A facile and efficient approach to N-protected-β-sulfinylenamines via C-sulfinylation of enamides and enecarbamates

Article abstract of DOI:10.1002/adsc.201000084

A practical method has been developed for the C-sulfinylation of enamides and enecarbamates using sodium phenylsulfinate/methyltrichlorosilane (PhSO ₂Na/MeSiCl₃) as the sulfinylating reagent and N,N-dimethylacetamide (DMAc) as the Lewis base promoter, which allows for the preparation of a variety of N-protected-β-sulfinylenamines in high yields and good stereoselectivities. The Lewis base is found to be important for both the in situ generation of the active sulfinylating species (PhSOCl) and the sulfinylation step.

Full text of DOI:10.1002/adsc.201000084

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DOI: 10.1002/adsc.201000084
A Facile and Efficient Approach to N-Protected-b-Sulfinyl-
enamines via C-Sulfinylation of Enamides and Enecarbamates
Yinhui Li,a,b Ke Cheng,a,b Xiaoxia Lu,a,* and Jian Suna,*
a
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041,
Peopleꢀs Republic of China
Fax : (+86)-28-8522-2753; e-mail: luxx@cib.ac.cn or sunjian@cib.ac.cn
Graduate School of Chinese Academy of Sciences, Beijing 100080, Peopleꢀs Republic of China
b
Received: February 1, 2010; Published online: July 28, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000084.
Abstract: A practical method has been developed
for the C-sulfinylation of enamides and enecarbam-
ACHTUNGTRENNUNG
nucleophiles to synthesize sulfoxides. Glaros[11] and
Lavilla[12] have reported that ketones and dihydropyri-
dines can be directly sulfinylated with sulfinyl chlo-
ride to produce sulfoxide derivatives which, however,
only give low yields. Herein, we present the first
highly effective method for C-sulfinylation of enam-
ides and enecarbamates with in situ generated phenyl
sulfinyl chloride (PhSOCl), which allows for the prep-
aration of N-protected-b-sulfinylenamines in high
yields (up to 99%) and good stereoselectivities.
ACHTUNGTRENNUNG
agent and N,N-dimethylacetamide (DMAc) as the
Lewis base promoter, which allows for the prepara-
tion of a variety of N-protected-b-sulfinylenamines
in high yields and good stereoselectivities. The
Lewis base is found to be important for both the in
situ generation of the active sulfinylating species
(PhSOCl) and the sulfinylation step.
Recently, in an attempt to use in situ generated
enecarbamate 1a from 1a’ as the nucleophile for
Keywords: enamides; enecarbamates; Lewis base;
chlorosilane-promoted Mannich-type reactions,[13]
a
sodium
phenylsulfinate/methyltrichlorosilane
new compound 2a was obtained as a by-product
(Scheme 1). We speculated that this side reaction
should be due to the nucleophilic attack of the ene-
carbamate 1a to an active sulfinyl species. To explore
if such a side reaction could be developed into a
useful new method for the preparation of functional-
(PhSO2Na/MeSiCl3); C-sulfinylation
Organic sulfoxides are an important class of com- ized vinyl sulfoxides, we directly treated isolated 1a
pounds that have found broad applications.[1] They with sodium phenylsufinate (PhSO2Na) and SiCl4 in
serve as key structural components in some drug mol- the presence of DMF in dry CH2Cl2. To our delight,
ecules.[2] Chiral sulfoxides are well known chiral auxil- the desired product 2a was achieved in 92% yield in
iaries and ligands for asymmetric synthesis.[3] Besides 1.5 h (entry 1, Table 1).
the oxidation of sulfides,[4] the sulfinylation of organo-
metallic nucleophiles (Li,[5] Cu,[6] Zn,[7] and Mg[8] re-
agents) with sulfinates represents the most important
method for the preparation of sulfoxides, which, how-
ever, suffers from limited practicality due to the use
of relatively expensive organometallics that typically
require low temperature and moisture-free conditions.
Sulfinylation of organometallics-free carbon nucelo-
philes with sulfinyl chloride is in principle a more
practical and cost-efficient method. Although the O-
sulfinylation[9] of alcohols and the N-sulfinylation[10] of
amines with sulfinyl chloride are well-known and effi-
cient approaches to sulfinates and sulfinamides, re-
spectively, so far there have been no effective meth-
ods available for the C-sulfinylation of organic carbon Cbz=benzyloxycarbonyl, Boc=tert-butoxycarbonyl.
Scheme 1. Observed C-sulfinylation of enecarbamate 1a.
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Adv. Synth. Catal. 2010, 352, 1876 – 1880

