Iodine/MeOH as a novel and versatile reagent system for the synthesis of α-ketothiocyanates

Article abstract of DOI:10.1016/j.tetlet.2007.05.143

Ketones possessing α-hydrogens undergo smooth thiocyanation with ammonium thiocyanate in the presence of molecular iodine in refluxing methanol to produce the corresponding α-ketothiocyanates in excellent yields with high selectivity. The use of iodine ma

Full text of DOI:10.1016/j.tetlet.2007.05.143

Tetrahedron Letters 48 (2007) 5243–5246
Iodine/MeOH as a novel and versatile reagent system for
the synthesis of a-ketothiocyanates
J. S. Yadav,* B. V. Subba Reddy, U. V. Subba Reddy and A. D. Krishna
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 8 January 2007; revised 14 May 2007; accepted 24 May 2007
Available online 31 May 2007
Abstract—Ketones possessing a-hydrogens undergo smooth thiocyanation with ammonium thiocyanate in the presence of mole-
cular iodine in refluxing methanol to produce the corresponding a-ketothiocyanates in excellent yields with high selectivity. The
use of iodine makes this procedure simple, convenient and cost effective.
ꢀ 2007 Published by Elsevier Ltd.
The direct a-thiocyanation of ketones is an important
carbon–heteroatom bond forming reaction in organic
synthesis.1 a-Ketothiocyanates are useful intermediates
in the synthesis of sulfur-containing heterocycles such
as thiazoles.2 Some of these heterocycles exhibit herbi-
cidal and other important biological activities.3 In addi-
tion to this, the thiocyanato group is found in several
anticancer natural products formed by deglycosylation
of glucosinolates derived from cruciferous vegetables.4
Thus, the direct thiocyanation of ketones is of prime
importance. Consequently, various methods have been
developed for the a-thiocyanation of ketones using a
variety of reagents under diverse reaction conditions.5,6
However, these classical methods involve multi-step syn-
thetic sequences and often harsh reaction conditions and
also the yields are typically low because of the poor
nucleophilicity of thiocyanate. Direct thiocyanation of
ketones has been reported using the dichloroiodobenz-
ene/lead(II) thiocyanate reagent system, which works
well with silyl enol ethers.7 Furthermore, many of these
reported methods involve 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.8 Since organosulfur com-
pounds have become increasingly useful and important
in the field of drugs and pharmaceuticals, the develop-
ment of simple, convenient, and efficient approaches
for their synthesis are desirable. Recently, molecular
iodine has received considerable attention as an inexpen-
sive, nontoxic, readily available reagent for various
organic transformations, affording the corresponding
products with high selectivity in excellent yields. The
mild Lewis acidity associated with iodine has led to its
use in organic synthesis in catalytic to stoichiometric
amounts.9
In continuation of our interest on the use of molecular
iodine for various transformations,10 we herein report
the first direct and metal catalyst-free synthesis of a-keto-
thiocyanates by a-thiocyanation of enolizable ketones
with ammonium thiocyanate under neutral conditions.
Initially, we studied the a-thiocyanation of acetophe-
none 1 as a model substrate with 2 equiv of ammonium
thiocyanate using 1 equiv of molecular iodine in reflux-
ing methanol. The reaction went to completion in 6 h
and the product, 1-phenyl-2-thiocyanatoethanone 2a,
was obtained in 85% yield (Table 1, entry a; Scheme 1).
The excellent catalytic activity of iodine in the thiocya-
nation of acetophenone prompted us to investigate its
use in reactions with other enolizable ketones. Interest-
ingly, various substituted ketones, such as 3-chloro-
acetophenone, 2-trifluoromethylacetophenone, and 2-
acetylnaphthalene, reacted efficiently with ammonium
thiocyanate to afford the corresponding a-thiocyanato-
ketones in high yields (Table 1, entries b–d). Like
acetophenones, cyclic ketones such as 1-tetralone, 2-
phenylchroman-4-one, cyclopentanone, 2-methylcyclo-
hexanone, 4,4-dimethylcyclohex-2-enone, cyclohepta-
none, and cyclododecanone reacted well under similar
Keywords: Thiocyanation; Ketones; Iodine catalysis; a-Ketothio-
cyanates.
*
Corresponding author. Fax: +91 40 27160512; e-mail: yadav@
iict.res.in
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.05.143

