Efficient preparation of isothiocyanates from dithiocarbamates using bromineless brominating reagent

Article abstract of DOI:10.1080/00397910903219476

For the first time, the crystal structure of a ditribromide reagent 1,1'-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) has been determined. Utilizing this thiophilic bromineless brominating agent EDPBT, highly useful synthetic intermediates (alkyl and aryl isothiocyanates) have been achieved directly from dithiocarbamates. EDPBT can be easily prepared from readily available reagents. It has been used as a thiophilic reagent, and its thiophilicity dominates over its brominating ability for substrates amenable to bromination. This is a sustainable process for the preparation of isothiocyantes because the spent reagent can be recovered, regenerated, and reused. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903219476

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Efficient Preparation of Isothiocyanates
From Dithiocarbamates Using
Bromineless Brominating Reagent
Ramesh Yella a , Harisadhan Ghosh a , Siva Murru a , Santosh K.
Sahoo a & Bhisma K. Patel a
a Department of Chemistry, Indian Institute of Technology,
Guwahati, Assam, India
Version of record first published: 17 Jun 2010.
To cite this article: Ramesh Yella, Harisadhan Ghosh, Siva Murru, Santosh K. Sahoo & Bhisma K. Patel
(2010): Efficient Preparation of Isothiocyanates From Dithiocarbamates Using Bromineless Brominating
Reagent, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:14, 2083-2096
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Synthetic Communications1, 40: 2083–2096, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903219476
EFFICIENT PREPARATION OF ISOTHIOCYANATES
FROM DITHIOCARBAMATES USING BROMINELESS
BROMINATING REAGENT
Ramesh Yella, Harisadhan Ghosh, Siva Murru,
Santosh K. Sahoo, and Bhisma K. Patel
Department of Chemistry, Indian Institute of Technology, Guwahati,
Assam, India
For the first time, the crystal structure of a ditribromide reagent 1,10-(ethane-1,2-diyl)
dipyridinium bistribromide (EDPBT) has been determined. Utilizing this thiophilic
bromineless brominating agent EDPBT, highly useful synthetic intermediates (alkyl and
aryl isothiocyanates) have been achieved directly from dithiocarbamates. EDPBT can be
easily prepared from readily available reagents. It has been used as a thiophilic reagent,
and its thiophilicity dominates over its brominating ability for substrates amenable to
bromination. This is a sustainable process for the preparation of isothiocyantes because
the spent reagent can be recovered, regenerated, and reused.
Keywords: Desulfurizing agent; dithiocarbamate; ditribromide; isothiocyanate
INTRODUCTION
A hypervalent iodine reagent, diacetoxyiodobenzene (DIB), has been reported
to be an efficient thiophilic and desulfurizing agent, which has been employed for
the oxidative N-acylation of 1,3-disubstituted thiourea,[1] in the preparation of
isothiocyanates from dithiocarbamates, and for the construction of various hetero-
cycles by a desulfurization strategy.[2] In spite of the superiority of the method,
the expensive nature of the hypervalent iodine reagent is the major impediment
for large scale requirements. Further, we have demonstrated that the hypervalency
of iodine is not really essential for the transformation of dithiocarbamate to isothio-
cyanates and that other thiophilic halogens such as molecular iodine can serve the
purpose.[3] We were inquisitive to know whether other halogens such as bromine
or its equivalents (tribromides) could be employed for this purpose. Handling
of molecular bromine is cumbersome because of its hazardous nature, and thus
special care is required for its use, storage, and transport. To overcome this problem,
several bromineless brominating reagents have been prepared.[4] However, they are
associated with certain drawbacks such as phase-transfer property and poor
Received April 23, 2009.
Address correspondence to Bhisma K. Patel, Department of Chemistry, Indian Institute of
Technology, Guwahati 781039, Assam, India. E-mail: patel@iitg.ernet.in
2083

