Seeking passe-partout in the catalytic asymmetric aziridination of imines: Evolving toward substrate generality for a single chemzyme

pubs.acs.org/joc

Seeking Passe-Partout in the Catalytic Asymmetric Aziridination of

Imines: Evolving Toward Substrate Generality for a Single Chemzyme

Munmun Mukherjee, Anil K. Gupta, Zhenjie Lu, Yu Zhang, and William D. Wulff*

Department of Chemistry, Michigan State University, East Lansing, Michigan 48824

wulff@chemistry.msu.edu

Received June 24, 2010

The asymmetric catalytic aziridination reaction (AZ reaction) of imines derived from dianisylmethyl

(DAM) amine and tetra-methyldianisylmethyl (MEDAM) amine were examined with boroxinate

catalysts preparedfrom boththe VANOL and VAPOL ligands. Thisincludedanevaluation of different

protocols for the preparation of the catalyst. The AZ reaction of DAM and MEDAM imines prepared

from nine different aryl and aliphatic aldehydes were examined. The MEDAM imines were superior to

the DAM imines in the AZ reaction, giving much higher asymmetric inductions and higher overall

yields of aziridines. The MEDAM imines were found to also be superior to the previously studied

diphenylmethyl (benzhydryl or Bh) and tetra-tert-butyldianisylmethyl (BUDAM) imines especially for

imines derived from aliphatic aldehydes. The average asymmetric induction over the nine different

MEDAM imines studied was 97% ee with the VAPOL catalyst and 96% ee with the VANOL catalyst.

The MEDAM iminescan be deprotectedtogiveN-Haziridines inall casesexcept for someelectron-rich

arylaldehydes. TheMEDAMiminesaremuchmore reactivethanbenzhydryl imines, and thiswasmost

evident when a diazoacetate ester is replaced by a diazoacetamide. The less reactive diazoacetamides

give very low yields in their reactions with benzhydryl imines but high yields with MEDAM imines.

Introduction

both acidic and basic conditions is facilitated by their ring

strain, and the result of this process is normally the stereo-

selective generation of a β-substituted alkyl amines.^1,2Although

the syntheses of aziridines has been continually honed over

the years,^1,2athe development of catalytic asymmetric meth-

ods had lagged behind.²Over the past several years we have

developed a general method for the catalytic asymmetric

synthesis of aziridines that is based on the reaction of diazo

compounds with imines and mediated by asymmetric cata-

lysts generated from the VANOL and VAPOL ligands and

Aziridines are attractive intermediates in organic synthesis

because their ring opening by a variety of nucleophiles under

(1) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (b) Osborn,

H. N. I.; Sweeney, J. B. Tetrahedron: Asymmetry 1997, 8, 1693–1715.

(c) McCoull, W.; Davies, F. A. Synthesis 2000, 1347–1365. (d) Zwanenburg,

B.; Holte, P. T. Top. Curr. Chem. 2001, 216, 93–124. (e) Sweeney, J. B. Chem.

Soc. Rev. 2002, 31, 247–258. (f) Duban, P.; Dodd, R. H. Synlett 2003, 1571.

€

(g) Hu, X. E. Tetrahedron 2004, 60, 2701–2743. (h) Mosser, C.; Bolm, C. In

Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-

VCH: Weinheim, 2006. (i) Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem.

Res. 2006, 39, 194–206. (j) Pineschi, M. Eur. J. Org. Chem. 2006, 4979–4988.

(k) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2007, 107, 2080–

2135. (l) Olsen, C. A.; Franzyk, H.; Jaroszewski, J. W. Eur. J. Org. Chem.

2007, 1717–1724. (m) Lu, P. Tetrahedron 2010, 66, 2549.

(2) (a) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;

€

Wiley-VCH: Weinheim, 2006. (b) Muller, P.; Fruit, C. Chem. Rev. 2003, 103,

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DOI: 10.1021/jo101160c

r

Published on Web 07/21/2010

J. Org. Chem. 2010, 75, 5643–5660 5643

2010 American Chemical Society

Mukherjee et al.

JOCArticle

SCHEME 1

SCHEME 2

various boron compounds (Scheme 1).^3-6Early on it was

determined that with imines derived from benzhydryl (Bh)

amine 5 and catalysts derived from triphenylborate, aziri-

dines could be obtained in high yields and asymmetric induc-

tions from the reaction of ethyl diazoacetate and other diazo

compounds.^3b,eThe reactions are also highly diastereoselec-

tive, giving cis-2,3-disubstituted aziridines, and in most cases

only trace amounts of the trans-aziridine can be detected.

The scope of the reaction is broad and includes imines deri-

ved from a variety of aldehydes including electron-rich and

electron-poor aromatic aldehydes and primary, secondary,

and tertiary aliphatic aldehydes.^3gThe imines from aromatic

aldehydes gave aziridines with 90-95% ee, and imines from

aliphatic aldehydes gave aziridines with 77-87% ee.^3gInter-

estingly, both VANOL- and VAPOL-derived catalysts are

equally effective and give nearly the same asymmetric induc-

tions for each substrate across the entire range of 12 sub-

strates examined.^3g

the success of this reaction, it does not represent the optimal

substituent since it was found that various diarylmethyl

groups were far more effective (Scheme 2). A collection of

14 different diarylmethyl substituents was screened for the

reaction of imines derived from benzaldehyde, and the optimal

selectivity (99% ee) was found for the tetra-tert-butyldiani-

sylmethyl (BUDAM) group.^3hWith the identification of the

BUDAM substituent as optimal for the imine from benzal-

dehyde, this substituent was in turn screened with imines

prepared from BUDAM amine 10 and 11 different alde-

hydes. The reactions of BUDAM imines from aromatic

aldehydes were definitely superior to their benzhydryl ana-

logues, giving 98-99% ee for most substrates with VAPOL-

derived catalysts; however, the reactions of BUDAM imines

from aliphatic aldehydes were not significantly different

from those with their benzhydryl analogues, giving ee’s gene-

rally in the 80s. Thus, the goal of the present work is to

identify the optimal diarylmethyl substituent that will pro-

vide universal access to optically pure aziridines from the AZ

reaction irrespective of the substrate.

More recent studies directed toward mapping the active

site of the chemzyme in this reaction have revealed that while

the use of a diphenylmethyl group on the imine is essential to

One of the great advantages of the BUDAM substituent is

that it can be easily cleaved under acidic conditions without

opening the aziridine ring. For example, the aziridine 9a (P =

BUDAM) can be deprotected to give the N-H aziridine 12a

in 97% yield by treatment with 4 equiv of triflic acid in

anisole at room temperature for 2 h (Scheme 2).^3hThe

corresponding benzhydryl aziridine (3a, R = Ph, Scheme 1)

leads to ring opening under all acidic conditions that were

screened.^3fThe facile cleavage of the BUDAM group under

acidic conditions can be attributed to the fact that a sig-

nificantly more stable diarylmethyl cation is formed during

the cleavage. Thus, in seeking the ideal diarylmethyl sub-

stituent for the imine, one of the characteristics that would be

most desired would be its ability to be removed from the

aziridine without causing any deleterious effects to the

aziridine. One of the other diarylmethyl groups that was

identified in our previous work as superior to the unsubsti-

tuted diphenylmethyl (benzhydryl or Bh) group in the AZ

reaction is the dianisylmethyl (DAM) group (Scheme 2).^3f

The presence of the methoxyl substituents in the DAM group

is sufficient to provide for the clean cleavage of the DAM

(3) For catalytic asymmetric aziridinations of imines and diazo com-

pounds with VANOL and VAPOL ligands, see: (a) Antilla, J. C.; Wulff,

W. D. J. Am. Chem. Soc. 1999, 121, 5099–5100. (b) Antilla, J. C.; Wulff,

W. D. Angew. Chem., Int. Ed. 2000, 39, 4518–4521. (c) Loncaric, C.; Wulff,

W. D. Org. Lett. 2001, 3, 3675–3678. (d) Patwardan, A.; Pulgam, V. R.;

Zhang, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2005, 44, 6169–6172.

(e) Deng, Y.; Lee, Y. R.; Newman, C. A.; Wulff, W. D. Eur. J. Org. Chem.

2007, 2068–2071. (f) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007,

129, 7185–7194. (g) Zhang, Y.; Desai, A.; Lu, Z.; Hu, G.; Ding, Z.; Wulff,

W. D. Chem.;Eur. J. 2008, 14, 3785–3803. (h) Zhang, Y.; Lu, Z.; Desai, A.;

Wulff, W. D. Org. Lett. 2008, 10, 5429–5432. (i) Hu, G.; Huang, L.; Huang,

R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009, 131, 15615–15617.

(4) For a review, see: Zhang, Y.; Lu, Z.; Wulff, W. D. Synlett 2009, 2715–

2739.

(5) For catalytic asymmetric aziridinations of imines and diazo com-

pounds with other ligands, see: (a) Rasumussen, K. G.; Jorgensen, K. A.

J. Chem. Soc., Perkin Trans. 1 1997, 1287. (b) Juhl, K.; Hazell, R. G.;

Jorgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1999, 2293. (c) Mayer, M. F.;

Hossain, M. M. J. Organomet. Chem. 2002, 654, 202. (d) Krumper, J. R.;

Gerisch, M.; Suh, J. M.; Bergman, R. G.; Tilley, T. D. J. Org. Chem. 2003, 68,

9705. (e) Redlich, M.; Hossain, M. M. Tetrahedron Lett. 2004, 45, 8987.

(f) Wipf, P.; Lyon, A. M. ARKIVOC 2007, xii, 91. (g) Hashimoto, T.;

Uchiyama, N.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 14380–14381.

(h) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445. (i) Zeng, X.;

Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009, 11, 3036.

(6) For a mechanistically different catalyst with imines and diazo com-

pounds, see: Ranocchiari, M.; Mezzetti, A. Organometallics 2009, 28, 3611.

5644 J. Org. Chem. Vol. 75, No. 16, 2010

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CHART 1. Protocols for Catalyst Preparation

SCHEME 3

original optimized protocol for catalyst formation called for

3 equiv of B(OPh)₃.^3bFurthermore, it was found that the

boroxinate 14 is formed by the reaction of the pyroborate 13

with the imine, with or without the presence of an additional

1 equiv of B(OPh)₃. In the catalyst protocols indicated in

Methods A and B in Chart 1, the exposure to high vacuum at

either 55 or 80 °C is not sufficient to remove the third

equivalent of B(OPh)₃after the pyroborate 13 is formed,

although the phenol produced in the alkoxy exchange be-

tween the ligand and B(OPh)₃is removed under either

condition. Armed with the knowledge of the catalyst struc-

ture, a new protocol for catalyst formation was drawn up

and is indicated as Method C in Chart 1; it will be tested for

the first time in the present study. The basic aspect of this new

method is that the ligand, B(OPh)₃, and all of the imine for

the reaction (Method C in Chart 1 is indicated for a reaction

with 3 mol % catalyst) are heated together in toluene at 80 °C

for 1 h, and then upon cooling to room temperature the

reaction is initiated by the addition of ethyl diazoacetate.

Another significant change in the procedure represented by

Method C is that the step involving the removal of volatiles

has been deleted. This was done for two reasons: one is our

unpublished observation that the presence of phenol does

not significantly affect the outcome of the AZ reaction (see

Table 5, entry 3 for an example in the present study), and the

second is that this greatly simplifies the procedure since

removing the solvent at 80 °C under high vacuum sometimes

occurs with splattering and loss of catalyst if one is not

careful. Finally, it should be noted that the water is left out in

Method C. Although the formation of a boroxinate does

require 3 equiv of water, studies in the efficiency in the

group under acidic conditions, as is illustrated by formation

of N-H aziridine 12a in 99% yield from the DAM aziridine

11a (P = DAM) (Scheme 2). We have previously examined

the scope of the aziridination of DAM imines from a variety

of aldehydes and found that these imines tend to give slightly

improved yields and asymmetric inductions than the corre-

sponding benzhydryl imines.^3fHowever, this survey was

conducted with methylene chloride and carbon tetrachlo-

ride as solvent. Because we have subsequently found that

toluene is in many respects superior to either methylene

chloride or carbon tetrachloride for the AZ reaction,^3gwe

decided to revisit the scope of the AZ reaction of DAM

imines.

The protocol for catalyst formation that was used in the

previous screen of the AZ reaction of DAM imines^3fwas

Method A shown in Chart 1 and is the optimized procedure

that was described in the initial report with a catalyst derived

from triphenylborate.^3bIt is interesting that the optimized

procedure involves 3 equiv of B(OPh)₃; at the time it was

assumed that the active catalyst involved a 1:1 stoichiometry

between the ligand and boron and that the excess B(OPh)₃

served to accelerate catalyst formation. Subsequently, it was

found that the major species formed under the conditions of

Method A was the pyroborate 13 (Scheme 3), which contains

one molecule of the ligand and two boron atoms linked by an

oxygen.^3gThis prompted an evaluation of the conditions

necessary to optimize the formation of the pyroborate

species, and the optimal procedure that was found is that

indicated in Method B in Chart 1.^3gSince the formation of a

B-O-B linkage requires 1 equiv of water, the use of water as

an additive became one of the parameters included in the

optimization. Therefore, the study of the AZ reaction of

DAM imines in toluene as solvent was begun with a catalyst

made by this new protocol prescribed by Method B.

1

formation of boroxinate 14 by H and ¹¹B NMR revealed

that there is sufficient partial hydrolysis in commercial

B(OPh)₃to provide the equivalent of three molecules of

water.³ⁱWe have never encountered a bottle of commercial

B(OPh)₃that was pure. This fact and the consistency of the

impure nature of commercial B(OPh)₃over the years have

been responsible for the success and reproducibility of the

AZ reaction. The reason that 4 equiv of B(OPh)₃is used in

Methods B and C in Chart 1 is to compensate for the fact that

B(OPh)₃in not pure as supplied from commercial suppliers.

In reality, we have not seen any significant difference in the

catalyst prepared with either 3 or 4 equiv of B(OPh)₃either in

1

reaction outcome or in its characterization by H or ¹¹B

NMR spectroscopy.³ⁱEven with 2 equiv of B(OPh)₃the

reaction outcome is not significantly affected. All of this

suggests that all of the boron that happens to be present is

converted to the boroxinate 14 even if this leaves some of the

ligand unreacted, and if any boron is left over, it not does

interfere in terms of background reaction.³ⁱ

It was during this time that we discovered³ⁱthat the active

catalyst for the AZ reaction was the boroxinate 14, which

contains three boron atoms, thus providing a reason why the

J. Org. Chem. Vol. 75, No. 16, 2010 5645

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TABLE 1. Asymmetric Aziridination with Aryl DAM Imines 15a-g^a

entry

series

R

ligand

catalyst (mol %)

% yield cis-11^b

% ee cis-11^c

cis:trans^d

% yield 16 (17)^e

1^f

2^g

3

4

5

a

b

c

d

e

f

Ph

(R)-VAPOL

(S)-VAPOL

(R)-VANOL

(S)-VAPOL

B (5)

C (3)

B (5)

C (3)

B (5)

C (3)

B (3)

B (5)

B (3)

B (2)

C (3)

B (5)

C (3)

95

90

70

90

80

94

90

87

89

85

80

-92

94

93

94

50:1

>50:1

50:1

1 (1)

2.7 (2.7)

1.4 (1.1)

1 (1)

2-MeC₆H₄

4-MeC₆H₄

4-MeOC₆H₄

4-BrC₆H₄

94

1 (1)

2 (1)

6

-93

97

94

95

7

3.2 (1.6)

<1 (< 1)

1 (1)

4.5 (2.7)

1.6 (1.6)

<1 (1 < 1)

1.6 (1.6)

8^h

9

10

11ⁱ

12

13

14

15

33:1

50:1

>50:1

4-NO₂C₆H₄

1-naphthyl

f

g

98

^aUnless otherwise specified, all reactions went to 100% completion and were performed with catalysts prepared by Methods B or C in Chart 1 with 1.0

mmol of imine 15 and 1.2 equiv of EDA (2) at room temperature for 24 h at 0.5 M in 15. All imines were purified by crystallization. ^bIsolated yield of cis-

11 after chromatography on silica gel. ^cDetermined on purified cis-15 by HPLC on a CHIRALPAK AD column. ^dRatio determined by integration of the

methine protons of the cis- and trans-aziridines in the ¹H NMR spectrum of the crude reaction mixture. ^eDetermined by integration of the NH signals of

16 and 17 relative to the methine proton of cis-11 in the ¹H NMR spectrum of the crude reaction mixture. ^fA separate reaction with 3 mol % catalyst was

complete in 2 h . ^gThis reaction was complete in 8 h. ^hCatalyst prepared by Method B in Chart 1 except that water was excluded during the preparation of

the catalyst. ⁱThe reaction was 97% complete.

