Efficient and novel method for thiocyanation of aromatic and heteroaromatic compounds using bromodimethylsulfonium bromide and ammonium thiocyanate

Article abstract of DOI:10.1055/s-2007-992367

Various aromatic and heteroaromatic compounds have been efficiently thiocyanated by using a novel combination of bromodimethylsulfonium bromide (BDMS) and ammonium thiocyanate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992367

2952
LETTER
Efficient and Novel Method for Thiocyanation of Aromatic and Hetero-
aromatic Compounds Using Bromodimethylsulfonium Bromide and
Ammonium Thiocyanate
New
Method for
T
i
hiocyanation of Aro
e
matic and
s
H
eteroaro
h
matic Compounds S. Bhalerao, Krishnacharya G. Akamanchi*
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, University of Mumbai, Matunga,
Mumbai 400 019, India
E-mail: kgap@rediffmail.com
Received 20 April 2007
the transformation of alcohols to the corresponding bro-
Abstract: Various aromatic and heteroaromatic compounds have
mides,7a oxidation of thiols to disulfides,7b deprotection of
been efficiently thiocyanated by using a novel combination of bro-
dithioacetals,7c preparation of a-bromoenones from the
modimethylsulfonium bromide (BDMS) and ammonium thiocyan-
corresponding enones,7d electrophilic aromatic bromina-
ate.
tion,7e and regioselective a-bromination of b-keto esters
Key words: bromodimethylsulfonium bromide, ammonium thio-
and 1,3-diketones.6b Herein, we wish to report a novel,
cyanate, aromatic thiocyanate, heteroaromatic thiocyanate, thiocy-
and efficient approach for the thiocyanation of aromatic
and heteroaromatic compounds using a novel combina-
tion of BDMS and ammonium thiocyanate (Scheme 1).
anation
The aromatic and heteroaromatic thiocyanato compounds
are useful intermediates in the synthesis of sulfur-contain-
ing heterocycles like 2-aminobenzothiazoles, 1,3-thiazine
derivatives, and 2-iminobenzoxathioles.1 Furthermore,
aryl thiocyanates can be easily transformed into various
sulfur-containing functional groups2 such as thiophenols,
thiocarbamates, and dithiourethanes. They are particular-
ly useful for producing drugs and pharmaceuticals.3 Sev-
eral methods have been developed for the thiocyanation of
arenes by using various reagents under certain conditions,
like arylthallium bistrifluoroacetates/potassium thiocyan-
ate,4a antimony(V) chloride/lead(II) thiocyanate,4b phen-
yliodine(III) bis(trifluoroacetate)/TMSNCS,4c and N-
bromosulfonamides/KSCN.4d Other reagents, such as bro-
mine/potassium thiocyanate,2b N-thiocyanatosuccinate,5a
ceric ammonium nitrate (CAN)/ammonium thiocyanate,5b
acidic montK10 clay/ammonium thiocyanate,5c iodine/
ammonium thiocyanate,5d ferric chloride/ammonium
thiocyanate,5e and Oxone/ammonium thiocyanate5f have
been applied to the thiocyanation of indoles and aromatic
amines. However, these methodologies suffer from some
drawbacks such as the requirement for strong oxidizing
reagents, toxicity of the reagents,4b and low yields for
some compounds.5d In case of molecular bromine which
is hazardous and difficult to handle, sometime reactions
need to be performed at –70 °C to –60 °C. Hence, a new
methodology for the thiocyanation of aromatic and het-
eroaromatic compounds could be a valuable addition.
BDMS, NH4SCN
ArSCN
ArH
MeCN, r.t.
Scheme 1
To begin our study, effect of various reaction parameters
on the aromatic thiocyanation of o-cresol (1) was exam-
ined as shown in Table 1. In the preliminary experiment,
the reaction using BDMS was compared with that involv-
ing molecular bromine. Reaction was carried out on o-
cresol (5 mmol) with bromine (7.5 mmol) or BDMS (7.5
mmol) and NH4SCN (15 mmol) in acetonitrile. When Br2
was added to the suspension of NH4SCN in acetonitrile,
an exothermic reaction occurred and the temperature rose
up to 47 °C. GC analysis showed that the reaction was not
selective and gave only 47% aromatic thiocyanation (en-
try 1), whereas with BDMS, no exothermic reaction oc-
curred and a 98% aromatic thiocyanation was obtained.
