Methyltrichlorosilane-DMSO: A facile and highly efficient recipe for the chlorination of enamides and enecarbamates

Article abstract of DOI:10.1055/s-0029-1218005

A facile and highly efficient method was developed for the chlorination of enamides and enecarbamates with the combined use of methyltrichlorosilane and DMSO, which allowed one-pot production of the corresponding β-chloro enamides and enecarbamates in hig

Full text of DOI:10.1055/s-0029-1218005

LETTER
2961
Methyltrichlorosilane–DMSO: A Facile and Highly Efficient Recipe for the
Chlorination of Enamides and Enecarbamates
R
ecipe for the Chl
e
orinationof
q
Enamides
a
i
ndEne
n
carbamate
s
g Lin,a Ke Cheng,a,b,c Xiaoxia Lu,*a Jian Sun*a
a
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax +86(28)85222753; E-mail: luxx@cib.ac.cn; E-mail: sunjian@cib.ac.cn
b
c
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Graduate School of Chinese Academy of Sciences, Beijing 100080, P. R. of China
Received 6 May 2009
bamates to synthesize b-chloroenamides/enecarbamate in
high yield (up to 99%) and good stereoselectivity (>8:1
ratio of Z/E) under mild reaction conditions.
Abstract: A facile and highly efficient method was developed for
the chlorination of enamides and enecarbamates with the combined
use of methyltrichlorosilane and DMSO, which allowed one-pot
production of the corresponding b-chloro enamides and enecarbam-
ates in high yield and good stereoselectivity. This method is easy to
operate and suitable for both cyclic and acyclic substrates.
NHR
NHR
NHR
HSiCl3–DMSO
CH2Cl2, 0 °C
+
Ph
Ph
Ph
Key words: MeSiCl3–DMSO, enamides, enecarbamates, chlorina-
tion, stereoselectivity
Cl
1
2
3
Scheme 1 Reaction of enamides/enecarbamates with HSiCl3 in the
presence of DMSO
b-Halogenated enamides and enecarbamates are useful
building blocks and intermediates for the synthesis of nat-
ural products and other biologically important organic
molecules.1–4 Preparation of this type of compounds, how-
ever, relies on a moderate yielding and low-to-moderate
stereoselective two-step sequence, namely oxidation of
the C=C bond by halogenating reagents such as NIS and
NBS, followed by a base-assisted isomerization,5–10
which moreover is mainly limited to iodination and bro-
mination of a-ester enamides/encarbamates. Although
this method was also reported to be applicable for the
chlorination, the use of hazardous chlorinating reagents
such as chlorine and tert-butyl hypochlorite further limits
the applications.8c,d In this context, the development of ef-
ficient and practical new chlorination methods is in great
demand. Herein, we present a highly efficient new proto-
col that allows for facile one-pot chlorination of both cy-
clic and acyclic enamides and enecarbamates under mild
conditions in high yields and with high stereoselectivities.
In the initial experiments, we screened different chloro-
silanes with 3 equivalents DMSO for the chlorination.
The reaction of enecarbamate 1h was selected as a mod-
el.12 All the screened chlorosilanes were found to be effec-
tive chlorination reagents to afford the desired product 2h
in high yield (Table 1, entries 1–6). In particular, methyl-
trichlorosilane (MeSiCl3) gave the highest yield of 99%
(entry 2).
Some other oxo-type Lewis bases such as DMF and
P(O)Ph3 were also examined in replace of DMSO for the
chlorination of 1h in the presence of MeSiCl3 in dichlo-
romethane at 0 °C. No desired product was observed, in-
dicating that DMSO is an indispensable reagent for this
transformation. In a control experiment, no chlorination
occurred when MeSiCl3 was used alone.
Next, the solvent effects were explored for the chlorina-
tion of 1h with MeSiCl3–DMSO. All the tested solvents,
including CH2Cl2, CHCl3, DCE, toluene, THF, MeCN,
and DMF, proved to be compatible with this chlorination
system, affording high yields in the level of 90% (Table 1,
entries 2 and 10–15). CH2Cl2 gave the best yield of 99%
and was thus used as the solvent of choice for further stud-
ies.
Recently, during our studies on the Lewis base catalyzed
hydrosilylation of enamides/enecarbamates 1,11 we ob-
served that treatment of 1 with trichlorosilane (HSiCl3) in
the presence of DMSO in CH2Cl2 at 0 °C resulted in the
chlorination product 2 instead of the expected reduction
product 3 (Scheme 1). Furthermore, we found that other
chlorosilanes could also furnish product 2 in the presence
of DMSO under similar conditions. Thus we were inter-
ested in developing this reaction into a useful new method
for the chlorination of enamide/enecarbamate. Herein, we
present that methyltrichlorosilane–DMSO was used as a
facile one-pot chlorinating system for enamides/enecar-
Other reaction parameters were also examined for optimi-
zation. The optimal molar ratio of 1h, MeSiCl3, and
DMSO was found to be 1:2.0:1.5 (Table 2, entry 7). Using
less than 1.0 equivalent of either MeSiCl3 or DMSO based
on 1h caused a significant decrease in yield. When the
reaction temperature was raised from 0 °C to room tem-
perature, the reaction became much faster and went to
completion in half an hour with a high yield of 98%
(Table 2, entry 11).
SYNLETT 2009, No. 18, pp 2961–2964
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x
.x
x
.2
0
0
9
Advanced online publication: 09.10.2009
DOI: 10.1055/s-0029-1218005; Art ID: W07009ST
© Georg Thieme Verlag Stuttgart · New York
Having established the optimal reaction conditions, we
next explored the substrate scope of this reaction. A vari-

