Phosgene-Free Synthesis of Verdazyl Radicals and Enantioselective

1,3-Dipolar Cycloaddition Reactions of Azomethine Imines

Generated in situ from Verdazyl Radicals

by

Beom Youn

A thesis submitted in conformity with the requirements

for the degree of Master of Science

Graduate Department of Chemistry

University of Toronto

© Copyright by Beom Youn (2012)

ii

Phosgene-free synthesis of verdazyl radicals and enantioselective

1,3-dipolar cycloaddition reactions of azomethine imines generated

in situ from verdazyl radicals

Beom Youn

Master of Science

Graduate Department of Chemistry

University of Toronto

2012

Abstract

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few

years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There

are now a number of generations of novel molecular scaffolds derived from verdazyl radicals.

Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine

and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from

being imported into certain countries, including Canada. A completely new alkyl hydrazine- and

phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously

reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to

derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar

cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still

in progress with the highest e.e. of > 90%.

iii

Table of Contents

Abstract ……………………………………………………………………………………………i

Table of Contents …………………………………………………………………………………ii

List of Schemes…………………………………………………………………………………....v

List of Figures…………………………………………………………………………………….vi

List of Tables……………………………………………………………………………………viii

List of Abbreviations……………………………………………………………………………..ix

Chapter 1 Verdazyl Radicals…………………………………………………………………...1

Chapter 1.1 The First Discovery of Persistent Radical Radicals ……………….…...….1

Chapter 1.2 The Discovery and First Synthesis of Verdazyl Radicals…………..……….2

Chapter 1.3 Neugebauer’s Synthesis of 6-Oxo and Thioverdazyl Radicals…….………..3

Chapter 1.4 Milcent’s Variation on Neugebauer’s Synthesis………………….…...…….6

Chapter 1.5 Brook’s Verdazyl Radical Synthesis…….……………………….…………7

Chapter 1.6 Inorganic Verdazyl Radicals…………………………….……….………….9

References………………………………………………………………………………..10

Chapter 2 1,3-Dipolar Cycloadditions…………………………………………….…………..12

Chapter 2.1 Introduction to Cycloadditions………………………………….………….12

Chapter 2.2 1,3-Dipolar Cycloaddition……….…………………………………………13

Chapter 2.3 Stereoselective 1,3-Dipolar Cycloaddition Reactions………….…………..23

Chapter 2.4 Concluding Remarks………………………….…………………………....34

References…………………………………………………………………………….....35

Chapter 3 Evolution of Verdazyl Radicals as Substrates for 1,3-Dipolar Cycloaddition

Reactions ………………………………………………………………………………………..38

Chapter 3.1 Discovery of the First 1,3-Dipolar Cycloaddition Reaction Initiated by an

Azomethine Imine Generated In Situ from a Verdazyl Radical…..………………….….38

Chapter 3.2 Second Generation of Unique Scaffolds Derived from Verdazyl

Radicals………………………………………………………………………………….40

iv

Chapter 3.3 Heteraphanes from Verdazyl Radicals……………………………………...41

Chapter 3.4 Summary……….………….………………………….…………………….43

References……………………………….………………………………………………44

Chapter 4 Phosgene Free Synthesis of Verdazyl Radicals…….……………………………..48

Chapter 4.1. Introduction……...…………...……………………………………………48

Chapter 4.2. Experimental Section…………..………………………………………….49

Chapter 4.3. Results and Discussion………..…………………………………………...68

References……..………………….……………………………………………………..71

Chapter 5 Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Imines Generated in

situ from Verdazyl Radicals…………...………..……………………………………………...72

Chapter 5.1. Introduction….………………………………….………………………….72

Chapter 5.2. Experimental Section …….…………………….………………………….75

Chapter 5.3. Results and Discussion………..………………………………………...…77

Chapter 5.4. Concluding Remark/Future Work ……………….………………………..85

References……………………………………………………………………………….88

v

List of Schemes

Chapter 1

Scheme 1-1. First discovery and synthesis of verdazyl radicals ………………………...2

Scheme 1-2. Neugebauer’s synthesis of tetrazinanones………………………...………..4

Scheme 1-3. Decomposition reactions of hydrazine………..………………….………...4

Scheme 1-4. Reversed regiochemical selectivity of a t-butyl substituted hydrazine….....6

Scheme1-5. Milcent’s variation of Neugebauer’s synthesis………………………..........7

Scheme 1-6. Brook’s synthesis of 1,5-diisopropyl substituted 6-oxoverdazyl radicals…8

Scheme 1-7. Modification of Brook’s synthesis for unsymmetrical verdazyl radicals .....8

Scheme 1-8. Synthesis of phosphaverdazyl radicals …………………………………....9

Scheme 1-9. Synthesis of borataverdazyl radicals …………………………………........9

Chapter 4

Scheme 4-1. Retrosynthsis of a phosgene-free verdazyl radical synthesis……………..46

Scheme 4-2. Phosgene-free synthesis of verdazyl radicals………………………..........46

Scheme 4-3. Our modification of Milcent variation on Neugebauer’s synthesis………69

Chapter 5

Scheme 5-1. Asymmetric 1,3-DC reactions with azomethine imines and β-unsaturated

aldehydes by Maruoka and et al………….…………………………………………......73

Scheme 5-2. Asymmetric 1,3-DC reaction with azomethine imines and homoallylic

alcohols by Inomata and et al………………………………..………………………….73

Scheme 5-3. Asymmetric 1,3-DC of nitrones to olefins by Furukawa et al………........75

vi

List of Figures

Chapter 2

Figure 2-1. Diels-Alder reaction between a butadiene and ethene……………………...12

Figure 2-1. 1,3-Dipoles of (a) propargyl-allenyl type, (b) allyl type with nitrogen as a

central atom, and (c) allyl type with an oxygen as a central atom……………………….13

Figure 2-2. An examples of a 1,3-DCcompound with a heteroatom containing

dipolarophile……………………………………………………………………………..14

Figure 2-3. Diradical mechanism of 1,3-DC……………………………………………15

Figure 2-4. Isoelectronic nature of allyl anion and 1,3-dipole…………………………..16

Figure 2-5. Directionless (or bidirectional) cyclic mechanism of 1,3-dipolar

cycloadditions……………………………………………………………………………17

Figure 2-6. (a) FMO phase matching and (b) coefficient matching in a cycloaddition

reaction…………………………………………………………………………………...18

Figure 2-7. HOMO/LUMO interaction between a 1,3-dipole and a dipolarophile……..18

Figure 2-8. Interaction of a filled orbital with (a) an empty orbital, and (b) with another

filled orbital………………………………………………………………………………19

Figure 2-9. Sustmann Type I, II, and III for cycloaddition reactions………………...…20

Figure 2-10. Effect of Lewis acid on HOMO and LUMO energy levels….……………21

Figure 2-11. Resonance structures of an azomethine imine….………………………....21

Figure 2-12. 1,3-Dipolar cycloaddition of an azomethine imine with an alkene………..22

Figure 2-13. Examples of azomethine imines…………………………………………...22

Figure 2-14. Uskokovic’s enantioselective intramolecular 1,3-DC reaction….….……..23

Figure 2-15. The first asymmetric 1,3-DC reaction using a chiral dipolarophile…….…24

Figure 2-16. The first catalytic enantioselective 1,3-DC reaction….…………………...25

Figure 2-17. Gothelf and Jorgenson’s catalysts for asymmetric 1,3-DC….………….....26

Figure 2-18. Gothelf and Jorgenson’s asymmetric 1,3-DC….………………...………..27

Figure 2-19. The first organocatalytic Diels-Alder reaction by MacMillan…………….29

Figure 2-20. Asymmetric 1,3-DC reaction of nitrones and α,β-unsaturated aldehydes by

MacMillan………………………………………………………………………………..30

vii

Figure 2-21. Activation and deactivation of the 1,3-DC reaction by coordination of a

Lewis acid…………………………………………………………………………….…31

Figure 2-22. Chiral tertiary amine thiourea catalysts for asymmetric 1,3-DC reactions by

Wang et al……………………………………………………………………………….32

Figure 2-23. Asymmetric 1,3-DC of azomethine ylides and N-arylmaleimides via a

postulated transition state by Wang et al……………………………………………..…32

Chapter 3

Figure 3-1. Attempted synthesis of 1-benzoyloxy-2-phenyl-2-(6-oxoverdazyl)ethane

unimer…………………………………………………………………………………....38

Figure 3-2. Reaction mechanism of the 1,3-dipolar cycloaddition reaction of an

azomethine imine generated in situ from a verdazyl radical…………………………….39

Figure 3-3. Trapping leucoverdazyl 3.3 by an alkylation reaction….…………………..39

Figure 3-4. NaH induced rearrangement of a cycloadduct derived from a verdazyl

radical….………………………………………………………………………………...40

Figure 3-5. Proposed mechanism for the rearrangement of 3.7 to 3.8………………….41

Figure 3-6. Synthesis of paraheteraphanes from verdazyl radicals…………………..…42

Figure 3-7. Versatility of verdazyl radicals: structural motifs derived from verdazyl

radicals….……………………………………………………………………………….43

Chapter 5

Figure 5-1. The second generation MacMillan catalyst…………………….…………..75

Figure 5-3. Working model of the transition state in the asymmetric 1,3-DC reaction of

azomethine imines and homoallylic alcohols by Maruoka…..………………………….80

Figure 5-4. De-alkylation of verdazyl by proline or proline-derived catalysts………....81

Figure 5-5. Equilibrium between a nitrone-metal complex and an olefin-metal

complex….………………………………………………………………………………82

Figure 5-6. Cyclophane coordination structure proposed by Anthony de Crsci……...…83

Figure 5-7. Coordination of verdazyl radicals to various metal centres by Robin

Hicks…………………………………………………………………………………….84

Figure 5-8. N-[3,5-Bis(trifluoromethyl)phenyl]-N′-[(8a,9S)-6′-methoxy-9-

cinchonanyl]thiourea….…………………………………………………………………86

viii

List of Tables

Table 4-1. Intermediates, products, and their yields for the phosgene-free verdazyl

radical synthesis….…………………………………………………………………….60

Table 5-1. Asymmetric 1,3-DC of 1,5-dimethyl-3-phenyl-6-oxoverdazyl with

methacrolein….………………………………………………………………………..70

ix

List of Abbreviations

1,3-DC 1,3-dipolar cycloaddition

Ar Aryl group

BOC t-butyloxycarbonyl

DCM dichloromethane

DIPT diisopropyl tartarate

DMF dimethyl foamide

DMSO dimethyl sulfoxide

e.e. enantiomeric excess

eq. equilvalence

EtOAc ethyl acetate

FMO frontal molecular orbital

HOMO highest occupied molecular orbital

iPr iso-propyl group

LUMO lowest unoccupied molecular orbital

Min. minutes

MO molecular orbital

[O] Oxidation

Ph phenyl group

r.t. room temperature

SOMO singly occupied molecular orbital

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Chapter 1 Verdazyl Radicals

Chapter 1.1 The First Discovery of Persistent Radical

Radicals are open shell molecules that have one or more unpaired electrons.[1] Due to

these unpaired electrons, radicals are highly reactive. However, there are a few classes of

radicals that defy this characterization and exhibit considerable stability. Radicals can be defined

in qualitative terms. For example, Ingold defined “persistent radicals” as those that are long-lived

and can be studied by conventional spectroscopic methods, but cannot be isolated. Radicals that

can be handled as pure compound and isolated are termed “stable radicals.” [2]

The first radical ever described was triphenylmethyl radical, 1.1, synthesized by

Gomberg (Figure 1-1).[3]

Figure 1-1. Triphenylmethyl radical

The stability of the triphenylmethyl radical comes from steric protection provided by the three

phenyl rings rotated at about 30o angle, much like a propeller.[4] Despite the protection, the

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triphenylmethyl radical is oxygen-sensitive and not long-lived enough to be isolated. Thus, it is

best described as a persistent radical rather than a stable radical.

Chapter 1.2 The Discovery and First Synthesis of Verdazyl Radicals.

Verdazyl radicals were first unintentionally discovered by Kuhn and Trischmann in 1963

while trying to alkylate triphenyl formazan (Scheme 1-1).[5]

Scheme 1-1. First discovery and synthesis of verdazyl radicals.[5]

When formazan is alkylated with a primary alkyl halide under basic condition, the initially

formed product, 1.3, spontaneously cyclizes at room temperature to give leucoverdazyl 1.6

(Scheme 1-1). Leucoverdazyl 1.6 is then oxidized (or dehydrogenated) by atmospheric oxygen

to yield verdazyl radical 1.7. These first verdazyl radicals were limited to those having triaryl

groups at the N-1, C-3, and N-5 positions (Figure 1-2) and were characteristically green in colour,

thus their name verdazyl. Subsequently synthesized verdazyl radicals with various functional

groups are violet, orange, yellow, or dark brown in colour.[5, 6]

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Figure 1-2. Numbering and substituents in verdazyl radicals.

While the stability of the triphenyl methyl radical comes from only sterics, the stability of

other verdazyl radicals results from delocalization of the unpaired electron over the four nitrogen

atoms as illustrated in structure 1.9 (Figure1-3).[7, 8] The unpaired electron does not delocalize

into the C-3 and C-6 positions due to the nodal plane passing through these positions in the

verdazyl radicals’ π SOMO system, 1.8 (Figure 1-3).[9]

Figure 1-3. (a) Nodal planes in verdazyl radicals and (b) delocalization of the unpaired electron.

Chapter 1.3 Neugebauer’s Synthesis of 6-Oxo and Thioverdazyl Radicals

In 1988, while using verdazyl radicals as spin probes, Neugebauer and his coworkers first

reported the synthesis of 6-thio and 6-oxoverdazyl radicals using an approach completely

different from that of Kuhn’s.[10] In this synthesis, Neugebauer reacted an alkyl hydrazine, 1.10,

- 4 -

with phosgene to give bis-alkylhydrazide 1.11, which was subsequently condensed with an alkyl

or aryl aldehyde to give tetrazinanones 1.12, the direct precursors to 6-oxoverdazyl radicals

(Scheme 1-2).[10] For 6-thiooxoverdazyls, thiophosgene was used in place of phosgene and the

rest of the synthesis was the same as the 6-oxoverdazyl synthesis.[10]

Scheme 1-2. Neugebauer’s synthesis of tetrazinanones.[10]

Although this synthesis gives a high-yielding and simple approach to verdazyl radicals, it

should be noted that this synthesis requires alkyl hydrazines and (tri)phosgenes. Hydrazine and

its derivatives are well-known rocket fuels. They exothermally decompose into ammonia,

hydrogen, and nitrogen gases, producing a large propelling force (Scheme 1-3). For this reason,

hydrazine importation is restricted in many parts of the world, including Canada.

1. 3N2H4(l) 4 NH3(g) + N2(g)

2. N2H4(l) N2(g) + 2 H2(g)

3. 4 NH3(g) + N2H4(l) 3 N2(g) + 8 H2(g)

Scheme 1-3. Decomposition reactions of hydrazine.

- 5 -

Phosgene, on the other hand, is infamous as a chemical weapon from World War I. It

reacts with water to make hydrochloric acid and carbon dioxide. Although triphosgene, solid at

ambient condition, is almost always preferred over phosgene, phosgene is still evolved when

triphosgene is hydrolyzed, even with atmospheric moisture. The fact that phosgene is a

colourless gas at room temperature makes it even more dangerous, although it does smell like

freshly mowed grass. However, the concentration at which it can be detected by the human nose

is approximately 10 times the safety level of 0.1 ppm.

While Kuhn’s synthesis was limited to N-1, C-3, N-5- triaryl verdazyl radicals,

Neugebauer’s synthesis allows for a variety of alkyl groups at N-1 and N-5.[11] This new

approach also permitted the introduction of thio or oxo functionality at C-6. However, it should

be noted that both Kuhn’s and Neugebauer’s syntheses are limited to symmetrical verdazyl

radicals, where the functionalities at N-1 and N-5 are identical. Moreover, since there are only a

few derivatives of mono-substituted hydrazines commercially available, there are a limited

number of different verdazyl radicals that can be synthesized by these approaches.

Mono-substituted hydrazine 1.10 (Scheme 1-2), reacts with electrophiles at the

substituted nitrogen, not at the terminal nitrogen. In other words, it is the substituted nitrogen that

does the nucleophilic attack on phosgene (Scheme 1-2). This regiochemical selectivity of 1.10 is

an electronic effect, where the substituted nitrogen is more nucleophilic than the terminal

nitrogen in the mono-substituted hydrazine due to the inductive electron-donating effect of the

alkyl group. As a result, there is an inherent limitation to this synthetic approach since the steric

environment imposed by larger alkyl groups on the substituted nitrogen greatly diminishes the

rate of reaction of the substituted nitrogen with phosgene and results in attack by the

unsubstituted nitrogen (Scheme 1-4). Bis-alkylhydrazide 1.14, obtained from the reaction

- 6 -

between phosgene and the terminal nitrogen, cannot condense with an aldehyde to give a

tetrazinanone, the direct precursor to a verdazyl radical. Therefore, bulky substituents on

hydrazine results in a reversed regiochemical selectivity and render this synthesis useless.