Results and Discussion

temperature for 24 h. Considering previous observations

that alkyl-substituted imines are generally slower, 5-10

mol % catalyst was used for imines 15h-15j. Unfortunately,

the results from the alkyl-substituted DAM imines 15 do not

represent an improvement in the asymmetric inductions over

those of the corresponding benzhydryl imines 1 and in fact

are slightly lower (Table 3). In addition, the aziridination of

the primary alkyl-substituted imine 15h essentially fails in the

case of the DAM imine (Table 2, entries 1-4). This reaction

produces a very complex mixture with both VANOL and

VAPOL catalysts with either Methods B or C and at both

room temperature and at 0 °C. A similar complex mixture

was produced with DAM imine 15h in carbon tetrachloride

solvent with the VAPOL catalyst prepared from Method A

in Chart 1 where the aziridine 11h was isolated in 11% yield

and in 63% ee.^3fThis is to be compared to the corresponding

reaction of the benzhydryl imine 1h (Scheme 1, R = n-Pr)

prepared from n-butanal, which gave the corresponding

aziridine 3h in 40% yield and 81% ee.^3gThe crude ¹H

NMR spectrum of the reaction of imine 15h in entries 1-4

in Table 2 reveals the presence of a small amount of aziridine

11h (6-14%) and small amounts of the unreacted imine 15h

and of the noncyclized enamine products 16h and 17h. The

The catalyticasymmetricaziridinations of the DAM imines

15 derived from aromatic aldehydes were screened in toluene

with catalysts made with Methods B and C, and the results are

presented in Table 1. All of the reactions were carried out for

24 h with 2-5 mol % catalyst, but not all substrates required

24 h to go to completion. The reaction of the phenyl imine 15a

was completein 2 h with3 mol% catalyst(Table 1, entry 1). In

all cases the reaction went to completion except for entry 11,

which went to 97% completion in 24 h with 2 mol % catalyst.

The catalyst with VANOL was used for the p-methoxyl

substrate 15d since it had been found in our previous studies

on DAM imines that this is the slowest substrate and that the

VANOL catalystisapproximately twiceasfastastheVAPOL

catalyst.^3fOne of the clear findings of this study isthat, at least

for DAM imines derived from aryl aldehydes, there is no

difference between Methods B and C for catalyst formation

(Chart 1). This is an important observation since Method C is

experimentally much more simple a procedure as it does not

involve the removal of solvent from the catalyst at high

temperature under vacuum. However, the asymmetric induc-

tions do not represent a significant improvement over those

previously observed with DAM imines from aryl aldehydes in

carbon tetrachloride solvent.^3fThis is not to ignore the fact

that toluene is a much more desirable solvent than carbon

tetrachloride for reasons of both safety and cost.

1

only other product as prominent as these in the crude H

NMR was, after some effort, identified as the vinyl imine 18,

whose structure was confirmed by independent synthesis (see

Supporting Information). The compound presumably re-

sults from the aldol-type condensation of two molecules of

imine 15h. In contrast, high yields of aziridines were obtained

with the secondary and tertiary aliphatic imines 15i and 15j,

but unfortunately, the asymmetric inductions were not sig-

nificantly different than those previously observed in carbon

tetrachloride.^3f

At this point we had not yet addressed the critical issue of

whether the DAM imines would provide higher inductions

for imines from aliphatic aldehydes, since we had only

screened the aryl imines shown in Table 1. The aziridinations

of the aliphatic DAM imines 15 with a catalyst prepared by

Methods B or C from either VANOL or VAPOL were

carried out as indicated in Table 2 in toluene at room

5646 J. Org. Chem. Vol. 75, No. 16, 2010

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TABLE 2. Asymmetric Aziridination with Alkyl DAM Imines 15h-j^a

catalyst

(mol %)

% yield

cis-11^b

% ee

cis-11^c

% yield

16 (17)^e

% yield

18^f

% unreacted

15^f

entry

series

R

ligand

cis:trans^d

1

2

h

i

j

n-propyl

cyclohexyl

tert-butyl

(R)-VANOL

(S)-VAPOL

(R)-VANOL

(S)-VANOL

(R)-VANOL

(S)-VANOL

(R)-VANOL

C (10)

B (10)

C (5)

B (5)

C (10)

B (10)

nd (6)

14 (14)

11 (11)

10 (10)

83

88

60

87

nd

-52

73

-66

82

-80

70

-83

nd

50:1

20:1

50:1

3 (1)

0 (2)

2 (1)

7

4

7

4

2

10

7

0

3^g

4^g

5

8

<1 (<1)

no

6^h

7ⁱ

8^h

25

0

^aUnless otherwise specified, all reactions were performed with 5-10 mol % catalyst prepared by Method B or C with 1.0 mmol of imine and 1.2 equiv

of EDA (2) in toluene at room temperature for 24 h at 0.5 M in imine. All imines were purified by crystallization except 15h, which is an oil and was used without

purification. nd = not determined. no = not observed. ^bIsolated yield of cis-11 after chromatography on silica gel. Yield in paranthesis are NMR yields with

Ph₃CH as internal standard. ^cDetermined on purified cis-11 by HPLC on a CHIRALPAK AD column. ^dRatio determined by integration of the methine

protons of the cis- and trans-aziridines in the ¹H NMR spectrum of the crude reaction mixture. ^eDetermined by integration of the NH signals of 16 and

1

17 relative to the methine proton of cis-11 in the H NMR spectrum of the crude reaction mixture. ^fDetermined by H NMR with Ph₃CH as internal

standard. ^gThe reaction was performed at 0 °C for 48 h. ^hThe reaction was carried out for 48 h. ⁱThe reaction was carried out for 55 h.

TABLE 3. Asymmetric Aziridination with Alkyl Imines

idination of the cyclohexyl and tert-butyl imines with the

benzhydryl, BUDAM, and DAM nitrogen-protecting groups

is presented in Table 3. The benzhydryl-substituted imines

react to give aziridines 3 in 81-87% ee over both substrates

and with catalysts prepared from both the VANOL and

VAPOL ligands. The corresponding reactions of the BUDAM

imines 8 gave aziridines 9 with inductions in essentially the

same range (78-89% ee). The DAM imines give aziridines

11i and 11j in 70-82% ee with the VANOL-derived catalyst.

In the course of studies directed at mapping both the sterics

and electronics of the active site of the catalyst, we had

prepared imines generated from tetra-methyldiphenylmethyl

(MEDPM) amine.^3hIn a subsequent screen directed at iden-

tifying a nitrogen substituent that would lead to higher

asymmetric induction for aliphatic imines, we were surprised

to find that the imine 19i from cyclohexane carboxaldehyde

and imine 19j from pivaldehyde both underwent asymmetric

aziridination with significantly enhanced inductions when

compared to the benzhydryl, BUDAM, and DAM imines

(Table 3). Although the dramatic effect of methyl groups in

this substituent was not understood, it was nonetheless an

important lead in our efforts to identify a substituent on

nitrogen that would serve as a master key and allow access to

all imines with high asymmetric inductions.

Although the success of the results from the MEDPM

imines of aliphatic aldehydes 19i and 19j shown in Table 3

served to kindle thoughts of investigating the general scope

of the aziridination of these imines, caution was exercised

against doing so since our experience told us that it would be

difficult to effect acid cleavage of the N-protecting group

from the aziridines 20, especially when the substituent R was

an aryl group. We had previously established that benzhy-

dryl protecting groups that have p-methoxy groups such as

BUDAM and DAM can be readily cleaved from aziridines

without ring opening (Scheme 2),^3f,hand thus we then decided

to target the preparation of the tetra-methyldianisylmethyl

(MEDAM) amine 25b (Scheme 4) and evaluate the AZ re-

action with imines derived therefrom. The MEDAM amine

Thus our attempts to improve the asymmetric inductions

with aliphatic imines by employing the DAM-substituted

imines were surceased. A summary of the asymmetric azir-

J. Org. Chem. Vol. 75, No. 16, 2010 5647

Mukherjee et al.

JOCArticle

TABLE 4. Asymmetric Aziridination with MEDAM Imine 26 with Method B (with and without H₂O)^a

entry

imine^b

R

ligand

catalyst (mol %)

% yield cis-27^c

% ee cis-27^d

cis:trans^e

% yield 28 (29)^f

1

2

3

4

5

6

7

8

26a

26b

26c

26d

26e

26f

26k

26h

8h

Ph

(S)-VAPOL

(R)-VANOL

(R)-BINOL

(S)-VAPOL

(R)-VANOL

(S)-VAPOL

(R)-VANOL

(S)-VAPOL

(R)-VANOL

(S)-VAPOL

(R)-VANOL

(S)-VAPOL

(R)-VANOL

(S)-VAPOL

(R)-VANOL

(S)-VAPOL

(R)-VANOL

(S)-VAPOL

(R)-VANOL

(S)-VAPOL

(R)-VANOL

5

3

5

3

5

2

3

5

3

10

3

10

98

94

72

91

90

95

94

85

83

89

95

97

95

96

95

67

64

72

73

75

69

75

98

94

95

97

95

99.8

-97

-38

98

-97

99.5

-97

98

-96

99.5

99.6

99.5

-97

99.7

-97

90

93

97

-94

-95

95

-93

91

>50:1

17:1

33:1

50:1

>50:1

50:1

2.0 (1.9)

2.1 (1.8)

14 (10)

4.5 (2.7)

2.7 (2.7)

3.8 (0.9)

3.6 (2.7)

1.0 (1.0)

3.3 (4.0)

1.0 (1.0)

2.0 (1.9)

1.0 (1.0)

1.2 (1.4)

1.2 (2.0)

0 (1.9)

nd

15.3 (8.3)

3.0 (1.5)

0 (1.5)

0 (0)

10.3(4.4)

nd (5.3)

nd

2-MeC₆H₄

4-MeC₆H₄

4-MeOC₆H₄

4-BrC₆H₄

4-NO₂C₆H₄

n-hexyl

n-propyl

9

33:1

10^g

11

12

13

14

15

16

17

18^h

19

20^h

21^h,i

22^h,i

23

24^h

25

26

27

28^h

>50:1

nd

8h

26i

26j

cyclohexyl

tert-butyl

>50:1

nd

>50:1

nd

0(3)

nd

-91

94

-96

0(3)

^aFor all reactions with 2 and 3 mol % catalyst, the catalyst was prepared by Method B in Chart 1 except that water was excluded during catalyst

preparation. For all reactions with 5 and 10 mol % catalyst, the catalyst was prepared by Method B in Chart 1. Unless otherwise specified, all reactions were

carried out with 1.0 mmol of 26 at 0.5 M in toluene with 1.2 equiv of 2 at 25 °C and went to completion in 24 h. ^bAll imines were purified by crystallization

except 26h, 26k, and 8h, which were oils and were used without purification. Imine 26k was prepared by method 1, and 26h and 8h were prepared by method 2

given in Supporting Information. ^cIsolated yield of cis-27 after chromatography on silica gel. ^dDetermined on purified cis-27 by HPLC on a CHIRAL CEL

OD-H column. ^eRatio determined by integration of the methine protons of the cis- and trans-aziridines in the ¹H NMR spectrum of the crude reaction mixture.

nd = not determined. ^fDetermined by integration of the NH signals of 28 and 29 relative to the methine proton of cis-27 in the ¹H NMR spectrum of the crude

reaction mixture. ^gReaction was 97% complete. ^hReaction performed at 0 °C for 24 h. ⁱImine prepared from BUDAM amine 10; product is aziridine 9h.

cially available nitrile 22b.⁷Alternatively, the nitrile 22b can

SCHEME 4

be prepared from the bromide 21b by the Shechter modifica-

tion of the Rosenmund-Van Braun reaction.⁸The key step

then involves the reaction of the nitrile 22b with the Grignard

reagent generated from the bromide 21b and in situ reduction

of the resulting adduct 24 to provide the amine 25b in 88%

yield from the nitrile 22b.

The scope of the AZ reactions of the 10 MEDAM imines

26 shown in Table 4 were performed in toluene at room

temperature with both VANOL and VAPOL catalysts (2-

10 mol %) prepared by Method B (with or without H₂O). Of

the MEDAM imines prepared from aryl aldehydes, four out

of six give 99% ee for the aziridine 27 with the VAPOL

catalyst and the other two give 98% ee. This level of asym-

metric induction rivals that observed for BUDAM imines of

aromatic aldehydes,^3hand likewise, both imines give slightly

lower inductions (∼97% ee) with the VANOL catalyst.

Another important feature that the MEDAM imines have in

common with the BUDAM imines is that they both give high

(7) Alternatively, bromide 21b can be made from the inexpensive 2,6-

dimethylphenol; see Supporting Information.

(8) Friedman, L.; Shechter, H. J. Org. Chem. 1961, 26, 2522.

25b can be prepared in one step from the commercially

available 4-bromo-2,6-dimethylanisole 21b and the commer-

5648 J. Org. Chem. Vol. 75, No. 16, 2010

Mukherjee et al.

