A convenient synthesis of chiral vinyl aziridines via aza-Barbier-Darzen type reaction

Article abstract of DOI:10.1016/j.tetlet.2013.04.046

A facile and efficient approach for the synthesis of chiral vinyl aziridines has been developed in moderate yields and high diastereoselectivities via Zn-promoted aza-Barbier-Darzen type reaction of (R)-N-tert-butanesulfinyl imines with 1,3-dibromoprop-1-ene.

Full text of DOI:10.1016/j.tetlet.2013.04.046

Tetrahedron Letters 54 (2013) 3586–3590
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A convenient synthesis of chiral vinyl aziridines via aza-Barbier–Darzen
type reaction
⇑
Wen-Jie Liu, Yun-Hui Zhao, Xing-Wen Sun
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient approach for the synthesis of chiral vinyl aziridines has been developed in moderate
yields and high diastereoselectivities via Zn-promoted aza-Barbier–Darzen type reaction of (R)-N-tert-
butanesulfinyl imines with 1,3-dibromoprop-1-ene.
Received 17 March 2013
Revised 8 April 2013
Accepted 15 April 2013
Available online 20 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aza-Barbier–Darzen type reaction
1,3-Dibromoprop-1-ene
(R)-N-tert-Butanesulfinyl imine
Vinyl aziridine
Vinyl aziridines have gained much attention in the past two
decades primarily due to their versatile reactivity for synthesizing
numbers of natural and non-natural products undergoing ring
opening1 or ring-expansion.2 They are also very important sub-
units in a huge amount of biologically active compounds.3 Conver-
sion of vinyl epoxides4, addition of nitrenoids to 1,3-dienes5, and
ylides addition to activated imines6 are popular ways for the con-
struction of vinyl aziridines. However, literatures on effective syn-
thesis of enantiomerically pure vinyl aziridines are less reported.
To the best of our knowledge, the reaction between ylide and N-
tert-butanesulfinyl imines proved to be one of the most powerful
protocols. Stockman and co-workers presented the reaction of allyl
sulfur ylides with chiral N-tert-butanesulfinyl imines achieving a
series of chiral vinyl aziridines in moderate to good yields (44–
82%) with high stereoselectivities (cis/trans up to 1/4.8) and excel-
lent diastereoselectivities (85 to 95% de)6g by employing the ap-
proach developed by Hou and Dai.6a–e Deng and co-workers
described the synthesis of optically active vinyl aziridines via N-
tert-butanesulfinyl imines with telluronium allylides in good to
excellent yields (56–98%) with excellent diastereoselectivities (up
to >98% de, cis/trans up to 30/1).6h Despite these considerable con-
tributions, a more efficient and convenient route to synthesize vi-
nyl aziridines is particularly appealing.
N-tert-butanesulfinyl imines developed by Ellman et al.8 at room
temperature. By simply changing the solvent, surprisingly
a
remarkable opposite stereocontrol was achieved with both up to
98% de as well as in good yields.7a Moreover, if 3-benzoyloxyallyl
bromide or 3-arylallyl bromide was employed,
or cinnamylation of N-tert-butanesulfinyl imines would be gained
also in excellent diastereoselectivities.7b–d Furthermore, when b,
disubstituted allyl bromide was used and followed by cyclization,
chiral -methylene-
-lactams would be obtained.7e In the mean-
a-hydroxyallylation
c-
a
c
time, it is revealed that DMF with the additive LiCl could replace
the unpleasant HMPA on stereocontrol.7d Encouraged by the suc-
cessful allylation above, we further envisioned that an aza-Barbier
reaction between imine 1 and allyl bromide 2 possessing a leaving
group in c-position might be carried out to give the corresponding
homoallylic amine intermediate I-1. Accordingly, nitrogen in I-1
might nucleophilically attack the carbon adjacent to the leaving
group (the former
c-position of the allyl bromide), and subse-
quently underwent a SN2-like reaction in a diastereoslective man-
ner to form the desired vinyl aziridines (Scheme 1). Herein, we
wish to report our development of a new and efficient approach
to chiral vinyl aziridine via Zn-mediated aza-Barbier–Darzen type
reaction.
In the past several years, we have been interested in the asym-
metric synthesis of various chiral amines via aza-Barbier reaction.7
For example, we successfully presented a highly diastereoselective
synthesis of chiral homoallylic amines by Zn-mediated allylation of
O
S
O
S
O
L
Br
S
N
BrZn
R
Zn,
aza-Barbier
N
2
Darzen-type
N
R
R
H
L
3
1
L = leaving group
I-1
⇑
Corresponding author. Tel.: +86 21 6564 2406.
E-mail address: sunxingwen@fudan.edu.cn (X.-W. Sun).
Scheme 1. Reaction proposal.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.046

