Trans-selective asymmetric aziridination of diazoacetamides and N-Boc imines catalyzed by axially chiral dicarboxylic acid

Article abstract of DOI:10.1021/ja805635c

Axially chiral dicarboxylic acid (R)-1d catalyzed reaction of diazoacetamides and N-Boc imines provided a novel organocatalytic means for the formation of enantiomerically enriched N-Boc protected trans aziridines. Copyright

Full text of DOI:10.1021/ja805635c

Published on Web 10/11/2008
Trans-Selective Asymmetric Aziridination of Diazoacetamides and N-Boc
Imines Catalyzed by Axially Chiral Dicarboxylic Acid
Takuya Hashimoto, Nanase Uchiyama, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received July 19, 2008; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Scheme 1. Preliminary Investigation of Dicarboxylic-Acid-Catalyzed
Aziridination of Diazoacetamides and N-Boc Imine
Enantiomerically pure aziridines constitute an important class
of chiral synthons, since they can be easily converted to various
types of important building blocks, such as functionalized R- or
ꢀ-amino acid derivatives.1 Hence, catalytic asymmetric aziridina-
tions have drawn attention as a means to access these valuable
compounds in a straightforward manner. One prevailing strategy
for this purpose is the asymmetric nitrogen transfer to alkene by
transition-metal catalysis2 or organocatalysis.3 Another attractive
but less-studied approach to this end is the use of chiral Lewis
acid-catalyzed asymmetric aziridination using imine and diazoac-
etate pioneered by Wulff et al.4-6 It is well-known that this sort of
aziridination including achiral acid catalysis7,8 almost has always
dominantly provided cis aziridine. In this context, we report herein
that axially chiral dicarboxylic acid-catalyzed reaction of N-Boc
imines and diazoacetamides offers a novel organocatalytic way for
the asymmetric aziridination with remarkably high enantioselectivity
and unique trans selectivity, hitherto unattainable using this strategy.
Table 1. Screening of Catalysts (R)-1a
entry
catalyst
solvent
2:3c
2 yieldd (%)
2 eee (%)
1
2
3
4
5
6
7
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1d
(R)-1d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
66:34
79:21
77:23
79:21
65:35
78:22
90:10
15
54
34
70
24
69
61
-19
68
66
92
72
Chiral Brønsted acid catalysis recently introduced a new
paradigm into the acid-catalyzed reaction of imine and diazoacetate.
Terada and co-workers reported that chiral phosphoric acid
facilitated the reaction of N-acyl imines and tert-butyl diazoacetate
to furnish the Friedel-Craft-type adduct with an excellent level of
enantioselectivity (path a).9 We revealed the catalytic activity of
axially chiral dicarboxylic acid (R)-1e in the similar reaction using
N-Boc imines and diazo compounds.10 The mode of these reactions
is considered to involve the hydrogen abstraction of the putative
intermediate A by the basic site of the catalyst as suggested by
Terada. Here, we envisaged that the course of the reaction might
be switched in favor of the formation of aziridine by lowering the
acidity of the R-proton of diazo carbonyls (path b), thereby realizing
unprecedented Brønsted-acid-catalyzed asymmetric aziridination.8
As diazo carbonyl derivatives capable of resisting the hydrogen
abstraction, we chose diazoacetamides in consideration of the lower
acidity of R-proton of amides compared to that of esters. Accord-
ingly, dicarboxylic acid (rac)-1-catalyzed reaction of several
diazoacetamides having different N,N-substituents and benzalde-
hyde N-Boc imine was initially investigated (Scheme 1). Although
the use of N,N-disubstituted diazoacetamides was not found fruitful,
we were encouraged by the result of the reaction using N-
monosubstituted diazoacetamides. Thus, the reaction of N-phenyl-
diazoacetamide with benzaldehyde N-Boc imine provided the
desired aziridine as a major product. Surprisingly, the trans isomer
was formed exclusively, in sharp contrast to the previous acid-
catalyzed aziridination which gives cis aziridine dominantly starting
95
97
toluene
a Reactions were performed with benzaldehyde N-Boc imine (0.10
mmol) and N-phenyldiazoacetamide (0.12 mmol) in the presence of 5
mol % (R)-1 (0.005 mmol). b Determined by 1H NMR analysis of the
crude material. c Determined by 1H NMR analysis of the crude material.
d Isolated yield. e Determined by chiral HPLC analysis.
from diazoacetates and N-aryl or N-alkyl imines.11 The stereo-
chemical relationship was unambiguously established by X-ray
crystallographic analysis (vide infra). Scrutiny of the byproduct led
to confirmation of the major component as the 1,2-aryl shift product
3, whereas a trace amount of 1,2-hydride shift product was also
observed (not shown). The aziridination also proceeded with
N-benzyldiazoacetamide, albeit in diminished yield.