Scheme 1-4. Reversed regiochemical selectivity of a t-butyl substituted hydrazine.

Chapter 1.4 Milcent’s Variation on Neugebauer’s Synthesis

In 1994, to circumvent the limitation of Kuhn’s and Neugebauer’s symmetrical tetrazanes,

Milcent and Barbier modified Neugebuer’s synthesis (Scheme 1-5).[10, 12] The key modification is

a reaction of the substituted hydrazine 1.15 first with an aldehyde to reduce the reactivity of the

terminal nitrogen in 1.16. The protected substituted hydrazine is then reacted with (tri)phosgene

to give chloroformylhydrazone 1.17. An unprotected alkyl hydrazine is then added to give the

intermediate 1.18, which spontaneously cyclizes to give tetrazinanone 1.19 (Scheme 1-5).

Subsequent oxidation by various oxidants or atmospheric oxygen gives the verdazyl radical.

- 7 -

Scheme1-5. Milcent’s variation of Neugebauer’s synthesis.

This synthesis not only overcomes the problem of bulky substituents, but also allows the

synthesis of N-1, N-5 unsymmetrical verdazyl radicals. However, it should be noted that the R2

substituent on the second added hydrazine cannot be a bulky group because if it is it will not

react with the carbamic chloride 1.17. Using hydrazine substituted with bulky group such as t-

butyl group would result in the formation of 1.20, which cannot lead to verdazyl radicals.

Although Milcent’s synthesis is a smart variation of Neugebauer’s original synthesis, it

still has the same limitations as Neugebauer’s synthesis; the dependence on mono-substituted

hydrazines and the need to work with (tri)phosgene.

Chapter 1.5 Brook’s Verdazyl Radical Synthesis

In 2005, Brook and his co-workers developed a synthesis that overcomes the inability of

Milcent’s approach to have bulky alkyl groups at both the N-1 and N-5 positions (Scheme 1-6).

In order to get around the problem of the regiochemical selectivity of bulky-substituent

substituted hydrazines, Brook chose t-BOC (tert-butyloxycarbonyl) as a protecting group to give

1.21, instead of a hydrazone as in Milcent’s variation. This effectively leaves only the isopropyl

substituted nitrogen on 1.21 as the sole nucleophile to react with phosgene. Once the t-BOC-

protected bishydrazide 1.22 is deprotected to give bishydrazide 1.23, the synthesis follows the

same pathway as Neugebauer’s synthesis; condensation with one molar equivalence of aldehyde

and subsequent oxidation to the verdazyl radical (Scheme 1-6).[6]

- 8 -

Scheme 1-6. Brook’s synthesis of 1,5-diisopropyl substituted 6-oxoverdazyl radicals[6].

Although Brook only synthesized symmetrical verdazyl radicals where the substituents at

N-1 and N-5 positions were both isopropyl groups[6], the synthesis can easily be modified to give

N-1, N-5 unsymmetrical verdazyl (Scheme 1-7).

Scheme 1-7. Modification of Brook’s synthesis for unsymmetrical verdazyl radicals.

Brook’s synthesis clearly overcomes the synthetic limitations of previous verdazyl

syntheses,[6, 10-12] yet, it still depends on mono-substituted carbazate and, even worse,

(tri)phosgene. Although carbazate can easily be purchased, there still are only a limited number

of its derivatives available.

Chapter 1.6 Inorganic Verdazyl Radical[13][14]

While verdazyl radical syntheses listed thus far have a carbon atom at the C-6 position,

there are verdazyl radicals with phosphorous or boron at the 6-position as well. These verdazyl

radicals are used especially to coordinate to a metal centre. Hicks and co-workers first reported

phosphorous and boron containing verdazyl radicals in 2002 and 2007, respectively.[13, 15] The

synthesis for the “phosphaverdazyl” resembles Neugebauer’s synthesis except for the fact that

aryl or aminophosphonic dichloride is used in place of (tri)phosgene (Scheme 1-2 and Scheme 1-

- 9 -

8).[10, 15] Likewise, the synthesis for the “borataverdazyl” resembles Kuhn’s initial synthesis for

triaryl verdazyl starting from formazan (Scheme 1-1 and Scheme 1-9).[5, 13]

Scheme 1-8. Synthesis of phosphaverdazyl radicals. [15]

Scheme 1-9. Synthesis of borataverdazyl radicals. [13]

- 10 -

References

[1] B. Zvonimir, D. C. Maksic, The Concept of the Chemical Bond, Springer-Verlag 1990.

[2] D. Griller, K. U. Ingold, Acc. Chem. Res. 1976, 9, 13-19.

[3] M. Gomberg, J. Am. 1900, 22, 757-771.

[4] R. G. Hicks, Org. Biomol. Chem. 2007, 5, 1321-1338.

[5] R. Kuhn, H. Trischmann, Angew. Chem. Int. Ed. Engl. 1963, 2, 155.

[6] E. C. Pare, D. J. R. Brook, A. Brieger, M. Badik, M. Schinke, Org. Biomol. Chem. O r g . B i

o m o l . C h e m . 2005, 3, 4258-4261.

[7] R. Kuhn, H. Trischmann, Angew. Chem. 1963, 75, 294-295.

[8] R. Kuhn, H. Trischmann, Monatsh. Chem. 1964, 95, 457-479.

[9] C. L. Barr, P. A. Chase, R. G. *. Hicks, M. T. Lemaire, C. L. and Stevens, J. Org. Chem.

1999, 64, 8893-8897.

[10] F. A. Neugebauer*, H. Fischer, R. Siegel, Chem. Ber. 1988, 121, 815-822.

[11] F. A. Neugebauer, H. Fischer, R. Siegel, C. Krieger, Chem. Ber. 1983, 116, 3461-3481.

[12] R. Milcent, G. Barbier, J. Heterocycl. Chem. 1994, 31, 319-324.

[13] J. B. Gilroy, M. J. Ferguson, R. McDonald, B. O. Patrickc, R. G. Hicks, Chem. Commun.

2007, 126-128.

[14] A. W. Niseham, Chem. Rev. 1955, 55, 355-483.

[15] T. M. Barclay, R. G. Hicks, A. S. Ichimura, G. W. Patenaude, Can. J. Chem. 2002, 80,

1501-1506.

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Chapter 2 1,3-Dipolar Cycloadditions

Chapter 2.1 Introduction to Cycloadditions

The cycloaddition reaction is one of three main classes of pericyclic reactions. The term

“pericyclic reaction” was first coined by Woodward and Hoffmann and they defined it as follows:

“A pericyclic reaction is a reaction in which all first order changes in bonding relationships take

place in concert on a closed curve.”[1] Due to its concerted mechanism, these reactions are highly

stereospecific. Furthermore, the electrons moving in a circular fashion lowers the energy of the

transition state when the number of electrons is 4n + 2 (where n is an integer). This relates to the

Hückel rule which states that a planar and circular molecule acquires an extra ground state

stability when it has 4n+2 electrons moving in planar and circular p-orbitals.[2, 3]

Two other categories of pericyclic reactions are sigmatropic rearrangements and

electrocyclic reactions. The three sub-categories of pericyclic reactions are characterized by the

number of sigma bonds they form or break. Cycloaddition reactions form two new σ bonds at a

cost of two π bonds. This, in fact, is the driving force behind cycloaddition reactions; two σ

bonds are inherently more stable and lower in energy than two π bonds. Conversely, reverse

cycloaddition reactions result in the breakage of two σ bonds and the formation of two π bonds.

Electrocyclic reactions result in the breakage or formation of one σ bond, while sigmatropic

rearrangements do not have any overall change in the number of σ bonds, as its name implies.

The feasibility of any pericyclic reactions can be predicted by the Woodward-Hoffmann

rule. In 1965, Woodward and Hoffmann came up with the rule that explains allowedness of

electrocyclic reactions.[4] They soon realized that the rule was applicable to the entire category of

pericyclic reactions.[1] The rule states that thermal pericyclic reactions, or equivalent ground state

- 12 -

pericyclic reactions, are symmetry allowed if the total number of (4q+2)s and (4r)a components is

odd, where q and r are integers, and subscripts s and a refer to suprafacial and antarafacial,

respectively.[1] This rule resembles the Hückel rule, especially because the number of the

antarafacial component is almost always zero and the number of the suprafacial component is

almost always one in practice. Thus, most of the time the only remaining term is the (4q + 2)s

term.

Cycloaddition reactions are by far the most prevalent and useful reactions of the three

pericyclic reactions. The Diels-Alder reaction is a classic example (Figure 2-1). As described

earlier, this reaction results in the formation of two new σ bonds at the cost of two π bonds. The

reaction is classified as a [4+2] reaction, where 4 and 2 represent the number of atoms directly

participating in the reaction as a diene and dienophile, respectively. On the other hand, this

reaction is also represented as π4s + π2s, referring to the number and type of electrons, and the

faciality the two components are reacting at.

Figure 2-1. Diels-Alder reaction between a butadiene and ethene.

Chapter 2.2 1,3-Dipolar Cycloaddition

A 1,3-dipolar cycloaddition (DC) reaction is a [3+2] cycloaddition particularly good for

making 5-membered heterocycles. It is also classified as a π4s + π2s reaction. In the latter

classification, it is the same class as the Diels-Alder reaction; both involve π4s + π2s electrons.

As the [3+2] designation suggests, the reaction involves a 1,3-dipole and a dipolarophile. A 1,3-

dipole is a species represented by zwitterionic resonance structures and participates in a 1,3-DC

- 13 -

reaction with a multiple bond system, i.e. a dipolarophile.[5] 1,3-Dipoles involve heteroatoms

(Figure 2-1), making the 1,3-DC reaction especially good for synthesizing 5-membered

heterocycles. There are two types of 1,3-dipoles; allenyl and allyl. Allenyl-type dipoles are linear

due to an sp-hybridized central nitrogen atom and restricted to a nitrogen atom as the central

atom, while allyl type dipoles are bent and can have any number of different heteroatoms such as

nitrogen, oxygen, or sulfur.

Figure 2-1. 1,3-Dipoles of (a) propargyl-allenyl type, (b) allyl type with nitrogen as a central

atom, and (c) allyl type with an oxygen as a central atom.

- 14 -

Moreover, dipolarophiles can be alkenes, alkynes, or multiple bonds containing

heteroatoms, such as carbonyl groups or nitriles (Figure 2-2). This further increases the

versatility of the 1,3-dipolar cycloaddition to make 5-membered heterocycles.

Figure 2-2. An example of a 1,3-DC reaction with a heteroatom containing dipolarophile.

The first reported 1,3-dipole was diazoacetic ester, discovered by Curtius in 1883.[6] Five

years later, the first 1,3-dipolar cycloaddition reaction was reported by Buchner.[7] However, it

was not until 1961 that the reaction was formally understood and recognized by Hüisgen.[8] For

this reason, the 1,3-dipolar cycloaddition reaction is also known as the Hüisgen reaction.[9, 10]

Unlike the Diels-Alder reaction, the mechanism of the 1,3-dipolar cycloaddition was

hotly debated until the end of 1960’s.[11, 12] In 1968, based on thermochemical and regiochemical

grounds, Firestone argued for a mechanism involving a spin-paired diradical intermediate.[11]

Hüisgen supported a concerted mechanism based on the absence of solvent and substituent

effects.[8] This argument, however, was also applicable to the diradical mechanism. The decisive

argument was based on the observation that the 1,3-DC reaction proceeded with retention of

configuration.[9] According to the diradical mechanism, rotation of a single bond would be

quicker than ring closure for 2.1 (Figure 2-3). This mechanism would result in non-stereospecific

addition, and give a mixture of products with different stereochemistries. Contrary to this, the

cycloadduct reaction with dimethyl fumarate gives exclusively the trans-product while dimethyl

maleate gives exclusively the cis-product. [5, 12]

- 15 -

Figure 2-3. Diradical mechanism of 1,3-DC.

Firestone’s diradical mechanism still should not be completely dismissed. Even

Hüisgen’s papers do agree that certain dipoles, such as ozone, posses some diradical character. [8,

9] Furthermore, it was later elucidated that a stepwise mechanism for the 1,3-DC reaction is

favoured over the concerted mechanism when the dipoles and dipolarophiles are highly

substituted.[13, 14]

In retrospect, the debate between Hüisgen and Firestone seems futile, since it is now

known that 1,3-dipolar cycloaddition is a sub-category of a pericyclic – and therefore, concerted

– reaction and the Woodward-Hoffmann rule, proposed in 1965, clearly states that the reaction is

thermally allowed. In the context of the Woodward-Hoffmann rule, the diene/dipole always has

4 π electrons reacting suprafacially and the dienenophile/dipolarophile always has 2 π electrons

reacting suprafacially. Since the 4πs component of the diene/dipole do not count, and there is

only one component of the 2πs, all these cycloadditions are allowed.

1,3-Dipoles are isoelectronic with allylic anions having four π electrons spread over three

conjugated p-orbitals. (Figure 2-4).

- 16 -

Figure 2-4. Isoelectronic nature of allyl anion and 1,3-dipole.

Although the name 1,3-dipole suggests that there are charges at opposite ends of the 1,3-dipole

molecule, their structures are most often represented as ylide forms rather than as dipoles (or

betaines). This is because in the ylide form all three atoms have complete octets. In the dipole

resonance structure the atom with the positive charge has only 6 electrons in the outer shell

(Figure 2-1). Therefore, the ylide form most likely contributes the most to the actual ground state

of the molecule, while the molecule reacts as a dipole with separate charges on each end.

In pericyclic reactions, electron flow can be in either direction. This means there is no

clear distinction which end of the diene in a Diels-Alder reaction is the “nucleophilic” or

“electrophilic” end. Likewise, the negatively charged end of a dipole does not necessarily act as

a nucleophile in 1,3-dipolar cycloadditions (Figure 2-5); either end of a dipole can be the

nucleophile or electrophile. Hüisgen calls such a character ambivalent.[9] Besides, resonance

structure can always be drawn such that each end is positive or negative. In Figure 2-5, the

dipole participating in the cycloaddition reaction is drawn as an ylide with a positive and

negative charged end. While two regioisomers might be expected on the basis of this charge

separation, only one is observed. This indicates that the direction of the circular electron flow in

pericyclic reaction mechanisms serve only to represent formation of bonds with the circular

electron flow going in either direction.

- 17 -

Figure 2-5. Directionless (or bidirectional) cyclic mechanism of 1,3-dipolar cycloadditions.

This leads to three determinants of pericyclic reactions based on frontier molecular orbital (FMO)

theory. FMO theory was devised by Fukui who simplified the concepts of the Woodward-

Hoffmann rule, molecular orbital (MO) theory, and perturbation theory. FMO theory is

concerned only about interaction of the highest occupied molecular orbital (HOMO) and the

lowest unoccupied molecular orbital (LUMO).[15-17] Despite the fact that FMO theory is an over-

simplification of all those theories, it is often more useful than even the Woodward-Hoffmann

rule. FMO theory allows the prediction of stereochemistry and regioselectivity.

In the context of the FMO theory, the three determinants of the rate and regioselectivity

of pericyclic reactions are as follows: first, the phases of the orbitals between the dipole/diene

and dipolarophile/dienophile must match (Figure 2-6 (a)). Second, the interaction between the

dipole/diene and the dipolarophile/dienophile must be such that the energy gap between the

HOMO and LUMO is minimal (Figure 2-7). Third, the orbital coefficient must match between

the dipole/diene and the dipolarophile/dienophile (Figure 2-6 (b)). As can be seen from Figure 2-

6, the dipole and the dipolarophile both react suprafacially. This is in accordance with the

- 18 -

Woodward-Hoffmann rule, since there is no (4r)a component and one (4q+2)s component, the

dipolarophile.

Figure 2-6. (a) FMO phase matching and (b) coefficient matching in a cycloaddition reaction.

Figure 2-7. HOMO/LUMO interaction between a 1,3-dipole and a dipolarophile.

The HOMO/LUMO interaction has another physical significance. As mentioned earlier,

the driving force for cycloaddition reactions is the formation of the more stable two σ bonds at

the expense of the less stable π bond. By interacting the HOMO and LUMO, the pair of electrons

initially in the HOMO move to the newly formed MO that is lower in energy than the initial

HOMO (Figure 2-8 (a)). This would not be true if the HOMO was interacting with another

HOMO or any other filled orbital to make two new molecular orbitals that are filled as well

- 19 -

(Figure 2-8 (b)). In such a case, there would be zero net stabilization. This, however, does not

happen in cycloaddition reactions. It would be symmetry-forbidden since the phases of the two

reaction components would not match.

Figure 2-8. Interaction of a filled orbital with (a) an empty orbital and (b) with another filled

orbital.

Much like dienes in the Diels-Alder reaction, a dipole usually has a high electron density

and uses its HOMO, while the dipolarophile typically has one or more electron-withdrawing

substituents and uses its LUMO to allow for a minimal energy difference between the HOMO

and LUMO. However, this is not to say that the dipole always uses its HOMO and the

dipolarophile always uses its LUMO. This typical orientation is classified as a Sustmann Type I

reaction (Figure 2-9), and azomethine ylides and azomethine imines, intermediates of particular

to us, tend to be this type.[18] Other dipoles, with electron-donating substituents - that increase the

energy levels of the HOMO and LUMO – also tend to be Sustmann Type I reactions. Sustmann

Type III reactions involve the use of the HOMO of the dipolarophile/dienophile and the LUMO

of the dipole/diene. Typical Sustmann Type III dipoles are ozone, nitrous oxide, and other

dipoles with electron-withdrawing substituents. Sustmann Type II reactions occur where there is

- 20 -

no significant difference in energy separation between the HOMO and the LUMO (Figure 2-9).