The reaction was carried out with different molar ratios of
BDMS–ammonium thiocyanate (entries 2–5). When a
lower molar ratio of ammonium thiocyanate was used
with respect to BDMS, the aromatic bromination led to
another product. In solvent study, we found that acetoni-
trile was the best general purpose solvent in this method-
ology. The time of addition of the substrate was found to
be critical to the outcome of the reaction. When we stirred
NH4SCN and BDMS mixture in acetonitrile for longer
time before addition of o-cresol, the yield of thiocyanate
1a was reduced with an increase in the by-product forma-
tion and recovery of the starting material (entries 6 and 7).
This observation shows that addition of the substrate must
be immediate. Whereas in chloroform as a solvent imme-
diate addition of the substrate gave thiocyanate 1a, bro-
mocresol 1b and byproduct with complete consumption
of the starting material (entry 8), while addition of the
substrate after 30 minutes led to a decrease in the aromatic
In recent years, the use of bromodimethylsulfonium bro-
mide (BDMS) has gained attention in synthetic organic
chemistry.6 The reagent BDMS is readily accessible, can
be conveniently stored, is less hazardous, easy to handle,
and crystalline solid. So far, BDMS has been utilized for
SYNLETT 2007, No. 19, pp 2952–2956
x
x
.x
x
.7
Advanced online publication: 08.11.2007
DOI: 10.1055/s-2007-992367; Art ID: D12507ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
New Method for Thiocyanation of Aromatic and Heteroaromatic Compounds
2953
Table 1 Optimization of Reagents and Reaction Conditions for Aromatic Thiocyanationa,b
reagent,
solvent
OH
OH
OH
other unidentified
products
+
+
r.t.
NCS
Br
1
1a
1b
Yield (%)
1b
Entry
Reagent/NH4SCN
molar ratio
Solvent
Time of o-cresol (1) Unreacted 1 1a
addition (min)
Other unidentified
products (%)d
c
1
2
1.5 Br2/3.0
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CHCl3
CHCl3
CHCl3
THF
–
–
–
–
47
09
51
69
98
53
27
13
62
48
23
–
48
90
39
21
–
5
–
c
c
c
c
1.5 BDMS /1.5
1.5 BDMS /2.0
1.5 BDMS /2.5
1.5 BDMS/3.0
1.5 BDMS/3.0
1.5 BDMS/3.0
1.5 BDMS/3.0
1.5 BDMS/3.0
1.5 BDMS/3.0
1.5 BDMS/3.0
1.5 BDMS/3.0
1.5 BDMS/3.0
3
–
–
9
4
–
–
8
5
–
–
–
6
30
60
–
33
50
–
–
13
20
22
–
7
–
c
c
8
63
3
9
30
60
–
33
50
61
100
100
10
11
12
13
1
–
13
–
–
THF
30
60
–
THF
–
–
–
a All reactions were performed at r.t.
b In each case reaction was worked up after 30 min of o-cresol addition and yield was determined by GC analysis on 5% OV-17 (length: 1.8 m;
i.d.: 0.32 cm) column, and FID detector.
c Immediate addition of o-cresol to the mixture of BDMS9 and NH4SCN in solvent was carried out.
d Quantity is specified only when >2%.
bromination and the yield of thiocyanate 1a increased position of aniline (entry 10). In case of N,N-diallylbenz-
with starting material recovery (entry 9). Addition of the enamine alkene group remained unaffected showing
substrate after 60 minutes showed further increase in re- chemoselectivity of the method (entry 11). In the case of
covery of the starting material (entry 10). In case of tet- para-substituted anilines, 2-aminobenzothiazoles were
rahydrofuran as solvent, immediate addition of the formed indicating ortho thiocyanation followed by cy-
substrate gave aromatic bromination, thiocyanation and clization (entries 12–14). Heteroaromatic compounds,
the reaction remained incomplete. The substrate remained such as indole, pyrrole, and thiophene were also easily
unaffected when addition was done after 30 minutes or transformed into the mono-thiocyanated products within
later (entries 11–13). All these observations could be at- 5–10 minutes (entries 15–17). The substrates containing
tributed to heterogeneity of the reaction mixture as electron-withdrawing group like nitro, ester, and nitrile
NH4SCN has low solubility and thiocyanating species are did not react, indicating the need for electron-donating
unstable.8
group (entries 18–20).