We then set out to investigate the viability of enantiomerically
pure dicarboxylic acid (R)-1 in this novel trans-selective aziridi-
nation as summarized in Table 1. Screening of the reaction with
benzaldehyde N-Boc imine and N-phenyldiazoacetamide in CH2Cl2
using 5 mol % of (R)-1 having 3,3′-diaryl substitutents led to the
identification of 3,3′-dimesityl substituted dicarboxylic acid (R)-
1d as optimal catalyst, giving the trans aziridine exclusively in 70%
yield with 92% ee (entry 4). Further optimization revealed the use
of toluene as solvent of choice (entries 7 vs 6).
The scope of this trans-selective asymmetric aziridination was
then examined using 5 mol % of (R)-1d as summarized in Table
9
14380 J. AM. CHEM. SOC. 2008, 130, 14380–14381
10.1021/ja805635c CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Trans-Selective Asymmetric Aziridinationa
Figure 2. Possible explanation of the observed trans selectivity.
entry
Ar1
Ar2
2:3c
2 yieldd (%)
2 eee (%)
N-Boc imine adopt antiperiplanar orientation. Synclinal orientation
would be destabilized by the steric repulsion (Figure 2).12 The
hydrogen-bonding between amide N-H bond and Boc group might
act as a secondary factor.13
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
4-tolyl
3-tolyl
2-Np
4-MeOC6H4
4-PivOC6H4
3-MeOC6H4
4-FC6H4
3-ClC6H4
Ph
2-Np
4-PivOC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
90:10
73:27
81:19
82:18
56:44
77:23
72:28
72:28
77:23
87:13
88:12
74:26
85:15
81:19
61
51
52
66
<20
49
55
31
50
61
71
57
60
70
97
99
98
99
N.D.
96
96
89
91
97
99
97
97
99
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. T.H. thanks a
Grant-in-Aid for Young Scientists (Start-up) and GCOE program
“Integrated Materials Science” for financial support.
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
2-Np
4-ClC6H4
a Reactions were performed with arylaldehyde N-Boc imine (0.10
mmol) and N-aryldiazoacetamide (0.12 mmol) in the presence of 5 mol
% (R)-1d (0.005 mmol). b Determined by 1H NMR analysis of the crude
material. c Determined by 1H NMR analysis of the crude material.
d Isolated yield. e Determined by chiral HPLC analysis. N.D. ) Not
determined
References
(1) (a) Aziridines and Epoxides in Organic Synthesis, Yudin, A. K., Ed.; Wiley-
VCH: Weinheim, Germany, 2006. (b) Watson, I. D. G.; Yu, L.; Yudin,
A. K. Acc. Chem. Res. 2006, 39, 194.
(2) (a) Jacobsen, E. N. in ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer, Berlin, 1999, Vol. 2, p.
607. (b) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905.
(3) (a) Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y. Angew. Chem., Int. Ed. 2006,
45, 8005. (b) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Co´rdova, A.
Angew. Chem., Int. Ed. 2007, 46, 778.
(4) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099. (b)
Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518. (c)
Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675. (d) Patwardhan, A. P.;
Pulgam, V. R.; Zhang, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2005, 44,
6169. (e) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129,
7185. (f) Zhang, Y.; Desai, A.; Lu, Z.; Hu, G.; Ding, Z.; Wulff, W. D.
Chem.sEur. J. 2008, 14, 3785.
Figure 1. Ortep representation of 2 (Ar1 ) 3-ClC6H4, Ar2 ) Ph) with
elipsoids shown at 50% probability level. Hydrogen atoms are omitted for
clarity.
(5) For other chiral Lewis acid catalyzed reactions, see:(a) Juhl, K.; Hazell,
R. G.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1999, 2293. (b)
Redlich, M.; Hossain, M. M. Tetrahedron Lett. 2004, 45, 8987. (c) Wipf,
P.; Lyon, M. A. ARKIVOC 2007, xii, 91.
