Corey-Chaykovsky Reaction of Chiral Sulfinyl Imines: A Convenient Procedure for the Formation of Chiral Aziridines

Article abstract of DOI:10.1055/s-2003-42028

The reaction of dimethylsulfonium methylide with a range of aromatic, heterocyclic and aliphatic tert-butylsulfinyl imines is presented. Aziridines were formed in 63-84% yield and 77-95% diastereomeric excess.

Full text of DOI:10.1055/s-2003-42028

LETTER
1985
Corey–Chaykovsky Reaction of Chiral Sulfinyl Imines: A Convenient
Procedure for the Formation of Chiral Aziridines
Ylide
A
zirination o
a
f
Chiral Su
n
lfinyl Imine
s
iel Morton,a David Pearson,b Robert A. Field,a Robert A. Stockman*a
a
School of Chemical Sciences and Pharmacy, University of East Anglia, , Norwich. NR4 7TJ, UK
Fax +44(1603)592003; E-mail: r.stockman@uea.ac.uk; E-mail: r.a.field@uea.ac.uk
b
Millennium Pharmaceuticals, Granta Park, Great Abington, Cambridge, CB1 6ET, UK
Received 6 June 2003
yield and 50–70% diastereomeric excess. Garcia-Ruano
reported on the use of p-toluenesulfinyl and tert-butyl
sulfinyl imines, derived from benzaldehyde and cinnam-
aldehyde, with both dimethyloxosulfinium methylide and
dimethylsulfonium methylide reactants. The best results
obtained were for the tert-butylsulfinyl imines, with
yields of 72% (70% de) and 72% (64% de) for the
benzaldehyde and cinnamaldehyde derived substrates
respectively, on reaction with dimethylsulfonium
methylide. Herein we report our findings on the scope of
this reaction, using chiral tert-butylsulfinyl imines
derived from a range of aromatic and aliphatic aldehydes.
Abstract: The reaction of dimethylsulfonium methylide with a
range of aromatic, heterocyclic and aliphatic tert-butylsulfinyl
imines is presented. Aziridines were formed in 63–84% yield and
77–95% diastereomeric excess.
Key words: aziridine, ylide, sulfinyl imine, Corey–Chaykovsky,
imine
As part of a programme directed at the exploitation of
aziridines as versatile synthetic intermediates in total
synthesis, we wished to synthesise a range of chiral non-
racemic aziridines. We were drawn to the reports by
Garcia-Ruano1 and Davis2 of the use of chiral sulfinyl
imines to direct a Corey–Chaykovsky3 type ylide
aziridination. Davis’ report studied the addition of
dimethyloxosulfonium methylide with p-toluenesulfinyl
imines, derived from benzaldehyde, 1-napthaldehyde and
butanal, and found that the best conditions gave 51–68%
Initially, we investigated the aziridination of benzyl and
cinnamyl tert-butylsulfinyl imines, as these had
previously been studied (Table 1). These sulfinyl imines
were formed using Ellman’s procedure.4 The best
conditions for the reaction of these imines with
trimethylsulfonium iodide were found to be sodium
Table 1 Reaction of Benzaldehyde and Cinnamaldehyde Sulfinyl Imines with Dimethylsulfonium Methylide under a Range of Conditionsa
O
O
Me3S+I-
S
S
N
N
Base, solvent, temp., time
2a : R = Ph
2b : R = CH=CHPh
1a : R = Ph
1b : R = CH=CHPh
R
R
Entry
Substrate
Solvent
Base
Temp (°C)
Time (hours)
Yield
De
1
2
3
4
DMSO
MeCN
THF
NaH
NaH
n-BuLi
n-BuLi
20
20
–20
–78
5
14
24
28
84%
0%b
56%
30%
86%
–
85%
79%
O
S
N
THF
Ph
Ph
5
6
7
8
DMSO
MeCN
THF
NaH
NaH
n-BuLi
n-BuLi
20
20
20
4
96
6
75%
60%
20%
55%
91%
77%
61%
70%
O
S
N
THF
–20
48
a In all reactions three equivalents of trimethylsulfonium iodide and base were used. Diastereomeric excess was determined by 1H NMR of the
crude reaction mixture. Yields quoted are of isolated pure products.
b Complex mixture of products.
SYNLETT 2003, No. 13, pp 1985–1988
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42028; Art ID: D13203ST.pdf
© Georg Thieme Verlag Stuttgart · New York