This often happens when the dipole/diene and dipolarophile/dienophile are substituted with

conjugated systems such as phenyl rings, since these substituents increase the HOMO energy

level and lower the LUMO energy level. It should be emphasized that although there are certain

dipoles that usually are of one specific Sustmann Type, their type can change depending on

substituents and/or additives, such as Lewis acids. Furthermore, the energy levels of the

dipolarophile also determine which MO the dipole will use since the energy levels of the

dipolarophile also change with electron-donating/withdrawing groups.

Figure 2-9. Sustmann Type I, II, and III for cycloaddition reactions.

Much like an electron-withdrawing substituent on a 1,3-dipole or dipolarophile will lower

the energy levels of the HOMO and LUMO, coordination of Lewis acid also has the same effect

(Figure 2-10). This property makes Lewis acids good catalysts for cycloaddition reactions and

allows the reaction to go faster and in higher yield under milder condition than in their absence.

This catalytic property is also important in enantioselective 1,3-dipolar cycloadditions that will

be discussed shortly.

- 21 -

Figure 2-10. Effect of Lewis acid on HOMO and LUMO energy levels.

Chapter 2.2 1,3-Dipolar Cycloadditions with Azomethine Imines

Azomethine imines are 1,3-dipoles with a backbone of two consecutive nitrogen atoms

and a carbon atom (Figure 2-11). This unique structure makes azomethine imines good

precursors to pyrazolidine and pyrazole structures when the azomethine imine reacts with an

alkene or alkyne, respectively (Figure 2-12).

Figure 2-11. Resonance structures of an azomethine imine.

Figure 2-12. 1,3-Dipolar cycloaddition of an azomethine imine with an alkene.

- 22 -

Azomethine imines do not necessarily have to be an open-chain structure. They can be a

part of a ring structure (Figure 2-13). A cycloadduct from this kind of azomethine imine would

naturally be bicyclic, making azomethine imine more versatile and attractive for organic

synthesis of heterocycles.

Figure 2-13. Examples of azomethine imines. [9]

Chapter 2.3 Stereoselective 1,3-Dipolar Cycloaddition Reactions

1,3-Dipolar cycloaddition reactions necessarily create a new chiral centre whenever the

participating dipole or dipolarophile is substituted. Therefore, when both the dipole and

dipolarophile are substituted, the 1,3-dipolar cycloaddition reaction generates up to four

stereogenic centres in one step. This is very economical and is a big advantage of

enantioselective 1,3-DC reactions. Since many drugs and naturally occurring compounds are

nitrogen containing heterocycles[19-22] and the 1,3-DC reaction is arguably one of the best

methods for making 5-membered heterocycles, it naturally leads to a necessity and demand for

enantioselective 1,3-dipolar cycloaddition, and this field has been rapidly expanding.

There are three broad categories of strategies for enantioselective 1,3-DC reactions. The

first and second methods are to incorporate chirality into the dipole – with the exceptions of

ozone and nitrous oxide – or dipolarophile, respectively. The third method is to use a chiral

- 23 -

catalyst. It is the third approach that receives the most attention, yet, it was the first and second

approaches that initially pioneered enantioselective 1,3-DC reactions in the early days.

In 1981, Uskokovic used the first approach, incorporation of chirality in the dipole, to

make L-daunosamine and L-acosamine, where the key intermediate was acquired by the

enantioselective intramolecular 1,3-DC reaction with a chiral nitrone (Figure 2-14).[23] The

nitrone was generated by formylating trans-propenyl acetate 2.2 with bis(di-methylamino)-tert-

butoxymethane to yield 2.3 (Figure 2-14). Compound 2.3 is essentially a masked aldehyde and

was reacted with the oxalate salt of (S)-(-)-N-hydroxy-α-methylbenzenemethanamine to give

nitrone 2.4. Now furnished with the 1,3-dipole and a dipolarophile, 2.4 spontaneously cyclized

intramolecularly under the reaction conditions to yield the bicyclic cycloadduct in an 82:18

mixture of diastereomers.

Figure 2-14. Uskokovic’s enantioselective intramolecular 1,3-DC reaction.

The second strategy for asymmetric 1,3-DC reactions, using chiral dipolarophiles, was

first reported in 1982 by Yoshii and his co-workers.[24] Yoshii took a chiral vinyl sulfoxide, 2.5,

derived from an asymmetric Michael addition reaction[25, 26] and reacted it with the acyclic nitrone

2.6 to get the isoxazolidine cycloadduct 2.7 (Figure 2-15). The reaction produced the two

diastereomers of the cycloadduct in 54 and 3 percent yields with a diastereomeric excess of 89%.

- 24 -

Figure 2-15. The first asymmetric 1,3-DC reaction using a chiral dipolarophile.[24]

The third strategy for an enantioselective 1,3-DC reaction, using a chiral catalyst, was the

last to be explored among the three strategies. Yet, it is this strategy that receives the most

attention nowadays. There are two broad categories of chiral catalysts for enantioselective 1,3-

DC reactions; metal-based catalysts and organocatalysts. In both cases, coordination or covalent

bond formation of a catalyst to the dipolarophile or dipole lowers the LUMO energy level of the

dipolarophile and accelerates the reaction. It was the metal based catalysts that received attention

first in 1992 for the cycloaddition of nitrones with α,β-unsaturated ketones.[27] While Kanemasa

was not successful in obtaining any enantioselectivity he was the first one to apply a Lewis acid

catalyst to the 1,3-DC reaction and successfully proved that the addition could accelerate the rate

of the 1,3-DC reaction and provide high regioselectivity.[27] Inspired by Kanemasa’s pioneering

work, several authors have used metal Lewis acid to catalyze enantioselective 1,3-DC reactions

with a chiral dipole or dipolarophile.[28-33] All these examples so far used chiral substituents in

starting materials and used metal catalysts only to accelerate the reactions.

In 1994, both Scheeren et al.49

and Gothelf et al.50

independently reported the very first

chiral induction from chiral ligands on a metal Lewis acid with an achiral dipole/dipolarophile

system. Scheeren employed the amino acid-derived chiral oxazaborolidines 2.8 to make β-amino

esters from nitrones 2.9 and ketene acetals 2.10, (Figure 2-16).[34] Since the dipolarophile 2.10 is

- 25 -

electron-rich, Scheeren reasoned that the FMO interaction must be a Sustmann Type III, where

nitrone 2.9 uses its LUMO and alkene 2.10 uses its HOMO. With addition of the catalyst 2.8

acceleration of the reaction rate was achieved along with high enantioselectivity. This

enantioselective 1,3-DC reaction was performed at -78 oC and yielded up to 74 %

e.e.(enantiomeric excess). The cycloadduct was then reductively cleaved to yield the target β-

amino esters product 2.12 (Figure 2-16).

Figure 2-16. The first catalytic enantioselective 1,3-DC reaction.[34]

Later in 1994, Gothelf and Jorgenson reported an asymmetric 1,3-DC reaction using

alkenes and nitrones with dichlorotitanium alkoxide (Figure 2-17 and 2.18). Since they had a

Sustmann Type I dipole/dipolarophile system, they focused on the activation of the dipolarophile

by using a Lewis acid catalysts that would coordinate to the dipolarophile. The chiral titanium

complexes were made by the deprotonation of the chiral diol ligands 2.13 and subsequent

addition of the iso-propoxides to form the dichlorotitanium tetraisopropoxides 2.14 (Figure 2-17).

- 26 -

Figure 2-17. Gothelf and Jorgenson’s catalysts for asymmetric 1,3-DC reaction.[35]

Gothelf and Jorgenson reported e.e.’s ranging from 4 to 62 %. Of special significance is

that the catalyst with a phenyl substituent, 2.15e, shows higher enantioselectivity than either of

catalysts with 2-naphthyl, 2.15g, and 4-biphenyl, 2.15h, substituents. Furthermore, there was no

change in yield and enantioselectivity when the catalyst loading was cut from 1 mol eq. to 0.1

mol eq. at 0 oC, which indicates that the catalyst has a high turn-over rate. Also, the catalyst with

2.15i as the chiral substituent – which had the most steric bulk and showed the highest

enantioselectivity for the Diels-Alder reaction – gave only e.e. of 22%. In contrast, the catalyst

with 2.15e showed 58% e.e. Considering that the difference between the two catalysts is only an

extra phenyl group at the position alpha to the acetal, this e.e. difference of 36 % is significant.

- 27 -

Figure 2-18. Gothelf and Jorgenson’s asymmetric 1,3-DC reaction.[35]

While the Scheeren and Gothelf groups took the same approach of using a chiral Lewis acid as

the catalysts their approaches were opposite to each other in terms of electronic demand. In

Scheeren’s case, an electron rich alkene and a nitrone were used and it was the nitrone dipole

that was activated by the catalyst to give a Sustmann Type III system. On the other hand, Gothelf

used a Sustmann Type I set-up with an electron poor bidentate alkene dipolarophile, which could

better coordinate to the metal complex. It is also noteworthy that both Scheeren and Gothelf took

chiral catalysts that were previously reported for use in asymmetric Diels-Alder reactions.[36, 37]

Ever since Scheeren and Gothelf pioneered the asymmetric 1,3-DC reaction with chiral catalysts,

the field has been expanding rapidly. Now, asymmetric 1,3-DC reactions have been performed

with chiral ligands on many metals such as copper[38], silver[39], nickel[40], zinc[41], boron[34],

calcium[42], magnesium[43], gold[44], titanium[35], cobalt[45], manganese[45], palladium[46], and

zirconium[47].

It took more than ten years to move from using chiral dipoles/dipolarophiles to using

metal catalysts with chiral ligands to induce asymmetric in 1,3-DC reactions.[23, 24, 34, 35] Also, the

catalysts initially tried for asymmetric 1,3-DC reactions were all from Diels-Alder reactions.[36, 37]

Yet, higher e.e.’s were always acquired for the Diels-Alder reactions relative to the 1,3-DC

reactions. This can be attributed to the fact that the 1,3-dipoles are generally much better Lewis-

bases than dienes, and therefore, 1,3-dipoles were at least partially deactivated by Lewis acid

- 28 -

metal catalysts. Nonetheless, multi-dentate dipolarophiles have been successfully used to push

the equilibrium between the Lewis acid-dipole and the Lewis acid-dipolarophile toward the latter

side to provide a Sustmann Type I interaction. Alternatively, electron-rich alkene can be used to

push the equilibrium to the opposite side to give a Sustmann Type III interaction.[47]

As mentioned earlier, chiral catalysts for enantioselective 1,3-DC are not limited to just

metal catalysts with chiral ligands. There are organocatalysts as well. It was the metal-based

catalysts that received attention first, but six years later, in 1994, organocatalysts were tried.[34, 35,

48] Despite their late introduction compared to the metal-based catalysts, organocatalysts have

their own merits, one important merit being that they are bench stable; stable to ambient aerobic

atmosphere with some humidity. They are also generally cheaper than metal-based catalysts.

Since they do not contain any heavy metals, they are environmentally benign as well.

Furthermore, they are stable to trace amount of water in the reaction mixture, and generally

much easier to handle than metal catalysts. In addition, recent developments in organocatalysts

include immobilization of the catalysts on polymer particle surfaces or silica gel, allowing easier

separation and re-use of the catalyst.[49, 50] Such a treatment is not possible with metal catalysts

because of their air and/or moisture sensitivity. For these reasons, the field of organocatalyst has

increased rapidly in recent years.[51-53]

It was only in 2000 that the first organocatalyst for the 1,3-DC reaction was reported by

MacMillan and his co-workers.[48] Much like other previous catalysts first tried for asymmetric

1,3-DC reaction, his chiral imidazolinone catalyst was also first tried in the Diels-Alder reaction.

(Figure2.19).[54]

- 29 -

Figure 2-19. The first organocatalytic Diels-Alder reaction by MacMillan.[54]

Yields ranging from 45 – 98 % and e.e.’s ranging from 20 – 99 % were reported by using the

catalyst shown in Figure 2-19, with nitrones and α,β-unsaturated aldehydes (Figure 2-20).[48] A

few interesting experimental results are noted. First, despite the fact that this was the first use of

an organocatalysis in an asymmetric 1,3-DC reaction, reaction yields were nearly quantitative

and the e.e.’s were as high as 99 %. Also, water was used as the co-solvent with nitromethane

when the catalysis was iminium-ion based; in the presence of water an iminium ion would

normally hydrolyze quicker than it would without water. There was also a small variation in

e.e. depending on the Bronsted acid co-catalyst, which the authors attributed to the extent of

iminium ion activation.[48] Of 6 different Bronsted acid co-catalysts, derivatives of HCl and

HClO4 showed the highest e.e., 90 % or higher.

- 30 -

Figure 2-20. Asymmetric 1,3-DC reaction of nitrones and α,β-unsaturated aldehydes by

MacMillan.[48]

From the stereochemistry of the product and computational modeling, it was deduced that

the iminium ion formed between the α,β-unsaturated aldehydes and the catalyst is the E-isomer,

so that there is less steric clash between the dipolarophile olefin and the gem-dimethyl group on

the catalyst backbone, 2.16 (Figure 2-20).[55] Due to the benzyl group on the catalyst blocking

one face of the dipolarophile, the nitrone has to come from the opposite side of the benzyl group,

the si-face of the dipolarophile. It is also clear that this reaction is a Sustmann Type I, where the

nitrone uses its HOMO and the α,β-unsaturated aldehyde uses its LUMO. This HOMO-LUMO

energy gap is lessened by the imnium ion formation that withdraws electron density away from

the dipolarophile and lowers its LUMO energy level. This effectively favours product formation

by an iminium-ion activated mechanism over the non-activated mechanism that leads to a

racemic mixture.

This MacMillan set-up of organocatalyst is especially suitable for systems where the

dipolarophile is a monodentate carbonyl and the dipole is a good Lewis base. In such a case, a

metal-based Lewis acid catalyst can preferentially coordinate with the dipole Lewis base, instead

- 31 -

of the dipolarophile, deactivating the dipole for the asymmetric 1,3-DC reaction.[55] In contrast,

the iminium ion based organocatalyst does not have such a disadvantage. It can only form the

iminium ion with the dipolarophile, effectively acting only to activate the asymmetric 1,3-DC

reaction without any competing coordination or deactivation effect (Figure 2-21). In either case,

both Lewis acid catalyst and iminium ion based organocatalyst have the same mechanism of

activation; they lower the energy level of the LUMO of the dipolarophile.

Figure 2-21. Activation and deactivation of the 1,3-DC reaction by coordination of a Lewis acid.

Organocatalysts are further categorized into covalent organocatalysts and non-covalent

organocatalysts. While MacMillan’s organocatalyst is an example of an organocatalysts that uses

a covalent iminium ion activation mechanism, thiourea organocatalysts are non-covalent

organocatalyst that use double hydrogen-bonding to induce enantioselectivity. Work by Jian-Fei

utilizes non-covalent organocatalyst, specifically chiral tertiary amine thioureas, for asymmetric

1,3-DC reactions of azomethine ylides with various N-arylmaleimides (Figure 2-22 and Figure

2-23).[56] This was the first metal-free asymmetric 1,3-DC of azomethine ylides. High yields, of

up to 89 %, and enantioselectivities, up to 96 %, are reported under optimized reaction

conditions.

- 32 -

Figure 2-22. Chiral tertiary amine thiourea catalysts for asymmetric 1,3-DC reactions by Wang

et al.[56]

Figure 2-23. Asymmetric 1,3-DC of azomethine ylides and N-arylmaleimides via a postulated

transition state by Wang et al.[56]

- 33 -

Iminium ion based organocatalysts such as proline and MacMillan’s catalysts can work

only on aldehydes or ketones, single carbonyl-substituted dipolarophiles. Yet, chiral tertiary

amine thiourea catalysts can form H-bond with more types of functionalities on dipolarophiles as

long as there is an electronegative atom with a lone-pair of electrons that can form a H-bond.

Chapter 2.4 Concluding Remarks.

Asymmetric 1,3-DC reactions have come a long way. There are now more than a dozen

different metals, and countless examples of chiral ligands, for metal catalysis of asymmetric 1,3-

DC reactions. There are also many examples of organocatalysts, especially derivatives of

prolines, imidazolinones, and chiral tertiary amine thioureas. However, each catalyst has a

limited range of substrates that it effectively catalyzes asymmetrically. Even within each catalyst

example discussed so far, variation of substrates in dipoles or dipolarophiles was very limited. It

even took eleven years to report the first successful organocatlayzed asymmetric 1,3-DC reaction

with an azomethine ylide, since the first report of MacMillan’s organocatalysis of asymmetric

1,3-DC on nitrones in 2000.[48, 56] This clearly points at the fact that even MacMillan’s catalyst

has a limited scope of substrates it can catalyze.