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J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 5243–5246
Table 1. Iodine-promoted thiocyanation of ketones with NH4SCN in methanol
Entry
a
Ketone
Producta
Time (h)
6.0
Yieldb (%)
85
O
O
SCN
Me
O
O
SCN
Cl
Cl
b
6.5
80
Me
CF3 O
CF3 O
SCN
c
6.5
6.0
82
79
Me
O
O
SCN
d
Me
O
O
O
SCN
e
f
5.5
6.0
84
85
O
O
SCN
Ph
Ph
O
O
O
SCN
g
5.5
5.0
83
86
O
O
SCN
Me
Me
h
O
O
SCN
i
j
5.0
6.5
81
75
Me
Me
Me
Me
O
O
SCN
SCN
O
O
k
7.0
5.0
82
84
OH
O
SCN
l
O
O
O
O
O
O
O
O
Me
Me
Me
Me
m
n
6.5
6.0
73
70
OMe
SCN
OMe
O
O
Me
Me
Me
Me
Me
Me
SCN
Me
a Al products were characterized by IR, 1H NMR and high resolution mass spectroscopy.
b Yield refers to pure products after chromatography.

J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 5243–5246
5245
In summary, molecular iodine has proved to be a useful
and novel reagent for selective thiocyanation of ketones
to produce a-ketothiocyanates in high yields. The experi-
mental procedure is simple, convenient, and the reaction
conditions are amenable to scale up.
O
O
SCN
I2
CH3
NH4SCN
+
MeOH, reflux
2a
1
Scheme 1.
Acknowledgements
U.V.S.R. and A.D.K. thank the CSIR, New Delhi, for
the award of fellowships.
O
O
SCN
O
I2
NH4SCN
+
O
MeOH, reflux
O
O
References and notes
Scheme 2.
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John Wiley & Sons: New York, 1946; Vol. 3, Chapter 6;
(b) Guy, R. G. In In the Chemistry of Cyanates and their
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2. Metzer, J. B. In Comprehensive Heterocyclic Chemistry;
Katritzky, A., Ed.; Pergamon: Oxford, 1984; Vol. 6, p 235.
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Hamada, T.; Shibata, H.; Satoh, R. Eur. Pat. 1991, Appl.
E. P. 446802; Chem. Abstr. 1992, 116, 59360j.
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C. J., Keelan, M. E., Eds.; American Chemical Society:
Washington, DC, 1984; Chapter 9, pp 1067–1286; (b)
Mehta, R. G.; Liu, J.; Constantinou, A.; Thomas, C. F.;
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399–405.
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–
1462.
conditions to give a-ketothiocyanates (Table 1, entries
e–k). Similarly, the b-keto ester, chroman-2,4-dione also
afforded the corresponding 3-thiocyanato-chroman-2,4-
dione in good yield (Table 1, entry l; Scheme 2).
Furthermore, sterically hindered substrates such as
methyl 4-methyl-3-oxopentanoate and t-butyl methyl
ketone also reacted efficiently under these reaction con-
ditions (Table 1, entries m and n). a-Thiocyanation of
cyclic ketones gave higher yields compared to acyclic
ketones. The best results were obtained with cyclohex-
ane derivatives in refluxing methanol. Although, the
reactions proceeded smoothly at room temperature,
the products were obtained in low yields (40–50%) after
long reaction times (16 h). However, no reaction was
observed in the absence of catalyst, even in refluxing
methanol over a long reaction time (12 h). As solvent,
methanol appeared to give the best results. The prod-
ucts were characterized by 1H NMR, IR, and mass spec-
troscopic data and also by comparison with authentic
samples.7 This method is very clean and free from side
products. Amongst the various oxidants such as
Mn(OAc)3Æ2H2O, Bi(NO3)3Æ5H2O and IBX tested,
molecular iodine was found to be the most effective in
terms of conversion and reaction rates. The scope and
generality of this process is illustrated with respect to
various enolizable ketones and ammonium thiocyanate
and the results are presented in Table 1.11
7. (a) Prakash, O.; Kaur, H.; Batra, H.; Rani, N.; Singh, S.
P.; Moriarty, R. M. J. Org. Chem. 2001, 66, 2019–2023;
(b) Prakash, O.; Rani, N.; Sharma, V.; Moriarty, R. M.
Synlett 1997, 1255–1256.
8. Atkins, E. F.; Dabbs, S.; Guy, R. G.; Mahomed, A. A.;
Mountford, P. Tetrahedron 1994, 50, 7253–7264.
9. (a) Togo, H.; Iida, S. Synlett 2006, 2159–2175; (b) Lin,
X.-F.; Cui, S.-L.; Wang, Y.-G. Tetrahedron Lett. 2006, 47,
4509–4512; (c) Chen, W.-Y.; Lu, J. Synlett 2005, 1337–
1339; (d) Royer, L.; De, S. K.; Gibbs, R. A. Tetrahedron
Lett. 2005, 46, 4595–4597; (e) Banik, B. K.; Fernandez,
M.; Alvarez, C. Tetrahedron Lett. 2005, 46, 2479–2482; (f)
Wang, S.-Y. Synlett 2004, 2642–2643; (g) Ko, S.; Sastry,
M. N. V.; Lin, C.; Yao, C.-F. Tetrahedron Lett. 2005, 46,
5771–5774.
10. (a) Yadav, J. S.; Reddy, B. V. S.; Hashim, S. R. J. Chem.
Soc., Perkin Trans. 1 2000, 3082–3084; (b) Yadav, J. S.;
Reddy, B. V. S.; Premalatha, K.; Swamy, T. Tetrahedron
Lett. 2005, 46, 2687–2690; (c) Yadav, J. S.; Reddy, B. V.
S.; Sabitha, G.; Reddy, G. S. K. K. Synthesis 2000, 1532–
1534; (d) Yadav, J. S.; Reddy, B. V. S.; Rao, C. V.; Chand,
P. K.; Prasad, A. R. Synlett 2001, 1638–1640.
11. General procedure: To a stirred solution of ammonium
thiocyanate (2 mmol), and iodine (1 mmol) in methanol
(10 mL), the ketone (1.0 mmol) was added and the mixture
was stirred at reflux for the appropriate time (Table 1).
After complete conversion as indicated by TLC, the
reaction mixture was quenched with water (15 mL) and
extracted with ethyl acetate (2 · 15 mL). The combined
extracts were washed with a 15% solution of aqueous
sodium thiosulfate, dried over anhydrous Na2SO4 and
The reaction most likely proceeds via the formation of
active thiocyanogen, (SCN)2 from molecular iodine
and ammonium thiocyanate as reported previously.12
Thiocyanogen reacts rapidly with the enolizable ketone
to produce a-ketothiocyanate (Scheme 3).
I2
2 NH4SCN
(SCN)2
2 NH4I
+
MeOH
O
O
SCN
(SCN)2
Scheme 3.

