Microwave-assisted synthesis of alkyl thiocyanates

Article abstract of DOI:10.1080/00397911.2011.622848

Microwave irradiation accelerated the reaction of t-alkyl, allyl, and benzyl halides with Zn(SCN)₂ to afford thiocyanates in excellent yields and high selectivity with the formation of isothiocyanates only in minor proportions. Because thiocyanates are stable intermediates to thiols, the method also affords facile access to corresponding thiols.

Full text of DOI:10.1080/00397911.2011.622848

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Microwave-Assisted Synthesis of Alkyl
Thiocyanates
a
a
a
D. James Bound , B. K. Bettadaiah & P. Srinivas
a
Plantation Products, Spices and Flavour Technology Department,
Central Food Technological Research Institute, Council of Scientific
and Industrial Research, Mysore, India
Accepted author version posted online: 22 Feb 2012.Version of
record first published: 21 Feb 2013.
To cite this article: D. James Bound , B. K. Bettadaiah & P. Srinivas (2013): Microwave-Assisted
Synthesis of Alkyl Thiocyanates, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:8, 1138-1144
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1
Synthetic Communications , 43: 1138–1144, 2013
Copyright # Central Food Technological Research Institute
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.622848
MICROWAVE-ASSISTED SYNTHESIS OF ALKYL
THIOCYANATES
D. James Bound, B. K. Bettadaiah, and P. Srinivas
Plantation Products, Spices and Flavour Technology Department, Central
Food Technological Research Institute, Council of Scientific and Industrial
Research, Mysore, India
GRAPHICAL ABSTRACT
Abstract Microwave irradiation accelerated the reaction of t-alkyl, allyl, and benzyl halides
2
with Zn(SCN) to afford thiocyanates in excellent yields and high selectivity with the
formation of isothiocyanates only in minor proportions. Because thiocyanates are stable
intermediates to thiols, the method also affords facile access to corresponding thiols.
Keywords Allyl; benzyl; halides; isothiocyanates; microwave; selectivity; t-alkyl; thiocya-
nates; zinc thiocyanate
INTRODUCTION
Thiocyanates are volatile flavor compounds of several Brassica species of
vegetables wherein they are formed from their precursors, glucosinolates. The latter
are thioethers consisting of a b-thioglucose moiety, whose enzymatic hydrolysis
followed by rearrangement of the alkyl group in the aglycone moiety results in the
[1]
formation of thiocyanates. Thiocyanates can be easily converted to thiols, which
again form a small yet significant class of flavor constituents of several fruits and
[
spices. A specific example is p-menth-1-ene-8-thiol, the characteristic flavor compo-
2]
nent of grapefruit juice, the strongest flavor compound reported to date with a thresh-
ꢀ
4
[3]
old value of less than 10 ppb. As thiols are labile and tend to undergo oxidation
easily, thiocyanates serve as stable precursors for their preparation. Nucleophilic sub-
stitution of alkyl halides with metal salts of thiocyanic acid is a general method of syn-
thesis of thiocyanates, as alkyl halides are readily obtained from olefins and terpenes.
Received May 6, 2011.
Address correspondence to P. Srinivas, Plantation Products, Spices and Flavour Technology
Department, Central Food Technological Research Institute, Cheluvamba Mansion, Mysore 570020,
India. E-mail: pullabhatla@yahoo.co.uk
1
138

