Iron(III) chloride as mild and efficient reagent for the α-thiocyanation of ketones: An expedient synthesis of α-oxo thiocyanates

Article abstract of DOI:10.1055/s-2008-1072517

A simple and efficient method for the α-thiocyanation of ketones has been developed; anhydrous iron(III) chloride is used under mild conditions to produce αoxo thiocyanates in good to high yields and with high selectivity. The use of inexpensive and readi

Full text of DOI:10.1055/s-2008-1072517

PAPER
1283
Iron(III) Chloride as Mild and Efficient Reagent for the a-Thiocyanation of
Ketones: An Expedient Synthesis of a-Oxo Thiocyanates
Synthesis
h
of
a
-OxoTh
i
iocyana
l
tes lu S. Yadav,* Basi V. Subba Reddy, Ummareddy V. Subba Reddy, Darshanoju N. Chary
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512.; E-mail: yadav@iict.res.in
Received 9 January 2008; revised 22 January 2008
Since organosulfur compounds have become increasingly
Abstract: A simple and efficient method for the a-thiocyanation of
ketones has been developed; anhydrous iron(III) chloride is used
under mild conditions to produce a-oxo thiocyanates in good to
high yields and with high selectivity. The use of inexpensive and
useful and important in the field of drugs and pharmaceu-
ticals, the development of simple, convenient, and effi-
cient approaches for their synthesis are desirable. In
readily available iron(III) chloride makes this procedure simple, recent years, iron(III) chloride has emerged as a powerful
convenient, and practical.
Lewis acid catalyst, and performs many useful organic
transformations under mild reaction conditions.11 More-
Key words: thiocyanation, ketones, iron(III) chloride, catalysis, a-
oxo thiocyanates
over, iron salts are inexpensive, easy to handle, and envi-
ronmentally friendly. However, there have been no
previous reports on the direct a-thiocyanation of enoliz-
able ketones with ammonium thiocyanate in the presence
of iron(III) chloride as a catalyst.
a-Oxo thiocyanates are versatile intermediates in the syn-
thesis of sulfur-containing heterocycles such as thiazoles
and 2-amino-1,3-thiazines.1,2 Some of these compounds
exhibit herbicidal and other important biological activi-
ties.3 Furthermore, the thiocyanato group occurs as an im-
portant functionality in several anticancer natural
products formed by deglycosylation of glucosinolates de-
rived from cruciferous vegetables.4 The thiocyanate func-
tionality is useful as a masked thiol group. Thiocyanation
is generally carried out by nucleophilic substitution with
thiocyanate anions. The low nucleophilicity of the thio-
cyanate anion requires rather harsh reaction conditions.
Metal thiocyanates and organic halides or sulfonates are
generally used to introduce the thiocyanate functionality
into an organic molecule.5 However, the thiocyanate
group is not stable under heating conditions, and normally
undergoes intramolecular rearrangement to form the ther-
modynamically favored isothiocyanate isomers.6 Thus,
the direct thiocyanation of ketones is of prime importance.
In this article, we report a direct, iron(III) chloride pro-
moted, selective a-thiocyanation of enolizable ketones
with ammonium thiocyanate under mild conditions. We
first attempted the thiocyanation of acetophenone (1) with
two equivalents ammonium thiocyanate (2) (Scheme 1).
The reaction was carried out with a stoichiometric amount
of iron(III) chloride in dichloromethane, and went to com-
pletion in 25 minutes at room temperature, giving the
product, 1-phenyl-2-thiocyanatoethanone (3a) in 75%
yield (Scheme 1).
O
O
SCN
FeCl3
Me
+
NH4SCN
CH2Cl2, r.t.