JOCArticle

TABLE 5. Asymmetric Aziridination with MEDAM Imine 26 with Method C^a

entry

imine^b

R

time (h)

% yield cis-27^c

% ee cis-27^d

cis:trans^e

% yield 28 (29)^f

1^g

2

26a

26b

26c

26d

26e

26f

26k

26i

Ph

3

0.25

24

0.5

24

2

94

93

94

e15

87

94

83

94

95

64

96

99

98.5

95.5

nd

96

99

97

99

>50:1

50:1

nd

33:1

>50:1

50:1

>50:1

nd

3.8 (1.9)

2.5 (2.0)

2.8 (2.8)

nd

5.0 (3.2)

3.0 (1.2)

1.2 (2.1)

1.5 (1.9)

1.2 (2.0)

10 (0)

3^h

4ⁱ

5^j

2-MeC₆H₄

4-MeC₆H₄

4-MeOC₆H₄

4-BrC₆H₄

4-NO₂C₆H₄

n-hexyl

6

7^k

8

9

0.75

24

3

10^l

11

12^m

86

89

92

cyclohexyl

tert-butyl

50:1

nd

26j

24

93

^aUnless otherwise specified, all reactions went to completion and were performed with 3 mol % catalyst prepared (Method C) by heating 3 mol % of

(S)-VAPOL with 12 mol % B(OPh)₃and 1 mmol of imine 26 as a 0.5 M solution in toluene at 80 °C for 1 h. The flask was cooled to room temperature,

and then 1.2 equiv of EDA (2) was added, and the mixture stirred for indicated time. nd = not determined. ^bAll imines were purified by crystallization

except 26k, which was an oil and was used without purification. Imine 26k was prepared by method 1 described in Supporting Information. ^cIsolated

yield after column chromatography on silica gel. ^dDetermined on purified cis-27 by HPLC on a CHIRAL CEL OD-H column. ^eRatio determined by

f

integration of the methine protons of the cis- and trans-aziridines in the ¹H NMR spectrum of the crude reaction mixture. Determined by integration of

the NH signals of 28 and 29 relative to the methine proton of cis-27 in the ¹H NMR spectrum of the crude reaction mixture. ^gA separate reaction with

1 mol % catalyst and 5 mmol of 26a that went to 67% completion in 0.5 h. ^h100 mol % PhOH was added just prior to EDA (2). Minimum reaction time

not determined, but the reaction did go to completion in 24 h. ⁱ100 mol % H₂O was added just prior to EDA (2). Reaction only went to 15% completion in

24 h. No further purification was carried out. ^j94% complete after 12 h. ^kReaction went to 97% completion. ^lReaction went to only 87% completion.

^m20% complete after 2 h, 44% complete after 8 h, and 98% complete after 24 h.

cis-selectivity with ortho-substituted aryl imines. Specifi-

cally, both give high selectivity for the cis-aziridine with

imines prepared from o-methylbenzaldehyde (Table 4, entry

4 and 5). This is in contrast to the corresponding benzhydryl

imine 1b (Scheme 1, R = 2-MeC₆H₄), which gives a 10:1

mixture of cis and trans aziridines.^3gMost importantly, the

high asymmetric inductions observed in the screen with the

MEDPM imines 19 with aliphatic aldehydes (Table 3) are

maintained and are essentially identical to those observed for

the corresponding MEDAM imines 26 (Table 4, entries

23-28 vs Table 3, entries 11-14). The asymmetric induction

could not be improved by lowering the temperature to 0 °C

for either the cyclohexyl or tert-butyl substrates (entries 24

and 28). Most importantly, the use of the MEDAM activat-

ing group allows for the efficient asymmetric aziridination of

imines with primary aliphatic substituents (entries 16-22).

In this case, the asymmetric induction could be slightly

increased by lowering the temperature to 0 °C as is illustrated

by the isolation of the aziridine 27h in 72% yield and 97% ee

(entry 18). A slightly lower result was observed for the BUDAM

imine 8h at this temperature (entry 21). The asymmetric

induction observed for the catalyst prepared from (R)-BI-

NOL was examined for the reaction of the phenyl imine 26a

(entry 3). The asymmetric induction of 38% ee with the

MEDAM imine 26a for the BINOL catalyst is to be com-

pared with 67% ee with the BUDAM imine 8a (R = Ph)^3h

and 20% ee with the benzhydryl imine 1a (R = Ph).^3b

The results of the evaluation of the catalytic asymmetric

aziridinations of MEDAM imines summarized in Table 4

reveal that VAPOL ligand gives slightly higher asymmetric

inductions than does the VANOL ligand. The catalyst gene-

rated from the VAPOL ligand was re-evaluated for the MEDAM

imines with the catalyst preparation procedure indicated by

Method C in Chart 1 since this procedure is experimentally

far easier to perform, and the results are given in Table 5. As

was the case with the DAM imines (Tables 1 vs 2), there was

very little difference between the two procedures, and thus

Method C becomes the protocol of choice for the AZ

reaction. As was the case with Method B, the aziridination

of MEDAM imines generated from aryl aldehydes with a

VAPOL catalyst Method C gives aziridines 27 in 99% ee for

four out of the six aryl imines and the other two give aziri-

dines in 96% and 97% ee. It is to be noted that the asym-

metric inductions for the MEDAM imines of aliphatic

aldehydes dropped off slightly (2-4% ee) with Method C

(Table 5) compared to Method B (Table 4), but they are

nonetheless superior to any of the other diaryl methyl amine

groups we have examined including DAM, BUDAM, and

benzhydryl groups. The minimum reaction times for all nine

MEDAM imine substrates in Table 5 were determined for

reactions with 3 mol % catalyst. The reactions of the aryl

imines were complete within 15-120 min with the exception

of the p-methoxyphenyl imine 26d, which required 24 h to go

to 97% completion (entry 7). The secondary and tertiary

alkyl-substituted imines 26i and 26j were in general slower

than the aryl imines, requiring 3-24 h to reach completion.

The reaction of the n-hexyl-substituted imine 26k was 87%

complete in 24 h. Finally the effect of added water and

phenol on the reactions of the MEDAM imines was exam-

ined. The addition of 100 mol % water to the reaction just

prior to the addition of ethyl diazoacetate essentially stops

the reaction of the phenyl imine 26a since it went to only 15%

J. Org. Chem. Vol. 75, No. 16, 2010 5649

Mukherjee et al.

JOCArticle

completion in 24 h (Table 5, entry 4). On the other hand, the

presence of phenol has only a small effect on the reaction.

The addition of 100 mol % phenol does not effect the yield of

the reaction and leads to only a slight drop in the asymmetric

induction (Table 5, entry 3); this reaction was allowed to run

for 24 h, and no attempt was made to determine the mini-

mum reaction time. This suggests that the removal of the

volatiles including phenol in Methods A and B for catalyst

formation does not have a significant beneficial effect on the

AZ reaction.

TABLE 6. Deprotection of MEDAM Aziridines 27^a

entry aziridine

R

time (h) temp (°C) % yield 12^b

1

2

3

4

5

6

7

8

9

27a

27b

27c

27d

27e

27f

27h

27i

Ph

2

1

0.5

0.7

25

65

95

97

c

2-MeC₆H₄

4-MeC₆H₄

4-MeOC₆H₄

4-BrC₆H₄

4-NO₂C₆H₄

n-propyl

The removal of the MEDAM group from the nitrogen in

the aziridines 27 to give the N-H aziridines 12 will be an

important aspect of the chemistry of MEDAM aziridines

that will serve to facilitate their application in synthesis.^1,2

This is especially true in those transformations that involve

nucleophilic opening of the aziridine under basic conditions,

since this type of reaction usually requires an electron-with-

drawing group on the nitrogen. The protocol for cleavage

involves treatment with 5 equiv of triflic acid in anisole and is

based on that developed for the deprotection of DAM

aziridines.^3fWe were pleased to see that the cleavage of the

phenyl-substituted MEDAM aziridine 27a proceeded under

this standard procedure to give the N-H aziridine 12a in 95%

yield. It was anticipated that deprotection of the electron-

rich p-methoxyphenyl aziridine 27d would be problematic

since this was the case with the corresponding DAM

aziridine.^3fIndeed attempted deprotection of 27d led to a

mixture of many products including ring-opening adducts

with anisole. This was also found to be the case with the

p-methylphenyl aziridine 27c, although interestingly, the de-

protection of the 2-methyl substituted aziridine 27b pro-

ceeded smoothly to give aziridine 12b in 97% yield. It is

possible that aziridines 27c and 27d could be deprotected by

the ozonolysis method we have previously reported for

benzhydryl aziridines, although this was not tested.⁹The

deprotection of the other aryl aziridines all occurred in yields

of at least 95%. The deprotection of the alkyl-substituted

aziridines was slower than that of the aryl aziridines and

required heating to 65 °C for short periods of time but

nonetheless gave good to excellent yields of the aziridines

12h-12j (Table 6, entries 7-9).

In addition to the finding that the MEDAM protecting

group provides the highest asymmetric inductions over the

broadest range of substrates for the catalytic asymmetric

aziridination of imines for any protecting group we have

screened to date, the MEDAM group on the imine was also

found to be the best group for asymmetric aziridinations

with the diazoacetamide 30. This diazoacetamide was exam-

ined in a view to develop an efficient method for the synthesis

of the natural product amathaspiramide F.¹⁰The benzhydryl

group was initially examined and was found to be very slow

in its reaction with diazoacetamide 30 (Table 7). Employing

10 mol % of the VANOL-B(OPh)₃-derived catalyst, the

reaction of imine 1a with 30 gave only a 16% yield of cis-

aziridine 31a in 77% ee after 24 h (entry 1).¹¹Switching to

the VAPOL-derived catalyst led to an enhancement of the

asymmetric induction to 88% ee (entry 2). Increasing the

c

96

97

72^d

90

88

cyclohexyl

tert-butyl

27j

^a0.15 M in 27. ^bIsolated yield after chromatography on silica gel.

^cMixtures of products observed including ring-opened products. ^dThe

yield of this reaction by ¹H NMR was 76% with Ph₃CH as internal

standard.

reaction time to 64 h and at the same time increasing the

catalyst loading to 20 mol % did not change the outcome

(entry 3). One explanation for the sluggishness of these

reactions is that there is product inhibition of the catalyst.

Thus, we decided to examine the effect of added B(OPh)₃on

this reaction since this had proved to be effective in amelior-

ating the product inhibition in a heteroatom Diels-Alder

reaction with the same catalyst.¹²Although there is essen-

tially no background reaction with B(OPh)₃(entry 7), the

addition of 200 mol % of B(OPh)₃did not change the yield of

the reaction in either CCl₄or in toluene (entries 4 and 5),

suggesting that if product inhibition is the problem, B(OPh)₃

is not successfully completing for binding with the product.

The reaction of the BUDAM imine 8a with diazoacetate 30

gives improved yield in the aziridination with diazoaceta-

mide 30 producing 32a in 40% yield after 24 h with 10 mol %

catalyst and also gave slightly higher induction (entry 8). The

MEDPM imine 19a was even more effective, giving a 66%

yield and 97% ee under the same conditions (entry 9). The

reaction of the MEDAM imine 26a is comparable, giving a

60% yield of aziridine 34a in 24 h and in 96% ee (entry 10).

This reaction only went to 68% completion, but if the

amount of catalyst is raised to 20 mol %, the reaction does

go to completion and gives aziridine 34a in 77% yield and

98% ee (entry 11).

The asymmetric inductions for the catalytic asymmetric

aziridination with the VANOL-derived catalyst are plotted

in Chart 2 for nine different substrates against the four

different N-substituents. This are a compilation of results

with the inductions for the benzhydryl imines^3gand BUDAM

imines^3htaken from previous publications and from the

present work for the DAM and MEDAM imines (see Table

S1 in Supporting Information for details on the data in

Chart 2). It is clear from Chart 2 that for imines derived

from the indicated six aryl aldehydes the BUDAM and

MEDAM imines are both superior substrates when com-

pared with the DAM and benzhydryl (Bh) imines. The

former give an average of 98% ee and 97% ee, respectively,

over the six aryl substituents, whereas the later both give an

(9) Patwardhan, A. P.; Lu, Z.; Pulgam, V. R.; Wulff, W. D. Org. Lett.

2005, 7, 2201–2204.

(10) Blackman, A. J.; Green, R. D. Aust. J. Chem. 1987, 40, 1655.

(11) The reactions of imines with secondary diazoacetamides have been

reported to give trans aziridines: see refs 5g and 5i.

(12) Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A.; Fielding, L.;

Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7216–7217.

5650 J. Org. Chem. Vol. 75, No. 16, 2010

Mukherjee et al.

JOCArticle

TABLE 7. Comparison of Various Imines in Aziridination with Diazoacetamide 30^a

^aUnless otherwise specified, all reactions were carried out at 0.5 M in imine with 1.05 equiv of 30 with a catalyst prepared by Method B unless

otherwise specified in Supporting Information The reactions in the first six entries all went to less than 50% completion. nd = not determined. ^bIsolated

yield after silica gel chromatography. ^cDetermined by HPLC on a Chiracel OD-H column. ^dDiazo amide 30 added slowly over 5 h by syringe pump. ^eThis

f

reaction went to <5% completion. This reaction went to 42% completion. ^gThis reaction went to 70% completion. ^hThis reaction went to 68%

completion. ⁱThis reaction went to 100% completion.

average of 91% ee over the same six substrates. The situation

is different for the three imines derived from aliphatic

aldehydes. The MEDAM imines give a much higher asym-

metric induction for the aliphatic substituents than do the

BUDAM, DAM, or benzhydryl imines. TheMEDAM imines

give an average of 94% ee for the three aliphatic imines,

whereas the BUDAM, DAM, and benzhydryl imines give

87%, 76%, and 83% ee, respectively (Table S3 in Supporting

Information).

The results of asymmetric inductions for the catalytic

asymmetric aziridination with the VAPOL-derived catalyst

are plotted in Chart 3 for nine different substrates against the

four different N-substituents. As was the case for the data

from the VANOL catalyst shown in Chart 2, the inductions

for the benzhydryl imines^3gand BUDAM imines^3hwere taken

from data in previous publications and from the present

work for the DAM and MEDAM imines (see Table S2 in

Supporting Information for details on the data in Chart 3).

The trends seen for the VAPOL ligand are very similar to

those observed for the VANOL ligand. For the six aromatic

substrates, MEDAM and BUDAM imines give the highest

inductions with an average of 99% ee and 98% ee, respec-

tively. The benzhydryl (Bh) and DAM imines give lower

average inductions of 89% ee and 94% ee, respectively. For

the three aliphatic imines, the MEDAM substituent was

clearly the most effective giving 94% ee averaged over the

primary, secondary, and tertiary aliphatic imines, which co-

incidentally was the same average observed for the VANOL

catalyst over the same substrates. The other N-substituents

were not nearly as effective with average inductions of 85%

ee for benzhydryl imines, 79% ee for the DAM imines, and

87% ee for the BUDAM imines (Table S3 in Supporting

Information).

Given the difference in size of the VANOL and VAPOL

ligands, it is quite remarkable that these ligands give nearly

identical asymmetric inductions over all nine substrates

shown in Charts 2 and 3 and over all four different protecting

groups on the imine (for numerical averages for yields and % ee,

see Table S3 in Supporting Information). For the BUDAM

and MEDAM imines, the VAPOL ligand gives only slightly

higher inductions on average (1% ee averaged over nine

substrates for each imine) and thus in the absence of any

other factors would be the ligand of choice for this reaction.

Considerations in favor of choosing the VANOL ligand is

the fact that its molecular weight is approximately 20% less

than that VAPOL, thus requiring less ligand per reaction at

J. Org. Chem. Vol. 75, No. 16, 2010 5651

Mukherjee et al.

JOCArticle

CHART 2. Distribution of Asymmetric Induction with Protecting Group for the VANOL Catalyst

CHART 3. Distribution of Asymmetric Induction with Protecting Group for the VAPOL Catalyst

least by weight. In addition, less ligand by mole percentage has

also been observed for the VANOL ligand. In side by side

comparisons, catalyst loading studies revealed that aziridina-

tion of the benzhydryl imine derived from p-bromobenzalde-

hyde could be brought to complete conversion at 0.5 mol %

loading with the VANOL catalyst, whereas complete conver-

sion with the VAPOL catalyst required 1.0 mol % loading.¹³

This may be related to a finding in a competition study that the

VANOL catalyst is two times faster than the VAPOL catalyst.^3f

The results of these studies have shown that the MEDAM

substituent is clearly the N-substituent of choice for the

catalytic asymmetric aziridination of imines with ethyl dia-

zoacetate. The aziridines 27 are obtained in very high asym-

metric inductions and cis-selectivities over a range of

MEDAM imines derived from both aromatic and aliphatic

aldehydes. The BUDAM and MEDAM imines give similar

inductions for aryl imines, but the MEDAM imines are

superior for aliphatic imines. The benzhydryl imines give

significantly lower yields and lower inductions than the

MEDAM imines (Table S3 in Supporting Information),

but the benzhydryl aziridines are often crystalline and their

optical purity can be enhanced in most cases to >99% ee by

crystallization.^3gThus, the benzhydryl group may be the N-

substituent of choice since the benzhydryl amine is commercially

available and the MEDAM amine is not, although it can be

ꢀ

(13) Desai, A.; Moran-Ramallal, R.; Wulff, W. D., Org. Synth., sub-

mitted for publication.

