosylate precursors.(Scheme 29 (1) and (2))21

There

are also findings where these -amino tosylates fall short of serving as precursor to the desired

phosphine products (Scheme 29 (3) and (4))25

A major drawback of this approach is the

formation of aziridine that cannot be re-opened by KPPh2. Changing the Boc protecting group to

phthalimide only led to the formation of the another side product via neighboring group

participation of the amide carbonyl group.

24 a) Saitoh, A.; Uda, T.; Morimoto, T. Tetrahedron: Asymmetry 1999, 10, 45014511. b) Quirmbach, M.;

Holz, J.; Tararov, V. I.; Borner, A.Tetrahedron 2000, 56, 775780.

25 a) Anderson, J. C.; Cubbon, R. J.; Harling, J. D. Tetrahedron: Asymmetry 2001, 12, 923935. b)

Christoffers, J. Helvetica Chimica Acta. 1998, 81, 845852.

20

Scheme 29. Previous literature reports on synthesis of chiral -aminophosphines via tosyl

displacement

21

To get around such these previous complications, Guo et al. demonstrated that a variety of chiral

1,2-aminoalcohols can be reliably converted to stable N-Boc protected cyclic sulfamidates. The

ring opening of these cyclic sulfamidates with potassium diphenylphosphide followed by the

deprotection of Boc affords chiral aminophosphines in good yields (Scheme 30).26

Scheme 30. Synthesis of chiral -aminophosphines via cyclic sulfamidates

However, the reaction was only demonstrated for diphenylphosphino and BINAP-phosphepine

moieties. Attempts to synthesize electron-deficient P,N-ligand by simply switching the

nucleophile to bis(4-(trifluoromethyl)phenyl)phosphanide failed to deliver any desired product.27

In light of this limitation, we set out to develop a modified version of this method that would

permit easy modification of the diaryl substituents on the phosphine group.

26 Guo, R.; Lu, S.; Chen, X.; Tsang, C.-W.; Jia, W.; Sui-Seng, C.; Amoroso, D.; Abdur-Rashid, K. J. Org.

Chem. 2010, 75, 937940.

27 J. Su, unpublished results

22

Scheme 31. The first successful ring-opening of cyclic sulfamidate with secondary phosphine

oxide

It was identified that the combination of potassium tert-butoxide and bis(4-

(trifluoromethyl)phenyl) phosphine oxides was able to open the cyclic sulfamidate (Scheme

31).24

Efforts towards optimizing the reaction conditions revealed two other competing pathways.

Firstly, it is known that penta-valent secondary phosphine oxides can tautomerize in solution to

trivalent phosphinous acids under neutral condition (Scheme 32).28

Under basic conditions, the

oxygen atom can potentially compete with the phosphorus atom that would otherwise give rise to

the desired product (Scheme 33 (1) and (2)). 24

Another side reaction is the oxidation of

secondary phosphine oxides (phosphinous acids) to phosphinic acids (Scheme 33 (3)) which is

hydrophilic and dissolves in the aqueous layer during workup.29

Scheme 32. Tautomerism of secondary phosphine oxides

28 Christiansen, A.; Li, C.; Garland, M.; Selent, D.; Ludwig, R.; Spannenberg, A.; Baumann, W.; Franke,

R.; Börner, A. Eur. J. Org. Chem. 2010, 2010, 27332741.

29 Tsvetkov, E. N.; Bondarenko, N. A.; Malakhova, I. G.; Kabachnik, M. I. Synthesis, 1986, 3, 198208.

23

Scheme 33. Competing reaction pathways in the ring-opening of cyclic sulfamidate with

secondary phosphine oxide

We reasoned that the use of “hard” metal cation that associates tighter with the oxygen atom

should suppress O-alkylation and favor the “soft” P-alkylation. Indeed, switching from KOtBu to

NaOtBu effectively suppressed O-alkylation as shown in Figure 3.

Figure 3. 31

P NMR spectra of ring-opening reaction using KOtBu and NaOtBu

B

A

B

A KOtBu NaOtBu

24

In addition, we carried out these ring-opening reactions in degassed THF under inert atmosphere

to minimize the oxidation of secondary phosphine oxides. Various secondary phosphine oxide

precursors were prepared by reacting the in situ generated Grignard reagents with diethyl

phosphite (Table 1). With the optimized reaction conditions, several sterically and electronically

differentiated aryl groups were installed on the phosphorus atom (Table 2).

Table 1. Scope for secondary phosphine oxides

Table 2. Scope for -substituted--aminophosphine oxides

25

The -aminophosphine oxides were then successfully reduced using diphenylsilane at 140 °C

(Table 3).30

Due to the air-sensitive nature of organophosphines, the final P,N-ligands are

purified through flash column chromatography using degassed eluent under argon.

Table 3. Scope for -substituted--aminophosphines

Electron-deficient P,N-ligands 1.32 and 1.36 were tested in the decarboxylative allylation

reaction of enol carbonate (Table 4). Both ligands promoted the reaction to full conversion.

However, the ee values were lower than what has been achieved using 1.20. To answer whether

or not functionalizing the primary amine group would improve the enantioselectivity, ligand 1.38

was prepared by reductive amination of ligand 1.27 followed by reduction of 1.37 (Scheme 34).

Unfortunately, ligand 1.38 did not display any catalytic activity. Considering the fact that

electron-withdrawing groups such as 4-trifluoromethylphenyl group on the phosphine has been

found to be optimal for these decarboxylative allylation reactions, we turned our attention toward

optimizing the enantioselectivity of the reaction further by introducing a second chirality centre

onto the carbon backbone of the P,N-ligand.

30 McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2010, 51,

55505554.

26

Table 4. Screening of P,N-ligands for decarboxylative allylic alkylation

Scheme 34. Reductive amination of P,N-ligand

3.2 Attempted Synthesis of ,-Disubstituted -Aminophosphines

Unfortunately, attempts to open 1,2-disubstituted cyclic sulfamidate 1.39 with our previously

optimized condition only resulted in full recovery of the starting material. Switching the base

back to KOtBu gave only O-alkylated side product (Scheme 35). The second phenyl substituent

most likely blocks the electrophilic carbon from the incoming phosphorus nucleophile. As a

result of this, only the smaller oxygen nucleophile can approach and thus open up the ring.

27

Scheme 35. Attempted ring-opening of 1,2-disubstituted cyclic sulfamidate with secondary

phosphine oxide

We were then prompted to reconsider the possibility of using an open-chain, conformationally

less rigid electrophile that could permit easier access for the incoming phosphorus nucleophile

through carbon-carbon bond rotation. However, the isolation of the benzylic tosylate

intermediate was not possible according to Guo et al., due to neighboring group participation of

the Boc group, which rapidly displaces the tosyl group to form oxazolidinone as the only product

(Scheme 36).23

Scheme 36. Decomposition pathway of benzylic tosylate

28

We considered whether we could install a less labile leaving group so that the intermediate

would be more resistant against the intramolecular cyclization of the Boc group, but at the same

time be adequately reactive towards intermolecular SN2 attack of the secondary phosphine oxide

nucleophile. Commonly employed leaving groups such as chloride and bromide naturally came

to mind. Although the required benzylic chloride and bromide had not been known in the

literature, the ring-opening of cyclic sulfamidates with a fluoride is precedented as a means to

prepare 18

F-labeled compounds for imaging through Positron Emission Tomography (PET)

(Scheme 37). 31

Scheme 37. Ring-opening of cyclic sulfamidates with fluoride

Knowing this, we decided to try opening the cyclic sulfamidate with tetra-n-butylammonium

chloride and bromide. Gratifyingly, the reactions proceeded to full conversion after stirring at

room temperature overnight and the products were isolated in 87 and 33 % yield, respectively

(Scheme 38). Next, to test whether the halides could be displaced by a phosphorus nucleophile,

the two intermediates were treated with secondary phosphine oxides under basic conditions. We

found that while the benzylic chloride was unreactive, the benzylic bromide afforded the product

in 40% yield. After deprotection of the Boc group, however, all efforts to reduce the

aminophosphine oxide 1.41 to the aminophosphine failed (Table 5). Heating 1.41 neat with

diphenylsilane at 140 °C resulted in the liberation of secondary phosphine oxide 1.21 through C–

P bond cleavage. Treatment of 1.41 with BH3▪SMe at 70 °C, led to the cleavage of C–C bond.32

The use of 1,1,3,3-tetramethyldisiloxane (TMDS) with catalytic amount of Ti(OiPr)4 also

31 VanDort, M. E.; Jung, Y.-W.; Sherman, P. S.; Kilbourn, M. R.; Wieland, D. M. J. Med. Chem. 1995, 38,

810815.

32 Hérault, D.; Nguyen, D. H.; Nuela, D.; Buono, G. Chem. Soc. Rev. 2015, 44, 25082528.

29

resulted in C–C bond cleavage.33

It seems that the phosphine oxide starting material is prone to

decomposition in the presence of a Lewis acid.

Scheme 38. Ring-opening and P-alkylation of cyclic sulfamidates

33 M. Berthod, A. Favre-Réguillon, J. Mohamad, G. Mignani, G. Docherty, M. Lemaire, Synlett, 2007,

15451548.

30

Table 5. Decomposition products isolated in the reduction of aminophosphine oxide

Another synthetic target that we examined was derived from 1-amino-2-indanol 1.42 (Scheme

39). The tosylate intermediate 1.43 was expected to be stable from ring-closure because the tosyl

group and the Boc group are locked in a cis configuration. The two known decomposition

pathways - aziridination and oxazolidinone formation - require the neighboring group to

approach from the opposite side. Surprisingly, treatment of tosylate 1.43 with secondary

phosphine oxide and base only resulted in the full recovery of the starting material. Switching to

a more reactive triflate group afforded the product 1.45 in modest yield. The attempt to remove

the Boc group with trifluoroacetic acid led to P–C bond cleavage, suggesting that the product is

unstable towards acidic conditions. Instead, stirring 1.45 with zinc bromide overnight

successfully hydrolyzed the Boc group and furnished the product 1.46 in good purity after work

up. It should be noted that, eluting the crude product through a silica gel column resulted in

complete decomposition of 1.46. Unfortunately, the desired phosphine product was not observed

31

by 31

P spectroscopy even with attempted reduction of the crude phosphine oxide mixture using

either diphenylsilane or BH3.

Scheme 39. Attempted synthesis of -disubstituted -aminophosphine derived from 1-amino-

2-indanol 1.42

3.3 Attempted C–H activation of (R)-2-phenylglycinol

Given the daunting synthetic challenge of -disubstituted -aminophosphines, we turned our

attention back to the ligand scaffold bearing a single chiral centre. By this time, we had almost

exhausted the small pool of commercially available chiral 1,2-aminoalcohols that could be

relevant to our research. We were therefore drawn to the idea of modifying the existing chiral

backbone through C–H activation. The power of this approach was demonstrated recently by Yu

and his collaborators in Bristol-Myers Squibb, where simple alanine was transformed into a

diverse range of non-natural amino acids through sequential sp3 C–H arylation. The resulting

32

amino acids were readily reduced to amino alcohols which were used to make novel BOX and

PyBOX ligands (Scheme 40).34

Scheme 40. -C−H arylation of alanine

For our system, we hypothesized using the primary amine to direct sp2 ortho-functionalization of

2-phenylglycinol (Scheme 41). If successful, the resulting novel amino alcohols could be

transformed into P,N-ligands using our established methodology.

34 Chen, G.; Shigenari, T.; Jain, P.; Zhang, Z.; Jin, Z.; He, J.; Li, S.; Mapelli, C.; Miller, M. M.; Poss, M.

A.; Scola, P. M.; Yeung, K.; Yu, J. Q. J. Am. Chem. Soc. 2015, 137, 33383351.

33

Scheme 41. Hypothetical divergent synthesis of -substituted -aminophosphines via C–H

activation

Although ortho-palladation of N,N-dialkylbenzylamines is well-known, the first synthetically

relevant C–H activation using primary benzylamine as the directing group was not reported until

2006 (Scheme 42).35

Under rather harsh reaction conditions, the ortho-diarylation of

benzylamines possessing only simple hydrocarbon backbones was realized and the products

were isolated as trifluoroacetamides in decent yields. More recently, Yu and coworkers reported

an enantioselective C–H iodination of benzyamines via kinetic resolution employing I2 as the

sole oxidant (Scheme 42).36

The C–H activation of one of the enantiomers is selectively

accelerated by the addition of matched ligand – either L or D mono-protected amino acid. The

drawback of this approach was the generation of a 1:1 mixture of mono- and di-iodinated

products. However, this limitation may not necessarily be a pitfall for an initial screening as it

effectively increases the chemical space covered by the ligand library.

35 Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 52115213.

36 Chu, L.; Xiao, K. J.; Yu, J. Q. Science. 2014, 346, 451455.

34

Scheme 42. Known C–H activation of primary benzylamines

With this hypothesis in mind, we decided to try the C–H iodination of enantiopure (R)-2-

phenylglycinol using the matched D-amino acid ligand. The synthesis of the starting materials is

presented in Scheme 40. The amino-alcohol 1.47 was sequentially protected with a triflyl and a

tert-butyldimethylsilyl group in 61% yield over two steps. D-leucine 1.50 was treated with

benzoyl chloride in aqueous sodium hydroxide to give N-Bz-(D)-Leu 1.51 in 75% isolated yield.

Scheme 43. Synthesis of starting materials for C–H activation

The C–H iodination reaction was set up using the conditions as reported by Yu and coworkers.

However, the reaction came to a halt at low conversion after stirring vigorously at room

temperature for 48 hours. The ratio of starting material, the mono- and diiodinated product ratio

was found to be around 2:1:0.25 by integration of the 1H NMR spectrum (Scheme 44). The

35

turnover number of the palladium catalyst was calculated to be around 4. Several attempts to

improve the conversion, including increasing the temperature, varying the palladium-to-ligand

ratio, and adjusting the solvent ratio, proved fruitless. The only way to improve the conversion

was by increasing the palladium loading. Based on these results, we suspected that the inactive

PdI2 formed after two catalytic cycles was not being effectively converted back to the reactive

Pd(OAc)2 by CsOAc, Na2CO3 and DMSO, a combination of reagents that was previously shown

to regenerate the active catalyst in a different reaction (Scheme 45).37

Scheme 44. Attempted C–H iodination using I2

Scheme 45. Regeneration of Pd(OAc)2 from PdI2

We wondered whether we could prevent the formation of PdI2 in the first place by using IOAc as

the oxidant. IOAc, generated by mixing I2 with AgOAc or PhI(OAc)2, had been employed by Yu

37 Wang, X.; Hu, Y.; Bonacorsi, S.; Hong, Y.; Burrell, R.; Yu, J. Q. J. Am. Chem. Soc. 2013, 135,

1032610329.

36

and coworkers as the C–H iodination reagent before they discovered the conditions (Scheme 45)

that enabled them to adopt the much more practical I2 for C–H iodination.38

The result we

obtained from the use of IOAc is presented in Scheme 46. We observed predominantly the di-

iodinated product along with a negligible amount of mono-iodinated product, and the turnover

number was improved to around 7. However, full conversion of the starting material was not

attained even with a 20 mol% Pd loading. From a practical perspective, no further C–H

iodination reaction was attempted beyond this point.

Scheme 46. Attempted C–H iodination using IOAc

4 Experimental

4.1 Procedures and Compounds

General procedure for preparing diaryl secondary phosphine oxides 1.21–1.24.

Bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.21)

Mg turnings (0.56 g, 23 mmol) were activated with iodine in diethyl ether (12 mL) and 1-bromo-

4-(trifluoromethyl)benzene (5 g, 22 mmol) was added at 0 °C. The mixture was stirred under

gentle reflux for 90 min. Diethyl phosphite (1.02 g, 7.4 mmol) was then added dropwise at 0 ºC.