MICROWAVE-ASSISTED SYNTHESIS OF ALKYL THIOCYANATES
1139
Alkali metal thiocyanates react with primary and secondary halides to afford corre-
[
4]
sponding thiocyanates in fairly good yields. However, because the thiocyanate
nucleophile is ambident, formation of isothiocyanates is observed in these reactions.
This is especially evident in reactions of thiocyanates of mercury, copper, and silver
[
5]
with t-alkyl halides, wherein substantial formation of isothiocyanates is observed.
Zinc salts have been shown to be effective in bringing about substitution of S 1-active
alkyl halides, especially tertiary halides, with a variety of nucleophiles to afford cor-
N
[
6]
responding alcohols, esters, and ethers in very good yields. The reaction has been
extended to the synthesis of alkyl thiocyanates from S 1-active tertiary halides using
N
zinc thiocyanate reagent in good yields with moderate selectivity as thiocyanates are
[
7]
formed as the major products compared to the isomeric isothiocyanates. Further-
more, it is shown that titanium thiocyanate reacts with t-alkyl halides under sonolytic
conditions, wherein the reaction is accelerated with improvement in the selectivity of
[
8]
the reaction with respect to preponderant formation of thiocyanates. However,
preparation of titanium thiocyanate, produced in situ from zinc thiocyanate and tita-
nium(IV) chloride, is cumbersome and difficult to effect in a large-scale synthesis.
Microwave heating has been shown to have an effect on the reaction rate of many
[9,10]
organic reactions.
We report the microwave-assisted reaction of t-alkyl, allyl,
and benzyl halides with zinc thiocyanate, which resulted in enhanced reaction rates
and improved yields of alkyl thiocyanates as products with superior selectivity.
RESULTS AND DISCUSSION
The reaction of 8-chloro-p-menth-1-ene (a-terpinyl chloride, 30 mmol), easily
prepared from reaction of (þ)-limonene with HCl in more than 90% yield, was car-
ried out in a solvent (60 ml) along with Zn(SCN) (30 mmol). Pyridine (30 mmol) was
2
added and the reaction flask, fitted with a condenser, was placed inside the cavity of
ꢁ
microwave reactor operating at 10 C above the normal boiling point of solvents
(
5
(
temperature monitored by a built-in infrared [IR] sensor) with an input power of
0–100 w. The progress of the reaction was monitored by thin-layer chromatography
TLC) and gas chromatography (GC) for the disappearance of the halide. After
completion of the reaction, the product was isolated and chromatographed on silica
ꢁ
gel (100–200 mesh) with mixtures of petroleum ether (60–80 C) and ethyl acetate as
the eluent. Results are summarized in Table 1. Dichloromethane was found to be the
solvent of choice as the yield, reaction time, and thiocyanate (SCN) to isothiocyanate
(NCS) ratio were superior compared to results of the reactions in other solvents.
The scope of the reaction was further explored with several other t-alkyl, allyl,
and benzyl halides. After completion of each reaction, the pure compounds were
1
isolated by silica-gel chromatography. They were characterized by their H NMR
[
7,8]
and mass spectral (MS) data and by comparison with those in the literature.
Thiocyanates and isothiocyanates were clearly distinguished by their characteristic
ꢀ
1
ꢀ1
IR absorption frequencies at 2140 cm (sharp) and 2105–2060 cm (broad) respect-
ively. The results indicated clearly that the microwave irradiation accelerated the
nucleophilic substitution of t-alkyl, allyl (Table 2) and benzyl halides (Table 3). Ther-
modynamically stable isothiocyanates were formed by isomerization of initially
formed thiocyanates as indicated by TLC. These were found to be minor products
in these reactions. With the t-alkyl halides (viz., t-butyl chloride, t-amyl chloride,

1140
D. J. BOUND, B. K. BETTADAIAH, AND P. SRINIVAS
Table 1. Microwave-assisted nucleophilic substitution reaction of 8-chloro-p-menth-1-ene with Zn(SCN)
in various solvents
2
ꢁ
Solvent
Reaction time (min)
Temperature ( C)
Yield (%)
SCN=NCS
Dioxane
Chloroform
7
15
9
111
71
50
76
79
85
84
86
71
71
5:1
5.4:1
6:1
Dichloromethane
Tetrahydrofuran
Di-isopropyl ether
12
25
4.7:1
2.4:1
Table 2. Microwave-assisted nucleophilic substitution reaction of tertiary and allyl halides with
Zn(SCN) in dichloromethane
2
Isolated
yield (%)
Time
(min)
R-SCN=
R-NCS
Entry
RX
Product
1
2
88
87
20
20
7:1
6.6:1
3
86
9
6:1
4
5
83
78
180
5:1
1:0
25