A Facile and Efficient Approach to N-Protected-b-Sulfinylenamines
Table 1. Effects of Lewis acids on C-sulfinylation.[a] Table 2. Effects of Lewis bases on C-sulfinylation.[a]
Yield [%][b]
Entry
Lewis acid (LA)
Yield [%][b]
Entry
Lewis base (LB)
1
2
3
4
5
6
7
8
9
SiCl4
92
96
84
–
–
–
–
–
–
1
2
3
4
5
6
7
DMF
DMAc
pyridine
HMAp
DMAP
TEA
92
>99
74
67
61
MeSiCl3
Me2SiCl2
Me3SiCl
Ph3SiCl
HSiCl3
AlCl3
trace
–
nr[c]
FeCl3
CuCl2
[a]
Unless stated otherwise, reactions were performed on a
0.1 mmol scale with 1a/PhSO2Na in a 1:2 ratio in
4.0 equiv. MeSiCl3 and 5 equiv. base in 1.0 mL of CH2Cl2
at 08C for 1.5 h.
Isolated yield of 2a as E/Z mixture based on 1a.
No reaction.
[a]
Unless stated otherwise, reactions were performed on a
0.1 mmol scale with 1a/PhSO2Na in a 1:2 ratio in
4.0 equiv. Lewis acid and 5 equiv. DMF in 1.0 mL of
CH2Cl2 at 08C for 1.5 h.
[b]
[c]
[b]
Isolated yield of 2a as E/Z mixture based on 1a.
Some other Lewis acids were also tested for this re- to excellent yields (entries 1–16). Moderate to good
action. Methyltrichlorosilane (MeSiCl3) was found to stereoselectivities with ratios of Z/E ranging from
be as highly effective as SiCl4, affording 96% yield in 1.5:1 to 15:1 were also observed. The stereochemis-
1.5 h (entry 2), and dimethyldichlorosilane (Me2SiCl2) tries of both isomers were unambiguously determined
1
to be slightly less effective (84% yield, entry 3), by 2D H-1H NOESY.
whereas other chlorosilanes such as Me3SiCl, Ph3SiCl
The sulfinylation of aromatic six-membered cyclic
and HSiCl3 were all shown to be totally inactive (en- substrates 1q–t could also proceed smoothly to afford
tries 4–6), as were transition metal Lewis acids such the corresponding products in high yield (entries 17–
as aluminium chloride, iron chloride, and copper chlo- 20). Substrate 1u with a five-membered ring could
ride also (entries 7–9). Thus, we selected MeSiCl3 as also undergo the sulfinylation, albeit with moderate
the Lewis acid promoter for further studies.
yield (entry 21).
Next, we examined the effects of different Lewis
The mechanistic pathway of the Lewis base-pro-
bases other than DMF on the sulfinylation of 1a with moted sulfinylation of 1 is proposed as follows
PhSO2Na/MeSiCl3 in CH2Cl2 at 08C. As shown in (Scheme 2): PhSO2Na first reacts with MeSiCl3 to
Table 2, the sulfinylation reaction went even more ef- give sulfinate A1, which, with the assistance of Lewis
ficiently with N,N-dimethylacetamide (DMAc) than base, gives rise to PhSOCl as the active sulfinylating
DMF, affording the product in quantitative yield species. PhSOCl then encounters the nucleophilic
(entry 2). Other Lewis bases such as pyridine, HMAP attack of the C=C bond of 1 to give intermediate A2,
and DMAP could also promote the reaction, but with which subsequently undergoes elimination and tauto-
lower efficiency, affording 74%, 67% and 61% yields, merization to furnish product 2 as an E/Z mixture.
respectively (entries 3–5). In contrast, triethylamine The involvement of PhSOCl as the actual sulfinylat-
(TEA) proved to be completely ineffective (entry 6). ing species was confirmed by the smooth sulfinylation
Notably, no reaction occurred in the absence of Lewis of 1a using the freshly prepared and distilled PhSOCl
base (entry 7), suggesting an indispensable role of (Scheme 3). Notably, when PhSOCl was directly used,
Lewis base for activation.
the sulfinylation could proceed in the absence of a
After having demonstrated that the sulfinylation of Lewis base, but only afforded moderate yield, where-
1a with PhSO2Na/MeSiCl3 could be furnished in high as in the presence of either N,N-diisopropylethyl-
efficiency and excellent yield with the assistance of
ACHTUNGTRENaNUNG mine (DIEA) or DMAc, high yields were again ob-
DMAc, we next explored the scope and limitation of tained. This clearly indicates that besides assisting the
this reaction for various enamides and enecarbamates generation of PhSOCl, the Lewis base also plays a
1a–u.[14] As shown in Table 3, the acyclic aromatic and role in promoting the sulfinylation, possibly through
aliphatic enecarbamates and enamides 1a–p, all un- the activation of the sulfinyl group by forming a posi-
derwent smooth sulfinylation to produce the desired tively charged active species (PhSOLBÈ). We thus en-
product N-protected-b-sulfinylenamines 2a–p in good visioned that an asymmetric version of this reaction
Adv. Synth. Catal. 2010, 352, 1876 – 1880
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Table 3. C-Sulfinylation of various enamides/enecarbamates 1.[a]
Entry
Substrate
Product
Yield [%][b]
E/Z[c]
1
2
3
4
5
1a
1b
1c
1d
1e
R3 =OCH2Ph
R3 =Me
R3 =t-Bu
R3 =Ph
99
90
99
94
99
7.8/1
15/1
6.7/1
6.6/1
4.5/1
OEt
6
1f
99
5.6/1
7
8
9
10
11
12
1g
1h
1i
1j
1k
1l
R1 =Ph
99
63
86
66
53
79
7.8/1
3.2/1
1.5/1
4.6/1
1.6/1
2.2/1
R1 =4-F-C6H4
R1 =2-Cl-C6H4
R1 =4-OAc-C6H4
R1 =4-Me-C6H4
R1 =2-naphthyl
13
14
15
1m
1n
1o
R2 =n-C3H7
R2 =Me
77
75
99
11.2/1
nd[d]
2.8/1
R2 =Bn
16
1p
87
10.3/1
17
18
19
20
1q
1r
1s
1t
R3 =OEt
R3 =Me
R3 =t-Bu
R3 =Ph
99
86
89
90
21
1u
51
[a]
Unless specified otherwise, all reactions were performed on a 0.1 mmol scale with 1/PhSO2Na in a 1:2 ratio and 4.0 equiv.
MeSiCl3 and 5.0 equiv. DMAc in 1.0 mL of CH2Cl2 at 08C for 0.5–9 h.
[b]
[c]
Isolated yield of 2 as E/Z mixture based on 1.
1
The E/Z ratio of 2 was analyzed by HPLC, the E and Z configuration were determined by 2D H-1H NOESY, details are
given in the Supporting Information.
The E and Z isomers were not distinguishable.
[d]
Scheme 2. Proposed mechanism of the Lewis base-promoted C-sulfinylation.
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Adv. Synth. Catal. 2010, 352, 1876 – 1880