As noted so far, there does not seem to be a definite rule for enantioselectivity. There are

cases where increased reaction temperature increased enantioselectivity[46], or where more steric

bulk reduces enantioselectivity[35]. Furthermore, it is just astonishing how subtle changes such as

solvent[35, 56] or addition of an extra co-solvent such as water[48] or alcohol[47] impacts

enantioselectivity. There are also examples where addition of powdered molecular sieves[35, 57] or

extra metal achiral catalyst was crucial for high enantioselectivity[58]. These finicky reaction

- 34 -

conditions in addition to a requirement for the right catalyst-substrate match make

enantioselective 1,3-DC reactions a challenging project.

- 35 -

References

[1] R. B. Woodward, R. Hoffmann, Angew. Chem. Internat. Edit. 1969, 8, 781-853.

[2] E. Huckel, Z. Elektrochem. Angew. Phys. Chem. 1937, 43, 752-788.

[3] W. Doering, F. L. Detert, J. Am. Chem. Soc. 1951, 73, 876-877.

[4] R. Woodward, R. Hoffmann, J. Am. Chem. Soc. 1965, 87, 395-&.

[5] R. Huisgen, J. Org. Chem. 1976, 41, 403-419.

[6] T. Curtius, Ber. Dtsch. Chem. Ges. 1883, 16, 2230.

[7] E. Buchner, Ber. Dtsch. Chem. Ges. 1888, 21, 2637.

[8] R. Huisgen, Proc. Chem. Soc. 1961, 357.

[9] R. Huisgen, Angew. Chern. interntrf. Edit. 1964, 2, 565-598.

[10] R. Huisgen, Angcw. Chem. internut. Edit. 1963, 2, 633-696.

[11] R. A. Firestone, J. Org. Chem. 1968, 33, 2285-2290.

[12] R. Huisgen, J. Org. Chem. 1968, 33, 2291-2297.

[13] G. Mloston, M. Jasinski, A. Linden, H. Heimgartner, Helv. Chim. Acta 2006, 89, 1304-1316.

[14] C. Di Valentin, M. Freccero, R. Gandolfi, A. Rastelli, J. Org. Chem. 2000, 65, 6112-6120.

[15] K. Fukui, H. Fujimoto, Bull. Chem. Soc. Jpn. 1969, 42, 3399. 1967, 40, 2018-2025.

[16] K. Fukui, H. Fujimoto, Bull. Chem. Soc. Jpn. 1969, 42, 3399. 1969, 42, 3399.

[17] K. Fukui, Acc. Chem. Res. 1971, 4, 57-64.

[18] K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98, 863-909.

[19] M. Frederickson, Tetrahedron 1997, 53, 403-425.

[20] A. Bianco, M. Maggini, G. Scorrano, C. Toniolo, G. Marconi, C. Villani, M. Prato, J. Am.

Chem. Soc. 1996, 118, 4072-4080.

[21] C. AlvarezIbarra, A. Csaky, I. deSilanes, M. Quiroga, J. Org. Chem. 1997, 62, 479-484.

[22] F. Felpin, J. Lebreton, Eur. J. Org. Chem. 2003, 2003, 3693-3712.

- 36 -

[23] P. M. Wovkulich, M. R. Uskokovic, J. Am. Chem. Soc. 1981, 103, 3956-3958.

[24] T. Koizumi, H. Hirai, E. Yoshii, J. Org. Chem. 1982, 47, 4004-4005.

[25] G. H. Posner, J. P. Mallamo, K. Miura, M. Hulce, Pure Appl. Chem. 1981, 53, 2307-2314.

[26] G. Tsuchihashi, S. Mitamura, S. Inoue, K. Ogura, Tetrahedron Lett. 1973, 14, 323-326.

[27] S. Kanemasa, T. Uemura, E. Wada, Tetrahedron Lett. 1992, 33, 7889-7892.

[28] O. Tamura, T. Yamaguchi, T. Okabe, M. Sakamoto, Synlett 1994, 620-622.

[29] S. Kanemasa, T. Tsuruoka, H. Yamamoto, Tetrahedron Lett. 1995, 36, 5019-5022.

[30] N. Katagiri, M. Okada, C. Kaneko, T. Furuya, Tetrahedron Lett. 1996, 37, 1801-1804.

[31] C. Castellari, M. Lombardo, G. Pietropaolo, C. Trombini, Tetrahedron: Asymmetry 1996, 7,

1059-1068.

[32] C. Camiletti, L. Poletti, C. Trombini, J. Org. Chem. 1994, 59, 6843-6846.

[33] F. Degiorgis, M. Lombardo, C. Trombini, Tetrahedron 1997, 53, 11721-11730.

[34] J. G. Seerden, A. W. A. Schotte op Reimer, H. W. Scheeren, Tetrahedron Lett. 1994, 35,

4419-4422.

[35] K. GOTHELF, K. JORGENSEN, J. Org. Chem. 1994, 59, 5687-5691.

[36] K. Narasaka, N. Iwasawa, M. Inoue, T. Yamada, M. Nkashima, J. Sugimori, J. Am. Chem.

Soc. 1989, 111, 5340-5345.

[37] J. G. Seerden, H. W. Scheeren, Tetrahedron Lett. 1993, 34, 2669-2672.

[38] S. Cabrera, R. Arrayas, J. Carretero, J. Am. Chem. Soc. 2005, 127, 16394-16395.

[39] C. Alemparte, G. Blay, K. Jorgensen, Org. Lett. 2005, 7, 4569-4572.

[40] J. Shi, M. Zhao, Z. Lei, M. Shi, J. Org. Chem. 2008, 73, 305-308.

[41] Y. Ukaji, K. Sada, K. Inomata, Chem. Lett. 1993, 1847-1850.

[42] T. Tsubogo, S. Saito, K. Seki, Y. Yamashita, S. Kobayashi, J. Am. Chem. Soc. 2008, 130,

13321-13332.

[43] K. Tanaka, T. Kato, Y. Ukaji, K. Inomata, Heterocycles 2010, 80, 887-893.

- 37 -

[44] M. Martín-Rodríguez, C. Nájera, J. M. Sansano, F. Wu, Tetrahedron: Asymmetry 2010, 21,

1184-1186.

[45] P. Allway, R. Grigg, Tetrahedron Lett. 1991, 32, 5817-5820.

[46] K. Hori, H. Kodama, T. Ohta, I. Furukawa, Tetrahedron Lett. 1996, 37, 5947-5950.

[47] S. Kobayashi, H. Shimizu, Y. Yamashita, H. Ishitani, J. Kobayashi, J. Am. Chem. Soc. 2002,

124, 13678-13679.

[48] W. Jen, J. Wiener, D. MacMillan, J. Am. Chem. Soc. 2000, 122, 9874-9875.

[49] H. Hagiwara, T. Kuroda, T. Hoshi, T. Suzuki, Adv. Synth. Catal. 2010, 352, 909-916.

[50] N. Haraguchi, Y. Takemura, S. Itsuno, Tetrahedron Lett. 2010, 51, 1205-1208.

[51] D. Enders, C. Grondal, M. . Hüttl, Angew. Chem. Int. Ed. 2007, 46, 1570-1581.

[52] S. J. Connon, Angew. Chem. Int. Ed. 2006, 45, 3909-3912.

[53] J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719-724.

[54] K. Ahrendt, C. Borths, D. MacMillan, J. Am. Chem. Soc. 2000, 122, 4243-4244.

[55] G. Lelais, D. W. C. MacMillan, Aldrichimica Acta 2006, 39, 79-87.

[56] J. Bai, L. Wang, L. Peng, Y. Guo, J. Ming, F. Wang, X. Xu, L. Wang, Eur. J. Org. Chem.

2011, 2011, 4472-4478.

[57] Y. -. Liu, H. Liu, W. Du, L. Yue, Y. -. Chen, Chem. Eur. J. 2008, 14, 9873-9877.

[58] K. Tanaka, T. Kato, S. Fujinami, Y. Ukaji, K. Inomata, Chem. Lett. 2010, 39, 1036-1038.

- 38 -

Chapter 3 Evolution of Verdazyl Radicals as Substrates for 1,3-Dipolar

Cycloaddition Reactions.

For the last few years, the Georges group has been focusing on using verdazyl radicals as

substrates for organic synthesis. [1-3] However, as mentioned earlier, verdazyl radicals had not

traditionally used as substrates for organic synthesis. It was serendipitous that verdazyl radical

came to be used as substrates for organic small molecule synthesis.

Chapter 3.1 Discovery of the First 1,3-Dipolar Cycloaddition Reaction Initiated by an

Azomethine Imine Generated In Situ from a Verdazyl Radical.

In the Georges group, verdazyl radicals were initially used as mediators in living radical

polymerizations (LRP). While trying to make 3.1 as an initiator for LRP, 3.2 was obtained as the

major product (Figure 3.1). It was proposed that two verdazyl radicals first undergo a

disproportionation reaction where one verdazyl radical extracts a hydrogen from a methyl group

of another verdazyl radical (Figure 3.2). This yields a leucoverdazyl, 3.3, and an azomethine

imine, 3.4. The azomethine imine 3.4 then goes through a 1,3-DC reaction with an added

dipolarophile to yield the novel tetrahydropyrazolotetrazinone heterocyclic structure 3.5.

Figure 3.1. Attempted synthesis of 1-benzoyloxy-2-phenyl-2-(6-oxoverdazyl)ethane unimer[1]

- 39 -

Figure 3.2. Reaction mechanism of the 1,3-dipolar cycloaddition reaction of an azomethine

imine generated in situ from a verdazyl radical.[1]

Supporting this mechanism are density functional theory calculations [B3LYP/6-31G(d)],

an insensitivity of the reaction rate to solvent effects and low yields under an atmosphere of an

inert gas, such as nitrogen or argon, with much improved yields under an atmosphere of O2.[1]

The presence of the leucoverdazyl 3.3, unstable in air, was shown indirectly by trapping it with

benzyl bromide in the presence of NaH to give 3.6 (Figure 3.3).[4]

Figure 3.3. Trapping leucoverdazyl 3.3 by an alkylation reaction.[4]

Various dipolarophiles were reacted with the azomethine imine to give a series of

tetrahydropyrazolotetrazinones in isolated yields ranging from 40% to 84%. Acrylonitriles

generally showed lower yields compared to acrylates, which generally gave yields in the 70 and

80 % range regardless of the sterics from the bulky substituents on the alkoxy moiety or the

- 40 -

presence of substituents alpha to the carbonyl centre. Electron rich dipolarophiles showed no

reactivity[1], clearly indicating that azomethine imines generated in situ from verdazyl radicals are

Sustmann Type I dipoles.

Chapter 3.2 Second Generation of Unique Scaffolds Derived from Verdazyl Radicals.

1,3-DC reactions by azomethine imines from verdazyl radicals fit the requirement for

diversity-oriented synthesis (DOS), a synthetic approach that can supply a diverse array of small

molecules for biological screening. 1,3-DC reactions from verdazyl radicals satisfies this

requirement in more than one way. Verdazyl radicals can have different functionalities at N-1, C-

3, N-5, and C-6 positions (Figure 1-1) and the azomethine imines generated from these verdazyl

radicals react with various dipolarophiles to give a library of novel heterocyclic structures. These

initial heterocyclic compounds constitute the first generation of small molecules derived form

verdazyl radicals and they can subsequently undergo a variety of interesting rearrangements to

give a second generation of unique molecular scaffolds (Figure3.4).

Figure 3.4. NaH induced rearrangement of a cycloadduct derived from a verdazyl radical.[2]

The proposed mechanism for this rearrangement is distinctive although it falls under the

broad category of the Dimroth rearrangement (Figure 3.5). The rearrangement is possible since

- 41 -

the bicyclic structure 3.7 flaps much like butterfly wings about the two nitrogens in the middle of

the bicyclic structure. This allows nucleophilic attack of the α-anion onto the carbonyl centre by

reducing the physical distance between the two reacting centres. The fact that a lithium

diisopropylamide induced reaction, followed by an aqueous work-up, also gives 3.8 clearly

suggests that mechanism involves an anion.[2]

Figure 3.5. Proposed mechanism for the rearrangement of 3.7 to 3.8.

Chapter 3.3 Heteraphanes from Verdazyl Radicals.

The synthetic versatility of verdazyl radicals extends to making macrocycles as well. Bis-

verdayzl radical 3.9 is formed by initially reacting a terephthaldehyde, 3.11, with two molar

equivalence of dimethylcarbonohydrazide, 3.10, followed by a subsequent oxidation (Figure 3.6).

The bis-verdazyl radical then goes through a tandem intermolecular-intramolecular 1,3-DC

reaction with bifunctional diacrylate or dimethylacrylate dipolarophiles to yield [12]-, [13]-, and

[21]-paraheteraphanes, 3.12.

- 42 -

Figure 3.6. Synthesis of paraheteraphanes from verdazyl radicals.[5]

Chapter 3.4 Summary

It was only four years ago that the very first use of verdazyl radicals as substrates for

organic synthesis was reported.[1] Now, there are libraries of various cycloadducts, rearrangement

products, and heteraphanes with unique molecular backbone structures (Figure 3.7). Furthermore,

there is a new phosgene-free verdazyl synthesis, which will be discussed shortly. The chemistry

of verdazyl radicals has been evolving and is continuing unabated.

- 43 -

Figure 3.7. Versatility of verdazyl radicals: structural motifs derived from verdazyl radicals.

- 44 -

References

[1] A. Yang, T. Kasahara, E. K. Y. Chen, G. K. Hamer, M. K. Georges, Eur. J. Org. 2008, 4571-

4574.

[2] E. K. Y. Chen, M. Bancerz, G. K. Hamer, M. K. Georges, Eur. J. Org. Chem. 2010, 5681-

5687.

[3] M. Bancerz, B. Youn, M. V. DaCosta, M. K. Georges, J. Org. Chem. 2012, 77, 2415-2421.

[4] F. A. Neugebauer, Angew. Chem. Int. Ed. Engl. 1973, 12, 455.

[5] A. A. Cumaraswamy, G. K. Hamer, M. K. Georges, Eur. J. Org. Chem. 2012, 1717-1722.

- 45 -

Chapter 4 Phosgene Free Synthesis of Verdazyl Radicals

Chapter 4.1 Introduction

All the chemistry in Georges’ group in the past few years has focused on verdazyl

radicals and their use as substrates for the synthesis of novel heterocyclic compounds. Until a

couple of years ago, our group had been using Neugebauer’s synthesis involving methyl

hydrazine and triphosgene as a starting material to make the verdazyl radicals.[1] However, due to

tightened homeland security by the U.S.A import of methyl hydrazine into Canada is now

restricted. Without methyl hydrazine, our chemistry was going to be stopped due to a lack of

starting material. Fortunately, this situation eventually led us to a new synthesis of verdazyl

radicals: a synthesis which has significant advantages over pre-existing verdazyl radical

syntheses and has resulted in advances in our verdazyl chemistry that would previously not have

been possible.

In developing a new synthetic route it was realized early in the thought process that we

needed a new backbone to start from. Retrosynthetically, it seemed that carbohydrazide 4.1

would be an ideal candidate (Scheme 4-1). The obvious advantage of carbohydrazide is that it

has a carbonyl group and four nitrogen atoms backbone assembled relative to one another in a

similar manner to what is observed in 6-oxoverdazyl radicals. Especially attractive is the fact that

carbohydrazide is commercially available and considerably cheaper than methyl hydrazine and

triphosgene, which provides the carbonobishydrazide backbone in Neugebauer’s synthesis and

all of its variations. [1-3]

- 46 -

Scheme 4-1. Retrosynthsis of a phosgene-free verdazyl radical synthesis.

Going forward, the synthesis starts with a protection of the terminal nitrogen from

alkylation, a subsequent and critical step in the synthesis, by condensation with an aldehyde that

will eventually be incorporated into the verdazyl radical backbone (Scheme 4-2). The

aforementioned alkylation at the remaining NH groups then yields 4.2. One of protected

nitrogens in 4.2 is de-protected under acidic conditions to regenerate the aldehyde used to protect

the primary nitrogens and the monoprotected 4.3 spontaneously undergoes an intramolecular

cyclization to afford the tetrazinanone, 4.4.

Scheme 4-2. Phosgene-free synthesis of verdazyl radicals.

- 47 -

Chapter 4.2 Experimental Section

General: Silica gel chromatography was performed with silica gel 60 (particle size 40–63 μm).

Carbo-di-N-benzylhydrazides were previously synthesized by simple condensation of

carbohydrazide with the appropriate aldehyde. NMR spectra were recorded at 23 °C, operating at

400 MHz for 1H NMR and 100 MHz for

13C NMR spectroscopy. Chemical shifts (δ) are reported

in parts per million (ppm) referenced to tetramethylsilane (δ = 0 ppm) for 1H NMR spectra and

CDCl3 (δ = 77.0 ppm) for 13

C NMR spectroscopy. Coupling constants (J) are reported in hertz

(Hz). Mass spectrometry was performed with an ESI source, MS/MS, and accurate mass

capabilities, associated with a capillary LC system.