MICROWAVE-ASSISTED SYNTHESIS OF ALKYL THIOCYANATES
1141
in
Table 3. Microwave-assisted nucleophilic substitution reaction of benzyl halides with Zn(SCN)
2
dichloromethane
Isolated Time R-SCN=
yield (%) (min) R-NCS
Entry
1
RX
Product
94
87
70
1:0
a
1:0
2
3
130
83
11
5:1
a
4
5
80
90
89
40
180
60
2:1
1:0
1:0
6
a
Reactions performed in chloroform.
and a-terpinyl chloride), the reaction was complete in very short time and this rate
was several fold (15–35 times) faster than reactions under sonolytic conditions at
ꢁ
ambient temperature and conventional reactions at 40 C. Though the microwave
reaction of 1-menthanyl chloride, (entry 4, Table 2) was slower (3 h), the same reac-
[7]
[8]
tion under conventional and sonolytic conditions took comparatively much
longer times (38 h & 27 h respectively). This apparently is due to the steric hindrance
offered by the substrate toward the incoming nucleophile. Reaction with allyl
bromide was rapid (25 min), and benzyl bromide reacted faster than benzyl chloride.
In both cases, the reaction was much faster than under conventional conditions and
corresponding thiocyanates were obtained exclusively in excellent yields. In the case
of a-phenylethyl chloride, a secondary benzyl halide, the reaction was complete in
1
1 min, with an SCN to NCS ratio of 5:1. In the case of benzyl bromides with different
substituents at the p-position (entries 4–6, Table 3), while the electron-donating
methyl and methoxy groups facilitated the reaction as shown by the improved
reaction rates, the electron-withdrawing nitro group had a decelerating effect.
In summary, microwave heating was effective in bringing about substitution of
SN1-active halides at rates much greater than for conventional reactions using heat

1142
D. J. BOUND, B. K. BETTADAIAH, AND P. SRINIVAS
or ultrasound in the case of ambident nucleophiles like thiocyanate in the form of
its zinc salt. The present study comprises a more efficient protocol for preparation
of t-alkyl, allyl, and benzyl thiocyanates in yields superior to hitherto known proce-
dures. Product selectivity is toward kinetically stable thiocyanates over the thermo-
dynamically stable isothiocyanates, the latter being almost absent or formed as
minor products. In addition, this protocol affords a facile route to thiols, with thio-
cyanates constituting stable precursors.
EXPERIMENTAL
Reagents and solvents used in the study were of analytical grade. All reactions
were performed in a microwave reactor (Milestone lab station, model Start S, Italy).
NMR spectra were recorded on a Bruker AM 500-MHz spectrometer. IR spectra
were recorded on a Fourier transform (FT) Raman Nicolet 5700 spectrometer as sam-
ple smear on KBr prism for liquid samples or as KBR pellet for solid samples. Chemi-
cal shifts (d) are reported in parts per million relative to tetramethylsilane (TMS) as
internal standard. Coupling constants (J) are reported in hertz (Hz). Multiplicities
are reported as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad),
and dt (double triplet). Mass spectra were recorded on a Perkin-Elmer AutoSystem
XL gas chromatograph coupled to TurboMass Gold mass spectrometer having a
quadrupole mass analyzer. A fused silica capillary poly(dimethylsiloxane) column
of 30 m ꢂ 0.25 mm i.d. and a film thickness of 0.25 mm (Elite-1) was used with helium
(
99.9995% pure) as carrier gas at a flow rate of 1 ml=min. Column oven temperature
ꢁ
ꢁ
ꢁ
was set initially at 60 C for 2 min, then raised to 220 C at the rate of 8 C=min, and
held for 2 min at the final temperature. The split ratio employed was 1:20. The mass
spectrometer was operated at an ionization potential of ꢀ70 eV in electron-impact
ionization (EI) scan mode with mass range set between 40 to 400 amu. The injection
ꢁ
ꢁ
port temperature was 180 C, and detector temperature was 220 C.
General Procedure for Microwave-Assisted Reaction of Alkyl Halides
with Zinc Thiocyanate
Zn(SCN) was prepared by mixing equimolar quantities of anhydrous ZnCl
2
2
(13.63 g, 0.1 mol) and KSCN (19.44 g, 0.2 mol) in dry benzene under reflux for 8 h
with azeotropic removal of water. After the removal of solvent, the salt was dried first
using a flash evaporator and then in a vacuum desiccator over P O for 12 h. In a typi-
cal experiment alkyl halide (30 mmol) was taken in dichloromethane (60 ml) along
2
5
with Zn(SCN) (30 mmol). Pyridine (30 mmol) was added, and the reaction flask fit-
2
ted with a condenser was placed inside the cavity of a Milestone microwave reactor
ꢁ
(model Start S, Italy) operating at 50 C with input power of 50–100 W. The progress
of the reaction was monitored by TLC and GC for the disappearance of the halide at
intervals of 3–5 min for short-duration reactions and 30–40 min for slow reactions.
After completion of the reaction, pyridine was removed by washing with 2 N HCl fol-
lowed by washing of the organic layer with saturated NaHCO . Then it was dried
3
over anhydrous Na SO and concentrated. The crude product was chromatographed
2
4
ꢁ
on silica gel (100–200 mesh) with mixtures of petroleum ether (60–80 C) and ethyl
acetate as the eluent.