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J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 5243–5246
concentrated in vacuo. The resulting product was purified
by column chromatography on silica gel (Merck, 100–200
mesh, ethyl acetate–hexane, 0.5:9.5) to afford the pure
thiocyanato derivative.
674 cmÀ1 1H NMR (200 MHz, CDCl3): d 4.90 (s, 2H),
.
7.64 (m, 2H), 7.94 (m, 4H), 8.44 (s, 1H). EIMS: m/z (%):
227 M+ (100), 99 (40), 66 (35). HRMS Calcd for
C13H10NOS: 228.0483. Found: 228.0492 (M+H+).
Spectral data for selected products: Compound 2b: 2-(3-
Chlorophenyl)-2-oxo-ethyl thiocyanate (Table 1, entry b):
Pale yellow solid, mp 68–70 ꢁC, IR (KBr): m 3065, 2988,
Compound 2i: 4,4-Dimethyl-6-thiocyanato-cyclohex-2-
enone (Table 1, entry i): Yellow liquid, IR (KBr): m
2965, 2928,2870, 2083, 1718, 1681, 813, 761 cmÀ1 1H
.
2929, 2152, 1680, 780, 678 cmÀ1
.
1H NMR (200 MHz,
NMR (300 MHz, CDCl3): d 1.27 (s, 3H), 1.34 (s, 3H), 3.75
(m, 2H), 4.47 (m, 1H), 5.93 (d, J = 10.1 Hz, 1H), 6.75 (d,
J = 10.1 Hz, 1H). EIMS: m/z (%): 181 M+ (100), 178 (15),
149 (20), 122 (40) 107 (65), 47 (60). HRMS Calcd for
C9H11NOSNa: 204.0459. Found: 204.0453 (M+Na+).
12. (a) Grant, M. S.; Snyder, H. R. J. Am. Chem. Soc. 1960,
82, 2742–2744; (b) Kelly, T. R.; Kim, M. H.; Curtis, A. D.
M. J. Org. Chem. 1993, 58, 5855–5857.
CDCl3): d 4.72 (s, 2H), 7.48 (m, 1H), 7.64 (d, J = 7.5 Hz,
1H), 7.82 (d, J = 7.5 Hz, 1H), 7.92 (s, 1H). EIMS: m/z (%):
210 M+ (100), 125 (70), 91 (80), 76 (20). HRMS Calcd for
C9H7NOSCl: 211.9936. Found: 211.9936 (M+H+).
Compound 2d: 2-(2-Naphthyl)-2-oxo-ethyl thiocyanate
(Table 1, entry d): Light yellow solid, mp 102–104 ꢁC IR
(KBr): m 3051, 2991, 2933, 2153, 1661, 1622, 739,