Direct α-thiocyanation of carbonyl and β-dicarbonyl compounds using potassium peroxydisulfate-copper(II)

Article abstract of DOI:10.1016/j.tetlet.2006.12.103

A convenient approach for the direct α-thiocyanation of carbonyl and β-dicarbonyl compounds has been developed using ammonium thiocyanate as the thiocyanating agent and potassium peroxydisulfate as the oxidant in the presence of a catalytic amount of copp

Full text of DOI:10.1016/j.tetlet.2006.12.103

Tetrahedron Letters 48 (2007) 1399–1401
Direct a-thiocyanation of carbonyl and b-dicarbonyl
compounds using potassium peroxydisulfate–copper(II)I
Atul Kumar,* P. Ahamd and R. A. Maurya
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 12 June 2006; revised 13 December 2006; accepted 19 December 2006
Available online 22 December 2006
Abstract—A convenient approach for the direct a-thiocyanation of carbonyl and b-dicarbonyl compounds has been developed using
ammonium thiocyanate as the thiocyanating agent and potassium peroxydisulfate as the oxidant in the presence of a catalytic
amount of copper(II) sulfate in aqueous acetonitrile. The catalyst and oxidizing agent used in the reaction are inexpensive and
provide good to excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Organic thiocyanates include not only biologically
important natural products such as anticancer natural
products1 formed by deglycosylation of glucosinolates
derived from cruciferous vegetables, but are also versa-
tile intermediates for the synthesis of various hetero-
cyclic compounds.2 Some of these heterocycles possess
herbicidal and other important biological activities.3
The traditional method for generating organic thio-
cyanates involves nucleophilic displacement using thio-
cyanate. Thus, the a-thiocyanation of carbonyl compounds
involves one additional step, functionalization at the
desired position before thiocyanation. Functionalization
has been carried out by bromination, tosylation4 and
with thiocyanate anions5,6 via SN2 displacement. All
these methods require drastic conditions due to the poor
nucleophilicity of the thiocyanate anion. Thiocyanates
can be synthesized via electrophilic or radical reactions
using thiocyanogen and thiocyanogen halides. Also, Fri-
edel Crafts catalysis7 involving heterolytic and homo-
lytic conditions8 are reported to generate thiocyanate
derivatives using different thiocyanogens such as dithio-
cyano compounds, lead(II) thiocyanate and thiocyano-
gen chloride. Rearrangement reactions9 including
fragmentation and reaction with diazonium salts10 have
also been reported. Recently, there was a report on the
direct thiocyanation of carbonyls using dichloroiodo-
benzene lead(II) thiocyanates.11 All the reported meth-
ods for thiocyanation of various chemical entities give
complex mixtures of products and require high temper-
atures, toxic chemicals, long reaction times, afford low
yields and are costly. Potassium peroxydisulfate has
been explored by Bhatt and Perumal for the conversion
of electron rich benzylic hydrocarbons to carbonyls.12
Several other investigations citing the oxidizing proper-
ties of potassium peroxydisulfate (PPDS) due to its
strong redox potential viz.; Elbs and Baeyer–Villiger
oxidation are reported.13
The peroxydisulfate ion is a versatile oxidizing agent
in aqueous solution14 and is used in many organic
reactions in the presence of metals acetates15 such as
cobalt(III), copper and iron.16 The reactions involving
these ions are generally slow at room temperature and the
rate of peroxydisulfate decomposition increases greatly
at a higher temperature.15 The standard oxidation–
reduction potential of PPDS in oxidation reactions is
estimated to be À2.01 V.14
We report here an efficient, selective and direct a-thio-
cyanation of carbonyl and b-dicarbonyl compounds with
ammonium or potassium thiocyanates using potassium
peroxydisulfate (PPDS) and copper(II) sulfate as the
oxidizing agent in aqueous acetonitrile (MeCN–H2O,
7:3) (Scheme 1).
Keywords: Thiocyanation; Peroxydisulfate–copper(II); Carbonyl and
b-dicarbonyl; Ammonium thiocyanate.
q CDRI Communication No. 7005.