38 Giri, R.; Chen, X.; Yu, J. Q. Angew. Chem. Int. Ed. 2005, 44, 21122115.

37

The reaction mixture was stirred at room temperature for 14 h. 2N Hydrochloric acid (12 mL)

was added dropwise at 0 ºC and the mixture was stirred at 23 ºC for 5 min. Extraction with

diethyl ether followed by purification by column chromatography (Hexanes /EtOAc, 3:1 v/v)

afforded phosphine oxide 1 (1.5 g, 61%) as a yellow solid.

1H NMR (300 MHz, CDCl3) δ 8 20 (d, J (P-H) = 492 Hz, 1H), 7.96 – 7.74 (m, 10H).

13C NMR

(101 MHz, CDCl3) δ 134 84 (dd J = 33.0, 3.0 Hz), 134.82 (d, J = 100.0 Hz), 131.19 (d, J = 12.0

Hz), 126.04 (dq, J = 13.2, 3.8 Hz), 123.30 (dd, J = 272.9, 1.1 Hz).31

P NMR (121 MHz, CDCl3) δ

17.81.

Di-o-tolylphosphine oxide (1.22)

Synthesized according to general procedure using 1-bromo-2-methylbenzene (5.68 g, 33.2

mmol), Mg turning (834 mg, 34.3 mmol) and diethyl phosphite (1.53 g, 11 mmol). Purified by

flash chromatography on silica gel (EtOAc /CH2Cl2, 1:4 v/v) to afford 1.22 (1.38 g, 55%) as a

white solid.

1H NMR (400 MHz, CDCl3) δ 8 19 (d J = 477.6 Hz, 1H), 7.70 (m, 2H), 7.45 (m, 2H), 7.31 (m,

2H), 7.23 (m, 1H), 2.36 (s, 6H). 13

C NMR (101 MHz, CDCl3) δ 141 08 (d J = 9.9 Hz), 132.52

(d, J = 2.7 Hz), 132.42 (d, J = 11.8 Hz), 131.22 (d, J = 10.3 Hz), 129.29 (d, J = 100.2 Hz),

126.04 (d, J = 12.8 Hz), 20.15 (d, J = 7.0 Hz). 31

P NMR (121 MHz, CDCl3) δ 17 64

Bis(4-methoxyphenyl)phosphine oxide (1.23)

Synthesized according to general procedure using 1-bromo-4-methoxybenzene (5.98 g, 32.0

mmol), Mg turning (802 mg, 33.0 mmol) and diethyl phosphite (1.47 g, 10.7 mmol). Purified by

flash chromatography on silica gel (100% EtOAc) to afford 1.23 (1.08 g, 39%) as a white solid.

38

1H NMR (400 MHz, CDCl3) δ 8 01 (d = 478 0 H 1H) 7 71 – 7.52 (m, 4H), 7.07 – 6.94 (m,

4H), 3.83 (s, 6H). 13

C NMR (101 MHz, CDCl3) δ 162 92 (d J = 2.9 Hz), 132.67 (d, J = 13.0 Hz),

122.92 (d, J = 108.0 Hz), 114.46 (d, J = 13.9 Hz), 55.39. 31


Diphenylphosphine oxide (1.24)

Synthesized according to general procedure using bromobenzene (5.98 g, 38.1 mmol), Mg

turning (957 mg, 39.4 mmol) and diethyl phosphite (1.75 g, 12.7 mmol). Purified by flash

chromatography on silica gel (100% EtOAc) to afford 1.24 (1.48 g, 57%) as a white solid.

1H NMR (300 MHz, CDCl3) δ 8 08 (d J = 480.2 Hz, 1H), 7.71 (m, 4H), 7.63 – 7.45 (m, 6H).

13C NMR (101 MHz, CDCl3) δ 131 26 (d J = 10.4 Hz), 130.74 (d, J = 11.4 Hz), 128.94 (d, J =

12.9 Hz), 128.29 (d, J = 13.3 Hz). 31


General procedure for preparing cyclic sulfamidates 1.25, 1.26, 1.39.

tert-Butyl (S)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.25)

A solution of (Boc)2O (520 mg, 2.4 mmol) in THF (4 mL) was added to a mixture of (S)-2-

amino-3-methyl-1-butanol (220 mg, 2.1 mmol) and sodium carbonate (0.5 g, 4.7 mmol) in

THF/H2O (1/1, 8 mL) at 0 ºC. The mixture was stirred at room temperature for 3 h. Water was

added to the mixture and was extracted with ethyl acetate. The combined organic layer was

washed with brine, dried over anhydrous MgSO4, and concentrated to afford the crude product in

quantitative yield as a colorless viscous liquid, which was used in the next step without

purification.

39

Pyridine (1 g, 10 mmol) was added dropwise to a solution of N-Boc-protected (S)-2-amino-3-

methyl-1-butanol (426mg, 2.10 mmol) and SOCl2 (621 mg, 5.2 mmol) in MeCN (6 mL) at -40

ºC. The reaction mixture was allowed to warm up and stirred at room temperature for 3 h. Water

was added to quench the reaction at 0 ºC. The aqueous layer was extracted with ethyl acetate.

The organic phase was dried over anhydrous MgSO4 and concentrated to afford an orange color

oil. The residual was azeotroped three times with toluene and was dried on high vacuum to

remove pyridine. The crude product was used for the next step without purification.

RuCl3∙3H2O (30 mg, 0.146 mmol) was added to a solution of cyclic sulfamidite (0.45 g) in

CH3CN/H2O (1:1, 10 mL) at 0 ºC. NaIO4 (0.67 g, 3.13 mmol) was added in one portion. The

reaction was stirred at room temperature for 14 h. The aqueous layer was extracted with diethyl

ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated.

The residual was re-dissolved in CH2Cl2 and was filtered through a short plug of silica to remove

Ru catalyst. The solvent was removed in vacuo to afford the final product (293mg, 53% over

three steps) as a white or slightly yellow crystalline solid.

1H NMR (400 MHz, CDCl3) δ 4 57 (dd J = 9.5, 6.4 Hz, 1H), 4.39 (dd, J = 9.5, 1.8 Hz, 1H), 4.19

(ddd, J = 6.4, 5.2, 1.8 Hz, 1H), 2.27 (pd, J = 6.9, 5.2 Hz, 1H), 1.55 (s, 9H), 1.02 (d, J = 6.9 Hz,

3H), 0.97 (d, J = 7.0 Hz, 3H). 13

C NMR (101 MHz, CDCl3) δ 149 10 85 34 67 02 62 01, 30.04,

27.89, 18.00, 16.46.

tert-Butyl (R)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.26)

Synthesized according to general procedure using (R)-2-amino-2-phenylethan-1-ol (364 mg, 2.65

mmol). The final product 1.26 (380 mg, 48% over three steps) was obtained as a white

crystalline solid.

40

1H NMR (300 MHz, CDCl3) δ 7 56 – 7.34 (m, 5H), 5.44 – 5.19 (dd, J = 6.7, 4.2 Hz, 1H), 4.87

(dd, J = 9.2, 6.7 Hz, 1H), 4.41 (dd, J = 9.2, 4.2 Hz, 1H), 1.43 (s, 9H). 13

C NMR (101 MHz,

CDCl3) δ 148 28 136 95, 129.26, 129.15, 126.17, 85.59, 71.79, 60.77, 27.83.

tert-Butyl (4R,5S)-4,5-diphenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.39)

Synthesized according to general procedure using (1S,2R)-2-amino-1,2-diphenylethan-1-ol (521

mg, 2.44 mmol). The final product 1.39 (666 mg, 72% over three steps) was obtained as a white

crystalline solid.

1H NMR (399 MHz, CDCl3) δ 7 16 (m 6H) 7 10 – 7.01 (m, 2H), 6.96 – 6.88 (m, 2H), 6.16 (d, J

= 5.6 Hz, 1H), 5.42 (d, J = 5.6 Hz, 1H), 1.49 (s, 9H). 13

C NMR (101 MHz, CDCl3) δ 148 24

133.53, 130.57, 129.31, 128.53, 128.42, 128.37, 128.27, 127.21, 126.27, 85.67, 83.36, 66.60,

27.89.

General procedure for preparing aminophosphine oxides 1.27–1.31.

(S)-(2-Amino-3-methylbutyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.27)

Bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.21 (186 mg, 0.55 mmol) was added to a

solution of sodium tert-butoxide (53 mg, 0.55 mmol) in degassed THF (5 mL) under inert

atmosphere. The mixture was stirred for 5 min. tert-Butyl (S)-4-isopropyl-1,2,3-oxathiazolidine-

3-carboxylate 2,2-dioxide 1.25 solid (146 mg, 0.55 mmol) was added and the reaction mixture

was stirred at 60 for 3 h. The reaction was quenched with 2N H2SO4 (4 mL) at room

41

temperature and the mixture was stirred for another 20 min. Extraction with diethyl ether

followed by purification by flash chromatography on silica gel (EtOAc /CH2Cl2, 1:4 v/v).

Trifluoroacetic acid (1.1 mL, 14.3 mmol) was added to a solution of the purified product in dry

CH2Cl2 (5 mL) at 0 °C. The reaction was allowed to warm up and stirred at room temperature for

3 h. Saturated Na2CO3 was added dropwise to the solution at 0 °C. The aqueous layer was

extracted with CH2Cl2. The combined organic layer was dried over MgSO4 and concentrated to

afford the final product 1.27 (160 mg, 69%) as colorless oil.

1H NMR (300 MHz, CDCl3) δ 7 98 – 7.82 (m, 4H), 7.79 – 7.68 (m, 4H), 3.07 (m, 1H), 2.67 –

2.18 (m, 2H), 1.91 (s, 2H), 1.67 (m, 1H), 0.88 (app dd, J = 6.8, 5.6 Hz, 6H). 13

C NMR (101

MHz, CDCl3) δ 137 69 (d J = 95.4 Hz), 136.53 (d, J = 96.3 Hz), 134.48 – 134.00 (m), 134.00 –

133.58 (m), 131.36 (d, J = 9.5 Hz), 131.03 (d, J = 9.8 Hz), 126.26 – 125.46 (m), 124.78, 122.06,

52.01 (d, J = 4.6 Hz), 34.71 (d, J = 12.7 Hz), 33.75 (d, J = 72.9 Hz), 18.29, 17.51. 31

P NMR

(121 MHz, CDCl3) δ 30 79 IR (neat, cm-1

): 3044 (w), 2961 (w), 1684 (w), 1400 (m), 1317 (s),

1183 (m), 1163 (s), 1117 (s), 1100 (s), 1060 (s), 1017 (s), 840 (m), 790 (m), 764 (m), 708 (s),

670 (m). Optical rotation: []D20

(c 1.15, CHCl3) = +26.8. HRMS (DART-TOF) m/z: [M + H]+

calcd for C19H21F6NOP 424.12649; found 424.12666.

(S)-(2-Amino-3-methylbutyl)di-o-tolylphosphine oxide (1.28)

Synthesized according to general procedure using di-o-tolylphosphine oxide 1.22 (115 mg, 0.5

mmol), sodium tert-butoxide (48 mg, 0.5 mmol) and tert-Butyl (S)-4-isopropyl-1,2,3-

oxathiazolidine-3-carboxylate 2,2-dioxide 1.25 (133 mg, 0.5 mmol). The intermediate was

purified by flash chromatography on silica gel (EtOAc /CH2Cl2, 1:3 v/v) before treatment of

trifluoroacetic acid. The final product 1.28 (67 mg, 42%) was isolated as a colorless oil.

1H NMR (300 MHz, CDCl3) δ 7 81 (ddd J = 12.5, 7.7, 1.5 Hz, 1H), 7.64 (ddd, J = 12.9, 7.7, 1.4

Hz, 1H), 7.46 – 7.34 (m, 2H), 7.34 – 7.24 (m, 2H), 7.24 – 7.12 (m, 2H), 3.21 – 2.89 (m, 1H),

2.49 – 2.45 (m, 2H), 2.46 – 2.34 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 1.79 – 1.61 (m, 1H), 0.87

42

(app t, 6H). 13

C NMR (101 MHz, CDCl3) δ 141 68 (d J = 8.4 Hz), 141.21 (d, J = 8.8 Hz),

132.43 (d, J = 9.6 Hz), 132.05 (d, J = 96.4 Hz), 132.01 , 131.91 , 131.89 , 131.87 , 131.30 (d, J =

11.1 Hz), 130.65 (d, J = 95.3 Hz), 125.79 (d, J = 6.6 Hz), 125.68 (d, J = 7.0 Hz), 52.16 (d, J =

4.0 Hz), 34.52 (d, J = 12.8 Hz), 32.37 (d, J = 71.9 Hz), 21.26 (d, J = 4.0 Hz), 21.15 (d, J = 4.4

Hz), 18.22, 17.88. 31

P NMR (121 MHz, CDCl3) δ 35 29 IR (neat, cm-1

): 2957 (m), 2871 (w),

1593 (m), 1568 (m), 1452 (s), 1385 (m), 1283 (m), 1174 (s), 1138 (s), 1084 (w), 1071 (w), 927

(m), 805 (m), 751 (s), 730 (s), 688 (m). Optical rotation: []D20

(c 1.45, CHCl3) = +68.7.

HRMS (DART-TOF) m/z: [M + H]+

calcd for C19H27F6NOP 316.18303, found 316.18342.

(S)-(2-Amino-3-methylbutyl)bis(4-methoxyphenyl)phosphine oxide (1.29)

Synthesized according to general procedure using bis(4-methoxyphenyl)phosphine oxide 1.23

(105 mg, 0.4 mmol), sodium tert-butoxide (39 mg, 0.4 mmol) and tert-Butyl (S)-4-isopropyl-

1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 1.25 (106 mg, 0.4 mmol). The intermediate was

purified by flash chromatography on silica gel (MeOH /CH2Cl2, 1:50 v/v) before treatment of


1H NMR (399 MHz, CDCl3) δ 7 69 – 7.54 (m, 4H), 6.93 (m, 4H), 3.80 (s, 3H), 3.77 (s, 3H), 3.00

(dddd, J = 11.7, 9.6, 4.9, 2.6 Hz, 1H), 2.69 (s, 3H), 2.36 – 2.09 (m, 2H), 1.65 (pd, J = 6.8, 4.8 Hz,

1H), 0.83 (app t, J = 6.7 Hz, 6H). 13

C NMR (100 MHz, CDCl3) δ 162 28 (d J = 2.8 Hz), 162.23

(d, J = 2.9 Hz), 132.73 (d, J = 10.5 Hz), 132.30 (d, J = 10.8 Hz), 125.41 (d, J = 105.3 Hz),

123.37 (d, J = 104.8 Hz), 55.31 (d, J = 1.6 Hz), 55.27 (d, J = 1.7 Hz), 52.00 (d, J = 4.3 Hz),

34.41 (d, J = 12.7 Hz), 33.91 (d, J = 72.8 Hz), 18.16, 17.74. 31


33.14. IR (neat, cm-1

): 2956 (m), 2839 (w), 1596 (s), 1570 (m), 1503 (s), 1463 (m), 1408 (m),

1292 (s), 1253 (s), 1173 (s), 1119 (s), 1026 (s), 930 (m), 829 (s), 802 (s), 762 (m), 729 (m), 660

(m). Optical rotation: []D20

(c 3.5, CHCl3) = +36.1. HRMS (DART-TOF) m/z: [M + H]+ calcd

for C19H27NO3P 348.17285, found 348.17327.