1986
D. Morton et al.
LETTER
hydride in anhydrous DMSO (entries 1 and 5), which gave The stereochemistry of the reaction appears to be
good yields and excellent diastereoselectivities. Use of controlled on steric grounds, with the more open Re-face
acetonitrile as a solvent gave a complex mixture of being attacked. The use of more polar solvents would
products with the benzaldimine, although results for stabilise the betaine intermediate, and thus favour kinetic
cinnimaldimine were fair. Use of butyl lithium in THF, as products, and this is borne out in the diastereoselectivities.
favoured by Davis2 for dimethyloxosulfonium methylide,
Having established that the use of sodium hydride in
was found to give lower yields and diastereoselectivities
DMSO gave the best yields and diastereoselectivities, we
with the dimethylsulfonium methylide employed in our
turned our attention to the scope of the reaction. Table 2
studies.
shows the results of the formation and aziridination of a
The stereochemistry generated at the aziridine C(2) was range of sulfinyl imines derived from aromatic and
confirmed as (S) by comparison of the optical rotation of aliphatic aldehydes.5 The sulfinyl imines were
2a, [a]D20 +298 (c 0.88, CHCl3), with the literature value synthesised from the aldehydes and (R)-tert-
20
of it’s enantiomer1b {[a]D –320 (c 0.5, CHCl3)}. An X- butylsulfinamide using either anhydrous copper sulfate in
ray crystal structure (Figure 1) of the major (RS, 2S) dichloromethane at 20 °C (Method A) or titanium(IV)
diastereomer of 2b obtained in entry 5, Table 1, also ethoxide in THF at 0 °C (Method B).
confirms this assignment.
The aziridination of the sulfinyl imines proceeded in gen-
erally good yields (63–77%).6 The two aliphatic sulfinyl
Table 2 Sulfinyl Imine Formation and Subsequent Aziridine Formation of a Range of Aldehydesa
O
S
O
Me3S+I–
H2N
O
O
S
S
N
N
NaH, DMSO, 20 °C, time
R
Method A or B
R
R
Entry
1
Substrate
Imine Formation
Method A
Yield of Imine
85%
Time (h) for
Aziridination
Yield of Aziridine de of Aziridine
3
65%
87%
O
MeO
2
3
Method A
Method B
72%
82%
3
5
77%
74%
90%
77%
O
O
N
N
4
5
Method B
Method B
78%
85%
4
72%
63%
91%
O
O
O
10
>95%
6
Method B
68%
6
65%
80%
O
a Method A: 3 equiv CuSO4, CH2Cl2, r.t., 18 h. Method B: 1.5 equiv Ti(OEt)4, 0 °C to r.t., 6 h. In all aziridination reactions 3.0 equivalents of
trimethylsulfonium iodide and sodium hydride were used. Diastereomeric excess was determined by 1H NMR of the crude reaction mixture.
Yields quoted are of isolated pure products.
Synlett 2003, No. 13, 1985–1988 © Thieme Stuttgart · New York

