NBS or DEAD as effective reagents in α-thiocyanation of enolizable ketones with ammonium thiocyanate

Article abstract of DOI:10.1016/j.tetlet.2011.01.035

Ketones possessing α-hydrogen undergo smooth thiocyanation with ammonium thiocyanate in the presence of N-bromosuccinimide (NBS) at room temperature in acetonitrile under neutral conditions to produce the corresponding α-ketothiocyanates in excellent yiel

Full text of DOI:10.1016/j.tetlet.2011.01.035

Tetrahedron Letters 52 (2011) 1432–1435
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Tetrahedron Letters
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NBS or DEAD as effective reagents in a-thiocyanation of enolizable ketones
with ammonium thiocyanate
⇑
B. V. Subba Reddy , S. Madhu Sudana Reddy, Ch. Madan
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Ketones possessing a-hydrogen undergo smooth thiocyanation with ammonium thiocyanate in the pres-
ence of N-bromosuccinimide (NBS) at room temperature in acetonitrile under neutral conditions to pro-
Received 18 November 2010
Revised 28 December 2010
Accepted 8 January 2011
Available online 14 January 2011
duce the corresponding -ketothiocyanates in excellent yields with high selectivity. The use of NBS
a
makes this procedure simple, convenient and cost effective. In addition, diethyl azodicarboxylate (DEAD)
was also found to promote this reaction under mild conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ketones
N-Bromosccinimide
Ammonium thiocyanate
a-Ketothiocyanates
Alkyl thiocyanates are important intermediates for the synthe-
Initially, we have attempted the thiocyanation of acetophenone
sis of sulfur-containing organic compounds. They are frequently
found in some biologically active natural products (Fig. 1).1
Thiocyanato functionality can be used as a masked mercapto
group or as a precursor for sulfur-containing heterocyclic com-
pounds, such as thiazolidine and cyclic thioureas.2 In particular,
(1) with ammonium thiocyanate (2) using NBS as a novel oxidant.
H
H
H
H
NCS
a-ketothiocyanates are useful intermediates in the synthesis of sul-
fur-containing heterocycles such as thiazoles.3 Some of these thia-
zoles exhibit herbicidal and other important biological activities.4
Thus, the direct thiocyanation of ketones is of prime importance.
SCN
4-Thiocyanato-9-cadinene
Carvernothiocyanate
Generally,
-halocarbonyl compounds5 or
etones7 and also by oxidative thiocyanation of enol ethers.8 How-
ever, the yields are typically low as result of the poor
nucleophilicity of the SCN anion. Subsequently, one-pot methods
have been reported for the -thiocyanation of enolizable ketones
a
-thiocyanato carbonyl compounds are prepared from
a
a
-tosyloxycarbonyls6 or
a-diazok-
SCN
H
a
SCN
a
H
using a variety of reagents.9,10 However, many of these methods in-
volve the use of toxic metal thiocyanates,8 expensive thiocyanating
agents9 and a large excess of strong oxidizing agents10 and also re-
sult in low conversions due to the formation of complex mixtures
of products. Therefore, the development of simple, convenient
and efficient approaches for their synthesis is desirable.
2-Thiocyanatoneopupukeanane
2-Thiocyanatopupukeanane
Figure 1. Examples of some natural products bearing thiocyanato functionality.
O
O
In this Letter, we wish to report a metal-free thiocyanation of
ketones using a readily available and inexpensive reagent, NBS.
NBS
CH3
NH4SCN
+
CH3CN, rt
SCN
Abbreviations: DEAD, diethyl azodicarboxylate; NBS, N-bromosuccinimide; NCS,
N-chlorosuccinimide; NIS, N-iodosuccinimide; NTS, N-thiocyanatosuccinimide.
1
2
3a
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
Scheme 1. a-Thiocyanation of acetophenone.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.035