General solvolysis procedure: Carbo-di(N'-benzylidene-N-methylhydrazide) (1) (5.00 g, 17

mmol) was dissolved in 250 mL of methanol. p-Toluenesulfonic acid (4.85 g, 26 mmol) and

carbohydrazide (2.30 g, 26 mmol) was adding to the solution and the reaction was allowed to stir

for 4 hours at room temperature. Once the reaction was complete sodium methoxide was added

incrementally until the solution was basic, pH ~8. Following this, the solvent was evaporated in

vacuo and the crude product was filtered through a short silica gel column (1:19 methanol in

ethyl acetate as the eluent) to yield a white solid (3.07 g, 88%).

Carbo-di(N'-benzylidene-N-methylhydrazide) (1)

Carbo-di-N-benzylhydrazide (5.1 g, 19 mmol) was added to a 500 mL round bottom flask and

dissolved in 200 mL of dried THF with stirring. Dimethylsulfate, 2.2 eq, (5.30 g, 3.9 ml, 42.0

- 48 -

mmol) was added followed by the slow addition of 3 eq. of sodium hydride (1.38 g, 57 mmol).

The solution was brought to reflux and allowed to react for 2 hours. The reaction mixture was

allowed to cool to 0 ºC and the unreacted sodium hydride was quenched by the slow addition of

methanol. The solution volume was reduced in vacuo and the resulting reaction mixture was

extracted with 200 mL of EtOAc and washed three times with 200 mL of water. The crude

extract was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The

crude product was filtered through a short silica gel column (3:2 EtOAc in hexanes as the eluent)

and recrystallized in 1:19 EtOAc in hexanes to yield off-white crystals (4.7 g, 85%) mp 131-

134 °C; FT-IR (ν, cm-1

, KBr) 3062, 3030, 2952, 2919, 1656, 1597, 1478; 1H NMR (400 MHz,

CDCl3) δ 7.74 (s, 2H), 7.66-7.60 (m, 4H), 7.32-7.27 (m, 6H), 3.49 (s, 6H); 13

C NMR (100MHz,

CDCl3) δ 158.4, 137.7, 135.3, 129.1, 128.6, 127.0, 32.9; HRMS (ESI): m/z [M+H]+ calc’d for

C17H19N4O 295.15589, found 295.15631.

Carbo-di(N'-2-thienylidene-N-methylhydrazide) (2)

Carbo-di-N-2-thienylhydrazide (1.00 g, 3.6 mmol) was added to a 100 mL round bottom flask

and dissolved in 50 mL of dried THF with stirring. Dimethylsulfate, 2.2 eq, (1.22 g, 0.92 mL, 7.9

mmol) was added followed by the slow addition of 3 eq. of sodium hydride (260 mg, 10.8 mmol).

The solution was brought to reflux and allowed to react for 2 hours. The reaction mixture was

allowed to cool to 0 ºC and the unreacted sodium hydride was quenched by the slow addition of

methanol. The solution volume was reduced in vacuo and the resulting reaction mixture was

extracted with 100 mL of EtOAc and washed three times with 100 mL of water The crude

- 49 -

extract was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The

crude product was isolated using silica gel column chromatography (2:3 EtOAc in hexanes as the

eluent) and recrystallized in 1:4 EtOAc in hexanes to yield white crystals (613 mg, 56%): mp

160-163 °C; FT-IR (ν, cm-1

, KBr) 3086, 3072, 1645, 1587, 1420; 1H NMR (400 MHz, CDCl3) δ

7.90 (s, 2H), 7.24-7.19 (m, 4H), 7.02-6.99 (m, 2H), 3.43 (s, 6H); 13

C NMR (100MHz, CDCl3) δ

157.6, 140.6, 132.8, 127.9, 126.9, 126.7, 33.1; HRMS (ESI): m/z [M+H]+ calc’d for

C13H15N4OS2 307.06873, found 307.06962.

Carbo-di(N'-benzylidene-N-benzylhydrazide) (3)

Carbo-di-N-benzylhydrazide (6.00 g, 22.5 mmol) was added to a 500 mL round bottom flask and

dissolved in 150 mL of anhydrous toluene with stirring. Benzylbromide, 2.2 eq, (8.5 g, 5.9 mL,

49.6 mmol) was added followed by the slow addition of 3 eq. of sodium hydride (1.62 g, 68

mmol). The solution was brought to reflux and allowed to react for 24 hours. The reaction

mixture was allowed to cool to 0 ºC and the unreacted sodium hydride was quenched by the slow

addition of methanol. The solution volume was reduced in vacuo and the resulting reaction

mixture was extracted with 200 mL of EtOAc and washed three times with 200 mL of water The

crude extract was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo.

The crude product was filtered through a short silica gel column (DCM as the eluent) and

recrystallized in methanol to yield colourless granular crystals (9.2 g, 91%). mp 117-120 °C; FT-

IR (ν, cm-1

, KBr) 3052, 2972, 2927, 1669, 1602, 1495; 1H NMR (400 MHz, CDCl3) δ 7.64 (s,

2H), 7.43-7.38 (m, 8H), 7.37-7.32 (m, 4H), 7.29-7.22 (m, 3H), 7.21-7.14 (m, 5H), 5.36 (s, 4H);

- 50 -

13C NMR (100MHz, CDCl3) δ 158.9, 139.1, 135.9, 134.9, 128.9, 128.7, 128.3, 127.0, 126.9,

126.3, 49.3; HRMS (ESI): m/z [M+H]+ calc’d for C29H27N4O 447.21849, found 447.21949.

Carbo-di(N'-benzylidene-N-ethylhydrazide) (4)

Carbo-di-N-benzylhydrazide (7.0 g, 26 mmol) was added to a 500 mL round bottom flask and

dissolved in 150 mL of anhydrous toluene with stirring. Diethylsulfate, 2.2 eq., (8.9 g, 7.4 mL,

58 mmol) was added followed by the slow addition of 3 eq. of sodium hydride (1.9 g, 79 mmol).

The solution was brought to reflux and allowed to react for 24 hours. The reaction mixture was

allowed to cool to 0 ºC and the unreacted sodium hydride was quenched by the slow addition of

methanol. The solution volume was reduced in vacuo and the resulting reaction mixture was

extracted with 200 mL of EtOAc and washed three times with 200 mL of water. The crude

extract was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The

crude product was filtered through a short silica gel column (1:199 methanol in DCM as the

eluent) and recrystallized in 1:19 EtOAc in hexanes to yield off-white crystals (6.95 g, 82%): mp

83-85 °C; FT-IR (ν, cm-1

, KBr) 3022, 2978, 2934, 2873, 1659, 1604, 1597, 1464; 1H NMR (400

MHz, CDCl3) δ 7.81 (s, 2H), 7.61-7.56 (m, 4H), 7.28-7.24 (m, 6H), 4.10-4.03 (q, J = 7.1 Hz, 4H),

1.34-1.28 (t, J = 7.1 Hz, 6H); 13

C NMR (100MHz, CDCl3) δ 157.8, 138.5, 135.2, 128.9, 128.4,

126.8, 39.8, 11.2; HRMS (ESI): m/z [M+H]+ calc’d for C19H23N4O 323.18719, found 323.18744.

Carbo-N'-benzylidene(N'-benzylidene-N-benzylhydrazide) (5)

- 51 -

Carbo-di-N-benzylhydrazide (5.00 g, 19 mmol) was added to a 500 mL round bottom flask and

dissolved in 250 mL of dried THF with stirring. Benzylbromide (3.53 g, 2.46 ml, 20.7 mmol)

was added followed by the slow addition of 2 eq. of sodium hydride (901 mg, 37.6 mmol). The

solution was heated to reflux and allowed to react for 4 hours. The reaction mixture was allowed

to cool to 0 ºC and the unreacted sodium hydride was quenched by the slow addition of methanol.

The solution volume was reduced in vacuo and the resulting reaction mixture was extracted with

300 mL of EtOAc and washed three times with 300 mL of water. The crude extract was dried

over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The crude product was

filtered through a short silica gel column (1:49 methanol in DCM as the eluent) and

recrystallized in 1:9 EtOAc in hexanes to yield off white crystals (5.35 g, 80%): mp 188-191 °C;

FT-IR (ν, cm-1

, KBr) 3338, 3029, 1708, 1607, 1498, 1485; 1H NMR (400 MHz, CDCl3) δ 10.02

(s, 1H), 8.15 (s, 1H), 7.82-7.77 (m, 2H), 7.58-7.51 (m, 3H), 7.42-7.21 (m, 11H), 5.30 (s, 2H); 13

C

NMR (100MHz, CDCl3) δ 152.4, 145.5, 138.8, 135.1, 133.9, 129.8, 129.7, 128.8, 128.6, 128.5,

127.33, 127.29, 126.8, 126.5, 45.3; HRMS (ESI): m/z [M+H]+ calc’d for C22H21N4O 357.17154,

found 357.17284.

Carbo-N'-benzylidene-N-benzylhydrazide(N'-benzylidene-N-methylhydrazide) (6)

- 52 -

Carbo-N'-benzylidene(N'-benzylidene-N-benzylhydrazide) (5) (2.40 g, 6.7 mmol) was added to a

250 mL round bottom flask and dissolved in 100 mL of anhydrous toluene with stirring.

Dimethylsulfate (934 mg, 0.70 mL, 7.40 mmol) was added followed by the slow addition of 2 eq.

of sodium hydride (323 mg, 13.5 mmol). The solution was heated to 85 °C and allowed to react

for 2 hours. The reaction mixture was allowed to cool to 0 ºC and the unreacted sodium hydride

was quenched by the slow addition of methanol. The solution volume was reduced in vacuo and

the resulting reaction mixture was extracted with 150 mL of EtOAc and washed three times with

150 mL of water. The crude extract was dried over anhydrous sodium sulfate and the solvent was

evaporated in vacuo. The crude product was filtered through a short silica gel column (DCM as

the eluent) and recrystallized from methanol to yield off-white crystals (2.20 g, 88%): mp 97-

99 °C; FT-IR (ν, cm-1

, KBr) 3061, 3024, 1708, 1667, 1604, 1423; 1H NMR (400 MHz, CDCl3) δ

7.76 (s, 1H), 7.62 (s, 1H), 7.54-7.46 (m, 4H), 7.39-7.30 (m, 4H), 7.28-7.17 (m, 7H), 5.30 (s, 2H),

3.53 (s, 3H); 13

C NMR (100MHz, CDCl3) δ 158.5, 139.1, 137.7, 135.9, 135.1, 134.9, 128.93,

128.90, 128.7, 128.4, 128.3, 127.0, 126.89, 126.86, 126.3, 49.3, 32.7; HRMS (ESI): m/z [M+H]+

calc’d for C23H23N4O 371.18719, found 371.18559.

Carbo-N'-benzylidene-N-benzylhydrazide(N'-benzylidene-N-ethylhydrazide) (7)

Carbo-N'-benzylidene(N'-benzylidene-N-benzylhydrazide) (5) (625 mg, 1.75 mmol) was added

to a 100 mL round bottom flask and dissolved in 20 mL of anhydrous toluene with stirring.

Diethylsulfate (324 mg, 0.27 mL, 2.10 mmol) was added followed by the slow addition of 2 eq.

of sodium hydride (84 mg, 3.5 mmol). The solution was heated to reflux and allowed to react for

- 53 -

10 hours. The reaction mixture was allowed to cool to 0 ºC and the unreacted sodium hydride

was quenched by the slow addition of methanol. The solution volume was reduced in vacuo and

the resulting reaction mixture was extracted with 200 mL of EtOAc and washed once with a cold

1M NaOH solution (100 mL) and two times with 100 mL of water. The crude extract was dried

over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The crude product was

filtered through a short silica gel column (DCM as the eluent) to yield an orange oil (510 mg,

75%): FT-IR (ν, cm-1

, KBr) 3061, 3025, 2974, 2933, 1665, 1598, 1426; 1H NMR (400 MHz,

CDCl3) δ 7.81 (s, 1H), 7.61 (s, 1H), 7.50-7.42 (m, 4H), 7.39-7.29 (m, 4H), 7.27-7.13 (m, 7H),

5.28 (s, 2H), 4.16-4.04 (q, J = 6.9 Hz, 2H), 1.36-1.29 (t, J = 6.8 Hz, 3H); 13

C NMR (100MHz,

CDCl3) δ 158.3, 139.1, 138.6, 136.2, 135.2, 135.1, 129.0, 128.9, 128.8, 128.5, 128.3, 127.05,

126.94, 126.93, 126.4, 49.6, 39.7, 11.2; HRMS (ESI): m/z [M+H]+ calc’d for C24H25N4O

385.20284, found 385.20202.

Carbo-N'-benzylidene-N-benzylhydrazide(N'-benzylidene-N-ethylhydrazide) (8)

Carbo-di-N-benzylhydrazide (5.00 g, 19 mmol) was added to a 500 mL round bottom flask and

dissolved in 250 mL of dried THF with stirring. Diethylsulfate (3.18 g, 2.65 ml, 20.7 mmol) was

added followed by the slow addition of 2 eq. of sodium hydride (902 mg, 37.6 mmol). The

solution was heated to reflux and allowed to react for 4 hours. The reaction mixture was allowed

to cool to 0 ºC and the unreacted sodium hydride was quenched by the slow addition of methanol.

The solution volume was reduced in vacuo and the resulting reaction mixture was extracted with

300 mL of EtOAc and washed three times with 300 mL of water. The crude extract was dried

- 54 -

over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The crude product was

filtered through a short silica gel column (1:99 methanol in DCM as the eluent) and

recrystallized in 1:9 EtOAc in hexanes to yield off white crystals (4.38 g, 79%): mp 128-130 °C;

FT-IR (ν, cm-1

, KBr) 3298, 3267, 3018, 2979, 1681, 1516, 1404; 1H NMR (400 MHz, CDCl3) δ

9.85 (s, 1H), 8.07 (s, 1H), 7.78-7.74 (m, 2H), 7.68-7.64 (m, 3H), 7.46-7.33 (m, 6H), 4.13-4.07 (q,

J = 7.1 Hz, 2H), 1.24-1.19 (t, J = 7.1 Hz, 3H); 13

C NMR (100MHz, CDCl3) δ 151.7, 145.1, 137.0,

134.3, 134.0, 129.63, 129.61, 128.7, 128.4, 127.2, 126.7, 35.4, 11.0; HRMS (ESI): m/z [M+H]+

calc’d for C17H19N4O 295.15589, found 295.25587.

Carbo-N'-benzylidene-N-ethylhydrazide(N'-benzylidene-N-methylhydrazide) (9)

Carbo-N'-benzylidene-N-benzylhydrazide(N'-benzylidene-N-ethylhydrazide) (8) (4.37 g, 14.8

mmol) was added to a 500 mL round bottom flask and dissolved in 200 mL of anhydrous toluene

with stirring. Dimethylsulfate (2.24 g, 1.68 ml, 17.8 mmol) was added followed by the slow

addition of 2 eq. of sodium hydride (710 mg, 30 mmol). The solution was heated to 85 °C and

allowed to react for 2 hours. The reaction mixture was allowed to cool to 0 ºC and the unreacted

sodium hydride was quenched by the slow addition of methanol. The solution volume was

reduced in vacuo and the resulting reaction mixture was extracted with 300 mL of EtOAc and

washed three times with 300 mL of water. The crude extract was dried over anhydrous sodium

sulfate and the solvent was evaporated in vacuo. The crude product was filtered through a short

silica gel column (1:199 methanol in DCM as the eluent) to yield off white crystals (4.0 g, 88%):

mp 99-101 °C; FT-IR (ν, cm-1

, KBr) 3062, 3023, 2980, 2933, 2903, 1651, 1598, 1427; 1H NMR

- 55 -

(400 MHz, CDCl3) δ 7.80 (s, 1H), 7.73 (s, 1H), 7.64-7.58 (m, 4H), 7.31-7.25 (m, 6H), 4.12-4.04

(q, J = 7.1 Hz, 2H), 3.47 (s, 3H), 1.34-1.29 (t, J = 7.0 Hz, 3H); 13

C NMR (100MHz, CDCl3) δ

158.0, 138.5, 137.3, 135.2, 135.1, 129.0, 128.8, 128.41, 128.36, 126.9, 126.8, 39.6, 33.0, 11.1;

HRMS (ESI): m/z [M+H]+ calc’d for C18H21N4O 309.17154, found 309.17245.

Carbo-N'-benzylidene-N-methylhydrazide(N'-benzylidene-N-propylhydrazide) (10)

Carbo-N'-benzylidene(N'-benzylidene-N-propylhydrazide) (11) (2.00 g, 6.5 mmol) was added to

a 250 mL round bottom flask and dissolved in 40 mL of anhydrous toluene with stirring.