LETTER
Ylide Azirination of Chiral Sulfinyl Imines
1987
(5) Representative Procedure as follows: To a solution of pre-
washed sodium hydride, (pentane, 3 equiv, 60% in mineral
oil), in DMSO, dry, (3 mL), was added trimethylsulfonium
iodide, (3 equiv). This was stirred at ambient temperature
under argon, and stirred for 10 min, until the cloudy mixture
went clear. At this point a solution of sulfinylimine, (1
equiv), in dry DMSO, (2 mL), was added dropwise to the
mixture. The reaction was then stirred at r.t. and the progress
monitored by thin layer chromatography. Once complete,
ice-cold brine (3 mL) was added, and the reaction stirred for
5 min. The resulting mixture was filtered through a pad of
celite, and the solution extracted with EtOAc (5 × 20 mL),
and concentrated under reduced pressure. The residue was
partitioned between 1:1 hexanes–Et2O and H2O, and the
organic fraction dried over Na2SO4, and concentrated under
reduced pressure. Purification by column chromatography
on alumina (Brockmann grade 3) eluting with hexanes–
EtOAc gave the products.
imines gave slightly decreased yields, which may be at-
tributable to their ability to enolise under the basic
reaction conditions. The increased steric bulk of the cy-
clohexyl imine is probably responsible for the higher
selectivity in this case (Table 2, entry 5).
In conclusion, the tert-butylsulfinyl group is a successful
acivating group/directing group for the synthesis of aziri-
dines from imines. Electron rich, electron poor, sterically
hindered and primary alkyl imines are all successful
substrates. Reports of our findings on the conversion of
these aziridines into functionalised heterocyclic scaffolds
will be reported in due course.
(6) Data for aziridines: N-[tert-Butyl-(R)-sulfinyl]-2-(S)-
phenylaziridine: [a]D20 +298 (c 0.88, CHCl3). IR: 1080,
2330, 2350, 2923 cm–1. MS: m/z (%) = [M + H ] 224.1(5),
104.0(100). HRMS: Calcd for C12H17NOS [M + H]
224.1109. Found: 224.1111. 1H NMR (400 MHz, CDCl3):
d = 1.18 (s, 9 H), 2.18 (d, 1 H, J = 3.6 Hz), 2.46 (d, 1 H,
J = 6.8 Hz), 3.61 (dd, 1 H, J = 3.6, 6.8 Hz), 7.30 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 22.9, 31.5, 31.9, 57.0,
126.9, 128.0, 128.8, 137.2. N-[tert-Butyl-(R)-sulfinyl]-2-
(S)-(2¢-phenylvinyl)-aziridine: [a]D20 +185 (c 0.5, CHCl3).
IR: 1070, 2360, 2918 cm–1. MS: m/z (%) = [M + H]
250.0(42), 96.1(100). HRMS: Calcd for C14H19NOS [M +
H]: 250.1256. Found: 250.1263. 1H NMR (400 MHz,
CDCl3): d = 1.18 (s, 9 H), 2.17 (broad, 1 H), 2.35 (d, 1 H,
J = 9.0 Hz), 3.20–3.30 (m, 1 H), 5.80–6.00 (dd, 1 H,
J = 11.4, 21.2 Hz), 6.80 (d, 1 H, J = 21.2 Hz), 7.30 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 22.1, 29.9, 35.0, 57.2,
126.6, 128.2, 128.9, 136.5. N-[tert-Butyl-(R)-sulfinyl]-2-
(S)-(4¢-methoxyphenyl)-aziridine: [a]D20 +68 (c 0.5,
CHCl3). IR, 2924, 1516, 1449, 1250, 1086 cm–1. MS: m/z
(%) = [M + H] 254.2(82), 149.2(100). HRMS: Calcd for
C13H19NO2S [M + H]: 254.1209. Found: 254.1209. 1H NMR
(400 MHz, CDCl3): d = 1.20 (s, 9 H), 2.08 (d, 1 H, J = 4 Hz),
2.36 (d, 1 H, J = 6.8 Hz), 3.50 (dd, 1 H, J = 4.0, 6.8 Hz), 3.74
(s, 3 H), 6.80 (s, 2 H), 7.12 (s, 2 H). 13C NMr (101 MHz,
CDCl3): d = 23.1, 31.4, 31.9, 55.5, 57.1, 114.2, 114.3, 128.0.
N-[tert-Butyl-(R)-sulfinyl]-2-(S)-(2¢-pyridyl)-aziridine:
[a]D20 +102 (c 1, CHCl3). IR: 1080, 1450, 1475, 2923 cm–1.
MS: m/z (%) = [M + H] 225.0(100). HRMS: Calcd for
C11H16N2OS: 225.1056. Found: 225.1058. 1H NMR (400
MHz, CDCl3): d = 1.18 (s, 9 H), 2.417 (d, 1 H, J = 6.8 Hz),
2.443 (d, 1 H, J = 4.0 Hz), 3.70 (dd, 1 H, J = 4.0, 6.8 Hz),
7.14 (dd, 1 H, J = 4.8, 7.6 Hz), 7.22 (d, 1 H, J = 8.0 Hz), 7.60
(dd, 1 H, J = 7.6, 8.0 Hz), 8.52 (d, 1 H, J = 4.8 Hz). 13C NMR
(75 MHz, CDCl3): d = 21.9, 28.7, 29.4, 56.1, 121.1, 121.9,
135.8, 149.1, 155.5. N-[tert-Butyl-(R)-sulfinyl]-2-(S)-(3¢-
pyridyl)-aziridine: [a]D20 +116 (c 1, CHCl3). IR: 1078,
1455, 1585, 2910 cm–1. MS: m/z (%) = [M + H] 225.1(4),
106.1(100). HRMS: Calcd for C11H16N2OS [M + H]:
225.1061. Found: 225.1061. 1H NMR (400 MHz, CDCl3):
d = 1.18 (s, 9 H), 2.23 (d, 1 H, J = 4.0 Hz), 2.52 (d, 1 H,
J = 6.8 Hz), 3.66 (1 H, J = 4.0, 6.8 Hz), 7.32 (m, 1 H), 7.58
(m, 1 H), 8.60 (broad, 2 H). 13C NMR (75 MHz, CDCl3):
d = 23.0, 29.5, 32.1, 57.2, 134.2, 148.9, 149.4. N-[tert-
Butyl-(R)-sulfinyl]-2-(S)-(2¢-furyl)-aziridine: [a]D20 +66
(c 0.5, CHCl3). IR: 1089, 2338, 2358, 2920 cm–1. MS: m/z
(%) = [M + H] 214.2(100). HRMS: Calcd for C10H15NO2S
[M + H]: 214.0896. Found: 214.0896. 1H NMR (400 MHz,
CDCl3): d = 1.14 (s, 9 H), 2.35 (dd, 1 H, J = 1.2, 7.2 Hz),
Figure 1 X-ray crystal structure of 2b
Acknowledgement
The authors thank Millennium Pharmaceuticals and EPSRC for a
CASE award (DM), 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 EPSRC’s
Chemical Database Service at Daresbury.7 We thank Dr. David
Hughes, University of East Anglia, for X-ray crystal structure deter-
mination.
References
(1) (a) García Ruano, J. L.; Fernández, I.; Hamdouchi, C.
Tetrahedron Lett. 1995, 36, 295. (b) García Ruano, J. L.;
Fernández, I.; del Prado Catalina, M.; Cruz, A. A.
Tetrahedron: Asymmetry 1996, 7, 3407.
(2) Davis, F. A.; Zhou, P.; Liang, C.-H.; Reddy, R. E.
Tetrahedron: Asymmetry 1995, 6, 1511.
(3) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87,
1353.
(4) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J.
A. J. Org. Chem. 1999, 64, 1278.
Synlett 2003, No. 13, 1985–1988 © Thieme Stuttgart · New York