5652 J. Org. Chem. Vol. 75, No. 16, 2010

Mukherjee et al.

JOCArticle

made in a single step from commercially available materials.

Nonetheless, there are fundamental limitations of the benz-

hydryl imines that can be addressed by the use of MEDAM

imines in the AZ reaction. The synthesis of aziridines that are

not crystalline will undoubtedly be most attractive with

methods that give the highest asymmetric inductions of

products directly from the reaction. Also, the benzhydryl

group cannot be removed from the aziridine in an efficient

manner to give N-H aziridines if the imine is derived from

an aryl aldehyde. This would be important in utilizing any of

the many ring-opening reactions of aziridines that require an

electron-withdrawing group on the nitrogen. Finally, the

MEDAM substituent is serving as not only a selectivity

auxiliary in the AZ reaction but also an activating group.

The rates of the aziridination reaction are much faster with

MEDAM imines compared to benzhydryl imines. In a

competition experiment, it was found that the MEDAM

imine from benzaldehyde reacted 11.5 times faster than the

corresponding benzhydryl imine.^3h

valve. The resulting mixture was stirred for 24 h at room

temperature. Immediately upon addition of ethyl diazoacetate

the reaction mixture became an intense yellow, which changed

to light yellow toward the completion of the reaction. The

reaction was dilluted by addition of hexane (6 mL). The reaction

mixture was then transferred to a 100 mL round-bottom flask.

The reaction flask was rinsed with dichloromethane (5 mL ꢀ 2),

and the rinse was added to the 100 mL round-bottom flask. The

resulting solution was then concentrated in vacuo followed by

exposure to high vacuum (0.05 mmHg) for 1 h to afford the

crude aziridine as an off-white solid.

A measure of the extent to which the reaction went to

completion was estimated from the H NMR spectrum of the

1

crude reaction mixture by integration of the aziridine ring

methine protons relative to either the imine methine proton or

the proton on the imine carbon. The cis:trans ratio was deter-

mined by comparing the ¹H NMR integration of the ring

methine protons for each aziridine in the crude reaction mixture.

The cis (J = 7-8 Hz) and the trans (J = 2-3 Hz) coupling

constants were used to differentiate the two isomers. The yields

of the acyclic enamine side products 28a and 29a were deter-

1

mined by H NMR analysis of the crude reaction mixture by

Experimental Section

integration of the N-H proton relative to the that of the cis-

aziridine methine protons with the aid of the isolated yield of the

cis-aziridine. Purification of the crude aziridine by silica gel

chromatography (35 mm ꢀ 400 mm column, 9:1 hexanes/

EtOAc as eluent, gravity column) afforded pure aziridine 27a

as a white solid (mp 107-108 °C on 99.8% ee material) in 98%

isolated yield (396 mg, 0.98 mmol); cis:trans >50:1. Enamine

side products: 2% yield of 28a and 1.9% yield of 29a. The optical

purity of 27a was determined to be 99.8% ee by HPLC analysis

(CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226

nm, flow rate 0.7 mL/min): retention times t_R= 9.26 min (major

enantiomer, 27a) and t_R= 12.52 min (minor enantiomer, ent-

27a). The AZ reaction of imine 26a with (R)-VANOL gave ent-

27a in 94% yield with 97% ee and cis:trans of >50:1. Perform-

ing the reaction with (R)-BINOL gave ent-27a in 72% yield with

38% ee and cis:trans of >17:1. Spectral data for 27a:³R_f= 0.42

(1:9 EtOAc/hexane). ¹H NMR (CDCl₃, 500 MHz) δ 0.98 (t, 3H,

J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.55 (d, 1H, J = 6.8 Hz),

3.10 (d, 1H, J = 6.6 Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H)

3.87-3.97 (m, 2H), 7.09 (s, 2H), 7.18 (s, 2H), 7.21-7.24 (m, 3H),

7.36 (d, 2H, J = 7.3 Hz); ¹³C (CDCl₃, 125 MHz) δ 14.0, 16.2,

16.2, 46.3, 48.2, 59.5, 59.6, 60.5, 77.0, 127.2, 127.4, 127.7, 127.8,

127.9, 130.6, 130.6, 135.3, 137.8, 138.0, 156.0, 156.1, 168.0; IR

(thin film) 2961 vs, 1750 vs, 1414 vs, 1202 vs cm^-1; mass

spectrum m/z (% rel intensity) 473 Mþ (0.27), 284(78), 283

(100), 268 (34), 253 (20), 237 (11), 210(10), 117 (18), 89 (11).

Anal. Calcd for C₃₀H₃₅NO₄: C, 76.08; H, 7.45; N, 2.96. Found:

C, 76.31; H, 7.28; N, 2.82. [R]²³_Dþ41.3 (c 1.0, EtOAc) on 99% ee

material (HPLC). These spectral data match those previously

reported for this compound.^3h

General Information. All reactions were carried out in flame-

dried glassware under an atmosphere of argon unless otherwise

indicated. Triethylamine, dichloromethane, and acetonitrile

were distilled over calcium hydride under nitrogen. Tetrahydro-

furan, dioxane, and ether were distilled from sodium and

benzophenone. Toluene was distilled from sodium under nitro-

gen. All reagents were purified by simple distillation or crystal-

lization with simple solvents unless otherwise indicated. Ethyl

diazoacetate 2 and triphenylborate were obtained from Aldrich

Chemical Co., Inc. and used as received. VAPOL and VANOL

were made according to published procedure.¹⁴The prep-

arations of the DAM imines 15 and the MEDAM imines 26

are given in Supporting Information, as are the syntheses of the

DAM aziridines 11 and the diazoacetamide 30.

General Procedure for the Synthesis of MEDAM Aziridines 27

and BUDAM Aziridine 9h via Method B, Illustrated for Aziridines

27a, 27h, and 9h. (2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethyl-

phenyl)methyl)-3-phenylaziridine-2-carboxylate 27a. To a 25 mL

flame-dried homemade Schlenk flask (see Supporting Informa-

tion) equipped with a stir bar and flushed with argon were added

(S)-VAPOL (27 mg, 0.05 mmol) and B(OPh)₃(58 mg, 0.2 mmol).

Under an argon flow through the side arm of the Schlenk flask,

dry toluene (2 mL) was added through the top of the Teflon

valve to dissolve the two reagents, and this was followed by the

addition of water (0.9 μL, 0.05 mmol). The flask was sealed by

closing the Teflon valve and then placed in an 80 °C (oil bath) for

1 h. After 1 h, a vacuum (0.5 mmHg) was carefully applied by

slightly opening the Teflon valve to remove the volatiles. After

the volatiles were removed completely, a full vacuum was

applied and maintained for a period of 30 min at a temperature

of 80 °C (oil bath). The flask was then allowed to cool to room

temperature and opened to argon through the side arm of the

Schlenk flask.

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-propylaziridine-2-carboxylate 27h. The imine 26h was an oil

and was generated and used in situ. To a 10 mL flame-dried

round-bottom flask filled with argon were added bis(4-meth-

oxy-3,5-dimethylphenyl)methanamine 25b (299 mg, 1 mmol),

To the flask containing the catalyst were added first the

aldimine 26a (387 mg, 1 mmol) and then dry toluene (2 mL)

under an argon flow through side arm of the Schlenk flask. The

reaction mixture was stirred for 5 min to give a light orange

solution. To this solution was rapidly added ethyl diazoacetate

(EDA) 2 (124 μL, 1.2 mmol) followed by closing the Teflon

˚

4 A MS (250 mg, freshly dried), and dry toluene (1.5 mL). After

stirring for 10 min, butanal 4h (78 mg, 1.05 mmol, freshly

distilled) was added. The reaction mixture was stirred at room

temperature for 3 h. The resulting imine 26h was used without

1

further purification. Spectral data for 26h: H NMR (CDCl₃

500 MHz) δ 0.94 (t, 3H, J = 7.3 Hz), 1.58 (sextet, 2H, J =

7.3 Hz), 2.23 (s, 12H), 2.28-2.32 (m, 2H), 3.67 (s, 6H), 5.09 (s,

1H), 6.92 (s, 4H), 7.75 (t, 1H, J = 4.9 Hz); ¹³C NMR (125 MHz,

CDCl₃) δ 13.8, 16.2, 19.5, 37.8, 59.6, 77.7, 127.8, 130.6, 139.2,

155.7, 164.9.

(14) (a) Bao, J. M.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant,

E. B.; Rob, A. C.; Whitcomb, M. C.; Yeung, S. M.; Ostrander, R. L.;

Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392–3405. (b) VANOL and

VAPOL are also commercially available from Aldrich Chemical Co., Inc.

and Strem Chemicals.

J. Org. Chem. Vol. 75, No. 16, 2010 5653

Mukherjee et al.

JOCArticle

To a 25 mL flame-dried homemade Schlenk flask (see

Supporting Information) equipped with a stir bar and flushed

with argon was added (S)-VAPOL (54 mg, 0.1 mmol) and

B(OPh)₃(116 mg, 0.4 mmol). Under an argon flow through

the side arm of the Schlenk flask, dry toluene (2 mL) was

added through the top of the Teflon valuve to dissolve the two

reagents, and this was followed by the addition of water

(1.8 μL, 0.1 mmol). The flask was sealed by closing the Teflon

valve and then placed in an 80 °C oil bath) for 1 h. After 1 h, a

vacuum (0.5 mmHg) was carefully applied by slightly opening

the Teflon valve to remove the volatiles. After the volatiles

were removed completely, a full vacuum was applied and

maintained for a period of 30 min at a temperature of 80 °C

(oil bath). The flask was then allowed to cool to room

temperature and opened to argon through side arm of the

Schlenk flask.

was generated in situ. To a 10 mL flame-dried round-bottom

flask filled with argon were added bis(3,5-di-tert-butyl-4-meth-

˚

oxyphenyl)methanamine 10 (468 mg, 1 mmol), 4 A MS (250 mg,

freshly dried), and dry toluene (1.5 mL). After stirring for

10 min, butanal 4h (78 mg, 1.05 mmol, freshly distilled) was

added. The reaction mixture was stirred at room temperature

for 4 h. The resulting imine 8h was used without further

purification. Spectral data for 8h: ¹H NMR (CDCl₃500 MHz)

δ 0.98 (t, 3H, J = 7.3 Hz), 1.35 (s, 36H), 1.63 (sextet, 2H, J =

7.3 Hz), 2.31-2.35 (m, 2H), 3.64 (s, 6H), 5.22 (s, 1H), 7.05 (s,

4H), 7.87 (t, 1H, J = 4.9 Hz).

To a 25 mL flame-dried homemade Schlenk flask (see Sup-

porting Information) equipped with a stir bar and flushed with

argon were added (S)-VAPOL (54 mg, 0.1 mmol) and B(OPh)₃

(116 mg, 0.4 mmol). Under an argon flow through the side arm

of the Schlenk flask, dry toluene (2 mL) was added through the

top of the Teflon valve to dissolve the two reagents, and this was

followed by the addition of water (1.8 μL, 0.1 mmol). The flask

was sealed by closing the Teflon valve and then placed in an

80 °C oil bath for 1 h. After 1 h, a vacuum (0.5 mmHg) was

carefully applied by slightly opening the Teflon valve to remove

the volatiles. After the volatiles were removed completely, a full

vacuum was applied and maintained for a period of 30 min at a

temperature of 80 °C (oil bath). The flask was then allowed to

cool to 0 °C and opened to argon through side arm of the

Schlenk flask.

The toluene solution of imine 26h (354 mg, 1 mmol, prepared

as described above) was then directly transferred from the

reaction flask in which it was prepared to the flask containing

the catalyst utilizing a filter syringe (Corning syringe filters,

˚

Aldrich) to remove the 4 A molecular sieves. The flask that had

contained imine 26h was then rinsed with toluene (0.5 mL), and

the rinse was transferred to the flask containing the catalyst

under argon flow through side arm of the Schlenk flask. The

reaction mixture was stirred for 5 min to give a light yellow

solution. To this solution was rapidly added ethyl diazoacetate

(EDA) 2 (124 μL, 1.2 mmol) followed by closing the Teflon

valve. The resulting mixture was stirred for 24 h at room

temperature. The reaction was dilluted by addition of hexane

(6 mL). The reaction mixture was then transferred to a 100 mL

round-bottom flask. The reaction flask was rinsed with dichlor-

omethane (5 mL ꢀ 2), and the rinse was added to the 100 mL

round-bottom flask. The resulting solution was then concentrated

in vacuo followed by exposure to high vacuum (0.05 mmHg) for

1 h to afford the crude aziridine as a pale yellow semisolid.

