Efficient α-thiocyanation of ketones using pyridinium hydrobromide perbromide

Article abstract of DOI:10.1080/10426507.2011.616561

The direct α-thiocyanation of ketones with ammonium thiocyanate has been achieved using pyridinium hydrobromide perbromide under mild and neutral conditions to produce α-ketothiocyanates in excellent yields and with high selectivity. Copyright

Full text of DOI:10.1080/10426507.2011.616561

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Efficient α-Thiocyanation of Ketones
Using Pyridinium Hydrobromide
Perbromide
Liqiang Wu a & Xiaojuan Yang b
a School of Pharmacy , Xinxiang Medical University , Xinxiang ,
Henan , China
b College of Chemistry and Chemical Engineering , Xinxiang
University , Xinxiang , Henan , China
Published online: 05 Apr 2012.
To cite this article: Liqiang Wu & Xiaojuan Yang (2012) Efficient α-Thiocyanation of Ketones Using
Pyridinium Hydrobromide Perbromide, Phosphorus, Sulfur, and Silicon and the Related Elements,
187:6, 748-753, DOI: 10.1080/10426507.2011.616561
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Phosphorus, Sulfur, and Silicon, 187:748–753, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.616561
EFFICIENT α-THIOCYANATION OF KETONES USING
PYRIDINIUM HYDROBROMIDE PERBROMIDE
Liqiang Wu1 and Xiaojuan Yang2
1School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China
2College of Chemistry and Chemical Engineering, Xinxiang University,
Xinxiang, Henan, China
GRAPHICAL ABSTRACT
O
O
PHPB
CH3CN, rt
R2
+
R2
NH4SCN
R1
R1
SCN
76--92%
Abstract The direct α-thiocyanation of ketones with ammonium thiocyanate has been achieved
using pyridinium hydrobromide perbromide under mild and neutral conditions to produce α-
ketothiocyanates in excellent yields and with high selectivity.
Keywords Thiocyanation; ketones; ammonium thiocyanate; pyridinium hydrobromide
perbromide; synthesis
INTRODUCTION
Thiocyanate is a versatile synthon which can be readily transformed into other func-
tional groups such as sulfide,1 aryl nitrile,2 thiocarbamate,3 and thionitrile.4 In particular,
α-ketothiocyanates are useful intermediates in the synthesis of sulfur-containing hetero-
cycles, such as thiazoles.5 Some of these thiazoles exhibit herbicidal and other important
biological activities.6 Thus, the direct thiocyanation of ketones is of prime importance. The
use of the bromodimethylsulfonium bromide/ammonium thiocyanate,7 oxone/ammonium
thiocyanate,8 heteropoly acid/ammonium thiocyanate,9 dichloroiodobenzene/lead(II) thio-
cyanate,10 potassium peroxydisulphate/copper(II) complex,11 I2/ammonium thiocyanate,12
FeCl3/ammonium thiocyanate,13 and NBS/ammonium thiocyanate14 reagent systems have
been reported for the direct thiocyanation of ketones. However, most of these reported
methods involve the use of a large excess of strong oxidizing agents and toxic metal thio-
cyanates, resulting in low conversions due to the formation of complex mixtures of products,
which limit their practical utility in organic synthesis. Since organosulfur compounds have
Received 31 May 2011; accepted 18 August 2011.
We are pleased to acknowledge the financial support from Xinxiang Medical University.
Address correspondence to Liqiang Wu, School of Pharmacy, Xinxiang Medical University, Xinxiang,
Henan 453003, China. E-mail: wliq1974@sohu.com
748