43

(S)-(2-Amino-3-methylbutyl)diphenylphosphine oxide (1.30)

Synthesized according to general procedure using diphenylphosphine oxide 1.24 (162 mg, 0.8

mmol), sodium tert-butoxide (77 mg, 0.8 mmol) and tert-Butyl (S)-4-isopropyl-1,2,3-

oxathiazolidine-3-carboxylate 2,2-dioxide 1.25 (212 mg, 0.8 mmol). The intermediate was

purified by flash chromatography on silica gel (MeOH /CH2Cl2, 1:50 v/v) before treatment of


1H NMR (400 MHz, CDCl3) δ 7 73 (m 4H) 7 57 – 7.35 (m, 6H), 3.04 (dddd, J = 12.0, 10.0, 4.9,

2.3 Hz, 1H), 2.48 (br s, 2H), 2.37 (ddd, J = 15.0, 9.2, 2.3 Hz, 1H), 2.26 (ddd, J = 15.0, 12.0, 10.0

Hz, 1H), 1.66 (m, 1H), 0.85 (app t, J = 7.1 Hz, 6H). 13

C NMR (101 MHz, CDCl3) δ 134.00 (d, J

= 98.7 Hz), 132.33 (d, J = 98.3 Hz), 131.77 (app t, J = 2.8 Hz), 130.93 (d, J = 9.1 Hz), 130.47 (d,

J = 9.3 Hz), 128.75 (d, J = 1.5 Hz), 128.63 (d, J = 1.6 Hz), 51.95 (d, J = 4.3 Hz), 34.57 (d, J =

12.7 Hz), 33.79 (d, J = 71.9 Hz), 18.20 , 17.66 . 31

P NMR (162 MHz, CDCl3) δ 32 83 IR (neat,

cm-1

): 2958 (m), 2871 (w), 1401 (m), 1591 (w), 1465 (w), 1437 (s), 1387 (s), 1179 (s), 1119 (s),

1028 (m), 997 (m), 930 (m), 744 (s), 719 (s). Optical rotation: []D20

(c 1.3, CHCl3) = +41.7.

HRMS (DART-TOF) m/z: [M + H]+ calcd for C17H23NOP 288.15173, found 288.15217.

(R)-(2-Amino-2-phenylethyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.31)

Synthesized according to general procedure using bis(4-(trifluoromethyl)phenyl)phosphine oxide

1.21 (244 mg, 0.72 mmol), potassium tert-butoxide (81 mg, 0.72 mmol) and tert-Butyl (R)-4-

phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 1.26 (180 mg, 0.6 mmol). The

intermediate was purified by flash chromatography on silica gel (EtOAc /CH2Cl2, 1:9 v/v) before

44

treatment of trifluoroacetic acid. The final product 1.31 (100 mg, 35%) was isolated as a white

solid.

1H NMR (300 MHz, CDCl3) δ 7 93 – 7.77 (m, 4H), 7.77 – 7.65 (m, 4H), 7.39 – 7.11 (m, 5H),

4.51 (ddd, J = 10.5, 9.0, 4.0 Hz, 1H), 2.90 – 2.60 (m, 2H), 1.94 (s, 2H). 13

C NMR (101 MHz,

CDCl3) δ 144 99 (s) 144 87 (s) 131 29 (d), 130.93 (d), 128.76, 127.78, 126.10, 125.71 (dt, J =

11.9, 3.8 Hz), 51.27 (d, J = 3.4 Hz), 39.52 (d, J = 69.9 Hz). 31


IR (neat, cm-1

): 2900 (w), 1496 (w), 1456 (w), 1400 (m), 1321 (s), 1165 (s), 1120 (s), 1100 (s),

1061 (s), 1017 (s), 835 (m), 789 (m), 768 (m), 742 (m), 708 (m), 696 (s). Optical rotation:

[]D20

(c 0.3, CHCl3) = –18.7. HRMS (DART-TOF) m/z: [M + H]+ calcd for C22H19F6NOP

458.11084, found 458.11092.

General procedures for preparing aminophosphines 1.32–1.36 through silane reduction

(S)-1-(Bis(4-(trifluoromethyl)phenyl)phosphanyl)-3-methylbutan-2-amine (1.32)

Diphenylsilane (0.29 g, 1.58 mmol) was added into a 2 dram vial containing (S)-(2-amino-3-

methylbutyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.27 (96 mg, 0.23 mmol). The

reaction was heated at 140 under inert atmosphere for 14 h. The reaction was allowed to cool

down to room temperature and the crude mixture was directly loaded onto silica gel column. The

eluent was degassed in advance through sparging with argon for 20 min. The crude product was

purified through silica gel flash column chromatography using 50:1 v/v CH2Cl2/MeOH under a

positive pressure of argon. The final product 1.32 (53 mg, 57%) was isolated as a colorless oil.

1H NMR (300 MHz, CDCl3) δ 7 78 – 7.41 (m, 8H), 2.63 (m, 1H), 2.33 (m, 1H), 2.04 (m, 1H),

1.72 (m, 1H), 0.90 (app dd, J = 7.9, 6.8 Hz, 6H). 13

C NMR (101 MHz, CDCl3) δ 143 81 (d J =

15.5 Hz), 142.57 (d, J = 16.8 Hz), 133.50 (d, J = 19.8 Hz), 132.64 (d, J = 18.4 Hz), 131.23 (d, J

= 32.4 Hz), 130.69 (d, J = 32.6 Hz), 125.89 – 124.91 (m), 54.19 (d, J = 13.1 Hz), 34.58 (d, J =

45

7.4 Hz), 34.37 (d, J = 12.3 Hz), 18.85, 17.05. 31

P NMR (121 MHz, Chloroform-d) δ -20.39.

HRMS (DART-TOF) m/z: [M + H]+ calcd for C19H21F6NP 408.13158, found 408.13147.

(S)-1-(Di-o-tolylphosphanyl)-3-methylbutan-2-amine (1.33)

Synthesized according to general procedure using diphenylsilane (0.26 g, 1.4 mmol) and (S)-(2-

amino-3-methylbutyl)di-o-tolylphosphine oxide 1.28 (63 mg, 0.20 mmol). Purified by flash

chromatography on silica gel (MeOH /CH2Cl2, 1:50 v/v) to afford 1.33 (36 mg, 61%) was

isolated as a colorless oil.

1H NMR (400 MHz, CDCl3) δ 7 25 – 7.10 (m, 8H), 2.81 – 2.63 (m, 1H), 2.45 (s, 3H), 2.43 (s,

3H), 2.25 (ddd, J = 13.8, 4.4, 1.6 Hz, 1H), 1.94 (ddd, J = 13.8, 9.2, 2.9 Hz, 1H), 1.83 (m, 1H),

0.95 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H). 13

C NMR (101 MHz, CDCl3) δ 142 74 (d J =

25.7 Hz), 142.00 (d, J = 25.6 Hz), 137.18 (d, J = 12.3 Hz), 136.38 (d, J = 13.4 Hz), 131.22 (d, J

= 7.7 Hz), 130.12 (d, J = 2.2 Hz), 130.07 (d, J = 2.0 Hz), 128.44 (d, J = 11.7 Hz), 126.07 (d, J =

0.8 Hz), 126.04(d, J = 0.8 Hz), 54.05 (d, J = 14.0 Hz), 34.28 (d, J = 7.4 Hz), 33.37 (d, J = 12.1

Hz), 21.40 (d, J = 7.7 Hz), 21.18 (d, J = 7.4 Hz), 19.02 , 17.04. 31

P NMR (162 MHz, CDCl3) δ -

44.02. IR (neat, cm-1

): 3055 (w), 2956 (m), 1589 (w), 1466 (m), 1451 (m), 1378 (m), 1270 (w),

1200 (w), 1130 (m), 1032 (m), 910 (w), 747 (s), 719 (m). Optical rotation: []D20

(c 1.25,

CHCl3) = +82.4. HRMS (DART-TOF) m/z: [M + H]+ calcd for C19H27NP 300.18811, found

300.18886.

(S)-1-(Bis(4-methoxyphenyl)phosphanyl)-3-methylbutan-2-amine (1.34)

46


amino-3-methylbutyl)bis(4-methoxyphenyl)phosphine oxide 1.29 (79 mg, 0.23 mmol). Purified

by flash chromatography on silica gel (MeOH /CH2Cl2, 1:30 v/v) to afford 1.34 (30 mg, 40%)

was isolated as a colorless oil.

1H NMR (300 MHz, CDCl3) δ 7 44 – 7.31 (m, 4H), 6.93 – 6.80 (m, 4H), 3.80 (s, 3H), 3.78 (s,

3H), 2.66 (m, 1H), 2.25 (m, 1H), 1.99 (m, 1H), 1.75 (m, 1H), 1.26 (br s, 2H), 0.91 (d, J = 9.1 Hz,

3H), 0.88 (d, J = 9.0 Hz, 3H). 13

C NMR (101 MHz, CDCl3) δ 160 28, 159.93, 134.50 (d, J =


4.7 Hz), 114.12 (d, J = 4.1 Hz), 55.18, 54.22, 54.08, 35.06 (d, J = 11.1 Hz), 34.19 (d, J = 7.6 Hz),

18.90, 17.17. 31

P NMR (121 MHz, CDCl3) δ -25.59. IR (neat, cm-1

): 2956 (m), 2835 (w), 1593

(s), 1568 (m), 1497 (s), 1462 (m), 1441 (m), 1401 (w), 1282 (s), 1245 (s), 1176 (s), 1094 (s),

1030 (s), 910 (w), 825 (s), 797 (m), 732 (m). Optical rotation: []D20

(c 2.65, CHCl3) = +71.4.

HRMS (DART-TOF) m/z: [M + H]+ calcd for C19H27NO2P 332.17794, found 332.17812.

(S)-1-(Diphenylphosphanyl)-3-methylbutan-2-amine (1.35)


amino-3-methylbutyl)diphenylphosphine oxide 1.30 (80 mg, 0.28 mmol). Purified by flash

chromatography on silica gel (MeOH /CH2Cl2, 1:30 v/v) to afford 1.35 (35 mg, 46%) was

isolated as a yellow oil.

1H NMR (400 MHz, CDCl3) δ 7 48 – 7.20 (m, 10H), 2.60 (m, 1H), 2.25 (m, 1H), 1.94 (m, 1H),

1.68 (m, 1H), 0.82 (app dd, 6H). 13

C NMR (101 MHz, CDCl3) δ 133 31 133 12 132 57 132 38

128.88, 128.54, 128.48, 128.46, 128.40, 128.38, 54.27, 54.13, 34.53, 34.41, 34.17, 34.09, 18.89,

17.11. 31

P NMR (162 MHz, CDCl3) δ -21.62.

(R)-2-(Bis(4-(trifluoromethyl)phenyl)phosphanyl)-1-phenylethan-1-amine (1.36)

47

Synthesized according to general procedure using diphenylsilane (0.69 g, 3.72 mmol) and (R)-(2-

amino-2-phenylethyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.31 (243 mg, 0.53 mmol).

Purified by flash chromatography on silica gel (MeOH /CH2Cl2, 1:50 v/v) to afford 1.36 (119 mg,

51%) was isolated as a slightly yellow solid.


4.03 (m, 1H), 2.67 – 2.41 (m, 2H), 1.82 (s, 2H). 13

C NMR (100 MHz, CDCl3) δ 133 31 (d J =

19.6 Hz), 132.81 (d, J = 18.9 Hz), 128.68 (s), 127.53(s), 126.05(s), 125.32 (m), 53.87 (d, J =

16.5 Hz), 39.43 (d, J = 14.7 Hz). 31


): 2935

(w), 2870 (w), 1606 (m), 1454 (w), 1398 (m), 1321 (s), 1165 (s), 1119 (s), 1104 (s), 1059 (s),

1015 (s), 952 (m), 879 (m), 828 (s), 769 (m), 724 (m), 699 (s). Optical rotation: []D20

(c 0.8,

CHCl3) = -26.0. HRMS (DART-TOF) m/z: [M + H]+ calcd for C22H19F6NP 442.11593, found

442.11624.

(S)-N-(1-(bis(4-(trifluoromethyl)phenyl)phosphanyl)-3-methylbutan-2-yl)cyclohexanamine

(1.38)

Cyclohexanone (46 mg, 0.47 mmol), sodium triacetoxyborohydride (125 mg, 0.59 mmol) and

acetic acid (4.8 mg, 0.08 mmol) were added sequentially to a solution of (S)-(2-amino-3-

methylbutyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.27 (168 mg, 0.39 mmol) in CH2Cl2

(2 mL). The reaction was stirred at room temperature for 2 h. Saturated Na2CO3 was added to the

reaction. The aqueous layer was extracted with CH2Cl2. The combined organic layer was dried

over anhydrous MgSO4, concentrated and purified through flash column chromatography on

48

silica gel (MeOH /CH2Cl2, 1:50 v/v) to afford 1.37 as a white solid (169 mg, 82%). 1.37 was

reduced with diphenylsilane (0.41 g, 2.23 mmol) using the general procedure to afford 1.38 (116

mg, 75%) as a colorless oil after column (MeOH /CH2Cl2, 1:50 v/v).


2.35 (tt, J = 10.1, 3.3 Hz, 1H), 2.25 (ddd, J = 13.8, 4.7, 2.0 Hz, 1H), 2.03 (ddd, J = 14.0, 8.6, 1.9

Hz, 1H), 1.99 – 1.89 (m, 1H), 1.70 – 1.58 (m, 4H), 1.59 – 1.44 (m, 1H), 1.22 – 1.04 (m, 3H),

1.04 – 0.90 (m, 2H), 0.89 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H). 13

C NMR (101 MHz,

CDCl3) δ 144 39 (d = 16 6 H ) 143 24 (d = 16 9 H ) 133 44 (d = 19 4 H ) 132 79 (d =


43.0 Hz), 125.79 – 124.60 (m), 56.42 (d, J = 12.8 Hz), 53.84, 34.31, 33.64, 30.80 (d, J = 13.0

Hz), 30.54 (d, J = 7.2 Hz), 26.07, 24.99 (d, J = 4.8 Hz), 18.41, 16.95. 31

P NMR (162 MHz,

CDCl3) δ -20.14.

tert-Butyl ((1R,2R)-2-bromo-1,2-diphenylethyl)carbamate (1.40)

Method A.

Tetra-n-butylammonium bromide (129 mg, 0.4 mmol) was added to a solution of tert-butyl

(4R,5S)-4,5-diphenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 1.39 (75 mg, 0.2 mmol) in

THF (1.5 mL). The reaction was stirred at room temperature for 10 h. 2N H2SO4 (1 mL) was

added to the solution and stirred for 20 min. Extraction with diethyl ether followed by

purification by column chromatography (Hexanes /EtOAc, 9:1 v/v) afforded 1.40 (22 mg, 30%)

as a white solid.

Method B.

18-Crown-6 (590 mg, 2.23 mmol) was added to a suspension of potassium bromide (664 mg,

5.58 mmol) and tert-butyl (4R,5S)-4,5-diphenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

1.39 (419 mg, 1.12 mmol) in THF (6 mL). The reaction was stirred at 60 °C for 5 h. Water was

added to the reaction and the aqueous layer was extracted with diethyl ether. The combined

49

organic layer was dried over anhydrous MgSO4, concentrated in vacuo to afford 1.40 (289 mg,

70%) as a white solid. The product was used in the next step without purification.


5.54 (d, J = 8.6 Hz, 1H), 5.24 (br, 2H), 1.43 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 154 97

138.89, 128.79, 128.50, 128.42, 128.35, 128.28, 128.13, 127.70, 126.92, 80.05, 60.24, 28.35.

HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H22BrNNaO2 398.0726, found 398.0722.

((1S,2R)-2-Amino-1,2-diphenylethyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.41)



atmosphere. The mixture was stirred for 5 min. tert-Butyl ((1R,2R)-2-bromo-1,2-

diphenylethyl)carbamate 1.40 solid (281 mg, 0.75 mmol) was added and the reaction mixture

was stirred at 60 °C for 3 h. The reaction was quenched with 2N H2SO4 (5 mL) at room

temperature and the mixture was stirred for another 20 min. The aqueous layer was extracted

with diethyl ether. The combined organic layer was dried over anhydrous MgSO4, concentrated

in vacuo to afford a white solid (460 mg). Trifluoroacetic acid (1.48 mL, 19.4 mmol) was added

to a solution of the crude product in dry CH2Cl2 (10 mL) at 0 °C . The reaction was allowed to

warm up and stirred at room temperature for 3 h. Saturated Na2CO3 was added dropwise to the

solution at 0 °C . Extraction with CH2Cl2 followed by purification by flash chromatography on

silica gel (MeOH /CH2Cl2, 1:40 v/v) afford the final product 1.41 (140 mg, 35%) as a white solid.

