Ti (II) Mediated Reactions in Organic Chemistry Chris Tarr University of North Carolina February 23,...

Ti (II) Mediated Reactions in Organic Chemistry

Chris Tarr

University of North Carolina

February 23, 2007

Outline of Topics Covered

• Background

• Cyclopropanation Reactions

• Olefin/Acetylene Functionalizations

• Reductive Couplings

Advantages of Titanium

• Titanium (IV) reagents are cheap and readily available

• Low toxicity compared to other transition metal catalysts

• Less reactive than Li or Mg organometallics

• More reactive than corresponding B or Zn organometallics

Notable Applications Not Covered

• Sharpless Asymmetric Epoxidation (TiIV)

• Lewis Acid Catalysis (TiIV)

• McMurry Coupling (TiIII Ti°)

• Tebbe Reagent (TiIV)

Crimmins M. T.; King, B. W., Tabet, E. A. J. Am. Chem. Soc. 1997, 119, 7883.

McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708.

Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I. Ed; VCH: New York, 1993; p. 103-158.

Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611.

OO

Ti TiORO

E

E

E

EOR

OO

Ti TiORO

E

E

E

E

O

ROR

O O

tBu

O

O

TiCl3

LAH

CH2OH

ORR

CH2OH

(+) DET

4A mol sieves

Ti(OiPr)4

tBuOOH

N O

1 eq. TiCl4amine base

2 eq TiCl4amine base

S

BnRCHO RCHO

O

N O

S

Bn

O

N O

S

Bn

O

R R

OH

Me

OH

Me

Cp2TiCl2 + 2AlMe3 Cp2TiCl

AlMe2

R R'

O R R'

Generation of Ti(II) from Ti(IV)

• Bercaw accessed and characterized the first Ti(II)-ethylene adduct:

X-ray crystal structure verifies existence as monomer

• Ti(II) was able to dimerize ethylene; however, was not effective as a promoter for further polymerization

Cohen, S. A.; Auburn, P. R.; Bercaw, J. E. J. Am. Chem. Soc. 1983, 105, 1136.

• Two limiting resonance structures: Ti(II) species may react as either a 1,2-dianion or a pi-bound alkene

TiCl

Cl

1. Na/Hg

2. ethylene atmTi

TiCp2 TiCp2

R R2 CO 2 HClCp2Ti(CO)2

Cp2TiCl2

+ +

R R

TiX2

R

R

TiX

RH

L

R

-RCH2CH3 TiX2

TiX2

R

R

XTiX2

X

2M'(CH2CH2R)

-2M'X

-X

Generation of Ti(II) via Reductive Alkylation

• Ti(IV) converted to Ti(II) via reductive alkylation: an organolithium or organomagnesium compound can be used to generate a dialkyl titanium complex which can lead to a Ti(II) species

X = halide, ORβ-hydride elimination

reductive elimination

Kulinkovich, O. G.; Meijere, A. Chem. Rev. 2000, 100, 2789.

2 M(CH2CH2R)


• Background

• Cyclopropane-forming Reactions



Kulinkovich Reaction

• Kulinkovich reaction: a facile method for cyclopropanol synthesis from esters

Ti(IV) can also be used catalytically (2 equiv. of Grignard reagent required)

Kulinkovich et al., Zh. Org. Khim. 1989, 25, 2244.Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.

R OR'

O

1. EtMgBr (3 equiv)

Ti(OiPr)4

Et2O, -78oC

2. H3O+

OH

R

Representative Examples

• Kulinkovich cyclopropanation

Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.

MeOH OH

OHOH OH OH

74%

Et

82%

C5H11

94% 85%

Ph

93% 90%

OH

OHHO

OHOH

Cl

TMS MeO

PhBnN

76%

67% 55% 60%

OH

OH

HO

90%

Ph

PhOH

Me

OH

Me

MeOH

Ph

60% 85%62% 61%

Mechanism of Kulinkovich Reaction

Kulinkovich et al. Zh. Org. Khim. 1989, 25, 2245.