MICROWAVE-ASSISTED SYNTHESIS OF ALKYL THIOCYANATES
1143
[7,8]
Characterization Data for Products 1a–11a
1
t-Butyl thiocyanate (1a). Pale yellow liquid; H NMR: d 1.60 (s, 9H); MS
m=z): 41 (56), 57 (100), 72 (2), 85 (1), 100 (4), 115 (5).
(
(
1
t-Butyl isothiocyanate (1b). Pale yellow liquid; H NMR: d 1.45 (s, 9H); MS
m=z): 41 (100), 57 (92), 72 (13), 84 (2), 100 (22), 115 (90).
1
t-Amyl thiocyanate (2a). Pale yellow liquid; H NMR: d 1.05 (t, J ¼ 7.5 Hz,
3
(
H), 1.52 (s, 6H), 1.80 (q, J ¼ 7.5 Hz, 2H); MS (m=z): 43 (100), 55 (40), 71 (74.5), 86
1), 100 (4), 114 (1), 129 (1).
1
t-Amyl isothiocyanate (2b). Pale yellow liquid; H NMR: d 1.05 (t,
J ¼ 7.5 Hz, 3H) 1.39 (s, 6H), 1.80 (q, J ¼ 7.5 Hz, 2H); MS (m=z): 43 (100), 55 (32),
7
1 (49), 86 (1), 100 (26), 114 (4), 129 (43).
1
a-Terpinyl thiocyanate (3a). Pale yellow liquid; H NMR: d 1.52 (s, 3H),
.58 (s, 3H), 1.67 (s, 3H), 1.8–2.4 (m, 7H), 5.4 (s, br, 1H); MS (m=z): 41 (39), 69
46), 81 (100), 93 (50), 107 (8), 121 (35), 136 (44), 137 (15), 138 (2), 180 (1), 195 (8).
1
(
1
a-Terpinyl isothiocyanate (3b). Pale yellow liquid; H NMR: d 1.39 (s, 3H),
.42 (s, 3H), 1.70 (s, 3H), 1.75–2.4 (m, 7H), 5.46 (s, br, 1H); MS (m=z): 41 (64), 43
14), 69 (42), 81 (71), 93 (77), 107 (15), 121 (100), 136 (39), 137 (10), 180 (8), 195 (98).
1
(
1
1
-Menthanyl thiocyanate (4a). Light brown liquid; H NMR: d 0.93 (d,
J ¼ 7.5 Hz, 6H), 1.54 (s, 3H), 1.0–1.5 and 1.7–2.1 (m, 10H); MS (m=z): 41 (67), 43
(23), 55 (79), 67 (86), 69 (76), 83 (96), 95 (100), 123 (21), 139 (43), 196 (1), 197 (1).
1
1
-Menthanyl isothiocyanate (4b). Light brown liquid; H NMR: d 0.93 (d,
J ¼ 7.5 Hz, 6H), 1.43 (s, 3H), 1.0–1.5 and 1.7–2.1 (m, 10H); MS (m=z): 41 (53), 43
(
1
24), 55 (79), 57 (33), 67 (87), 69 (75), 83 (100), 95 (90), 97 (25) 123 (20), 139 (40),
96 (1).
1
Allyl thiocyanate (5a). Light brown liquid; H NMR: d 3.57 (d, J ¼ 7.2 Hz,