1H NMR (300 MHz, CDCl3) δ 7 81 (dd J = 10.6, 8.1 Hz, 2H), 7.63 – 7.51 (m, 4H), 7.42 (dd, J =

8.4, 2.5 Hz, 2H), 7.38 – 7.30 (m, 2H), 7.17 (dd, J = 4.9, 1.9 Hz, 3H), 7.12 – 7.06 (m, 2H), 7.02

(m, 3H), 4.85 (t, J = 6.6 Hz, 1H), 3.78 (t, J = 6.4 Hz, 1H), 1.71 (s, 2H). 13

C NMR (100 MHz,

CDCl3) δ 141 86 (d J = 6.9 Hz), 137.14 (d, J = 22.2 Hz), 136.20 (d, J = 18.3 Hz), 133.57 –

50

132.45 (m), 131.15 (d, J = 9.0 Hz), 130.94 (d, J = 8.8 Hz), 130.66 (d, J = 7.0 Hz), 128.53 (d, J =

1.3 Hz), 128.12 , 127.82 , 127.75 (d, J = 1.9 Hz), 127.41 , 125.47 – 125.11 (m), 125.10 – 124.70

(m), 56.16 , 54.46 (d, J = 69.2 Hz). 31

P NMR (121 MHz, CDCl3) δ 29 26 IR (neat, cm-1

): 3065

(w), 3025 (w), 1401 (m), 1321 (s), 1169 (s), 1123 (s), 1062 (s), 1369 (w), 1018 (m), 837 (m), 791

(m), 756 (m), 710 (s), 670 (s). Optical rotation: []D20

(c 0.79, CHCl3) = +13.9. HRMS (ESI-

TOF) m/z: [M + H]+ calcd for C28H23F6NOP 534.1416, found 534.1420.

(1R,2S)-1-((tert-Butoxycarbonyl)amino)-indan-2-yl trifluoromethanesulfonate (1.44)

A solution of (Boc)2O (321 mg, 1.47 mmol) in THF (2 mL) was added to a mixture of (1R,2S)-

(+)-cis-1-amino-2-indanol 1.42 (200 mg, 1.34 mmol) and sodium carbonate (0.31 g, 2.9 mmol)

in THF/H2O (1/1, 4 mL) at 0 ºC. The mixture was stirred at room temperature for 3 h. Water was

added to the mixture and was extracted with ethyl acetate. The combined organic layer was

washed with brine, dried over anhydrous MgSO4, and concentrated to afford the crude product in

quantitative yield as a white solid, which was used in the next step without purification.

Trifluoromethanesulfonic anhydride (56 mg, 0.2 mmol) was added dropwise to a solution of

pyridine (19 mg, 0.24 mmol) and N-Boc protected (1R,2S)-(+)-cis-1-amino-2-indanol (50 mg,

0.2 mmol) in dry CH2Cl2 (1 mL) at –40 ºC. The reaction was stirred at –40 ºC for 1 h. Saturated

NH4Cl was added to quench the reaction. The aqueous layer was extracted with CH2Cl2. The

combined organic layer was dried over anhydrous MgSO4, and concentrated to afford the

product 1.44 (67mg, 89%) as a yellow or orange solid.

1H NMR (300 MHz, CDCl3) δ 7 31 (m 4H) 5 67 (br s 1H) 5 46 (dd J = 9.3, 4.5 Hz, 1H), 5.04

(d, J = 9.3 Hz, 1H), 3.45 – 3.14 (m, 2H), 1.51 (s, 9H). 19

F NMR (282 MHz, CDCl3) δ -75.13.

51

((1R,2R)-1-Amino-indan-2-yl)bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.45)



atmosphere. The mixture was stirred for 5 min. (1R,2S)-1-((tert-Butoxycarbonyl)amino)-indan-

2-yl trifluoromethanesulfonate 1.44 solid (556 mg, 1.46 mmol) was added and the reaction

mixture was stirred at 60 ºC for 3 h. The reaction was quenched with 2N H2SO4 (8 mL) at room

temperature and the mixture was stirred for another 10 min. Extraction with diethyl ether

followed by purification by flash chromatography on silica gel (EtOAc /CH2Cl2, 1:9 v/v) afford

the final product 1.45 (216 mg, 26%) as a white solid.

1H NMR (300 MHz, CDCl3) δ 7 82 (t J = 9.1 Hz, 2H), 7.76 – 7.64 (m, 4H), 7.61 (dd, J = 8.5,

2.7 Hz, 2H), 7.30 – 7.20 (m, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 8.5 Hz, 2H), 5.84 (d, J =

6.2 Hz, 1H), 3.04 – 2.68 (m, 3H), 2.07 (dt, J = 17.4, 9.0 Hz, 1H), 1.55 – 1.39 (m, 2H), 1.25 (s,

9H). 31

P NMR (121 MHz, CDCl3) δ 32 83 HRMS (ESI-TOF) m/z: [M + H]+ calcd for

C28H27F6NO3P 570.1627, found 570.1614.

(R)-N-(2-((tert-Butyldimethylsilyl)oxy)-1-phenylethyl)-1,1,1-trifluoromethanesulfonamide

(1.49)

To a stirred solution of the (R)-2-amino-2-phenylethan-1-ol (685 mg, 5 mmol) in CH2Cl2 (10 mL)

was added triethylamine (556 mg, 5.5 mmol) at -78 °C under inert atmosphere. After stirring for

10 min at -78 °C, trifluoromethanesulfonic anhydride (1.41 g, 5 mmol) was added dropwise and

the mixture was stirred for 1 h at that temperature before being quenched by water (20 mL). The

organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined

52

organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated to give the

trifluoromethanesulfonamide without purification.

To a 50 mL round bottle was added the crude product from the previous step, tert-

butyldimethylsilyl chloride (825 mg, 5.5 mmol), DMAP (60 mg, 0.5 mmol) and CH2Cl2 (12 mL).

The mixture was cooled to 0 °C and Et3N (560 mg, 5.5 mmol) was added dropwise. The solution

was warmed to room temperature and stirred for 12 h. Then the reaction was quenched with

water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The

combined organic layer was washed with brine and concentrated under reduced pressure to give

the crude product, which was purified by column chromatography on silica gel (EtOAc/hexanes,

1:20 v/v) to afford 1.49 (1.19 g, 62% over 2 steps) as a colorless oil.

1H NMR (300 MHz, CDCl3) δ 7 43 – 7.27 (m, 5H), 5.91 (d, J = 6.5 Hz, 1H), 4.72 (m, 1H), 3.97

(dd, J = 10.4, 4.2 Hz, 1H), 3.79 (dd, J = 10.4, 4.7 Hz, 1H), 0.86 (s, 9H), -0.03 (s, 3H), -0.04 (s,

3H).

Benzoyl-D-leucine (1.51)

Benzoyl chloride (281 mg, 2 mmol) was added dropwise to a suspension of D-leucine (262 mg, 2

mmol) in aqueous 2N NaOH (5 mL) at 0 °C. The reaction was stirred at room temperature for 3h.

Then the reaction was acidified with 1N HCl until pH<2. Extraction with EtOAc followed by

column chromatography on silica gel (MeOH/ CH2Cl2, 1:50 v/v) afforded product 1. 51 (176 mg,

75%) as a white solid.

1H NMR (399 MHz, CDCl3) δ 10 79 (br s, 1H), 7.77 (d, J = 7.3 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H),

7.38 (t, J = 7.5 Hz, 2H), 6.88 (d, J = 8.0 Hz, 1H), 4.82 (td, J = 8.1, 4.2 Hz, 1H), 2.02 – 1.57 (m,

2H), 0.96 (d, J = 2.1 Hz, 3H), 0.95 (d, J = 2.2 Hz, 3H).

4.2 1H NMR, 13C NMR and 31P NMR Spectra

83

Chapter 2

Synthesis of Bifunctional Thiourea-Phosphine

Organocatalysts and Their Applications in the

Asymmetric Morita-Baylis-Hillman (MBH) Reaction

1 Introduction

1.1 Mechanism of the Morita-Baylis-Hillman (MBH) Reaction

The Morita-Baylis-Hillman (MBH) reaction is a carbon-carbon bond forming reaction between

an aldehyde and an activated alkene catalyzed by tertiary amines or phosphines.39

If an activated

imine is used instead of an aldehyde, the reaction is commonly referred to as the aza-Morita-

Baylis-Hillman (aza-MBH) reaction (Scheme 47).

Scheme 47. The Morita-Baylis-Hillman reaction

The mechanism of a tertiary amine-catalyzed MBH reaction is presented in Scheme 48.40

The

conjugate addition of tertiary amine A to the Michael acceptor generates the zwitterionic

39 a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815. b) Morita, K. Japan Patent,

6803364, 1968. b) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972.

40 Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed. 1983, 22, 795.

84

ammonium-enolate intermediate B, which then attacks the incoming aldehyde and forms

intermediate C. Intramolecular proton transfer and subsequent elimination affords the product

and regenerates the tertiary amine catalyst A.

Scheme 48. Mechanism of MBH reaction proposed in 1980s

The aldol addition step was proposed to be the rate-determining step by Hill and Issac. They

observed that the rate of reaction was first order in acetaldehyde, acrylonitrile and DABCO, and

the kinetic isotope effect (KIE) at the -position of the acrylonitrile was low (Scheme 49).41

Scheme 49. Kinetic study of MBH reaction by Hill and Issac

However, this theory has been challenged by McQuade et al. and Aggarwal et al., who proposed

that the proton transfer step is rate limiting based on both kinetic and theoretical studies.

41 J. S. Hill, N. S. Isaacs, J. Phys. Org. Chem. 1990, 3, 285288.

85

McQuade observed a large normal KIE for the -position of methyl acrylate and a large inverse

KIE for the aldehyde proton (Scheme 50). In addition, the reaction was found to be second-order

in aldehyde and first-order in DABCO and acrylate in all tested solvents (DMSO, DMF, MeCN,

THF, CHCl3).42

Scheme 50. Kinetic study performed by McQuade et al.

McQuade therefore proposed that the mechanism involves the formation of a hemiacetal adduct

with a second equivalent of aldehyde and the -proton is abstracted in the rate determining step

via a six-membered transition state (Scheme 51).40

42 a) Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7, 147150. b) Price,

K. E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org. Chem. 2005, 70, 39803987.

86

Scheme 51. Mechanism of MBH reaction revised by McQuade and Aggarwal

Aggarwal et al. suggested that protic additives can act as proton shuffles to accelerate the -

deprotonation (Scheme 51).43

The proton transfer step is rate limiting only at the beginning of

the reaction (<20% conversion). Once the allylic alcohol product, which can act as a proton

shuffle, has built up to a certain extent, the aldol addition step becomes the rate-determining step.

They observed that the normal acrylate is consumed faster than the -deuterated acrylate in up to

20% conversion.41a

In a subsequent computational study, Aggarwal and Harvey confirmed that

under aprotic conditions, the formation of hemiacetal and the proton transfer via a cyclic

transition state proposed by McQuade is the most likely operating mechanism. In the presence of

methanol however, a slightly lower energy pathway in which the alcohol serves as a shuttle to

transfer the proton from carbon to oxygen was found.41b

Most recently, Singleton refuted the

proton-shuttle mechanism and questioned the usefulness of computational study in predicting the

thermodynamics and kinetics of MBH reactions. A two-step acid-base mechanism involving

proton transfer to and from protic solvent was fully supported by their experiments. Their study

also suggested the involvement of competitive rate-limiting steps in the methanol mediated

43 a) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew. Chem. Int. Ed. 2005, 44, 17061708. b)

Robiette, R.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc. 2007, 129, 1551315525.

87

MBH reactions. The proton transfer of the elimination step was found to be rate-limiting at 25 °C,

while the aldol addition became the primary rate-limiting step at low temperatures.44

1.2 The Asymmetric Morita-Baylis-Hillman (MBH) Reaction

Since the seminal discovery of a highly enantioselective MBH reaction using a bifunctional

catalyst derived from quinidine in 1999, several acid-base cocatalysts and bifunctional catalyst

systems have been developed to improve the efficiency and expand the scope of the initial

reaction. In the following sections, progress in the asymmetric MBH and aza-MBH reactions

will be presented separately for clarity purposes, although there is considerable overlap between

research in both fields, as the catalyst systems initially developed for MBH reaction often found

successful application later in the aza-MBH reaction and vice versa. Each catalyst system will be

presented in the chronological order of its discovery.

In 1999, Hatakeyama et al. discovered that a hydroxylated chiral amine, -isocupreidine (ICD)

2.1, confered considerable rate acceleration and asymmetric induction in the MBH reaction.

Excellent enantioselectivities were achieved using hexafluoroisopropyl acrylate with several

aromatic and aliphatic aldehydes despite modest yields (Scheme 52).45

The phenolic hydroxyl

group was believed to stabilize oxyanion intermediate through hydrogen bonding, which not

only accelerates the aldol reaction, but also creates an asymmetric environment together with the

chiral amine scaffold to enable enantioseletive addition to the aldehyde.

44 Plata, R. E.; Singleton, D. A. J. Am. Chem. Soc. 2015, 137, 3811−3826

45 Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121,

1021910220.

88

Scheme 52. Asymmetric MBH reaction using a quinidine derivative as a bifunctional catalyst

Guided by this principle, Wang and coworkers designed the binaphthyl thiourea-tertiary amine

catalyst 2.2 that is effective for the MBH reaction of cyclohexenone and aliphatic aldehydes.

Lower yields and enantioselectivities were obtained when aromatic aldehydes were used,

however (Scheme 53).46

Scheme 53. Asymmetric MBH reaction using quinidine binaphthyl thiourea-tertiary amine 2.2

Another thiourea-phosphine catalyst 2.3 bearing a 1,2-cyclohexane backbone developed by Wu

et al. performed well with methyl vinyl ketone as the activated alkene. Considerable rate

acceleration was achieved with 2.3, where most reactions were completed within one hour

(Scheme 54).47

46 Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 42934296.

47 Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y. J.; Wu, X. Y. Tetrahedron Lett. 2008, 49, 62626264.

89

Scheme 54. Asymmetric MBH reaction using cyclohexyl thiourea-phosphine 2.3

Finally, a class of threonine derived thiourea-phosphine catalysts reported by Lu et al. expanded

the substrate scope to include simple acrylates. Excellent yields and very good ee’s were

achieved in the reactions of acrylates with electron-deficient aromatic aldehydes. The use of

benzaldehyde required longer reaction time and resulted in a lower yield without much erosion

of enantioselectivity (Scheme 55).48

Scheme 55. Asymmetric MBH reaction using threonine derived thiourea-phosphine 2.4

48 Han, X.; Wang, Y.; Zhong, F.; Lu, Y. Org. Biomol. Chem. 2011, 9, 67346740.

90

Parallel to the research in bifunctional catalysis, the development of acid-base cocatalysis also

led to several breakthroughs in asymmetric MBH reaction.49

Schaus pioneered the use of a

BINOL-derived chiral Brønsted acid 2.5 as the catalyst along with triethylphosphine as the

nucleophilic promoter for MBH reaction of cyclohexenone with aldehydes. Excellent yields and

enantioselectivities were achieved only for aliphatic aldehydes.47a

A complimentary cocatalyst

system discovered by Connell employing u’s chiral MA catalyst 2.6 and magnesium iodide

as Lewis acid exhibited high yields and enantioselectivities in reactions of cyclopentenone with

aromatic aldehydes.47b

Ito demonstrated for the first time that high enantioselectivities could be

obtained in the reactions of cyclohexenone with both aromatic and aliphatic aldehydes using a

bis-thiourea 2.7/DABCO cocatalyst system (Scheme 56).47c

49 a) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 1209412095. b) Bugarin, A.; Connell,

B. T. Chem. Commun. 2010, 46, 26442646. c) Nakayama, Y.; Gotanda, G.; Ito, K. Tetrahedron Lett. 2011,

52, 62346237.