H3O+R

HO

EtMgBr

OTi(OiPr)2R

OR'

BrMg+

-

R'OMgBr

Ti(OiPr)2

O

R

R

O(PrOi)2TiEtMgBr

(iPrO)2Ti(C2H5)2

R

BrMgO

Kulinkovich, O. Pure Appl. Chem. 2000, 72, 1715.

Ti(OiPr)2

2EtMgBrTi(OiPr)2

HC2H6

Ti(OiPr)2

OTi(OiPr)2MeO

R

R OMe

O

O R

Ti(O iPr)2MeOH3O

+R

OH

Ti(OiPr)4

Mechanism of Kulinkovich Reaction

Kulinkovich et al. Zh. Org. Khim. 1989, 25, 2245.

Kulinkovich, O. Pure Appl. Chem. 2000, 72, 1715.

Ti(OiPr)2

2 EtMgBrTi(OiPr)2

HC2H6

Ti(OiPr)2

OTi(OiPr)2MeO

R

R OMe

O

Ti(OiPr)4

H3O+R

HO

EtMgBr

OTi(OiPr)2R

OR'

BrMg+

-

R'OMgBr

Ti(OiPr)2

O

R

R

O(iPrO)2Ti

de Meijere Mechanism

• Key mechanistic difference

Chaplinski, V.; de Meijere, A. Angew. Chem. Int. Ed. 1996, 35, 413.

• de Meijere modification: access to cyclopropylamines

R NR'2

O

1. EtMgBr (2 equiv.) Ti(OiPr)4

Et2O

2. H3O+

NR'2

R

R NR'2

O

EtMgBr (2 equiv.)Ti(OiPr)4

Ti(OiPr)2

OR

R'2NTi(OiPr)2

R'2N

-O

+

NR'2

R

R

Substrate Scope

• de Meijere modification


NBn2

NBn2

NBn2

iPr2N

NMe2

NBn2

NBn2

95% 77% 86%

Ph

47% 42% 50%

Ph2P O

80%

NMe2 NBn2

NMe2

TrO

NMe2

BnO

O NH2

74%54% 72% 89% 53%

Computational Study on Selectivity of Kulinkovich Reaction

• Computed with B3LYP/HW3 method• Cyclopropane forming step, determines stereochemistry and is the

rate determining step• T.S. cis is 2.5 kcal/mol more favored because of agostic interaction

between ester R group and Ti

Wu, Y. D.; Yu, Z. H. J. Am. Chem. Soc. 2001, 123, 5777.

Ti-H 2.44 Å Ti-H 2.96 Å

Ligand Exchange in Kulinkovich Reaction

• Allows for a wider range of substitution in cyclopropanols

• Substrates with which alkene exchange has been successful


Ti(OiPr)2

R

Ti(OiPr)2R

R' OR"

O

RR'

OH

Ph TMS

Bu3SnP(OEt)2HO RO

O

Intramolecular Nucleophilic Acyl Substitution

• Typically difficult to balance the necessary reactivity and functional group tolerance

• Exchange of the initial alkene with a second alkene tethered to an ester leads to new products with trans alkyl/(aryl) groups

Generation of1,4 diols

Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 34, 6079.

O Ph

OTi(OiPr)2

O Ph

O(OiPr)2Ti

O

O-

Ph

Ph

OHOH

Ph

(iPrO)2Ti

Ph

O

O-

Ti(OiPr)2

O

Ti(OiPr)2O

Additional INAS reactions

• Generation of fused bicyclic cyclopropanols

• Use of an alkyne versus an alkene leads to methylene-lactone or α,β-unsaturated carbonyl

Okamoto, S.; Kasatkin, A.; Zubaidha, P.; Sato, F. J. Am. Chem. Soc. 1996, 118, 2208.

O

OMe

Ti(OiPr)2

O

OMe

Ti(O iPr)2

O

Ti(OR)3

OH

Ti(OiPr)2

R

O OEt

O

n

(iPrO)2Ti

R

O

OOEt

nO

OR

(iPrO)2Ti

R

CO2Et

O-

(iPrO)2Ti

n

n

+

OEt

nO

OR

R

CO2Et

OHn

+

Enantioselective Catalytic Kulinkovich Reaction

• Corey demonstrated limited success in achieving an asymmetric reaction based on catalyst control

• Very limited catalyst screen and substrate scope• Only moderate yields and enantiomeric induction are achieved

TADDOL-based pre-catalystAr = 3,5-bis(trifluoromethyl)phenyl

With ethyl acetatesubstrate:65% yield70-80% ee

Corey, E. J.; Rao, S. A.; Noe, M. S. J. Am. Chem. Soc. 1994, 116, 9345.

