Thiourea catalysis of NCS in the synthesis of chlorohydrins

Article abstract of DOI:10.1016/j.tetlet.2007.11.211

Thiourea catalysis of reactions utilizing N-succinimides is demonstrated with NCS chlorination of olefins in the presence of water to afford chlorohydrins.

Full text of DOI:10.1016/j.tetlet.2007.11.211

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Tetrahedron Letters 49 (2008) 1425–1427
Thiourea catalysis of NCS in the synthesis of chlorohydrins
Paul A. Bentley *, Yujiang Mei, Juan Du
Department of Chemistry and Chemical Biology, MSC03 2060, University of New Mexico, Albuquerque, NM87131-0001, USA
Received 26 March 2007; revised 27 November 2007; accepted 29 November 2007
Available online 8 December 2007
Abstract
Thiourea catalysis of reactions utilizing N-succinimides is demonstrated with NCS chlorination of olefins in the presence of water to
afford chlorohydrins.
Ó 2007 Published by Elsevier Ltd.
Why are organohalides an important synthetic goal?
They allow the incorporation of a variety of functional
groups containing carbon, nitrogen, sulfur and oxygen.1
In drug design halogen replacement of proton or methyl
groups attached to carbon has often provided a more
metabolically stable compound invariably without loss of
biological activity.2 Vicinal halohydrins have also been
key intermediates to a number of marine natural products.3
Synthetically halohydrins have been useful in 1,2-alkyl shift
with formation of a ketone,4 ring contraction with alde-
hyde formation mediated by silver oxide,5 cis-diol forma-
tion via a ketene acetal6 and epoxidation7 among other
reactions.
Chlorohydrins have been extensively prepared by epox-
ide opening with metal halides.8 Alternatively, hypohalous
acids and hypohalite reactions with an olefin also have pro-
vided halohydrins.9 In addition NaIO4/NaCl,10 N-methyl-
morpholine-N-oxide/cyanuric chloride,11 Pd(II)-complex/
CuCl2,12 trichloroisocyanuric acid13 and N-chlorosaccha-
rins14 have all proven good sources of chlorine to form
chlorohydrins.
ponding preparation of chlorohydrins from NCS is not
documented in the literature. We wondered if an organo-
catalytic approach to this opportunity would prove
effective.
A reinvigorated interest in organocatalysis17,18 in recent
years has resulted in a plethora of new catalytic processes
often carried out with excellent stereoselectivity. Proline
based systems have been successfully employed in the prep-
aration of a-halocarbonyl,19,20 while interest in thiourea
catalytic applications has grown.
Urea and its derivatives21 were first used to catalyze sulf-
oxide allylation22 and Claisen rearrangements.23 These
catalysts then saw expanded utilisation in Diels–Alder,24
1,3-dipolarcycloaddition,25
nitrone
TMSCN
addi-
tion,26 Strecker,27 Mannich,28,29 aza-Henry,30 hydrophos-
phonylation,31 Pictet–Spengler32 Michael addition,33–35
Baylis–Hillman36–38 and reductive amination39 reactions.
Several mechanisms have invoked thiourea hydrogen
bonding capability with a carbonyl oxygen40 and reactions
with N-halosuccinimides were catalyzed by Brønsted
acids41 suggestive of mechanisms with Figure 1 as a key
step.
N-Halosuccinimides have constituted some of the most
popular sources of halogens. Indeed, bromohydrins have
been produced by olefin reaction with NBS in THF and
water.15 Interestingly, while NCS has been useful16 for a-
chlorination of carbonyl, thioether, sulfoxide, sulfone and
chlorination of aromatic compounds or amines, the corres-
Styrene (1) reacted with NCS in a wet solvent very slowly
to give chlorohydrin 5 in a negligible yield (Table 1, entry 1)
and unfortunately the addition of urea offered only mar-
ginal catalysis (Table 1, entry 2). A notable improvement
was observed with the use of either thiourea (2) or N,N-di-
methylthiourea (3) as catalysts.42 Both gave a fast reaction
with excellent regiocontrol (the other regioisomer was not
observed) in moderate yields (Table 1, entries 3 and 4).
*
Corresponding author. Tel.: +1 505 277 0369; fax: +1 505 277 2609.
E-mail address: pabco21@gmail.com (P. A. Bentley).
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.211

