Stereoselective tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform: Practical synthesis of α-tribromomethyl amines

Article abstract of DOI:10.1016/j.tetlet.2012.06.100

The unprecedented nucleophilic tribromomethylation of N-(tert- butanesulfinyl)imines with bromoform has been shown to be a highly stereoselective and practical method for the synthesis of enantiomerically pure α-tribromomethyl amines. THF has proven to be the best solvent in this addition reaction. By changing the reaction solvent from THF to DMF, 2,2-dibromoaziridines can also be synthesized directly from bromoform and N-(tert-butanesulfinyl)imines under similar reaction conditions.

Full text of DOI:10.1016/j.tetlet.2012.06.100

Tetrahedron Letters 53 (2012) 4711–4714
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective tribromomethylation of N-(tert-butanesulfinyl)imines with
bromoform: practical synthesis of a-tribromomethyl amines
Ya Li a,b, , Yingchao Ma a, Zhifeng Lu a, Le Wang a, Xinfeng Ren a, Zhihua Sun a,
⇑
⇑
a College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The unprecedented nucleophilic tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform
Received 12 April 2012
Revised 27 May 2012
Accepted 21 June 2012
Available online 28 June 2012
has been shown to be a highly stereoselective and practical method for the synthesis of enantiomerically
pure a-tribromomethyl amines. THF has proven to be the best solvent in this addition reaction. By chang-
ing the reaction solvent from THF to DMF, 2,2-dibromoaziridines can also be synthesized directly from
bromoform and N-(tert-butanesulfinyl)imines under similar reaction conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Amines
Tribromomethylation
Diastereoselectivity
Nucleophilic addition
Sulfinylimine
Introduction
as substitution and elimination.5 While brominated natural prod-
ucts are attracting increasing attention as targets for chemical syn-
Considered bizarre and rare only about 50 years ago, more than
2100 brominated natural products of both marine and terrestrial
origin have been discovered to date. These compounds exhibit a
wide range of biological activity, including antitumor, antibiotic
or cytotoxic and analgesic activity.1 Even though the concentration
of bromide is only 0.3% of that for chloride in sea water, organobro-
mine compounds are more prevalent in marine organisms than
organochlorine derivatives, which can be attributed to the easier
oxidation of bromide to the equivalent of bromonium ion (Br+)
by peroxidase.2 As our understanding of the function and toxicity
of natural organobromines continues to unfold and novel natural
organobromine compounds are discovered and evaluated for their
biological activity, it holds promise that new brominated antibiot-
ics, anticancer and antifungal agents and medicinal drugs will be
discovered.3
thesis, the development of methods for the stereoselective
introduction of the tribromomethyl group or bromine atom(s) into
organic compounds significantly lags behind.6 To the best of our
knowledge, we are not aware of any reports of stereoselective tri-
bromomethylation. The lack of sophistication in this area, coupled
with the broad range of important brominated natural and non-nat-
ural products, drives our laboratory to develop new methods for the
stereoselective introduction of the tribromomethyl group into or-
ganic scaffolds. Herein, we wish to disclose the highly stereoselec-
tive and practical tribromomethylation reaction using bromoform
and Ellman’s N-(tert-butanesulfinyl)imines which has enabled us
to efficiently synthesize enantiomerically pure
amines.
a-tribromomethyl
Results and discussion
The tribromomethyl group existed in
a lot of bioactive
compounds, and it was found to be the key component for potent
activity in some cases.4 For example, 1-tribromomethyl-1,2,3,4-tet-
rahydro-b-carboline (TaBro) has been shown to be the most potent
toxin in vitro and in vivo, compared with its 1-trifluromethyl- and
1-trichloromethyl-1,2,3,4-tetrahydro-b-carboline counterparts.4a
Moreover, the tribromomethyl group is synthetically very useful,
which can undergo many synthetically useful transformations such
Very recently, our group has successfully developed a highly
efficient and practical method for the asymmetric synthesis of
a-
trichloromethyl amines based on nucleophilic trichloromethyla-
tion of N-(tert-butylsulfinyl)imines with chloroform.7 The trichlo-
romethyl anion generated in situ from chloroform and sodium
bis(trimethylsilyl)amide (NaHMDS) in THF solvent at a low reac-
tion temperature showed reasonable thermal stability and very
good nucleophilicity. This remarkable trichloromethylation reac-
tion inspired us to investigate whether bromoform could act as
the tribromomethyl anion source in a similar manner to afford
⇑
Corresponding authors. Tel.: +86 21 67791220; fax: +86 21 67791432.
E-mail addresses: ya.li@sues.edu.cn (Y. Li), sungaris@gmail.com (Z. Sun).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.100