OTi

OO

OO

O

O

OArAr

Ar ArAr

Ar

Ar Ar

Substrate controlled INAS Reaction

• Stereoselectivity can be transferred from starting material to the final products

Cao, B.; Xiao, D.; Joullie, M. M. Org. Lett. 1999, 1, 1799.

Quan, L. G.; Kim, S. H.; Lee, J. C.; Cha, J. K. Angew. Chem. Int. Ed. 2002, 41, 2160.

3 : 1

Mizojiri, R.; Urabe, H.; Sato, F. Angew. Chem. Int. Ed. 1998, 71, 1673.

Ar

NMe2

O

NBn

MgBr

ArCO2H

NH2

3 steps

N N

Me2N

Bn

Ar Ar

Bn

Me2N

+

Ti(O iPr)4

SO2

N

O

C5H11

Ti(O iPr)2 C5H11OH

R

OH

R

OTi(OiPr)3

RMgCl Ti OO iPr

RR' OR"

O

OH

R

R'

HO

Ti(OiPr)4

Cyclopropylamines from Nitriles

• Initial adduct can lead to tertiary amines and ketones

• Addition of a BF3 Lewis acid results in the formation of cyclopropylamines

Bertus, P.; Szymoniak, J. Chem. Comm. 2001, 1792.Laroche, C.; Behr, J. B.; Szymoniak, J.; Bertus, P.; Plantier-Royon, R. Eur. J. Org. Chem. 2005, 5084.

Ph CN Ti(OiPr)2+Ti(OiPr)2

NPh

BF3OEt2 H2O

EtMgBr EtEt

Ph

NH2

EtPh

O

Ti(O iPr)2N

PhBF3

H2NPh

Cyclopropylamines from Nitriles

• Nitriles can easily be installed in carbohydrate backbones; this strategy allows the synthesis of cyclopropylamine substituted sugars

Laroche, C.; Behr, J. B.; Szymoniak, J.; Bertus, P.; Plantier-Royon, R. Eur. J. Org. Chem. 2005, 5084.

OO

OO

BnO

CN O

O

O OCN

OBn

OPiv

OBn

NC

BnO

CN

BzOOBz

OBz

OO

OO

OBn

O

O

O O

OBn

OPiv

BnOBnO BzO OBz

BzONH2

NH2 H2N

57% 62% 54% 55%

NH2

First Access to Spirocyclopropyl Iminosugar

• Iminosugars are potent glycosidase inhibitors and have been identified as possible anti-diabetes, anti-retroviral, and anti-tumor targets

• High cytotoxicities preclude their use• Cyclopropane ring is a key pharmacophore that induces

binding in other bioactive molecules

6 steps13% overall yield

Laroche, C.; Plantier-Royon, R.; Szymoniak, J.; Bertus, P.; Behr, J.-B. Synlett 2006, 2, 223.

O

OBn

OH

BnO

BnO NH2OH HCl

NaHCO3

OBn

OH

NOHOBn

BnO

OBn

OPiv

N

OBn

BnO

PivCl

OBn

OPiv

NH2

OBn

BnO

Ti(OiPr)2HN

HO OH

HO

Vinylogous Kulinkovich Reaction

• Cha has recently developed a procedure for a vinylogous Kulinkovich reaction

• When toluene and a Lewis acid are employed, a vinyl cyclopropane is formed

• Reaction produces a spirocyclic cyclopropane ring with no directly bound heteroatom

Masalov, N.; Wei, F.; Cha, J. K. Org. Lett. 2004, 6, 2365.

