Thiourea catalysis of NCS in the synthesis of β-chloroethers

Article abstract of DOI:10.1016/j.tetlet.2008.02.040

Thiourea catalysis of olefin chlorination with NCS in an alcohol gives β-chloroethers with a very fast reaction of high yield.

Full text of DOI:10.1016/j.tetlet.2008.02.040

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Tetrahedron Letters 49 (2008) 2653–2655
Thiourea catalysis of NCS in the synthesis of b-chloroethers
Paul A. Bentley *, Yujiang Mei, Juan Du
Department of Chemistry and Chemical Biology, MSC03 2060, University of New Mexico, Albuquerque, NM 87131-0001, USA
Received 14 December 2007; revised 7 February 2008; accepted 7 February 2008
Available online 13 February 2008
Abstract
Thiourea catalysis of olefin chlorination with NCS in an alcohol gives b-chloroethers with a very fast reaction of high yield.
Ó 2008 Published by Elsevier Ltd.
Table 1
Organocatalysts allow environmentally friendly cata-
lysis in a number of synthetic transformations.1 The
Optimized catalysis of olefin chlorination
Cl
organocatalytic properties of urea were initially applied
to sulfoxide allylation2 and Claisen rearrangement,3 but
has since seen as an expanded role.4–19 However, the
synthesis of b-chloroethers by chlorination remains unex-
plored. Non-organocatalytic methods to prepare b-chlo-
roethers with an alcohol20–37 have failed to achieve a
product in high yield at a very rapid rate.
X
O
1
2, X=O
3, X=S
NH2
RO
H2N
+
N Cl
ROH, 74 mmol
O
1.0 mmol
Entry
R, Temp.
Catalyst
(mol %)
NCS
(mmol)
Time
Yield
(%)
(°C)
Our studies have embraced catalyzed chlorination with
N-chlorosuccinimide (NCS, 1). We have demonstrated
the synthesis of halohydrin with water and NCS catalyzed
by thiourea.38 Subsequently, a broader profile of reactions
was sought for this technique. The reaction of NCS with
styrene in methanol provided the b-chloroether in very
poor yield after a long time (Table 1, entry 1). Like the
halohydrin synthesis,38 urea (2) offered no significant cata-
lytic advantage when b-chloroethers were formed, with
only a marginal improvement in yield (Table 1, entry 2).
By contrast, thiourea (3) allowed the very fast chlorination
of styrene with very good yield and complete regiocontrol
(Table 1, entry 3). The amount of thiourea was diminished
to 5 mol % to afford a more slowly converted reaction; but
with a notably improved yield (Table 1, entries 4 and 5).
However, even lower levels of catalyst were detrimental
to the reaction’s performance (Table 1, entry 6). Less
NCS gave a slower reaction and lower yield (Table 1,
1
2
3
4
5
6
7
8
9
10
11
12
a
Me, 23
Me, 23
Me, 23
Me, 23
Me, 23
Me, 23
Me, 23
Me, 23
Et, 23
—
0
20
20
10
5
2
5
5
5
4
4
4
4
4
4
2
1.2
2
96 h
96 h
10 min
15 min
30 min
96 h
45 min
96 h
3 h
33
48
85
91
96
78
83
61
75
53
44
45a
2
3
3
3
3
3
3
3
3
3
3
iPentyl, 23
tBu, 28
Ph, 42
5
5
5
2
2
2
24 h
24 h
4 h
1.7:1.0 Ratio of regioisomers.
entries 7 and 8). Economy, reaction speed and yield were
evaluated when conditions were selected as optimal (Table
1, entry 7).
Next, the alcohol was varied and the effect on the reac-
tion observed. Methanol replacement with ethanol (Table
1, entry 9) reduced the reaction rate with a slightly lower
yield. At a higher temperature, phenol also reacted with
similar speed, but afforded the b-chloroether in only mod-
erate yield (Table 1, entry 12). However, chlorination in
*
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 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.02.040