*
In the absence of metal ions the thiocyanation of car-
Corresponding author. Tel.: +91 522 2621411; fax: +91 522
2623405; e-mail: dratulsax@gmail.com
bonyl and b-dicarbonyls was less effective. Therefore,
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.103

1400
A. Kumar et al. / Tetrahedron Letters 48 (2007) 1399–1401
Table 2. a-Thiocyanation of carbonyl compounds
O
X
O
K2S2O8 -Cu(II)
SCN
Entry Carbonyl
compound
Thiocyanoketone
Yield Time
aq. CH3CN / NH4SCN
(%)
(h)
R1
R1
X
O
O
SCN
1
86
1
O
O
K2S2O8 -Cu(II)
SCN
O
O
aq. CH3CN / NH4SCN
O
O
R2O
SCN
SCN
R2O
2
82
68
1
3
Scheme 1.
MeO
MeO
O
O
3
we used potassium peroxydisulfate–copper(II) sulfate
for the reaction which increased the rate of the reaction
in comparison to peroxydisulfate alone. The presence of
copper(II) might increase the rate of decomposition of
peroxydisulfate into radical anions.
HO
HO
O
O
SCN
4
84
78
1.5
2
O
O
The influence of various solvents on the yield of the
reaction was investigated using the carbonyl compound
from entry 1, Table 2 as an example. The results ob-
tained showed that aqueous acetonitrile was the best
choice. This may be due to the enhanced solubilizing
power of this solvent for the oxidant as well as the sub-
strate (Table 1). Potassium peroxydisulfate (PPDS)
mediated thiocyanation of cyclic ketones occurred rap-
idly to afford a-thiocyanoketones in good yields (Table
2). Thiocyanation of b-dicarbonyl compounds occurred
in moderate yields (Table 3). The thiocyanation of cyclic
ketones gave better yields in comparison with acyclic
ketones. The best results were obtained with six-membered
rings. The presence of the heteroatom in the six-mem-
bered ring did not affect a-thiocyanation.
O
O
O
SCN
SCN
5
MeO
HO
O
MeO
O
O
O
6
70
3
HO
O
O
O
S
SCN
7
57
72
4
3
S
O
O
O
8
SCN
SCN
Typical experimental procedure: Potassium peroxydisul-
fate (20 mmol) and copper sulfate (2.5 mmol) in water
were added to a solution of ammonium thiocyanate
(15 mmol) in acetonitrile–water (7:3). The reaction
mixture was stirred at room temperature for 10 min
followed by the addition of a solution of carbonyl
compound (10 mmol) in acetonitrile (15 ml). The reac-
tion mixture was stirred at 60–70 °C for 1–5 h. The reac-
tion was diluted with water and extracted with ethyl
MeO
MeO
MeO
O
9
70
5
O
O
MeO
O
O
10
CH3
CH2
SCN
65
67
5
5
MeO
O
MeO
O
CH3
CH3
11
CH2
CH
SCN
Table 1. Effect of solvent on the reaction yield of 1 with peroxy-
disulfate and peroxydisulfate–Cu(II)
Entry Solvent
Peroxydisulfatea Peroxydisulfate–Cu(II)a
yieldb (%)
yieldb (%)
1
2
3
4
5
6
7
CHCl3
CH2Cl2
THF
MeOH
CH3CN
15
22
31
38
42
30
37
44
50
68
57
86
acetate. The concentrated residue was purified by
column chromatography (elution with EtOAc–hexane
1:9) to afford the thiocyanoketone in a good yield
(Tables 2 and 3). The analytical data was in a good
agreement with the product structures.17
Aq MeOH 44
Aq CH3CN 51
a Reaction conditions: carbonyl compound 1 (10 mmol), peroxydi-
sulfate (20 mmol), Cu(II) (2.5 mmol), ammonium thiocyanate (15
mmol), 70 °C, 1 h.
In conclusion, this report offers a simple, efficient and
direct a-thiocyanation of carbonyl and b-dicarbonyl
compounds. The oxidant, potassium peroxydisulfate–
copper(II) [PPDS–Cu(II)] is cost effective and provides
good yields.
b The yield reported is after isolation by column chromatography on
silica gel.