O

O

R MgX

O

O Ti

Rtoluene

LA

THF

O

OH

R

O OR'R'

LA

O

R

TiOR'O

+

O

R

Ti(OiPr)4

Ring Expansions to Cyclobutanones

• Acid mediated ring expansion/cyclization of Kulinkovich reaction products

• Pinacol-type rearrangement to access chiral α-substituted cyclobutanones

Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337.

Youn, J. H.; Lee, J.; Cha, J. K. Org. Lett. 2001, 3, 2935.

>90% chirality transfer

HO

CHO

H+

OH

O

R CO2Et

OH

EtMgBrR

OH

OH

MsCl

pyridine O

RClTi(O iPr)3


• Background




Olefin-imide Coupling• Ti (II) can react with imides,

however only poor regioselectivity is obtained

Kim, S.; Park, Y.; Choo, H.; Cha, J. K. Tetrahedron Lett. 2002, 43, 6657.

• Intramolecular trapping provides poor diastereoselectivity; however, reduction with H2/PtO2 leads to the same product arising from both diastereomers

NH

O

OEtMgBr

NH

O

O Ti(O iPr)2

NH

O

O

(iPrO)2Ti

+ H2O NH

O

OH

NH

O

HO

2 : 1

+ClTi(OiPr)3

NH

O

OEtMgBr

NH

O

O Ti(O iPr)2

NH

O

O

Ti(OiPr)2

+ H2O NH

O

OH

NH

O

HO

2 : 1

BnOBnO

BnO

BnO BnO

+ClTi(OiPr)3

N

O

O

EtMgBrNN

O O

OHOH

+

1 : 1

H2PtO2

N

O

H

90% yield

ClTi(OiPr)3

• Cha also developed a diastereoselective cyclization between imides and substituted tethered olefins

• When R = H, poor diastereoselectivities are achieved; however, larger R groups such as Me or Ph higher diastereoselectivities were obtained

Olefin-imide Coupling

Santra, S.; Masalov, N.; Epstein, O. L.; Cha, J. K. Org. Lett. 2005, 7, 5901.

N

O

O

R

N

O

R

OH

m

n nm

m,n = 1,2R = Me, Ph

Ti(OiPr)4nBuLi

Olefin-imide Coupling

Santra, S.; Masalov, N.; Epstein, O. L.; Cha, J. K. Org. Lett. 2005, 7, 5901.

N

O

O

R

N

O

R

OH

m

n nm

m,n = 1,2R = Me, Ph

Ti(OiPr)4nBuLi

N

O

H

OH

N

OH

Ph

O

67% yield12:1 d.r.

N

OH

H

O

77% yield2 : 1 d.r.

N

O

Me

OH

N

O

Ph

OH

87% yield3:1 d.r.

70% yield5:1 d.r.

65% yield9:1 d.r.

N

OH

O

60% yield21:1 d.r.

Ph

Addition of Imine-Based Titanocyclopropanes

• Addition to an imine followed by trapping with acetylene leads to allyl and alkynyl amines, as well as pyrroles

• Asymmetric induction from chiral R group

• Stereochemical model for observed products

Ohkubo, M.; Hayashi, D.; Oikawa, D.; Fukuhara, K.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2006, 47, 6209.Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145.

Ar

NR

Ti(OiPr)2N

Ti(O iPr)2

Ar

R

R'

X

Ti(O iPr)2

N

Ti(O iPr)2

N

R

R

X

R'

Ar

Ar+

H+

H+

Ar R'

NHR

Ar

NHR

X

X

N R

R'

Ar

X

-HX

HN

Ar

Ti ONAr

H H

Ph

MeiPrO

OiPr

H

N Ti(OiPr)2

OMeN Ti(OiPr)2

HAr

Ph

R

X

Ph

Ar

H

RX

Ti(O iPr)2

Ar

N Ph

OMe

R

X

HN

R

Ph

OMe

HAr

HN

C

Ph

OMe

HAr

R'R

R'

R

Diastereoselectivity of Allyl Amine Formation

R d.r. Yield (%)