Dimethylsulfate (1.15 g, 0.86 ml, 9.1 mmol), 1.4 eq., was added followed by the slow addition

of 2.2 eq. of sodium hydride (340 mg, 14 mmol). The solution was heated to 85 °C and allowed

to react for 2 hours. The reaction mixture was allowed to cool to 0 ºC and the unreacted sodium

hydride was quenched by the slow addition of methanol. The solution volume was reduced in

vacuo and the resulting reaction mixture was extracted with 150 mL of EtOAc and washed three

times with 150 mL of water. The crude extract was dried over anhydrous sodium sulfate and the

solvent was evaporated in vacuo. The crude product was filtered through a short silica gel

column (1:99 methanol in DCM as the eluent) to yield a light yellow oil (1.67 g, 80%): FT-IR (ν,

cm-1

, KBr) 3059, 3027, 2962, 2932, 2874, 1666, 1598, 1572, 1422; 1H NMR (400 MHz, CDCl3)

δ 7.74 (s, 1H), 7.65 (s, 1H), 7.63-7.56 (m, 4H), 7.24-7.17 (m, 6H), 4.98-4.91 (t, J = 7.4 Hz, 2H),

3.37 (s, 3H), 1.79-1.68 (sextet, J = 7.4 Hz, 2H), 1.00-0.93 (t, J = 7.4 Hz, 3H); 13

C NMR

(100MHz, CDCl3) δ 158.2, 138.3, 137.3, 135.3, 135.2, 129.0, 128.8, 128.42, 128.37, 126.89,

- 56 -

126.85, 46.3, 33.0, 19.2, 11.2; HRMS (ESI): m/z [M+H]+ calc’d for C19H23N4O 323.1866, found

323.1866.

Carbo-N'-benzylidene(N'-benzylidene-N-propylhydrazide) (11)

Carbo-di-N-benzylhydrazide (2.50 g, 9.4 mmol) was added to a 500 mL round bottom flask and

dissolved in 100 mL of dried THF with stirring. Iodopropane (1.92 g, 1.10 ml, 11.3 mmol) was

added followed by the slow addition of 2 eq of sodium hydride (451 mg, 19 mmol). The solution

was heated to reflux and allowed to react for 24 hours. The reaction mixture was allowed to cool

to 0 ºC and the unreacted sodium hydride was quenched by the slow addition of methanol. The

solution volume was reduced in vacuo and the resulting reaction mixture was extracted with 200

mL of EtOAc and washed three times with 200 mL of water. The crude extract was dried over

anhydrous sodium sulfate and the solvent was evaporated in vacuo. The crude product was

filtered through a short silica gel column (2:98 methanol in DCM as the eluent) and

recrystallized in 1:9 EtOAc in hexanes to yield off white crystals (2.14 g, 74%): mp 114-116 °C;

FT-IR (ν, cm-1

, KBr) 3327, 2960, 2937, 2874, 1695, 1608, 1511, 1402; 1H NMR (400 MHz,

CDCl3) δ 9.88 (s, 1H), 8.05 (s, 1H), 7.77-7.73 (m, 2H), 7.67-7.63 (m, 2H), 7.61 (s, 1H), 7.45-

7.31 (m, 6H), 4.02-3.96 (t, J = 7.5 Hz, 2H), 1.70-1.59 (sextet, J = 7.5 Hz, 2H), 1.00-0.95 (t, J =

7.4 Hz, 3H); 13

C NMR (100MHz, CDCl3) δ 152.1, 145.1, 137.1, 134.2, 134.0, 129.6, 128.7,

128.4, 127.2, 126.7, 42.1, 18.9, 11.0; HRMS (ESI): m/z [M+H]+ calc’d for C18H21N4O

309.17154, found 309.17177.

- 57 -

Carbo-di(N'-3-phenylpropionyl-N-methylhydrazide) (24)

Carbo-di-N-3-phenylpropionylhydrazide (0.815 g, 2.52 mmol) was added to a 100 mL round

bottom flask and dissolved in 50 mL of dried THF with stirring. Dimethylsulfate (0.73 g, 0.55

mL, 5.79 mmol), 2.2 eq., was added followed by the slow addition of 3 eq. of sodium hydride

(0.182 g, 7.58 mmol). The solution was brought to reflux and allowed to react for 2 hours. The

reaction mixture was allowed to cool to 0 ºC and the unreacted sodium hydride was quenched by

the slow addition of methanol. The solution volume was reduced in vacuo and the resulting

reaction mixture was extracted with 200 mL of EtOAc and washed three times with 200 mL of

water. The crude extract was dried over anhydrous sodium sulfate and the solvent was

evaporated in vacuo. The crude product was filtered through a short silica gel column (3:2

EtOAc in hexanes as the eluent) and recrystallized in 1:19 EtOAc in hexanes to yield a yellow

oil (0.80 g, 90%); FT-IR (ν, cm-1

, KBr) 3060, 3025, 2926, 1623, 1479, 1453, 1385, 1334, 1081,

750, 699; 1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 4H), 7.22-7.17 (m, 6H), 7.03 (t, 2H),

3.18 (s, 6H), 2.86 (t, 4H), 2.65 (m, 4H); 13

C NMR (100MHz, CDCl3) δ 158.8, 141.1, 140.9,

128.5, 128.4, 126.1, 34.5, 33.4, 33.1; HRMS (ESI): m/z [M+H]+ calc’d for C17H19N4O

351.21849, found 351.21844.

2,4-Dimethyl-6-phenyl-1,2,4,5-tetrazinan-3-one (12)

- 58 -

Carbo-di(N'-benzylidene-N-methylhydrazide) (1) (5.00 g) was reacted according to the general

solvolysis procedure to yield a white solid (3.07 g, 88%): mp 103-105 °C; FT-IR (ν, cm-1

, KBr)

3254, 3218, 2967, 2938, 2877, 1598, 1506, 1451; 1H NMR (400 MHz, CDCl3) δ 7.55-7.51 (d, J

= 7.3 Hz, 2H), 7.42-7.34 (m, 3H), 5.09-5.02 (t, J = 9.9 Hz, 1H), 4.40-4.35 (d, J = 10.0 Hz, 2H),

3.17 (s, 6H); 13

C NMR (100MHz, CDCl3) δ 155.4, 135.2, 128.72, 128.67, 126.5, 69.4, 38.1;

HRMS (ESI): m/z [M+H]+ calc’d for C10H15N4O 207.12459, found 207.12373.

2,4-Dimethyl-6-(thiophen-2-yl)-1,2,4,5-tetrazinan-3-one (13)

Carbo-di(N'-2-thienylidene-N-methylhydrazide) (193 mg) was reacted according to the general

solvolysis procedure to yield a white solid (82 mg, 62%): mp 123-125 °C; FT-IR (ν, cm-1

, KBr)

3246, 2970, 2923, 2875, 1602, 1507, 1434; 1H NMR (400 MHz, CDCl3) δ 7.32-7.29 (d, J = 4.9

Hz, 1H), 7.16-7.13 (m, 1H), 7.04-7.00 (t, J = 4.5 Hz, 1H), 5.24-5.18 (t, J = 8.8 Hz, 1H), 4.58-

4.53 (d, J = 8.8 Hz, 2H), 3.15 (s, 6H); 13

C NMR (100MHz, CDCl3) δ 155.1, 138.1, 127.1, 126.0,

125.8, 66.9, 38.1; HRMS (ESI): m/z [M+H]+ calc’d for C8H13N4OS 213.08101, found 213.08115.

2,4-Dibenzyl-6-phenyl-1,2,4,5-tetrazinan-3-one (14)

- 59 -

Carbo-di(N'-benzylidene-N-benzylhydrazide) (3) (1.50 g) was reacted according to the general

solvolysis procedure to yield a white solid (1.09 g, 91%): mp 147-150 °C; FT-IR (ν, cm-1

, KBr)

3256, 3249, 3227, 1594, 1501, 1449; 1H NMR (400 MHz, CDCl3) δ 7.45-7.24 (m, 15H), 4.82-

4.67 (m, 5H), 4.23-4.17 (d, J = 10.8 Hz, 2H); 13

C NMR (100MHz, CDCl3) δ 154.0, 137.6, 134.8,

128.6, 128.4, 128.3, 127.3, 126.1, 69.5, 53.1; HRMS (ESI): m/z [M+H]+ calc’d for C22H23N4O

359.18719, found 359.18893.

2,4-Diethyl-6-phenyl-1,2,4,5-tetrazinan-3-one (15)

Carbo-di(N'-benzylidene-N-ethylhydrazide) (4) (347 mg) was reacted according to the general

solvolysis procedure to yield a white solid (252 mg, 82%): mp 70-72 °C; FT-IR (ν, cm-1

, KBr)

3231, 3063, 3034, 2972, 2930, 2868, 1600, 1496, 1452, 1421; 1H NMR (400 MHz, CDCl3) δ

7.56-7.52 (m, 2H), 7.43-7.34 (m, 3H), 4.94-4.86 (t, J = 11.2 Hz, 1H), 4.19-4.13 (d, J = 11.3 Hz,

2H), 3.73-3.63 (sextet, J = 7.0 Hz, 2H), 3.56-3.45 (sextet, J = 7.0 Hz, 2H), 1.23-1.18 (t, J = 7.0

Hz, 6H); 13

C NMR (100MHz, CDCl3) δ 154.4, 135.4, 128.8, 128.7, 126.3, 70.4, 44.6, 12.4;

HRMS (ESI): m/z [M+H]+ calc’d for C12H19N4O 235.15589, found 235.15581.

2-Benzyl-4-methyl-6-phenyl-1,2,4,5-tetrazinan-3-one (16)

- 60 -

Carbo-N'-benzylidene-N-benzylhydrazide(N'-benzylidene-N-methylhydrazide) (6) (6.10 g) was

reacted according to the general solvolysis procedure to yield a white solid (2.11 g, 45%): mp

98-100 °C; FT-IR (ν, cm-1

, KBr) 3238, 3030, 2909, 1687, 1597, 1514; 1H NMR (400 MHz,

CDCl3) δ 7.48-7.27 (m, 10H), 4.99-4.92 (t, J = 10.4 Hz, 1H), 4.79-4.73 (d, J = 14.5 Hz, 1H),

4.69-4.63 (d, J = 14.5 Hz, 1H), 4.35-4.30 (d, J = 10.4 Hz, 1H), 4.24-4.19 (d, J = 10.3 Hz, 1H),

3.21 (s, 3H); 13

C NMR (100MHz, CDCl3) δ 154.4, 137.7, 134.9, 128.62, 128.57, 128.5, 128.3,

127.2, 126.2, 69.4, 53.5, 37.9; HRMS (ESI): m/z [M+H]+ calc’d for C16H19N4O 283.15589,

found 283.15616.

2-Benzyl-4-ethyl-6-phenyl-1,2,4,5-tetrazinan-3-one (17)

Carbo-N'-benzylidene-N-benzylhydrazide(N'-benzylidene-N-ethylhydrazide) (7) (290 mg) was

reacted according to the general solvolysis procedure to yield an orange oil ( 154 mg, 69%); FT-

IR (ν, cm-1

, KBr)3234, 3062, 3030, 2971, 2927, 1613, 1495, 1451; 1H NMR (400 MHz, CDCl3)

δ 7.46-7.20 (m, 10H), 4.82-4.56 (m, 3H), 4.35-4.27 (m, 2H), 3.73-3.62 (sextet, J = 7.0 Hz, 1H),

3.46-3.36 (sextet, J = 7.0 Hz, 1H), 1.19-1.14 (d, J = 7.0 Hz, 3H); 13

C NMR (100MHz, CDCl3) δ

154.0, 137.8, 135.1, 128.5, 128.4, 128.3, 127.2, 126.2, 69.8, 53.5, 44.6, 12.3; HRMS (ESI): m/z

[M+H]+ calc’d for C17H21N4O 279.17154, found 279.17162.

2-Ethyl-4-methyl-6-phenyl-1,2,4,5-tetrazinan-3-one (18)

- 61 -

Carbo-N'-benzylidene-N-ethylhydrazide(N'-benzylidene-N-methylhydrazide) (9) (200 mg) was

reacted according to the general solvolysis procedure to yield a white solid (70 mg, 49%) mp 78-

80 °C; FT-IR (ν, cm-1

, KBr) 3251, 3226, 2972, 2932, 2871, 1593, 1490, 1450, 1430; 1H NMR

(400 MHz, CDCl3) δ 7.54-7.48 (m, 2H), 7.40-7.28 (m, 3H), 4.89-4.81 (t, J = 10.0 Hz, 1H), 4.78-

4.72 (d, J = 10.0 Hz, 1H), 4.64-4.58 (d, J = 10.0 Hz, 1H), 3.75-3.55 (sextet, J = 7.0 Hz, 1H),

3.41-3.30 (sextet, J – 7.0 Hz, 1H), 3.10 (s, 3H), 1.18-1.10 (t, J = 6.9 Hz, 3H); 13

C NMR

(100MHz, CDCl3) δ 154.6, 135.3, 128.4, 126.4, 69.7, 44.5, 37.8, 12.4; HRMS (ESI): m/z

[M+H]+ calc’d for C11H17N4O 221.14024, found 221.13961.

2-Methyl-6-phenyl-4-propyl-1,2,4,5-tetrazinan-3-one (19)

Carbo-N'-benzylidene-N-methylhydrazide(N'-benzylidene-N-propylhydrazide) (10) (500 mg)

was reacted according to the general solvolysis procedure to yield a yellow-orange oil (262 mg,

72%); FT-IR (ν, cm-1

, KBr) 3235, 3061, 3032, 2961, 2930, 2873, 1690, 1616, 1451; 1H NMR

(400 MHz, CDCl3) δ 7.54-7.48 (m, 2H), 7.40-7.28 (m, 3H), 4.92-4.84 (t, J = 9.9 Hz, 1H), 4.77-

4.69 (d, J = 10.1 Hz, 1H), 4.62-4.54 (d, J = 9.9 Hz, 1H), 3.55-3.44 (m, 1H), 3.37-3.26 (m, 1H),

3.11 (s, 3H), 1.68-1.55 (sextet, J = 7.3 Hz, 2H) 0.93-0.84 (t, J = 7.3 Hz, 3H); 13

C NMR (100MHz,

CDCl3) δ 154.8, 135.5, 128.6, 126.5, 69.7, 51.6, 38.0, 20.7, 11.3; HRMS (ESI): m/z [M+H]+

calc’d for C12H19N4O 235.1553, 235.1558 found.

- 62 -

Methyl N',2-dibenzylidene-1-methylhydrazinecarbohydrazonothioate (20)

Thiocarbo-di-N-benzylhydrazide (1.00 g, 3.54 mmol) was added to a 250 mL round bottom flask

and dissolved in 75 mL of dried THF with stirring. Dimethylsulfate (0.98 g, 0.72 mL, 7.8 mmol)

was added followed by the slow addition of 3 eq. of sodium hydride (254 mg, 10.6 mmol). The

solution was brought to reflux and allowed to react for 2 hours. The reaction mixture was

allowed to cool to 0 ºC and the unreacted sodium hydride was quenched by the slow addition of

methanol. The solution volume was reduced in vacuo and the resulting reaction mixture was

extracted with 100 mL of EtOAc and washed three times with 100 mL of water. The extract was

dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The crude product

was recrystallized in 1:9 EtOAc in hexanes to yield bright yellow crystals (1.03 g, 94%): mp 64-

65 °C; FT-IR (ν, cm-1

, KBr) 3055, 3020, 2925, 1593, 1567, 1510, 1406; 1H NMR (400 MHz,

CDCl3) δ 8.30 (s, 1H), 7.79-7.73 (m, 2H), 7.70-7.65 (d, J = 7.3 Hz, 2H), 7.62 (s, 1H), 7.42-7.34

(m, 5H), 7.34-7.28 (t, J = 7.2 Hz, 1H), 3.55 (s, 3H), 2.63 (s, 3H); 13

C NMR (100MHz, CDCl3) δ

164.0, 155.7, 136.3, 135.3, 135.1, 129.9, 128.8, 128.6, 128.5, 127.7, 126.6, 33.4, 17.8; HRMS

(ESI): m/z [M+H]+ calc’d for C17H19N4S 311.13304, found 311.13254.

Carbo-N'-benzylidene(N'-benzylidene-N-allylhydrazide) (21)

- 63 -

Carbo-di-N-benzylhydrazide (2.800 g, 10.5 mmol) was added to a 250 mL round bottom flask

and dissolved in 100 mL of dried THF with stirring. Allylbromide (6.36 g, 4.55 ml, 52.5 mmol),

5 eq., was added followed by the slow addition of 2 eq. of sodium hydride (876 mg, 21.0 mmol).

The solution was heated to reflux and allowed to react for 24 hours. The reaction mixture was

allowed to cool to 0 ºC and the unreacted sodium hydride was quenched by the slow addition of

methanol. The solution volume was reduced in vacuo and the resulting reaction mixture was

extracted with 200 mL of EtOAc and washed three times with 200 mL of water. The extract was

dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The crude product

was filtered through a short silica gel column (1:49 methanol in DCM as the eluent) and

recrystallized in 1:9 EtOAc in hexanes to yield yellow crystals (1.80 g, 56%): mp 43-45 °C; FT-

IR (ν, cm-1

, KBr) 3347.1, 3060.6, 3024.6, 1678.5, 1510.4, 1486.3; 1H NMR (400 MHz, CDCl3) δ

9.95 (s, 1H), 8.08 (s, 1H), 7.78-7.73 (m, 2H), 7.66-7.62 (m, 2H), 7.58 (s, 1H), 7.44-7.32 (m, 6H),

5.84-5.73 (m, 1H), 5.22-5.12 (m, 2H), 4.69-4.65 (m, 2H); 13

C NMR (100MHz, CDCl3) δ 151.9,

145.4, 138.7, 134.1, 134.0, 130.5, 129.71, 129.69, 128.7, 128.4, 127.2, 126.8, 117.0, 43.5;

HRMS (ESI): m/z [M+H]+ calc’d for C18H19N4O 307.1553, found 307.1558.