2654
P. A. Bentley et al. / Tetrahedron Letters 49 (2008) 2653–2655
Table 2
Me
Me
O
H
O
H
A variety of alkenes chlorinated with NCS
O
S
H
H
S
N
N
R1 R2
R4 R3
N
Cl
H
H
O
H2N
NH2
R2
R2
O
MeO
R1
Cl
1
5 mol%
3
2 mmol
R3
R3
Cl
N
R1
Methanol (3.0 cm3), 23 o
C
R4
R4
O
=
Hydrogen bonding
Entry Olefin, solvent
Chloroethera
Time Yield
(min) (%)
Fig. 1. Speculated key step in the catalytic process.
OMe
Cl
1
90
94
95
the proton at the para position of styrene with a halogen
(Table 2, entry 1) that provided a slower reaction with a
higher yield. A similar proton replacement with a methyl
group caused an even slower reaction (Table 2, entry 2).
The phenyl group of styrene was replaced with an aliphatic
functionality that gave a faster reaction rate and an excel-
lent yield of the b-chloroethers (Table 2, entry 3) with a loss
of regioselectivity. Subsequently, disubstituted olefins were
scrutinized with the reaction of stilbene (7 or 8) that pro-
vided a significantly faster reaction than styrene and notice-
ably higher yield (Table 2, entries 4 and 5). However,
digeminal substituted olefin 9 offered the fastest reaction
with a very good yield (Table 2, entry 6). Next, cyclic ole-
fins were explored and provided variable results. Indene
(10) reacted more slowly than styrene but with identical
yield. However, cyclohexane 11 gave a faster reaction than
styrene with complete stereocontrol in a moderate yield. In
general, excellent regioselectivity was demonstrated in a
wide range of substrates (except 6) and the reactions were
achieved rapidly and in good yield.
4 Cl
12 Cl
OMe
Cl
2
120
5
13
OMe
Cl
Cl
nOctyl
OMe
nOctyl
nOctyl
3
15
15
100
95
6
14a/b (1.7:1.0)
OMe
7
4
Cl
15
16
(2.0:1.0)
OMe
5
15
98
Cl
8
(3.0:1.3)
In light of the propensity of thiourea to hydrogen bond
with carbonyls39 and the capacity for reactions with N-
halosuccinimides to be catalyzed by Brønsted acids,40 we
speculate that a key step in the mechanism may include
hydrogen bonds between amidic oxygen and thiourea pro-
tons as shown in Figure 1.38 Polar protic solvents may pro-
vide an extended and strong hydrogen bond network.
Thiourea is adept at the catalysis of NCS reactions and
affords the fastest chlorination of alkenes to give b-chloroe-
thers with excellent yields. To optimize conditions, the
influence on the reaction of different amounts of NCS
and thiourea has been discerned. A diverse array of olefins
and a number of alcohols, including very effective primary
alcohols, have been shown to be applicable to the tech-
nique. Further thiourea catalyzed NCS chlorinations are
under investigation and NBS has shown some distinctly
different facets in the way it interacts with thiourea that
are currently under further examination. An enantiopure
derivative of thiourea is being designed to afford asymmet-
ric reactions.
MeO
Cl
6
5
94
83
9
17
18
OMe
Cl
7
90
10
(3.0:1.0)
OMe
Cl
8
15
56
11
19
Ratios determined by 1H NMR.
a
pentan-3-ol or t-butanol gave a much slower reaction with
only moderate yield (Table 1, entries 10 and 11) despite an
elevated temperature. Overall bulkier alkyl/aryl (R) func-
tionality gave reduced reaction rate and yield, probably
due to steric hindrance, although reactions would be
improved with more catalysts or NCS.
Ultimately, styrene was replaced with alternative olefins
and the modified substrate’s influence upon the reaction
was investigated.
Acknowledgements
Monosubstituted olefins with various electronic envi-
ronments were studied initially with the replacement of
Financial support from the Department of Chemistry
and Chemical Biology and the Research Allocation

P. A. Bentley et al. / Tetrahedron Letters 49 (2008) 2653–2655
2655
19. Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.; Rudolph, S.
Org. Lett. 2006, 8, 741.
Committee, University of New Mexico, is gratefully
acknowledged.
20. Methods for the synthesis of b-chloroether include hypervalent iodine
reagents, hypochlorous acids and hypochlorites reactions, NaIO4/
NaCl, phenylselenyl chloride, nitrobenzenesulfonyl peroxide and
tetraethylammonium chloride, electrolysis with sodium chlorides,
chlorine, N-methylmorpholine-N-oxide/cyanuric chloride, Pd(II)-
complex/CuCl2, trichloroisocyanuric acid and N-chlorosaccharins.
21. Yusubov, M. S.; Drygunova, L. A.; Zhdankin, V. V. Synthesis 2004,
2289.
Supplementary data
Experimental procedures with 1H and 13C NMR spectra
for all products are available. Supplementary data associ-
ated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2008.02.040.
22. Yusubov, M. S.; Yusubov, R. J.; Filimonov, V. D.; Chi, K.-W. Synth.
Commun. 2004, 34, 443.
23. Yusubov, M. S.; Yusubova, R. Y.; Filimonov, V. D.; Ki-Whan, C.
Russ. J. Org. Chem. 2002, 38, 902.
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