TMS 97:3 81

Hexyl 98:2 82

Ph 98:2 84

CO2Et 96:4 63

SO2Tol 94:6 28


Ar

NTi(O iPr)2

Ar R

HN

RH+

Ph

OMe

Ph

OMe

Diastereoselectivity of Allenyl Amine Formation

Ar R/R’/X d.r. Yield

Ph H/H/Br 98:2 74

o-iodophenyl H/H/Br 98:2 61

1-naphthyl H/H/Br 98:2 59

p-OTBS-phenyl H/H/Br 98:2 62

Ph Hexyl/H/OP(O)(OEt)2 98:2 49

Ph Ph/H/OP(O)(OEt)2 98:2 62

Ar

NTi(O iPr)2

Ar

HN

H+

Ph

OMe

Ph

OMe

R'X

R R'

RC


Diene Functionalization

• Titanium can add into a diene to form a cyclopentenyltitanium species which can add to an aldehyde with good regio- and diastereoselectivity

• The resulting species can be opened via protonolysis

• Good asymmetric induction was achieved by tethering a chiral 8-phenylmenthol ester to the diene backbone

Urabe, H.; Mitsui, K.; Ohta, S.; Sato, F. J. Am. Chem. Soc. 2003, 125, 6074.

SiR3

tBuO2C

C6H13

Ti(O iPr)2

tBuO2C

C6H13

SiR3

R'CHO

O Ti(O iPr)2

SiR3

tBuO2C

H

R' C6H13H+(iPrO)2Ti R SiR3

H OH

tBuO2CC6H13

1. Ti(OiPr)4iPrMgBr (2 equiv.)O

O SiR3

C6H13

O

SiR3R'

O C6H13

HH OH

69% yield88% ee

2. R'CHO

3. H+

DIBALR'

OH

HO C6H13

Ph Ph

KOtBu

Addition to Acetylenes

• Reaction of alkynes with Ti(II) allows for trapping with two subsequent electrophiles

• Reaction with dichlorophosphites leads to cyclic phosphites

• Reaction with sec-BuOH followed by a second electrophile leads to one C-C or C-X and one C-H bond

Urabe, H.; Hamada, T.; Sato, F. J. Am. Chem. Soc. 1999, 121, 2931.

Ti(OiPr)4

R

R

RPCl2 PR

R

R

R

R'iPrMgBr

Ti(O iPr)2

R

R

1. E1+

2. E2+

R

R'

E1

E2

Ti(OiPr)4

TMS

R

H

I

Ti(OiPr)2

TMS

R

sBuOHTMS

R TiX3

H

I2

PhCHO

O

O

O

Br

TMS

R

H O

O

TMS

R

H

OTMS

R

H

OH

Li2Cu(CN)Cl2 (cat)

Li2Cu(CN)Cl2 (cat)

Regioselectivity of Titanacyclopropene Opening

• When unsymmetrical acetylenes are used to form the titanacyclopropene, electrophilic ring opening can occur with a high degree of regioselectivity

Urabe, H.; Hamada, F.; Sato, F. J. Am. Chem. Soc. 1999, 121, 2931.

Ti(O iPr)2

Ti(OiPr)2

Ti(O iPr)2 Ti(OiPr)2

Ti(OiPr)2 Ti(O iPr)2

TMS

tBuO2C

TMS

tBuO2C

C6H13

Ph

Me

Bu3Sn

TMS

C6H13

EtO OEt

OTHP

7

93 14

86 2

98

98

2

90

10

0

100

El = PhCHO El = c-C6H11CHO El = PhCHO

El = PhCHOEl = EtCHOEl = PhCHO

Cross Coupling Reactions

• Recently, the Ti(II)-cyclopropene complex has been found to undergo a newly developed cross coupling reaction

• Treatment with aryl iodide and a Ni(COD)2 complex leads to a mixture of mono- and di-arylated products with mono-coupled products predominating

Obora, Y.; Moriya, H.; Tokunaga, M.; Tsuji, Y. Chem. Comm. 2003, 2820.

Yields 40 – 80%Selectivities range from 10:1 to 1:1

R

Rn-BuLi

Ti(OiPr)4

R

R

ArI

Ni(COD)2

50oC

R R

H Ar

R R

Ar Ar+

thermally stable

Ti(OiPr)4

Ni0Ar-I

Ni-Ar

M-R

M-I

Ar-Ni-R

R-Ar

Enyne Cyclization

• A tethered alkyne and alkene can be used in an annulation reaction

• Depending on the substitution of enyne, 1,2-difuntionalized rings and variously functionalized bicyclic rings can be achieved

Okamoto, S.; Ito, H.; Tanaka, S.; Sato, F. Tetrahedron Lett. 2006, 47, 7537.