Under the optimized conditions, a wide range of sub- To conclude, we have developed a novel method for aro-
strates were investigated as shown in Table 2.10 Anilines matic and heteroaromatic thiocyanation using a combina-
and phenols underwent thiocyanation under these condi- tion of bromodimethylsulfonium bromide and ammonium
tions giving selectively para-thiocyanation (entries 1– thiocyanate. The method is mild, and gives mono- and re-
11). When the reaction was performed on N-benzyl-N- gioselective thiocyanate products in good to excellent
methylbenzenamine, thiocyanation occurred at the para yields within short reaction time.
Synlett 2007, No. 19, 2952–2956 © Thieme Stuttgart · New York

2954
D. S. Bhalerao, K. G. Akamanchi
LETTER
Table 2 Thiocyanation of Aromatic and Heteroaromatic Com-
pounds Using BDMS/Ammonium Thiocyanate in Acetonitrile at
Room Temperaturea
Table 2 Thiocyanation of Aromatic and Heteroaromatic Com-
pounds Using BDMS/Ammonium Thiocyanate in Acetonitrile at
Room Temperaturea (continued)
Entry Substrate
Product
Time Yield
(min) (%)b
Entry Substrate
Product
Time Yield
(min) (%)b
OH
OH
OH
NH2
N
S
NH2
12
25
35
94
92
1
2
20
25
95
88
NCS
MeO
MeO
1
2
1a
12a
12
OH
NH2
N
S
NH2
13
Me
13
NCS
Me
2a
13a
OMe
OMe
NH2
N
S
NH2
3
4
25
30
92
95
14
Br
40
10
91
92
NCS
Br
3
4
3a
14a
14
OMe
SCN
SCN
OMe
15
N
N
H
H
15
15a
4a
OMe
NH2
OMe
NH2
NH2
16
17
18
5
10
–
91
92
–
SCN
N
H
N
H
5
6
25
15
90
92
16
17
16a
NCS
5
6
5a
SCN
S
S
17a
NCS
NO2
6a
NRc
NRc
NRc
NH2
18
19
20
7
8
15
15
96
94
COOEt
CN
NCS
19
20
–
–
–
–
7
8
9
7a
NH2
NH2
NCS
8a
a All products were characterized by 1H NMR, IR and their physical
properties compared with the reported values.
b Isolated yield.
N
N
9
20
15
98
95
NCS
c NR: no reaction.
9a
N
N
Acknowledgment
10
The authors wish to thank the University Grants Commission
(UGC), India, for financial support.
NCS
10
11
10a
N
References and Notes
N
(1) See reviews: (a) Wood, J. L. In Organic Reactions, Vol. 3;
Wiley: New York, 1967, 240–266. (b) Kelly, T. R.; Kim, M.
H.; Certis, A. D. M. J. Org. Chem. 1993, 58, 5855.
(2) (a) Toste, F. D.; Laronde, F.; Still, W. J. Tetrahedron Lett.
1995, 36, 2949. (b) Grant, M. S.; Snyder, H. R. J. Am. Chem.
Soc. 1960, 82, 2742.
11
15
92
SCN
11a
Synlett 2007, No. 19, 2952–2956 © Thieme Stuttgart · New York

LETTER
New Method for Thiocyanation of Aromatic and Heteroaromatic Compounds
2955
(3) Guy, R. G. In The Chemistry of Cyanates and Their Thio
Derivatives, Part 2; Patai, S., Ed.; John Wiley and Sons: New
York, 1977, Chap. 18, 819–886.
(4) (a) Taylor, E. C.; Kienzle, F. Synthesis 1972, 38.
(b) Uemura, S.; Onoe, A.; Okazaki, H.; Okano, M. Bull.
Chem. Soc. Jpn. 1975, 48, 619. (c) Kita, Y.; Takada, T.;
Mihara, S.; Whelan, B. A.; Tohma, H. J. Org. Chem. 1995,
60, 7144. (d) Khazei, A.; Alizadeh, A.; Vaghei, R. G.
