Y.-M. Pu et al. / Tetrahedron Letters 51 (2010) 418–421
419
the acidic and aqueous medium. A less common protocol entails
starting with the combination of the oxidant-chlorinating agent,
Table 2
a
Oxidative chlorination of arylbenzyl sulfide 1 with DCDMH
10
11
12
Cl
such as KNO
3
–TMSCl,
3
KNO –SO
2
Cl
2
2
H O
2
–SOCl
2
,
Oxone–
N
NH
1
3
14
O
N
Cl
O
O
N
O
SOCl
2
,
or Br
2
–Cl
3
PO.
H
O
O
For our initial investigation of the proposed synthetic route to 3,
we chose 1a as the test substrate, which was obtained via a multi-
S
R'
R
S
CH
5 to 20 C
3
CN-HOAc-H
o
2
O
R
Cl
5
step sequence. Having made the requisite 1a, we then explored
R = Aryl or Heteroaryl
R' = Benzyl, Methyl
the key step in the synthesis. We commenced our research on this
transformation with the standard chlorinolysis protocol (Table 1,
entry 1). As expected, desired product 2b was obtained in very
good yield. However, this transformation was found indeed to be
extremely exothermic. We then focused on other known dual-
function agents. A number of the oxidants were examined to
Entry
Substrate
% yieldb
1
2
3
4
5
6
7
8
9
1a
85
90
92
90
88
86
86
84
0
6 5 2 6 5
C H –S–CH –C H
4-CF
3-CF
3
–C
–C
6
H
H
4
–S–CH
–S–CH
2-CF –C H –S–CH –C H
2
–C
–C
6
H
H
5
5
5
3
6
4
2
6
achieve oxidative chlorination of 1a, including the use of SO
NCS, and NaOCl in CH Cl –HOAc–H
O at ꢀ5 °C. The results were
shown in the Table 1. Sulfuryl chloride (SO Cl ) was effective in
converting 1a to the corresponding sulfoxide 2a in high yield with
.0 equiv of the reagent, but it was ineffective in breaking the C–S
2
Cl
2
,
3
6
4
2
6
4-CH
3
6 4 2 2 6 5
O–C H –CH –S–CH C H
2
2
2
2-Naphthalenyl–S–CH
3-Quinolinyl –S–CH
4-Br–C –S–CH
2 6 5
C H
C H
2 6 5
2
2
6
H
4
3
3
a
Reaction conditions: 4.0 mmol of the benzylsulfide and 2.0 equiv oxidation
agent in CH CN–HOAc–H O (40.0 mL:1.5 mL:1.0 mL) at 5 °C for 2 h.
bond required for the formation of sulfonyl chloride. Use of an
additional 3.0 equiv of this reagent did not have a positive influ-
ence on the outcome of the reaction (Table 1, entry 2). Although
N-chlorosuccinimide (NCS) has been reported to effect a similar
transformation, it gave little or no desired product (Table 1, entry
3
2
b
The assayed yields are the average of two runs.
strate. From these studies, the reaction stalled at 10% completion in
IPA, presumably due to decomposition of DCDMH. On the other ex-
treme, the starting material was completely consumed and no de-
sired product detected in DMF. The reaction proceeded cleanly to
give the desired product 2b in acetonitrile within 1 h at 5 °C, and
was less effective in isopropyl acetate. The reaction is much slower
3
). The starting material was recovered and found to be un-
changed. We observed that sodium hypochlorite solution (NaOCl)
afforded 95% of 2a and 5% of the desired product 2b with 3.0 equiv
of this reagent, but the conversion to the sulfonyl chloride required
6
.0 equiv of the reagent (Table 1, entry 4). However, the concentra-
tion of commercially available sodium hypochlorite solution is
generally not high and varied. For the best results, the solution
has to be titrated prior to use.
2 2
in non-polar solvents, such as CH Cl and toluene. Overall, it was
found that the oxidative chlorination reaction of 1a with DCDMH
in the aqueous acetonitrile is mild and effective. Under these con-
ditions, both chlorine atoms of DCDMH are consumed during the
reaction.
To further demonstrate the effectiveness and scope of oxidative
chlorination reactions of DCDMH, we prepared several arylbenzyl
sulfides 1, and carried out the oxidative chlorination on these sub-
strates under the optimized reaction conditions. The results are re-
ported in Table 2. In all cases, the oxidative chlorination proceeded
smoothly to afford the desired sulfonyl chlorides in good yields
(Table 2, entries 1–8). It is noted that no desired product was
formed from p-bromophenylmethyl sulfide (Table 2, entry 9). In-
Unsatisfied with the initial screening results, we began to
search for an alternative, effective and easy to use oxidative chlo-
rination agent. 2,4-Dichloro-5,5-dimethyl hydantoin (DCDMH) is
an inexpensive and readily available compound. It has been pri-
marily used as a swimming pool-treatment agent. Although it
15
was occasionally reported as chlorination agent or oxidation
1
6
agent , its use as an effective oxidative chlorination agent has
been largely unexplored. Remarkably, when 1a was subjected to
the standard reaction conditions with 3.0 equiv of DCDMH, the de-
sired product 2b was formed in very good yield and purity (Table 1,
entry 5), similar to those from chlorine gas.
stead,
a mixture of a-chloromethyl, a,a-dichloromethyl and
We then screened several different solvents (toluene, CH
2
Cl
2
,
a,a,a-trichloromethyl p-bromophenyl sulfoxides was obtained.
IPAC, IPA, CH CN, and DMF) to achieve the optimal reaction condi-
tion in combination with acetic acid and water, using 1a as a sub-
3
These results could be rationalized by the reaction mechanism pro-
posed in Scheme 2. The reactions proceed, in general, by the inter-
Table 1
a
Initial screening on oxidative chlorination agents with 1a
Boc
Boc
O
S
Boc
N
N
O
O
S
N
SO
2
CH
3
2
SO CH
S
N
3
2 3
SO CH
Cl
+
S
S
O
2
N
2
O N
S
O
2
1
a
2a
2b
b
Entry
Reagent
Cl
SO
Conversionb (%)
Sulfoxideb 2a (%)
Sulfonyl chloride , 2b (%)
1
2
2
100
100
0
100
0
2
Cl
2
100
100
0
95
5
c
1
0
00
0
3
4
NCS
NaClO
0
5
95
100
00
100
c
1
5
DCDMH
0
100
a
b
c
Reaction conditions: 4.0 mmol of the benzylsulfide 1a and 3.0 equiv agent in CH
The product distributions are the average of two runs, and are analyzed by HPLC against a pure and characterized standard.
equiv agent used.
2 2 2
Cl –AcOH–H O (15.0 mL:2.0 mL:4.0 mL) at 5 °C for 20 h.
6