A

X

R

Ti(OiPr)2

R

AX

A = H

A = FG

R

TiX3

R

TiX3

A

E+

R

E

A = CO2R

A = CH2X

R

O

R

n n

n

n

n

n

n

Diversity of Enyne Cyclization Manifold

• 1,2 substituted acrylynes can also undergo titanium mediated cyclization to form exocyclic cyclopentenes, [3.3.0]-bicyclooctanes, and [3.1.0]-bicyclohexanes

Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997, 119, 10014.

X

R

CO2R'R' = bulky

X

CO2R'

ElH

X

R

CO2R' R' = smallX O

H El

X

CO2R

R

R' = small

X

R

CO2R'El El

R

TMS

H

OH

CO2tBu

62% yield

TMS

H

CO2tBu

TMS

H

OH

CO2tBu

TMS

H

CO2tBu

83% yield 61% yield 52% yield

OCO2Et

CO2EtCO2Et

BnNCO2Et

C5H11

C5H11

53% yield 76% yield 74% yield 51% yield

O

TMS

O

TMS

O

TMS

O

C5 H11

80% yield

C4H9H

89% yield97:3 d.r.

TBSO H

69 % yield9:1 d.r.

73 % yield

Asymmetric Metallo-ene Reaction

• Metallo-ene reaction, difficult to achieve enantioselectivity

• Ti-mediated cyclization: does allow for asymmetirc induction

• Camphor esters gave poor ee’s; however, chiral acetals gave high ee’s• Acetals offer a convenient synthetic handle for further product

manipulation

Takayama, Y.; Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1999, 121, 3559.

R

MM

X

M

RO

R

TiTi

RO

Ti

RO

R

TiLn

C5H11

O

O

Ph

Ph

Ti(OiPr)2

C5H11

O

OHPh

H

96 % ee20:1 E/Z87% yield

PPTS

Ph

C5H11

O

O

Ph

Ph H

Ac2OTsOH

C5H11

HMeOOMe

1. (CO2H)2

2. Jones ox.3. (COCl)2

4. SnCl4

O

C5H11

H

Normal Metallo-ene Reaction Titanium (II) Equivalent

Siloxy-enyne Cyclization

• Phillips and co-workers developed a siloxy-enyne cyclization• Cleavage of the C-Si bond allows for the installation of an anti-methyl

group alpha to a hydroxy group• This strategy has been applied to natural product synthesis

O’Neil, G. W.; Phillips, A. J. Tetrahedron Lett. 2004, 45, 4253.O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340.

R

OSi

R2

R3R4

ClTi(OiPr)3

iPrMgCl

O Si

R

R2

R3 R4O SiR3 R4

R Ti(OiPr)2

R2 H+

HO

OH OH

OO

OH

Dictyostatin Synthesis

• Dictyostatin, an anti-cancer marine macrocycle synthesized by Phillips

• Two 3° stereocenters set by siloxy-enyne reaction

HO

OPMB

O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340.

R

OSi

R2

R3R4

ClTi(OiPr)3

iPrMgCl

O Si

R

R2

R3 R4O SiR3 R4

R Ti(OiPr)2

R2 H+

OPMB

O(MeO)2P

O

2+2+2 Cyclization• Trapping of cyclopentadienyl-titanium species with another

unsaturated molecule results in a 2+2+2 cyclization

• Rothwell developed a 2+2+2 reaction; however, the product is formed with only poor regioselectivity due to metal-assisted 1,5-hydride shifts under reaction conditions

Johnson, E. S.; Balaich, G. J.; Rothwell, I. P. J. Am. Chem. Soc. 1997, 119, 7685.