W.-J. Liu et al. / Tetrahedron Letters 54 (2013) 3586–3590
3587
As bromo group is an ideal leaving group for many reactions
and, most importantly, 1,3-dibromoprop-1-ene 2a is commercially
available, it was chosen as the allyl bromide reagent. Initially, we
examined the reaction of (R)-N-tert-butanesulfinyl imine 1a and
3 equiv of 1,3-dibromoprop-1-ene 2a (purchased from AldrichÒ
with the proportion of 60% (E)-isomer and 40% (Z)-isomer) in
THF in the presence of 3 equiv of zinc at room temperature to
check the potential of our hypothesis, yet desperately, no reaction
happened (Table 1, entry 1). When the temperature was raised to
50 °C, to our delight, the reaction proceeds smoothly as we ex-
pected that the desired vinyl aziridine product 3a was indeed iso-
lated in 54% yield and confirmed by NMR spectra. It is noteworthy
that the tandem aza-Babier–Daezen type reaction of (R)-N-tert-
butanesulfinyl imine (1a) with 1,3-dibromoprop-1-ene 2a oc-
curred in a region and stereoselective fashion to give a single vinyl
aziridine diastereomer. The absolute stereochemistry of the ob-
tained product was identified unambiguously through X-ray crys-
tallographic analysis of vinyl aziridine 3a,11 of which newly
generated stereocenters were determined to be (R, R), and a trans
configuration was found (Fig. 1).
Figure 1. X-ray crystal structure of 3a.
When the reaction temperature was raised to 60 °C, a slightly
lower yield of 48% was obtained (entry 8). Under similar reaction
conditions, the amount and ratio of zinc and 1,3-dibromoprop-1-
ene 2a was examined at 50 °C. Three equivalents of zinc and
three equivalents of 1,3-dibromoprop-1-ene 2a were found to
be the best (Table 1, entries 4–7). Furthermore, it was noticeable
that the rotation speed made an important role in this reaction
that the yields increased with the increasing stir rate until it
reached a platform which once mentioned by Jacobsen and
cyclyl group, and heterocyclyl group gave the unsatisfactory re-
sults (Table 2, entries 8–10).
To better understand the reaction pathway as well as the ob-
served relative stereochemistry, we further conducted a support-
ing experiment. When the reaction between (R)-N-tert-
butanesulfinyl imine 1d with 2 equiv of both allyl bromide reagent
2a and zinc was tested, three products were found as fellows: the
desired vinyl aziridine 3d, the homoallylic amine 4d, and the dia-
mine compound 5d. However, the imaginary intermediate homo-
allylic amine 6d did not appear (Fig. 2a). It might indicate that
the intermediate I-1 and zinc might generate another allylic zinc
reagent which could react with (R)-N-tert-butanesulfinyl imine
1d or be protonated by water. Although the detailed mechanistic
pathway is not clear, Figure 2b could account for the selectivity
of the tandem reaction. As described in our studies7a of simple ally-
lation of N-sulfinyl imines with allyl bromide, in a THF system a
six-membered cyclic chair transition state model was believed to
be preferred and the allylzinc was thought to coordinate both to
the imine nitrogen and to sulfinyl oxygen (Fig. 2b).
9
co-workers and that 1000 r/min was the suitable rate (Table 1,
entries 3, 9–12).
With the optimal condition established, we set out to explore
the scope of N-tert-butanesulfinyl imines. Thus, a wide range of
(R)-N-tert-butanesulfinyl imines 1 were examined to react with
1,3-dibromoprop-1-ene 2a (3 equiv) in the presence of zinc
(3 equiv) in anhydrous THF with the rotation speed of 1000 r/min
at 50 °C for 2 h as summarized in Table 2. Inspiringly, all the reac-
tions went smoothly and afforded the desired vinyl aziridines in
moderate yields. Better yields were observed when electron-with-
drawing groups were on the phenyl ring in both para- and ortho-
positions or the phenyl ring only existed (Table 2, entries 1–7,
11). Whereas phenyl group bearing electron-donating group, fused
Table 1
Screening and optimization of the reaction conditions
O
S
O
S
N
N
Zn, THF, 2h
+
Br
Br
Br
Br
1a
2a
3a
Entrya
2 (equiv)
Zn (equiv)
Temperature (°C)
Rotation Speedb (r/min)
Yieldc (%)
1
2
3
4
5
6
7
8
9
3
3
3
2
4
3
3
3
3
3
3
3
3
3
3
2
4
4.5
2
3
3
rt
1000
1000
1000
1000
1000
1000
1000
1000
300
NR
NR
54
29
52
51
38
48
32
45
50
54
40
50
50
50
50
50
60
50
50
50
50
10
11
12
3
3
3
500
700
1200
a
b
c
The reaction was performed with imine 1a (0.25 mmol), 1,3-dibromoprop-1-ene 2a, and Zn in 1 mL dry THF.
The reactions were operated on IKAÒ (MST Digital).
Isolated yield.