2. The reaction of 3- and 4-tolualdehyde N-Boc imine provided
the trans aziridine in moderate yields with high enantioselectivities
(entries 2 and 3). 2-Naphthaldehyde N-Boc imine was converted
to the aziridine in 66% yield with 99% ee (entry 4). Although the
use of N-Boc imine bearing the electron-donating 4-methoxyphenyl
moiety led to poor conversion (entry 5), use of 4-pivaloyloxyben-
zaldehyde N-Boc imine as an alternative gave the aziridine having
4-oxygenated aryl group in 49% yield with 96% ee (entry 6).
3-Methoxybenzaldehyde N-Boc imine could be utilized uneventfully
(entry 7). As for arylaldehyde N-Boc imines bearing electron-
withdrawing group, subsititution at para position led to the
diminished yield regardless of the prolonged reaction time of 8 h
(entry 8). The reaction of 3-chlorobenzaldehyde N-Boc imine was
completed within 5 h, giving the trans aziridine in 50% yield with
91% ee (entry 9). Both electron-donating and withdrawing groups
were tolerated as N-aryl substituents of diazoacetamide in the
reaction with a range of N-Boc imines (entries 10-14).
(6) For asymmetric aziridination with chiral sulfur ylides, see:(a) Aggarwal,
V. K.; Thompson, A.; Jones, R. V. H.; Standen, M. C. H. J. Org. Chem.
1996, 61, 8368. (b) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.;
Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433.
(7) For achiral Lewis acid catalyzed reactions, see:(a) Casarrubios, L.; Pe´rez,
J. A.; Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61, 8358. (b)
Gunnoe, T. B.; White, P. S.; Templeton, J. L.; Casarrubios, L. J. Am. Chem.
Soc. 1997, 119, 3171. (c) Gunnoe, T. B.; Surgan, M.; White, P. S.;
Templeton, J. L.; Casarrubios, L. Organometallics 1997, 16, 4865. (d)
Rasmussen, K. G.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1997,
1287. (e) Rasmussen, K. G.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A.
J. Chem. Soc., Perkin Trans. 2 1998, 1347. (f) Ha, H.-J.; Suh, J.-M.; Kang,
K.-H.; Ahn, Y.-G.; Han, O. Tetrahedron 1998, 54, 851. (g) Nagayama, S.;
Kobayashi, S. Chem. Lett. 1998, 27, 685. (h) Mayer, M. F.; Hossain, M. M.
J. Org. Chem. 1998, 63, 6839. (i) Mayer, M. F.; Wang, Q.; Hossain, M. M.
J. Organomet. Chem. 2001, 630, 78. (j) Xie, W.; Fang, J.; Li, J.; Wang,
P. G. Tetrahedron 1999, 55, 12929. (k) Sengupta, S.; Mondal, S.
Tetrahedron Lett. 2000, 41, 6245. (l) Kubo, T.; Sakaguchi, S.; Ishii, Y.
Chem. Commun. 2000, 625. (m) Akiyama, T.; Ogi, S.; Fuchibe, K.
Tetrahedron Lett. 2003, 44, 4011.
(8) For achiral Brønsted acid catalyzed cis-aziridination using benzhydrylimines,
see: Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612.
Use of benzhydrylimine in our catalytic system led to the poor conversion
and low trans/cis selectivity (∼1:1)
While (R)-1d catalyzed Friedel-Craft-type reaction proceeded
via the attack of diazoacetate from the si-face of N-Boc imines,10
this trans-selective aziridination furnished the compound stemming
from the re-face selective nucleophilic addition of diazoacetamide
(9) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005, 127,
9360.
(10) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054.
(11) Trans/cis ratio was >20/1, as determined by 1H NMR analysis of the crude
material.
as determined by X-ray crystallographic analysis of 2 (Ar1
)
3-ClC6H4, Ar2 ) Ph) (Figure 1). This inverted enantiofacial
selectivity is indicative of the intervention of a different mechanism
as suggested (vide supra).
(12) Diazoacetates having a bulky ester moiety are known to give the trans
aziridine favorably (see ref 7m).
(13) In the aziridination using sulfur ylides and sufonylimines, similar internal
CH-O hydrogen bonding was indicated by a computational study, see:
Robiette, R. J. Org. Chem. 2006, 71, 2726.
We speculated the trans selectivity arises from the preference
of a rotamer wherein the carboxamide group and the aryl group of
JA805635C
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J. AM. CHEM. SOC. VOL. 130, NO. 44, 2008 14381