A Facile and Efficient Approach to N-Protected-b-Sulfinylenamines
Acknowledgements
We are grateful for financial supports from the National Sci-
ence Foundation of China (20732006, 20972152 and
20972153).
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ACHTUNGTRENNUNGylenamines via Lewis base-promoted C-sulfinylation
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General Procedure for the C-Sulfinylation of
Enamides/Enecarbamates 1a–u
Under an argon atmosphere, methyltrichlorosilane (50 mL,
0.4 mmol) was added dropwise to a stirred solution of enam-
ide/enecarbamate 1 (0.10 mmol), sodium phenylsulfinate
(32.8 mg, 0.20 mmol) and DMAc (47 mL, 0.50 mmol) in an-
hydrous CH2Cl2 at 08C. The mixture was allowed to stir at
the same temperature for 0.5–9 h. The reaction was
quenched with a saturated aqueous solution of NaHCO3
(5 mL) and extracted with ethyl acetate. The combined ex-
tracts were washed with brine and dried over anhydrous
MgSO4 and the solvents were evaporated under vacuum.
Purification by column chromatography (silica gel, PE/
EtOAc) afforded pure N-protected-b-sulfinylenamines 2.
The E/Z ratio values were determined by using established
HPLC techniques.
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Adv. Synth. Catal. 2010, 352, 1876 – 1880