1988
D. Morton et al.
LETTER
21.2, 37.9, 56.5. N-[tert-Butyl-(R)-sulfinyl]-2-(S)-
2.44 (d, 1 H, J = 4.4 Hz), 3.6 (dd, 1 H, J = 4.4, 7.2 Hz), 6.27
(m, 2 H), 7.20 (m, 1 H). 13C NMR (75 MHz, CDCl3): d =
22.6, 25.8, 28.5, 57.1, 108.7, 110.7, 142.7. N-[tert-Butyl-
(R)-sulfinyl]-2-(S)-cyclohexylaziridine: [a]D20 –62 (c 0.5,
CHCl3). IR: 1080, 1460, 2920 cm–1. MS: m/z (%) = [M + H]
230.0 (18), 56.9 (100). HRMS: Calcd for C12H23NOS [M +
H]: 230.1573. Found: 230.1573. 1H NMR (400 MHz,
CDCl3): d = 0.86 (m, broad, 4 H), 1.25 (s, 9 H), 1.50 (m, 1
H), 1.60–1.80 (m, 6 H), 1.92 (d, 1 H, J = 4.4 Hz), 1.94 (dd,
1 H, J = 1.2, 7.2 Hz), 2.58 (m, 1 H, J = 7.2 Hz). 13C NMR (75
MHz, CDCl3): d = 22.7, 22.9, 25.9, 26.1, 26.4, 28.4, 29.8,
pentylaziridine: [a]D20 –80 (c 0.5, CHCl3). IR: 2920, 1741,
1505, 1357, 1260, 1086 cm–1. MS: m/z = [M + H] 218.0 (12),
191.0(100). HRMS: Calcd for C11H23NOS [M + H]:
218.1573. Found: 218.1572. 1H NMR (400 MHz, CDCl3):
d = 0.87 (m, 3 H), 1.18 (s, 9 H), 1.32 (m, 8 H), 1.82 (d, 1 H,
J = 4.0 Hz), 2.03 (d, 1 H, J = 6.8 Hz), 2.65 (m, 1 H, J = 4.0,
6.8 Hz). 13C NMR (101 MHz, CDCl3): d = 14.2, 22.8, 23,
25.8, 26.2, 28.8, 31.8, 36.3, 57.
(7) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf.
Comput. Sci. 1996, 36, 746.
Synlett 2003, No. 13, 1985–1988 © Thieme Stuttgart · New York