Molecules 2001, 6, 253.
2925, 2159 (SCN), 1597, 1495, 1275, 815 cm–1.
4-Thiocyanatophenol (2a): solid; mp 51–52 °C (lit.11 52–53
°C). 1H NMR (60 MHz, CDCl3): d = 5.62 (br s, 1 H), 6.79 (d,
J = 8.4 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H). IR (KBr): 3363,
3009, 2158 (SCN), 1585, 1492, 1212, 828, 756 cm–1.
1-Methoxy-4-thiocyanatobenzene (3a): solid; mp 33–34
°C (lit.12 33–34 °C). 1H NMR (60 MHz, CDCl3): d = 3.74 (s,
3 H), 6.69 (d, J = 9.0 Hz, 2 H), 7.31 (d, J = 9.0 Hz, 2 H). IR
(KBr): 2985, 2155 (SCN), 1587, 1475, 1267, 818, 712 cm–1.
1-Methoxy-4-thiocyanatonaphthalene (4a): solid; mp
104–106 °C (lit.4c 106–107 °C). 1H NMR (60 MHz, CDCl3):
d = 4.08 (s, 3 H), 6.71–6.75 (m, 1 H), 7.62–8.29 (m, 5 H). IR
(KBr): 2978, 2152 (SCN), 1591, 1271, 1063, 807, 771 cm–1.
1-Methoxy-2-methyl-4-thiocyanatobenzene (5a):oil (lit.4c
oil). 1H NMR (60 MHz, CDCl3): d = 2.50 (s, 3 H), 3.91 (s, 3
H), 6.81–7.16 (m, 3 H). IR (KBr): 2990, 2153 (SCN), 1596,
1485, 1260, 880 cm–1.
(5) (a) Toste, F. D.; Stefano, V. D.; Still, I. W. J. Synth.
Commun. 1995, 25, 1277. (b) Nair, V.; George, T. G.; Nair,
L. G.; Panicker, S. B. Tetrahedron Lett. 1999, 40, 1195.
(c) Chakrabarty, M.; Sarkar, S. Tetrahedron Lett. 2003, 44,
8131. (d) Yadav, J. S.; Reddy, S. B. V.; Shubashree, S.;
Sadashiv, K. Tetrahedron Lett. 2004, 45, 2951. (e) Yadav,
J. S.; Reddy, B. V. S.; Krishna, A. D.; Reddy, C. S.;
Narsaiah, A. V. Synthesis 2005, 961. (f) Wu, G.; Liu, Q.;
Shen, Y.; Wu, W.; Wu, L. Tetrahedron Lett. 2005, 46, 5831.
(6) (a) Das, B.; Holla, H.; Srinivas, Y. Tetrahedron Lett. 2007,
48, 61. (b) Khan, A. T.; Ali, M. A.; Goswami, P.; Chaudhari,
L. H. J. Org. Chem. 2006, 71, 8961. (c) Chaudhari, L. H.
Synlett 2006, 1619. (d) Khan, A. T.; Mondal, E.; Ghosh, S.;
Islam, S. Eur. J. Org. Chem. 2004, 2002. (e) Khan, A. T.;
Mondal, E.; Borah, B. M.; Ghosh, S. Eur. J. Org. Chem.
2003, 4113.
(7) (a) Furukawa, N.; Inoue, T.; Aida, T.; Oae, S. J. Chem. Soc.,
Chem. Commun. 1973, 212. (b) Olah, G. A.; Vankar, Y. D.;
Arvanaghi, M.; Surya Prakash, G. K. Synthesis 1979, 720.
(c) Olah, G. A.; Arvanaghi, M.; Vankar, Y. D. Synthesis
1979, 721. (d) Chow, Y. L.; Bakker, B. H. Can. J. Chem.
1982, 60, 2268. (e) Majetich, G.; Hicks, R.; Reister, S.
J. Org. Chem. 1997, 62, 4321.
(8) Epstein, I. R.; Kustin, K. J. Phys. Chem. 1992, 96, 6326.