1a
2
3a
Scheme 1
Consequently, various methods have been developed for
the a-thiocyanation of ketones, with a variety of reagents
and under diverse reaction conditions.7,8 However, these
classical methods involve multi-step synthetic sequences
and often harsh reaction conditions, and the yields are typ-
ically low, because of the poor nucleophilicity of thiocy-
anate. The use of the (dichloroiodo)benzene/lead(II)
thiocyanate reagent system has been reported for the di-
rect thiocyanation of ketones, and works well with silyl
enol ethers.9 However, most of these reported methods in-
volve the use of a large excess of strong oxidizing agents
and toxic metal thiocyanates, resulting in low conversions
due to the formation of complex mixtures of products,10
which limit their practical utility in organic synthesis.
This prompted us to study further reactions, with other
enolizable ketones. Interestingly, various substituted ke-
tones, such as 3-chloroacetophenone (1b), 4-hydroxyace-
tophenone (1c), 2,5-dichloroacetophenone (1d), 2-
acetylnaphthalene (1e), and 2-methoxyacetophenone (1f)
reacted readily with ammonium thiocyanate to provide
the corresponding a-thiocyanato ketones 3b–f in good
yields (Table 1, entries 2–6). Like the acetophenones,
cyclic ketones such as 1-tetralone (1g) (Scheme 2), 2-phe-
nylchroman-4-one (1h), cyclopentanone (1i), cyclo-
hexanone (1j), 4,4-dimethylcyclohex-2-enone (1k), 2-
methylcyclohexanone (1l), cycloheptanone (1m), and cy-
clododecanone (1n) reacted well under similar conditions
to give a-oxo thiocyanates 3g–n (Table 1, entries 7–14).
SYNTHESIS 2008, No. 8, pp 1283–1287
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.03.2008
DOI: 10.1055/s-2008-1072517; Art ID: Z00708SS
© Georg Thieme Verlag Stuttgart · New York

1284
J. S. Yadav et al.
PAPER
Table 1 Thiocyanation of Ketones with Ammonium Thiocyanate Promoted by Iron(III) Chloride
Entry
1
Ketone
1
Producta
3
Time (min) Yieldb (%)
O
O
SCN
1a
3a
25
30
23
75
72
78
Me
O
O
Cl
Cl
SCN
SCN
2
3
4
5
6
1b
1c
1d
1e
1f
3b
3c
3d
3e
3f
Me
Me
O
O
HO
Cl
HO
Cl
O
O
SCN
SCN
30
25
25
70
75
76
Me
Cl
Cl
O
O
Me
OMe
OMe
O
O
O
O
SCN
Me
7
1g
SCN
3g
35
80
O
O
O
SCN
Ph
8
9
1h
1i
3h
3i
45
40
35
82
78
84
Ph
O
O
O
O
O
SCN
SCN
10
1j
3j
O
O
SCN
11
1k
3k
30
80
Me
Me
Me
O
Me
Me
O
Me
SCN
12
13
1l
3l
30
40
78
75
O
O
SCN
1m
3m
O
O
SCN
14
1n
3n
50
68
Synthesis 2008, No. 8, 1283–1287 © Thieme Stuttgart · New York

PAPER
Synthesis of a-Oxo Thiocyanates
1285
Table 1 Thiocyanation of Ketones with Ammonium Thiocyanate Promoted by Iron(III) Chloride (continued)
Entry
15
Ketone
1
Producta
3
Time (min) Yieldb (%)
O
O
1o
3o
40
80
SCN
t-Bu
Me
t-Bu
a Products were characterized by 1H NMR and IR spectroscopy and MS.
b Yields are of pure products after chromatography.
O
O
Melting points were recorded on a Buchi R-535 apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR
240-c spectrophotometer using KBr optics. 1H and 13C NMR spec-
tra, of samples in CDCl3 with TMS as internal standard, were re-
corded on a Gemini-200 spectrometer (200 MHz). Mass spectra
were recorded on a Finnigan MAT 1020 mass spectrometer operat-
ing at 70 eV. Column chromatography was performed on Merck sil-
ica gel (60–120 mesh).
SCN
FeCl3
NH4SCN
+
CH2Cl2, r.t.