TiArO

ArO Cl

Cl2 Na/Hg

Ti(OAr)2

PhEtEt+

(ArO)2TiCl2 Et

Et

Ph

Et

Et

Et Et

Et

Ph

Et

Et

Ph

Et

Et

Et

10% 55% 35%Ti Ti

HHTi

H

2+2+2 Cyclization

Yields ~50-80%

• Cha developed a 2+2+2 coupling reaction with tethered acetylenes β-hydroxy olefins• The reaction proceeds in good to moderate yields• No double bond migration occurs, so initially formed cyclohexadienes can be isolated

Sung, M. J.; Pang, J. H.; Park, S. B.; Cha, J. K. Org. Lett. 2003, 5, 2137.

+OH

R c-C5H9MgCl

TiO R

OiPrOH

R

TMS

TMS

TMS

TMS

ClTi(OiPr)3

Synthesis of Titanated Benzene Rings

Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123, 7925.

CO2tBu

C6H13 C6H13

Ti(OiPr)2

Ti(OiPr)2

CO2tBuC6H13

C6H13

SO2Tol C6H13

CO2tBu

TiX3

C6H13

C6H13

CO2tBu

I

C6H13

C6H13

C6H13

C6H13

CO2tBu

C6H13

I256%

PhCHO

49%

O

Ph

O

H+

57%

Ti(OiPr)2

CO2tBuC6H13

C6H13

SO2Tol

4+2

insertion

X2Ti

TiX2

CO2tBu

C6H13

SO2TolC6H13

CO2tBuC6H13

C6H13SO2Tol

C6H13

CO2tBu

TiX3

C6H13

TiX2SO2Tol

C6H13

C6H13

tBuO2C

Two Mechanisms for Alkyne Addition

Synthesis of Aromatic Rings

• Sato developed a regioselective coupling between an acetylene and a nitrile, followed by trapping with another unsaturated molecule

• A single intermediate allows access to pyridine, furan, and pyrrole containing molecules

Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7474.

N

R

R'

R"

EtMgBr (2 equiv.) NTi(OiPr)2

R"

R'R

+

SO2Tol

N

OMe

R'''CHO

H(D)+ N

O

NH

R''

R'

R

TiX3

R''

R' R

R'''

R''

R' R

CHO

R'H(D)

R

OR''

Ti(OiPr)4

Mechanism for Pyridine Formation

• Tosyl acetylenes lead to titanated pyridines, which allow for the regiocontrolled synthesis of tetrasubstituted pyridines

• Reaction conditions also allow for the preparation of chiral pyridine rings starting from the easily accessible optically active propargyl alcohols


NTi(OiPr)2

C4H9

C4H9SO2Tol

NR''

R'

R

TiX3

OMe

N

Ti

C4H9

C4H9

OMe

SO2TolN

C4H9

C4H9

OMe

SO2TolTiX3

N

C4H9

C4H9

H(D) N

C6H13

TMS

H(D)

N

C6H13

TMS

H N

Ph

TMS

H N

C6H13

TMS

H

N

C6H13

TMS

I

OMe

Cl OMe OMe

OMe OMe

C8H17

76% 58%50%

53% 56% 57%

N

C4H9

C4H9

H(D)Me

OTBS

N

C4H9

C4H9

IMe

OTBS

N

Ph

TMS

H(D)Me

OTBS

N

Ph

TMS

IMe

OTBS

73% (99%) 69%(99%)

69%(99%) 58%(99%)

Furan Formation

• Interception of the cyclopentadienyl intermediate with an aldehyde leads to an insertion, followed by protonolysis, ring closing, and aromatization

• The reaction produces moderate yields of tetrasubstituted furan rings


NTi(OiPr)2

C4H9C4H9

OMe

PhCHO

N TiO

OMe

C4H9

C4H9 Ph

H+

MeONH2

Ph

OH

C4H9

C4H9

H+

OH3NMeO

C4H9 C4H9

Ph

H

O Ph

C4H9C4H9

MeO

O Ph

C4H9C4H9

MeO

O C8H17

C4H9C4H9

MeO

O Ph

C4H9C4H9

MeO

O Ph

TMSC6H13

MeO

O Ph

PhPh

MeO

O C8H17

TMSC6H13

MeO

68% 60% 57%

55% 54% 66%

C8H17

C8H17

Pyrrole Formation

• Nitrile insertion leads to a di-imine product after hydrolysis, which under acidic conditions cyclizes to the formyl pyrrole