91

Scheme 56. Asymmetric MBH reaction using acid-base co-catalyst systems

1.3 The Asymmetric aza-Morita-Baylis-Hillman (aza-MBH) Reaction

Shi and coworkers demonstrated that quinidine derivative ICD 2.1 was effective in the

asymmetric aza-MBH reaction of N-(benzylidene)-4-methylbenzenesulfonamide with methyl

vinyl ketone and methyl acrylate.50

In 2008, Zhu and Masson showed that using a new variant of

quinidine derivative ICD 2.8 high yields and enantioselectivities were realized for aryl and

alkyl imines with naphthyl acrylate (Scheme 57).51

50 Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 45074510.

51 Abermil, N.; Masson, G.; Zhu, J. J. Am. Chem. Soc. 2008, 130, 12596–12597.

92

Scheme 57. Asymmetric aza-MBH reaction using quinidine derivatives

Shi reported that in the presence of a BINOL-derived phosphine catalyst 2.8, the aza-MBH

reaction of N-sulfonylated imines with methyl vinyl ketone could be obtained in high yields and

enantioselectivities at low temperature. Using a modified catalyst 2.9, the same reaction could be

carried out at room temperature in shorter times. Although the catalyst was less effective for

acrylates, high yield and enantioselectivity were achieved for acrolein.52

Sasai independently

reported an equally effective BINOL-derived catalyst 2.10 containing a tertiary amine and a

pyridyl group, which gave even higher yields and enantioselectivities for certain substrates

(Scheme 58).53

52 Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 37903800.

53 Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680–3681.

93

Scheme 58. Asymmetric aza-MBH reaction using BINOL derived bifunctional catalyst

Jacobsen et al. reported that for the first time excellent enantioselectivity could be achieved with

methyl acrylates using a chiral thiourea catalyst 2.11 in combination with stoichiometric amount

of DABCO. However, the product yields were only modest (< 50%) (Scheme 59).54

54 Raheem, I. T.; Jacobsen, E. N. Adv. Synth. Catal. 2005, 347, 17011708.

94

Scheme 59. Asymmetric aza-MBH reaction using thiourea/DABCO cocatalyst system

Lu et al. discovered a threonine-derived phosphine-sulfonamide catalyst 2.12 was effective for

promoting the asymmetric aza-MBH reaction of 2-naphthyl acrylate with activated imines. The

desired aza-MBH adducts were obtained in high yields and with excellent enantioselectivities

(Scheme 60).55

Scheme 60. Asymmetric aza-MBH reaction using phosphine-sulfonamide catalyst 2.12

55 Zhong, F.; Wang, Y.; Han, X.; Huang, K. -W.; Lu, Y. Org. Lett. 2011, 13, 13101313.

95

1.4 Asymmetric Transformations Related to the Morita-Baylis-Hillman

(MBH) Reaction

The application of bifunctional organocatalysts is not limited to asymmetric MBH/aza-MBH

reactions. Given the particular relevance of amino acid-derived phosphine catalysts to our

research, a brief survey of their utility outside MBH/aza-MBH reactions is presented in the

following section. The reactions listed below are related mechanistically to the MBH reaction.

Lu and coworkers prepared a series of five-membered carbocycles with a chiral quaternary

centre through highly enantioselective [3+2] annulations of an allenoate and an -substituted

acrylate using a novel dipeptide derived phosphine catalyst 2.13. They further demonstrated the

synthetic value of the cycloaddition product by converting it in three steps into a cytotoxic agent

containing a spirooxindole core (Scheme 61).56

Scheme 61. Enantioselective [3+2] annulation of allenoate with acrylate

The proposed mechanism is shown in Scheme 62. The phosphonium enolate intermediate A

attacks the less hindered terminus of the activated alkene B. The catalyst 2.13 presumably

positions B in a particular orientation relative to the A through favourable hydrogen-bonding

56 Han, X.; Wang, Y.; Zhong, F.; Lu, Y. J. Am. Chem. Soc. 2011, 133, 1726–1729.

96

interactions so that enolate A preferentially adds to one face of the olefin. Subsequent proton

transfer and elimination yield the product and regenerate the catalyst as in the MBH reaction.

Scheme 62. Mechanism of [3+2] annulation of allenoate with acrylate

Lu reported the first asymmetric Michael addition mediated by the chiral phosphine 2.14

(Scheme 63). They envisioned that the in situ generated phosphonium enolate A could act as a

base to deprotonate the pronucleophile and form a tight ion pair between enolate nucleophile B

and chiral phosphonium C. Efficient chirality transfer during the Michael addition step affords

the enantio-enriched adduct D, which then abstracts a proton from the pronucleophile to generate

the final product E and completes the catalytic cycle (Scheme 64).57

Scheme 63. Asymmetric Michael addition of oxindoles catalyzed by chiral phosphine

57 Zhong, F.; Dou, X.; Han, X.; Yao, W.; Zhu, Q.; Meng, Y.; Lu, Y. Angew. Chem., Int. Ed. 2013, 52, 943–

947.

97

Scheme 64. Mechanism of asymmetric Michael addition catalyzed by chiral phosphine

A similar idea was explored by Zhao and coworkers in the asymmetric Mannich and aza-Henry

reactions. They employed catalytic amount of both the thiourea-phosphine and methyl acrylate,

which combine to form a zwitterionic base in situ which then abstracts the proton from the

pronucleophile. Excellent chirality transfer was achieved from the phosphonium-nucleophile ion

pair to the final Mannich or aza-Henry adduct (Scheme 65).58

Scheme 65. Asymmetric Michael addition reaction and aza-Henry reaction catalyzed by chiral

phosphines

58 Wang, H.-Y.; Zhang, K.; Zheng, C.-W.; Chai, Z.; Cao, D.-D.; Zhang, J.-X.; Zhao, G. Angew. Chem. Int.

Ed., 2015, 54, 1775–1779.

98

2 Objectives

Amino acid-derived bifunctional phosphine-thiourea catalysts were found to be very efficient in

promoting asymmetric MBH reaction of acrylates with aromatic aldehydes. Valine-based

catalyst 2.17 displayed high reactivity and enantioselectivity, although the best catalyst was

found to be the threonine-derived 2.4 (Scheme 66).43

Scheme 66. Asymmetric MBH reaction catalyzed by amino acid based thiourea-phosphines

So far, the refinement of these catalysts has been limited to modification of the carbon backbone

as well as the thiourea component. We were interested to investigate whether tuning the

electronic property of the phosphine moiety could impart any improvement on the reactivity and

enantioselectivity of the catalyst. Thus, a small library of ligands analogous to 2.17 with different

diaryl substituents on the phosphorus atom were prepared and tested in the asymmetric MBH

reaction.

3 Results and Discussion

Previously prepared P,N-ligands were coupled with 4-nitrophenyl isothiocyanate to afford

thiourea-phosphine catalysts 2.172.20 in good yields (Table 6).

99

Table 6. Scope for thiourea-phosphine catalysts

These bifunctional organocatalysts were tested in the MBH reaction of 4-nitrobenzaldehyde with

methyl acrylate. Unfortunately, no improvement of enantioselectivity was achieved by variation

of P-aryl substituent in these thiourea-phosphines. Electron-rich catalyst 2.18 gave an identical

ee as the unmodified catalyst 2.17. The use of another electron-rich catalyst 2.19 led to both

lower yield and ee. Electron deficient catalyst 2.20 was unable to promote the reaction,

presumably due to the diminished nucleophilicity of the phosphine (Table 7).

Table 7. Screening of bifunctional catalysts in the MBH reaction

100

Around the same time, a novel P-stereogenic thiourea-phosphine catalyst 2.21 made in our lab

gave an improved enantioselectivity of 86% ee (Scheme 67).24

Encouraged by this result, we

decided to make another P-chiral catalyst 2.29, by replacing one of the aryl groups on the

phosphorus atom with a linear alkyl chain. As a result, the steric properties of the two

substituents would be further differentiated, which might impose higher level of enantio-

discrimination in the reaction. In addition, the aliphatic substituent should increase the

nucleophilicity of the catalyst, which can potentially promote reactions of less reactive substrates

that are otherwise sluggish with diarylphosphino-thiourea catalysts. Of course, we recognized the

synthetic challenges associated with making electron-rich P-chiral phosphines, mainly due to

their air sensitivity and the tendency for them to racemize at higher temperatures.

Scheme 67. P-chiral phosphino-thiourea catalysts

Addition of triethyl phosphite 2.22 to in situ generated phenyl Grignard reagent followed by

hydrolysis of the resulting phosphonite intermediate under acidic conditions afforded phenyl-H-

phosphinate 2.23. Treatment with n-butyllithium displaced the ethoxy group and generated the

unsymmetrical secondary phosphine oxide 2.24 (Scheme 68).

Scheme 68. Synthesis of unsymmetrical secondary phosphine oxide

Ring opening of the cyclic sulfamidate with 2.24 in the presence of NaOtBu afforded a 1:1

diastereomeric mixture of the products 2.25 in modest yield (Scheme 69). Separation of the

diastereomers proved to be very difficult. Using 1% THF:diethyl ether as the eluent, only a small

fraction of the less polar diastereomer could be isolated in pure form. We then carried the

mixture of diastereomers forward, hoping that the separation could be accomplished through

101

recrystallization of the HCl salts of 2.26. Unfortunately, several recrystallization attempts in

different solvent systems only resulted in the formation of oil droplets instead of crystalline

solids. The ineffective crystallization can most likely be attributed to the flexible n-butyl chain.

The diastereomeric mixture of 2.26 was then reduced and protected in situ as the phosphine-

borane complex 2.27. Gratifyingly, we were able to separate the diastereomers at this stage using

flash column chromatography on silica gel. The less polar diastereomer 2.27a was then coupled

with 4-nitrophenyl isothiocyanate to afford crystalline thiourea 2.28a. We managed to grow a

single crystal of 2.28a through liquid-liquid diffusion. Diethyl ether was slowly added into a

solution of 2.28a in dichloromethane, forming a bilayer solvent mixture. Slow diffusion of the

two solvents induces the precipitation of the solute and an X-ray quality crystal of 2.28a was

obtained after standing at room temperature for 24 hours. The relative configuration of the P-

chirality centre was determined by X-ray crystallography. Interestingly, the N-H hydrogens are

in a disordered conformation in the crystal structure, suggesting that the thiourea group does not

contribute to the crystal packing through hydrogen bonding interactions (Figure 4).

Figure 4. X-ray crystal structure of thiourea-phosphine-borane 2.28a

Attempts to deprotect the phosphine-borane compounds 2.28a/2.28b using 2.5 equivalents of

DABCO resulted in full recovery of the starting material after heating at 40 ˚C for 6 hours.

Considering that both raising the temperature and prolonged heating might risk racemizing or

102

oxidizing the P-chiral phosphine product, a large excess of DABCO (30 equivalents) was used to

drive the equilibrium towards DABCO-BH3 adduct in order to liberate the phosphine. The

reaction went to completion after 6 hours and the crude reaction mixture was directly subjected

to column chromatography to minimize exposure to air. The final product 2.29a/2.29b was

isolated in 50% yield.

Scheme 69. Synthesis of P-chiral phosphine-thiourea catalysts

The two diastereomeric P-chiral catalysts 2.29a and 2.29b were then tested in the MBH reaction.

To our disappointment, however, both catalysts displayed low activity along with significantly

lower enantioselectivities (Table 8). These suggest that diarylphosphino-thiourea is probably

optimal for this particular MBH reaction. Based on this, a P-chiral catalyst bearing a phenyl

group and a 2-naphthyl group could be a promising target to make in the future.

103

Table 8. Screening of P-chiral bifunctional catalysts in the MBH reaction

Given the relative scarcity of P-chiral ligands in asymmetric catalysis, the methodology our

laboratory has developed to access P-chiral aminophosphines is still of significant value. We

intended to use our P-chiral aminophosphine in the modular synthesis of C2-symmetrical

bisphosphine ligands by coupling two equivalents of the aminophosphine with one equivalent of

a dicarboxylic acid or a diacyl chloride. The resulting Trost-type ligand could be applied to

asymmetric allylic alkylation (AAA) reactions. P-chiral building block 2.27a/2.27b was coupled

with isophthaloyl dichloride and the resulting phosphine-borane complex 2.30a/2.30b was

successfully deprotected using HBF4•OEt2 (Scheme 70).

Scheme 70. Synthesis of P-chiral C2-symmetrical bisphosphine ligands

The final bisphosphine ligands 2.31a and 2.31b were tested in the AAA reaction of 1,3-

diphenylallyl acetate with diethyl malonate. The catalysts induced good levels of

104

enantioselectivity but displayed low catalytic activity (Table 9). Nevertheless, 1,3-diphenylallyl

acetate is known to be a challenging substrate for the Trost ligand 2.32, giving the alkylation

product in only 9% yield with 53% ee (Scheme 71).59

The same ligand performs much better for

smaller 1,3-dimethylallyl acetate and cyclic substrates. It would be interesting to test our ligands

on these types of substrates.

Table 9. Screening of P-chiral C2-symmetrical bisphosphine ligand in Pd-catalyzed AAA

reaction

Scheme 71. AAA reactions using Trost ligand

59 Trost, B. M.; Kruegger, A. C.; Bunt, R. C.; Zambrano, J. J. Am. Chem. Soc. 1996, 118, 6520-6521.

105

4 Conclusion and Future Work

A small library of -aminophosphines bearing different chiral carbon backbones and different

diaryl substituents on the phosphine group was prepared through ring-opening of cyclic

sulfamidates with secondary phosphine oxides. The electron-deficient -substituted P,N-ligands

were tested in the asymmetric decarboxylative allylation reaction. Although the new ligands

derived from (S)-valinol and (R)-phenylglycinol demonstrated excellent catalytic activity, they

were less enantioselective than the original ligand derived from (S)-tert-valinol. Attempts to

prepare ,-disubstituented P,N-ligands derived from (1S,2R)-2-amino-1,2-diphenylethanol and

(1R,2S)-1-amino-2-indanol failed at the final reduction step. As for future work, it would be

worthwhile to examine the use of secondary phosphine-borane and butyllithium in the opening

of cyclic sulfamidates and displacement of halides or sulfonates. The deprotection of

aminophosphine-borane complex can be achieved under much milder condition than the

reduction of corresponding aminophosphine oxide.

A series of phosphine-thiourea bifunctional catalysts derived from -aminophosphines were

prepared and applied in the asymmetric MBH reaction. Attempts to improve the

enantioselectivity of the original catalyst by tuning the electronic properties of the phosphine

moiety were fruitless. The P-chiral catalyst bearing a phenyl group and an n-butyl group

displayed lower activity and enantioselectivity. These results suggest that electronically

unmodified diarylphosphino-thiourea is probably optimal for this particular MBH reaction. A

future direction will be to incorporate two sterically differentiated diaryl groups, such as one

phenyl group and one 2-naphthyl group, on the phosphorous donor of the P-chiral catalyst.

The P-chiral aminophosphines were employed as building blocks in the modular synthesis of C2-

symmteric bisphophine ligands. The performance of these ligands in the Pd-catalyzed AAA

reaction remains to be explored for 1,3-dimethylallyl acetate and cyclic substrates. Morimoto

reported the use of ligand in the Rh-catalyzed asymmetric hydrosilylation of ketones (Scheme

72).9 It would be interesting to see if our P-chiral catalyst can impart any improvement on the

activity and enantioselectivity of the same reaction. Finally, P-chiral P,N-ligands could be used

to construct PNP’ pincer ligands which could form active metal complexes for the asymmetric

hydrogenations of ketones and imines.

106

Scheme 72. Rh-catalyzed asymmetric hydrosilylation of ketones

5 Experimental

5.1 Procedures and Compounds

General procedures for preparing thiourea-phosphines 2.17-2.20, 2.29a, 2.29b

(S)-1-(1-(Diphenylphosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea (2.17)

4-Nitrophenyl isothiocyanate (26 mg, 0.14 mmol) was added to a solution of (S)-1-

(diphenylphosphanyl)-3-methylbutan-2-amine 1.35 (35 mg, 0.13 mmol) in degassed CH2Cl2 (2

mL) under argon. The reaction was stirred at room temperature for 14 h. The reaction mixture

was directly loaded onto silica gel. The eluent was degassed in advance through sparging with

argon for 20 min. The crude product was purified through silica gel flash column

chromatography (Hexanes/EtOAc, 5:1 v/v) under a positive pressure of argon. The final product

(48 mg, 82%) was isolated as a yellow solid.

