Synthesis of chiral non-racemic substituted vinyl aziridines

Article abstract of DOI:10.1016/j.tetlet.2008.05.090

Synthesis of a range of chiral non-racemic vinyl aziridines with varying substitutions on the alkene has been achieved by the reaction of (S_S)-tert-butylphenylsulfinimine with a range of ylides derived by deprotonation of substituted allyltetrahydrothiophenium salts. Yields of the substituted vinyl aziridines range from 0% to 90%, with trans:cis ratios between 1:1 and 0:100 and diastereomeric excesses of up to 99%.

Full text of DOI:10.1016/j.tetlet.2008.05.090

Tetrahedron Letters 49 (2008) 4768–4770
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Tetrahedron Letters
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Synthesis of chiral non-racemic substituted vinyl aziridines
Kordi Chigboh a, Daniel Morton a, Alan Nadin b, Robert A. Stockman a,
*
a School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK
b Merck, Sharpe and Dohme, Terlings Park, Harlow CM20 2QR, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of a range of chiral non-racemic vinyl aziridines with varying substitutions on the alkene has
been achieved by the reaction of (SS)-tert-butylphenylsulfinimine with a range of ylides derived by depro-
tonation of substituted allyltetrahydrothiophenium salts. Yields of the substituted vinyl aziridines range
from 0% to 90%, with trans:cis ratios between 1:1 and 0:100 and diastereomeric excesses of up to 99%.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 21 April 2008
Revised 14 May 2008
Accepted 20 May 2008
Available online 24 May 2008
There has been much interest in the synthesis of vinyl aziridines
over the past two decades due to their highly functionalised nature
and versatile reactivity. For example, vinyl aziridines have several
sites at which nucleophiles can attack, and undergo ring-opening
in SN21 and SN202 modes with regioselectivity dictated by judicious
choice of nucleophile. Vinyl aziridines can also be transformed into
a wide range of heterocycles, including b-lactams,3 pyrrolines,4 tet-
rahydropyridines5 and azepines6 (Scheme 1).
Synthetic approaches to vinyl aziridines include nitrenoid addi-
tions to 1,3-dienes,7 conversion of vinyl epoxides,8 reduction or
alkylation of a
–b unsaturated oximes,9 intramolecular SN20 substi-
tutions,10 olefination of oxo-aziridines11 and carbenoid additions
to imines.12 However, since the pioneering work of Hou and Dai
on the addition of ylides to activated imines,13 this approach has
become the most successful and general.14 We have previously
reported on the addition of tetrahydrothiophenium allylide to a
range of activated imines,15 including the chiral tert-butylsulfini-
mines.16 Herein we report on the addition of sulfur allylides which
bear substitution on the alkene17 to
sulfinimine.
a chiral non-racemic
NHTs
Substituted allyl sulfonium salts 1a–f (Table 1) were formed by
reaction of the corresponding allyl halide or tosylate with tetrahy-
drothiophene in dichloromethane for 3–5 days17 (Method A) and,
when necessary, with the addition of 1 equiv of silver tetrafluoro-
borate in order to push the reaction to completion (Method B). We
have previously reported on the addition of allyltetrahydrothi-
ophenium ylide to a range of chiral sulfinimines,16 during which
study we were able to ascertain that lithium tert-butoxide was
the base of choice. In that study, we found that THF as solvent
tended to give the best compromise of stereoselectivity and con-
version, with DMSO giving the best conversion at the expense of
trans:cis selectivity. In this study, we found that this generally re-
mained the case.18 It is very noticeable the effect that substitution
of the alkene has on the rate of reaction of the ylide. In both THF
and DMSO, the unsubstituted ylide 2a reacts with (SS)-tert-butyl-
phenylsulfinimine in 30 min or less in both DMSO and THF. Substi-
tution of the ylide, even with a simple methyl group (2b),
effectively halts the reaction in THF at room temperature, and this
trend is seen across the other substituents also. With the hindered
ylides (2b–d) reaction was only seen in DMSO. The electronically
activated ylide 2e was able to react in THF, albeit significantly
more slowly than in DMSO. The ylide derived from 2e gave excel-
lent trans:cis selectivity and diastereoselectivity. In general, while
MeO2C
R'
NR
R'
Ref. 2
Bu
BuLi
R''
n
O
Me
NR
R'
Fe (CO)
2
MeMgBr
9
Ref. 1
R
N
R'''
R''
R'
Ref. 3
R''
R'
EWG
Pd(0)
LDA
Ph
NH
N
Ts
Ref. 4
H
R'
N
CO2tBu
Me
EWG
Ref. 6
Ref. 5
Scheme 1. Synthetic applications of vinyl aziridines.