4712
Y. Li et al. / Tetrahedron Letters 53 (2012) 4711–4714
O
S
CBr3
Ph
Table 1 (continued)
EntrySulfinylimine 2
1
O
S
HCBr3 (1.5 equiv.)
H
Product 3
Yielda drb
(%)
NaHMDS (1.5 equiv.)
tBu
N
H
3a
tBu
N
Ph
THF, -60 o
C
2a
O
S
H
H
H
O
S
CBr3
CBr3
CBr3
82 % yield, 93 : 7 dr
11
12
72
51
62
90:10
tBu
tBu
tBu
tBu
tBu
N
N
H
Ph
Scheme 1. Tribromomethylation of 2a using HCBr3.
Ph
2k
3k
O
S
O
S
90:10
N
N
H
2l
3l
Table 1
Tribromomethylation of N-(tert-butylsulfinyl) aldimines 2 using HCBr3
O
S
O
S
13 tBu
N
N
H
Nc
O
S
CBr3
R
O
S
H
HCBr3 (1.5 equiv.)
2m
3m
tBu
N
H
3
tBu
NaHMDS (1.5 equiv.)
THF, -60 oC, 1h
N
R
a
Yields of isolated pure material.
b
Diastereomeric ratios were determined by 1H NMR spectroscopy and HPLC–MS
2
analysis on the crude reaction mixture. For more details, see the Supplementary
data.
c
Not determined.
EntrySulfinylimine 2
Product 3
Yielda drb
(%)
the corresponding
out that, currently, the few known methods for the synthesis of
a-tribromomethyl amines. It should be pointed
O
S
H
H
O
S
CBr3
a-
1
2
tBu
tBu
N
tBu
tBu
82
85
93:7
N
H
tribromomethyl amines are mainly based on the use of 2,2,2-trib-
romoethanimine derivatives as precursors or a tribromomethyl an-
ion equivalent such as tribromoacetic acid.8 With this in mind,
compound 2a was used as a model compound and its tribromom-
ethylation reaction was carried out under similar reaction condi-
tions for the above mentioned trichloromethylation reaction. As
expected, this addition reaction proceeded smoothly and the corre-
sponding product 3a could be obtained in 82% yield with diastere-
oselectivity up to 93:7 (Scheme 1). Further optimization using
different bases such as lithium bis(trimethylsilyl)amide (LiHMDS)
and potassium bis(trimethylsilyl)amide (KHMDS) did not get bet-
ter results. The yield for this addition reaction was lower as com-
pared to its trichloromethylation analogue, which can be
associated with the relatively weak nucleophilicity of this bulky
anion and the facile decomposition of the tribromomethyl anion
to dibromocarben at room temperature and even below.
Next, we used the reaction conditions shown in Scheme 1 as the
standard condition, and studied the scope of the reaction between
bromoform and a variety of structurally diverse imines.9 The re-
sults are shown in Table 1. In most cases, the tribromomethylated
products 3 were obtained in very good isolated yields with high
diastereoselectivities (except 3l and 3m). A remarkable feature of
this reaction is that it works pretty well for non-enolizable imines
(entries 1–11). For enolizable imines (2l and 2m), this reaction
proceeded to give expected product in moderate to good yields,
which is in contrast to our reported chloroform chemistry: trichlo-
romethylation of enolizable imines (such as 2l and 2m) usually
delivered the addition products in very good yields.7b Also, the
electronic donating/withdrawing nature of the substituents
(including methoxy, methyl, chloro and extremely electron-with-
drawing nitro group) on the aromatic ring had little effect on both
the yield and diastereoselectivity. The configuration of the addition
product was assigned to be (Rs, S), based on our recent research on
2a
3a
O
S
Cl
O
S
CBr3 Cl
CBr3
N
N
H
3b
97:3
99:1
98:2
96:4
2b
O
S
H
H
H
O
S
tBu
tBu
tBu
N
tBu
tBu
tBu
N
H
3
4
5
81
79
70
2c
3c
Cl
Cl
Cl
O
S
Cl
O
S
CBr3 Cl
CBr3
N
N
H
2d
3d
Cl
O
S
O
S
N
N
H
2e
3e
NO2
NO2
O
S
O
S
CBr3
CBr3
H
H
tBu
tBu
N
tBu
tBu
N
H
3f
6
7
78
84
90:10
93:7
2f
O
S
O
S
N
N
H
3g
2g
O
O
O
S
H
O
S
CBr3
8
9
80
81
83
91:9
89:11
93:7
tBu
tBu
N
tBu
tBu
tBu
N
H
2h
3h
O
S
H
H
O
S
CBr3
O
trichloromethylation that
a similar non-chelation controlled
O
N
transition state was proposed in which the tribromomethyl anion
attack the Re face of the imine leading to the Cram products
(Fig. 1).7 The sulfinyl oxygen in s-cis arrangement with respect to
the C@N bond is supposed to be the most stable conformation
mainly due to the contribution of intramolecular hydrogen bond-
ing of the oxygen with the iminic hydrogen, based on recent
computational studies.7a,10
N
N
H
3i
2i
O
S
O
S
CBr3
N
10 tBu
N
N
H
3j
2j