2962
D. Lin et al.
LETTER
Table 2 Optimization of the Reaction Conditionsa
Table 1 Screening of Chlorination Reagentsa
NHCO2Et
NHCO2Et
Cl
NHCO2Et
NHCO2Et
Cl
MeSiCl3–DMSO
CH2Cl2
chlorosilane–additive
CH2Cl2, 0 °C, 4 h
1h
2h
2h
1h
Entry
MeSiCl3
(equiv)
DMSO
(equiv)
Temp
(°C)
Time
(h)
Yield
(%)b
Entry
1
Chlorosilaneb Additive
Solvent
Yield (%)c
SiCl4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
96
99
92
97
88
89
–
1
2
4.0
4.0
4.0
4.0
0.5
1.0
1.5
2.0
2.0
2.0
0.5
1.0
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
0
4
48
89
99
96
46
79
95
96
99
98
2
MeSiCl3
HSiCl3
0
4
3
3
0
4
4
AllylSiCl3
Me2SiCl2
Me3SiCl
MeSiCl3
MeSiCl3
MeSiCl3
MeSiCl3
MeSiCl3
MeSiCl3
MeSiCl3
MeSiCl3
MeSiCl3
4
0
4
5
5
0
4
6
6
0
4
7
7
0
4
8
DMF
–
10
11
12
0
4
9
P(O)Ph3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
–
0
1
10
11
12
13
14
15
93
97
96
97
93
90
r.t.
0.5
a Conditions: [1h] = 0.1 M in CH2Cl2.
b Isolated yield based on 1h.
toluene
THF
Table 3 The Chlorination of Various Enamides/Enecarbamatesa
MeCN
DMF
NHR3
NHR3
MeSiCl3–DMSO
CH2Cl2, r.t., 1 h
R2
Cl
R1
R1
R2
a Conditions: [1h] = 0.1 M, [silane] = 0.4 M, [additive] = 0.3 M, at 0
°C for 4 h.
1a–i
2a–i
b All chlorosilanes were used directly without purification.
c Isolated yield based on 1h.
Entry Substrate
R2
R3
Yield Z/E
(%)b of 2c
ety of enamide/enecarbamate compounds were chlorinat-
ed under the optimal conditions.13 As shown in Table 3,
the chlorination of all acyclic and cyclic enamides and
enecarbamates proceeded smoothly to afford the corre-
sponding b-chloro enamides and enecarbamates in excel-
lent yields in one hour at room temperature. For the
acyclic substrates 1a–d, both Z- and E-isomeric products
could be obtained. Generally, good stereoselectivities
with ratios of Z/E ranging from 8:1 to 10:1 were observed
(entries 1–4). The stereochemistries of both isomers were
unambiguously determined by 2D 1H–1H NOESY.
1
1a
1b
1c
1d
H
Bz
COOBn
COPh
90
99
95
95
10:1
10:1
10:1
8:1
2
3
4
NHR3
Me
Me
Me
R2
Ph
COMe
5
R1 = 4-F3CC6H4 1e
Me
Bz
94
8:1
6
7
8
9
10
1f
1g
1h
1i
1j
COOBn
COPh
COMe
COOEt
99
98
99
99
–
–
–
–
–
NHR3
COOt-Bu 98
NHR3
11
1k
n-Pr
COOt-Bu 52
n.d.d
On the basis of the experimental data and the formation of
dimethyl sulfide as a side product judged by the strong
characteristic smell, a plausible mechanism for the b-chlori-
nation of enamide/enecarbamate using the MeSiCl3–
DMSO system was proposed (Scheme 2). The reaction
begins with the known formation of a sulfonium cation
A1 from dimethylsulfoxide and oxygenophilic chlorosi-
lane.14 Sulfonium cation A1 then undergoes an electro-
philic attack on the C=C bond of enamides/enecarbamates
1 to give intermediate A2,15 which is subsequently sub-
jected to a nucleophilic attack by Cl– generated in the sul-
R2
H
a Conditions: [1h] = 0.1 M, [MeSiCl3] = 0.2 M, [DMSO] = 0.15 M, in
CH2Cl2 at r.t. for 1 h.
b Isolated yield.
c Determined by 1H NMR.
d Not determined.
fonium formation step to provide b-chloro ketimine A3
and concomitantly release dimethyl sulfide and methyldi-
chlorosiloxane. The final tautomerization step furnishes
Synlett 2009, No. 18, 2961–2964 © Thieme Stuttgart · New York