* Corresponding author at present address: School of Chemistry, University of
Nottingham, Nottingham NG7 2RD, UK. Tel.: +44 115 9513252; fax: +44 115
9513564.
E-mail address: robert.stockman@nottingham.ac.uk (R. A. Stockman).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.090

K. Chigboh et al. / Tetrahedron Letters 49 (2008) 4768–4770
4769
Table 1
Synthesis of substituted vinyl aziridines
O
S
N
S
O
CH2Cl2, rt
H
R1
S
N
X
R1
R3
(Method A)
S
CH2Cl2,
AgBF4,rt
X
R2
S
R2
R2
t
R3
RT
LiO Bu, solvent,
or
R3
R1
X=Br, OTs or Cl
3a-f
2a-f
1a-f
(Method B)
.
Substrate
Salt formation method
Sulfonium salt
Br
91%15
Aziridine product
Solvent
Time
Yielda
Cis:trans
dr of trans
O
Allyl bromide 1a
A
S
THF
DMSO
30 min
30 min
68%
75%
3:7
1:1
95:5
60:40
S
N
2a
3a
O
Br
94%15
S
N
S
Crotyl bromide 1b
A
B
THF
DMSO
18 h
15 min
Trace
85%
—
1:2
—
60:40
2b
3b
O
O
S
N
BF4
S
S
Cinnamyl Chloride 1c
THF
DMSO
18 h
5 min
Trace
75%
—
2:3
—
51:49
2c
76%15
3c
Br
S
N
Prenyl bromide 1d
A
THF
DMSO
DMSO
24 h
2.5 h
18 h
Trace
39%
66%
—
3:7
3:7
—
68:32
68:32
2d
81%15
3d
O
O
OTs
S
N
TsO
Si
S
S
Si
A
A
THF
DMSO
18 h
3 h
90%
70%
1:12
5:6
100:0
50:50
1e
2e
Si
68%
3e
Br
S
N
Br
THF
DMSO
18 h
1 h
56%
63%
3:7
2:3
100:0
100:0
1f
47%15
3f
2f
a
Yields quoted are of the purified mixtures of diastereomers.
THF always gave better diastereoselectivities, the greater the steric
bulk on the ylide and the closer the bulk is to the sulfur, the higher
the diastereoselectivity became in DMSO, to the point where the 2-
methyl ylide 2f gives excellent levels of diastereoselectivity albeit
with almost no trans:cis selectivity. The assignment of stereo-
chemistry was by analogy with our previous work.16a
Acknowledgements
The authors thank Merck, Sharpe and Dohme and EPSRC for
funding (K.C.).
References and notes
In conclusion, the addition of substituted sulfur allylides to tert-
butylphenylsulfinimine gives a range of substituted chiral vinyl
aziridines in good yields and moderate to excellent selectivities.
Further studies on the exploitation of substituted vinyl aziridines
as building blocks for synthesis are on-going in these laboratories
and will be published in due course.
1. Atkinson, R. S.; Ayscough, A. P.; Gattrell, W. T.; Raynham, T. M. Tetrahedron Lett.
1998, 39, 497.
2. Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875.
3. Ley, S. V.; Middleton, B. Chem. Commun. 1998, 1995.
4. Fugami, K.; Morizawa, Y.; Ishima, K.; Nozaki, H. Tetrahedron Lett. 1985, 26, 857.
5. Ahman, J.; Somfai, P. J. Am. Chem. Soc. 1994, 116, 9781.

4770
K. Chigboh et al. / Tetrahedron Letters 49 (2008) 4768–4770
6. Hassner, A.; Chau, W. Tetrahedron Lett. 1982, 23, 1989.
brine, and was stirred for 10 min. The reaction solution was extracted with
diethyl ether (2 ꢀ 25 mL). The organic residues were then evaporated under
reduced pressure and re-dissolved in 1:1 petroleum ether/diethyl ether and
washed with brine before being dried over anhydrous sodium sulfate and
concentrated under reduced pressure. Purification by column chromatography
over neutral alumina eluting with 1% ethyl acetate/petroleum ether gave the
7. Hudlicky, T.; Seoane, G.; Price, J. D.; Gadamesetti, K. G. Synlett 1990, 433;
Hudlicky, T.; Seoane, G.; Lovelace, T. J. Org. Chem. 1988, 53, 2094; Hudlicky, T.;
Frazier, J. O.; Seoane, G.; Tiedje, M.; Seoane, A.; Kwart, L. D.; Beal, J. E. J. Am.