Purification of the crude aziridine by silica gel chromatography

(35 mm ꢀ 400 mm column, 4:2:0.1 hexanes/CH₂Cl₂/EtOAc as

eluent, gravity column) afforded pure cis-aziridine 27h as a

semisolid in 64% isolated yield (281 mg, 0.64 mmol); cis:trans

not determined. Enamine side products: 15.3% yield of 28h and

8.3% yield of 29h. The optical purity of 27h was determined to

be 93% ee by HPLC analysis (CHIRALCEL OD-H column,

99:1 hexane/2-propanol at 226 nm, flow rate 0.7 mL/min):

retention times t_R= 4.73 min (major enantiomer, 27h) and

The toluene solution of imine 8h (522 mg, 1 mmol, prepared as

described above) was then directly transferred from the reaction

flask in which it was prepared to the flask containing the catalyst

utilizing a filter syringe (Corning syringe filters, Aldrich) to

˚

remove the 4 A molecular sieves. The flask that had contained

imine 8h was then rinsed with toluene (0.5 mL), and the rinse was

transferred to the flask containing the catalyst under argon flow

through the side arm of the Schlenk flask. The reaction mixture

was stirred for 5 min to give a light yellow solution. To this

solution was rapidly added ethyl diazoacetate (EDA) 2 (124 μL,

1.2 mmol) followed by closing the Teflon valve. The resulting

mixture was stirred for 24 h at room temperature. The reaction

was dilluted by addition of hexane (6 mL) at 0 °C. The reaction

mixture was then warmed to room temperature and transferred

to a 100 mL round-bottom flask. The reaction flask was rinsed

with dichloromethane (5 mL ꢀ 2), and the rinse was added to the

100 mL round-bottom flask. The resulting solution was then

concentrated in vacuo followed by exposure to high vacuum

(0.05 mmHg) for 1 h to afford the crude aziridine as a pale yellow

semisolid. Purification of the crude aziridine by silica gel chro-

matography (35 mm ꢀ 400 mm column, 4:2:0.1 hexanes/

CH₂Cl₂/EtOAc as eluent, gravity column) afforded pure cis-

aziridine 9h as a semisolid in 69% isolated yield (419 mg,

0.69 mmol); cis:trans not determined. Enamine side products:

10.3% yield of 35 and 4.4% yield of 36. The optical purity of 9h

was determined to be 95% ee by HPLC analysis (Pirkle covalent

(R,R) Whelk-O 1 column, 99.5:0.5 hexane/2-propanol at

226 nm, flow rate 0.7 mL/min): retention times t_R= 7.46 min

(major enantiomer 9h) and t_R= 6.60 min (minor enantiomer,

ent-9h). The reaction of imine 9h with (R)-VANOL gave ent-9h

in 75% yield with 93% ee. Spectral data for 9h: R_f= 0.23 (2:1

t

_R= 5.68 min (minor enantiomer, ent-27h). The AZ reaction of

imine 26h with (S)-VAPOL at 0 °C gave 27h in 72% yield with

97% ee. With (R)-VANOL, ent-27h was obtained in 73% yield

with 94% ee (at room temperature) and 75% yield and 95% ee

(at 0 °C). For the reaction at 0 °C, the catalyst was precooled to

0 °C followed by the addition of the imine solution and EDA at

0 °C. Spectral data for 27h: R_f= 0.28 (4:2:0.1 hexanes/CH₂Cl₂/

EtOAc); ¹H NMR (CDCl₃, 500 MHz) δ 0.72 (t, 3H, J = 7.6 Hz),

0.98-1.08 (m, 1H), 1.11-1.20 (m, 1H), 1.23 (t, 3H, J = 7.1 Hz),

1.38-1.45 (m, 1H), 1.49-1.55 (m, 1H), 1.95 (q, 1H, J = 6.6 Hz),

2.18 (d, 1H, J = 6.8 Hz) 2.22 (s, 12H), 3.39 (s, 1H), 3.65 (s, 3H),

3.67 (s, 3H), 4.12-4.23 (m, 2H), 6.99 (s, 2H), 7.07 (s, 2H); ¹³

C

NMR (CDCl₃, 125 MHz) δ 13.6, 14.3, 16.1, 16.2, 20.3, 29.9,

43.5, 46.8, 59.6, 59.6, 60.6, 77.3, 127.4, 128.1, 130.4, 130.47,

137.8, 138.2, 155.8, 156.1, 169.7; IR (thin film) 2957vs, 1744s,

1483s, 1221s, 1182vs cm^-1; HRMS (ESI-TOF) m/z 440.2817

[(M þ H^þ) calcd for C₂₇H₃₈NO₄440.2801]; [R]²³_Dþ95.3 (c 1.0,

EtOAc) on 97% ee material (HPLC).

1

hexane/CH₂Cl₂); H NMR (CDCl₃, 300 MHz) δ 0.82 (t, 3H,

J = 7.5 Hz), 1.31 (t, 3H, J = 7.1 Hz), 1.50-1.74 (m, 2H), 1.45 (s,

18 h), 1.46 (s, 18 h) 1.55-1.73 (m, 2H), 2.15 (q, 1H, J = 6.6 Hz),

2.36 (d, 1H, J = 6.6 Hz), 3.68 (s, 1H), 3.70 (s, 3H), 3.72 (s, 3H),

4.12-4.29 (m, 2H), 7.22 (s, 2H), 7.36 (s, 2H); ¹³C NMR (CDCl₃,

75 MHz) δ 13.7, 14.4, 20.6, 29.9, 32.1, 32.2, 35.8, 35.8, 43.4, 47.3,

60.7, 64.1, 64.1, 77.6, 125.6, 126.2, 136.4, 137.0, 142.9, 142.9,

158.3, 158.7, 170.0; IR (thin film) 2961vs, 1747s, 1448s, 1221s,

1182 vs cm^-1; HRMS (ESI-TOF) m/z 608.4665 [(M þ H^þ) calcd

for C₃₉H₆₂NO₄608.4679]; [R]²³_D-61.6 (c 1.0, EtOAc) on 93%

ee material (HPLC) of ent-9h.

The MEDAM aziridines 27b-h were also prepared according

to Method B utilizing 5-10 mol % catalyst loading. These

results including the yields and optical purity for all of MEDAM

aziridines 27 are given in Table 4.

(2R,3R)-Ethyl-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-

3-propylaziridine-2-carboxylate 9h. The imine 8h was an oil and

5654 J. Org. Chem. Vol. 75, No. 16, 2010

Mukherjee et al.

JOCArticle

General Procedure for the Synthesis of MEDAM Aziridines 27

via Method B (without water), Illustrated for Aziridines 27b and

27k. (2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-(o-tolyl)aziridine-2-carboxylate 27b. Imine 26b (401.5 mg, 1 mmol)

was reacted according to the general Method B described above with

(S)-VAPOL as ligand with the following differences: (a) water was

excluded during the preparation of the catalyst and (b) 3 mol %

catalyst loading was utilized. Purification of the crude aziridine by

silica gel chromatography (35 mm ꢀ 400 mm column, 9:1 hexanes/

EtOAc as eluent, gravity column) afforded pure cis-aziridine 27b as a

white solid (mp 59-60 °C on 98% ee material) in 91% isolated yield

(444 mg, 0.91 mmol); cis:trans 33:1. Enamine side products: 4.5%

yield of 28b and 2.7% yield of 29b. The optical purity of 27b was

determined to be 98% ee by HPLC analysis (CHIRALCEL OD-H

column, 99:1 hexane/2-propanol at 226 nm, flow rate 0.7 mL/min):

prepared to the flask containing the catalyst. The flask that had

contained imine 26k was then rinsed with toluene (0.5 mL), and

the rinse was transferred to the flask containing the catalyst

under argon flow through the side arm of the Schlenk flask. The

reaction mixture was stirred for 5 min to give a light yellow

solution. To this solution was rapidly added ethyl diazoacetate

(EDA) 2 (124 μL, 1.2 mmol) followed by closing the Teflon

valve. The resulting mixture was stirred for 24 h at room

temperature. The reaction was dilluted by addition of hexane

(6 mL). The reaction mixture was then transferred to a 100 mL

round-bottom flask. The reaction flask was rinsed with dichlo-

romethane (5 mL ꢀ 2), and the rinse was added to the 100 mL

round-bottom flask. The resulting solution was then concen-

trated in vacuo followed by exposure to high vacuum (0.05 mmHg)

for 1 h to afford the crude aziridine as a pale yellow semisolid.

Purification of the crude aziridine by silica gel chromatography

(35 mm ꢀ 400 mm column, 4:2:0.1 hexanes/CH₂Cl₂/EtOAc as

eluent, gravity column) afforded pure cis-aziridine 27k as a

semisolid in 67% isolated yield (323 mg, 0.67 mmol); cis:trans

not determined. Enamine side products: not determined. The

optical purity of 27k was determined to be 90% ee by HPLC

analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propa-

nol at 226 nm, flow rate 0.7 mL/min): retention times t_R= 9.27 min

(major enantiomer, 27k) and t_R= 11.17 min (minor enantio-

mer, ent-27k). Spectral data for 27k: R_f= 0.30 (4:2 hexane/

CH₂Cl₂); ¹H NMR (CDCl₃, 300 MHz) δ 0.84 (t, 3H, J =

7.2 Hz), 0.99-1.03 (m, 1H), 1.14-1.24 (m, 7H), 1.27 (t, 3H, J =

7.1 Hz), 1.48-1.56 (m, 2H), 1.97-2.00 (m, 1H), 2.23 (d, 1H, J =

6.8 Hz), 2.26 (s, 12H), 3.43 (s, 1H), 3.69 (s, 3H), 3.70 (s, 3H),

4.16-4.25 (m, 2H), 7.04 (s, 2H), 7.12 (s, 2H); ¹³C NMR (CDCl₃,

75 MHz) δ 13.9, 14.2, 16.0, 16.1, 22.3, 27.1, 27.8, 28.7, 31.7, 43.5,

46.9, 59.4, 60.5, 77.2, 127.3, 128.0, 130.3, 130.4, 137.7, 138.1,

155.7, 156.0, 169.6 (one sp3 carbon not located); IR (thin film)

2928vs, 1746s, 1483s, 1221s, 1181s cm^-1; mass spectrum m/z (%

rel intensity) 481 Mþ (0.5), 283 (100), 268 (13), 253 (7), 142 (7),

55 (13), 41 (16); [R]²³_Dþ78.3 (c 1.0, CH₂Cl₂) on 90% ee material

(HPLC).

MEDAM aziridines 27d, 27e, 27i, and 27j were also prepared

according to the Method B (without water) utilizing 2-3 mol %

catalyst loading and the results are presented in Table 4.

General Procedure for the Synthesis of MEDAM Aziridines 27

via Method C, Illustrated for Aziridines 27a-27f and 27i-27k.

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-

phenylaziridine-2-carboxylate 27a. To a 25 mL flame-dried home-

made Schlenk flask (see Figure 1 in the Supporting Information)

equipped with a stir bar and flushed with argon were added (S)-

VAPOL (16 mg, 0.03 mmol), B(OPh)₃(35 mg, 0.12 mmol), and

aldimine 26a (387 mg, 1 mmol). Under an argon flow through the

side arm of the Schlenk flask, dry toluene (2 mL) was added

through the top of the Teflon valve to dissolve the reagents. The

flask was sealed by closing the Teflon valve and then placed in an 80

°C oil bath for 1 h. The catalyst mixture was then allowed to cool to

room temperature and opened to argon through the side arm of the

Schlenk flask. To this solution was rapidly added ethyl diazoacetate

(EDA) 2 (124 μL, 1.2 mmol) followed by closing the Teflon valve.

The resulting mixture was stirred for 15 min at room temperature.

Immediately upon addition of ethyl diazoacetate the reaction

mixture became an intense yellow, which changed to light yellow

toward the completion of the reaction. The reaction was dilluted by

addition of hexane (6 mL). The reaction mixture was then trans-

ferred to a 100 mL round-bottom flask. The reaction flask was

rinsed with dichloromethane (5 mL ꢀ 2), and the rinse was added to

the 100 mL round-bottom flask. The resulting solution was then

concentrated in vacuo followed by exposure to high vacuum

(0.05 mmHg) for 1 h to afford the crude aziridine as an off-white

solid. Purification of the crude aziridine by silica gel chromatogra-

phy (35 mm ꢀ 400 mm column, 9:1 hexanes/EtOAc as eluent,

gravity column) afforded pure cis-aziridine 27a as a white solid

retention times t_R= 9.45 min (major enantiomer, 27b) and t_R

=

12.21 min (minor enantiomer, ent-27b). The AZ reaction of imine

26b with (R)-VANOL (via Method B and 5 mol % catalyst loading)

gave ent-27b in 90% yield with 97% ee and cis:trans of 50:1. Spectral

data for 27b: R_f= 0.38 (1:9 EtOAc/hexane). ¹H NMR (CDCl₃, 500

MHz) δ 0.89 (t, 3H, J = 7.1 Hz), 2.20 (s, 6H), 2.24 (s, 6H), 2.26 (s,

3H), 2.61 (d, 1H, J = 6.8 Hz), 3.08 (d, 1H, J = 6.6 Hz), 3.62 (s, 3H),

3.66 (s, 1H), 3.68 (s, 3H), 3.88 (q, 2H, J = 7.1 Hz), 7.01 (d, 1H, J =

6.6 Hz), 7.06-7.09 (m, 2H), 7.13 (s, 2H), 7.18 (s, 2H), 7.53 (d, 1H,

J = 6.3 Hz); ¹³C (CDCl₃, 125 MHz) δ 13.9, 16.2, 16.2, 18.8, 45.6,

47.2, 59.5, 59.6, 60.4, 77.3, 125.3, 127.1, 127.3, 128.0, 128.6, 129.1,

130.6, 130.6, 133.45, 136.0, 137.9, 138.0, 155.9, 156.2, 168.7; IR (thin

film) 2937vs, 1749s, 1485s, 1221s, 1192vs cm^-1; HRMS (ESI-TOF)

m/z 488.2801 [(M þ H^þ) calcd for C₃₁H₃₈NO₄488.2801]

[R]²³_Dþ46.4 (c 1.0, EtOAc) on 97% ee material (HPLC).

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-hexylaziridine-2-carboxylate 27k. The imine 26k was an oil

and was generated in situ. To a 10 mL flame-dried round-bottom

flask filled with argon were added bis(4-methoxy-3,5-dimethyl-

phenyl)methanamine 25b (299 mg, 1 mmol), MgSO₄(200 mg,

1.7 mmol, freshly flame-dried), and dry CH₂Cl₂(3 mL). After

stirring for 10 min, heptanal 4k (120 mg, 1.05 mmol, freshly

distilled) was added. The reaction mixture was stirred at room

temperature for 3 h. The reaction mixture was filtered through

Celite, the Celite bed was washed with CH₂Cl₂(1 mL ꢀ 3), and

then the filtrate was concentrated by rotary evaporation to give

the crude imine as a pale yellow viscous oil which was dried

under high vacuum (∼ 0.2 mmHg) for 1 h to remove any excess

aldehyde, 100% crude yield. The resulting imine 26k was used

1

without further purification. Spectral data for 26k: H NMR

(CDCl_3,300 MHz) δ 0.84 (t, 3H, J = 6.7 Hz), 1.25-1.33 (m, 6H)

1.50-1.55 (m, 2H), 2.22 (s, 12H), 2.28-2.34 (m, 2H), 3.66 (s,

6H), 5.08 (s, 1H), 6.91 (s, 4H), 7.74 (t, 1H, J = 5.0 Hz); ¹³C

NMR (75 MHz, CDCl₃) δ 14.0, 16.1, 22.6, 26.0, 29.0, 31.6, 35.9,

59.6, 77.7, 127.7, 130.53, 139.2, 155.7, 165.0.

To a 25 mL flame-dried homemade Schlenk flask (see Sup-

porting Information) equipped with a stir bar and flushed with

argon were added (S)-VAPOL (16 mg, 0.03 mmol) and B(OPh)₃

(35 mg, 0.12 mmol). Under an argon flow through the side arm

of the Schlenk flask, dry toluene (2 mL) was added through the

top of the Teflon valve to dissolve the two reagents. The flask

was sealed by closing the Teflon valve and then placed in an

80 °C oil bath for 1 h. After 1 h, a vacuum (0.5 mmHg) was

carefully applied by slightly opening the Teflon valve to remove

the volatiles. After the volatiles were removed completely, a full

vacuum was applied and maintained for a period of 30 min at a

temperature of 80 °C (oil bath). The flask was then allowed to

cool to room temperature and opened to argon through the side

arm of the Schlenk flask.

Meanwhile, to the flask containing imine 26k (396 mg,

1 mmol, prepared as described above) was added dry toluene

(1.5 mL), and the resultant toluene solution of imine 26k was

then directly transferred from the reaction flask in which it was

J. Org. Chem. Vol. 75, No. 16, 2010 5655

Mukherjee et al.

JOCArticle

(mp 107-108 °C on 99.8% ee material) in 93% isolated yield (440

mg, 0.93 mmol); cis:trans >50:1. Enamine side products: 2.5%

yield of 28a and 2.0% yield of 29a. The optical purity of 27a was

determined to be 98.5% ee by HPLC analysis (CHIRALCEL OD-

H column, 99:1 hexane/2-propanol at 226 nm, flow rate 0.7 mL/

min): retention times t_R= 9.26 min (major enantiomer, 27a) and

t_R= 12.52 min (minor enantiomer, ent-27a). Spectral data for 27a

given above in procedure for Method B.