1g
2
3g
Scheme 2
Furthermore, the sterically hindered acyclic ketone tert-
butyl methyl ketone (1o) also afforded the corresponding cedure
Thiocyanates 3 by a-Thiocyanation of Ketones 1; General Pro-
The appropriate ketone 1 (1.0 mmol) was added to a soln of
thiocyanate 3o in good yield (Table 1, entry 15). a-Thio-
cyanation of bulky substrates such as cyclododecanone
(1n) gave comparatively low yields (Table 1, entry 14).
The best conversions were obtained with cyclohexanone
derivatives. It is noteworthy that the reactions were slug-
gish and the products were obtained in low yields (30–
NH4SCN (2; 2 mmol) and FeCl3 (1 mmol) in CH2Cl2 (10 mL), and
the resulting mixture was stirred at r.t. for the appropriate time
(Table 1). After completion of the reaction as indicated by TLC, the
reaction mixture was quenched with H2O (15 mL) and extracted
with EtOAc (2 × 15 mL). The combined extracts were dried
(Na2SO4) and concentrated in vacuo. The resulting product was pu-
40%) when a catalytic amount of iron(III) chloride (10 rified by column chromatography (silica gel, EtOAc–hexane,
0.5:9.5); this afforded the corresponding pure thiocyanate deriva-
tive 3.
mol%) was used in the reaction. Best conversions were
obtained with a stoichiometric amount of iron(III) chlo-
ride. However, no reaction was observed in the absence of
catalyst, even under reflux over a long reaction time (12
2-Oxo-2-phenylethyl Thiocyanate (3a)
Pale yellow solid; mp 67–69 °C.
h). As solvent, dichloromethane appeared to give the best
IR (KBr): 3423, 2984, 2934, 2361, 2155, 1676, 1593, 1448, 955,
results. The products were characterized by 1H NMR and
755 cm–1.
IR spectroscopy and mass spectrometry and also by com-
1H NMR (300 MHz, CDCl3): d = 7.94 (d, J = 7.5 Hz, 2 H), 7.66 (t,
J = 7.5 Hz, 1 H), 7.53 (t, J = 7.5 Hz, 2 H), 4.75 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 42.9, 111.7, 128.4, 129.1, 133.8,
134.7, 190.7.
parison with authentic samples.9,12 This method was clean
and free of side products. Among the various oxidants
tested, such as (diacetoxyiodo)benzene, manganese(III)
acetate, and iron(III) nitrate, anhydrous iron(III) chloride
was found to be the most effective in terms of conversion.
MS (EI, 70 eV): m/z = 200 [M+ + Na], 178 [M+ + H].
Various metal triflates such as bismuth(III)-, indium(III)-,
samarium(III)-, ytterbium(III)-, and scandium(III) triflate
were also found to be ineffective for this conversion. The
advantages of this procedure include mild conditions,
short reaction times, easy workup, and good yields. The
scope and generality of this process is illustrated with re-
spect to various enolizable ketones and ammonium thio-
cyanate (Table 1).
HRMS (EI): m/z calcd for C9H8NOS: 178.0326; found: 178.0332.
2-(3-Chlorophenyl)-2-oxoethyl Thiocyanate (3b)
Pale yellow solid; mp 68–70 °C.
IR (KBr): 3065, 2988, 2929, 2152, 1680, 780, 678 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.92 (s, 1 H), 7.82 (d, J = 7.5 Hz,
1 H), 7.64 (d, J = 7.5 Hz, 1 H), 7.48 (m, 1 H), 4.72 (s, 2 H).
MS (EI, 70 eV): m/z = 211 [M+].
In summary, anhydrous iron(III) chloride has proved to be
a useful and highly efficient catalyst for a facile a-thiocy-
anation of ketones with ammonium thiocyanate under
mild reaction conditions. In addition to its simplicity and
efficiency, this method produces a-oxo thiocyanates in
good yields in short reaction times. This method provides
an access to a wide range of potentially valuable a-oxo
thiocyanates.