Carbo-N'-benzylidene-N-methylhydrazide(N'-benzylidene-N-allylhydrazide) (22)

Carbo-N'-benzylidene(N'-benzylidene-N-allylhydrazide) (11) (1.30 g, 4.2 mmol) was added to a

100 mL round bottom flask and dissolved in 50 mL of anhydrous THF with stirring.

Dimethylsulfate (643 mg, 0.48 mL, 5.10 mmol) was added followed by slow addition of 2 eq. of

sodium hydride (204 mg, 8.48 mmol). The solution was heated to reflux and allowed to react for

- 64 -

3 hours. The reaction mixture was allowed to cool to 0 ºC and the unreacted sodium hydride was

quenched by the slow addition of methanol. The solution volume was reduced in vacuo and the

resulting reaction mixture was extracted with 150 mL of EtOAc and washed three times with 150

mL of water The crude extract was dried over anhydrous sodium sulfate and the solvent was

evaporated in vacuo. The crude product was filtered through a short silica gel column (1:99

methanol in DCM as thr eluent) to yield a light orange oil (1.17 g, 86%): FT-IR (ν, cm-1

, KBr)

3060.1, 3024.1, 1664.3, 1606.0, 1421.5, 1384.4; 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.64

(s, 1H), 7.63-7.55 (m, 4H), 7.22-7.16 (m, 6H), 5.92-5.80 (m, 1H), 5.34-5.26 (d, J = 17.3 Hz, 1H),

5.22-5.16 (d, J = 10.6 Hz, 1H), 4.64-4.60 (m, 2H), 3.37 (s, 3H); 13

C NMR (100MHz, CDCl3) δ

158.0, 138.7, 137.5, 135.3, 135.1, 131.5, 129.0, 128.9, 128.4, 126.93, 126.89, 116.8, 47.2, 32.8;

HRMS (ESI): m/z [M+H]+ calc’d for C19H21N4O 321.1709, found 321.1710.

2-Methyl-6-phenyl-4-allyl-1,2,4,5-tetrazinan-3-one (23)

Carbo-N'-benzylidene-N-methylhydrazide(N'-benzylidene-N-allylhydrazide) (22) (1.04 g, 4.48

mmol) was reacted according to the general solvolysis procedure to yield white crystals (632 mg,

84%); FT-IR (ν, cm-1

, KBr) 3250.3, 3226.1, 3084.0, 3009.3, 2971.4, 2910.4, 1696.4, 1488.8; 1H

NMR (400 MHz, CDCl3) δ 7.52-7.48 (m, 2H), 7.37-7.27 (m, 3H), 5.89-5.77 (m, 1H), 5.25-5.18

(dd, J = 17.1 Hz, 1.5 Hz, 1H), 5.16-5.11 (dd, J = 10.2 Hz, 1.3 Hz, 1H), 4.92-4.80 (m, 2H), 4.77-

4.70 (d, J = 8.9Hz, 1H), 4.14-4.06 (m, 1H), 4.01-3.93 (m, 1H), 3.09 (s, 3H); 13

C NMR (100MHz,

CDCl3) δ 154.4, 135.3, 133.5, 128.4, 126.5, 117.1, 69.5, 52.6, 37.8; HRMS (ESI): m/z [M+H]+

calc’d for C12H17N4O 233.1396, 233.1395 found.

- 65 -

Chapter 4.3 Results and Discussion

The first step of this new phosgene-free verdazyl radical synthesis, the condensation of

carbohydrazide with aldehydes, proceeds in nearly quantitative yield with all the aldehydes tried

to date. The alkylation reaction is also generally high yielding, except for cases where the

condensed aldehyde is a heterocycle or is substituted with secondary alkyl groups, such as an

isopropyl group (entry 2 and 12 Table 4-1). Deprotection and cyclization of bishydrazone 4.2,

initially was difficult since 4.2 and the resulting tetrazinanone were in an equilibrium with each

other that favoured the bishydrazone. In order to push the equilibrium toward the tetrazinanone,

carbohydrazide was added as a trap for the expelled aldehyde. The trap product is essentially a

non-alkylated bishydrazone and can be fed back into the reaction scheme (Scheme 4-2).

Fortunately, the singly alkylated bishydrazone is much less reactive than the unalkylated

bihydrazone. This permits the synthesis of unsymmetrical verdazyl radicals with different N-1

and N-5 functionalities (entries 5-8, 10 Table 4-1). All that is required for unsymmetrical

verdazyl radical synthesis is 1 mol eq. of an alkyl sulfate and NaH, followed by another

equivalent of a second alkylating reagent and NaH once the first alkylation is completed.

As it turns out the purification of the dialkylated bishydrazone product is relatively easy.

The product readily crystallizes out and the need to run a silica gel column is unnecessary. This

somewhat compromises the yield of the reaction, but it allows for a higher purity product. The

next intermediate, the tetrazinanone, initially required two columns for purification; first with a

95:5 mixture of EtOAc and MeOH, followed by a 97:3 mixture of DCM and MeOH. The second

column was required because the unalkylated bishydrazones has the same Rf as the

tetrazinanones in the first column eluent. While trying to run an NMR in CDCl3 on the

- 66 -

tetrazinanone after the first column, it was observed that some white solid precipitated out. 1H

NMR and 13

C NMR showed this was pure tetrazinanone. After this observation, the procedure

was optimized to omit the second column and replace it with a recrystalization in CDCl3.

Various examples of tetrazinanones and intermediates with their yields are shown in the

following Table 4-1.[4]

Table 4-1. Intermediates, products, and their yields for the phosgene-free verdazyl radical

synthesis.[4]

Entry Product of first

alkylation

% Yield of

first

alkylation

Product of

second

alkylation

% Yield of

second

alkylation

Product of

solvolysis

% Yield of

solvolysis

1

85 N/A N/A

88

2

56 N/A N/A

62

3

91 N/A N/A

91

4

82 N/A N/A

82

5

80

88

45

- 67 -

6

79

88

49

7

74

80

72

8

80

75

69

9

94 N/A N/A N/A N/A

10

56

86

84

11

90 N/A N/A

46

12

14 N/A N/A

64

A significant advantage of this new synthesis is the ability to introduce various alkyl

groups at the N-1 and N-5 positions. Neugebauer’s and Milcent’s syntheses relied on alkyl

hydrazines for N-1 and N-5 substituents. However, since the import of methyl hydrazine is

- 68 -

restricted in many parts of the world, including Canada, and there are only a few variants of alkyl

hydrazine to begin with, these synthetic approaches are limited. On the other hand, with this new

phosgene-free synthesis, all that is required is a generic alkylating or allylating agent. Among the

many methylating or ethylating reagents, alkyl sulfates – dimethyl sulfate and diethyl sulfate –

showed the cleanest reactions. However, this is not to say that other alkylating agents do not

work. Other alkylating reagents, such as alkyl halide, are also compatible with this reaction

scheme. Regardless of the kind of alkylation or alkylating reagent, using a weak base, such as

sodium carbonate, in refluxing toluene gives clean, high-yielding reactions. Milcent’s variation

on Neugebauer’s synthesis does allow different functionalities at these positions but the second

incoming alkyl hydrazine cannot be protected with bulky groups as it would result in the open-

chain 1.20 (Scheme 1-5). This means that only the first equivalent of alkyl hydrazine is allowed

to have a bulky alkyl substituent and the second incoming alkyl hydrazine must have substituents

with little steric hindrance.

All of Neugebauer’s, Milcent’s, and Brook’s syntheses produce bishydrazone, 4.2, as a

side-product.[1-3] This side product can be recycled with our new synthesis. This feature is

important when the aldehyde being used is expensive and/or requires multiple steps to synthesize.

In addition, Milcent’s variation on Neugebauer’s synthesis can be modified with our

methanolysis procedure so that both N-1 and N-5 can be furnished with bulky substituents

(Scheme 4-3). Previously, this modification was not possible, since there was no known

procedure to cyclize a bishydrazone, such as 4.5, into a tetrazinanone.

- 69 -

Scheme 4-3. Our modification of Milcent variation on Neugebauer’s synthesis.

This new phosgene-free verdazyl radical synthesis clearly has its own advantages over

pre-existing verdazyl syntheses. Nonetheless, there are still limitations and drawbacks to this

synthesis as well. The first limitation is that aldehydes must be introduced at the first step of the

synthesis and effectively half of the aldehyde is often wasted in the de-protection/cyclization step

(Scheme 4-2). This usually is not a drawback unless the aldehyde being used is expensive or

difficult to synthesize. Also, the fact that the aldehyde is introduced at the first step means more

aldehyde is wasted – other than what has been just mentioned – as the following steps are not

quantitative and some is wasted as side-products. Thus, although this synthesis appears very

cost-effective compared to syntheses involving alkyl hydrazine and triphosgene, its cost-

effectiveness can be reduced due to the wasted aldehyde. Nevertheless, this synthesis is still

much less expensive than pre-existing syntheses involving alkyl hydrazine and phosgene.

In addition, the 6-thioverdazyl radical cannot be made with this new synthesis (entry 9,

Table 4-1). Thicarbohydrazide was used in place of carbohydrazide to furnish a C=S group at C-

- 70 -

6 instead of a C=O group. However, alkylation on the sulfur atom at the C-6 position occurs in

preference to the second N-alkylation reaction thus limiting the use of this intermediate.

Despite these limitations, the advantages of this synthesis far outweigh the disadvantages.

After all, this new synthesis has saved our lab from abandoning the verdazyl chemistry due to

lack of methyl hydrazine. Furthermore, it has provided a new way to furnish verdazyl radicals

with two different bulky substituents at N-1 and N-5 positions, a feature that pre-existing

syntheses did not allow without relying on phosgene or alkyl hydrazine.

- 71 -

References

[1] F. A. Neugebauer*, H. Fischer, R. Siegel, Chem. Ber. 1988, 121, 815-822.

[2] R. Milcent, G. Barbier, J. Heterocycl. Chem. 1994, 31, 319-324.

[3] E. C. Pare, D. J. R. Brook, A. Brieger, M. Badik, M. Schinke, Org. Biomol. Chem. O r g . B i

o m o l . C h e m . 2005, 3, 4258-4261.

[4] M. Bancerz, B. Youn, M. V. DaCosta, M. K. Georges, J. Org. Chem. 2012, 77, 2415-2421.

- 72 -

Chapter 5 Enantioselective 1,3-Dipolar Cycloaddition of Azomethine

Imines Generated in situ from Verdazyl Radicals

Chapter 5.1 Introduction

1,3-DC reactions of the azomethine imine derived from verdazyl radicals yields

pyrazolidine. Pyrazolidines exhibit many significant biological activities such as anti-microbial,

anti-fungal, anti-amoebic, anti-inflammatory, anti-convulsant, analgesic, anti-depressant, and

anti-cancer activities.[1-9] Pyrazolidines can also be reductively cleaved to yield 1,3-diamines[10],

which can be used as chiral ligands[11] or cis-platin derivatives.[11] Despite these many

applications of pyrazolidines, attempts to make them enantioselectively remained unexplored

until 2002.[11] This is quite an oddity considering metal Lewis acid catalyzed asymmetric 1,3-DC

reactions were first reported in 1994, and since then the field has been very active, especially

with nitrones and nitrile oxides dipoles.[12, 13]

In order to apply pre-existing literature procedures to our system to provide

enantiomerically pure pyrazolidines, the choice of catalysts for the the asymmetric 1,3-DC

reaction was made considering the electronic demand and starting material molecular structures.

Azomethine imines generated in situ from verdazyl radicals are Sustmann Type I dipoles, and

therefore react with electron poor dipolarophiles. Since 2002, there have been several reports of

asymmetric 1,3-DC reactions of azomethine imines.[11, 13-15] The first system to be tried was

Maruokoa’s work with C, N-cyclic azomethine imines with α, β-unsaturated aldehydes (Scheme

5-1). Titanium binolate, generated in situ from Ti(OiPr)4 and (S)-BINOL, was used as the

catalyst. High yields, ranging from 83 to 95 %, and high e.e.’s of 60 to 90 %, were reported with

reaction times of one to two hours.

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Scheme 5-1. Asymmetric 1,3-DC reactions with azomethine imines and β-unsaturated aldehydes

by Maruoka and et al.[13]

Another literature example that I tried was the work of Inomata et al.[12] Inomata’s

substrates were azomethine imines reacted with homoallylic alcohols (Scheme 5-2). These

homoallylic alcohols are quite different from the dipolarophiles that our group has been

traditionally using. Despite this fact, the procedure was chosen since it involves N, N’-cyclic

azomethine imines unlike Maruoka’s work with C, N-azomethine imines. Thus, although the

dipolarophile used in the paper is much different, the structures of Inomata’s azomethine imines

more closely resemble the structures of our azomethine imines; both are N, N’-cyclic azomethine

imines in a 5-membered ring structure, and both have a negatively charged nitrogen in the ylide

ground state configuration, alpha to a carbonyl centre. Using alkyl magnesium halide,

diisopropyl tartarate (DIPT), and MgBr2 in refluxing propyl nitrile, yields ranging from 24 to 96 %

and e.e’s ranging from 85 to 99 % are reported by Inomata.[12]

- 74 -

Scheme 5-2. Asymmetric 1,3-DC reaction with azomethine imines and homoallylic alcohols by

Inomata and et al.[12]

In our laboratory verdazyl radicals are either oxidized and crashed out of a MeOH/H2O

solvent or oxidized in a two-phase solvent of water and DCM or EtOAc. The first method is

preferred since verdazyl radicals are prone to decomposition when heated or concentrated under

vacuo. Furthermore, the first method gives verdazyl radicals in a solid state, while the second

two-phase solvent method gives verdazyl solutions. In either case, verdazyl radicals are quite wet

when first synthesized and this would seem to be something that could ruin metal catalysts and

affect the organocatalysts that involve an iminium ion intermediate. I suspect that this is the

reason why Maruoka used 3.0 molar equivalence of Grignard reagent in his asymmetric 1,3-DC

reactions (Scheme 5-2).[12]

Because of this system’s apparent sensitivity to water, two more candidates were chosen,

another metal catalyst and a set of organocatalysts. Since late-transition metal based

organocatalysts tend to be resistant to trace amount of water[16], palladium seemed to be a good

candidate to investigate. There are no examples of asymmetric 1,3-DC reactions of azomethine

imines catalyzed by palladium. Thus, Furukawa’s experimental procedure with nitrones as the

dipole with Pd(II)/BINAP was employed with our azomethine imine (Scheme 5-3).[16]

- 75 -

Scheme 5-3. Asymmetric 1,3-DC of nitrones to olefins by Furukawa et al.[16]

A set of organocatalysts was chosen for our unavoidably wet verdazyl. First, proline was

tried with varying success but we were able to show that the iminium ion mechanism catalysis

works with our system. The biggest advantage of proline is that it is inexpensive and can be

easily modified to fine-tune its steric bulk. Encouraged by the proline catalysis results, the

second generation of MacMillan’s catalyst, Figure 5-1, was also employed.

Figure 5-1. The second generation MacMillan catalyst.

Chapter 5.2 Experimental Section

General: Silica gel chromatography was performed with silica gel 60 (particle size 40–63 μm).

Carbo-di-N-benzylhydrazides were previously synthesized by simple condensation of

- 76 -

carbohydrazide with the appropriate aldehyde. NMR spectra were recorded at 23 °C, operating at

400 MHz for 1H NMR and 100 MHz for

13C NMR spectroscopy. Chemical shifts (δ) are reported

in parts per million (ppm) referenced to tetramethylsilane (δ = 0 ppm) for 1H NMR spectra and

CDCl3 (δ = 77.0 ppm) for 13

C NMR spectroscopy. Coupling constants (J) are reported in hertz

(Hz). Mass spectrometry was performed with an ESI source, MS/MS, and accurate mass

capabilities, associated with a capillary LC system.

1,5-Dimethyl-3-phenyl-6-oxoverdazyl radical

1,5-Dimethyl-3-phenyl-1,2,4,5-tetrazinan-6-one (150 mg, 0.73 mmol) was dissolved in 1.5 mL

of MeOH. K3(Fe(CN)6) (717 mg, 2.2 mmol) and Na2CO3 (231 mg, 2.2 mmol) were dissolved in

6 mL of water. The two solutions were mixed and cooled in an ice-water bath without stirring for

30 minutes. The reaction mixture was then filtered in a medium fritted filter and washed with

cold water to afford the 6-oxoverdazyl radical as a red solid in 80 % yield. Please do it and

delete the note in the parenthesis. The isolated verdazyl radical was subsequently placed under

high vacuum for 12 hours.

