Desulfurization and transformation of isothiocyanates to cyanamides by using sodium bis(trimethylsilyl)amide

Article abstract of DOI:10.1016/j.tetlet.2008.08.106

Sodium bis(trimethylsilyl)amide was first used as the desulfurizing agent for the conversion of isothiocyanates to cyanamides in a 'one-flask' reaction. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2008.08.106

Tetrahedron Letters 49 (2008) 6505–6507
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Tetrahedron Letters
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Desulfurization and transformation of isothiocyanates to cyanamides
by using sodium bis(trimethylsilyl)amide
c
d
b,
Chun-Yen Chen b, Fung Fuh Wong a, , Jiann-Jyh Huang , Shao-Kai Lin , Mou-Yung Yeh
*
*
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan, ROC
b Department of Chemistry, National Cheng Kung University, No. 1, Ta Hsueh Road, Tainan 70101, Taiwan, ROC
c Development Center for Biotechnology, No. 101, Lane 169, Kangning Street, Xizhi City, Taipei County 221, Taiwan, ROC
d Sustainable Environment Research Center, National Cheng Kung University, No 500, Sec. 3, An-ming Road, Tainan City 709, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Sodium bis(trimethylsilyl)amide was first used as the desulfurizing agent for the conversion of isothio-
cyanates to cyanamides in a ‘one-flask’ reaction.
Received 13 June 2008
Revised 22 August 2008
Accepted 29 August 2008
Available online 3 September 2008
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Keywords:
Cyanamides
Isothiocyanates
Sodium bis(trimethylsilyl)amide
Desulfurization
1. Introduction
group, NaN(SiMe3)2 can convert aromatic esters to nitriles16 by act-
ing as a ‘nitrogen donor’, or acts as an extraordinary oxidizing
Cyanamides (RR0N–C„N) are important intermediates in the
synthesis of herbicides1 and key precursors in the synthesis of N-
alkyl or N-aryl imides.2 They also exhibit apparent tumor growth
inhibition activity3 except for being a sole synthetic intermediate.
The wide applications of cyanamides result in the development
of many reagents for their synthesis.4–7 Traditional method for
the preparation of cyanamides is achieved by the reaction of gas-
eous cyanogen chloride or cyanogen bromide with amines or with
imide salts.1a,8 Though straightforward, this method does not pro-
duce cyanamides in good yields and requires tedious procedures
for purification.
agent to transform aromatic aldehydes to nitriles.17 In these trans-
formations, the silyl group in the base will react with the alkoxide
generated after the nucleophilic attack and result in ‘deoxygen-
ation’ by 1,2-elimination then transferring nitrogen to the reaction
center.18
Besides alkoxides,19 sulfide20 also shows significant affinity to-
ward silyl group. As a result, NaN(SiMe3)2 might also act as a desul-
furization reagent and
a nitrogen donor. The synthesis of
cyanamides was thus envisioned by use of isothiocyanates as the
starting material. In this Letter, sodium bis(trimethylsilyl)amide
was first used as a desulfurization agent toward isothiocyanates.21
The reaction mechanism also involved 1,2-elimination.18 The new
methodology can be applied in aliphatic isothiocyanates (1a and
1b), aromatic isothiocyanates (1c–k), benzyl isothiocyanate (1l),
and diisothiocyanate (1m) to provide the corresponding cyan-
amides 2a–m in good to excellent yields (see Scheme 1 and
Chart 1).
Sodium bis(trimethylsilyl)amide [NaN(SiMe3)2] was a strong
hindered base commonly used in organic synthetic chemistry.9–14
Its nucleophilicity is lower than conventional LDA and in some or-
ganic transformations, provide better selectivity.15 The trimethyl-
silyl group is bulkier than isopropyl and exert
a-stabilization
effect toward adjacent Nꢀ, thus reducing the nucleophilicity of
ꢀN(SiMe3)2.15 Nevertheless, NaN(SiMe3)2 is also a good nucleophile
at elevated temperature and can be used in functional group trans-
formation. It can selectively mono-O-demethylate dimethoxy are-
nes in high efficiency.15 For electrophilic functionality like carbonyl
1. NaN(SiMe3)2
THF, r.t.
R
NCS
R NHCN
2. H3O
* Corresponding authors. Tel.: +886 4 220 53366x5603; fax: +886 4 220 78083
R = aryl, benzoyl, benzyl, t-butyl, cyclohexyl, naphthyl
(F.F.W.).
E-mail addresses: ffwong@mail.cmu.edu.tw, wongfungfuh@yahoo.com.tw
(F. F. Wong).
Scheme 1.
0040-4039/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.106

