Thiourea catalysis of NCS in the synthesis of α-chloroketones

Article abstract of DOI:10.1016/j.tetlet.2008.03.154

Thiourea catalyzes NCS α-chlorination of alkyl ketones to provide α-chloroketones in very high yields at exceptionally rapid reaction speeds.

Full text of DOI:10.1016/j.tetlet.2008.03.154

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Tetrahedron Letters 49 (2008) 3802–3804
Thiourea catalysis of NCS in the synthesis of a-chloroketones
*
Yujiang Mei, Paul A. Bentley , Juan Du
Department of Chemistry and Chemical Biology, MSC03 2060, University of New Mexico, Albuquerque, NM 87131-0001, USA
Received 25 February 2008; revised 31 March 2008; accepted 31 March 2008
Available online 4 April 2008
Abstract
Thiourea catalyzes NCS a-chlorination of alkyl ketones to provide a-chloroketones in very high yields at exceptionally rapid reaction
speeds.
Ó 2008 Published by Elsevier Ltd.
Table 1
a-Chlorinated carbonyl compounds are important inter-
Chlorination of styrene with thiourea/urea catalysts in water
mediates in organic synthesis because they can be con-
1
,2
verted into a diverse array of molecules.
They also
2 X=O
X
3
X=S
serve as metabolically more stable alternatives to hydrogen
and methyl functionality in drugs without loss of therapeu-
1.0 mmol
O
O
O
O
H2N
NH2
Cl
Cl
Cl
+
N
Cl
cm3 solvent, 23 ºC
+
3
3
tic efficacy. Such benefits have created considerable syn-
H
thetic interest in chlorination catalysis including the
1
O
4
5
4
–10
11,12
innovative use of organocatalyts,
Lewis acids,
Entry Solvent NCS
Catalyst
Reaction Conv./
Molar
1
3
14,15
amberlyst, transitional metal complexes
and inor-
a
(
mmol) (mmol)
time
yield (%) ration,
1
6–18
ganic reagents.
However, the need remains for a faster
4:5
reaction that provides chlorides in higher yields. To
address this desire we sought to exploit the capacity of
thiourea to catalyze the reactions of N-halosuccinimides,
demonstrated with chlorohydrin and b-chloroether
1
2
3
4
5
6
7
8
9
0
MeOH 2.5
MeOH 4.0
MeOH 4.0
MeOH 3.0
MeOH 2.5
MeOH 2.5
MeOH 2.5
MeOH 2.0
MeOH 1.2
—
72 h
72 h
100
78/—
100/—
53:1
12:1
3:1
4:1
5:1
2 (0.3)
3 (0.3)
3 (0.3)
3 (0.2)
3 (0.05)
3 (0.02)
3 (0.02)
3 (0.02)
3 (0.3)
3 (0.3)
3 (0.3)
3 (0.3)
1
<5 min
<5 min
<5 min
<5 min
10 min
20 min
20 min
48 h
b
100
b
1
9,20
100
synthesis.
b
100
9:1
Thiourea and its derivatives activate nitro, imine and
carbonyl functionality via hydrogen bonding in organocat-
b
100
10:1
11:1
53:1
13:1
11:1
4:1
b
100
2
1–39
c
alytic reactions,
whilst reactions that involve N-halo-
100/90
62/—
67/—
100/—
100/—
40
1
DCM
THF
4.0
4.0
succinimides are catalyzed by Brønsted acids. We
speculated that NCS could be activated by thiourea
hydrogen bonding to NCS oxygens.
The non-catalyzed a-chlorination of ketones (e.g., 1) is a
4
1
11
48 h
8 h
4.5 h
1
1
2
3
a
EtOAc 4.0
MeCN 4.0
1
9
3:1
Molar ratio determined by H NMR.
The yield of mixture of 4 and 5 was 100%.
90% yield of 4.
4
2
slow reaction (Table 1, entry 1) and whilst the addition of
urea retarded the reaction further (Table 1, entry 2), the
inclusion of thiourea gave a dramatic increase in the reac-
tion rate (Table 1, entry 3). However, a significant amount
b
c
of the dichloride (5) was observed. Chemoselectivity was
improved with the use of less NCS and thiourea, with a
reduction in the reaction time (Table 1, entries 4–9). It
was hoped that the examination of alternative solvents
*
Corresponding author. Tel.: +1 505 277 0369; fax: +1 505 277 2609.
E-mail address: pabco21@gmail.com (P. A. Bentley).
0
040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.03.154

Y. Mei et al. / Tetrahedron Letters 49 (2008) 3802–3804
3803
(
Table 1, entries 10–13) would speed up the reaction, but
1,3-diketones and b-ketoesters were studied. A clear trend
was discernable with 1,3-diketones reacting very rapidly
(Table 2, entry 4), faster than b-ketoesters that reacted fas-
ter (Table 2, entry 5) than ketones (7). The most reactive
substrate was diketone 13 that was transformed to the
dichloride in a comparable time to that for the conversion
of other substrates to chloride (Table 2, entry 8).
protic polar methanol proved optimal. This is rationalized
by further hydrogen bonding of methanol with thiourea to
give even stronger hydrogen bonds.
These refined conditions (Table 1, entry 9) were clearly
effective with comparatively little organocatalyst (2%/
mmol). They were applied to a variety of substrates (Table
2
0
2
). Acyclic dicarbonyl 6 was chlorinated at the slowest
We have demonstrated a low organocatalyst loading
approach to a-chlorination of ketones with unprecedented
rapidity and yield under mild conditions by thiourea catal-
ysis of NCS. Polar protic solvents were ideal for such trans-
formations. A similar catalytic strategy is being applied to
other halogenations with enantioselective versions of these
reactions using enantiopure derivatives of thiourea.
reaction rate (Table 2, entry 1) and gave a small amount
of the dichloride in addition to the chloride. Other cyclic
ketones proved more fruitful, with tetralone 7 twice as fast
as indanone 1 at chlorination and gave a higher yield
(
(
Table 2 entry 2). The methoxy derivative (8) was slower
Table 2, entry 3) than 7. A range of more acidic cyclic
Table 2
Thiourea catalyzed a-chlorination reactions of ketones
O
O
Thiourea, NCS
MeOH, 23 ºC
Cl
R2 R3
R1
R1
R2 R3
Entry
1
Ketone
Reaction time (min)
30
Chloride/yield (%)
O
O
O
O
O
O
OEt
OEt
OEt
+
Cl
Cl
Cl
6
1
4
15
82, 12
O
O
Cl
2
3
10
20
7
16
100
O
O
Cl
1
7 MeO
8
9
MeO
1
00
O
O
O
O
O
O
O
O
Cl
Cl
4
5
<5
10
18
100
O
OMe
OMe
19
1
0
1
00
O
O
O
Cl
6
7
OEt
10
10
15
OEt
1
1
2
20
21
86
O
O
O
Cl
O
1
OMe
OMe 95
O
O
O
Cl
Cl
8
a
1
3
22
O
51
a
In this case only 1.2 mmol of NCS was employed, but an optimal yield of the dichloride can only be obtained with+2.0 mmol of NCS. If the reaction’s
efficiency were the same, 2.0 mmol of NCS would give the dichloride in 85% yield.

3
804
Y. Mei et al. / Tetrahedron Letters 49 (2008) 3802–3804
13. Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J. S.
Acknowledgements
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The financial support from the Department of Chemis-
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