Chem. Soc. 1986, 108, 3755; Kim, N. S.; Kang, C. H.; Cha, J. K. Tetrahedron Lett.
1994, 35, 3489; Knight, J. G.; Muldowney, M. P. Synlett 1995, 949; Pearson, W.
H.; Celebuski, J. E.; Poon, Y. F.; Dixon, B. R.; Glans, J. H. Tetrahedron Lett. 1986,
27, 6301; Pearson, W. H.; Bergmeier, S. C.; Degan, S.; Lin, K. C.; Poon, Y. F.;
Schkeryantz, J. M.; Williams, J. P. J. Org. Chem. 1990, 55, 5719; Pearson, W. H.;
Bergmeier, S. C.; Williams, J. P. J. Org. Chem. 1992, 57, 3977; Schneiner, P. J. Org.
Chem. 1967, 32, 2628; Schultz, A. G.; Staib, R. R.; Eng, K. K. J. Org. Chem. 1987, 52,
2968.
8. Stogryn, E. L.; Brois, S. J. J. Am. Chem. Soc. 1967, 89, 605; Wipf, P.; Fritch, P. C. J.
Org. Chem. 1994, 59, 4875; Pommlet, J. C.; Chuche, J. Tetrahedron Lett. 1974,
3897.
9. Chaabouni, R.; Laurent, A. Synthesis 1975, 464; Ferrero, L.; Rouillard, M.;
Decouzon, M.; Azzaro, M. Tetrahedron Lett. 1974, 131; Ricart, G. Bull. Soc. Chim.
Fr. 1974, 2607.
products. Aziridine 3a: mp 75–76 °C. ½a D23
ꢂ95 (c 1.0, CHCl3). mmax (thin film)/
ꢁ
cmꢂ1 1601, 1460, 1355, 1080. MS (EI/CI): m/z [M+H] 250 (25%), 228 (100%).
HRMS calcd for C14H20NOS (M+H) 250.1265, found 250.1266. dH (400 MHz;
CDCl3) trans: 7.24 (5H, m), 6.20 (1H, ddd, J 17.0, 10.0, 9.5), 5.39 (1H, d, J 16.9),
5.28 (1H, d, J 10.3), 3.47 (1H, d, J 3.6), 3.09 (1H, dd, J 9.4, 3.6), 1.21 (9H, s). dC
(100 MHz; CDCl3) trans: 130.4, 126.4, 125.6, 124. 5, 119.6, 55.0, 48.1, 36.5,
20.6. Aziridine 3b: ½a D23
ꢁ
ꢂ51 (c 0.8, CHCl3). mmax (thin film)/cmꢂ1 1450, 1070;
MS (EI/CI): m/z 264 [M+H, 100%]. HRMS calcd for C15H22NOS (M+H), 264.1417,
found 264.1418. dH (400 MHz; CDCl3) trans: 7.3–7.2 (5H, m), 5.95 (1H, dq, J
15.2, 6.4), 5.60 (1H, dd, J 15.2, 9.2), 3.64 (1H, d, J 3.6), 3.0 (1H, dd, J 9.2, 3.6), 1.76
(3H, d, J 6.4), 1.14, (9H, s). dC (75 MHz; CDCl3) trans: 135.8, 131.8, 126.6, 125.7,
123.5, 54.9, 48.2, 35.9, 20.6, 15.9. Aziridine 3c: ½a D23
ꢂ25 (c 0.1, CHCl3). mmax
ꢁ
10. Hortmann, A. G.; Koo, J. J. Org. Chem. 1974, 39, 3781; Spears, G. W.; Nakanishi,
K.; Ohfune, Y. Synlett 1991, 91.
11. Lindström, U. M.; Somfai, P. Synthesis 1998, 109.
12. Cantrill, A. A.; Jarvis, A. N.; Osborn, H. M. I.; Ouadi, A.; Sweeney, J. B. Synlett
1996, 847.