2084
R. YELLA ET AL.
stability, and recycling of the spent reagent is the major setback, thereby making the
overall process expensive. We have recently designed a ditribromide reagent,
1,2-dipyridiniumditribromide-ethane or 1,10-(ethane-1,2-diyl)dipyridinium bistribro-
mide (EDPBT), which is superior to all known tribromides and have several advan-
tages over molecular bromine and other tribromides.[5] This reagent has been utilized
as catalyst and reagent for acylation of alcohols,[6a] regioselective enolate addition to
9-phenyl-9H-xanthene-9-ol,[6b,c] synthesis of various thiazolidene-2-imine derivati-
ves,[6d–f] synthesis of 1,4-dithiins and 1,4-benzodithiins,[6g] construction of
1,3-oxathiolan-2-ylidenes,[6h] and conversion of urazole to triazonediones.[6i]
Isothiocyanates are important precursors for the construction of pharmaceuti-
cally important heterocycles and are frequently encountered in many natural
products.[7] Because of their unique reactivity toward –OH and –NH2 nucleophiles
present in nucleic acids and proteins, they serve as chemoselective electrophiles in
bioconjugate and neoglycoconjugate chemistry, particularly for biological assays.[8]
The conventional method for the preparation of isothiocyanate involves the reaction
of deadly toxic thiophosgene with amine.[9] High toxicity of thiophosgene, difficulties
in handling, and incompatibility with many functional groups has led to the devel-
opment of many of its synthetic equivalents,[10] and the thiocarbonyl transfer
reagents are a case in point.[11] In addition, they are also prepared by decomposition
of dithiocarbamates with diverse reagents such as uranium- and phosphonium-based
coupling agents,[12] tosylchloride,[13] di-tert-butyl dicarbonate,[14] hydrogen
peroxide,[15] and ethylchlorocarbonate.[16]
Thus, preparation of this synthetically useful intermediate isothiocyante
involves extremely arduous reaction conditions, toxic and expensive reagents, and high
reaction temperatures, gives poor yields, and requires tedious purification procedures.
Taking cues from the thiophilic and desulfurizing ability of hypervalent iodine and
molecular iodine, we wondered if the same could be achieved with other halogens,
particularly bromine or its equivalent such as 1,10-(ethane-1,2-diyl)dipyridinium
bistribromide (EDPBT).[5] In this article, we report bromineless bromine–mediated
preparation of organic isothiocyanates from corresponding dithiocarbamates.
RESULTS AND DISCUSSION
It is essential to understand the remarkable stability of 1,10-(ethane-1,2-diyl)
dipyridinium bistribromide (EDPBT) reagent through an x-ray crystallographic
structural analysis (given in the Experimental section). Although the crystal structure
of several inorganic tribromides are known, structures of only few organic
ammonium tribromides have been reported.[17] All the reported organic ammonium
tribromides are in 1:1 stoichiometry with respect to cations and are nearly linear
molecules. To reconfirm the stoichiometry and investigate factors that control the
intramolecular interactions over the crystal engineering, the x-ray crystal structure
of 1,10-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) was determined. It
crystallized in the space group monoclinic P2(1)=c. The ORTEP (Oak Ridge
Thermal Ellipsoid Program) diagram with atomic numbering scheme is shown in
Fig. 1. In the asymmetric unit, only one half of the molecule is present. A unit cell
representation is shown in Fig. 2.

ISOTHIOCYANATES FROM DITHIOCARBAMATES
2085
Figure 1. ORTEP view with atomic numbering scheme of EDPBT.
The two pyridinium rings are nearly planar and are parallel to each other. Each
tribromide is nearly linear with a bond angle of 176.82o between Br2–Br1–Br3.
Pointing away from each other, tribromides are held parallel in the opposite faces
of the bispyridyl moiety (Figs. 2 and 3). The linear tribromide is not symmetrically
placed to the pyridine nitrogen atoms of the bispyridyl moiety. One of the terminal
bromine atoms (Br3) of the tribromide is closer to one of the nitrogen atoms, which
˚
˚
is at a distance of 4.157 A, and the distance with respect to other nitrogen is 4.255 A.
From one face of the molecule (Br3), three intermolecular C-H . . . Br interactions
form with H1 of one pyridyl, H5 of the other pyridyl, and the bridging methylene
H6A and also intramolecularly with H2 of the adjacent molecule, whereas the cen-
tral bromine (Br1) atom with CH . . . Br contacts intramolecularly with H6A and
intermolecularly with H4 of the adjacent molecule. The other terminal bromine atom
(Br2) forms only intramolecular CH . . . Br interactions with the methylene hydrogen
H6B of adjacent molecule. The same interaction occurs from the other face of the
molecule, which contributes to the crystal packing (Fig. 3).
Figure 2. Unit cell representation of EDPBT.

