Direct synthesis of aliphatic vinyl aziridines

Article abstract of DOI:10.1016/j.tetlet.2004.01.002

The synthesis of vinyl aziridines, by the reactions of a range of diphenylphosphinyl and p-toluenesulfonyl alkyl aldimines with the ylide derived from S-allyl tetrahydrothiophenium bromide, are reported.

Full text of DOI:10.1016/j.tetlet.2004.01.002

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1589–1591
Direct synthesis of aliphatic vinyl aziridines
Louise G. Arini,a Alex Sinclair,a Peter Szetob and Robert A. Stockmana,*
aSchool of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
Received 18 November 2003; revised 19 December 2003; accepted 5 January 2004
Abstract—The synthesis of vinyl aziridines, by the reactions of a range of diphenylphosphinyl and p-toluenesulfonyl alkyl aldimines
with the ylide derived from S-allyl tetrahydrothiophenium bromide, are reported.
Ó 2004 Elsevier Ltd. All rights reserved.
Vinyl aziridines are increasingly being utilised as useful
building blocks for synthesis. Some recent examples of
the versatility of vinyl aziridines include SN20 ring
opening with organo-cuprates,1 conversion to amino-
methylene cyclopropanes,2 SN2 ring opening to form
amino-alcohols3 and ring expansion to tetrahydropyri-
dines4 and azepines.5
sulfonium salt derived from tetrahydrothiophene and
allyl bromide, are shown in Table 1. The alkyl sulfonyl
imines were sensitive to hydrolysis, and thus were used
immediately, without further purification. Several base/
solvent combinations were tried for the aziridination
reaction,9 with the only successful conditions found to
be deprotonation with butyllithium at low tempera-
ture.10 The s-butyl, cyclohexyl and t-butyl tosylimines
produced the desired product in 58%, 53% and 49%
yields, respectively, after chromatography over silica gel
(Table 1). The n-pentyl vinyl aziridine was formed in
51% yield, but was found to be unstable over a period of
a day. Interestingly the reaction showed a preference for
the formation of trans vinyl aziridines, which is in con-
trast to the findings of Hou and Dai on the aromatic
substrates. Our conditions use much lower tempera-
tures, and thus it is possible that the trans vinyl aziri-
dines are the kinetically favoured products. The use of
other, potentially more easily removed sulfonyl groups,
such as o-nitrobenzenesulfonyl or trimethylsilyl-
ethanesulfonyl gave poor results (<5%), with large
amounts of sulfonamide being isolated. We surmised
that these sulfonyl groups were too electron withdraw-
ing, thus leading to hydrolysis of the imine. The study
was then turned to investigate the use of diphenyl-
phosphinylimines as substrates for the aziridination.
As part of a programme directed at a number of natural
product syntheses, we required a range of N-protected
aliphatic vinyl aziridines. The recent work of Hou and
Dai has shown that aryl aldimines react well with allyl
sulfur ylides to form vinyl aziridines in good yield
(Scheme 1).6 In this paper we report the extension of this
methodology to alkyl derived aldimines.
We initially investigated alkyl sulfonyl imines as sub-
strates. These were synthesised from the corresponding
aldehydes according to the procedure of Chemla et al.7
or in the case of pivaldehyde, the method of Proctor and
MacKay8 was used. The results of our investigations
into the aziridination of alkyl sulfonyl imines, with the
Br
S
NTs
Ts
N
R
Ar
The synthesis of N-diphenylphosphinylimines was car-
ried out by conversion of the aldehyde to the corre-
sponding oxime,11 and subsequent conversion to the
phosphinylimine following the procedure of Boyd
et al.12 Initially, N-diphenylphosphinylpivaldimine was
reacted with the sulfonium salt derived from tetrahy-
drothiophene and allyl bromide with a range of bases
and solvents.9 Optimal conditions were found to be the
use of potassium tert-butoxide in acetonitrile at room
KOH, MeCN
36-96%, up to 3:1 cis/trans
Scheme 1.