α-THIOCYANATION OF KETONES USING PYRIDINIUM HYDROBROMIDE PERBROMIDE 749
become increasingly useful and important in the field of drugs and pharmaceuticals, the
development of simple, convenient, and efficient approaches for their synthesis is desirable.
Pyridinium hydrobromide perbromide (PHPB) is a solid complex of pyridine with
bromine which is used as a source of bromine. It is more convenient to use definite
small amounts of active bromine with this stable reagent than with bromine itself. It had
been employed for bromination of ketones, acetals, alkenes, activated phenols, anilines
and heterocycles as well as oxidation/dehydrogenation reagent.15 However, the literature
describing α-thiocyanation of ketones using PHBP is not available. In connection with our
work on hydrobromide perbromide and bromide perbromide reagents,16 we report herein
the efficient α-thiocyanation of ketones using this reagent (Scheme 1).
O
O
PHPB
CH3CN, r.t.
R2
+
R2
NH4SCN
R1
R1
SCN
1
2
3
Scheme 1
RESULTS AND DISCUSSION
Since the nature of solvent influences the rate of reaction, α-thiocyanation of ace-
tophenone as a model substrate was performed in various solvents at room temperature.
According to the data presented in Table 1, CH3CN has been chosen as the best solvent for
this purpose.
The next step was the optimization of the NH4SCN:PHBP molar ratio for the thio-
cyanation reaction in CH3CN. The results presented in Table 2 show that the optimized
molar ratio of NH4SCN:PHBP is 2:1. These data also show that an increase in the amount
of NH4SCN affected the yield or the rate of the reaction.
Encouraged by this result, we turned our attention to various acetophenones. Interest-
ingly, several substituted acetophenones such as 4-chloro-, 4-nitro-, 4-methoxy-, 4-methyl-,
2-chloro-, 3-bromo-, and 2,4-dichloroacetophenone and 1-phenylbutan-1-one reacted
rapidly with ammonium thiocyanate to afford the corresponding 2-thiocyanatoethanone
Table 1 Solvent optimization for the synthesis of 1-phenyl-2-thiocyanatoethanonea
Solvent
Time (h)
Yield (%)b
CHCl3
CH2Cl2
EtOAc
n-Hexane
THF
1
1
1
3
2
1
5
87
90
88
42
85
91
29
CH3CN
—
aReaction conditions: acetophenone (1 mmol), NH4SCN (2 mmol), and PHBP (1 mmol), r.t.
bIsolated yield.

750
L. WU AND X. YANG
Table 2 Optimization of NH4SCN:PHBP molar ratio for the α-thiocyanation of acetophenone
Molar ratio NH4SCN:PHBP
Time (h)
Yield (%)
1:2
1:1
3
2
2
2
1
1
1
23
53
65
79
91
90
90
1.2:1
1.5:1
2:1
2.1:1
2.2:1
derivatives (Table 3, entries b–i). In addition, various cyclic ketones, such as cy-
clohexanone, cyclopentanone, 1-tetralone, and indanone (Table 3, entries j–m), also
participated effectively in this reaction. It is noteworthy that aliphatic ketones also gave
the corresponding α-thiocyanated products in 76–87% yield (Table 3, entries n–o). In all
cases, the reactions proceeded rapidly at room temperature with high regioselectivity. No
bromination of the ketones was observed under the reaction conditions. All the products
1
were characterized by H NMR, IR, elemental analysis as well as by comparison with
authentic samples. The IR spectra showed the characteristic peak of –SCN at 2122–2168
cm−1
.
Mechanistically, the reaction may proceed via the electrophilic substitution of ace-
tophenone by NCS+ intermediately generated in situ from PHPB and ammonium thio-
cyanate (Scheme 2).
CH3CN
NCS+
-
NH+
NH SCN
Br3
+
4
r.t.
O
O
R2
CH3CN
r.t.
R1
+
R2
+
NCS
R1
SCN
3
Scheme 2
To illustrate the efficiency of the proposed method, Table 4 compares some of our
results with some of those reported for relevant reagents in the literature, which demonstrates
its significant superiority. Compared with some of the reported methods in Table 4, the
present method has a better yield and a higher selectivity.
EXPERIMENTAL
NMR spectra were obtained with a Bruker AV-400 spectrometer at room temperature
using TMS as internal standard. Coupling constants (J) are given in Hertz. Elemental anal-
yses were performed with a Vario-III elemental analyzer. Melting points were determined
with a XT-4 binocular microscope and are uncorrected. PHPB was prepared according to
Englert and McElvain (1929).17 Commercially available reagents were used throughout
without further purification unless otherwise stated.