2086
R. YELLA ET AL.
Figure 3. Inter- and intramolecular CH . . . Br interactions.
As shown in Figs. 3 and 4, the crystal-packing diagrams are quite fascinating.
The crystal packing comprises two different layers growing in opposite directions,
each held by pꢀp stacking interactions as viewed from projection along the c axis
(Fig. 4). The perpendicular intermolecular distance between the planes of one of
˚
the pyridine molecule to that of neighboring molecules is estimated to be 3.651 A,
suggesting the existence of noncovalent pꢀp interactions. The clear pꢀp interactions
between the molecules nearby play an important role in guiding the compound
EDPBT to an extremely ordered crystal packing and hence the remarkable stability
of the compound as compared to simple pyridinium tribromide, which is not so
stable and is reported to have a different bromine composition with different
melting points.
Having understood the exceptional stability of EDPBT, we explored its thio-
philic property for synthetically useful transformations. The thiophilicity of bromine
Figure 4. The pꢀp stacking interactions of EDPBT. Hydrogen atoms are omitted for clarity.

ISOTHIOCYANATES FROM DITHIOCARBAMATES
2087
Scheme 1. Proposed reaction mechanism of formation of isothiocyanate.
is expected to be similar to that of molecular iodine and hypervalent iodine. When
dithiocarbamate 1 (1 mmol) was treated with EDPBT (0.5 mmol) in the presence
of triethylamine (2 mmol) in acetonitrile, isothiocyanate 1a was obtained in nearly
quantitative yields (96% after purification). Triethylamine is sufficiently basic (pKa
10.78) compared to aromatic amines 1–10 (pKa 2.46–5.63), aliphatic and benzylic
amines 11–17 (pKa 9.33–10.77), and the acidity of the dithiocarbamate-bound
NH proton was expected to increase upon salt formation. The proposed reaction
mechanism for the formation of isothiocyanate is shown in Scheme 1. This reaction
is associated with the formation of elemental sulfur, which supports the mechanism.
The consumed EDPDB quantitatively precipitated out from the reaction
medium (CH3CN solvent), leaving the products and other by-products soluble in
acetonitrile. Quantitative recovery of the spent reagent can be achieved by filtration.
The isolated spent reagent can be recycled by the addition of requisite amount of
KBr and Oxone.[5] The mother liquor containing isothiocyanate was evaporated
and mixed with water, and the desired isothiocyanate was extracted with hexane.
Further purification was achieved by passing it through a short column of silica gel.
The scope of this interesting transformation with different substituted aryl
dithiocarbamates was evaluated (Table 1). In general, all the reactions were very
clean, and the isothiocyanates were obtained in excellent yields under the optimized
reaction conditions. The yields obtained are almost comparable to the yield obtained
using diacetoxyiodobenzene (DIB) and molecular iodine.[2a,3]
Substrates containing fluoro (2) and chloro (3, 4, and 6) substituents gave their
corresponding isothiocyanates 2a, 3a, 4a, and 6a, respectively, in excellent yields.
Deactivating the substrate with nitro functionality (5) efficiently yielded the corre-
sponding isothiocyanate (6). Activated substrates 7 and 8 are usually prone to ring
bromination with EDPBT.[5] However, in these cases, its thiophilicity seems to be
predominate over its brominating ability as demonstrated by the isolation of exclus-
ive isothiocyanates 7a and 8a without any traces of brominated products. The deac-
tivated substrate with carbonyl functionality (9) furnished its isothiocyanate (9a)
without undergoing a-bromination. Hindered and disubstituted dithiocarbamate
(10) efficiently gave isothiocyanate (10a) in excellent yields. o-Iodoisothiocyanates
are useful precursors for the construction of various heterocycles.[18]
As shown in Table 2, dithiocarbamates of aliphatic amines (11 and 12) and
benzylic amines (13 and 14) gave their isothiocyanates in good yields. Dithiocarbamate

2088
R. YELLA ET AL.
Table 1. Preparation of isothiocyanates from dithiocarbamates and EDPBTa
Substrate
Productb
Yield (%)c [Ref.]
96[3]
85[3]
95[3]
96[3]
95[3]
92[3]
91[13]
94[3]
88[23]
95
aReactions were monitored by TLC.
bConfirmed by IR, 1H NMR, and 13C NMR.
cIsolated yield.
salts derived from chiral amines (15 and 16) resulted in their isothiocya-
nates 15a and 16a in excellent yields with retention of optical activity,
as shown in Scheme 2. The dextrorotatory R-(þ)-a-methylbezylamine (15) gave
levorotatory R-(–)-a-methylbenzylisothiocyanate (15a), where as the levorotatory

ISOTHIOCYANATES FROM DITHIOCARBAMATES
2089
Table 2. Preparation of isothiocyanates from dithiocarbamates and EDPBTa
Substrate
Productb
Yield (%)c [Ref.]
70[3]
85[3]
96[3]
93
92[24a,b]
93[24b]
75
83[25]
aReactions were monitored by TLC.
bConfirmed by IR, 1H NMR, and 13C NMR.
cIsolated yield.
S-(–)-a-methylbenzylamine (16) gave dextrorotatory S-(þ)-a-methylbenzylisothiocya-
nate (16a). As expected, the specific rotation for R-(ꢀ)-a-methylbenzylisothiocyanate
(15a) is equal and opposite of its enantiomer S-(þ)-a-methylbenzylisothiocyanate
(16a) (Scheme 2).
Scheme 2. Specific rotations of chiral amines and their isothiocyanates.

