Environmentally benign one-pot synthesis of cyanamides from dithiocarbamates using I2 and H2O2

Article abstract of DOI:10.1080/00397911.2010.532276

An environmentally benign reaction is devised for the synthesis of cyanamides from dithiocarbamate salts using iodine and H₂O ₂. Taylor & Francis Group, LLC.

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Environmentally Benign One-Pot
Synthesis of Cyanamides from
Dithiocarbamates Using I2 and H2O2
Latonglila Jamir a , Upasana Bora Sinha a , Jayashree Nath b &
Bhisma K. Patel c
a Department of Chemistry, Nagaland University, Lumami Campus,
Nagaland, India
b Centre for the Environment, Indian Institute of Technology
Guwahati, Guwahati, Assam, India
c Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati, Assam, India
Accepted author version posted online: 30 Aug 2011. Version of
record first published: 16 Dec 2011
To cite this article: Latonglila Jamir, Upasana Bora Sinha, Jayashree Nath & Bhisma K. Patel (2012):
Environmentally Benign One-Pot Synthesis of Cyanamides from Dithiocarbamates Using I2 and H2O2 ,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:7, 951-958
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Synthetic Communications1, 42: 951–958, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.532276
ENVIRONMENTALLY BENIGN ONE-POT SYNTHESIS
OF CYANAMIDES FROM DITHIOCARBAMATES
USING I2 AND H2O2
Latonglila Jamir,1 Upasana Bora Sinha,1 Jayashree Nath,2 and
Bhisma K. Patel3
1Department of Chemistry, Nagaland University, Lumami Campus,
Nagaland, India
2Centre for the Environment, Indian Institute of Technology Guwahati,
Guwahati, Assam, India
3Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati, Assam, India
GRAPHICAL ABSTRACT
Abstract An environmentally benign reaction is devised for the synthesis of cyanamides
from dithiocarbamate salts using iodine and H2O2.
Keywords Cyanamide; dithiocarbamate salt; hydrogen peroxide; iodine; isothiocyanate
INTRODUCTION
The applications of organic cyanamides in organic synthesis are now well
documented. They are useful intermediates in the synthesis of N-mono- and N-
di-substituted-2-aminothiazoles[1] and N-substituted hydantoins, which have impor-
tant pharmaceutical activities such as antitumour,[2] antiarrhythmic,[3] anticonvul-
sants,[4] and herbicidal activities.[5] They are important precursors in the synthesis
of N-alkyl and N-aryl imides[6] and also find widespread applications as protecting
groups in the syntheses of secondary and tertiary amines containing heterocycles
because of the easy removal of the cyano group.[7] Cyanamides have been employed
in multicomponent Biginelli-type reactions as convenient building blocks to synthe-
size 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine systems (I) (Fig. 1) containing
the N-cyanoguanidinyl moiety in their structure.[8] The cyanoguanidine moiety
is organic cyanamide, which is found in other biologically active molecules such
as KATP channel activator, pinacidil (II),[9] and the potential antimycotic agent
N-cyanoiminopyrimidine (III) (Fig. 1).[10]
Received June 1, 2010.
Address correspondence to Upasana Bora Sinha, Department of Chemistry, Nagaland University,
Lumani Campus, 798 601, Nagaland, India. E-mail: u.borasinha@gmail.com
951

952
L. JAMIR ET AL.
Figure 1. Some cyanamides of pharmaceutical importance.
Unfortunately, until very recently, the synthesis of these compounds depended
on procedures that involved toxic chemicals. One of the most common methods was
cyanation of amines or imide salts using highly toxic cyanogen halide[11] or its syn-
thon CNþ. Commonly used CNþ equivalents are 2-chlorobenzyl thiocyanate,[12]
3-tosyl cyanide,[13] 1-cyanobenzotriazole,[14] 1-cyanoimidazole,[15] and 2-cyanopyri-
dazin-3(2H)-ones,[16] most of which also involve the indirect use of the toxic cyano-
gen halide. There are a few other methods as well,[17,18] but these methods again
involve the use of extremely basic conditions or highly flammable and corrosive
reagents=solvents, and follow tedious reaction and workup procedures.