A. Kumar et al. / Tetrahedron Letters 48 (2007) 1399–1401
1401
Table 3. a-Thiocyanation of b-dicarbonyl compounds
Entry b-Dicarbonyl Thiocyanoketone Yield Time
13. (a) Behrman, E. C.; Chen, S.; Behrman, E. J. Tetrahedron
Lett. 2002, 43, 3221; (b) Dhar, D. N.; Munjal, R. Synthesis
1973, 542–543.
(%)
(h)
14. House, D. A. Chem. Rev. 1962, 62, 185.
O
O
15. Giordano, C.; Belli, A. J. Org. Chem. 1979, 44, 2314.
16. Heiba, E. I.; Dessau, R. M.; Kochl, W. J., Jr. J. Am.
Chem. Soc. 1969, 91, 6830.
O
O
1
2
65
5
H3C
OCH3
H3C
OCH3
SCN
O
17. Spectral data of a-thiocyanation of carbonyl (Table 2).
Compound 1: 1H NMR (CDCl3, 200 MHz): 1.92–2.07 (m,
2H), 2.51–2.65 (m, 2H), 4.35 (dd, J = 6.3, 5.6 Hz, 1H),
6.89–6.98 (m, 2H), 7.38–7.47 (m, 2H). 13C NMR (CDCl3,
50 MHz): d 191.6, 138.4, 137.3, 132.8, 128.4, 128.2, 124.3,
111.7, 57.1, 31.7, 28.9. MS (FAB): m/z = 203. Compound
2: IR (KBr, cmÀ1) 2937, 2150, 1660. 1H NMR (CDCl3,
200 MHz): 2.07–2.18 (m, 2H), 2.57–2.66 (m, 2H), 3.80 (s,
3H), 4.50 (dd, J = 6.4, 5.6 Hz, 1H), 6.35 (d, J = 2.2 Hz,
1H), 6.50 (dd, J = 2.2, 8.8 Hz, 1H), 7.76 (d, J = 8.8 Hz).
13C NMR (CDCl3, 50 MHz): d 190.0, 165.2, 146.4, 130.3,
124.2, 114.4, 113.2, 112.0, 56.0, 55.0, 31.2, 29.0; UV (284,
226 and 205 nm); MS(FAB): m/z = 233. Compound 4: IR
O
SCN
O
70
5
O
C2H5O
C2H5O
O
O
3
4
63
60
5
5
SCN
O
O
O
O
SCN
O
O
H3CO
H3CO
1
(KBr, cmÀ1): 2928, 2156, 1650, 1600. H NMR (CDCl3,
200 MHz): d 3.20 (m, 2H), 4.41 (dd, J = 6.2, 5.4 Hz, 1H),
6.90 (d, J = 9.6 Hz, 1H), 7.20–7.32 (m, 2H, ArH), 7.49–
7.58 (m, 1H). MS(FAB): m/z = 205. Compound 5: IR
(KBr, cmÀ1): 2155, 1668, 1604. 1H NMR (CDCl3,
200 MHz): d 1.26 (s, 6H), 3.85 (s, 3H), 4.11 (s, 1H), 6.37
(d, J = 2.3 Hz, 1H), 6.51 (dd, J = 2.3 Hz, 8.8 Hz, 1H), 7.78
(d, J = 8.8 Hz). MS (FAB): m/z = 263. Compound 7: IR
(KBr, cmÀ1): 2161, 1677, 1600. 1H NMR (CDCl3,
200 MHz): d 3.40 (m, 2H), 4.41 (m, 1H), 7.00–7.08 (m,
1H), 7.23–7.38 (m, 2H), 7.46 (d, J = 10 Hz, 1H). MS
(FAB): m/z = 221. Compound 8: IR (KBr, cmÀ1): 2158,
References and notes
1. Mehta, R. G.; Liu, J.; Constantinou, A.; Thomas, C. F.;
Hawthorne, M.; You, M.; Gerhaeusers, C.; Pezzuto, J.
