Highly efficient asymmetric trans-selective aziridination of diazoacetamides and N-Boc-imines catalyzed by chiral bronsted acids

Article abstract of DOI:10.1021/ol901047w

A clean and fast (10 min) aziridination of diazoacetamides with N-Boc-imines, as well as N-Cbz-imines, catalyzed by chiral phosphoric acid (R)-5g in DCM at room temperature was developed. The excellent yields (89-97%), diastereoselectivities (trans/cis >

Full text of DOI:10.1021/ol901047w

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3036-3039
Highly Efficient Asymmetric
Trans-Selective Aziridination of
Diazoacetamides and N-Boc-imines
Catalyzed by Chiral Brønsted Acids
Xiaofei Zeng, Xin Zeng, Zhenjiang Xu, Min Lu, and Guofu Zhong*
DiVision of Chemistry & Biological Chemistry, School of Physical & Mathematical
Sciences, Nanyang Technological UniVersity, 21 Nanyang link,
Singapore 637371, Singapore
guofu@ntu.edu.sg
Received May 12, 2009
ABSTRACT
A clean and fast (10 min) aziridination of diazoacetamides with N-Boc-imines, as well as N-Cbz-imines, catalyzed by chiral phosphoric acid
(R)-5g in DCM at room temperature was developed. The excellent yields (89-97%), diastereoselectivities (trans/cis > 50:1), chemoselectivities
(3:4 ) >95:5), and enantioselectivities (88-98% ee) were achieved in the reaction.
Chiral aziridines are important intermediates in organic
synthesis as they may be easily converted to optically pure
amines, R-amino acids, amino alcohols, diamines, and a
variety of other amino compounds.1 For instance, the
enantiopure aziridines are the key intermediates in the
synthesis of the cell adhesion inhibitor BIRT-3772,8a and
some important optically pure amino acids (Figure 1).3
Figure 1. Some important compounds derived from chiral aziri-
dines.
(1) (a) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, 2006. (b) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599. (c) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In
ComprehensiVe Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon Press:
Oxford, 1996; Vol. 1A, pp 1-60. (d) Rai, K. M. L.; Hassner, A. In
ComprehensiVe Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon Press:
Oxford, 1996; Vol. 1A, pp 61-96.
(2) (a) Yee, N. K. Org. Lett. 2000, 2, 2781. (b) Kapadia, S. R.; Spero,
D. M.; Eriksson, M. J. Org. Chem. 2001, 66, 1903. (c) Stehle, S.; Nummy,
L.; Yee, N. Tetrahedron: Asymmetry 2001, 12, 101. (d) Stehle, S.; Nummy,
L.; Yee, N. Tetrahedron Lett. 2001, 42, 3231. (e) Yee, N.; Nummy, L. J.;
Frutos, R. P.; Song, J. J.; Napolitano, E.; Byrne, D. P.; Jones, P. J.; Farina,
V. Tetrahedron: Asymmetry 2003, 14, 3495. (f) Chowdari, N. S.; Barbas,
Previous research revealed that most of the optically pure
aziridines were derived from other chiral materials,4 and only
a few methods are available for catalytic asymmetric
aziridination.5 The most reported strategy among them is
the asymmetric nitrogen transfer to alkene catalyzed by
transition-metal catalysis6 or organocatalysis.7 An alternative
C. F., III. Org. Lett. 2005, 7, 867
.
(4) Sweeney, J.; Osborn, H. M. I. Tetrahedron: Asymmetry 1997, 8,
1693.
(3) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099.
10.1021/ol901047w CCC: $40.75
Published on Web 06/17/2009
 2009 American Chemical Society