In recent years, with there being environmental legislation on the use of toxic
chemicals, more benign reagents were sought for the synthesis of cyanamides, and in
this context the use of hypervalent iodine as reagent began to be reported. In an
interesting piece of work, our group reported its synthesis from dithiocarbamate
salts by a double desulfurization strategy employing the hypervalent iodine reagent,
diacetoxyiodobenzene (DIB).[19] Subsequent improvement of this protocol led to the
replacement of the expensive hypervalent iodine with environmentally benign and
less expensive iodine.[20] Though this method is high yielding, efficient, and superior
to other methods reported so far, there is still room for improvement, if seen from a
green chemistry perspective. The drawbacks of the protocol include use of triethyla-
mine, which is a toxic organic base, and also the use of the expensive and toxic
acetonitrile as solvent.
Thus, in what could be described as ‘‘further greening’’ of the synthetic proto-
col, we now describe the method for synthesis of cyanamides from dithiocarbamates
using I2 and H2O2. The method follows a desulfurization strategy in the presence of
molecular iodine and sodium bicarbonate for the formation of isothiocyanates,
which, in turn, gives 1-phenylthiourea on treatment with aqueous ammonia. The
1-phenylthiourea a thus formed gives the corresponding cyanamide on treatment
with H2O2. The oxidant H2O2 has, over the years, been employed as a
desulfurizing=oxidizing agent in diverse applications. Catalyzed by ZrCl4, it has been
used in the deprotection=desulfurization of thioamides into amides[21] as well as in
conversion of dithioesters into carboxylic acids=esters under an alkaline con-
dition.[22] Hydrogen peroxide in combination with acetic acid is reported to desulfur-
ize cyclic thioureas and related compounds existing as thiol-thione tautomeric
mixtures[23] as well as cyclic dithiocarbamates and dithiocarbazates to the
corresponding 2-oxo-analogs with or without the addition of Na2WO4.[24]
Taking cues from its oxidative desulfurizing ability, we considered it worth-
while to investigate the prospects of H2O2 as an environmentally benign, cheap,
effective oxidizing agent for the transformation of in situ–generated phenylthiourea
(a, Scheme 1) into cyanamide. Li et al. has reported the use of hydrogen peroxide as

DESULFURIZATION USING I2 AND H2O2
953
a desulfurizing agent in the synthesis of isothiocyanates from dithiocarbamate
salts.[25] However, when we tried to use H2O2 for the first step of our reaction, we
found that we could not reproduce the good yields reported, and the method could
not be applied to a wide range of substrates. We therefore followed a modified
version of our environmentally benign, cost-effective protocol for the synthesis of
isothiocyanates from the corresponding dithiocarbamic acid salts via a desulfuriza-
tion strategy using molecular iodine and sodium bicarbonate in water=ethylacetate
biphasic medium.[20]
In this approach, a suspension of a freshly prepared alkyl=aryl dithiocarba-
mate salt and NaHCO3 was treated with I2 in an ethylacetate and water biphasic sol-
vent to give the corresponding isothiocyanate. Precipitation of elemental sulfur was
observed during this period, which is in line with literature reports.[19,20] The in situ–
generated isothiocyanate was then treated with aqueous NH3 to afford the corre-
sponding 1-phenylthiourea. The thioamide thus formed undergoes further oxidative
desulfurization promoted by H2O2 to give the stable cyanamide. The intermediacy of
the isothiocyanate was clearly evident from the infrared (IR) spectra (2120 cmꢀ1).
The plausible reaction mechanism proposed for the conversion of dithiocarba-
mate to cyanamide is illustrated in Scheme 1. The thioamide (a) generated by the
reaction of isothiocyanate and ammonia probably undergo oxidation to its disulfide
(b), which is then further oxidized (c) followed by desulfurization to give the
cyanamide.