M.; Moon, R. C.; Moriarty, R. M. Carcinogenesis 1995,
16, 399.
2. (a) Wood, J. L. Org. React. 1946, 3, 240; (b) Kelly, T. R.;
Kim, M. H.; Curtis, A. D. M. J. Org. Chem. 1993, 58,
5855.
3. (a) Leblanc, B. L.; Jursic, B. C. Synth. Commun. 1998, 28,
3591; (b) Newman, A. A. Chemistry and Biochemistry of
Thiocyanic Acid and its Derivatives, 1st ed.; Academic
Press, 1975.
4. Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996,
61, 4439.
1
1713, 1600. H NMR (CDCl3, 200 MHz): d 2.80–3.00 (m,
2H), 3.80 (s, 3H), 4.17 (m, 1H), 6.37 (d, J = 2.4 Hz, 1H),
6.51 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz). MS
(FAB): m/z = 219. Compound 9: IR (KBr, cmÀ1): 2158,
1
1704, 1600. H NMR (CDCl3, 200 MHz): d 3.81 (s, 3H),
4.13 (s, 1H), 6.37 (d, J = 2.3 Hz, 1H), 6.51 (dd, J = 2.3 Hz,
5. Guy, R. G. In The Chemistry of Cyanates and their Thio
Derivatives, Part 2; Patai, S., Ed.; Wiley: New York, 1977;
Chapter 18, p 819.
6. Toaste, F. D.; Laronde, F.; Still, W. J. Tetrahedron Lett.
1995, 36, 2949.
7. (a) Christopfel, R. C.; Miller, L. L. J. Org. Chem. 1984, 49,
5198–5202; (b) Methionine, L.; Guillerm, D.; Guillerm, G.
Tetrahedron Lett. 1992, 33, 5047.
8. Lattrell, R.; Lohaus, G. Leibigs Ann. Chem. 1974, 901.
9. Nikiforov, T. T.; Connolly, B. A. Tetrahedron Lett. 1991,
32, 2505.
10. Kagabu, S.; Maehara, M.; Sawahara, K.; Saito, K. J.
Chem. Soc., Chem. Commun. 1988, 1485.
11. Prakash, O.; Kaur, H.; Batra, H.; Singh, S. P.; Moriarty,
R. A. J. Org. Chem. 2001, 66, 2019.
12. Bhatt, M. V.; Perumal, P. T. Tetrahedron Lett. 1981, 22,
2605–2608.
8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H). MS (FAB): m/z =
221. Compound 10: H NMR (CDCl3, 200 MHz): d 3.70
1
(s, 3H), 4.34 (s, 2H), 6.89–6.92 (m, 2H), 7.57–7.62 (m, 2H).
Compound 11: 1H NMR (CDCl3, 200 MHz): d 1.23 (d,
J = 6.2 Hz, 3H), 4.74 (q, J = 6.2 Hz, 1H), 7.31–7.46 (m,
3H) 7.75–7.88 (m, 2H). Spectral data for the a-thiocyana-
tion of b-dicarbonyl compounds (Table 3). Compound 12:
1H NMR (CDCl3, 200 MHz): d 2.57 (s, 3H), 3.42 (s, 3H),
5.43 (s, 1H). Compound 13: IR (KBr, cmÀ1): 2953, 2157,
1666, 1600 cmÀ1 1H NMR (CDCl3, 200 MHz): d 1.34
.
(t, J = 7.2 Hz, 3H), 4.12 (q, J = 7.2 Hz, 2H), 5.47 (s, 1H),
1
7.24–7.49 (m, 3H), 7.74–7.81 (m, 2H). Compound 14: H
NMR (CDCl3, 200 MHz): d 1.23 (s, 6H), 2.34 (s, 4H), 5.41
(s, 1H). 13C NMR (CDCl3, 50 MHz): d 205.2, 203.1, 112.4,
73.8, 53.4, 53.7, 23.6, 17.6. Compound 15: 1H NMR
(CDCl3, 200 MHz): d 3.67 (s, 3H), 5.49 (s, 1H), 7.20–7.42
(m, 3H), 7.74–7.81 (m, 2H).