Stereoselective aza-Darzens reactions of tert-butanesulfinimines: Convenient access to chiral aziridines

Article abstract of DOI:10.1039/c1ob05561e

Stereoselective synthesis of 2,3-di- and 2,2′,3-tri-substituted aziridines in good yields and excellent diastereoselectivities are achieved through aza-Darzens reactions of a range of tert-butanesulfinyl aldimines and ketimines with ethyl bromoacetate. Th

Full text of DOI:10.1039/c1ob05561e

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Stereoselective aza-Darzens reactions of tert-butanesulfinimines: convenient
access to chiral aziridines†
Toni Moragas Sola´,a Ian Churcher,b William Lewisa and Robert A. Stockman*a
Received 8th April 2011, Accepted 17th May 2011
DOI: 10.1039/c1ob05561e
Stereoselective synthesis of 2,3-di- and 2,2¢,3-tri-substituted
aziridines in good yields and excellent diastereoselectivities
are achieved through aza-Darzens reactions of a range of
tert-butanesulfinyl aldimines and ketimines with ethyl bro-
moacetate.
Scheme 1 Davis’s aza-Darzens reactions of p-tolylsulfinimines.
Synthetic interest in aziridines as potentially versatile interme-
Table 1 Aza-Darzens reaction of tert-butanesulfinyl aldimines
diates has increased over the past decade,1 prompted by the
increasing numbers of methods for the stereoselective synthesis of
chiral functionalised aziridines.2 A number of methodologies have
been developed for the synthesis of chiral aziridines, including
many catalytic asymmetric methods.3 However, one of the sim-
plest methodologies for the stereoselective synthesis of aziridines
Entry R
Time (h) Yielda (%) de (%)a Z/Eb
Product
is the addition of a carbenoid to chiral sulfinimines.4 Sulfin-
imines are simple to synthesise from the commercially available
tert-butanesulfinamide and aldehydes under simple dehydrating
conditions,5 or can be synthesised in a few steps from commodity
chemicals using auxiliary-based methodologies.6 Two main vari-
ants of sulfinimines are commonly used: the p-toluenesulfinimines
developed by Davis and the tert-butanesulfinimines introduced by
Ellman. The p-toluenesulfinimines have the advantage that they
are UV active, and thus enable easy monitoring of the reaction,
whilst the tert-butanesulfinimines generally have been found to
confer a greater degree of stereoselectivity due to their increased
steric bulk.4
1
2
3
4
5
6
7
8
9
Ph
2.75
2
79
81
69
56
55
86
56
66
49
77
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
91 : 9
92 : 8
98 : 2
71 : 29
83 : 17
86 : 14
90 : 10
80 : 20
90 : 10
95 : 5
2a
2b
2c
2d
2e
2f
Cyclohexyl
4-MeOPh
4-NO2Ph
2-Pyridyl
2-Furanyl
Cyclopropyl
n-Octyl
3c
2.5
3d
3c
2
2
2
2.5
2g
2h
2i
Methyl
tert-Butyl
10
2j
a Major isomer. b cis/trans Ratio determined from the 1H NMR of the
crude mixture. c After 2 h solution was allowed to reach r.t. d Solution was
allowed to reach r.t. after imine addition.
As part of a programme aimed at the exploitation of aziridines
as versatile synthetic intermediates for the synthesis of a range
of amino acid derivatives, we required an efficient and concise
access to chiral aziridines bearing an ester at the 2-position. We
were drawn to the reports of Davis on the aza-Darzens reactions
of p-toluenesulfinimines with a-bromoesters (Scheme 1),7 and
wondered if the increased steric bulk of tert-butanesulfinimines
would provide an increase in stereoselectivity. We herein report
our initial findings in this area, the publication of which has been
prompted by Njardarson’s recent report of similar work on the
synthesis of vinyl aziridines.8
We first thought to look at the synthesis of 1,2-disubstituted
aziridines through the reaction of sulfinyl aldimines with ethyl-
bromoacetate under basic conditions. The tert-butanesulfinimines
were synthesised by Ellman’s protocol,5 using commercially pur-
chased tert-butanesulfinamide. The results of our investigation
into the scope of the aza-Darzens reaction of sulfinylaldimines is
summarised in Table 1.