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-(o-tolyl)aziridine-2-carboxylate 27b. Imine 26b (401.5 mg, 1

mmol) was reacted according to the general Method C described

above with (S)-VAPOL as ligand. Purification of the crude

aziridine bysilica gel chromatography(35mmꢀ 400 mm column,

9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-

aziridine 27b as a white solid (mp 59-60 °C on 98% ee material)

in 87% isolated yield (424 mg, 0.87 mmol); cis:trans 33:1.

Enamine side products: 5.0% yield of 28b and 3.2% yield of

29b. The optical purity of 27b was determined to be 96% ee by

HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-

propanol at 226 nm, flow rate 0.7 mL/min): retention times t_R=

9.45 min (major enantiomer, 27b) and t_R= 12.21 min (minor

enantiomer, ent-27b). Spectral data for 27b given above in

procedure for Method B (without H₂O).

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-(p-tolyl)aziridine-2-carboxylate 27c. Imine 26c (401.5 mg, 1

mmol) was reacted according to the general Method C described

above with (S)-VAPOL as ligand. Purification of the crude

aziridine bysilica gel chromatography(35mmꢀ 400 mm column,

9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-

aziridine 27c as a white solid (mp 116-117 °C on 99.5% ee

material) in 94% isolated yield (458 mg, 0.94 mmol); cis:trans

>50:1. Enamine side products: 3.0% yield of 28c and 1.2% yield

of 29c. The optical purity of 27c was determined to be 99% ee by

HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-

propanol at 226 nm, flow rate 0.7 mL/min): retention times t_R=

9.22 min (major enantiomer, 27c) and t_R= 11.62 min (minor

enantiomer, ent-27c). Spectral data for 27c: R_f= 0.30 (1:9

155.9, 156.1, 158.9, 168.1 (one sp²carbon not located); IR (thin

film) 2942vs, 1743s, 1514s, 1250s, 1180vs cm^-1; HRMS (ESI-TOF)

m/z 504.2744 [(M þ H^þ) calcd for C₃₁H₃₈NO₅504.2750] [R]²³

D

-25 (c 1.0, EtOAc) on 96% ee material (HPLC) on ent-27d.

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-(4-bromophenyl)aziridine-2-carboxylate 27e. Imine 26e (466.4

mg, 1 mmol) was reacted according to the general Method C

described above with (S)-VAPOL as ligand. Purification of the

crude aziridine by silica gel chromatography (35 mm ꢀ 400 mm

column, 5:1 hexanes/EtOAc as eluent, gravity column) afforded

pure cis-aziridine 27e as a white solid (mp 145-146 °C on 99.6%

ee material) in 94% isolated yield (519 mg, 0.94 mmol); cis:trans

>50:1. Enamine side products: 1.5% yield of 28e and 1.9% yield

of 29e. The optical purity of 27e was determined to be 99% ee by

HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/

2-propanol at 226 nm, flow rate 0.7 mL/min): retention times t_R=

8.41 min (major enantiomer, 27e) and t_R= 11.96 min (minor

enantiomer, ent-27e). Spectral data for 27e: R_f= 0.32 (1:9

1

EtOAc/hexane). H NMR (CDCl₃, 500 MHz) δ 1.02 (t, 3H,

J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.56 (d, 1H, J = 6.6 Hz),

3.03 (d, 1H, J = 6.8 Hz), 3.62 (s, 3H), 3.66 (s, 1H), 3.68 (s, 3H),

3.89-3.98 (m, 2H), 7.06 (s, 2H), 7.16 (s, 2H), 7.26 (d, 2H, J = 8.5

Hz), 7.35 (d, 2H, J = 8.5 Hz); ¹³C (CDCl₃, 125 MHz) δ 14.1,

16.2, 16.2, 46.4, 47.5, 59.6, 59.6, 60.6, 121.2, 127.4, 127.7, 129.6,

130.7, 130.8, 134.4, 137.6, 137.8, 156.0, 156.2, 167.7 (one sp²and

one sp³carbon not located); IR (thin film) 2942vs, 1745vs,

1485vs, 1221vs cm^-1; HRMS (ESI-TOF) m/z 552.1733 [(M þ

H^þ) calcd for C₃₀H₃₅NO₄⁷⁹Br 552.1749] [R]²³þ12.8 (c 1.0,

D

EtOAc) on 99% ee material (HPLC).

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-(4-nitrophenyl)aziridine-2-carboxylate 27f. Imine 26f (432.5

mg, 1 mmol) was reacted according to the general Method C

described above with (S)-VAPOL as ligand. Purification of the

crude aziridine by silica gel chromatography (35 mm ꢀ 400 mm

column, 5:1 hexanes/EtOAc as eluent, gravity column) afforded

pure cis-aziridine 27f as a white solid (mp 174-175 °C on 99.7%

ee material) in 95% isolated yield (493 mg, 0.95 mmol); cis:trans

>50:1. Enamine side products: 1.2% yield of 28f and 2.0% yield

of 29f. The optical purity of 27f was determined to be 99% ee by

HPLC analysis (CHIRALCEL OD-H column, 99:1 hexane/2-

propanol at 226 nm, flow rate 0.7 mL/min): retention times t_R=

17.12 min (major enantiomer, 27f) and t_R= 27.13 min (minor

enantiomer, ent-27f). Spectral data for 27f: R_f= 0.30 (1:9

1

EtOAc/hexanes). H NMR (CDCl₃, 500 MHz) δ 1.01 (t, 3H,

J = 7.1 Hz), 2.18 (s, 6H), 2.24 (s, 6H), 2.26 (s, 3H), 2.52 (d, 1H,

J = 6.6 Hz), 3.07 (d, 1H, J = 6.8 Hz), 3.62 (s, 3H), 3.64 (s, 1H),

3.68 (s, 3H) 3.93 (dq, 2H, J = 3.2 Hz, 7.1 Hz), 7.02 (d, 2H, J =

7.8 Hz), 7.08 (s, 2H), 7.17 (s, 2H), 7.24 (d, 2H, J = 8.0 Hz); ¹³

C

(CDCl₃, 125 MHz) δ 14.1, 16.2, 16.2, 21.1, 46.2, 48.2, 59.5, 59.6,

60.4, 77.1, 127.4, 127.7, 127.8, 128.4, 130.5, 130.6, 132.3, 136.8,

137.9, 138.0, 155.9, 156.1, 168.1; IR (thin film) 2978vs, 1748s,

1483s, 1221s, 1190vs cm^-1; HRMS (ESI-TOF) m/z 488.2806

[(M þ H^þ) calcd for C₃₁H₃₈NO₄488.2801]; [R]²³_Dþ29.4 (c 1.0,

EtOAc) on 99.8% ee material (HPLC).

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-(4-methoxyphenyl)aziridine-2-carboxylate 27d. Imine 26d (417.5

mg, 1 mmol) was reacted according to the general Method C des-

cribed above with (S)-VAPOL as ligand. Purification of the crude

aziridine by silica gel chromatography (35 mm ꢀ 400 mm column,

9:1 hexanes/EtOAc as eluent, gravity column) afforded pure cis-

aziridine 27d as a white solid (mp 56-57 °C on 98% ee material) in

83% isolated yield (418 mg, 0.83 mmol); cis:trans >50:1. Enamine

side products: 1.2% yield of 28d and 2.1% yield of 29d. The optical

purity of 27d was determined to be 97% ee by HPLC analysis

(CHIRALCEL OD-H column, 99:1 hexane/2-propanol at 226 nm,

flow rate 0.7 mL/min): retention times t_R= 12.07 min (major

enantiomer, 27d) and t_R= 19.20 min (minor enantiomer, ent-27d).

1

EtOAc/hexane). H NMR (CDCl₃, 500 MHz) δ 1.02 (t, 3H,

J = 7.1 Hz), 2.18 (s, 6H), 2.25 (s, 6H), 2.68 (d, 1H, J = 6.8 Hz),

3.15 (d, 1H, J = 6.8 Hz), 3.62 (s, 3H), 3.68 (s, 3H), 3.71 (s, 1H),

3.93 (dq, 2H, J = 2.2, 7.1 Hz), 7.06 (s, 2H), 7.16 (s, 2H), 7.57 (d,

2H, J = 8.8 Hz), 8.10 (d, 2H, J = 8.8 Hz); ¹³C (CDCl₃, 125

MHz) δ 14.1, 16.2, 16.2, 46.8, 47.3, 59.6, 59.6, 60.9, 76.9, 123.0,

127.3, 127.6, 128.8, 130.8, 130.9, 137.3, 137.5, 142.8, 147.3,

156.1, 156.3, 167.2; IR (thin film) 2984 vs, 1745 vs, 1603 s,

1522 vs, 1221 vs cm^-1; HRMS (ESI-TOF) m/z 519.2505 [(M þ

H^þ) calcd for C₃₀H₃₅N₂O₆519.2495] [R]²³_D-4.8 (c 1.0, EtOAc)

on 99.8% ee material (HPLC).

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-cyclohexylaziridine-2-carboxylate 27i. Imine 26i (393.5 mg,

1 mmol) was reacted according to the general Method C described

above with (S)-VAPOL as ligand. Purification of the crude

aziridine by silica gel chromatography (35 mm ꢀ 400 mm

column, 2:1 hexanes/CH₂Cl₂as eluent, gravity column) af-

forded pure cis-aziridine 27i as a white solid (mp 47-49 °C on

91% ee material) in 96% isolated yield (461 mg, 0.96 mmol); cis:

trans 50:1. Enamine side products: not determined. The optical

purity of 27i was determined to be 89% ee by HPLC analysis

(CHIRALCEL OD column, 99:1 hexane/2-propanol at 223 nm,

flow rate 0.7 mL/min): retention times t_R= 10.06 min (major

enantiomer, 27i) and t_R= 12.37 min (minor enantiomer, ent-

27i). Spectral data for 27i: R_f= 0.21 (2:1 hexane/CH₂Cl₂); ¹H

1

Spectral data for 27d: R_f= 0.28 (1:9 EtOAc/hexane). H NMR

(CDCl₃, 500 MHz) δ 1.02 (t, 3H, J = 7.1 Hz), 2.19 (s, 6H), 2.24 (s,

6H), 2.51 (d, 1H, J= 6.8 Hz), 3.06 (d, 1H, J=6.8Hz), 3.63(s, 3H),

3.65 (s, 1H), 3.68 (s, 3H), 3.74 (s, 3H), 3.89-3.99 (m, 2H), 6.77 (d,

2H, J = 9.5 Hz), 7.09 (s, 2H), 7.18 (s, 2H), 7.29 (d, 2H, J = 8.8 Hz);

¹³C(CDCl₃, 125 MHz) δ14.1, 16.2, 16.2, 46.2, 47.9, 55.2, 59.5, 59.6,

60.5, 77.1, 113.2, 127.4, 127.8, 128.9, 130.6, 130.6, 137.8, 138.0,

5656 J. Org. Chem. Vol. 75, No. 16, 2010

Mukherjee et al.

JOCArticle

NMR (CDCl₃, 300 MHz) δ 0.46-0.57 (m, 1H), 0.87-1.19 (m,

4H), 1.21 (t, 3H, J = 7.1 Hz), 1.22-1.32 (m, 2H), 1.40-1.60 (m,

4H), 1.71-1.76 (m, 1H), 2.16 (m, 1H), 2.19 (s, 6H), 2.20 (s, 6H),

3.35 (s, 1H), 3.60 (s, 3H), 3.63 (s, 3H), 4.10-4.25 (m, 2H), 6.95 (s,

2H), 7.10 (s, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 13.9, 15.6, 15.7,

24.9, 25.1, 25.7, 29.7, 30.9, 35.9, 43.0, 51.8, 59.0, 59.1, 60.1, 77.0,

126.9, 128.1, 129.8, 130.0, 137.2, 137.7, 155.3, 155.8, 169.3; IR

Enamine side products: 10% yield of 28k and 0% yield of 29k.

The optical purity of 27k was determined to be 86% ee by HPLC

analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propa-

nol at 226 nm, flow rate 0.7 mL/min): retention times t_R= 9.27

min (major enantiomer, 27k) and t_R= 11.17 min (minor

enantiomer, ent-27k). Spectral data for 27k is given above under

the procedure for Method B (without H₂O).

(thin film) 2928vs, 1744s, 1483s, 1221s, 1181s, 1017 m cm^-1

;

General Procedure for the deprotection of N-MEDAM azir-

idines 27 to give N-H aziridines 12. (2R,3R)-Ethyl 3-phenyla-

ziridine-2-carboxylate 12a. To a 25 mL flame-dried round-

bottom flask filled with argon were added aziridine 27a (237

mg, 0.5 mmol, 99% ee) and anisole (5.4 mL, freshly distilled) at

room temperature. The flask was cooled to 0 °C, and triflic acid

(200 μL, 2.5 mmol) was added. The ice-bath was removed, and

the reaction mixture was stirred for 2 h. The reaction mixture

was quenched by addition of saturated aqueous Na₂CO₃solu-

tion until the pH was greater than 9. After addition of ether (3

mL) and water (1 mL), the organic layer was separated, and the

water layer was extracted with ether (5 mL ꢀ 3). The combined

organic layer was washed with saturated aqueous NaCl solution

(10 mL ꢀ 3) and dried over anhydrous MgSO₄. The ether was

removed by rotary evaporation, and most of the anisole was

removed by high vacuum for a short period of time (∼15 min)

leaving an off-white sticky residue. Exposure to high vacuum for

extended periods results in loss of 12a to sublimation. Purifica-

tion by silica gel chromatography (18 mm ꢀ 230 mm, 1:1 ether/

hexanes as eluent) afforded 12a as a white solid (mp 58-59 °C)

in 95% isolated yield (91 mg, 0.475 mmol). The optical purity of

12a was determined to be 99% ee by HPLC analysis

(CHIRALCEL OD-H column, 98:2 hexane/2-propanol at 228

nm, flow rate 1.0 mL/min): retention times t_R= 3.99 min (major

enantiomer, 12a) and t_R= 3.47 min (minor enantiomer, ent-

mass spectrum m/z (% rel intensity) 479 Mþ (0.7), 283 (100), 268

(25), 253 (12), 237 (7), 210 (7), 195 (9), 141 (8), 95 (10), 67 (16), 55

(10), 41 (16); [R]²³_Dþ107.4 (c 1.0, CH₂Cl₂) on 89% ee material

(HPLC).