6506
C.-Y. Chen et al. / Tetrahedron Letters 49 (2008) 6505–6507
X
X
X
Y
X
1a X = NCS
1b X = NCS
1c X = NCS
1d X = NCS, Y = Me
2d X = NHCN, Y = Me
1e X = NCS, Y = Cl
2e X = NHCN, Y = Cl
2a X = NHCN
2b X = NHCN
2c X = NHCN
X
X
Y
1f X = NCS, Y = Me
2f X = NHCN, Y = Me
1h X = NCS, Y = OMe, 2h X = NHCN, Y = OMe
1i X = NCS, Y = Br, 2i X = NHCN, Y = Br
1j X = NCS, Y = NO2, 2j X = NHCN, Y = NO2
1g X = NCS, Y = NO2
2g X = NHCN, Y =NO2
Y
O
X
CH2X
X
X
X
1k X = NCS
1m X = NCS
2m X = NHCN
1l X = NCS
1n X = NCS
2k X = NHCN
2l X = NHCN
2n X = NHCN
Chart 1.
In this new method, a series of isothiocyanates were reacted
with 1.5 or 3.0 equiv of NaN(SiMe3)2 in THF at room temperature
for 1.0–2.0 h. After workup, the crude product was purified with
column chromatography in silica gel to give the desired cyana-
mide. For aliphatic isothiocyanates 1a and 1b, the reaction pro-
vided the corresponding cyanamides 2a and 2b in 91% and 47%
yields, respectively (see Table 1). For aromatic isothiocyanates
bearing various substituents including CH3, Br, Cl, NO2, and OCH3
at ortho or meta or para position to –N@C–S (1c–j), the reaction
also provided the corresponding cyanamides 2c–j in good yield
(81–97%). Reaction of 1-naphthyl isothiocyanate (1k) and benzyl
isothiocyanate (1l) with NaN(SiMe3)2 produced the corresponding
cyanamides 2k and 2l in 95% and 82% yield, respectively. For aro-
matic compound having two isothiocyanate groups (–N@C@S, 1m
in Table 1), the reaction also provided the corresponding cyana-
mide 2m in 84% yield. The cyanamides 2a–m were reported and
fully characterized by spectroscopic methods.22–32 For example,
compound 2k possessed characteristic peak at 123.72 ppm, which
represented the 13C in NH–C„N. The IR absorptions of 2k showed
peaks at 2226 cmꢀ1 for stretching of the –C„N group and at
3365 cmꢀ1 for stretching of the –NH group.
We then explored the possibility of converting isothiocyanate
group from benzoyl isothiocyanate 1n, in which the carbonyl
group unit is connected to a isothiocyanate. The corresponding
N-cyanocarboxamide 2n was obtained in 73% yield (see Table 1).
Using excess amount of alkali amide (3.0 equiv) under the same
conditions to 1m did not improve the yield, a similar result was
provided. Benzoyl cyanamide 2m was identified by spectroscopic
methods and consistent with the literature report.33 Compound
2m possessed characteristic resonance d 175.24 ppm for the aro-
matic 13C@O(NHC„N) and at 122.94 ppm for the –C„N in 13C
NMR spectrogram. Its IR absorptions showed peaks at 1657 cmꢀ1
for stretching of the –C@O group, at 2220 cmꢀ1 for stretching of
H
N
C S
N
C N
NaN(SiMe3)2
THF, rt
Table 1
Transformations of isothiocyanates to the corresponding cyanamides by use of
NaN(SiMe3)2 in THF at room temperature
1c
NaN
2c
Isothiocyanate
Equiv of NaN(SiMe3)2
Cyanamide
Yielda (%)
SiMe3
SiMe3
H3O
N
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
1l
2m
2n
91
47b
85
84
82
81
88
96
83
97
95
82
84
73
S
N
C
C N
N
SiMe3
Me3Si
X
5
7
Me3SiSSiMe3
Me3SiS
SiMe3
N
N
C
Compounds 2a–n were reported previously,22–33 our spectroscopic data (2a–
c,22,23 2e,25 2h–j,28–30 2l–n23,32,33) are consistent with those of an authentic sample
or published data in the literature.
a
6
b
By-product thiourea was isolated in 38% yield.
Scheme 2.

C.-Y. Chen et al. / Tetrahedron Letters 49 (2008) 6505–6507
6507
the –C„N group, and at 3371 cmꢀ1 for stretching of the –NH
group.
7. Davis, W. A.; Cava, M. P. J. Org. Chem. 1983, 48, 2774.
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We proposed a plausible mechanism for the conversion of
isothiocyanate 1c to cyanamide 2c as shown in Scheme 2, which
accounted for our approach and design. NaN(SiMe3)2 underwent
nucleophilic attack toward isothiocyanate 1c to give adduct 5.34
The intramolecular 1,2-elimination would take place at Si–N–C–Sꢀ
moiety of 5 to give silyl-carbodiimide 6 and Me3SiSꢀ. This step is
similar to Krüger’s report in a deoxygenating step involving the
Si–N–C–Oꢀ moiety.35 Then, Me3SiSꢀ which is generated in situ dur-
ing the conversion of 1c?5, attacks the terminal silyl group in 6 to
afford cyanamide anion 7 and (Me3Si)2S. After aqueous workup,
cyanamide 2c was provided in light yellow solid in 85% yield. In a
control experiment for the conversion of 1c?2c, we were able to
identify N-(trimethylsilyliminomethylene)aniline 6 as a intermedi-
ate and hexamethyldisilthiane ((Me3Si)2S, bp 164 °C) as a by-prod-
uct by GC–mass spectroscopic technique.
In conclusion, sodium bis(trimethylsilyl)amide was first devel-
oped as a desulfurizing agent for the conversion of isothiocyanates
to cyanamides. The newly developed reaction proceeded in ‘one-
flask’ at room temperature. This reaction is easily manipulated
and could be applied in aliphatic isothiocyanates, aromatic isothio-
cyanates, diisothiocyanate, and benzoyl isothiocyanate to give the
corresponding cyanamides in good to excellent yields.
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21. Standard procedure for the formation of cyanamides:
A isothiocyanate
(1.0 mmol) and sodium bis(trimethylsilyl)amide (1.0 M in THF, 1.5 or
3.0 mmol) were added into a two-necked flask at room temperature under
nitrogen gas for 1.0–2.0 h. The reaction mixture was diluted with water at
room temperature, and extracted with EtOAc (2 ꢁ 10 mL). The combined
organic layers were washed with saturated aqueous NaCl (5 mL), dried over
MgSO4(s), filtered, and concentrated under reduced pressure. The residue was
purified by gravity column chromatograph packed with silica gel to provide the
desired cyanamide compound.
22. Ruppert, I. Tetrahedron Lett. 1977, 18, 1987.
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.08.106.
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