• Trapping by two different nitriles leads to regioselective formation of the aldehyde at the least substituted side chain


NH

R R'

OMeOHC

NH

R'R

MeOCHO +

1 : 1

NH

C4H9

CHO NH3NMeO

C4H9 C4H9

NTi(O iPr)2

C4H9C4H9

OMe

NOMe

NTi(OiPr)2

N

C4H9C4H9

OMeMeO

MeO OMe

H

NH NH

C4H9 C4H9

OMe

OH2

H+

H+

C4H9

MeO

NMeO

Ti(OiPr)2

R

R'

3 equivalents

MeO OMeNH NH

Ha Hb

R R'

NMeO

Ti(OiPr)2

R

R'

1 equivalent

MeO OMeNH NH

Ha Hb

R R'

NH

R R'

OMeOHC

NMeO

1 equivalent

C4H9

C4H9

x

C4H9

exclusively formed


• Background




Pinacol Coupling

• Pinacol reaction: coupling of two carbonyl radicals

• Titanium mediated pinacol couplings lead to high selectivities for the dl isomer over the meso compound via a di-oxo-titanium intermediate

Mukaiyama, T.; Yoshimura, N.; Igarashi, K.; Kagayama, A. Tetrahedron 2001, 57, 2499.

R

O2

O- O-

RR

OH

OH

R H

O+ TiX2 + Cu2 O

TiO

H R

R HHO

OHHH

R

Rdl selective

TiI4 TiI2 + 2CuICu

Pinacol Coupling (cont.)

94% (99:1) 76% (99:1)76% (98:2)98% (85:15)93% (99:1)

80% (81:19) 72% (80:20)92% (85:15)98% (84:16)85% (75:25)

Mukaiyama, T.; Yoshimura, N.; Igarashi, K.; Kagayama, A. Tetrahedron 2001, 57, 2499.

H

O

H

O

Cl

H

O

H

O

O

O

H

H OH

O

H

O

H

O

O

H

R

O2 TiI4, 2 Cu

RR

OH

OH

RR

OH

OHdl meso

Reformatsky Reaction

O

R

X

Me

H

Ti O

R

H

X

Me

Ti

Kagayama, A. et al. Bull. Chem. Soc. Jpn. 2000, 73, 2579.

• Reformatsky Reaction: An aldol surrogate, enolate is formed via insertion into a C-X bond

• Mukaiyama et al. developed a Ti-based Reformatsky-type reaction that displays high diastereoselectivity

E-enolatedisfavored

Z-enolatefavored

R

O

X

Zn

R

O

ZnX R

OZnX

R

O

Br TiCl2Cu R

O TiX3

PhCHOR

O

Ph

OH

RBr

O

X

R

OTi

R

OTi

OTiO

OTiX2O

RR2

R

R2

H

X

R

O OH

Substrate Scope for Reformatsky Reaction

TiCl2, Cu

aldehyde

96% (96:4) 89% (91:9) 94% (91:9)

84% (84:16) 92% (85:15)

TiCl2, Cu

aldehyde

81% (63:37)74% (64:36)

21% (82:18) 69% (74:26)

Kagayama, A. et al. Bull. Chem. Soc. Jpn. 2000, 73, 2579.

Br

O O

R

OH

EtSBr

O

EtS

O

R

OH

CHO CHOCHO

CHO

CHO

CHO CHO

CHO

CHO

Summary

• Titanium (II) complexes can easily be generated from readily available and inexpensive starting materials

• The chemistry of Ti (II) complexes allows entry into several intriguing reaction manifolds including:– Cyclopropanation

– Alkene/acetylene/imine functionalization

– Synthesis of novel aromatic rings

– Various reductive coupling reactions

• Titanium (II) chemistry is amenable to the synthesis of interesting natural products

Acknowledgements

• Dr. Jeffrey Johnson• Johnson Group Members• UNC Chemistry

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Ti (II) Mediated Reactions in Organic Chemistry Chris Tarr University of North Carolina February 23,...

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