(9) Preparation of Bromodimethylsulfonium Bromide
(BDMS):7a Dimethyl sulfide (3.69 mL, 50 mmol) was taken
in anhyd CH2Cl2 (10 mL) into a 150-mL conical flask. Then,
bromine (2.56 mL, 50 mmol) dissolved in anhyd CH2Cl2 (10
mL) was added slowly into the above solution at ice-bath
temperature over a period of 10 min. During the addition,
light orange crystals of bromodimethylsulfonium bromide
begin to separate out. After the addition of bromine was
complete, the crystals of bromodimethylsulfonium bromide
were collected by filtration, washed with anhyd hexane and
dried under vacuum; yield: 8.6 g (77%); mp 80–82 °C (lit.7a
81–82 °C).
(10) General Experimental Procedure for Thiocyanation: To
a yellow suspension of BDMS (1.66 g, 7.5 mmol) and
ammonium thiocyanate (1.14 g, 15 mmol) in anhyd MeCN
(50 mL) the substrate (5 mmol) was added immediately in
one portion. The reaction mixture was stirred at r.t. until
complete consumption of starting material as observed by
TLC. After completion of the reaction, it was quenched with
sat. solution of NaHCO3 (50 mL) and the solid residue was
removed by filtration and the residue was washed with
EtOAc. The organic layer was separated, washed with H2O
(50 mL), brine (50 mL) and dried over anhyd Na2SO4 and
concentrated under reduced pressure to give the crude
thiocyanato product. Pure product was obtained after
column chromatography (silica gel, mesh size 60–120,
eluent EtOAc–hexane, 10:90).
4-Thiocyanatobenzenamine (6a): solid; mp 50–52 °C (lit.5f
51–52 °C). 1H NMR (60 MHz, CDCl3): d = 3.82 (br s, 2 H),
6.67 (d, J = 8.8 Hz, 2 H), 7.33 (d, J = 8.8 Hz, 2 H). IR (KBr):
3403, 3350, 2137 (SCN), 1627, 1591, 1432, 818 cm–1.
2-Methyl-4-thiocyanatobenzenamine (7a): solid; mp 70–
71 °C (lit.13 70–71 °C). 1H NMR (60 MHz, CDCl3): d = 2.44
(s, 3 H), 3.75 (br s, 2 H), 6.43–6.62 (m, 2 H), 7.18–7.52 (m,
1 H). IR (KBr): 3354, 3243, 2145 (SCN), 1628, 1592, 1492,
1298, 821 cm–1.
2,6-Dimethyl-4-thiocyanatobenzenamine (8a): solid; mp
85–87 °C (lit.14 87–88 °C). 1H NMR (60 MHz, CDCl3): d =
2.44 (s, 6 H), 3.87 (br s, 2 H), 6.62 (s, 1 H), 7.22 (s, 1 H). IR
(KBr): 2928, 2147 (SCN), 1615, 1592, 1460, 1288 cm–1.
N,N-Dimethyl-4-thiocyanatobenzenamine (9a): solid; mp
72–74 °C (lit.5f 73–74 °C). 1H NMR (60 MHz, CDCl3): d =
2.99 (s, 6 H), 6.76 (d, J = 9.0 Hz, 2 H), 7.51 (d, J = 9.0 Hz,
2 H). IR (KBr): 2922, 2137 (SCN), 1586, 1503, 1362, 1077,
802 cm–1.
N-Benzyl-N-methyl-4-thiocyanatobenzenamine (10a):
solid; mp 68–70 °C. 1H NMR (60 MHz, CDCl3): d = 3.07 (s,
3 H), 4.57 (s, 2 H), 6.69 (d, J = 9.0 Hz, 2 H), 7.05 (s, 5 H),
7.39 (d, J = 9.0 Hz, 2 H). IR (KBr): 3014, 2144 (SCN), 1599,
1460, 1023, 824 cm–1. Anal. Calcd for C15H14N2: C, 70.83;
H, 5.55; N, 11.01. Found: C, 70.85; H, 5.54; N, 10.98.