We found that in all cases, good Z : E ratios (4 : 1 to 19 : 1)
and outstanding diastereoselectivities were achieved (judged by 1H
NMR of the crude reaction product). This compares favourably
with the p-toluenesulfinimines which gave diastereoselectivities in
the range of 52–98%, and Z : E ratios in the range 2 : 1 to 11 : 1,7
confirming our hypothesis that the tert-butanesulfinimines would
confer a greater sense of stereocontrol. We were fortunate that
several of the products were crystalline, and thus we obtained
an X-ray crystallographic analysis of 2c to confirm the absolute
stereochemistry (Fig. 1). Yields in general were good, with the
aSchool of Chemistry, University of Nottingham, Nottingham, UK, NG7
2RD. E-mail: robert.stockman@nottingham.ac.uk; Fax: +44 (0) 115
953564; Tel: +44 (0) 115 9513252
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, UK, SG1 2NY
† Electronic supplementary information (ESI) available: Experimental
procedures for the synthesis of aziridines. See DOI: 10.1039/c1ob05561e
5034 | Org. Biomol. Chem., 2011, 9, 5034–5035
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Table 2 Aziridination of tert-butanesulfinyl ketimines
The bulky cyclohexylketimine, 3h, was found not to react, showing
the limitations of the method. The two cyclic ketimines were
also relatively poor substrates, again presumably due to steric
hindrance.
Conclusions
In conclusion we have found that the aza-Darzens reaction of
tert-butanesulfinyl aldimines and ketimines is a reliable and stere-
oselective method for the synthesis of 2,3-disubstituted and 2,2¢,3-
trisubstituted aziridines. Our investigations into the synthesis of
even more highly substituted aziridines using this method, and the
use of these as chiral building-blocks for synthesis are on-going
and will be reported in due course.
Entry R, R¢
Time (h) Yielda (%) dea (%) Z/Eb
Product
1
2
3
4
5
6
7
Ph, Ph
2
95
36
23
65
43
50
—
96
76
—
—
—
1a
1b
1c
-(CH2)5-
-(CH2)6-
Ph, Me
3.5c
4c
62
2.5d
>98
>98
>98
—
85 : 15 1d
93 : 7 1e
71 : 29 1f
2-thiophene, Et 5c
Heptyl, Me
3
Cyclohexyl, Et 6c
—
—
a Major isomer. b cis/trans Ratio determined from the 1H NMR of the
crude mixture. c Reaction at r.t. d Solution was allowed to reach r.t. after
2.5 h.
Notes and references
1 For reviews on the area of the use of aziridines in synthesis, see: C.
Schneider, Angew. Chem., Int. Ed., 2009, 48, 2082–2084; C. A. Olsen,
H. Franzyk and J. W. Jaroszewski, Eur. J. Org. Chem., 2007, 1717–1724;
D. M. Hodgson, P. G. Humphreys and S. R. Hughes, Pure Appl. Chem.,
2007, 79, 269–279; M. Pineschi, Eur. J. Org. Chem., 2006, 4979–4988; H.
Ohno, in Aziridines and Epoxides in Organic Synthesis, ed. A. K. Yudin,
Wiley-VCH, Weinheim, 2006, pp. 37–72; X. E. Hu, Tetrahedron, 2004,
60, 2701–2743.
2 J. B. Sweeney, in Compounds with One Saturated Carbon-Heteroatom
Bond. Amines and Ammonium Salts, ed. D. Enders, Georg Thieme Verlag,
Stuttgart-New York, 2008, pp. 643–772.
3 For reviews on the synthesis of aziridines see: J. Sweeney, Eur. J. Org.
Chem., 2009, 4911–4919; G. S. Singh, M. D’Hooghe and N. De Kimpe,
Chem. Rev., 2007, 107, 2080–2135; I. D. G. Watson, L. L. Yu and A.
K. Yudin, Acc. Chem. Res., 2006, 39, 194–206; X. L. Hou, J. Wu, R. H.
Fan, C. H. Ding, Z. B. Luo and L. X. Dai, Synlett, 2006, 181–193; V. K.