1,3-Dipolar cycloaddition procedure:

- 77 -

1,5-Dimethyl-3-phenyl-6-oxoverdazyl radical (100 mg, 0.49 mmol) was dissolved in 5 mL of an

appropriate solvent. An appropriate catalyst and methacrolein (40.7 uL, 0.492 mmol) were then

added in order in a glove bag when necessary. The reaction mixture was left un-stirred in a walk-

in fridge or a freezer for an appropriate reaction time, which typically was 3 or more days.. The

reaction mixture was purified by column chromatography (9:1 ethyl acetate/hexane) to yield

yellow solids. 1H NMR (400 MHz, CDCl3)s, 1H), 7.66-7.62 (m, 2H), 7.48-7.35 (m, 3H),

4.12 (septet, J = 4.20 Hz, 1H), 3.62 (m, 1H), 3.39 (s, 3H), 2.33 (septet, J = 4.60 Hz, 1H), 1.90 (m,

1H), 1.26 (s, 3H); 13

C NMR (100 MHz, CDCl3)

Chapter 5.3 Results and Discussion

Table 5-1. Asymmetric 1,3-DC of 1,5-dimethyl-3-phenyl-6-oxoverdazyl with methacrolein

Entry Temperature

(oC)

Solvent Catalyst Catalyst

loading

(mol

eq.)

Yield

(%)

e.e.

(%)

1 24 Toluene Ti(OiPr)/ BINOL 1 10 14

2 4 Toluene Ti(OiPr)/ BINOL 1 8 16

3 -20 Toluene Ti(OiPr)/ BINOL 1 5 16

4 4 THF MgBr2, DIPT, MeMgCl 3 13 14

5 -20 THF MgBr2, DIPT, MeMgCl 3 6 20

6 45 DMSO Proline 3 7 40

7 24 DMSO Proline 3 14 33

8 4 THF Proline 3 3 21

- 78 -

9 -20 THF Proline 3 ~1 12

10 24 DMSO Methyl ester proline 1 2 26

11 4 THF Methyl ester proline 1 2 17

12 24 DMSO t-Butyl ester proline 1 2 20

13 24 DMSO Benzyl ester proline 1 2 14

14 4 THF Benzyl ester proline 1 1 12

15 24 DMSO Prolinol 0.5 11 30

16 -20 THF MacMillan’s catalyst, 5.1 0.1 7 3

17 24 EtOAc MacMillan’s catalyst, 5.1 0.05 30 5

18 24 DMSO MacMillan’s catalyst, 5.1 1 6 6.5

19 4 THF MacMillan’s catalyst, 5.1 1 1 22

20 -20 DMF MacMillan’s catalyst, 5.1 0.1 6 3

21 -20 Et2O MacMillan’s catalyst, 5.1 0.1 3 2

22* -20 EtOAc MacMillan’s catalyst, 5.1 0.1 18 56

23* -20 THF MacMillan’s catalyst, 5.1 0.1 13 >90

e.e. was determined by HPLC analysis with Chiracel ADH, 3% iPrOH/hexanes, 1 mL/min, 254

nm

*1,3-DC reaction was done with diethyl phenyl verdazyl, instead of dimethyl phenyl verdazyl.

The chiral catalysts and conditions from Maruoka’s paper were first chosen since the set

up was applied to azomethine imines and his dipole/dipolarophile electronic demand was the

same as that of our system. Maruoka’s dipole-dipolarophile system is a Sustmann Type I for the

azomethine imine and reacts with various α,β-unsaturated aldehydes. Likewise, our system is

also a Sustmann Type I with azomethine imines that react with electron-poor dipolarophiles that

- 79 -

generally involve α, β-unsaturated carbonyl compounds.[17] In contrast, Maruoka’s azomethine

imines are C, N-cyclic azomethine imines, while our azomethine imines are N, N’-cyclic

azomethine imine. Titanium binolate gave only minimal enantioselectivity (Entries 1-3, Table 5-

1), which I suspect was largely due to the wetness of the verdazyl radical. Verdazyl radicals were

initially dried under house-vacuum overnight and there was no enantioselectivity in reactions

with those verdazyl radicals. A slight enantioselectivity with e.e. of 16 % was observed only

after drying the verdazyl radicals under high vacuum for 12 hours. Lower temperature did not

seem to improve the enantioselectivity when using titanium binolate with our system. An e.e. of

14% was observed when the reaction was performed at r.t., while an e.e. of 16% was observed at

4 and -20 oC (Entry 1-3, Table 5-1).

In contrast to the experiments employing titanium binolate as the chiral catalyst, the e.e.’s

from experiments employing MeMgBr and DIPT as the chiral catalyst increased from 14 % to

20 % by lowering the reaction temperature from 4 oC to - 20

oC (Entry 4 and 5, Table 5-1). In

order to improve the e.e. a large excess of MeMgBr was used, as I suspected that Maruoka used

3 mol eq. excess of MeMgBr[13] to overcome trace amounts of water in his reaction mixture. Still

the e.e. never exceeded 20%. Maruoka has provided a working model for his transition state,

Figure 5-3, where a deprotonated homoallylic alcohol coordinates to a magnesium centre to

which the azomethine imine is also coordinated. This model has both the dipole and

dipolarophile coordinated to a metal centre, making the 1,3-DC reaction an intramolecular

reaction. This results in lower energy levels for the HOMO and LUMO of the azomethine imine

and dipolarophile. Lower energy levels of Sustmann Type I dipoles can potentially de-activate

1,3-DC reactions, but this is compensated for by lowering the energy levels of the dipolarophiles

and by making the reaction an intramolecular reaction. As mentioned in the introduction,

- 80 -

Maruoka’s azomethine imine structure is quite similar to our azomethine imines. However, his

dipolarophiles are quite different from ours. Our carbonyl-based dipolarophiles do not coordinate

to magnesium as well as the deprotonated homoallylic alcohol. Furthermore, it is also possible

that even if our carbonyl based dipolarophile coordinates, the distance between the azomethine

imine and the olefin part of our dipolarophile is too large. This is actually the reason why I

suspect that Maruoka specifically used homoallylic alcohols instead of allylic alcohols (Figure 5-

3).

Figure 5-3. Working model of the transition state in the asymmetric 1,3-DC reaction of

azomethine imines and homoallylic alcohols by Maruoka.[13]

The e.e. increased consistently with increasing temperature when proline was employed

as a chiral catalyst (Entry 6-9, Table 5-1) with our system; e.e. of 12 % at – 20 oC, 21 % at 4

oC,

33 % at 24 oC, and 40 % at 45

oC. The same trend was observed with the methyl ester of proline

(Entry 10-11 Table 5-1), and the benzyl ester of proline (Entry 13-14 Table 5-1). This, again, is

contrary to the general understanding of enantioselective reactions, but increasing

- 81 -

enantioselectivity with increasing temperature is not unheard of in the literature.[16] Methyl, t-

butyl, and benzyl esters of proline were used at r.t. to see the effect of sterics on the

enantioselectivity. As seen in entries 7, 10, 12, 13 (Table 5-1) the e.e.’s decrease with increasing

steric bulk on the proline or proline-derived catalysts. Thus, among proline and proline-derived

catalysts, proline showed the highest e.e. of 40 % at 45 oC (Entry 6 Table 5-1). Increasing the

temperature higher than 45 oC yielded no cycloadducts. Instead we obtained a de-alkylated

product, whose mechanism of formation is not clear (Figure 5-4).

Figure 5-4. De-alkylation of verdazyl by proline or proline-derived catalysts.

In contrast to proline catalysis, e.e.’e increased with decreasing temperature down to 4 oC

when MacMillan’s catalyst was used with a dimethyl phenyl verdazyl radical (Entry 17-19,

Table 5-1). Oddly, the same trend was not observed at – 20 oC (Entry 16, 20, 21, Table 5-1).

However, the e.e. drastically increased as diethyl phenyl verdazyl was used with the

MacMillan’s catalyst. An e.e. of 56 % was observed under the reaction conditions of – 20 oC in

EtOAc and 0.1 molar eq. of the catalyst (Entry 22 Table 5-1). Using dry THF instead of EtOAc

provided an e.e. of >90 % under the same reaction conditions (Entry 23, Table 5-1).

In contrast to the organocatalysts, the metal catalysts have been rather disappointing,

providing very low e.e.’s. This can be partially attributed to the fact that our azomethine imines

- 82 -

are fairly good Lewis-bases with four nitrogen atoms and a carbonyl oxygen that can coordinate

to a metal centre. This azomethine imine-metal complex de-activates asymmetrically catalyzed

1,3-DC reactions. This problem could be resolved by raising the reaction temperature, as

suggested by Furukawa, who observed large increases in e.e. with increases in temperature. He

reasoned that the high temperature might favour the formation of 5.3 over 5.4 (Figure 5-5).[16]

This is supported by his experimental results where a negligible e.e., below 10 %, was observed

at r.t. while the e.e.’s jumped up to 89 % in refluxing chloroform.[16] This competing equilibrium

explanation might be the reason for the occasional observation in the literature where

enantioselectivity increases with reaction temperature.

Figure 5-5. Equilibrium between a nitrone-metal complex and an olefin-metal complex.[16]

The competing equilibrium for metal catalysts is more complex with our system than with

Furukawa’s. In the un-catalyzed 1,3-DC reaction of azomethine imines generated in situ from

verdazyl radicals, the disproportionation reactions to generate azomethine imines is the slowest

- 83 -

step (Figure 3-2). In other words, there is only a limited concentration of azomethine imine

present at any given moment while the rest of the starting material remains as the verdazyl

radical. In other words, there are now three species that can coordinate to the metal centre; the

verdazyl radical, the azomethine imine and the olefin. As mentioned in the introduction,

coordination of the metal catalyst to a verdazyl radical or an azomethine imine would deactivate

the 1,3-DC reaction by lowering the HOMO and LUMO of the dipole in the Sustmann Type I

system.

Supporting this equilibrium argument with our verdazyl radical system is Anthony de

Crisci’s un-published work on Julie Lukkarila’s cyclophane with Me3PtI and AgBF4 (Figure 5-6).

Figure 5-6. Cyclophane coordination structure proposed by Anthony de Crsci

It is in fact known in the literature that verdazyl radicals do coordinate to metals such as iron and

ruthenium (Figure 5-7). [18-20]

- 84 -

Figure 5-7. Coordination of verdazyl radicals to various metal centres reportes by R. Hicks.[18-20]

All these works – Furukawa’s competing equilibrium explanation10 (Figure 5-5),

Anthony De Crisci’s work on cyclophane with Me3PtI and AgBF4 (Figure 5-6), and Robin Hicks’

examples of metal-verdazyl radical complex[18-20] (Figure 5-7) – point to the fact that serious

fine-tuning is required with metal catalysts for asymmetric 1,3-DC reactions with the azomethine

imines derived from verdazyl radicals. Higher temperature in refluxing solvent might help

contrary to the general understanding in enantioselective synthesis that the reactions should be

performed at lower temperatures. Furthermore, using bidentate ligand may help through better

coordination and activation of the olefin by a metal catalyst.

Alternatively, these arguments outlining the difficulty of asymmetric 1,3-DC catalyzed

by metal catalysts explain why organocatalysts and metal catalysts show such a contrast in their

- 85 -

e.e.’s with our system. The higheset e.e. obtained with metal catalysts in our work to date is 20 %

(Entry 5 Table 5-1) with MeMgBr and DIPT. On the other hand, an e.e. of over 90 % has been

obtained using the MacMillan’s catalyst (Entry 23, Table 5-1). This difference is attributed to the

fact that the effective concentrations of catalysts are different in each reaction mixture. As

explained, much of the metal catalysts in our system is bound to the verdazyl radical or the

azomethine imine thus limiting the coordination of the carbonyl-based dipolarophile. In contrast,

there is no such competing equilibrium for the catalysts in organocatalyzed reaction mixtures,

which is reflected in the contrasting e.e.’s from metal catlayzed reactions and organocatalyzed

reactions.

Chapter 5.4 Concluding Remark/Future Work

A lot of work still remains to be done to fully understand the asymmetric 1,3-DC reaction

with azomethine imines. In the case of the azomethine imine derived from verdazyl radicals, it

will be important to find the best catalyst for the reaction. Once that is done, then the best

dipolarophiles will have to be defined.

It would also be interesting to return to the very early method of asymmetric 1,3-DC;

incorporation of chirality into the dipole or dipolarophile. This method does not receive much

attention anymore. However, transesterification on acrylates with prolinol would produce a

chiral dipolarophile that may show some promising results. The advantage of this method is that

even if the prolinol gets hydrolyzed, it will still act as an asymmetric catalyst. Furthermore,

among all the catalysts tried so far, prolinol showed the highest e.e. of 30 % (Entry 15 Table 5-1)

when reaction temperature was at 24 oC with our system.

- 86 -

It was also observed that whenever an excess of the proline or proline-derived catalysts

are used or whenever the reaction temperature exceeded 45 oC, de-alkylation, as high as 30%, of

the verdazyl backbone was observed (Figure 5-4). The mechanism of this de-alkylation reaction

remains to be elucidated.

Another organocatalyst that should be investigated further is the cinchona-based thiourea,

Figure 5-8. This catalyst has been shown to overcome some of the limitations of the proline and

MacMillan’s catalyst, being that iminium-ion based organocatalysts can work only on

dipolarophiles with aldehyde or ketone groups. In contrast, chiral tertiary amine thiourea can

asymmetrically catalyze any dipolarophile that can form H-bonds.

Figure 5-8. N-[3,5-Bis(trifluoromethyl)phenyl]-N′-[(8a,9S)-6′-methoxy-9-cinchonanyl]thiourea

Lastly, but importantly, a procedure that affords cleaner diethyl verdazyl radical is

necessary. The e.e.’s of so many of the cycloadducts from diethyl phenyl verdazyl radical could

not be determined due to impure HPLC spectra. Considering the fact that the procedure and

reagents used for the formation of dimethyl phenyl verdazyl and diethyl phenyl verdazyl are the

same, the reason for the poor HPLC spectra is likely to be impure verdazyl radical with at least 4

distinguishable spots on TLC when first synthesized. These impurities also significantly decrease

- 87 -

the yields of the cycloadditions. Without knowing the exact identities of the side products from

the verdazyl radical synthesis, the effects that the side products have on asymmetric the 1,3-DC

reaction can only be surmised. Therefore, there is an urgent need for a clean oxidation procedure

that can yield solid dry verdazyl radical.

- 88 -

References

[1] S. Kumar, S. Bawa, S. Drabu, R. Kumar, H. Gupta, Recent Pat Antiinfect Drug Discov. 2009,

4, 154-163.

[2] F. E. Goda, A. R. Maarouf, El Bendary, Saudi Pharmaceutical Journal 2003, 11, 111-117.

[3] A. M. Gilbert, A. Failli, J. Shumsky, Y. Yang, A. Severin, G. Singh, W. Hu, D. Keeney, P. J.

Petersen, A. H. Katz, J. Med. Chem. 2006, 49, 6027-6036.

[4] H. Fahmy, G. Soliman, Arch. Pharm. Res. 2001, 24, 180-189.

[5] M. Kornet, J. Thorsten, W. Lubawy, J. Pharm. Sci. 1974, 63, 1090-1093.

[6] B. Le Bourdonnec, E. Meulon, S. Yous, J. Goossens, R. Houssin, J. Henichart, J. Med. Chem.

2000, 43, 2685-2697.

[7] C. Cauvin, B. Le Bourdonnec, B. Norberg, J. Henichart, F. Durant, Acta Crystallogr. Sect. C-

Cryst. Struct. Commun. 2001, 57, 1330-1332.

[8] B. Le Bourdonnec, C. Cauvin, E. Meulon, S. Yous, J. Goossens, F. Durant, R. Houssin, J.

Henichart, J. Med. Chem. 2002, 45, 4794-4798.

[9] J. Buolamwini, J. Addo, S. Kamath, S. Patil, D. Mason, M. Ores, Curr. Cancer Drug Targets

2005, 5, 57-68.

[10] N. C. Giampietro, J. P. Wolfe, J. Am. Chem. Soc. 2008, 130, 12907-12911.

[11] S. Kobayashi, H. Shimizu, Y. Yamashita, H. Ishitani, J. Kobayashi, J. Am. Chem. Soc. 2002,

124, 13678-13679.

[12] K. Tanaka, T. Kato, S. Fujinami, Y. Ukaji, K. Inomata, Chem. Lett. 2010, 39, 1036-1038.

[13] T. Hashimoto, Y. Maeda, M. Omote, H. Nakatsu, K. Maruoka, J. Am. Chem. Soc. 2010, 132,

11824-11824.

[14] K. Tanaka, T. Kato, Y. Ukaji, K. Inomata, Heterocycles 2010, 80, 887-893.

[15] R. Shintani, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 10778-10779.

[16] K. Hori, H. Kodama, T. Ohta, I. Furukawa, Tetrahedron Lett. 1996, 37, 5947-5950.

[17] A. Yang, T. Kasahara, E. K. Y. Chen, G. K. Hamer, M. K. Georges, Eur. J. Org. 2008,

4571-4574.

- 89 -

[18] B. Koivisto, A. Ichimura, R. McDonald, M. Lemaire, L. Thompson, R. Hicks, J. Am. Chem.

Soc. 2006, 128, 690-691.

[19] T. M. Barclay, R. G. Hicks, M. T. Lemaire, L. K. Thompson, Inorg. Chem. 2001, 40, 5581-

5584.

[20] S. D. J. McKinnon, B. O. Patrick, A. B. P. Lever, R. G. Hicks, J. Am. Chem. Soc. 2011, 133,

13587-13603.