LETTER
Recipe for the Chlorination of Enamides and Enecarbamates
2963
Me
Cl Si Cl
Cl
R1
Me
R2
Me2S + MeSiCl2OH
R1
Cl
Cl
Cbz
Cbz
H
Si
N+
O
S
N
NHCbz
••
Me
Cl
S
O
S+
O
Si
Cl
H
Cl–
R1
– Cl–
Cl
R2
R2
A2
A3
NHCbz
R2
NHCbz
Cl
+
R1
R1
R2
Cl
E-isomer (minor)
Z-isomer (major)
Scheme 2 The proposed mechanism of the chlorination with MeSiCl3–DMSO
(8) (a) Torrini, I.; Pagani Zecchini, G.; Paglialunga Paradasi, M.
Synth.Commun. 1989, 19, 695. (b) Richards, K. D.; Kolar,
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Chem. 1976, 41, 3674. (c) Kolar, A. J.; Olaen, R. K. J. Org.
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Francis, G. Tetrahedron Lett. 1990, 31, 3739.
(9) (a) Coleman, R. S.; Carpenter, A. J. J. Org. Chem. 1993, 58,
4452. (b) Miossec, B.; Danion-Bougot, R.; Danion, D.
Synthesis 1994, 1171.
(10) Silva, N. O.; Abreu, A. S.; Ferreira, P. M. T.; Monteiro,
L. S.; Queiroz, M.-J. R. P. Eur. J. Org. Chem. 2002, 2524.
(11) For our recent work on Lewis base catalyzed
hydrosilylation, see: (a) Wang, Z.; Ye, X.; Wei, S.; Wu, P.;
Zhang, A.; Sun, J. Org. Lett. 2006, 8, 999. (b) Wang, Z.;
Cheng, M.; Wu, P.; Wei, S.; Sun, J. Org. Lett. 2006, 8, 3045.
(c) Pei, D.; Wang, Z.; Zhang, Y.; Wei, S.; Sun, J. Org. Lett.
2006, 8, 5913. (d) Zhou, L.; Wang, Z.; Wei, S.; Sun, J.
Chem. Commun. 2007, 2977. (e) Wang, Z.; Wei, S.; Wang,
C.; Sun, J. Tetrahedron: Asymmetry 2007, 18, 705. (f) Pei,
D.; Zhang, Y.; Wei, S.; Wang, M.; Sun, J. Adv. Synth. Catal.
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Chem. Eur. J. 2008, 14, 8789.
the b-chloro enamides/enecarbamate product, which fa-
vors the formation of the thermodynamically more stable
Z-isomer.16,17
In summary, we have developed a highly efficient method
for the chlorination of enamides and enecarbamates with
MeSiCl3–DMSO, which allows for facile one-pot produc-
tion of b-chloro enamide and enecarbamate products un-
der mild conditions in high yields and with high
stereoselectivities. This method is easy to operate and
suitable for both cyclic and acyclic substrates.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (20672107 and 20732006).
(12) General Procedure for the Chlorination of Enamides
and Enecarbamtes
References and Notes
To a solution of enamide or enecarbamte (0.1 mmol) in
CH2Cl2 (1 mL) was added DMSO (0.15 mmol) and
chlorosilane (0.2 mmol). After stirring at r.t. for 1 h, the
reaction solution was quenched by sat. aq NaHCO3 (1 mL).
The resulting mixture was extracted with EtOAc (3 × 5 mL).
The combined organic layer was washed with brine (3 × 5
mL), dried over MgSO4, and concentrated under reduced
pressure. The residue was purified through column
chromatography on silica gel to give the desired b-
chlorinated enamide or enecarbamate.
(1) (a) Ashley, E. R.; Cruz, E. G.; Stoltz, B. M. J. Am. Chem.
Soc. 2003, 125, 15000. (b) Roff, G. J.; Lloyd, R. C.; Turner,
N. J. J. Am. Chem. Soc. 2004, 126, 4098. (c) Crawley, M.