α-THIOCYANATION OF KETONES USING PYRIDINIUM HYDROBROMIDE PERBROMIDE 751
Table 3 α-Thiocyanation of ketones promoted by PHBPa
Entry
Ketone
Product
Time (h) Yield (%)b
Referencec
a
1
91
89
Bhalerao
et al. (2010)7
b
c
1.5
Bhalerao
et al. (2010)7
2
2
92
83
Bhalerao
et al. (2010)7
d
Bhalerao
et al. (2010)7
e
f
2
1.5
2
83
87
84
Bhalerao
et al. (2010)7
Chaskar
et al. (2010)9
g
Chaskar
et al. (2010)9
h
i
2
87
80
Bhalerao
et al. (2010)7
2.5
Kumar
et al. (2008)8
j
0.5
0.5
90
92
Bhalerao
et al. (2010)7
k
Bhalerao
et al. (2010)7

752
L. WU AND X. YANG
Table 3 α-Thiocyanation of ketones promoted by PHBPa (Continued)
Entry
Ketone
Product
Time (h)
1.5
Yield (%)b
93
Referencec
l
Chaskar
et al. (2010)9
m
1.5
90
Chaskar
et al. (2010)9
n
o
2
2
76
87
Kumar
et al. (2008)8
Kumar
et al. (2008)8
aReaction conditions: ketone (1.0 mmol), NH4SCN (2.0 mmol), and PHBP (1.0 mmol), r.t., CH3CN.
bIsolated yield.
cAll of the isolated products are known compounds and their spectra and physical data have been reported in
the literature.7–9
α-Thiocyanation of Ketones: General Procedure
To a stirred solution of ammonium thiocyanate (2 mmol) and◦PHPB (1 mmol) in
acetonitrile (10 mL) was added the respective ketone (1 mmol) at 0 C and the resulting
mixture was stirred at room temperature for the appropriate time (Table 3). After complete
conversion, as indicated by TLC, the reaction mixture was quenched with water. The
reaction mixture was successively extracted with ethyl acetate and dried over anhydrous
Na2SO4. The solvent was then removed under reduced pressure. The resulting product was
purified by column chromatography on silica gel (200–300 mesh, ethyl acetate:hexane =
1:20) to afford pure 3.
• 1-Phenyl-2-thiocyanatoethanone (3a)
IR (KBr): v = 2946, 2150 (–SCN), 1672, 1591, 1420, 996, 760 cm−1; 1H NMR (CDCl3,
400 MHz): δ = 8.02–7.80 (m, 2H), 7.66–7.25 (m, 3H), 4.78 (s, 2H); Anal. Calcd. for
C9H7NOS: C 60.99, H 3.98, N 7.90, S 18.09%; Found: C 70.06, H 3.92, N 7.95, S
18.00%.
Table 4 PHBP-promoted α-thiocyanation of acetophenone compared with methods reported in the literature
Catalyst and conditions
Solvent
CH2Cl2
MeOH
ClCH2CH2Cl
CH3CN
Time (h)
Yield (%)
Reference
FeCl3 (100 mol%), r.t.
Oxone (100 mol%), r.t.
Heteropolyacid (25 mol%), r.t.
NBS (100 mol%), r.t.
0.5
6
0.3
4
75
86
86
85
91
Yadav et al. (2008)13
Kumar et al. (2008)8
Chaskar et al. (2010)9
Reddy et al. (2011)14
This work
PHBP (100 mol%), r.t.
CH3CN
1

α-THIOCYANATION OF KETONES USING PYRIDINIUM HYDROBROMIDE PERBROMIDE 753
• 2-Thiocyanatocyclohexanone (3k)
IR (KBr): v = 2925, 2154 (–SCN), 1702, 1455, 1129, 546; 1H NMR (CDCl3, 400 MHz):
δ = 4.35–4.20 (m, 1H), 2.85–2.38 (m, 3H), 2.20–1.73 (m, 5 H); Anal. Calcd. for
C7H9NOS: C 54.17, H 5.84, N 9.02 S 20.66%; Found: C 54.11, H 5.92, N 9.12 S
20.60%.
CONCLUSION
In conclusion, we have found a convenient and selective method for α-thiocyanation
of ketones using PHBP, a versatile, stable, inexpensive, and commercially available reagent.
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