3588
W.-J. Liu et al. / Tetrahedron Letters 54 (2013) 3586–3590
Table 2
Diastereoselective synthesis of vinyl aziridines10
O
S
O
S
N
Zn, THF, 50°C
2h, 1000r/min
N
+
Br
Br
R
R
1
2a
3
Entrya
1
3
Yieldb (%)
drc
O
S
O
S
N
N
1
54
>20:1
Br
Br
1a
O
3a
O
S
N
S
N
2
3
4
5
42
48
52
63
>20:1
>20:1
>20:1
>20:1
F
F
1b
3b
O
S
O
S
N
N
Cl
Cl
1c
3c
O
S
O
S
N
N
1d
3d
O
S
O
S
N
N
F3C
F3C
1e
3e
O
S
O
S
N
N
6
7
8
55
45
27
>20:1
>20:1
>20:1
NC
NC
1f
3f
O
S
O
S
N
N
MeOOC
MeOOC
1g
3g
O
S
O
S
N
N
Me
Me
1h
3h

W.-J. Liu et al. / Tetrahedron Letters 54 (2013) 3586–3590
3589
Table 2 (continued)
Entrya
1
3
Yieldb (%)
drc
O
S
O
S
N
N
9
37
>20:1
>20:1
1i
3i
O
S
O
S
N
N
10
25
48
S
S
1j
3j
O
S
O
S
N
N
11
>20:1
Br
Br
1k
3k
a
Reaction was performed with imine 1 (0.25 mmol), Zn (0.75 mmol) and 1,3-dibromoprop-1-ene 2a (0.75 mmol) in 1 mL dry THF at 50 °C.
Isolated yield.
Determined by NMR.
b
c
O
S
N
O
S
a:
Supplementary data
HN
∗
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
04.046.
O
S
+
+
30%
39%
4d
N
3d
2eq
Br
Br
O
S
O
2eq Zn, THF,50°C
2h, 1000r/min
S
References and notes
HN
HN
O
S
1d
∗
∗
Br
HN
+
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∗
29%
Not Found
5d
6d
b:
O
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O
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aza-Barbier
O
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BrZn
Ar
Br
Br
N
Zn,
SN2-like
N
Ar
THF
Ar
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Br
O
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Br
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or, Zn Zn,
H2O
Ar
side aza-Barbier or protonation
Figure 2. Mechanistic proposals relating to reaction stereocontrol.
In summary, we have developed a facile and efficient approach
for the synthesis of chiral vinyl aziridines via zinc promoted aza-
Barbier–Darzen type reaction of (R)-N-tert-butanesulfinyl imines
with 1,3-dibromoprop-1-ene. This protocol provided an easy ac-
cess to optically active trans-2-subtituted vinyl aziridines directly
from imines and commercially available allyl bromide reagent.
Mild condition, along with good yields and excellent stereoselec-
tivities, makes this tandem approach attractive in the synthesis
of vinyl aziridines.
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Acknowledgments
Financial support from the National Nature Science Foundation
of China (21072031 and 21103023) and the Shanghai Municipal
Committee of Science and Technology (10ZR1404100) is gratefully
acknowledged. The authors are also thankful to Dr. Xiao-Di Yang
for her assistance with X-ray crystallography.

3590
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NaHCO3, water, and brine and dried over anhydrous Na2SO4. Concentrated in
vacuo, the residue was purified by flash column chromatography to afford the
desired product.
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10. General procedure for the preparation of tert-butylsulfinyl-vinyl-aziridines: Under
11. Crystallographic data for 4d (C14H18BrNOS): CCDC 921102; T = 296(2) K;
wavelength: 0.71073 Å; formula weight: 328.26; crystal system: monoclinic;
space group: P2(1); unit cell dimensions: a = 5.735(3) Å, b = 10.136(6) Å,
c = 13.289(7) Å,
a = 90°, b = 100.133(7)°, c
= 90°, V = 760.5(7) Å3; Z value = 2;
Dcalcd: 1.434 Mg/m3; absorption coefficient: 2.829 mmÀ1; F(000) = 336; crystal
size: 0.25 Â 0.21 Â 0.18 mm; h range: 2.54–25.50°; limiting indices: À66h66,
À126k68,
À166l616;
reflections
collected/unique:
3785/2075
[R(int) = 0.0321]; completeness to h = 25.50: 98.8%; absorption correction:
semi-empirical from equivalents; max. and min. transmission: 0.6260 and
0.5644; refinement method: full-matrix least-squares on F2; data/restraints/
parameters: 2075/1/167; goodness-of-fit on F2: 0.962; final
R
indices
[I > 2r(I)]: R1 = 0.0370, wR2 = 0.0838; R indices (all data): R1 = 0.0609,
Argon, 1,3-dibromoprop-1-ene 2a (75
suspension of activated zinc powder (49 mg, 0.75 mmol) and (R)-N-tert-
butanesulfinylimine (0.25 mmol) in anhydrous tetrahydrofuran (1 mL) with
l
L, 0.75 mmol) was added to
a
wR2 = 0.0943; absolute structure parameter: 0.006(14); extinction
coefficient: 0.008(2); largest diff. peak and hole: 0.265 and À0.366 e.AÀ3
.