2090
R. YELLA ET AL.
Isothiocyanate of homoveratrylamine (17a) was obtained successfully in
good yield from its dithiocarbamate salt (17). 4-Pyridyl isothiocyanate was found
to be too unstable to isolate by this method, an observation consistent with
others.[19] However, 3-pyridyl isothiocyanate (18a) could be synthesized in excellent
yields from its dithiocarbamate salt (18).
CONCLUSION
In conclusion, we have reported the x-ray crystal structure of a ditribromide
reagent 1,10-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT), which helps in
understanding its stability and reactivity. For the first time, this bromineless
brominating reagent has been used as a thiophilic reagent for sustainable
preparation of both alky and aryl isothiocyanates from dithiocarbamate salts. The
ease of preparation of this reagent, facile isolation of products, and recyclability
of spent reagent make these methods environmentally acceptable.
EXPERIMENTAL
General Information
All the reagents were commercial grade and purified according to the
established procedures. Organic extracts were dried over anhydrous sodium sulfate.
Solvents were removed in a rotary evaporator under reduced pressure. Silica gel
(60–120 mesh) was used for the column chromatography. Reactions were monitored
by thin-layer chromatography (TLC) on silica gel 60F254(0.25 mm). NMR spectra
were recorded in CDCl3 or dimethylsulfoxide (DMSO-d6) with tetramethylsilane
1
(TMS) as the internal standard for H NMR (400 MHz) CDCl3 and DMSO-d6 sol-
vent as the internal standard for 13C NMR (100 MHz). Mass spectra were recorded
using a Waters mass spectrometry (MS) system, Q-TOF premier, and data were
analyzed using Mass Lynx 4.1. Specific rotations were recorded on a Perkin-Elmer
model 343 polarimeter. Elemental analysis was performed with a Perkin-Elmer
2400 elemental analyzer. Melting points were recorded on a Buchi B-545 melting-
point apparatus and are uncorrected. Infrared (IR) spectra were recorded in KBr
or neat on a Nicolet Impact 410 spectrophotometer.
Typical Experimental Procedure
EDPBT (0.666 g, 1 mmol) was added to a stirred suspension of dithiocarba-
mate salt 1 (0.542 g, 2 mmol) in acetonitrile (8 mL) containing triethylamine
(0.556 mL, 4 mmol) pinch by pinch over a period of 10 min under ice-cold conditions.
After completion of the reaction, as judged from TLC, the reaction mixture was
allowed to stand, and the precipitated spent reagent was filtered, washed with acet-
onitrile (2 ꢁ 1 mL), and kept aside for recycling. Acetonitrile was evaporated and
admixed with water (10 mL), and the product was extracted with hexane (2 ꢁ 10 mL).
The hexane layer was dried over anhydrous Na2SO4, concentrated under reduced
pressure, and purified over a short column of silica gel (100% hexane) to give