1H NMR (300 MHz, CDCl3) δ 8 65 (br s 1H) 8 21 – 8.07 (m, 2H), 7.50 – 7.39 (m, 4H), 7.38 –

7.27 (m, 8H), 6.43 (br s, 1H), 4.61 (br s, 1H), 2.51 (m, 1H), 2.31 (m, 1H), 2.18 (m, 1H), 0.95 (s,

3H), 0.92 (s, 3H). 13

C NMR (101 MHz, CDCl3) δ 179 47 144 12 143 16 133 02 132 83

132.78, 132.59, 129.14, 129.00, 128.74, 128.67, 125.42, 122.17, 58.87, 58.72, 32.08, 30.77,

18.59. 31

P NMR (121 MHz, CDCl3) δ -24.40.

107

(S)-1-(1-(di-o-tolylphosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea (2.18)

Synthesized according to general procedure using 4-nitrophenyl isothiocyanate (16 mg, 0.09

mmol) and (S)-1-(di-o-tolylphosphanyl)-3-methylbutan-2-amine 1.33 (25 mg, 0.08 mmol).

Purification through silica gel flash column chromatography (Hexanes/EtOAc, 5:1 v/v) afforded

the product (29 mg, 73%) as a yellow solid.

1H NMR (399 MHz, CDCl3) δ 8 50 (br s 1H) 8 21 – 8.09 (d, 2H), 7.33 (m, 4H), 7.25 – 7.06 (m,

6H), 6.32 (br s, 1H), 4.57 (s, 1H), 2.41 (s, 6H), 2.37 – 2.33 (m, 1H), 2.32 – 2.26 (m, 1H), 2.24 –

2.15 (m, 1H), 0.95 (s, 1H), 0.93 (s, 1H). 31


):

2959 (w), 1595 (m), 1505 (s), 1468 (s), 1450 (m), 1422 (m), 1325 (s), 1300 (s), 1255 (s), 1174

(s), 1111 (s), 1032 (w), 909 (w), 850 (m), 746 (s), 717 (s). Optical rotation: [D(cCHCl3)

= +18.3

(S)-1-(1-(bis(4-methoxyphenyl)phosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea

(2.3)


mmol) and (S)-1-(bis(4-methoxyphenyl)phosphanyl)-3-methylbutan-2-amine 1.34 (53 mg, 0.16

mmol). Purification through silica gel flash column chromatography (Hexanes/EtOAc, 2:1 v/v)

afforded the product (55 mg, 67%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ 8 45 (s 1H) 8 23 – 8.03 (m, 2H), 7.46 – 7.22 (m, 6H), 6.90 –

6.75 (m, 4H), 6.36 (s, 1H), 4.61 (s, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 2.43 (ddd, J = 14.3, 4.5, 2.4

Hz, 1H), 2.27 – 2.11 (m, 2H), 0.94 (d, J = 6.8 Hz, 6H).13

C NMR (101 MHz, CDCl3) δ 160 41

160.31 , 144.01 , 134.24 (d, J = 20.8 Hz), 133.98 (d, J = 20.6 Hz), 125.38 , 121.86 , 114.37 (d, J

108

= 7.7 Hz), 59.02 (d, J = 13.2 Hz), 55.18 , 32.08 , 30.99 , 18.70 , 18.58. 31

P NMR (121 MHz,

cdcl3) δ -28.39. IR (neat, cm-1

): 3294 (w), 2959 (w), 2836 (w), 1593 (s), 1568 (m), 1496 (s),

1462 (m), 1441 (m), 1326 (s), 1300 (s), 1283 (s), 1243 (s), 1175 (s), 1109 (s), 1094 (s), 1026 (s),

909 (m), 850 (m), 823 (s), 797 (s), 724 (s). Optical rotation: [D(cCHCl3) = +31.7.

HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H31N3O4PS 512.1767, found 512.1775.

(S)-1-(1-(bis(4-(trifluoromethyl)phenyl)phosphanyl)-3-methylbutan-2-yl)-3-(4-

nitrophenyl)thiourea (2.4)


mmol) and (S)-1-(bis(4-(trifluoromethyl)phenyl)phosphanyl)-3-methylbutan-2-amine 1.32 (50

mg, 0.12 mmol). Purification through silica gel flash column chromatography (Hexanes/EtOAc,

9:1 v/v) afforded the product (43 mg, 61%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ 8 20 – 8.12 (m, 2H), 8.10 (s, 1H), 7.68 – 7.61 (m, 2H), 7.57 (m,

2H), 7.52 – 7.40 (m, 6H), 3.19 (tdd, J = 9.5, 5.9, 3.4 Hz, 1H), 2.66 (ddd, J = 14.0, 9.5, 1.0 Hz,

1H), 2.47 (ddd, J = 14.0, 3.4, 1.1 Hz, 1H), 2.08 – 1.91 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H), 0.92 (d,

J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 148 99 140 96 133 23 (d J = 10.4 Hz),

133.04 (d, J = 10.4 Hz), 128.72 , 125.33 (dd, J = 7.0, 3.6 Hz), 125.17 – 124.81 (m), 123.62 ,

75.35 (d, J = 13.3 Hz), 34.30 (d, J = 9.2 Hz), 32.28 (d, J = 12.8 Hz), 19.44 , 18.56 . 31P NMR

(162 MHz, CDCl3) δ -19.05. IR (neat, cm-1

): 2963 (w), 2873 (w), 1644 (w), 1603 (m), 1522 (m),

1396 (m), 1345 (m), 1320 (s), 1163 (s), 1121 (s), 1059 (s), 1015 (s), 951 (m), 827 (s), 748 (m),

695 (m). Optical rotation: [D(cCHCl3) = +110.0. HRMS (ESI-TOF) m/z: [M + H]

+

calcd for C26H25F6N3O2PS 588.1304, found 588.1294.

Butyl(phenyl)phosphine oxide (2.9)

109

n-Butyllithium (0.84 mL, 2.1 mmol) was added dropwise into a solution of ethyl

phenylphosphinate 2.8 (170 mg, 1.0 mmol) in dry pentane (5 mL) at 78 ºC. The reaction was

stirred at this temperature for 5 h. Saturated NH4Cl was added to quench the reaction. Extraction

with CH2Cl2 followed by flash column chromatography on silica gel (CH2Cl2/MeOH, 40:1 v/v)

afforded the product (109 mg, 60%) as colorless oil.

1H NMR (400 MHz, CDCl3) δ 7 49 (m 2H) 7 26 (d J = 463.3 Hz, 1H), 7.38 – 7.22 (m, 3H),

1.78 (m, 2H), 1.47 – 1.30 (m, 2H), 1.27 – 1.07 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H). 31

P NMR (162

MHz, CDCl3) δ 27 46 13

C NMR (101 MHz, CDCl3) δ 132 16 (d J = 2.9 Hz), 130.98 (d, J =


14.6 Hz), 23.31 (d, J = 3.8 Hz), 13.38.

(S)-1-(Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-amine (2.12)

Butyl(phenyl)phosphine oxide 2.9 (320 mg, 1.75 mmol) was added to a solution of potassium

tert-butoxide (196 mg, 1.75 mmol) in degassed THF (8 mL) under inert atmosphere. The mixture

was stirred for 5 min. tert-Butyl (S)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

1.25 solid (464 mg, 1.75 mmol) was added and the reaction mixture was stirred at 60 ºC for 3 h.

The reaction was quenched with 2N H2SO4 (8 mL) at room temperature and the mixture was

stirred for another 20 min. Extraction with diethyl ether followed by purification by flash

chromatography on silica gel (EtOAc /CHCl3, 1:3 v/v) afforded diastereo-mixture 2.10 (200 mg,

31%) as a white solid. Trifluoroacetic acid (1.96 g, 17.2 mmol) was added to a solution of 2.10

(244 mg, 0.66 mmol) in dry CH2Cl2 (5 mL) at 0 ºC. The reaction was allowed to warm up and

stirred at room temperature for 3 h. Saturated Na2CO3 was added dropwise to the solution at 0

ºC. The aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over

MgSO4 and concentrated to afford the diastereo-mixture 2.11 (168 mg, 95%) as colorless oil.

BH3▪SMe was added to a solution of 2.11 (168 mg, 0.63 mmol) in dry THF (10 mL). The

reaction was stirred at 70 ºC for 14 h. Saturated NH4Cl was added to quench the reaction.

110

Extraction with CH2Cl2 followed by flash column chromatography on silica gel (CH2Cl2/MeOH,

50:1 v/v) afforded 2.12a (65 mg, 38%) and 2.12b (65 mg, 38%) as colorless oil.

(S)-1-((R)-Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-amine (2.12a)

1H NMR (400 MHz, CDCl3) δ 7 79 (m 2H) 7 57 – 7.44 (m, 3H), 3.01 (m, 1H), 2.02 (m, 1H),

1.96 – 1.79 (m, 3H), 1.66 (m, 1H), 1.58 – 1.48 (m, 1H), 1.42 (br, 2H), 1.40 – 1.23 (m, 3H), 0.91

(d, J = 2.9 Hz, 3H), 0.90 (J = 2.9 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)

δ 131 96 (d J = 8.8 Hz), 131.30 (d, J = 2.5 Hz), 128.86 (d, J = 9.6 Hz), 52.53 (d, J = 0.9 Hz),


24.20 (d, J = 13.6 Hz), 18.45, 17.40, 13.55. 31P NMR (121 MHz, CDCl3) δ 12 83 (d J = 89.6

Hz).

(S)-1-((S)-Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-amine (2.12b)

1H NMR (300 MHz, CDCl3) δ 7 73 (m 2H) 7 48 (m 3H) 2 79 (tdd J = 11.9, 5.3, 2.7 Hz, 1H),

2.28 (br, 2H), 2.08 (td, J = 14.5, 2.5 Hz, 1H), 1.90 (m, 2H), 1.84 – 1.73 (m, 1H), 1.64 – 1.43 (m,

2H), 1.41 – 1.19 (m, 3H), 0.98 – 0.80 (m, 6H), 0.76 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,

CDCl3) δ 132 06 (d J = 8.6 Hz), 131.34 (d, J = 2.5 Hz), 128.79 (d, J = 9.6 Hz), 52.28 , 34.31 ,


18.19 , 17.27 , 13.52. 31P NMR (121 MHz, CDCl3) δ 13 15 (br d J = 83.1 Hz).

1-((S)-1-((R)-Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-yl)-3-(4-

nitrophenyl)thiourea (2.13a)

111

Synthesized according to the general procedure using 4-nitrophenyl isothiocyanate (20 mg, 0.113

mmol) and 2.12a (30 mg, 0.113 mmol). Purification through silica gel flash column

chromatography (Hexanes/EtOAc, 2:1 v/v) afforded the product (42 mg, 84%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ 8 41 (br s 1H) 8 19 (d J = 9.0 Hz, 2H), 7.75 (m, 2H), 7.67 –

7.41 (m, 5H), 6.83 (br s, 1H), 4.71 (br s, 1H), 2.25 (m, 2H), 2.07 – 1.84 (m, 3H), 1.57 – 1.38 (m,

1H), 1.33 (q, J = 7.2 Hz, 2H), 1.20 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H),

0.80 – 0.66 (m, 3H). 13

C NMR (101 MHz, CDCl3) δ 179 61 144 17 131 97 (d J = 8.9 Hz),

131.73, 129.06 (d, J = 9.7 Hz), 125.08, 122.66, 57.05, 31.98, 28.20 (d, J = 33.0 Hz), 25.21 (d, J

= 37.5 Hz), 24.69, 24.08 (d, J = 14.0 Hz), 18.92, 18.44, 13.53. 31


9.95.

1-((S)-1-((S)-Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-yl)-3-(4-

nitrophenyl)thiourea (2.13b)

Synthesized according to the general procedure using 4-nitrophenyl isothiocyanate (10 mg, 0.057

mmol) and 2.12b (15 mg, 0.057 mmol). Purification through silica gel flash column

chromatography (Hexanes/EtOAc, 2:1 v/v) afforded the product (22 mg, 88%) as a yellow solid.

1-((S)-1-((R)-Butyl(phenyl)phosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea

(2.14a)

112

Degassed toluene (0.5 mL) was added into a Schlenk tube containing 2.13a (13 mg, 0.029 mmol)

and DABCO (98 mg, 0.87 mmol) under argon. The reaction was stirred at 40 ºC for 6 h. The

crude mixture was directly loaded onto silica gel and was purified through flash column

chromatography using degassed CH2Cl2 as eluent under a positive pressure of argon. The final

product (6 mg, 50%) was isolated as a yellow solid.

1H NMR (400 MHz, Chloroform-d) δ 8 20 (m, 3H), 7.55 (m, 2H), 7.48 – 7.29 (m, 5H), 6.28 (d,

J = 9.1 Hz, 1H), 4.66 (s, 1H), 2.23 – 1.91 (m, 3H), 1.88 – 1.70 (m, 2H), 1.48 – 1.29 (m, 2H),

1.11 – 0.71 (m, 9H). 13

C NMR (101 MHz, Chloroform-d) δ 144 28 132 59 (d J = 19.5 Hz),

129.39 , 128.65 (d, J = 7.2 Hz), 125.56 , 122.18 , 59.03 (d, J = 14.9 Hz), 32.56 , 30.94 , 28.18 (d,

J = 9.7 Hz), 27.86 (d, J = 12.9 Hz), 24.20 (d, J = 12.1 Hz), 18.53 , 13.75. 31

P NMR (162 MHz,

CDCl3) δ -31.93. MS (DART-TOF) m/z: [M + H]+calcd for C22H31N3O2PS 432.2, found 432.2.

1-((S)-1-((S)-Butyl(phenyl)phosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea

(2.14b)

Degassed toluene (0.5 mL) was added into a Schlenk tube containing 2.13b (22 mg, 0.049 mmol)

and DABCO (166 mg, 1.48 mmol) under argon. The reaction was stirred at 40 ºC for 6 h. The

crude mixture was directly loaded onto silica gel and was purified through flash column

chromatography using degassed CH2Cl2 as eluent under a positive pressure of argon. The final

product (10 mg, 50%) was isolated as a yellow solid.

1H NMR (400 MHz, Chloroform-d) δ 8 25 (s 2H) 8 24 – 8.15 (m, 2H), 7.53 (m, 3H), 7.44 –

7.27 (m, 4H), 6.19 (s, 1H), 4.41 (s, 1H), 2.29 – 2.06 (m, 2H), 1.88 (ddd, J = 14.4, 8.1, 3.6 Hz,

1H), 1.74 (m, 2H), 1.47 – 1.21 (m, 4H), 0.96 (d, J = 6.7, 3H), 0.92 – 0.78 (m, 6H). 13

C NMR

(101 MHz, Chloroform-d) δ 144 18 132 68 (d J = 19.6 Hz), 129.39, 129.05 (d, J = 1.9 Hz),

128.94 , 128.62 (d, J = 7.4 Hz), 125.49 , 122.12 , 58.93 , 31.62 , 30.58 , 28.22 (d, J = 9.3 Hz),

28.14 (d, J = 13.9 Hz), 24.24 (d, J = 12.5 Hz), 18.74, 18.61, 13.77. 31

P NMR (162 MHz, CDCl3)

113

δ -34.01. HRMS (DART-TOF) m/z: [M + H]+

calcd for C22H31N3O2PS 432.18852, found

432.18746.

N1,N

3-Bis((S)-1-((R)-butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-yl)isophthalamide

(2.15a)

Et3N (9.6 mg, 0.095 mmol) was added into a solution of 2.12a (24 mg, 0.090 mmol) and

Isophthaloyl dichloride (9 mg, 0.045 mmol) in dry CH2Cl2. The reaction was stirred at room

temperature for 14 h. Then the reaction mixture was directly loaded onto silica gel without work-

up. Purification through flash column chromatography on silica gel (MeOH/CH2Cl2, 1:50 v/v)

afforded the final product 2.15a (22 mg, 74%) was isolated as a white solid.