Keywords: Aziridine; Ylide; Vinylaziridine.
* Corresponding author. Tel.: +44-1603-593890; fax: +44-1063-5920-
15; e-mail: r.stockman@uea.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.002

1590
L. G. Arini et al. / Tetrahedron Letters 45 (2004) 1589–1591
Table 1
Br
S
1. TsNH2, PhSO2Na
NTs
Ts
N
O
HCO2H, H2O
2. Na2CO3
BuLi, THF, -78 C
˚
2a, 58%, 1:2 cis/trans
1a, 72%
Ts
N
NTs
O
O
1b 76%
2b, 53%, 1:2 cis/trans
NTs
Ts
N
H11C5
H11C5
H11C5
1c, 77%
2c, 51%, 1:2 cis/trans
NTs
Ts
N
O
TsNH2,BF3.Et2O
benzene, reflux
1d, 68%
2d, 49%, 1:4 cis/trans
Br
S
1. NH2OH.HCl,
py, EtOH
Dpp
N
NDpp
O
2. ClPPh2, Et3N,
CH2Cl2, hexanes,
- 40 ˚C
tBuOK, MeCN
3a, 70%
4a, 56%, 1:3 cis/trans
Dpp
N
NDpp
O
O
3b 96%
4b, 52%, 1:3 cis/trans
Dpp
N
NDpp
H11C5
H11C5
H11C5
3c, 96% - used immediately
4c, 4%, 1:1 cis/trans
Dpp
N
O
NDpp
3d, 77%
4d, 42%, 1:3 cis/trans
All imines were used immediately without further purification. All vinyl aziridines were purified by column chromatography, and yields are of fully
purified compounds characterised by 1H and 13C NMR, IR, MS and HRMS.
temperature, giving a yield of 56% with a 3:1 ratio of
trans to cis products.13 These optimised conditions were
then used to convert aldimines 3 to vinyl aziridines 4, as
shown in Table 1. Yields for the transformation were
generally similar to those found with the sulfonyl imines,
ranging from 42% to 56%, with the trans product being
favoured in all cases by a ratio of 3:1 except for the
n-pentyl vinyl aziridine, which gave a 1:1 ratio of the
trans to cis products, which were found to be unstable to
chromatography, resulting in a disappointing yield of
purified product. It should be noted that the N-Dpp
imines are relatively unstable to hydrolysis, and were
therefore used directly, although storage for a short
period in a freezer is possible, except in the case of the
n-pentyl derivative, which is unstable over a period of
hours. The N-Dpp vinyl aziridines were purified by
column chromatography over neutral alumina.
In conclusion, we have found that alkyl tosylimines and
alkyl diphenylphosphinylimines can be transformed into

L. G. Arini et al. / Tetrahedron Letters 45 (2004) 1589–1591
1591
ature and stirred for 24 h. A saturated aqueous solution of
ammonium chloride (30 mL) and ethyl acetate (30 mL)
were added. The organic layer was separated, washed with
brine (30 mL), dried over anhydrous magnesium sulfate,
and evaporated in vacuo. Purification by column chro-
matography over silica gel (eluting with 12:1 hexane/ethyl
acetate) gave p-toluenesulfonyl-2-cyclohexyl-3-vinyl aziri-
dine (0.36 g, 1.17 mmol, 53%) as a colourless oil and as a
2:1 mixture of diastereoisomers (trans and cis aziridines);
N-protected vinyl aziridines in a concise manner. The
moderate yields and diastereoselectivity are partly offset
by the simple procedures and high convergency of this
approach, which should allow a wide variety of vinyl
aziridines to be accessed. Studies on the use of these
vinyl aziridines as synthetic building blocks for natural
product synthesis, and use of chiral sulfinyl imines as
substrates for the ylide aziridination14 are on-going in
these laboratories, and our results will be published in
due course.