method is the chiral Lewis or Brønsted acid catalyzed
asymmetric aziridinations of imines and diazoacetyl com-
pounds, which were reported by Wulff et al.,3,8 Maruoka et
al.,9 and Akiyama et al.10 trans- or cis-aziridines can be
obtained by these methodologies in high diastereo- and
enantioselectivities, but the yields and chemoselectivities of
the aziridination reactions of N-Boc-imines and diazoacetyl
compounds still need to be improved. In this context, we
report an (R)-BINOL-derived chiral phosphoric acid cata-
lyzed reaction of N-Boc-imines and diazoacetamides, provid-
ing a highly efficient organocatalytic method for the asym-
metric aziridination in excellent yields and remarkably high
chemo-, enantio-, and trans-selectivities.
Table 1. Aziridination Reaction of Benzaldehyde N-Boc-imine
and N-PMP-diazoactamide Catalyzed by Different Chiral
Phosphoric Acids in Toluenea
Recently, chiral Brønsted acid catalysis has become a
rapidly growing area.11 Chiral BINOL-derived chiral phos-
phoric acids, pioneered by Akiyama et al. and Terada et al.,
have received considerable attention and been applied in a
wide range of asymmetric organic transformations.12,13 In
particular, Terada and co-workers demonstrated that chiral
phosphoric acid is a highly efficient catalyst for the reaction
of N-acylimines and tert-butyl diazoacetate to furnish the
Friedel-Crafts-type adduct with excellent enantioselectiv-
ity.14 We hypothecized that chiral phosphoric acids should
be efficient catalysts for the reaction of N-Boc-imines and
-diazoacetamides with the possibility of improvement in the
yield and chemoselectivity of the aziridination reaction.
To validate this, we started to investigate the reaction of
N-Boc-imines and -diazoacetamides catalyzed by chiral
phosphoric acid catalysts as the model reaction using N-(4-
methoxyphenyl)diazoacetamide and benzaldehyde-derived
N-Boc-imine. In the presence of 5 mol % of catalysts (R)-
5a-g in toluene, a fast, clean, and complete reaction occurred
at room temperature within 10 min, furnishing the aziridi-
nation product 3a in good selectivities, as shown in Table
1. From this survey, we observed that the sterically more
entry
catalyst
time (min)
yieldb (%)
3:4c
eed (%)
1
2
3
4
5
6
7
(R)-5a
(R)-5b
(R)-5c
(S)-5d
(R)-5e
(R)-5f
(R)-5g
10
10
10
10
10
10
10
80
71
81
85
89
90
90
80:20
69:31
82:18
85:15
89:11
88:12
90:10
45
30
56
-65
70
78
80
a Reactions were performed with benzaldehyde N-Boc-imine (0.12
mmol) and N-(4-methoxyphenyl)diazoacetamide (0.05 mmol) in the presence
of 5 mol % of (R)-5 (0.005 mmol) in 1.0 mL of toluene at 23 °C (room
temperature). b Isolated yield. c Determined by 1H NMR analysis of the
crude product. d Determined by chiral HPLC analysis.
hindered phosphoric acids emerged as catalysts with better
yields (81-90%) and diastereo- (trans:cis > 50:1) and
enantioselectivitives (from 56-80%) (Table 1, entries 3 and
5-7). The best result was obtained with (R)-5g as catalyst,
which afforded the trans-selective aziridination product in
excellent yield (90%) diastereoselectivity (trans:cis > 50:1)
and slightly better enantioselectivity (80% ee). However, the
chemoselectivity between 3 and 4 is still unsatisfied (3:4 less
than 90:10).
(5) For a review of methods in aziridination, see: (a) Evans, D. A.; Faul,
M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742. (b) Watson,
I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194.
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Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 2, p 607. (b) Muller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905.
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Ed. 2006, 45, 8005. (b) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.;
Cordova, A. Angew. Chem., Int. Ed. 2007, 46, 778. (c) Wipf, P.; Lyon,
M. A. ARKIVOC 2007, 12, 91. (d) Fabio Pesciaioli, F. V.; Patrizia, G.;
Giorgio, B.; Giuseppe, B.; Andrea, M.; Paolo, M. Angew. Chem., Int. Ed.
2008, 47, 8703.
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see: Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed.
2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356. (c) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int.
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D.W. C. J. Am. Chem. Soc. 2006, 128, 84. (e) Terada, M.; Sorimachi, K.;
Uraguchi, D. Synlett 2006, 133. (f) Terada, M.; Machioka, K.; Sorimachi,
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Chem., Int. Ed. 2006, 45, 4193. (h) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew.
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Chem. Soc. 2006, 128, 13368. (k) Akiyama, T.; Morita, H.; Fuchibe, K.
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Jiang, Y. Z.; Gong, L. Z. Org. Lett. 2006, 8, 6023. (m) Terada, M.;
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A.; You, S.-L. J. Am. Chem. Soc. 2007, 129, 1484. (o) Rowland, G. B.;
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Wanner, M. J.; Haas, R. N. S.; Cuba, K. R.; Maarseveen, J. H.; Hiemstra,
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Org. Lett., Vol. 11, No. 14, 2009
3037