B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 1432–1435
1433
The reaction proceeded smoothly at room temperature under mild
and neutral conditions to afford the 1-phenyl-2-thiocyanatoetha-
none 3a in 85% yield (Scheme 1).
Similarly, other substituted acetophenones, such as p-bromo-,
p-nitro- and 3,4-dimethoxyacetophenone derivatives underwent
smooth thiocyanation to furnish the corresponding
a
-thiocyanok-
etones in good yields (Table 1, entries b–d). The excellent reactivity
of NBS in the thiocyanation of aryl methyl ketones prompted us to
extend this method for other enolizable ketones. Interestingly, cyc-
lic ketones, such as
a-tetralone and 6-methoxy-1-tetralone gave
Table 1
NBS-promoted efficient synthesis of
a-thiocyanatoketones
Entry
Ketone
Product (3)a
Time (h)
4.0
Yieldb (%)
85
O
O
SCN
a
Me
O
O
SCN
Me
b
c
7.0
5.0
75
72
Br
Br
O
O
SCN
Me
O2N
MeO
MeO
O2N
MeO
O
O
SCN
d
e
f
Me
6.0
7.0
7.0
85
80
85
MeO
O
O
SCN
O
O
SCN
MeO
O
MeO
O
SCN
g
4.5
4.5
80
75
O
O
O
h
SCN
O
SCN
i
6.0
70
O
O
Me
Me
SCN
j
5.0
6.0
5.0
5.0
85
76
70
75
O
O
k
l
Ph
O
Ph
O
SCN
SCN
O
O
SCN
m
a
All products were characterized by 1H NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
b