1H NMR (400 MHz, CDCl3) δ 8 00 (t J = 1.8 Hz, 1H), 7.85 (dd, J = 7.7, 1.7 Hz, 2H), 7.78 (m,

4H), 7.48 – 7.35 (m, 7H), 6.54 (d, J = 8.9 Hz, 2H), 4.35 – 4.12 (m, 2H), 2.42 (ddd, J = 15.0, 11.2,

8.8 Hz, 2H), 2.19 – 2.07 (m, 2H), 2.06 – 1.83 (m, 6H), 1.55 – 1.41 (m, 2H), 1.35 – 1.16 (m, 6H),

0.91 (d, J = 6.7 Hz, 6H), 0.81 (t, J = 7.2 Hz, 6H), 0.77 (d, J = 6.7 Hz, 6H). 13

C NMR (101 MHz,

CDCl3) δ 165 56 134 00 132 08 (d J = 8.8 Hz), 131.41 (d, J = 2.5 Hz), 130.45 , 128.90 (d, J =

9.6 Hz), 128.43 (d, J = 52.1 Hz), 124.71 , 52.06 (d, J = 2.4 Hz), 32.64 (d, J = 7.2 Hz), 28.99 (d, J

= 33.7 Hz), 25.32 (d, J = 37.3 Hz), 24.76, 24.13 (d, J = 14.0 Hz), 18.83, 18.62, 13.50. 31

P NMR

(162 MHz, CDCl3) δ 11 30 HRMS (DART-TOF) m/z: [M – H2 + H]+

calcd for C38H59B2N2O2P2

659.42379, found 659.42462.

N1,N

3-Bis((S)-1-((S)-butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-yl)isophthalamide

(2.15b)

114

Et3N (6 mg, 0.06 mmol) was added into a solution of 2.12b (15 mg, 0.056 mmol) and

Isophthaloyl dichloride (6 mg, 0.028 mmol) in dry CH2Cl2. The reaction was stirred at room

temperature for 14 h. Then the reaction mixture was directly loaded onto silica gel without work-

up. Purification through flash column chromatography on silica gel (MeOH/CH2Cl2, 1:50 v/v)

afforded the final product 2.15b (13 mg, 72%) was isolated as a white solid.

1H NMR (400 MHz, CDCl3) δ 7 87 (m 2H) 7 85 (d J = 1.7 Hz, 1H), 7.65 (m, 4H), 7.47 – 7.41

(m, 2H), 7.40 – 7.30 (m, 5H), 6.30 (d, J = 8.5 Hz, 2H), 4.03 (m, 2H), 2.37 – 2.17 (m, 4H), 2.09

(m, 2H), 2.03 – 1.91 (m, 4H), 1.61 – 1.47 (m, 2H), 1.46 – 1.28 (m, 6H), 0.95 (d, J = 6.8 Hz, 6H),

0.93 – 0.87 (m, 12H).13

C NMR (101 MHz, CDCl3) δ 165 52 133 85, 131.89 (d, J = 8.8 Hz),

131.40 (d, J = 2.5 Hz), 130.56, 128.87 (d, J = 9.9 Hz), 127.40 (d, J = 52.4 Hz), 124.91, 51.24 (d,

J = 3.3 Hz), 32.86 (d, J = 7.6 Hz), 27.83 (d, J = 34.1 Hz), 25.54 (d, J = 37.1 Hz), 24.82 , 24.25 (d,

J = 13.9 Hz), 18.49, 18.15, 13.58. 31

P NMR (162 MHz, CDCl3) δ 11 39 HRMS (DART-TOF)

m/z: [M – H2 + H]+ calcd for C38H59B2N2O2P2 659.42379, found 659.42585.

N1,N

3-Bis((S)-1-((R)-butyl(phenyl)phosphanyl)-3-methylbutan-2-yl)isophthalamide (2.16a)

HBF4• Et2 (24 mg, 0.15 mmol) was added into a solution of 2.15a (10 mg, 0.015 mmol) in

degassed CH2Cl2. The reaction was stirred at room temperature for 14 h. The reaction was

quenched with degassed sodium bicarbonate. The aqueous layer was extracted with CH2Cl2. The

combined organic layer was directly loaded onto silica gel. Purification through flash column

115

chromatography (MeOH/CH2Cl2, 1:50 v/v) afforded the final product 2.16a (7.5 mg, 80%) as a

white solid.

1H NMR (400 MHz, CDCl3) δ 7 94 – 7.90 (m, 1H), 7.62 (dd, J = 7.7, 1.8 Hz, 2H), 7.58 – 7.50

(m, 4H), 7.35 (t, J = 7.8 Hz, 1H), 7.32 – 7.27 (m, 6H), 5.94 (d, J = 9.1 Hz, 2H), 4.21 (m, 2H),

2.03 – 1.93 (m, 6H), 1.78 – 1.67 (m, 4H), 1.41 – 1.16 (m, 8H), 0.96 (d, J = 6.8 Hz, 6H), 0.89 (d,

J = 6.8 Hz, 6H), 0.82 (t, J = 7.1 Hz, 6H). 13

C NMR (101 MHz, CDCl3) δ 165 83 138 60 (d J =

15.0 Hz), 134.88 , 132.65 (d, J = 20.0 Hz), 129.55 , 129.08 , 128.59 , 128.58 , 128.52 , 53.30 (d,

J = 12.3 Hz), 32.90 (d, J = 7.4 Hz), 31.82 (d, J = 14.4 Hz), 28.28 (d, J = 10.9 Hz), 27.95 (d, J =

13.4 Hz), 24.24 (d, J = 12.0 Hz), 18.86, 18.05, 13.75. 31

P NMR (162 MHz, CDCl3) δ -31.26.

HRMS (DART-TOF) m/z: [M + H]+calcd for C38H55N2O2P2 633.37388, found 633.37428.

N1,N

3-Bis((S)-1-((S)-butyl(phenyl)phosphanyl)-3-methylbutan-2-yl)isophthalamide (2.16b)

HBF4• Et2 (54 mg, 0.33 mmol) was added into a solution of 2.15b (22 mg, 0.033 mmol) in

degassed CH2Cl2. The reaction was stirred at room temperature for 14 h. The reaction was

quenched with degassed sodium bicarbonate. The aqueous layer was extracted with CH2Cl2. The

combined organic layer was directly loaded onto silica gel. Purification through flash column

chromatography (MeOH/CH2Cl2, 1:50 v/v) afforded the final product 2.16b (18 mg, 86%) as a

white solid.

1H NMR (300 MHz, Chloroform-d) δ 7 93 (m 1H) 7 64 (dd J = 7.7, 1.8 Hz, 2H), 7.54 (td, J =

7.5, 2.1 Hz, 4H), 7.38 (t, J = 7.7 Hz, 1H), 7.34 – 7.27 (m, 6H), 5.95 (d, J = 9.0 Hz, 2H), 4.23 –

3.85 (m, 2H), 2.19 – 1.97 (m, 4H), 1.90 (m, 2H), 1.82 – 1.63 (m, 4H), 1.46 – 1.22 (m, 8H), 0.96

(d, J = 6.7 Hz, 6H), 0.92 – 0.82 (m, 12H). 13

C NMR (101 MHz, Chloroform-d) δ 165 85

138.06 (d, J = 15.1 Hz), 134.99 , 132.68 (d, J = 19.7 Hz), 129.34 (d, J = 37.0 Hz), 128.58 ,

128.58 (d, J = 7.2 Hz), 125.16 , 52.98 (d, J = 10.6 Hz), 32.33 (d, J = 7.3 Hz), 32.09 (d, J = 14.7

Hz), 28.22 (d, J = 14.6 Hz), 28.07 (d, J = 9.9 Hz), 24.30 (d, J = 12.4 Hz), 19.06, 18.17, 13.77.

116

31P NMR (121 MHz, cdcl3) δ -33.16. HRMS (DART-TOF) m/z: [M + H]

+ calcd for

C38H55N2O2P2 633.37388, found 633.37324.

5.2 1H NMR, 13C NMR and 31P NMR spectra

139

5.3 X-Ray Crystallography Data

Table 1. Crystal data and structure refinement for d15113.

Identification code d15113

Empirical formula C22 H33 B N3 O2 P S

Formula weight 445.35

Temperature 147(2) K

Wavelength 1.54178 Å

Crystal system Orthorhombic

Space group P21212

140

Unit cell dimensions a = 15.0286(5) Å = 90°.

b = 22.2881(8) Å = 90°.

c = 7.3704(3) Å = 90°.

Volume 2468.78(16) Å3

Z 4

Density (calculated) 1.198 Mg/m3

Absorption coefficient 1.947 mm-1

F(000) 952

Crystal size 0.200 x 0.200 x 0.100 mm3

Theta range for data collection 3.547 to 67.154°.

Index ranges -17<=h<=17, -26<=k<=26, -8<=l<=8

Reflections collected 42609

Independent reflections 4363 [R(int) = 0.0344]

Completeness to theta = 67.154° 99.2 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.7529 and 0.6642

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 4363 / 5 / 310

Goodness-of-fit on F2 1.049

Final R indices [I>2sigma(I)] R1 = 0.0252, wR2 = 0.0666

R indices (all data) R1 = 0.0257, wR2 = 0.0670

Absolute structure parameter 0.011(16)

141

Extinction coefficient n/a

Largest diff. peak and hole 0.317 and -0.196 e.Å-3

142

Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103)

for d15113. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________________________

x y z U(eq)

________________________________________________________________________________

S(1) 5812(1) 2783(1) 1363(1) 25(1)

P(1) 8737(1) 2918(1) 3102(1) 22(1)

O(1) 3852(1) 4802(1) -6095(3) 58(1)

O(2) 3358(1) 4969(1) -3376(3) 60(1)

N(1) 6521(1) 3192(1) -1750(2) 25(1)

N(2) 7361(1) 2525(1) -238(2) 23(1)

N(3) 3865(1) 4720(1) -4450(4) 42(1)

C(1) 6595(1) 2839(1) -253(3) 20(1)

C(2) 7655(1) 2097(1) 1136(3) 24(1)

C(3) 7584(2) 1444(1) 437(3) 32(1)

C(4) 8145(2) 1330(1) -1238(4) 42(1)

C(5) 6613(2) 1273(1) 99(4) 46(1)

C(6) 8612(1) 2244(1) 1720(3) 25(1)

C(7) 9928(1) 2972(1) 3506(3) 29(1)

C(8) 10159(2) 3601(2) 4200(6) 35(1)

C(9) 11110(2) 3633(2) 4881(5) 44(1)

C(10) 11379(3) 4280(2) 5324(8) 71(2)

143

C(7A) 9928(1) 2972(1) 3506(3) 29(1)

C(8A) 10326(6) 3459(3) 4719(10) 30(2)

C(9A) 10178(5) 4098(3) 4092(9) 35(2)

C(10A) 10747(6) 4546(3) 5160(12) 52(2)

C(11) 8460(1) 3552(1) 1680(3) 25(1)

C(12) 8924(2) 3650(1) 69(3) 33(1)

C(13) 8721(2) 4144(1) -988(3) 43(1)

C(14) 8060(2) 4535(1) -471(4) 47(1)

C(15) 7598(2) 4439(1) 1116(4) 46(1)

C(16) 7796(2) 3950(1) 2202(3) 34(1)

C(17) 5832(1) 3569(1) -2331(3) 22(1)

C(18) 5331(1) 3926(1) -1161(3) 25(1)

C(19) 4674(1) 4296(1) -1860(3) 29(1)

C(20) 4540(1) 4314(1) -3709(3) 30(1)

C(21) 5039(2) 3973(1) -4901(3) 31(1)

C(22) 5685(1) 3598(1) -4196(3) 26(1)

B(1) 8092(2) 2856(1) 5333(3) 32(1)

________________________________________________________________________________

144

Table 3. Bond lengths [Å] and angles [°] for d15113.

_____________________________________________________

S(1)-C(1) 1.6791(19)

P(1)-C(11) 1.807(2)

P(1)-C(7A) 1.819(2)

P(1)-C(7) 1.819(2)

P(1)-C(6) 1.824(2)

P(1)-B(1) 1.914(2)

O(1)-N(3) 1.226(3)

O(2)-N(3) 1.231(3)

N(1)-C(1) 1.360(3)

N(1)-C(17) 1.402(3)

N(1)-H(1N) 0.77(3)

N(2)-C(1) 1.347(3)

N(2)-C(2) 1.461(3)

N(2)-H(2N) 0.82(3)

N(3)-C(20) 1.464(3)

C(2)-C(6) 1.536(3)

C(2)-C(3) 1.547(3)

C(2)-H(2A) 1.0000

C(3)-C(4) 1.517(4)

C(3)-C(5) 1.528(3)

145

C(3)-H(3A) 1.0000

C(4)-H(4A) 0.9800

C(4)-H(4B) 0.9800

C(4)-H(4C) 0.9800

C(5)-H(5A) 0.9800

C(5)-H(5B) 0.9800

C(5)-H(5C) 0.9800

C(6)-H(6A) 0.9900

C(6)-H(6B) 0.9900

C(7)-C(8) 1.532(4)

C(7)-H(7A) 0.9900

C(7)-H(7B) 0.9900

C(8)-C(9) 1.517(5)

C(8)-H(8A) 0.9900

C(8)-H(8B) 0.9900

C(9)-C(10) 1.532(6)

C(9)-H(9A) 0.9900

C(9)-H(9B) 0.9900

C(10)-H(10A) 0.9800

C(10)-H(10B) 0.9800

C(10)-H(10C) 0.9800

C(7A)-C(8A) 1.528(6)

146

C(7A)-H(7A1) 0.9900

C(7A)-H(7A2) 0.9900

C(8A)-C(9A) 1.514(6)

C(8A)-H(8AA) 0.9900

C(8A)-H(8AB) 0.9900

C(9A)-C(10A) 1.533(7)

C(9A)-H(9AA) 0.9900

C(9A)-H(9AB) 0.9900

C(10A)-H(10D) 0.9800

C(10A)-H(10E) 0.9800

C(10A)-H(10F) 0.9800

C(11)-C(16) 1.389(3)

C(11)-C(12) 1.394(3)

C(12)-C(13) 1.382(4)

C(12)-H(12A) 0.9500

C(13)-C(14) 1.375(4)

C(13)-H(13A) 0.9500

C(14)-C(15) 1.377(4)

C(14)-H(14A) 0.9500

C(15)-C(16) 1.385(4)

C(15)-H(15A) 0.9500

C(16)-H(16A) 0.9500

147

C(17)-C(22) 1.394(3)

C(17)-C(18) 1.394(3)

C(18)-C(19) 1.384(3)

C(18)-H(18A) 0.9500

C(19)-C(20) 1.379(4)

C(19)-H(19A) 0.9500

C(20)-C(21) 1.383(3)

C(21)-C(22) 1.383(3)

C(21)-H(21A) 0.9500

C(22)-H(22A) 0.9500

B(1)-H(1) 1.07(3)

B(1)-H(2) 1.16(3)

B(1)-H(3) 1.06(3)

C(11)-P(1)-C(7A) 105.65(10)

C(11)-P(1)-C(7) 105.65(10)

C(11)-P(1)-C(6) 107.23(9)

C(7A)-P(1)-C(6) 104.31(9)

C(7)-P(1)-C(6) 104.31(9)

C(11)-P(1)-B(1) 115.99(11)

C(7A)-P(1)-B(1) 111.24(11)

C(7)-P(1)-B(1) 111.24(11)

148

C(6)-P(1)-B(1) 111.61(11)

C(1)-N(1)-C(17) 130.93(18)

C(1)-N(1)-H(1N) 117(2)

C(17)-N(1)-H(1N) 112(2)

C(1)-N(2)-C(2) 127.15(17)