Further examination focused on the investigation of the
solvent effect in the reaction. With 5 mol % of (R)-5g at
room temperature, the reaction proceeded smoothly in all
common solvents such as toluene (80% ee), DCM (86% ee),
CHCl3 (70% ee), and Et2O (85% ee) except MeOH (no
reaction). DCM was then chosen as the optimal solvent, and
the reaction in DCM led to the highest yield (96%),
chemoselectivity (>95:5), and enantioselectivity (86% ee,
Table 2, entry 2). This tendency is in agreement with our
Table 3. Aziridination Reaction of Various N-Boc-imines and
Diazoactamides Catalyzed by 5 mol % of (R)-5g in DCM at rta
entry
Ar
R1
3:4b
yield of 3c (%) eed
1
2
3
Ph
4-FC6H4
4-MeOC6H4 4-MeOC6H4
4-MeOC6H4 >95:5
4-MeOC6H4 >95:5
97 (3a)
91 (3b)
messy
93
94
Table 2. Reaction of Benzaldehyde N-Boc-imine and
N-PMP-dizaoactamide Catalyzed by 5 mol % of (R)-5g in
Different Solventsa
4
5
6
7
8
9
10
11
12
13
14
15
16e
3-MeOC6H4 4-MeOC6H4 >95:5
96 (3c)
90 (3d)
95 (3e)
96 (3f)
91 (3g)
89 (3h)
95 (3i)
95 (3j)
96 (3k)
93 (3l)
94 (3m)
81 (3n)
92 (3o)
96
88
90
90
88
98
92
94
88
92
96
95
96
4-MeC6H4
4-BrC6H4
3-MeC6H4
2-Np
4-BrC6H4
Ph
4-MeOC6H4 >95:5
4-MeOC6H4 >95:5
4-MeOC6H4 >95:5
4-MeOC6H4 >95:5
3,5-ClC6H3
>95:5
>95:5
>95:5
>95:5
Ph
Ph
Ph
2-ClC6H4
4-ClC6H4
concentration time 3 yieldc
3:4d eee (%)
Ph
Ph
2-MeOC6H4 >95:5
3-MeOC6H4 >95:5
entry solvent
(M)
(min)
(%)
1
2
3
4
5
6
7
8
9
10
toluene
DCM
CHCl3
Et2O
MeOH
DCM
DCM
DCM
DCM
DCM
0.1
0.1
0.1
0.1
10
10
30
60
60
10
10
10
10
10
93
96
81
85
90:10
>95:5
85:15
89:11
no reaction
>95:5
>95:5
>95:5
>95:5
>95:5
80
86
70
85
Ph
Ph
3,5-ClC6H3
3,5-ClC6H3
>95:5
>95:5
a Reactions were performed with N-Boc-imine (0.12 mmol) and
diazoacetamide (0.05 mmol) in the presence of 5 mol % of (R)-5g (0.005
mmol) at rt, and all of the reactions finished in 10 min. b Determined by 1H
NMR analysis of the crude product. c Isolated yield. d Determined by chiral
HPLC analysis. e The reaction was carried out on a 1.5 mmol scale.
0.1
0.05
0.025
0.0175
0.0125
0.01
95
96
95
97
96
87
88
90
93
89
4-methoxyphenyl moiety leading to poor conversion (Table
3, entry 3), which is similar to the result reported by
Maruoka.9 We also tried different diazoacetamides with
benzaldehyde N-Boc-imine in the aziridination reaction
(Table 3, entries 9-13). The reaction turned out to be highly
tolerant to arene substitution on the diazoacetamides as all
ortho-, meso-, and para-substituted diazoacetamides gave
excellent results. However, slightly lower enantioselectivities
were obtained for the diazoacetamides with electron-
withdrawing groups (Table 3, entries 11 and 12), despite the
excellent yields and diastereoselectivities that were achieved.
The ee values were obtained by chiral-phase HPLC, and the
absolute configuration of the aziridination products was
a Reactions were performed with benzaldehyde N-Boc-imine (0.12
mmol) and N-(4-methoxyphenyl)diazoacetamide (0.05 mmol) in the presence
of 5 mol % of (R)-5g (0.005 mmol) at rt. b Determined by 1H NMR analysis
of the crude product. c Isolated yield. d Determined by 1H NMR analy-
sis of the crude product. e Determined by chiral HPLC analysis.
earlier observations: halogenated and aromatic solvents often
gave superior selectivities in the chiral phosphoric acid
catalyzed organic reactions. Next, we tested the effect of
reaction concentration in DCM (Table 2). It was observed
that a decrease in reaction concentration in DCM from 0.1
to 0.0125 M caused the enantioselectivities to be increased
from 86% to 93% (entries 6-9). Further reduction of the
concentration to 0.01 M led to slightly lower ee (89%). Thus,
the best result was achieved with 5 mol % of (R)-5g in 0.0125
M DCM solution at room temperature in 10 min.
Having identified the optimized reaction conditions, we
explored the reaction scope with different N-Boc-imines and
-diazoacetamides under optimal conditions to furnish the
aziridination products. Experimental results were summarized
in Table 3. For the N-Boc-imines derived from different
aldehydes, all of the reactions gave excellent yields (90-97%),
diastereoselectivities (all with trans:cis > 50:1), and enan-
tioselectivities (88-96% ee) (Table 3, entries 1, 2, and 4-8)
except for the N-Boc-imine bearing the electron-donating
Scheme 1
. Aziridination Reaction of N-Cbz-imine and
Diazoactamides Catalyzed by 5 mol % of (R)-5g in DCM at rt
(14) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005,
127, 9360.
3038
Org. Lett., Vol. 11, No. 14, 2009