A wide variety of aromatic and aliphatic cyanamides has been prepared from
their parent dithiocarbamate salts with this method, which is summarized in Table 1.
Phenyl cyanamide 1a was obtained in excellent yield from its dithiocarbamate 1.
Monosubstituted substrates 2–9 readily underwent this reaction to produce the desired
cyanamides 2a–9a in good yields. A noteworthy aspect is that the method worked well
for substrates containing a deactivating group such as 5 as well as for substrates con-
taining sensitive functionalities such as keto 9. Hindered and disubstituted dithiocar-
bamates 10–15 gave their corresponding cyanamides 10a–15a in good yields. This
approach was further extended toward fused-ring dithiocarbamate 16 as well as
benzylic salts 17 to obtain the preferred products 16a and 17a in moderate yields.
We further investigated the efficacy of this method toward aliphatic dithiocarbamates.
Benzyl 18, cyclohexyl 19, and n-butyl 20 dithiocarbamates gave their corresponding
cyanamides 18a, 19a, and 20a respectively under similar reaction conditions.
Scheme 1. Proposed mechanism for transformation of dithiocarbamate to cyanamide.

954
L. JAMIR ET AL.
a
Table 1. Preparation of cyanamides from dithiocarbamate salts using I2 and H2O2
Substrate
Productb Yield (%)c
1, R1 ¼ H, R2 ¼ H, R3 ¼ H, R4 ¼ H, R5 ¼ H;
2, R1 ¼ Cl, R2 ¼ H, R3 ¼ H, R4 ¼ H, R5 ¼ H;
3, R1 ¼ H, R2 ¼ H, R3 ¼ Cl, R4 ¼ H, R5 ¼ H;
4, R1 ¼ H, R2 ¼ H, R3 ¼ Br, R4 ¼ H, R5 ¼ H;
5, R1 ¼ H, R2 ¼ NO2, R3 ¼ H, R4 ¼ H, R5 ¼ H;
6, R1 ¼ H, R2 ¼ CF3, R3 ¼ H, R4 ¼ H, R5 ¼ H;
7, R1 ¼ H, R2 ¼ H, R3 ¼ CF3, R4 ¼ H, R5 ¼ H;
8, R1 ¼ H, R2 ¼ H, R3 ¼ OMe, R4 ¼ H, R5 ¼ H;
9, R1 ¼ H, R2 ¼ H, R3 ¼ COCH3, R4 ¼ H, R5 ¼ H;
10, R1 ¼ CH3, R2 ¼ H, R3 ¼ CH3, R4 ¼ H, R5 ¼ H;
11, R1 ¼ H, R2 ¼ CH3, R3 ¼ CH3, R4 ¼ H, R5 ¼ H;
12, R1 ¼ Br, R2 ¼ H, R3 ¼ CH3, R4 ¼ H, R5 ¼ H;
13, R1 ¼ I, R2 ¼ H, R3 ¼ CH3, R4 ¼ H, R5 ¼ H;
14, R1 ¼ Br, R2 ¼ H, R3 ¼ OMe, R4 ¼ H, R5 ¼ H;
15, R1 ¼ F, R2 ¼ H, R3 ¼ F, R4 ¼ H, R5 ¼ H;
1a
2a
72
70
71
78
77
70
68
88
65
78
84
73
79
70
72
3a
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
15a
16, a-Naphthyl
17, Piperonyl
18, Benzyl
16a
17a
18a
19a
20a
75
67
64
62
60
19, Cyclohexyl
20, n-Butyl
aReactions were monitored by TLC.
bConfirmed by IR, 1H NMR, and 13C NMR.
cIsolated yield.
CONCLUSION
The use of H2O2, an extremely benign reagent, which is easily available and
much cheaper than other desulfurizing agents is a noteworthy feature. Furthermore,
the use of any environmentally hazardous solvents and toxic bases such as triethyla-
mine, which are generally used for such transformations, have been avoided in
this case. In addition, the workup procedure and the isolation=purification of the
products are much simpler.