C(1)-N(2)-H(2N) 115.8(15)

C(2)-N(2)-H(2N) 117.1(15)

O(1)-N(3)-O(2) 123.9(2)

O(1)-N(3)-C(20) 118.2(2)

O(2)-N(3)-C(20) 117.9(2)

N(2)-C(1)-N(1) 112.11(17)

N(2)-C(1)-S(1) 123.71(15)

N(1)-C(1)-S(1) 124.16(15)

N(2)-C(2)-C(6) 109.74(16)

N(2)-C(2)-C(3) 111.27(17)

C(6)-C(2)-C(3) 111.09(16)

N(2)-C(2)-H(2A) 108.2

C(6)-C(2)-H(2A) 108.2

C(3)-C(2)-H(2A) 108.2

C(4)-C(3)-C(5) 110.9(2)

C(4)-C(3)-C(2) 112.93(19)

C(5)-C(3)-C(2) 110.79(18)

149

C(4)-C(3)-H(3A) 107.3

C(5)-C(3)-H(3A) 107.3

C(2)-C(3)-H(3A) 107.3

C(3)-C(4)-H(4A) 109.5

C(3)-C(4)-H(4B) 109.5

H(4A)-C(4)-H(4B) 109.5

C(3)-C(4)-H(4C) 109.5

H(4A)-C(4)-H(4C) 109.5

H(4B)-C(4)-H(4C) 109.5

C(3)-C(5)-H(5A) 109.5

C(3)-C(5)-H(5B) 109.5

H(5A)-C(5)-H(5B) 109.5

C(3)-C(5)-H(5C) 109.5

H(5A)-C(5)-H(5C) 109.5

H(5B)-C(5)-H(5C) 109.5

C(2)-C(6)-P(1) 115.38(13)

C(2)-C(6)-H(6A) 108.4

P(1)-C(6)-H(6A) 108.4

C(2)-C(6)-H(6B) 108.4

P(1)-C(6)-H(6B) 108.4

H(6A)-C(6)-H(6B) 107.5

C(8)-C(7)-P(1) 109.76(18)

150

C(8)-C(7)-H(7A) 109.7

P(1)-C(7)-H(7A) 109.7

C(8)-C(7)-H(7B) 109.7

P(1)-C(7)-H(7B) 109.7

H(7A)-C(7)-H(7B) 108.2

C(9)-C(8)-C(7) 111.6(3)

C(9)-C(8)-H(8A) 109.3

C(7)-C(8)-H(8A) 109.3

C(9)-C(8)-H(8B) 109.3

C(7)-C(8)-H(8B) 109.3

H(8A)-C(8)-H(8B) 108.0

C(8)-C(9)-C(10) 111.4(4)

C(8)-C(9)-H(9A) 109.3

C(10)-C(9)-H(9A) 109.3

C(8)-C(9)-H(9B) 109.3

C(10)-C(9)-H(9B) 109.3

H(9A)-C(9)-H(9B) 108.0

C(9)-C(10)-H(10A) 109.5

C(9)-C(10)-H(10B) 109.5

H(10A)-C(10)-H(10B) 109.5

C(9)-C(10)-H(10C) 109.5

H(10A)-C(10)-H(10C) 109.5

151

H(10B)-C(10)-H(10C) 109.5

C(8A)-C(7A)-P(1) 121.9(4)

C(8A)-C(7A)-H(7A1) 106.9

P(1)-C(7A)-H(7A1) 106.9

C(8A)-C(7A)-H(7A2) 106.9

P(1)-C(7A)-H(7A2) 106.9

H(7A1)-C(7A)-H(7A2) 106.7

C(9A)-C(8A)-C(7A) 115.6(5)

C(9A)-C(8A)-H(8AA) 108.4

C(7A)-C(8A)-H(8AA) 108.4

C(9A)-C(8A)-H(8AB) 108.4

C(7A)-C(8A)-H(8AB) 108.4

H(8AA)-C(8A)-H(8AB) 107.4

C(8A)-C(9A)-C(10A) 112.0(5)

C(8A)-C(9A)-H(9AA) 109.2

C(10A)-C(9A)-H(9AA) 109.2

C(8A)-C(9A)-H(9AB) 109.2

C(10A)-C(9A)-H(9AB) 109.2

H(9AA)-C(9A)-H(9AB) 107.9

C(9A)-C(10A)-H(10D) 109.5

C(9A)-C(10A)-H(10E) 109.5

H(10D)-C(10A)-H(10E) 109.5

152

C(9A)-C(10A)-H(10F) 109.5

H(10D)-C(10A)-H(10F) 109.5

H(10E)-C(10A)-H(10F) 109.5

C(16)-C(11)-C(12) 119.6(2)

C(16)-C(11)-P(1) 120.24(17)

C(12)-C(11)-P(1) 120.14(16)

C(13)-C(12)-C(11) 119.7(2)

C(13)-C(12)-H(12A) 120.2

C(11)-C(12)-H(12A) 120.2

C(14)-C(13)-C(12) 120.5(2)

C(14)-C(13)-H(13A) 119.7

C(12)-C(13)-H(13A) 119.7

C(13)-C(14)-C(15) 120.0(2)

C(13)-C(14)-H(14A) 120.0

C(15)-C(14)-H(14A) 120.0

C(14)-C(15)-C(16) 120.3(2)

C(14)-C(15)-H(15A) 119.8

C(16)-C(15)-H(15A) 119.8

C(15)-C(16)-C(11) 119.8(2)

C(15)-C(16)-H(16A) 120.1

C(11)-C(16)-H(16A) 120.1

C(22)-C(17)-C(18) 119.94(19)

153

C(22)-C(17)-N(1) 116.43(18)

C(18)-C(17)-N(1) 123.57(18)

C(19)-C(18)-C(17) 119.6(2)

C(19)-C(18)-H(18A) 120.2

C(17)-C(18)-H(18A) 120.2

C(20)-C(19)-C(18) 119.4(2)

C(20)-C(19)-H(19A) 120.3

C(18)-C(19)-H(19A) 120.3

C(19)-C(20)-C(21) 122.1(2)

C(19)-C(20)-N(3) 119.3(2)

C(21)-C(20)-N(3) 118.6(2)

C(22)-C(21)-C(20) 118.3(2)

C(22)-C(21)-H(21A) 120.8

C(20)-C(21)-H(21A) 120.8

C(21)-C(22)-C(17) 120.6(2)

C(21)-C(22)-H(22A) 119.7

C(17)-C(22)-H(22A) 119.7

P(1)-B(1)-H(1) 108.5(18)

P(1)-B(1)-H(2) 102.9(16)

H(1)-B(1)-H(2) 112(2)

P(1)-B(1)-H(3) 108.8(16)

H(1)-B(1)-H(3) 114(2)

154

H(2)-B(1)-H(3) 110(2)

_____________________________________________________________

Symmetry transformations used to generate equivalent atoms:

155

Table 4. Anisotropic displacement parameters (Å2x 103) for d15113. The anisotropic

displacement factor exponent takes the form: -22[ h2 a*2U11 + ... + 2 h k a* b* U12 ]

______________________________________________________________________________

U11 U22 U33 U23 U13 U12

______________________________________________________________________________

S(1) 21(1) 33(1) 22(1) 4(1) 4(1) 2(1)

P(1) 21(1) 26(1) 20(1) -1(1) 2(1) 3(1)

O(1) 68(1) 41(1) 66(1) -1(1) -40(1) 13(1)

O(2) 33(1) 48(1) 98(2) 5(1) 0(1) 17(1)

N(1) 22(1) 31(1) 21(1) 4(1) 6(1) 8(1)

N(2) 21(1) 27(1) 21(1) 2(1) 3(1) 4(1)

N(3) 31(1) 25(1) 71(2) 2(1) -18(1) -2(1)

C(1) 20(1) 20(1) 21(1) -3(1) -2(1) -1(1)

C(2) 24(1) 24(1) 24(1) 4(1) -1(1) 4(1)

C(3) 36(1) 25(1) 36(1) 1(1) -10(1) 5(1)

C(4) 49(1) 35(1) 42(1) -12(1) -12(1) 13(1)

C(5) 46(2) 28(1) 65(2) 1(1) -21(1) -4(1)

C(6) 23(1) 27(1) 24(1) 0(1) 0(1) 4(1)

C(7) 24(1) 31(1) 32(1) -1(1) -1(1) 2(1)

C(8) 28(2) 41(3) 35(2) -4(2) -2(2) -2(2)

C(9) 32(2) 64(3) 35(2) -2(2) -6(2) -10(2)

C(10) 61(3) 83(4) 68(3) 8(3) -20(3) -43(3)

156

C(7A) 24(1) 31(1) 32(1) -1(1) -1(1) 2(1)

C(9A) 43(4) 24(4) 36(4) -7(3) 4(3) -1(3)

C(11) 25(1) 25(1) 24(1) -3(1) -2(1) 1(1)

C(12) 41(1) 32(1) 27(1) -1(1) 3(1) 1(1)

C(13) 66(2) 36(1) 28(1) 2(1) -1(1) -7(1)

C(14) 70(2) 27(1) 44(2) 7(1) -16(1) 1(1)

C(15) 50(2) 29(1) 60(2) -2(1) -6(1) 12(1)

C(16) 32(1) 30(1) 39(1) -3(1) 2(1) 3(1)

C(17) 20(1) 20(1) 26(1) 4(1) 1(1) 0(1)

C(18) 26(1) 21(1) 29(1) 1(1) 4(1) -2(1)

C(19) 22(1) 20(1) 44(1) 0(1) 6(1) -1(1)

C(20) 21(1) 19(1) 48(1) 4(1) -6(1) -1(1)

C(21) 33(1) 26(1) 32(1) 4(1) -8(1) -2(1)

C(22) 27(1) 26(1) 25(1) 0(1) 1(1) 2(1)

B(1) 31(1) 45(2) 21(1) -2(1) 10(1) 2(1)

______________________________________________________________________________

157

Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3)

for d15113.

________________________________________________________________________________

x y z U(eq)

________________________________________________________________________________

H(1N) 6872(19) 3144(12) -2500(40) 36(8)

H(2N) 7696(15) 2584(10) -1100(30) 17(5)

H(2A) 7260 2139 2220 29

H(3A) 7813 1175 1419 39

H(4A) 8764 1442 -990 63

H(4B) 8117 904 -1557 63

H(4C) 7917 1571 -2249 63

H(5A) 6264 1350 1197 69

H(5B) 6377 1514 -905 69

H(5C) 6576 847 -212 69

H(6A) 8981 2290 616 29

H(6B) 8850 1899 2411 29

H(7A) 10110 2668 4414 35

H(7B) 10255 2891 2366 35

H(8A) 10076 3895 3208 41

H(8B) 9748 3709 5197 41

158

H(9A) 11515 3470 3945 53

H(9B) 11171 3383 5984 53

H(10A) 11995 4287 5759 106

H(10B) 11329 4527 4228 106

H(10C) 10985 4440 6266 106

H(7A1) 10120 2581 4012 35

H(7A2) 10216 3011 2304 35

H(8AA) 10071 3415 5951 36

H(8AB) 10975 3388 4816 36

H(9AA) 9541 4202 4241 42

H(9AB) 10325 4129 2786 42

H(10D) 10632 4953 4715 78

H(10E) 10595 4523 6451 78

H(10F) 11378 4449 4997 78

H(12A) 9377 3380 -300 40

H(13A) 9040 4213 -2080 52

H(14A) 7922 4871 -1210 56

H(15A) 7141 4709 1467 56

H(16A) 7479 3886 3301 40

H(18A) 5439 3916 109 30

H(19A) 4320 4534 -1073 34

H(21A) 4940 3995 -6173 37

159

H(22A) 6032 3357 -4990 31

H(1) 7420(20) 2717(14) 5030(50) 53(8)

H(2) 8480(20) 2492(15) 6120(50) 60(9)

H(3) 8133(19) 3270(13) 6020(40) 45(8)

________________________________________________________________________________

160

Table 6. Torsion angles [°] for d15113.

________________________________________________________________

C(2)-N(2)-C(1)-N(1) -178.97(18)

C(2)-N(2)-C(1)-S(1) -0.7(3)

C(17)-N(1)-C(1)-N(2) 177.5(2)

C(17)-N(1)-C(1)-S(1) -0.8(3)

C(1)-N(2)-C(2)-C(6) -130.5(2)

C(1)-N(2)-C(2)-C(3) 106.2(2)

N(2)-C(2)-C(3)-C(4) 60.1(2)

C(6)-C(2)-C(3)-C(4) -62.5(2)

N(2)-C(2)-C(3)-C(5) -65.0(2)

C(6)-C(2)-C(3)-C(5) 172.4(2)

N(2)-C(2)-C(6)-P(1) 71.85(19)

C(3)-C(2)-C(6)-P(1) -164.69(14)

C(11)-P(1)-C(6)-C(2) -66.98(16)

C(7A)-P(1)-C(6)-C(2) -178.73(15)

C(7)-P(1)-C(6)-C(2) -178.73(15)

B(1)-P(1)-C(6)-C(2) 61.06(18)

C(11)-P(1)-C(7)-C(8) 51.8(2)

C(6)-P(1)-C(7)-C(8) 164.7(2)

B(1)-P(1)-C(7)-C(8) -74.9(2)

P(1)-C(7)-C(8)-C(9) 169.6(3)

161

C(7)-C(8)-C(9)-C(10) 172.0(4)

C(11)-P(1)-C(7A)-C(8A) 70.9(4)

C(6)-P(1)-C(7A)-C(8A) -176.3(3)

B(1)-P(1)-C(7A)-C(8A) -55.8(4)

P(1)-C(7A)-C(8A)-C(9A) -61.9(7)

C(7A)-C(8A)-C(9A)-C(10A) -168.7(6)

C(7A)-P(1)-C(11)-C(16) -125.50(18)

C(7)-P(1)-C(11)-C(16) -125.50(18)

C(6)-P(1)-C(11)-C(16) 123.67(17)

B(1)-P(1)-C(11)-C(16) -1.8(2)

C(7A)-P(1)-C(11)-C(12) 53.23(19)

C(7)-P(1)-C(11)-C(12) 53.23(19)

C(6)-P(1)-C(11)-C(12) -57.59(19)

B(1)-P(1)-C(11)-C(12) 176.96(17)

C(16)-C(11)-C(12)-C(13) 0.2(3)

P(1)-C(11)-C(12)-C(13) -178.53(19)

C(11)-C(12)-C(13)-C(14) -0.6(4)

C(12)-C(13)-C(14)-C(15) 0.4(4)

C(13)-C(14)-C(15)-C(16) 0.1(4)

C(14)-C(15)-C(16)-C(11) -0.5(4)

C(12)-C(11)-C(16)-C(15) 0.3(3)

P(1)-C(11)-C(16)-C(15) 179.06(19)

162

C(1)-N(1)-C(17)-C(22) -144.1(2)

C(1)-N(1)-C(17)-C(18) 38.8(3)

C(22)-C(17)-C(18)-C(19) 1.6(3)

N(1)-C(17)-C(18)-C(19) 178.60(18)

C(17)-C(18)-C(19)-C(20) -1.4(3)

C(18)-C(19)-C(20)-C(21) 0.2(3)

C(18)-C(19)-C(20)-N(3) -178.00(17)

O(1)-N(3)-C(20)-C(19) 168.4(2)

O(2)-N(3)-C(20)-C(19) -9.8(3)

O(1)-N(3)-C(20)-C(21) -9.9(3)

O(2)-N(3)-C(20)-C(21) 171.9(2)

C(19)-C(20)-C(21)-C(22) 0.7(3)

N(3)-C(20)-C(21)-C(22) 178.94(18)

C(20)-C(21)-C(22)-C(17) -0.4(3)

C(18)-C(17)-C(22)-C(21) -0.7(3)

N(1)-C(17)-C(22)-C(21) -177.89(19)

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Symmetry transformations used to generate equivalent atoms:

Modular Synthesis of Chiral -Aminophosphine PN Ligands and ... · Modular Synthesis of Chiral...

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