confirmed to be 2R,3S by comparison with the data reported
in the literature.9
aziridination reactions were obtained while the diastereo-
and enantioselectivities were kept at excellent levels.
Further investigations to clarify the reaction mechanism
and other types of imines in this reaction, and its
application to synthesis of other important chiral com-
pounds, are underway.
Furthermore, the N-Cbz-protected imine was also tested
in the aziridination reaction (Scheme 1). The reaction
proceeded well and excellent yields and enantio- and
diastereoselectivities were obtained for benzaldehyde-
derived N-Cbz-imine with N-(4-methoxyphenyl)- and
N-(2-chlorophenyl)diazoacetamides (for 3p, yield 95%, dr
>50:1, ee 97%; for 3q, yield 94%, dr >50:1, ee 94%).
The N-Cbz-protected imine is also thus a perfect substrate
for this transformation.
In conclusion, a highly efficient, clean, and fast aziri-
dination reaction of diazoacetamides and N-Boc-imines,
as well as N-Cbz-imines, catalyzed by chiral phosphoric
acid in DCM at room temperature, was developed. In all
cases, excellent yields and chemoselectivities of the
Acknowledgment. Research support from the MOE in
Singapore (ARC12/07, no. T206B3225) and NTU (URC,
RG53/07) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901047W
Org. Lett., Vol. 11, No. 14, 2009
3039