L.; Goljer, I.; Jenkins, D. J.; Mehlmann, J. F.; Nogle, L.;
Dooley, R.; Mahaney, P. E. Org. Lett. 2006, 8, 5837.
(2) (a) Collier, N. C.; Patel, I.; Taylor, R. J. K. Tetrahedron Lett.
2001, 42, 5953. (b) Aitken, D. J.; Faure, S.; Roche, S.
Tetrahedron Lett. 2003, 44, 8827. (c) Singh, J.; Kronenthal,
D. R.; Schwinden, M.; Godfrey, J. D.; Fox, R.; Vawter, E. J.;
Zhang, B.; Kissick, T. P.; Patel, B.; Mneimne, O.; Humora,
M.; Papaioannou, C. G.; Szymanski, W.; Wong, M. K. Y.;
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(3) Cernak, T. A.; Gleason, J. L. J. Org. Chem. 2008, 73, 102.
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(5) Hoerrner, R. S.; Askin, D.; Volante, R. P.; Reider, P. J.
Tetrahedron Lett. 1998, 39, 3455.
(6) (a) Miossec, B.; Danion-Bougot, R.; Danion, D. Synthesis
1994, 1171. (b) Yamada, M.; Nakao, K.; Fukui, T.; Nunami,
K. Tetrahedron 1996, 52, 5751.
(13) Spectroscopic Data for (Z)-2b and 2h
Compound (Z)-2b: 1H NMR (300 MHz, CDCl3): d = 7.40–
7.30 (m, 8 H), 7.20 (s, 2 H), 6.70 (s, 1 H), 5.00 (s, 2 H), 2.09
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 153.3, 135.8,
135.0, 131.5, 128.9, 128.4, 128.2, 128.1, 128.0, 118.6,
67.1, 21.9; mp 80–82 °C. ESI-HRMS: m/z calcd for
C17H16ClNO2Na: 324.0767; found: 324.0762.
Compound 2h: 1H NMR (300 MHz, CDCl3): d = 7.24–7.11
(m, 4 H), 6.06 (s, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 2.96 (t,
J = 8.0 Hz, 2 H), 2.72 (t, J = 8.0 Hz, 2 H), 1.28 (t, J = 5.7 Hz,
3 H). 13C NMR (75 MHz, CDCl3): d = 154.4, 134.1, 131.6,
128.9, 127.9, 127.5, 127.3, 126.5, 122.9, 61.6, 31.4, 28.3,
14.4; mp 175–178 °C. ESI-HRMS: m/z calcd for
(7) (a) Das, J.; Reid, J. A.; Kronenthal, D. R.; Singh, J.;
Panaegrau, P. D.; Mueller, R. H. Tetrahedron Lett. 1992, 33,
7835. (b) Bland, J.; Shah, A.; Bortolusei, A.; Stammer, C. H.
J. Org. Chem. 1988, 53, 992.
C13H14ClNO2Na: 274.0611; found: 274.0605.
(14) Numata, T.; Togo, H.; Oae, S. Chem. Lett. 1979, 329.
(15) It should be noted that the hydrogen bonding in A2 may not
be very important since an N-methylated substrate 1l
(Figure 1) was also found to undergo smooth chlorination
Synlett 2009, No. 18, 2961–2964 © Thieme Stuttgart · New York

2964
D. Lin et al.
LETTER
under identical conditions, albeit with lower yield (79%) and
stereoselectivity (Z/E = 4:1).
(16) Calò, V.; Nacci, A.; Monopoli, L.; Lopez, A.; di Cosmo, A.
Tetrahedron 2001, 57, 6071.
(17) As pointed out by one referee, another possible pathway via
a direct attack of the enamide on the choro of a chloro-
dimethylsulfonium intermediate could not be excluded, see:
(a) Fraser, R. R.; Kong, F. Synth. Commun. 1988, 18, 1071.
(b) Akaji, K.; Tatsumi, T.; Yoshida, M.; Kimura, T.;
Fujiwara, Y.; Kiso, Y. J. Am. Chem. Soc. 1992, 114, 4137.
NMeCbz
1l
Figure 1
Synlett 2009, No. 18, 2961–2964 © Thieme Stuttgart · New York

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