Synthesis of nitriles via the iodine-mediated dehydrosulfurization of thioamides

Article abstract of DOI:10.1248/cpb.c20-00228

A simple general method for the synthesis of nitriles using the inexpensive and easy to handle iodine (I2) is described herein. The reaction of thioamides with I2 in the presence of triethylamine at room temperature under aerobic conditions afforded various nitriles bearing aryl, vinyl, and alkyl groups in good-to-excellent yields. This method was also effective for conversion from thioureas to cyanamides.

Full text of DOI:10.1248/cpb.c20-00228

Vol. 68, No. 7
Chem. Pharm. Bull. 68, 679–681 (2020)
679
Note
Synthesis of Nitriles via the Iodine-Mediated Dehydrosulfurization of
Thioamides
Yuki Murata, Hitomi Iwasa, Mio Matsumura, and Shuji Yasuike*
School of Pharmaceutical Sciences, Aichi Gakuin University; 1–100 Kusumoto-cho, Chikusa-ku, Nagoya 464–8650, Japan.
Received March 11, 2020; accepted April 1, 2020
A simple general method for the synthesis of nitriles using the inexpensive and easy to handle iodine (I2)
is described herein. The reaction of thioamides with I in the presence of triethylamine at room temperature
2
under aerobic conditions afforded various nitriles bearing aryl, vinyl, and alkyl groups in good-to-excellent
yields. This method was also effective for conversion from thioureas to cyanamides.
Key words iodine; thioamide; nitrile; cyanamide; dehydrosulfurization
Introduction
less toxic reagent compared to the above hypervalent iodine
Nitriles are important compounds in organic chemistry compounds, and so has also been used as a mild desulfur-
and widely used as precursors to obtain various functional ization agent. For example, Patel and colleagues reported
groups, such as amines, amides, aldehydes, tetrazoles, and the I -mediated synthesis of cyanamides and isothiocyanates
2
1)
36,37)
amidines. In addition, the nitrile group is present in a range from dithiocarbamate salts,
while Nembenna and col-
of natural products, pharmaceuticals, and functional ma- leagues carried out the synthesis of bulky N,Nʹ-diaryl car-
2
–5)
38)
terials,
and so numerous methods have been developed bodiimides by reacting the corresponding thioureas with I2.
6
–10)
for their preparation.
For example, the nucleophilic dis- Furthermore, Ning and colleagues developed the synthesis of
placement reaction of diazonium salts or aryl halides with guanidines via the I -mediated desulfurization of N,Nʹ-di-tert-
2
39)
a cyanide source (i.e., the Sandmeyer and Rosenmund-von butoxycarbonyl (Boc)-thioureas. Synthesis of nitriles into
6
,10)
Braun reactions) is one example of a common protocol.
thioamides is also possible, and interconversion reaction be-
However, the cyanating agents used in these reactions, such
as KCN and CuCN, have received particular attention from
the viewpoint of heavy metal waste and toxicity. Further-
more, alternative methods for the synthesis of aryl nitriles
that do not require cyanide sources have been reported, for
a)
Table 1. Screening of Reaction Conditions
11)
1
2,13)
14)
example, the dehydration of amides
or aldoximes, the
15)
oxidative coupling of alcohols with ammonia, the conversion
16)
of carboxylic acids to nitriles, and the dehydrosulfurization
of thioamides. The last of these examples is a particularly
efficient approach, and involves the treatment of thioamides
with diverse desulfurizing agents such as the transition metal
b)
Entry
Reagent
Et N (eq) Solvent Time (h) Yield (%)
3
1
2
3
4
5
6
7
8
9
I2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
2
CH Cl
0.5
2
99
99
2
2
2
2
2
2
2
2
PhI(OAc)
CH Cl
2
2
c)
17)
18,19)
18)
18)
IBX
CH
2
Cl
0.5
1
88
reagents MnO2,
AgOAc,
Hg(OAc)2,
and Cu(OAc) ,
2
d)
h)
TBAI
CH Cl
48 (39)
93
2
0,21)
2
heavier main group reagents such as nBu SnO,
phorus tetraiodide, telluroxide, and tellurinic acid anhy-
diphos-
2
Ph Bi(OAc)
CH Cl
2
2
2)
23)
3
2
2
Ph Sb(OAc)
CH Cl
2
73
2
4,25)
13)
26)
3
2
2
dride,
a combination of Zn(OTf)2 or In(OTf)3 with
Ph SbCl
CH Cl
1
76
3
2
2
N-methyl-N-(trimethylsilyl)trifluoroacetamide, a combination
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
DCE
1
95
2
7)
of sulfur with sodium nitrite, and other reagents such as
Toluene
THF
2
71
benzotriazol-1-yloxytris(pyrrolidinol)phosphonium hexafluoro-
10
11
12
13
14
2
84
2
8)
phosphate,
hydrochloride,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
CH CN
1
90
3
2
9)
30)
and formamide chlorides.
Moreover, an
MeOH
DMF
0.5
2
85
efficient method for the conversion of thioamides to nitriles
94
g)
using the organobismuth reagent, triphenylbismuth dichlo-
CH Cl
0.5
2
91
2
2
2
2
2
2
2
31)
32)
e)
h)
ride, or gold nanoparticles has been recently reported by
Doris and colleagues, respectively. However, these reagents
present disadvantages, such as high costs and toxicities, long
reaction times or harsh reaction conditions. In addition, hyper-
valent iodine reagents such as diacetoxyiodobenzene (PIDA)
and 2-iodoxybenzoic acid (IBX) have been reported to act as
oxidative desulfurization agents, converting dithiocarbamate
salts and thioureas into isothiocyanates, cyanamides, and car-
15
16
17
18
19
CH Cl
27 (68)
80
2
CH Cl
2
2
h)
h)
—
3
CH Cl
24
11 (69)
— (85)
82
2
—
CH Cl
24
1
2
f)
I
3
CH Cl
2
2
a) 1a (0.5mmol), dehydrosulfurization reagent (0.5mmol), Et N (1.5mmol). b)
3
GC yield using dibenzyl as internal standard. c) IBX=2-Iodoxybenzoic acid. d)
TBAI=Tetrabutylammonium iodide. e) I (30mol%). f) 1a (30mmol), I (30mmol),
2
2
Et N (90mmol). −20°C. Isolated yield. g) Diisopropylethylamine was used instead of
3
33–35)
triethylamine. h) The values in parentheses show the yields of recovery of 1a.
bodiimides.
However, iodine (I ) is an inexpensive and
2
*
To whom correspondence should be addressed. e-mail: s-yasuik@dpc.agu.ac.jp
©
2020 The Pharmaceutical Society of Japan