HRMS (EI): m/z calcd for C9H7NOSCl: 211.9939; found: 211.9939.
2-(4-Hydroxyphenyl)-2-oxoethyl Thiocyanate (3c)
Colorless solid; mp 160–162 °C.
IR (KBr): 3280, 2970, 2924, 2166, 1668, 1599, 1442, 1279, 1203,
833, 561 cm–1.
1H NMR (300 MHz, CDCl3): d = 10.14 (s, 1 H), 7.83 (d, J = 8.7 Hz,
2 H), 6.84 (d, J = 8.7 Hz, 2 H), 4.87 (s, 2 H).
13C NMR (50 MHz, CDCl3 + DMSO): d = 42, 111, 114, 124, 129,
162, 188.
Synthesis 2008, No. 8, 1283–1287 © Thieme Stuttgart · New York

1286
J. S. Yadav et al.
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MS (EI, 70 eV): m/z = 216 [M+ + Na], 194 [M+ + 1], 195 [M+ + 2],
137.
1H NMR (300 MHz, CDCl3): d = 4.22–4.29 (m, 1 H), 2.77–2.85 (m,
1 H), 2.61–2.68 (m, 1 H), 2.36–2.46 (m, 1 H), 1.70–2.22 (m, 5 H).
MS (EI, 70 eV): m/z = 178 [M+ + Na], 156 [M+ + H].
2-(2,5-Dichlorophenyl)-2-oxoethyl Thiocyanate (3d)
Colorless solid; mp 190–192 °C.
HRMS (EI): m/z calcd for C7H10NOS: 156.0483; found: 156.0482.
IR (KBr): 3150, 2925, 2853, 2155, 1649, 1575, 1377, 1106, 824,
706 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70–7.74 (m, 1 H), 7.49–7.53 (m,
1 H), 7.39–7.43 (m, 1 H), 4.64 (s, 2 H).
4,4-Dimethyl-6-thiocyanatocyclohex-2-enone (3k)
Yellow liquid.
IR (neat): 2965, 2928, 2870, 2083, 1718, 1681, 813, 761 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.75 (d, J = 10.1 Hz, 1 H), 5.93 (d,
J = 10.1 Hz, 1 H), 4.47 (m, 1 H), 3.75 (m, 2 H), 1.34 (s, 3 H), 1.27
(s, 3 H).
MS (EI, 70 eV): m/z = 247 [M+ + H].
HRMS (EI): m/z calcd for C9H6Cl2NOS: 247.0452; found:
247.0459.
13C NMR (75 MHz, CDCl3): d = 25.4, 30.3, 43.9, 51.5, 99.7, 124.8,
160.6, 192.7.
2-(2-Naphthyl)-2-oxoethyl Thiocyanate (3e)
Pale yellow solid; mp 102–104 °C.
MS (EI, 70 eV): m/z = 181 [M+].
IR (KBr): 3051, 2991, 2933, 2153, 1661, 1622, 739, 674 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.44 (s, 1 H), 7.94 (m, 4 H), 7.64
(m, 2 H), 4.90 (s, 2 H).
HRMS (EI): m/z calcd for C9H11NOSNa: 204.0459; found:
204.0453.
3-Methyl-2-oxocyclohexyl Thiocyanate (3l)
Pale yellow liquid.
MS (EI, 70 eV): m/z = 228 [M+ + H].
HRMS (EI): m/z calcd for C13H10NOS: 228.0483; found: 228.0492.
IR (neat): 2923, 2852, 2154, 1713, 1458, 1380, 760, 565 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.17–4.33 (m, 1 H), 1.24–2.81 (m,
7 H), 1.12 (d, J = 1.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 20.7, 21.7, 33.6, 34.9, 43.7, 49.2,
99.9, 207.0.
2-(2-Methoxyphenyl)-2-oxoethyl Thiocyanate (3f)
Colorless solid; mp 85–87 °C.