m
max(thin film)/cmꢀ1 1327, 1161; 1H NMR (400 MHz;
CDCl3; TMS), d 7.82 (2H, d, J 8), 7.31 (2H, d, J 8), 6.15
(1H, ddd, J 17.2, 10 and 10, trans isomer), 5.62 (1H, ddd,
J 18, 10.4 and 7.5, cis isomer), 5.49 (1H, d, J 17.2, trans
isomer), 5.42 (1H, d, J 17.2, cis isomer), 5.54 (1H, d,
J 10.4, trans isomer), 5.40 (1H, d, J 10.4, cis isomer),
3.36 (1H, dd, J 7.5 and 7.5, cis isomer), 3.12 (1H, dd, J 10
and 4.4, trans isomer), 2.82 (1H, dd, J 8 and 4.4, trans
isomer), 2.62 (1H, dd, J 7.5 and 7.5, cis isomer), 2.44 (3H,
s), 1.70–1.41 and 1.25–0.83 (11H, m); 13C NMR
(100 MHz; CDCl3; TMS), d 136.9 (cis isomer), 132.1
(trans isomer), 131.6, 130.1, 129.4, 127.7, 121.6 (trans
isomer), 121.2 (cis isomer), 53.0 (trans isomer), 51.2
(trans isomer), 50.5 (cis isomer), 45.6 (cis isomer), 39.5 (trans
isomer), 35.7 (cis isomer), 30.3, 29.7, 25.9, 25.5, 25.3, 21.6;
m=z (EI) 306 (M+1, 98%); HRMS: Found: 306.1526.
C17H23NO2S (M+H) Requires 306.1528.
Acknowledgements
The author thanks GlaxoSmithKline for a CASE award
(LGA), and the EPSRC Mass Spectrometry Service at
the University of Wales, Swansea for carrying out high
resolution mass spectra. The author also acknowledges
the use of the EPSRCÕs Chemical Database Service at
Daresbury.15
11. Yang, S. H.; Chang, S. Org. Lett. 2001, 3, 4209.
12. Boyd, D. R.; Malone, J. F.; McGuckin, M. R.; Jennings,
W. B.; Rutherford, M.; Saket, B. M. J. Chem. Soc., Perkin
Trans. 2 1988, 1145.
References and notes
1. Aoyama, H.; Mimura, N.; Ohno, H.; Ishii, K.; Toda, A.;
Tamamura, H.; Otaka, A.; Fujii, N.; Ibuka, T. Tetra-
hedron Lett. 1997, 38, 7383.
2. Harada, S.; Kowase, N.; Tabuchi, N.; Taguchi, T.;
Dobashi, Y.; Dobashi, A.; Hanzawa, Y. Tetrahedron
1998, 54, 753.
13. Typical procedure: To
a
solution of N-cyclo-
hexylmethylenediphenylphosphinamide (0.83 g, 2.66 mmol)
and 1-allyltetrahydrothiophenium bromide (0.82 g,
3.99 mmol, 1.5 equiv) in anhydrous acetonitrile (30 mL)
at room temperature under an atmosphere of argon, was
added potassium tert-butoxide (0.45 g, 3.99 mmol,
1.5 equiv). The reaction mixture was stirred at room
temperature for 24 h, then concentrated in vacuo. Water
(30 mL) and ethyl acetate (30 mL) were added. The
organic layer was separated, washed with brine (30 mL),
dried over anhydrous sodium sulfate and evaporated in
vacuo. Purification by column chromatography over
neutral alumina (eluting with 15:1–1:1 hexane/ethyl ace-
tate) gave 1-diphenylphosphinyl-2-cyclohexyl-3-vinyl aziri-
dine (0.49 g, 1.40 mmol, 52%) as a colourless liquid and as
a 3:1 mixture of diastereoisomers (trans and cis aziridines);
3. Olofson, B.; Khamrai, U.; Somfai, P. Org. Lett. 2000, 2, 4087.
ꢀ
ꢀ
4. Ahman, J.; Jarevang, T.; Somfai, P. J. Org. Chem. 1996,
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€
5. Lindstrom, U. L.; Somfai, P. Chem. Eur. J. 2001, 7, 94.
6. (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.
7. Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75.
8. MacKay, W. R.; Proctor, G. R. J. Chem. Soc., Perkin
Trans. 1 1987, 2435.
max(thin film)/cmꢀ1 1119, 960 (P@O); 1H NMR
9. Other bases/solvents tried include KOH, t-BuOK, NaH,
DBU, KHMDS, acetonitrile, dichloromethane and DMF.
The trans product preference for vinyl aziridine formation
was also noted by Sweeney and co-workers on their
studies of an aza-Darzens type reaction of diphenylphos-
phinyl imines with lithiated allyl bromide in the presence
of zinc chloride: Cantrill, A. A.; Jarvis, A. N.; Osbourn, H.
M. I.; Ouadi, A.; Sweeney, J. B. Synlett 1996, 847; Hou
and Dai also noted a preference for trans vinyl aziridin-
ation using aromatic diphenylphosphinyl imines with
silylated sulfur ylide substrates: Hou, X.-L.; Yang, X.-F.;
Dai, L.-X.; Chen, X.-F. Chem. Commun. 1998, 747.
10. Typical procedure: To a solution of 1-allyl-tetrahydrothio-
phenium bromide (0.45 g, 2.19 mmol, 1 equiv) in anhy-
drous tetrahydrofuran (30 mL) at )78 °C under an
atmosphere of argon, was added n-butyl lithium
(1.05 mL of a 2.5 M solution in hexanes, 2.62 mmol,
1.2 equiv). The reaction mixture was stirred for 30 min,
then re-cooled to )78 °C. A solution of N-cyclohexyl-
methylene-4-methylbenzenesulfonamide (0.58 g, 2.19mmol)
in anhydrous tetrahydrofuran (10 mL) was added and the
reaction mixture was allowed to warm to room temper-
m
(400 MHz; CDCl3; TMS), d 7.94–7.86 and 7.48–7.38
(10H, m), 6.04 (1H, ddd, J 17.2, 10 and 9, trans isomer),
5.78 (1H, ddd, J 16, 10 and 8, cis isomer), 5.39 (1H, dd, J
16 and 1.2, cis isomer), 5.27 (1H, dd, J 10 and 1.2, cis
isomer), 5.21 (1H, dd, J 17.2 and 1.2, trans isomer), 5.02
(1H, dd, J 10 and 1.2, trans isomer), 3.28 (1H, ddd, JH–P
16, J 8 and 7, cis isomer), 3.03 (1H, ddd, JH–P 15.6, J 9 and
3.2, trans isomer), 2.68 (1H, ddd, JH–P 16, J 7.2 and 3.2,
trans isomer), 2.62 (1H, ddd, JH–P 16, J 8 and 7, cis
isomer), 1.70–1.54 and 1.29–0.75 (11H, m); 13C NMR
(100 MHz; CDCl3; TMS), d 136.2 (cis isomer), 135.7 (trans
isomer), 133.1, 131.7, 129.6, 128.2, 120.1 (cis isomer),
119.1 (trans isomer), 48.1 (trans isomer), 46.8 (trans
isomer), 46.0 (cis isomer), 41.5 (cis isomer), 40.3 (trans
isomer), 36.8 (cis isomer), 30.7, 30.3, 26.3, 25.9 and 25.7;
m=z (EI) 352 (M+1, 100%); HRMS: Found: 352.1830
C22H26NOP (M+H) Requires 352.1825.
14. Preliminary communication: Morton, D.; Pearson, D.;
Field, R. A.; Stockman, R. A. Synlett 2003, 1985.
15. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem.
Inf. Comput. Sci. 1996, 36, 746.