EXPERIMENTAL
All the reagents were of commercial grade and purified according to estab-
lished procedures. Organic extracts were dried over anhydrous sodium sulfate. Sol-
vents were removed in a rotary evaporator under reduced pressure. Silica gel (60–120
mesh) was used for the column chromatography. Reactions were monitored by

DESULFURIZATION USING I2 AND H2O2
955
thin-layer chromatography (TLC) on silica gel 60 F254 (0.25 mm). NMR spectra were
1
recorded in CDCl3 with tetramethylsilane as the internal standard for H NMR
(400 MHz) and CDCl3 solvent as the internal standard for 13C NMR (100 MHz).
IR spectra were recorded in KBr or neat on a Nicolet Impact 410 spectrophot-
ometer. Elemental analysis was performed with a Perkin-Elmer 2400 elemental ana-
lyzer. Melting points were recorded on a Buchi B-545 melting-point apparatus and
are uncorrected.
General Experimental Procedure
To a suspension of freshly prepared phenyl dithiocarbamate salt (540 mg,
2 mmol) and sodium bicarbonate (336 mg, 4 mmol) in an ethylacetate and water
(5:1, 6 mL) biphasic solvent, iodine (506 mg, 2 mmol) was added in pinches over a
period of 10–15 min. During this period, precipitation of elemental sulfur was
observed. After complete addition of iodine, 25% aqueous NH3 (2.5 mL) was added
dropwise to the stirred reaction mixture to give 1-phenylthiourea. After stirring for
10 min at room temperature, the excess of NH3 was removed in a rotary evaporator,
whereby the solvent ethylacetate was also simultaneously removed, leaving behind
the aqueous layer. Ethylacetate (5 mL) was added to the crude reaction mixture fol-
lowed by the dropwise addition of 2 mL of 30% aqueous H2O2. The conversion of
the 1-phenylthiourea to phenylcyanamide (1a) was observed within 10 min of the
complete addition of H2O2. Completion of the reaction was confirmed by TLC.
Ethylacetate (10 mL) was further added to the reaction mixture. The organic layer
was washed with water (2 ꢁ 5 mL), dried over anhydrous Na2SO4, concentrated
under reduced pressure, and purified over a short column of silica while eluting it
with hexane–ethylacetate (97:3) gel to give the pure product 1a (170 mg, 72%). Oily
1
liquid: H NMR (CDCl3, 400 MHz) d (ppm) 7.02–7.07 (m, 3H), 7.28–7.33 (m, 2H),
7.64 (brs, 1H); 13C NMR (CDCl3, 100 MHz) d (ppm) 112.2, 115.5, 123.6, 129.8,
137.4; IR (KBr) 3175, 2919, 2227, 1600, 1501, 1249, 748, 689; elemental analysis
for C7H6N2 (118.13): calcd. C, 71.17;H, 5.12;N, 23.71; found: C, 71.27; H, 5.09;
N, 23.67.
Spectral Data
Compounds 1a–3a, 5a, 8a–10a, 12a–13a, and 15a–20a are previously reported
compounds.[20]
The spectral data (1H NMR, 13C NMR, IR, and CHNS) of the new
compounds are given here.
1
4-Bromo-phenyl cyanamide (4a). White solid. Mp: 110–111 ꢂC. H NMR
(400 MHz CDCl3) d ¼ 6.90 (d, J ¼ 8.4 Hz, 2H), 7.11 (brs, 1H), 7.43 (d, J ¼ 8.4 Hz,
2H). 13C NMR (100 MHz, CDCl3) d ¼ 111.2, 116.4, 117.2, 132.8, 136.5. IR (neat)
3153, 3078, 2958, 2884, 2228, 1594, 1503, 1493, 1394, 1281, 1251, 1073, 813. Elemen-
tal analysis for C7H5BrN2 (197.03): calcd. C, 42.67; H, 2.55; N, 14.21. Found: C,
42.61; H, 2.62; N, 14.11.