1426
P. A. Bentley et al. / Tetrahedron Letters 49 (2008) 1425–1427
Table 2
S
Chlorination of a variety of olefin substrates in water
N
H
N
H
O
R
S
R2
2
O
N Cl
R2
R
R3
HO
R1
H2N NH2
R
O
R3
Cl
R1
Cl
N
23 o
R
THF/H2O
C
R4
6-14
R4
15-23
O
= Hydrogen bonding
Entry Substrate
Time Product, Yield (%)
(h)
Fig. 1. Possible key step of the mechanism.
OH
1
2.0
Cl
The investigation then focused upon optimisation of reac-
tion conditions. Catalyst loading was altered with less cata-
lyst responsible for a slower reaction (Table 1, entry 5) and
more catalyst responsible for a faster reaction with slightly
lower yield (Table 1, entry 6). Half the mass of NCS in a
reaction gave a drastic increase in the reaction’s duration
and a significant loss of reaction yield (Table 1, entry 7).
The replacement of THF with acetonitrile caused a minimal
change of reaction yield (Table 1, entry 8); however, with
water as the only solvent a slow reaction with a limited yield
was observed (Table 1, entry 9).
The initial conditions prior to attempted optimisation
proved to be the best. The reaction conditions were applied
to a variety of substrates containing different substituted
olefins (9–14) with varied electronic environments.
Styrene derivatives with replacement functional groups
at the para position of the phenyl ring were studied. A
F
6
7
F
15
16
(55)
OH
Cl
2
3
4
5
1.0
5.0
1.0
1.0
(60)
Cl
OH
OH
Cl
nHexyl
4 : 3 (34)
nHexyl
nHexyl
8
9
17a : 17b
OH
Cl
18
(82)
Cl
OH
OH
Cl
Table 1
10
11
3 : 2 (53)
Chlorination of styrene with thiourea/urea catalysts in water
19a : 19b
S
or
NH2
S
or
O
Cl
H2N
N
N
H2N
NH2
1
O
OH
H
H
3
HO
2
4
6
1.5
Catalyst
5
N Cl
a(56)
+
Cl
20
21
23 oC
O
1.0 mmol
Entry Catalyst
(Mol %)
NCS
(mmol)
Solvent
(3 cm3)
Time
(h)
Yield
(%)
O
OH O
Cl
7
8
9
0.5
1.5
0.5
1
2
3
4
5
6
7
8
9
—
4.0
THF/H2O
(1:1)
THF/H2O
(1:1)
THF/H2O
(1:1)
THF/H2O
(1:1)
THF/H2O
(1:1)
THF/H2O
(1:1)
THF/H2O
(1:1)
MeCN/H2O
(1:1)
12.0
36.0
3.0
5
21
54
69
67
57
46
66
43
b(48)
12
4 (20)
3 (20)
2 (20)
2 (10)
2 (50)
2 (20)
2 (20)
2 (20)
4.0
4.0
4.0
4.0
4.0
2.0
4.0
4.0
OH
3.0
13
14
Cl
22
23
(32)
9.0
OH
1.5
Cl
c(64)
48.0
3.0
a
b
c
cis:trans ratio 5:6.
cis:trans ratio 1.5:3.
cis:trans ratio 2:9.
H2O
10.0

P. A. Bentley et al. / Tetrahedron Letters 49 (2008) 1425–1427
1427
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tionality change to an aliphatic moiety such as n-hexyl (8)
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In summary, the organocatalysis of reactions involving
N-succinimides have been demonstrated, with cheap and
commercially available reagents. NCS showed unprece-
dented chlorination of olefins in the presence of water
and gave chlorohydrins in moderate to good yields when
catalyzed by thiourea or its derivatives. Work is currently
focused towards other chlorination or bromination reac-
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Acknowledgments
Financial support from the Department of Chemistry
and Biological Chemistry and the Research Allocation
Committee, University of New Mexico is greatly
acknowledged.
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Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.211.
References and notes
42. This trend maybe ascribed to the difference in pKa (urea is 26.9 and
thiourea is 21.0, both in DMSO) given the earlier mechanistic
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