N,N-Diallyl-4-thiocyanatobenzenamine (11a): oil; 1H
NMR (60 MHz, CDCl3): d = 3.78–3.97 (m, 4 H), 4.96–5.26
(m, 4 H), 5.55–6.06 (m, 2 H), 6.63 (d, J = 9.0 Hz, 2 H), 7.35
(d, J = 9.0 Hz, 2 H). IR (KBr): 3082, 2916, 2148 (SCN),
1641, 1591, 1504, 1238, 811 cm–1. Anal. Calcd for
C13H14N2S: C, 67.79; H, 6.13; N, 12.16. Found: C, 67.82; H,
6.15; N, 12.18.
2-Amino-6-methoxybenzothiazole (12a): solid; mp 158–
160 °C (lit.15 161–162 °C). 1H NMR (60 MHz, CDCl3): d =
3.82 (s, 3 H), 5.05 (br s, 2 H), 6.80–7.53 (m, 3 H). IR (KBr):
3435, 3312, 1596, 1230 cm–1.
2-Amino-6-methylbenzothiazole (13a): solid; mp 130–132
°C (lit.16 131–132 °C). 1H NMR (60 MHz, CDCl3): d = 2.23
(s, 3 H), 5.26 (br s, 2 H), 6.92–7.69 (m, 3 H). IR (KBr): 3325,
3413, 1590 cm–1.
2-Amino-6-bromobenzothiazole (14a): solid; mp 212–213
°C (lit.16 213–214 °C). 1H NMR (60 MHz, CDCl3): d = 4.93–
5.31 (br s, 2 H), 7.32–7.85 (m, 3 H). IR (KBr): 3320, 3430,
1605 cm–1.
Caution!! Reaction generates odorous dimethyl sulfide. All
operations should be carried out in well-ventilated hood. The
effluent should be treated with bleach before disposal.
Spectral Data for Thiocyanated Products
2-Methyl-4-thiocyanatophenol (1a): solid; mp 70–72 °C
(lit.11 71–72 °C). 1H NMR (60 MHz, CDCl3): d = 3.24 (s, 3
H), 6.14 (br s, 1 H), 6.64–7.25 (m, 3 H). IR (KBr): 3378,
2-Methyl-3-thiocyanato-1H-indole (15a): solid; mp 101–
102 °C (lit.5f 102–103 °C). 1H NMR (60 MHz, CDCl3): d =
2.50 (s, 3 H), 7.70–7.75 (m, 3 H), 7.64–7.69 (m, 1 H), 8.56
(br s, 1 H). IR (KBr): 3323, 3061, 2152 (SCN), 1614, 1583,
1408, 1228, 741 cm–1.
2-Thiocyanato-1H-pyrrole (16a): oil (lit.5f oil). 1H NMR
(60 MHz, CDCl3): d = 6.26 (m, 1 H), 6.61 (m, 1 H), 6.95 (m,
Synlett 2007, No. 19, 2952–2956 © Thieme Stuttgart · New York

2956
D. S. Bhalerao, K. G. Akamanchi
LETTER
1 H), 8.83 (br s, 1 H). IR (neat): 3340, 2952, 2159 (SCN),
1530, 1422, 1029, 737 cm–1.
(14) Kissman, H. M.; Tarbell, D. S.; Williams, J. J. Am. Chem.
Soc. 1953, 75, 2959.
(15) Charris, J.; Monasterios, M.; Dominguez, J.; Infante, W.;
Castro, N. D. Heterocycl. Commun. 2002, 8, 275.
(16) Jordan, A. D.; Luo, C.; Reitz, A. B. J. Org. Chem. 2003, 68,
8693.
2-Thiocyanatothiophene (17a): oil (lit.17 oil). 1H NMR (60
MHz, CDCl3): d = 7.50–8.12 (m, 3 H). IR (neat): 3012, 2158
(SCN), 1412, 1215, 850, 728 cm–1.
(11) Kaji, A. Nippon Kagaku Zasshi 1961, 82, 382; Chem. Abstr.
1962, 56, 10054h.
(12) Nelson, M. J.; Pullin, A. D. E. J. Chem. Soc. 1960, 604.
(13) Zaboev, S. A.; Kudryavtzev, N. A. J. Gen. Chem. USSR
(Engl. Transl.) 1935, 5, 1607; Chem. Abstr. 1936, 30, 21824.
(17) Karade, N. N.; Tiwari, G. B.; Shirodkar, S. G.; Dhoot, B. M.
Synth. Commun. 2005, 35, 1197.
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