1434
B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 1432–1435
Table 2
DEAD-promoted synthesis of
O
O
a-thiocyanatoketones
SCN
NBS
Entry Ketone
Product (3)a
Time Yieldb
+
NH4SCN
(h)
(%)
CH3CN, rt
( )n
n = 1,2,3
( )n
O
O
SCN
O
e
8.0
58
Scheme 2.
a-Thiocyanation of cyclic ketones.
the corresponding
a
-thiocyanoketones in excellent yields (Table 1,
O
entries e and f). Other cyclic ketones, such as cyclohexanone, cyclo-
pentanone, cycloheptanone, 2-methylcyclohexanone and 4-phenyl
cyclohexanone also participated well in this reaction (Table 1, en-
tries g–k, Scheme 2).
In the case of cyclic ketones, the corresponding a-thiocyanatok-
etones were obtained in good yields with high selectivity (Table 1,
SCN
f
8.0
60
MeO
O
MeO
O
SCN
g
10
10
55
65
entries g–k). Remarkably, 2-cyclohexen-1-one also underwent
smooth thiocyanation selectively at
a-position without affecting
O
O
the olefin functionality (Table 1, entry l). Interestingly, acyclic ke-
tone i.e. butan-2-one also gave the respective thiocyanate in 75%
yield (Table 1, entry m). Next we examined the reactivity of various
oxidants, such as PhI(OAc)2, NCS, NIS, DDQ and oxone for this con-
version. Of these, NBS was found to be superior in terms of conver-
sion. For instance, treatment of acetophenone with ammonium
thiocyanate using either 1 equiv of NCS and or NIS over 4 h gave
the thiocyanoketone 3a 75% and 80% yields, respectively. The re-
sults are summarized in Table 1 after optimizing the reaction con-
ditions. The maximum yield of 3a was obtained when the reaction
was carried out using equimolar ratios of ketone, NBS and NH4SCN
(1:1:1).11 The above optimized conditions were then applied for
the thiocyanation of various ketones. It was found that all the reac-
tions proceeded well under mild conditions and gave the corre-
sponding products in good yields (Table 1).
Among various solvents, such as acetonitrile, tetrahydrofuran
and dichloromethane used for this transformation, acetonitrile
proved to be the best solvent. In all cases, the reactions were clean
and free from side products such as nuclear bromination or side
chain bromination. The major advantages of the present method
are high yields, cleaner reaction profiles, operational simplicity
and low cost of the reagents. Mechanistically, we assume that
NBS reacts initially with ammonium thiocyanate to generate elec-
trophilic NTS. Subsequently ketones react rapidly with NTS to give
Me
M
e
SCN
j
O
O
k
9.0
9.0
60
68
Ph
O
SCN
Ph
O
SCN
m
All products were characterized by 1H NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
a
b
venient and cost-effective. This method is applicable for a wide
range of substrates including cyclic and acyclic ketones. DEAD
can also be used for the thiocyanation of enolizable ketones.
Acknowledgements
S.M.S.R. thanks the CSIR, New Delhi for the award of a fellow-
ship. Authors also thank Dr. J. S. Yadav, Director, IICT, Hyderabad
for his kind encouragement and support.
the desired a-thiocyanatoketone (Scheme 3).
References and notes
Inspired by the reactivity of the DEAD in the thiocyanation of
indoles,12 we attempted the thiocyanation of enolizable ketones.
Interestingly, various enolizable ketones underwent smooth thio-
cyanation in the presence of DEAD and ammonium thiocyanate
and the results are presented in Table 2.
In summary, NBS has proved to be a mild and effective reagent
for the thiocyanation of enolizable ketones under neutral condi-
tions. The use of NBS makes this procedure quite simple, more con-
1. (a) Shahidi, F. In Sulphur Compounds in Foods; Mussinan, C. J., Keelan, M. E., Eds.;
American Chemical Society: Washington, DC, 1994; p 106. Chapter 9; (b) 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; (c) Garson, M. J.; Simpson, J. S.; Flowers, A. E.; Dumdei, E. J. In Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier, 2000; Vol. 21, p 329.;
(d) Yasman, Y.; Edrada, R. A.; Wray, V.; Proksch, P. J. Nat. Prod. 2003, 66, 1512.
2. (a) Wood, J. L. Org. React. 1946, 3, 240; (b) Kelly, T. R.; Kim, M. H.; Curtis, A. D. M.
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Chemistry; Katritzky, A., Ed.; Pergamon: Oxford, 1984; Vol. 6, p 235; (d) Li, L.;
Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 11648; (e) Falck, J. R.; Gao, S.;
Prasad, R. N.; Reddy, K. S. Bioorg. Med. Chem. Lett. 2008, 18, 1768.
3. (a) Kodomari, M.; Aoyama, T.; Suzuki, Y. Tetrahedron Lett. 2002, 43, 1717; (b)
Aoyama, T.; Murata, S.; Arai, I.; Araki, N.; Takido, T.; Suzuki, Y.; Kodomari, M.
Tetrahedron 2006, 62, 3201; (c) Aoyama, T.; Murata, S.; Takido, T.; Kodomari, M.
Tetrahedron 2007, 63, 11933.
O
O
Br-SCN
N
+
NH4
+
N
Br
NH4SCN
+
4. (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.
O
O
5. Dittmer, D. C. In Comprehensive Heterocyclic Chemistry; Katritzky, A., Ed.;
Pergamon: Oxford, 1984; Vol. 7, p 178.
6. Prakash, O.; Saini, N. Synth. Commun. 1993, 23, 1455.
:
OH
O
O
7. Yadav, J. S.; Reddy, B. V. S.; Srinivas, M. Chem. Lett. 2004, 33, 882.
8. (a) Prakash, O.; Kaur, H.; Batra, H.; Singh, S. P.; Moriarty, R. A. J. Org. Chem. 2001,
66, 2019; (b) Prakash, O.; Rani, N.; Sharma, V.; Moriarty, R. M. Synlett 1997,
1255; (c) Iranpoor, N.; Firouzabadi, H.; Shaterian, H. Synlett 2000, 10, 65.
9. Tanabe, Y.; Makita, T.; Mori, K. Chem. Lett. 1994, 2275.
SCN
+
NH4Br
NCS
N
O
10. (a) Kumar, A.; Ahamd, P.; Maurya, R. A. Tetrahedron Lett. 2007, 48, 1399; (b)
Yadav, J. S.; Reddy, B. V. S.; Reddy, U. V. S.; Krishna, A. D. Tetrahedron Lett. 2007,
Scheme 3. A plausible reaction mechanism.