ISOTHIOCYANATES FROM DITHIOCARBAMATES
2091
1
259 mg (96% yield) of 1a.[3] Oily liquid; H NMR (400 MHz, CDCl3): 7.21–7.37 (m,
5H).13C NMR (100 MHz, CDCl3): 125.8, 127.4, 129.6, 131.3, 135.3. IR (KBr, cmꢀ1):
3064, 2164, 2063, 1591, 1489, 1474, 1451, 1070, 927, 905, 749, 684 cmꢀ1. C7H5NS
(135.19): calcd. C, 62.19; H, 3.72; N, 10.36; S, 23.72. Found: C, 62.12; H, 3.66; N,
10.45; S, 23.62.
Crystallographic Description
Crystal data were collected with Bruker Smart Apex-II CCD diffractometer
˚
using graphite monochromated MoKa radiation (k ¼ 0.71073 A) at 298 K. Cell
parameters were retrieved using SMART[20] software and refined with SAINT[20]
on all observed reflections. Data reduction was performed with the SAINT software
and corrected for Lorentz and polarization effects. Absorption corrections were
applied with the program SADABS.[21] The structure was solved by direct methods
implemented in SHELX-97[22] program and refined by full-matrix least-squares
methods on F2. All nonhydrogen atomic positions were located in difference
Fourier maps and refined anisotropically. The hydrogen atoms were placed in their
geometrically generated positions. Orange crystals were isolated in rectangular
shapes from acetonitrile at room temperature.
Crystallographic description of EDPBT. Crystal dimension (mm):
0.48 ꢁ 0.28 ꢁ 0.19; C12H14Br6N2, Mr ¼ 665.71; monoclinic, space group P2(1)=c;
˚
˚
˚
a ¼ 8.3171(7) A, b ¼ 13.7174(11) A, c ¼ 8.6130(7) A; a ¼ c ¼ 90, b ¼ 108.025(4),
V ¼ 934.42(13) A ; Z ¼ 2; qcal ¼ 2.366 mg=m3; m (mmꢀ1) ¼ 12.882; F (000) ¼ 620;
3
˚
reflection collected=unique ¼ 7461=2820; refinement method ¼ full-matrix least-
squares on F2; final R indices [I > 2rl] R1 ¼ 0.0392, wR2 ¼ 0.0898, R indices (all
data) R1 ¼ 0.0795, wR2 ¼ 0.1027; goodness of fit ¼ 1.013. CCDC No. 718734.
Spectral Data
The new compounds were fully characterized by IR, NMR (1H, 13C), MS, and
elemental analysis.
2-Iodo-1-isothiocyanato-4-methylbenzene (10a). White solid; mp
1
62–65 ꢂC; H NMR (400 MHz, CDCl3): 2.30 (s, 3H), 7.13 (m, 2H), 7.62 (s, 1H).
13C NMR (100 MHz, CDCl3): 20.9, 94.2, 126.7, 130.1, 132.3, 136.1, 139.1, 139.9.
IR (KBr, cmꢀ1): 2916, 2134, 1633, 1474, 1042, 929, 811. C8H6INS (275.11): calcd.
C, 34.92; H, 2.20; N, 5.09; S, 11.65. Found: C, 35.02; H, 2.24; N, 4.98; S, 11.59.
MS (ESI): 275 (Mþ).
1
5-(Isothiocyanatomethyl)benzo[d][1,3]dioxole (14a). Oily liquid; H NMR
(400 MHz, CDCl3): 4.59 (s, 2H), 5.98 (s, 2H), 6.74–6.80 (m, 3H). 13C NMR
(100 MHz, CDCl3): 48.7, 101.5, 107.7, 108.6, 120.7, 128.0, 132.1, 147.8, 148.2. IR
(KBr, cmꢀ1): 2895, 2087, 1503, 1445, 1369, 1322, 1251, 1101, 1028, 924. C9H7NO2S
(193.23): calcd. C, 55.95; H, 3.65; N, 7.25; S, 16.56. Found: C, 56.12; H, 3.71; N,
7.18; S, 16.50. MS (ESI): 194 (M þ Hþ).
4-(2-Isothiocyanato-ethyl)-1,2-dimethoxy benzene (17a). Oily liquid;
1H NMR (400 MHz, CDCl3): 2.90 (t, 2H, J ¼ 6.6 Hz), 3.68 (t, 2H, J ¼ 6.6 Hz),

2092
R. YELLA ET AL.
3.85 (s, 3H), 3.88 (s, 3H), 6.79 (m, 3H). 13C NMR (100 MHz, CDCl3): 36.0, 46.6,
55.85, 55.87, 111.3, 111.9, 120.8, 129.5, 130.3, 148.0, 148.9. IR (KBr, cmꢀ1): 3000,
2935, 2835,, 2181, 2100, 1592, 1515, 1455, 1347, 1263, 1142, 1028, 909. C11H13NO2S
(223.30) calcd.: C, 59.17; H, 5.87; N, 6.27; S, 14.36. Found: C, 59.08; H, 5.89; N,
6.22; S, 14.33.
ACKNOWLEDGMENTS
B. K. P. acknowledges support of this research from the Department of
Science and Technology, New Delhi (SR=S1=OC-15=2006), and the Council
of Scientific and Industrial Research (CSIR) [01(2270)=08=EMR-II]. R. Y. H. G.
and S. M. thank the CSIR for fellowships. Thanks are due to CIF Indian Institute
of Technology Guwahati for NMR spectra and the Department of Science and
Technology, Funding for Infrastructure in Science and Technology, for the
X-ray diffraction facility.
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