Aggarwal, D. M. Badine and V. A. Moorthie, in Aziridines and Epoxides
in Organic Synthesis, ed. A. K. Yudin, Wiley-VCH, Weinheim, 2006, pp.
1–36; J. B. Sweeney, Chem. Soc. Rev., 2002, 31, 247–258.
4 For reviews on sulfinimine chemistry see: (a) M. T. Robak, M. A.
Herbage and J. A. Ellman, Chem. Rev., 2010, 110, 3600–3740; (b) F.
Ferreira, C. Botuha, F. Chemla and A. Pe´rez-Luna, Chem. Soc. Rev.,
2009, 38, 1162–1186; (c) D. Morton and R. A. Stockman, Tetrahedron,
2006, 62, 8869–8905; (d) F. A. Davis, J. Org. Chem., 2006, 71, 8993–
9003; (e) C. H. Senanayake, D. Krishnamurthy, Z.-H. Lu, Z. Hou and
I. Gallou, Aldrichim. Acta, 2005, 38, 93–104; (f) P. Zhou, B.-C. Chen
and F. A. Davis, Tetrahedron, 2004, 60, 8003–8030; (g) J. A. Ellman, T.
D. Owens and T. P. Tang, Acc. Chem. Res., 2002, 35, 984–995; (h) F. A.
Davis, P. Zhou and B.-C. Chen, Chem. Soc. Rev., 1998, 27, 13–18.
5 G. Liu, D. A. Coogan and J. A. Ellman, J. Am. Chem. Soc., 1997, 119,
9913–9914.
Fig. 1 X-Ray structure of 2c.
more sterically encumbered substrates giving the best yields. We
found no examples that failed to give the expected aziridine
product. The major product in each case was the cis aziridine, in
line with Davis’s findings on the p-toluenesulfinimines, suggesting
that the closed-transition state model put forward by Davis is
operating in these examples (Fig. 2).7
6 C. Roe, H. Hobbs and R. A. Stockman, Chem.–Eur. J., 2011, 17, 2704–
2708; L. Sasraku-Neequaye, D. MacPherson and R. A. Stockman,
Tetrahedron Lett., 2008, 49, 1129–1132; Z. Han, D. Krishnamurthy,
P. Grover, Q. K. Fang, X. Su, H. S. Wilkinson, Z. H. Lu, D. Magiera
and C. H. Senanayake, Tetrahedron, 2005, 61, 6386–6408; Z. Han, D.
Krishnamurthy, P. Grover, H. S. Wilkinson, Q. K. Fang, X. Su, Z.-H.
Lu, D. Magiera and C. H. Senanayake, Angew. Chem. Int. Ed., 2003,
115, 2078–2081; Z. Han, D. Krishnamurthy, P. Grover, Q. K. Fang, D.
Pflum and C. H. Senanayake, Tetrahedron Lett., 2003, 44, 4195–4197; Z.
Han, D. Krishnamurthy, P. Grover, Q. K. Fang and C. H. Senanayake,
J. Am. Chem. Soc., 2002, 124, 7880–7881; Z. Han, D. Krishnamurthy,
D. Pflum, P. Grover, S. A. Wald and C. H. Senanayake, Org. Lett., 2002,
4, 4025–4028.
Fig. 2 Closed transition state.
We next decided to look at a class of substrates not investigated
by Davis: sulfinylketimines. These substrates should yield trisub-
stituted aziridines, and we were keen to discover if the decreased
reactivity of ketimines vs. aldimines would be tolerated. Our results
are summarised in Table 2.
Once again, we were pleased to find that most substrates
prepared gave aziridines in high diastereoselectivity. Yields were
predictably lower than for the aldimines substrates, due to
increased steric interactions and lower reactivity of the ketimines.
7 F. A. Davis, H. Liu, P. Zhou, T. Fang, G. V. Reddy and Y. Zhang, J. Org.
Chem., 1999, 64, 7559–7567.
8 M. Brichacek, M. N. Villalobos, A. Plichta and J. T. Njardarson, Org.
Lett., 2011, 13, 1110–1113.
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