6
80
Chem. Pharm. Bull.
Vol. 68, No. 7 (2020)
a)
Table 2. Dehydrosulfurization of Thioamides with I2
a) 1 (2mmol), I (2mmol), Et N (6mmol). b) Isolated yield. c) −20°C.
2
3
tween thioamide and nitrile is one of the important reactions 2a was hardly obtained without these reagents. (entries 17 and
in the field of organic synthesis. Inspired by the aforemen- 18). When the reaction did not proceed smoothly, by-products
tioned reports, we herein present the facile dehydrosulfuriza- were not obtained and a considerable amount of thioamide 1a
tion of thioamides using I for the synthesis of aryl nitriles was recovered (entries 4, 15, 17, 18). This dehydrosulfurization
2
under mild reaction conditions.
process was also successfully scale-up to 30mmol to give 2a
in good yields of up to 82%, and generating up to 2.54g of the
desired product (entry 19). The Gram-scale reaction was found
Results and Discussion
We initially focused our attention on determination of the to exotherm during the reaction at room temperature, and the
optimal conditions for the dehydrosulfurization of benzothio- yield of 2a was reduced to 52% yield. Therefore, this reaction
amide 1a. The standard reaction conditions involved the use of was operated under cooling at −20°C. When benzamide was
various reagents containing I , antimony, and bismuth in the used instead of benzthioamide, the starting material was re-
2
presence of triethylamine as a base at room temperature under covered, and the corresponding nitrile was not obtained.
aerobic conditions. The reagent and solvent screening results
To demonstrate the efficiency and generality of the above-
for the synthesis of benzonitrile 2a from 1a are summarized mentioned protocol, the reactions of various thioamides 1
in Table 1. Initially, the reaction of 1a with various reagents (2mmol) and I (2mmol) were investigated under the opti-
2
was carried out in CH Cl to compare their reactivity (entries mized conditions, and the results are summarized in Table 2.
2
2
1–7). All reagents gave the expected benzonitrile 2a in good- The reaction of aryl thioamides 1b–1i bearing electron-
to-excellent yields. Among them, I was found to be the best donating and electron-withdrawing substituents on the ben-
2
reagent for this dehydrosulfurization process, producing 2a in zene ring afforded the corresponding aryl nitriles 2b–2i in
9
9% yield. Subsequent solvent screening showed that the reac- good-to-excellent yields. The electronic nature (electron-rich
tion took place effectively in all solvents examined, among or electron poor) of the substituents in the p-position did not
which CH Cl gave the optimal results in terms of the yield affect the outcome of the reaction. The dehydrosulfurization
2
2
31)
and reaction time (entries 8–13). Using diisopropylethylamine reaction of phenol 1c using Ph BiCl2 reported by Doris and
3
instead of triethylamine as a base also gave 2a in high yield colleagues gave a complex mixture. In contrast, the smooth
(
entry 14). This reaction was found to be stoichiometric, and progress of this reaction using I indicates the superiority of
2
as an example, decreasing the loading of I to 0.3eq signifi- this method. In addition, phenol derivative 1c gave a complex
2
cantly reduced the yield of 2a (entries 1 and 15). Furthermore, mixture when the dehydrosulfurizing agent was changed from
31)
the use of triethylamine as a base gave superior results when 3 I to Ph BiCl , suggesting the superiority of the described
2
3
2
equivalents were employed (entries 1 and 16). Moreover, it was protocol. Furthermore, sterically hindered ortho-substituted
found that I and triethylamine were essential for the reaction, thioamides reacted to give the corresponding nitriles 2j and
2

Vol. 68, No. 7 (2020)
Chem. Pharm. Bull.
681
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1
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