2
H), 5.36 (d, J ¼ 10 Hz, 1H), 5.4 (d, J ¼ 16.8 Hz, 1H), 5.93 (m, J ¼ 16.8 Hz,
1
J ¼ 10 Hz, J ¼ 7.2 Hz, 1H); MS (m=z): 41 (100), 72 (17), 98 (4), 99 (28).
2
3
1
Benzyl thiocyanate (6a). Colorless solid; H NMR: d 4.19 (s, 2H), 7.38–7.43
m, H); MS (m=z): 91 (100), 149 (11).
(
1
a-Phenylethyl thiocyanate (7a). Pale yellow liquid; H NMR: d 1.91 (d,
J ¼ 7.5 Hz, 3H), 4.63 (q, J ¼ 7.5 Hz, 1H), 7.38–7.44 (m, 5H); MS (m=z): 77 (11), 89
1), 105 (100), 106 (9), 148 (4.2), 163 (9).
(
1
a-Phenylethyl isothiocyanate (7b). Pale yellow liquid; H NMR: d 1.70 (d,
J ¼ 7.5 Hz, 3H), 4.94 (q, J ¼ 7.5 Hz, 1H), 7.38–7.44 (m, 5H); MS (m=z): 77 (11), 89
(3), 105 (100), 148 (2), 163 (7).
1
p-Methoxybenzyl thiocyanate (8a). Yellow liquid; H NMR: d 3.83 (s, 3H),
.65 (s, 2H), 6.9–7.0 (m, 4H); MS (m=z): 77 (11), 91 (11), 104 (5), 121 (100), 179 (11).
4
1
p-Methoxybenzyl isothiocyanate (8b). Yellow liquid; H NMR: d 3.83
s, 3H), 4.45 (s, 2H), 6.9–7.0 (m, 4H); MS (m=z): 77 (11), 91 (11), 104 (5), 121
100), 179 (11).
(
(

1144
D. J. BOUND, B. K. BETTADAIAH, AND P. SRINIVAS
1
p-Nitrobenzyl thiocyanate (9a). Off-white crystalline solid; H NMR: d
.22 (s, 2H), 7.58 (d, 2H, J ¼ 8.6 Hz), 8.29 (d, 2H, J ¼ 8.6 Hz); MS (m=z): 77 (6),
0 (28), 91 (6), 121 (9), 136 (100), 194 (13).
4
9
1
p-Methylbenzyl thiocyanate (10a). Light brown liquid; H NMR: d 2.38 (s,
H), 4.15 (s, 2H), 7.2 (d, 2H, J ¼ 7.6 Hz), 7.25 (d, 2H, J ¼ 7.6 Hz); MS (m=z): 77 (9),
1 (2), 105 (100), 148 (2), 163 (4).
3
9
ACKNOWLEDGMENTS
D. James Bound is grateful to the Council of Scientific and Industrial
Research, New Delhi, for the fellowship grant. The authors thank J. R. Manjunatha
for the NMR spectral studies. Help in recording IR and MS of the compounds by
Ms. Asha and Mr. Shivaswamy of Central Instrumentation Facility and Services,
is gratefully acknowledged.
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