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-tert-butylaziridine-2-carboxylate 27j. Imine 26j (367.5 mg,

1 mmol) was reacted according to the general Method C des-

cribed above with (S)-VAPOL as ligand. Purification of the crude

aziridine bysilica gel chromatography(35mmꢀ 400 mm column,

4:2:0.1 hexanes/CH₂Cl₂/ether as eluent, gravity column) afforded

pure cis-aziridine 27j as a semisolid in 93% isolated yield (422 mg,

0.93 mmol); cis:trans 50:1. Enamine side products: not deter-

mined. The optical purity of 27j was determined to be 92% ee by

HPLC analysis (CHIRALCEL OD column, 99:1 hexane/2-pro-

panol at 226 nm, flow rate 1.0 mL/min): retention times t_R= 6.8

min (major enantiomer, 27j) and t_R= 10.55 min (minor enan-

tiomer, ent-27j). Spectral data for 27j: R_f= 0.28 (1:2 hexane/

CH₂Cl₂); ¹H NMR (CDCl₃, 300 MHz) δ 0.72 (s, 9H), 1.29 (t, 3H,

J = 7.1 Hz), 1.70 (d, 1H, J = 7.3 Hz), 2.11 (d, 1H, J = 7.2 Hz),

2.24 (s, 6H), 2.26 (s, 6H), 3.38 (s, 1H), 3.63 (s, 3H), 3.66 (s, 3H),

4.05-4.26 (m, 2H), 7.04 (s, 2H), 7.30 (s, 2H); 13C NMR (CDCl₃,

75 MHz) δ 13.9, 15.8, 16.0, 27.2, 31.4, 43.2, 55.9, 59.2, 59.3, 60.2,

78.2, 127.3, 128.2, 130.0, 137.8, 138.7, 155.5, 156.0, 169.7 (one sp2

carbon not located); IR (thin film) 2953vs, 1747s, 1481s, 1221s,

1181s, 1017 m cm^-1; mass spectrum m/z (% rel intensity) 453 Mþ

(1), 283 (100), 268 (45), 253 (26), 237 (17), 225 (11), 210 (13), 195

(17), 164 (9) 141 (26), 132 (11), 127 (12), 91 (11), 69 (18), 55 (37),

1

12a). Spectral data for 12a: R_f= 0.13 (1:1 Et₂O/hexane); H

NMR (CDCl₃, 300 MHz) δ 0.99 (t, 3H, J = 7.1 Hz), 1.87 (br, s,

1H), 3.00 (d, 1H, J = 6.1 Hz), 3.47 (d, 1H, J = 6.1 Hz),

3.90-4.00 (m, 2H), 7.24-7.33 (m, 5H); ¹³C (CDCl₃, 75 MHz) δ

41 (55); [R]²³þ110.0 (c 1.0, CH₂Cl₂) on 94% ee material

D

13.9, 29.7, 37.1, 61.1, 127.5, 127.6, 128.0, 134.8, 169.0; [R]²³

(HPLC).

D

-12.4 (c 1.0, EtOAc) on 99% ee material (HPLC). These

spectral data match those previously reported for this

compound.^3f

(2R,3R)-Ethyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

3-hexylaziridine-2-carboxylate 27k. To a 25 mL flame-dried

homemade Schlenk flask (see Figure 1 in the Supporting

Information) equipped with a stir bar and flushed with argon

were added (S)-VANOL (16 mg, 0.3 mmol) and B(OPh)₃(35

mg, 0.12 mmol). Meanwhile, to the flask containing imine 26k

(396 mg, 1 mmol, prepared as described above) was added dry

toluene (1.5 mL), and the resultant toluene solution of imine 26k

was then directly transferred from the reaction flask in which it

was prepared to the flask containing the ligand and B(OPh)₃.

The flask that had contained imine 26k was then rinsed with

toluene (0.5 mL), and the rinse was transferred to the flask

containing the ligand and B(OPh)₃under argon flow through

the side arm of the Schlenk flask. The flask was sealed by closing

the Teflon valve and then placed in an 80 °C oil bath for 1 h. The

catalyst mixture was then allowed to cool to room temperature

and opened to argon through the side arm of the Schlenk flask.

To this solution was rapidly added ethyl diazoacetate (EDA) 2

(124 μL, 1.2 mmol) followed by closing the Teflon valve. The

resulting mixture was stirred for 24 h at room temperature. The

reaction was dilluted by addition of hexane (6 mL). The reaction

mixture was then transferred to a 100 mL round-bottom flask.

The reaction flask was rinsed with dichloromethane (5 mL ꢀ 2),

and the rinse was added to the 100 mL round-bottom flask. The

resulting solution was then concentrated in vacuo followed by

exposure to high vacuum (0.05 mmHg) for 5 min to afford the

crude aziridine as a pale yellow semisolid. Purification of the

crude aziridine by silica gel chromatography (35 mm ꢀ 400 mm

column, 4:2:0.1 hexanes/CH₂Cl₂/EtOAc as eluent, gravity

column) afforded pure cis-aziridine 27k as a semisolid in 64%

isolated yield (308 mg, 0.64 mmol); cis:trans not determined.

(2R,3R)-Ethyl 3-(o-tolyl)aziridine-2-carboxylate 12b. Aziri-

dine 27b (244 mg, 0.5 mmol, 99% ee) was reacted according to

the general method described above except that the reaction time

was 1 h. Purification by silica gel chromatography (18 mm ꢀ 230

mm, 1:1 ether/hexanes as eluent) afforded 12b as a white solid

(mp 84.5-85.5 °C) in 97% isolated yield (100 mg, 0.485 mmol).

The optical purity of 12b was determined to be 99% ee by HPLC

analysis (CHIRALCEL OD-H column, 90:10 hexane/2-propa-

nol at 228 nm, flow rate 0.7 mL/min): retention times t_R= 6.4

min (major enantiomer, 12b) and t_R= 5.5 min (minor enantio-

mer, ent-12b). Spectral data for 12b: R_f=0.11 (1:1 Et₂O/

1

hexane); H NMR (CDCl₃, 300 MHz) δ 0.94 (t, 3H, J = 7.1

Hz), 1.72 (br, s, 1H), 2.32 (s, 3H), 3.04 (d, 1H, J = 6.1 Hz), 3.35

(d, 1H, J = 6.1 Hz), 3.92 (q, 2H, J = 7.1 Hz), 7.09-7.17 (m, 3H),

7.23-7.24 (m, 1H); ¹³C (CDCl₃, 75 MHz) δ 13.9, 18.8, 29.7,

36.5, 61.1, 125.5, 127.2, 127.6, 129.5, 133.3, 136.9, 169.3; [R]²³

D

-96.9 (c 1.0, EtOAc) on 99% ee material (HPLC). These spectral

data match those previously reported for this compound.^3f

(2R,3R)-Ethyl 3-(4-bromophenyl)aziridine-2-carboxylate 12e.

Aziridine 27e (276 mg, 0.5 mmol, 99.5% ee) was reacted

according to the general method described above except that

the reaction time was 1 h. Purification by silica gel chromatog-

raphy (18 mm ꢀ 230 mm, 1:1 ether/hexanes as eluent) afforded

12e as a white solid (mp 78.5-79 °C) in 96% isolated yield (130 mg,

0.48 mmol). The optical purity of 12e was determined to be

99.5% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10

hexane/2-propanol at 228 nm, flow rate 0.7 mL/min): retention

times t_R= 8.24 min (major enantiomer, 12e) and t_R= 7.07 min

J. Org. Chem. Vol. 75, No. 16, 2010 5657

Mukherjee et al.

JOCArticle

(minor enantiomer, ent-12e). Spectral data for 12e: R_f= 0.12

(1:1 Et₂O/hexane); ¹H NMR (CDCl₃, 300 MHz) δ 1.02 (t, 3H,

J = 7.1 Hz), 1.67 (br, s, 1H), 3.01 (d, 1H, J = 6.6 Hz), 3.40 (d,

1H, J = 6.4 Hz), 3.93-3.98 (m, 2H), 7.20 (d, 2H, J = 8.5 Hz),

7.41 (d, 2H, J = 8.5 Hz); ¹³C (CDCl₃, 75 MHz) δ 13.9, 37.1, 39.0,

time was 0.5 h, the reaction temperature was 65 °C, and an air

condenser was utilized. Purification by silica gel chromatogra-

phy (18 mm ꢀ 230 mm, 1:1 ether/hexanes as eluent) afforded 12j

as a colorless oil in 88% isolated yield (75 mg, 0.44 mmol). The

optical purity of 12j was determined to be 97% ee by HPLC

analysis (CHIRALCEL OD-H column, 99:1 hexane/2-propa-

nol at 228 nm, flow rate 1.0 mL/min): retention times t_R= 9.95

min (major enantiomer, 12) and t_R= 8.38 min (minor enantio-

mer, ent-12j). Spectral data for 12j: R_f= 0.10 (1:1 Et₂O/hexane);

¹H NMR (CDCl₃, 300 MHz) δ 0.89 (s, 9H), 1.23 (t, 3H, J = 6.9

Hz), 1.48 (br, s, 1H), 2.09 (d, 1H, J = 6.1 Hz), 2.61 (d, 1H, J =

6.6 Hz), 4.04-4.23 (m, 2H); ¹³C (CDCl₃, 75 MHz) δ 14.0, 27.4,

31.5, 35.3, 47.4, 61.0, 170.2; [R]²³_D-23.7 (c 1.0, EtOAc) on 97%

ee material (HPLC). These spectral data match those previously

reported for this compound.^3f

General Procedure for the Aziridination of Diazoacetamides,

Illustrated for Aziridines 31a, 32a, 33a, and 34a. (2R,3R)-1-Benz-

hydryl-N-benzyl-N-methyl-3-phenylaziridine-2-carboxamide 31a.

To a 25 mL flame-dried homemade Schlenk flask (see Supporting

Information) equipped with a stir bar and flushed with argon were

added (S)-VAPOL (54 mg, 0.1 mmol) and B(OPh)₃(87 mg, 0.3

mmol). Under an argon flow through the side arm of the Schlenk

flask, dry CCl₄(2 mL) was added through the top of the Teflon

valve to dissolve the two reagents. The flask was sealed by closing

the Teflon valve and then placed in an 85 °C oil bath for 1 h. After

1 h, a vacuum (0.5 mmHg) was carefully applied by slightly

opening the Teflon valve to remove the volatiles. After the volatiles

were removed completely, a full vacuum was applied and main-

tained for a period of 30 min at a temperature of 85 °C (oil bath).

The flask was then allowed to cool to room temperature and

opened to argon through side arm of the Schlenk flask.

61.1, 121.5, 129.2, 131.0, 133.9, 168.6; [R]²³þ11.92 (c 1.0,

D

EtOAc) on 99.5% ee material (HPLC). These spectral data

match those previously reported for this compound.^3f

(2R,3R)-Ethyl 3-(4-nitrophenyl)aziridine-2-carboxylate 12f.

Aziridine 27f (259 mg, 0.5 mmol, 97% ee) was reacted according

to the general method described above except that the reaction

time was 1 h. Purification by silica gel chromatography (18 mm ꢀ

230 mm, 1:1 ether/hexanes as eluent) afforded 12f as a white

solid (mp 89-90.5 °C) in 97% isolated yield (115 mg, 0.485

mmol). The optical purity of 12f was determined to be 97% ee by

HPLC analysis (CHIRALCEL OD-H column, 90:10 hexane/

2-propanol at 228 nm, flow rate 0.7 mL/min): retention times t_R=

13.75 min (major enantiomer, 12f) and t_R= 11.92 min (minor

enantiomer, ent-12f). Spectral data for 12f: R_f= 0.07 (1:1 Et₂O/

hexane); ¹H NMR (CDCl₃, 300 MHz) δ 1.01 (t, 3H, J = 7.1 Hz),

1.80 (br, s, 1H), 3.13 (d, 1H, J = 6.3 Hz), 3.56 (d, 1H, J = 6.6

Hz), 3.92-3.97 (m, 2H), 7.54 (d, 2H, J = 8.3 Hz), 8.15 (d, 2H,

J = 8.8 Hz); ¹³C (CDCl₃, 75 MHz) δ 13.8, 37.4, 61.1, 122.9,

128.6, 142.6, 147.1, 168.1; [R]²³_D-15.6 (c 1.0, EtOAc) on 97% ee

material (HPLC). These spectral data match those previously

reported for this compound.^3f

(2R,3R)-Ethyl 3-propylaziridine-2-carboxylate 12h. Aziridine

27h (220 mg, 0.5 mmol, 93% ee) was reacted according to the

general method described above except that the reaction time

was 1 h, the reaction temperature was 65 °C, and an air

condenser was utilized. Purification by silica gel chromatogra-

phy (18 mm ꢀ 230 mm, 1:3 ether/pentane as eluent) afforded 12h

as a light yellow liquid in 72% isolated yield (57 mg, 0.36 mmol).

The optical purity of 12h was determined to be 93% ee by HPLC

analysis (CHIRALCEL OD-H column, 98:2 hexane/2-propa-

nol at 222 nm, flow rate 0.7 mL/min): retention times t_R= 5.06

min (major enantiomer, 12h) and t_R= 5.88 min (minor en-

antiomer, ent-12h). The yield of 12h was determined to be 76%

by ¹H NMR analysis of the crude reaction mixture with Ph₃CH

as internal standard. Spectral data for 12h: R_f= 0.13 (1:1 Et₂O/

hexane). ¹H NMR (CDCl₃, 300 MHz) δ 0.79 (t, 3H, J = 7.1 Hz),

1.16 (t, 3H, J = 7.1 Hz), 1.22-1.40 (m, 3H), 1.40-1.50 (m, 2H),

2.04-2.10 (m, 1H), 2.49 (d, 1H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1

Hz); ¹³C (CDCl₃, 75 MHz) δ 13.5, 14.0, 20.7, 29.6, 34.3, 38.3,

61.0, 170.7. These spectral data match those previously reported

for this compound.^3f

(2R,3R)-Ethyl 3-(cyclohexyl)aziridine-2-carboxylate 12i.

Aziridine 27i (240 mg, 0.5 mmol, 99% ee) was reacted according

to the general method described above except that the reaction

time was 0.5 h, the reaction temperature was 65 °C, and an air

condenser was utilized. Purification by silica gel chromatogra-

phy (18 mm ꢀ 230 mm, 1:1 ether/hexanes as eluent) afforded 12i

as a white solid (mp 58-59 °C) in 90% isolated yield (89 mg, 0.45

mmol). The optical purity of 12i was determined to be 99% ee by

HPLC analysis (CHIRALCEL OD-H column, 98:2 hexane/2-

propanol at 228 nm, flow rate 1.0 mL/min): retention times t_R=

3.99 min (major enantiomer, 12i) and t_R= 3.47 min (minor

enantiomer, ent-12i).-Spectral data for 12i: R_f= 0.19 (1:1

Et₂O/hexane); ¹H NMR (CDCl₃, 300 MHz) δ 0.90 (br, s, 1H),

1.09-1.20 (m, 6H), 1.24 (t, 3H, J = 7.1 Hz), 1.43-1.46 (m, 1H),

1.61-1.70 (m, 3H), 1.86-1.92 (m, 2H), 2.60 (d, 1H, J = 6.1 Hz),

4.18 (q, 2H, J = 7.1 Hz); ¹³C (CDCl₃, 75 MHz) δ 14.1, 25.4, 25.4,

26.0, 30.8, 31.6, 34.2, 36.9, 44.0, 61.1, 171.0; [R]²³_D-62.3 (c 1.0,

EtOAc) on 99% ee material (HPLC). These spectral data match

those previously reported for this compound.^3f

To the flask containing the catalyst were first added the

aldimine 1a (271 mg, 1 mmol) and then dry CCl₄(2 mL) under

an argon flow through side arm of the Schlenk flask. The

reaction mixture was stirred for 5 min to give a light orange

solution. To this solution was rapidly added diazoacetamide 30

(200 mg, 1.05 mmol) (see Supporting Information) followed by

closing the Teflon valve. The resulting mixture was stirred for

24 h at room temperature. The reaction was dilluted by addition

of hexane (6 mL). The reaction mixture was then transferred to a

100 mL round-bottom flask. The reaction flask was rinsed with

dichloromethane (5 mL ꢀ 2), and the rinse was added to the

100 mL round-bottom flask. The resulting solution was then

concentrated in vacuo followed by exposure to high vacuum

(0.05 mmHg) for 5 min to afford the crude aziridine as an off-

white solid. Purification of the crude aziridine by silica gel

chromatography (25 mm ꢀ 550 mm column, 5:1 hexanes/

EtOAc as eluent) afforded pure cis-aziridine 31a as a white solid

(mp 179-180 °C on 88% ee material) in 14% isolated yield (61

mg, 0.14 mmol). Only the cis isomer was observed from ¹H

NMR analysis of the crude reaction mixture. Enamine side

products: not determined. The optical purity of 31a was deter-

mined to be 88% ee by HPLC analysis (CHIRALCELL OD-H

column, 95:5 hexane/2-propanol at 225 nm, flow rate 0.7 mL/

min): retention times t_R= 26.44 min (major enantiomer, 31a)

and t_R= 18.30 min (minor enantiomer, ent-31). Compound 31a

appeared as a mixture of two rotamers in the ¹H NMR spectrum

at the room temperature in a 2.5: 1 molar ratio. The ¹H NMR

data given below is for the major rotamer and was extracted

1

from the H NMR spectrum of the mixture. Spectral data for

31a: R_f= 0.15 (1:5 EtOAc/Hexane); H NMR (CDCl₃, 300

1

MHz) (major rotamer) δ 2.72 (s, 3H), 2.81 (d, 1H, J = 6.6 Hz),

3.17 (d, 1H, J = 6.8 Hz), 3.68 (d, 1H, J = 15.1 Hz), 4.01 (s, 1H),

5.02 (d, 1H, J = 14.9 Hz), 6.47 (d, 2H, J = 6.9 Hz), 7.01-7.52

(m, 16H), 7.78 (d, 2H, J = 7.1 Hz); mass spectrum, m/z (% rel

intensity) 432 M^þ(0.06), 284 (5), 265 (100), 194 (7), 181 (9), 167

(2R,3R)-Ethyl 3-(tert-butyl)aziridine-2-carboxylate 12j. Azir-

idine 27j (227 mg, 0.5 mmol, 99% ee) was reacted according to

the general method described above except that the reaction

(72), 152 (31), 188 (30), 91 (100), 77 (18), 65 (18), 42(14); [R]²³

þ71.2 (c 1.0 in CH₂Cl₂) on 88% ee material (HPLC).