1
3-Trifluoromethyl phenyl cyanamide (6a). White solid. Mp: 82–85 ꢂC. H
NMR (400 MHz, CDCl3): d ¼ 6.97 (brs, 1H), 7.21–7.26 (m, 2H), 7.36 (d, J ¼ 8.0 Hz,

956
L. JAMIR ET AL.
1H), 7.48 (t, J ¼ 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d ¼ 111.1, 112.5, 118.7,
120.5, 122.3, 125.0, 130.6, 132.41 (q, J ¼ 32.8 Hz), 138.1. IR (neat): 3116, 2998, 2928,
2240, 1620, 1490, 1332, 1165, 1130, 877, 794, 695. Elemental analysis for C8H5F3N2
(186.13): calcd. C, 51.62; H, 2.71; N, 15.05. Found: C, 51.55; H, 2.73; N, 15.01.
1
4-Trifluoromethyl phenyl cyanamide (7a). Gummy. H NMR (400 MHz,
CDCl3): d ¼ 7.1 (d, J ¼ 8.4 Hz, 2H), 7.2 (s, 1H), 7.6 (d, J ¼ 8.4 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d ¼ 112.92, 116.81, 123.32, 125.90 (J ¼ 48 Hz), 127.35, 138.3.
IR (neat): 3153, 3093, 2972, 2904, 2248, 1618, 1525, 1329, 1262, 1167, 1117, 1065,
833. Elemental analysis for C8H5F3N2 (186.13): calcd. C, 51.62; H, 2.71; N, 15.05.
Found: C, 51.57; H, 2.70; N, 15.03.
3,4-Dimethyl phenyl cyanamide (11a). White solid. Mp: 65–67 ꢂC. 1H
NMR (400 MHz, CDCl3,): d ¼ 2.18 (s, 3H), 2.20 (s, 3H), 6.75 (dd, J1 ¼ 2.4 Hz,
J2 ¼ 2.4 Hz, 1H), 6.80 (d, J ¼ 2.0 Hz, 1H), 7.03 (d, J ¼ 8.4 Hz, 1H), 7.17 (brs, 1H).
13C NMR (100 MHz, CDCl3): d ¼ 19.07, 19.9, 112.5, 112.9, 116.8, 130.7, 131.8,
135.07, 138.3. IR (neat): 3197, 2944, 2227, 1620, 1508, 1446, 1297, 1258, 1212,
1022, 857, 807. Elemental analysis for C9H10N2 (146.19): calcd. C, 73.94; H, 6.89;
N, 19.16. Found: C, 73.89; H, 6.82; N, 19.11.
2-Bromo, 4-methoxy phenyl cyanamide (14a). White solid. Mp:
107–111 ꢂC. 1H NMR (400 MHz, CDCl3): d ¼ 3.78 (s, 3H), 6.16 (brs, 1H), 6.92
(dd, J1 ¼ 6.0 Hz, J2 ¼ 2.8 Hz, 1H), 7.08 (d, J ¼ 2.8 Hz, 1H), 7.22 (d, J ¼ 8.8 Hz,
1H). 13C NMR (100 MHz, CDCl3): d ¼ 56.01, 104.1, 115.2, 122.8, 130.06, 130.3,
135.1, 157.4. IR (neat): 3287, 2925, 2251, 2220, 1611, 1507, 1399, 1286, 1218,
1036, 870, 794. Elemental analysis for C8H7BrN2O (227.05): calcd. C, 42.32; H,
3.11; N, 12.34. Found: C, 42.28; H, 3.15; N, 12.31.
ACKNOWLEDGMENTS
B. K. P. acknowledges the support 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]. L. J. thanks the CSIR for
fellowship. Thanks are also given to CIF, Indian Institute of Technology, Guwahati
for NMR spectra.
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