(thin film)/cmꢂ1 1430, 1350, 1050. MS (EI/CI): m/z 326 [M+H, 100%]. HRMS
calcd for C20H24NOS (M+H) 326.1573, found 326.1573. dH (400 MHz; CDCl3)
trans: 7.40–7.18 (10H, m), 6.72 (1H, d, J 15.6), 6.30 (1H, dd, J 15.6, 9.2), 3.76
(1H, d, J 3.6), 3.16 (1H, dd, J 9.2, 3.6), 1.21 (9H, s). dC (75 MHz; CDCl3) trans:
136.9, 136.5, 135.5, 128.7, 128.6, 128.0, 127.9, 126.6, 126.4, 125.2, 57.4, 54.7,
13. (a) Li, A.-H.; Dai, L.-X.; Hou, X.-L. Chem. Commun. 1996, 491; (b) Li, A.-H.; Dai,
L.-X.; Hou, X.-L.; Chen, M.-B. J. Org. Chem. 1996, 61, 4641; (c) Wang, D.-K.; Dai,
L.-X.; Hou, X.-L. Chem. Commun. 1997, 1231; (d) Li, A.-H.; Zhou, Y.-G.; Dai, L.-X.;
Hou, X.-L.; Xia, L.-J.; Tang, M.-H. J. Org. Chem. 1998, 63, 4338; (e) Hou, X.-L.;
Yang, X.-F.; Dai, L.-X.; Chenu, X.-F. Chem. Commun. 1998, 747.
14. (a) Zheng, J.-C.; Liao, W.-W.; Sun, X.-X.; Sun, X.-L.; Tang, Y.; Dai, L.-X.; Deng, J-G.
J.-G. Org. Lett. 2005, 7, 5789. and references are cited therein.
15. Arini, L. G.; Sinclair, A.; Szeto, P.; Stockman, R. A. Tetrahedron Lett. 2004, 45,
1589.
16. (a) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Org. Lett. 2004, 6, 2377;
(b) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Chem. Commun. 2006,
1833.
17. Chigboh, K.; Nadin, A.; Stockman, R. A. Synlett 2007, 2879.
18. General procedure for the synthesis of vinyl aziridines: To a solution of sulfonium
salt in DMSO (2 equiv, 0.16 M, 3 mL) under argon was added the imine
(1 equiv), followed by lithium tert-butoxide (2 equiv). Progress of the reaction
was monitored by TLC. Upon complete disappearance of the imine as
monitored by TLC, the reaction was quenched by the addition of ice cold
44.4, 23.1. Aziridine 3d: ½a D23
ꢁ
ꢂ89 (c 0.9, CHCl3). mmax (thin film)/cmꢂ1 1450,
1350, 1100. MS (EI/CI): m/z 278[M+H, 100%]. HRMS calcd for C16H24NOS (M+H)
278.1573, found 278.1571. dH (400 MHz; CDCl3) trans: 7.4–7.2 (5H, m), 5.30
(1H, d, J 8.4), 3.63 (1H, d, J 4.0), 3.16 (1H, dd, J 8.4, 4.0), 1.79, (3H, s), 1.78 (3H, s),
1.21 (9H, s). dC (100 MHz; CDCl3) trans: 142.4, 138.2, 129.6, 128.2, 127.7, 118.1,
57.0, 47.1, 38.4, 26.0, 23.0, 18.2. Aziridine 3e: ½a D23
ꢂ70 (c 0.25, CHCl3). mmax
ꢁ
(thin film)/cmꢂ1 1450, 1350, 1230. MS (EI/CI): m/z 322 [M+H, 15%], 106 (83%),
90 (100%). HRMS calcd for C17H28NOS28Si (M+H) 322.1655, found 322.1658. dH
(360 MHz; CDCl3) trans: 7.40–7.32 (5H, m), 6.40 (1H, dd, J 18.4, 9.0), 6.18, (1H,
d, J 18.4), 3.62 (1H, d, J 3.6), 3.22 (1H, dd, J 9.0, 3.6), 1.32 (9H, s), 0.00 (9H, s). dC
(90 MHz; CDCl3) trans: 141.2, 139.4, 138.5, 130.0, 129.4, 127.8, 58.8, 57.6, 46.3,
24.4, 0.0. Aziridine 3f: ½a D23
ꢁ
ꢂ15 (c 1.35, CHCl3). mmax (thin film)/cmꢂ1 1450,
1360, 1170. MS (EI/CI): m/z 264 [M+H, 28%], 145 (100%). HRMS calcd for
C
15H22NOS (M+H) 264.1417, found 264.1415. dH (400 MHz; CDCl3) trans: 7.33
(5H, m), 5.18 (2H, s), 3.59 (1H, d, J 4.0), 3.18 (1H, d, J 4.0), 1.93 (3H, s), 1.12 (9H,
s). dC (100 MHz; CDCl3) trans: 137.8, 133.5, 127.6, 127.3, 126.9, 115.6, 55.6,
49.5, 44.1, 21.2, 19.0.