D

5658 J. Org. Chem. Vol. 75, No. 16, 2010

Mukherjee et al.

JOCArticle

(2R,3R)-N-Benzyl-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)-

methyl)-N-methyl-3-phenylaziridine-2-carboxamide 32a. To a

25 mL flame-dried homemade Schlenk flask (see Supporting

Information) equipped with a stir bar and flushed with argon

were added (S)-VAPOL (27 mg, 0.05 mmol) and B(OPh)₃

(58 mg, 0.2 mmol). Under an argon flow through the side arm

of the Schlenk flask, dry toluene (2 mL) was added through the

top of the Teflon valve to dissolve the two reagents, and this was

followed by the addition of water (0.9 μL, 0.05 mmol). The flask

was sealed by closing the Teflon valve and then placed in an

80 °C oil bath for 1 h. After 1 h, a vacuum (0.5 mmHg) was

carefully applied by slightly opening the Teflon valve to remove

the volatiles. After the volatiles were removed completely, a full

vacuum was applied and maintained for a period of 30 min at a

temperature of 80 °C (oil bath). The flask was then allowed to

cool to room temperature and opened to argon through side arm

of the Schlenk flask.

temperature in a 3: 1 molar ratio. The ¹H NMR data given below is

for the major rotamer and was extracted from the ¹H NMR

spectrum of the mixture. Spectral data for 33a: R_f= 0.45 (1:3

EtOAc/Hexane); ¹H NMR (CDCl₃, 300 MHz) (major rotamer) δ

2.26 (s, 6H), 2.38 (s, 6H), 2.79 (s, 3H), 2.81 (d, 1H, J = 6.8 Hz), 3.17

(d, 1H, J = 6.8 Hz), 3.80 (d, 1H, J = 14.9 Hz), 3.89 (s, 1H), 5.01 (d,

1H, J = 14.9 Hz), 6.54 (d, 2H, J = 7.3 Hz), 6.82 (s, 1H), 6.92 (s,

1H), 7.09-7.15 (m, 2H), 7.22 (s, 2H), 7.31-7.33 (m, 3H), 7.46 (s,

2H), 7.49-7.51 (m, 3H); ¹³C (CDCl₃, 75 MHz) δ 21.3, 21.4, 33.2,

47.4, 48.0, 50.2, 78.2, 125.3, 126.7, 127.1, 127.4, 128.0, 128.2, 128.5,

128.6, 128.7, 128.8, 135.7, 136.7, 137.57, 137.7, 142.5, 142.8, 165.7;

IR (thin film) 2919s, 1659vs, 1452s, 731s cm^-1; mass spectrum, m/z

(% rel intensity) 488 M^þ(0.04), 340 (5), 265 (100), 239 (10), 223

(75), 208 (33), 193 (62), 178 (15), 120 (22), 91 (100), 65 (16), 42 (25).

Anal. Calcd for C₃₄H₃₆N₂O: C, 83.57; H, 7.43; N, 5.73. Found: C,

83.20; H, 7.90; N, 5.52; [R]²³_Dþ58.3 (c 1.0 in CH₂Cl₂) on 97% ee

material (HPLC).

The rest of the procedure was the same as that followed for

aziridine 31a utilizing imine 8a (278 mg, 0.5 mmol) and diazoa-

cetamide 30 (100 mg, 0.525 mmol) (see Supporting Information)

and toluene (1 mL). Purification of the crude aziridine by silica

gel chromatography (25 mm ꢀ 400 mm column, 1:20:20 EtOAc/

CH₂Cl₂/hexanes as the first eluent to remove a strong UV

absorpting fraction, then change to 1:3 Et₂O/hexanes as the

second eluent) afforded pure cis-aziridine 32a as a white solid

(mp 169-170 °C on 93% ee material) in 40% isolated yield

(145 mg, 0.2 mmol). This reaction went to 42% completion in

24 h. Only the cis isomer was observed from ¹H NMR analysis of

the crude reaction mixture. Enamine side products: not deter-

mined. The optical purity of 32a was determined to be 93% ee by

HPLC analysis (CHIRALCELL OD-H column, 90:10 hexane/

2-propanol at 228 nm, flow rate 0.7 mL/min): retention times

t_R= 9.94 min (major enantiomer, 32a) and t_R= 8.45 min

(minor enantiomer, ent-32a). Compound 32a appeared as a

mixture of two rotamers in the ¹H NMR spectrum at the room

temperature in a 3: 1 molar ratio. The ¹H NMR data given below

is for the major rotamer and was extracted from the ¹H NMR

spectrum of the mixture. Spectral data for 32a: R_f= 0.65 (1:3

EtOAc/hexanes); ¹H NMR (CDCl₃, 300 MHz) (major rotamer)

δ 1.34 (s, 18H), 1.47 (s, 18H), 2.80 (s, 3H), 2.87 (d, 1H, J = 6.8

Hz), 3.16 (d, 1H, J = 6.7 Hz), 3.63 (s, 3H), 3.70 (s, 3H), 3.95 (s,

1H), 3.98 (d, 1H, J = 14.9 Hz), 4.82 (d, 1H, J = 14.9 Hz), 6.57

(d, 2H, J = 7.0 Hz), 7.08-7.13 (m, 3H), 7.30-7.33 (m, 3H), 7.41

(s, 2H), 7.54-7.56 (m, 2H), 7.62 (s, 2H); ¹³C (CDCl₃, 75 MHz) δ

32.0, 32.2, 33.3, 35.7, 35.8, 47.7, 48.2, 50.2, 63.9, 64.0, 77.6,

125.5, 125.8, 126.7, 126.9, 127.2, 127.4, 127.6, 128.1, 128.2,

136.7, 136.8, 137.1, 142.8, 143.0, 158.0, 158.1, 165.7; IR (thin

film) 2961vs, 1663s, 1414s, 1221s cm^-1; mass spectrum, m/z (%

rel intensity) 716 M^þ(0.36), 451 (26), 265 (29), 120 (14), 118 (13),

91 (100), 58 (84), 42 (24); [R]²³_Dþ14.3 (c 1.0 in CH₂Cl₂) on 97%

ee material (HPLC).

(2R,3R)-N-Benzyl-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-

N-methyl-3-phenylaziridine-2-carboxamide 34a. Imine 26a (194

mg, 0.5 mmol) was reacted with diazoacetamide 30 (100 mg,

0.525 mmol) following the procedure used for aziridine 32a

(given above) except that 20 mol % catalyst loading was utilized.

Purification of the crude aziridine by silica gel chromatography

(25 mm ꢀ 400 mm column, 1:20:20 EtOAc/CH₂Cl₂/hexanes as

the first eluent to remove a strong UV absorpting fraction, then

change to 1:2 Et₂O/hexanes as the second eluent) afforded pure

cis-aziridine 34a as a white solid (mp 164-165 °C on 98% ee

material) in 77% isolated yield (213 mg, 0.39 mmol). Only the cis

isomer was observed from ¹H NMR analysis of the crude

reaction mixture. Enamine side products: not determined. The

optical purity of 34a was determined to be 98% ee by HPLC

analysis (CHIRALCELL OD-H column, 90:10 hexane/2-pro-

panol at 222 nm, flow rate 1.0 mL/min): retention times t_R

=

18.80 min (major enantiomer, 34a) and t_R= 13.80 min (minor

enantiomer, ent-34a). The same reaction with 10 mol % of (S)-

VAPOL/B(OPh)₃catalyst went to 68% completion and gave

34a in 60% yield with 96% ee in 24 h. The compound 34a

appeared as a mixture of two rotamers in the ¹H NMR spectrum

at the room temperature in a 3: 1 molar ratio. The ¹H NMR data

given below is for the major rotamer and was extracted from the

¹H NMR spectrum of the mixture. Spectral data for 34a: R_f=

0.28 (1:3 EtOAc/Hexane); ¹H NMR (CDCl₃, 500 MHz) (major

rotamer) δ 2.20 (s, 6H), 2.31 (s, 6H), 2.76 (d, 1H, J = 6.8 Hz),

2.77 (s, 3H), 3.12 (d, 1H, J = 6.8 Hz), 3.65 (s, 3H), 3.72 (s, 3H),

3.78 (s, 1H), 3.79 (d, 1H, J = 14.4 Hz), 4.98 (d, 1H, J = 14.9 Hz),

6.51 (d, 2H, J = 7.2 Hz), 7.05-7.12 (m, 3H), 7.18 (s, 2H),

7.26-7.30 (m, 3H), 7.42 (s, 2H), 7.45-7.47 (m, 2H); ¹³C (CDCl₃,

125 MHz) δ 16.2, 16.2, 33.2, 47.4, 48.1, 50.2, 59.5, 59.6, 77.4,

126.7, 127.2, 127.4, 127.7, 127.7, 127.9, 128.0, 128.1, 128.2,

130.4, 130.5, 135.8, 136.7, 137.9, 138.3, 155.9, 165.8; IR (thin

film) 2928vs, 1659vs, 1483s, 1221s cm^-1; mass spectrum, m/z (%

rel intensity) 548 M^þ(0.05), 400 (7), 283 (100), 265 (33), 253 (9),

120 (11), 91 (100), 43 (11); [R]²³_Dþ51.6 (c 1.0 in CH₂Cl₂) on 98%

ee material (HPLC).

(2R,3R)-N-Benzyl-1-(bis(3,5-dimethylphenyl)methyl)-N-methyl-

3-phenylaziridine-2-carboxamide 33a. Imine 19a (164mg, 0.5mmol)

was reacted with diazoacetamide 30 (100 mg, 0.525 mmol) follow-

ing the procedure used for aziridine 32a (given above). Purification

of the crude aziridine by silica gel chromatography (25 mm ꢀ 400

mm column, 1:20:20 EtOAc/CH₂Cl₂/hexanes as the first eluent to

remove to remove a strong UV absorpting fraction, then change to

1:3 Et₂O/hexanes as the second eluent) afforded pure cis-aziridine

33a as a white solid (mp 168-169 °C on 97% ee material) in 66%

isolated yield (161 mg, 0.33 mmol). Only the cis isomer was observed

from ¹H NMR analysis of the crude reaction mixture. Enamine side

products: not determined. The optical purity of 33a was determined

to be 97% ee by HPLC analysis (CHIRALCELL OD-H column,

90:10 hexane/2-propanol at 228 nm, flow rate 0.7 mL/min): reten-

tion times t_R= 15.84 min (major enantiomer, 33a) and t_R= 11.77

min (minor enantiomer, ent-33a). The compound 33a appeared as a

¹H NMR studies in C₆D₆at 25 and 80 °C. ¹H NMR (C₆D₆, 500

MHz, 25 °C) (major rotamer): δ 2.08 (s, 6H), 2.19 (s, 3H), 2.32 (s,

6H), 2.42 (d, 1H, J = 6.7 Hz), 2.82 (d, 1H, J = 6.7 Hz), 3.15 (s,

3H), 3.30 (s, 3H), 3.48 (d, 1H, J = 15.0 Hz), 3.77 (s, 1H), 5.00 (d,

1H, J = 14.9 Hz), 6.42 (d, 2H, J = 7.8 Hz), 6.93-6.95 (m, 4H),

7.05 (t, 2H, J = 7.9 Hz), 7.41 (s, 2H), 7.52 (d, 2H, J = 7.7 Hz),

7.90 (s, 2H). ¹H NMR (C₆D₆, 500 MHz, 25 °C) (minor rotamer):

δ 2.06 (s, 6H), 2.27 (s, 6H), 2.40 (s, 3H), 2.60 (d, 1H, J = 6.7 Hz),

2.76 (d, 1H, J = 6.6 Hz), 3.14 (s, 3H), 3.25 (s, 3H), 3.68 (s, 1H),

3.86 (d, 1H, J = 16.1 Hz), 4.19 (d, 1H, J = 16.1 Hz), 6.53-6.55

(m, 2H), 6.97-7.00 (m, 4H), 7.10 (t, 2H, J = 7.7 Hz), 7.35 (s,

2H), 7.56 (d, 2H, J = 7.7 Hz), 7.77 (s, 2H). The ¹H NMR

spectrum at 80 °C indicated the presence of one species: ¹H

NMR (C₆D₆, 500 MHz, 80 °C): δ 2.07 (s, 6H), 2.26 (s, 6H), 2.33

1

mixture of two rotamers in the H NMR spectrum at the room

J. Org. Chem. Vol. 75, No. 16, 2010 5659

Mukherjee et al.

JOCArticle

(s, 3H), 2.52 (s, 1H), 2.85 (d, 1H, J = 6.2 Hz), 3.23 (s, 3H), 3.35

(s, 3H), 3.78 (s, 2H), 4.74 (s, 1H), 6.57 (s, 2H), 6.94-6.99 (m,

1H), 6.97-7.01 (m, 1H), 7.06 (t, 2H, J = 7.2 Hz), 7.13 (s, 2H),

7.32 (s, 2H), 7.48 (d, 2H, J = 7.3 Hz), 7.73 (s, 2H).

Supporting Information Available: Procedures for the pre-

paration for the DAM imines 15 and the MEDAM imines 26,

for the syntheses of the DAM aziridines 11 and the diazoace-

tamide 30, and for the data used in Charts II and III, as well

as ¹H and ¹³C NMR spectra for all new compounds. This mate-

rial is available free of charge via the Internet at http://

pubs.acs.org.

Acknowledgment. This work was supported by a grant

from the National Science Foundation (CHE-0750319).

5660 J. Org. Chem. Vol. 75, No. 16, 2010

Article Doi

Seeking passe-partout in the catalytic asymmetric aziridination of imines: Evolving toward substrate generality for a single chemzyme

DOI: 10.1021/jo101160c

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Article abstract of DOI:10.1021/jo101160c

Full text of DOI:10.1021/jo101160c

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