B. V. Subba Reddy et al. / Tetrahedron Letters 52 (2011) 1432–1435
1435
48, 5243; (c) Yadav, J. S.; Reddy, B. V. S.; Reddy, U. V. S.; Chary, D. N. Synthesis
2008, 1283.
2:8) to afford the pure thiocyanatoketone derivative. Spectroscopic data of
selected compounds: 3b, Table 1: 1-(4-Bromophenyl)-2-thiocyanatoethanone:6
11. General procedure: Method A: To a stirred solution of ammonium thiocyanate
(1 mmol, 0.076 g) and NBS (1 mmol, 0.178 g) in acetonitrile (10 mL) was added
acetophenone (1 mmol, 0.12 g) at 0 °C and the resulting mixture was stirred at
room temperature for the appropriate time (Table 1). After complete
conversion as indicated by TLC, the reaction mixture was quenched with
water (10 mL) and extracted with ethyl acetate (2 Â 10 mL). The combined
extracts were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. The resulting product was purified by column
chromatography on silica gel (Merck, 60–120 mesh, ethyl acetate/hexane,
2:8) to afford the pure thiocyanatoketone derivative.
Yellow solid, mp 139–142 °C; 1H NMR (300 MHz, CDCl3):
d
7.81 (d, 2H,
J = 8.7 Hz), 7.68 (d, 2H, J = 8.7 Hz), 4.70 (s, 2H); 13C NMR (75 MHz, CDCl3): d
189.9, 135.9, 132.5, 130.3, 129.8, 111.5, 42.6; IR (KBr):
m 3084, 2919, 2840,
2135, 1661, 1580, 1561, 1403, 1318, 1291, 1205, 1070, 996, 812 cmÀ1; EIMS:
m/z (%): 256 [M+1]. Compound 3e, Table 1: 2-Thiocyanato-3,4-
dihydronaphthalen-1(2H)-one:10b 1H NMR (300 MHz, CDCl3): d 8.02 (dd, 1H,
J = 7.5, 1.5 Hz), 7.54 (dt, 1H, J = 7.5, 1.5 Hz), 7.23–7.41 (m, 2H), 4.53 (dd, 1H,
J = 13.6, 4.5 Hz), 3.17–3.82 (m, 2H), 2.83–2.93 (m, 1H), 2.37–2.51 (m, 1H); 13C
NMR (75 MHz, CDCl3): d 192.3, 139.2, 137.6, 133.1, 128.6, 128.4, 124.6, 111.9,
57.2, 31.9, 29.1; IR (KBr):
m 2920, 2851, 2153, 1679, 1598, 1453, 1312,
General procedure: Method B: To a stirred solution of ammonium thiocyanate
(1 mmol, 0.076 g) and DEAD (1 mmol, 0.174 g) in acetonitrile (10 mL) was
added cyclohexanone (1 mmol, 0.098 g), the resulting mixture was stirred at
room temperature for the appropriate time (Table 2). After complete
conversion as indicated by TLC, the reaction mixture was quenched with
water (10 mL) and extracted with ethyl acetate (2 Â 10 mL). The combined
extracts were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. The resulting product was purified by column
chromatography on silica gel (Merck, 60–120 mesh, ethyl acetate/hexane,
1220 cmÀ1
; EIMS: m/z (%): 226 [M+Na]. 3 k (Table 1): 4-Phenyl-2-
thiocyanatocyclohexanone: 1H NMR (300 MHz, CDCl3): d 7.12–7.37 (m, 5H),
4.46 (dd, 1H, J = 13.0, 6.0 Hz), 3.12–3.25 (m, 1H), 2.84–2.95 (m, 1H), 2.55–2.58
(m, 2H), 1.94–2.39 (m, 3H); 13C NMR (75 MHz, CDCl3): d 203.3, 142.1, 128.8,
127.2, 126.5, 111.6, 57.4, 43.0, 42.7, 40.6, 33.9; IR (KBr):
m 2925, 2153, 1714,
1491, 1449, 1211, 1132 cmÀ1; EIMS: m/z (%): 232 [M+1].
12. Iranpoor, N.; Firouzabadi, H.; Khalili, D.; Shahin, R. Tetrahedron Lett. 2010, 51,
3508.