IR (KBr): 2923, 2852, 2157, 1644, 1461, 1014, 756, 623 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.90–7.96 (m, 1 H), 7.51–7.60 (m,
1 H), 6.97–7.10 (m, 2 H), 4.80 (s, 2 H), 4.05 (s, 3 H).
MS (EI, 70 eV): m/z = 170 [M+ + H].
MS (EI, 70 eV): m/z = 230 [M+ + Na].
2-Oxocycloheptyl Thiocyanate (3m)
Liquid.
2-Oxo-1,2,3,4-tetrahydro-2-naphthyl Thiocyanate (3g)
IR (neat): 2929, 2152, 1700, 1451, 953, 766, cm–1.
1H NMR (300 MHz, CDCl3): d = 4.42 (m, 1 H), 2.41–2.74 (m, 3 H),
1.62–2.17 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 23.9, 28.1, 29.5, 32.7, 41.7, 61.0,
100.1, 205.0.
MS (EI, 70 eV): m/z = 170 [M+ + H].
Colorless liquid.12
IR (neat): 3064, 2924, 2154, 1681, 1598, 1221, 745, 607 cm–1.
1H NMR (300 MHz, CDCI3): d = 8.0–8.03 (m, 1 H), 7.52–7.57 (m,
1 H), 7.25–7.39 (m, 2 H), 4.54 (dd, J = 4.5, 5.2 Hz, 1 H), 3.17–3.20
(m, 2 H), 2.84–2.88 (m, 1 H), 2.35–2.44 (m, 1 H).
MS (EI, 70 eV): m/z = 204 [M+ + H].
2-Oxocyclododecyl Thiocyanate (3n)
Liquid.
IR (neat): 2933, 2858, 2152, 1692, 1464, 1036, 736, 618 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.29–4.35 (m, 1 H), 2.92–3.05 (m,
1 H), 1.95–2.42 (m, 4 H), 1.08–1.72 (m, 15 H).
MS (EI, 70 eV): m/z = 262 [M+ + Na], 240 [M+ + H].
4-Oxo-2-phenyl-3,4-dihydro-2H-chromen-3-yl Thiocyanate
(3h)
Colorless liquid.
IR (neat): 3036, 2924, 2854, 2157, 1693, 1606, 1463, 1301, 761,
698, 618 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.96–8.06 (m, 1 H), 7.44–7.62 (m,
6 H), 7.03–7.19 (m, 2 H), 5.49 (d, J = 11.3 Hz, 1 H), 4.40 (d,
J = 11.3 Hz, 1 H).
HRMS (EI): m/z calcd for C13H21NOSNa: 262.1205; found:
262.1211.
MS (EI, 70 eV): m/z = 281 [M+].
3,3-Dimethyl-2-oxobutyl Thiocyanate (3o)
Liquid.
IR (neat): 2970, 2929, 2157, 1706, 1474, 1292, 1061, 724, 570 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.33 (s, 2 H), 1.23 (s, 9 H).
MS (EI, 70 eV): m/z = 158 [M+ + H].
HRMS (EI): m/z calcd for C16H11NO2SNa: 304.0408; found:
304.0418.
2-Oxocyclopentyl Thiocyanate (3i)
Colorless liquid.9
IR (neat): 2924, 2854, 2155, 1746, 1635, 1453, 1148, 813, 513 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.65–3.74 (m, 1 H), 2.62–2.71 (m,
1 H), 1.95–2.45 (m, 5 H).
References
MS (EI, 70 eV): m/z = 142 [M+ + H].
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2-Oxocyclohexyl Thiocyanate (3j)
Pale yellow liquid.9
IR (neat): 2925, 2860, 2154, 1710, 1449, 1125, 536 cm–1.
Synthesis 2008, No. 8, 1283–1287 © Thieme Stuttgart · New York

PAPER
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Synthesis of a-Oxo Thiocyanates
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Synthesis 2008, No. 8, 1283–1287 © Thieme Stuttgart · New York