Y. Li et al. / Tetrahedron Letters 53 (2012) 4711–4714
4713
-
this reaction can be applied to both non-enolizable and enolizable
imines. Generally, moderate to good yields can usually be obtained
for imines with electron-donating or moderate electron-withdraw-
ing substituents on the aromatic ring.
The reaction of imine 2e containing a strong electron-with-
drawing nitro group also gave the expected product 4c, albeit in
lower yield (39%). To our knowledge, this is the first case for asym-
metric synthesis of 2,2-dibromoaziridines.12 The structure and
configuration of the cyclization product were determined by sin-
gle-crystal X-ray analysis (Fig. 2).13
"CBr
"
3
O
S
H
N
Ph
Figure 1. Depiction of its stereoselective formation of compound 3a.
Next we went on to explore whether iodoform could undergo
similar reactions. However, the addition reaction between iodo-
form and imine 2a cannot proceed at all, which may be due to
the ready decomposition of the triiodomethyl anion generated un-
der the specified reaction conditions as indicated by the dark
brown solution once the base was added to the reaction mixture.
In conclusion, we have developed a highly practical and stereo-
Table 2
Synthesis of 2,2-dibromoaziridines 4 from imines 2 and bromoform
O
S
HCBr3 1 (2.0 equiv.)
O
S
H
N
tBu
Br
N
NaHMDS (2.0 equiv.)
DMF, -30 oC
tBu
N
R
R
Br
selective synthesis of
a-tribromomethyl amines and 2,2-dibro-
2
4
moaziridines from bromoform. Nucleophilic tribromomethylation
of N-(tert-butanesulfinyl)imines with bromoform in THF solvent
O
S
O
affords
a-tribromomethyl amines in very good yields with high
S
tBu
Br
tBu
Br
N
diastereoselectivities. By simply changing the reaction solvent to
DMF, 2,2-dibromoaziridines can be synthesized directly from
bromoform and N-(tert-butanesulfinyl)imines under similar reac-
tion conditions.
Br
Br
Cl
4b
, 51 %
O
4a
, 58 %
O
Acknowledgments
S
S
tBu
Br
tBu
Br
N
N
Support of our work by the National Natural Science Foundation
of China (21102089), Research Innovation Program of Shanghai
Municipal Education Commission (12YZ155), the Special Scientific
Foundation for Outstanding Young Teachers in Shanghai Higher
Education Institutions (gjd10003, shgcjs023), Key Laboratory of
Organofluorine Chemistry (Chinese Academy of Sciences), Innova-
tion Program of University Students in Shanghai University of Engi-
neering Science (cs1104020), and Start-up Funding of Shanghai
University of Engineering Science, is gratefully acknowledged.
Br
Br
O2N
Me
4d
, 67 %
4c
, 39 %
O
O
S
S
tBu
Br
tBu
N
N
Br
Br
Br
4f
, 50 %
4e
, 53 %
Supplementary data
Supplementary data associated with this article can be found, in
theonline version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.100.
References and notes
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Figure 2. The X-ray crystal structure of compound 4a.
The chemical outcome of the reaction between bromoform and
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mixture of the imine 2a (1.0 mmol) and bromoform (2.0 equiv, 2.0 mmol) in
DMF (3.0 mL) at À30 °C. Reaction mixtures were stirred over 0.5 h. Then water
(10 mL) was added at lower temperature and the quenched reaction mixture
was extracted three times with ethyl acetate. The combined organic layers
were dried over anhydrous MgSO4. Evaporation of the solvent afforded the
crude product, which was subject to flash chromatography to give pure 2,2-
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data for this Letter. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.