Three-component reaction between isocyanides, aliphatic amines and elemental sulfur: Preparation of thioureas under mild conditions with complete atom economy

Article abstract of DOI:10.1055/s-0034-1379327

The reaction of isocyanides with aliphatic amines in the presence of elemental sulfur was found to proceed efficiently at, or near, room temperature to produce thioureas in excellent yields and with complete atom economy.

Full text of DOI:10.1055/s-0034-1379327

3172▌
FEATURE ARTICLE
fTeahturreearetic-lCe omponent Reaction between Isocyanides, Aliphatic Amines and
Elemental Sulfur: Preparation of Thioureas under Mild Conditions with
Complete Atom Economy
Thioureas from Isocyanides, Aliphatic Amines and Elemental Sulfur
Thanh Binh Nguyen,* Ludmila Ermolenko, Ali Al-Mourabit*
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91198 Gif-sur-Yvette
Cedex, France
Fax +33(1)69077247; E-mail: nguyen@icsn.cnrs-gif.fr; E-mail: ali.almourabit@cnrs.fr
Received: 05.08.2014; Accepted after revision: 26.09.2014
nides, which are described by two resonance structures,
Abstract: The reaction of isocyanides with aliphatic amines in the
one with a triple bond between the nitrogen and the carbon
presence of elemental sulfur was found to proceed efficiently at, or
(Scheme 1), would react with amines and elemental sulfur
near, room temperature to produce thioureas in excellent yields and
in a similar manner. Indeed, such an approach has been
described for anilines in refluxing ethanol;12 at this tem-
perature, isothiocyanates are formed in situ from isocya-
nides and elemental sulfur even without external
activation,13 and subsequently react with the anilines to
provide the corresponding N-arylthioureas (Scheme 1).
Very recently, a set of catalytic conditions [Co(acac)2 (20
mol%), 1,4-dioxane, 75 °C, ultrasonic activation14] for
such transformations has been described (Scheme 1).15
Although, in principle, no external oxidizing agent is re-
quired for this transformation, tert-butyl hydroperoxide (1
equiv) was used in the presence of sodium carbonate (2
equiv). Finally, isocyanides can be transformed into
thioureas by a two-step sequence via isothiocyanates (by
the reaction with sulfur catalyzed by selenium).16
with complete atom economy.
Key words: multicomponent reactions, elemental sulfur, isocya-
nides, thioureas, atom economy, sulfur–amine interaction
The thiourea group constitutes an important motif found
in various biologically active compounds.1 Additionally,
thioureas are key intermediates in the preparation of nitro-
gen- and/or sulfur-containing compounds, including het-
erocycles.2 Recently, thiourea derivatives have emerged
as one of the most efficient and popular classes of organo-
catalysts.3
Consequently, a number of methods4 are commonly em-
ployed for the formation of this linkage, including the ad-
dition of amines to isothiocyanates,5 thiophosgene,6
carbon disulfide7 and other thioacylating reagents.8
our previous work
R2
Reactions involving elemental sulfur as a reaction compo-
nent are highly interesting from practical, cost-effective
and synthetic convenience points of view. First, elemental
sulfur is a readily available and inexpensive reagent, even
in high degrees of purity.9 Second, being a nontoxic, free-
flowing and stable solid under normal conditions, sulfur is
easy to handle. Finally, although elemental sulfur itself is
only weakly reactive, its reactivity towards other func-
tional groups can be enhanced profoundly in the presence
of catalysts or activators of both Lewis acidic or basic na-
tures. Among these activators, aliphatic amines are re-
markable candidates due to their strong interaction with
elemental sulfur10 as well as their presence in reaction
mixtures as reaction components.
R2
H
N
R1
C
R3
N
R3
R1
C
CH
+
+
+
S
S
R2
N
this work
H
N
R2
H
R1
C
R3
N
R1
N
C
C
S
+
R3
S
R
2 = alkyl
R3 = alkyl, H
R1
N
r.t. and near r.t.
autocatalytic
literature precedents
From this analysis, we were particularly interested in a
multicomponent combination using elemental sulfur and
aliphatic amines for the construction of thioureas with re-
spect to the concept of atom economy. The present study
was inspired partially by our recent investigation on the
autocatalyzed three-component reaction between alkynes,
aliphatic amines and elemental sulfur leading to the corre-
sponding thioamides.11 We hypothesized that isocya-
Co(acac)2 (20 mol%)
Na2CO3 (2 equiv)
t-BuOOH (1 equiv)
1,4-dioxane
EtOH
reflux
))), 75 °C
H
H
H
H
N
N
N
N
R1
C
Ar/Alk
R1
C
Ar
S
S
ref. 12
with aromatic amines
ref. 14
complex reaction conditions
SYNTHESIS 2014, 46, 3172–3179
Advanced online publication: 31.10.2014
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0
3
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1
1
4
3
7
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2
1
0
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DOI: 10.1055/s-0034-1379327; Art ID: ss-2014-z0482-fa
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Thioureas from isocyanides, sulfur and amines

FEATURE ARTICLE
Thioureas from Isocyanides, Aliphatic Amines and Elemental Sulfur
3173
Herein, we report the first example of the autocatalytic of a range of functional groups, including aromatic chloro
three-component reaction between isocyanides, aliphatic (3ab, 3ac, 3cb), hydroxy (3al), anilino (3am), double
amines and elemental sulfur at, or near, room temperature. bond (3an) and ester (3dh) groups. Primary (2a–g, 2l–p)
The notable features of this reaction are its simplicity, and secondary (2h–k) amines were competent substrates
generality for aliphatic amines, atom efficiency and mild at ambient temperature. Notably, even for the substrates
reaction conditions.
bearing sterically demanding groups (isocyanide 1c,
amines 2e–k), good reactivities were still observed al-
though a gentle heating (40–50 °C) may be necessary to
accelerate the reactions. Ethyl isocyanoacetate (1d) was
shown to be extremely reactive; its reaction with N-ben-
zylmethylamine (2h) was achieved in less than 30 minutes
of mixing at room temperature, giving thiourea 3dh in
93% yield (Scheme 2).
In accordance with our hypothesis, we commenced this
study with the reaction of cyclohexyl isocyanide (1,
R = Cy), 2-phenethylamine [2; R1 = (CH2)2Ph, R2 = H]
and elemental sulfur, S8. To our delight, the reaction pro-
ceeded smoothly and slightly exothermically at room tem-
perature to provide the desired thiourea quantitatively.
The substrate scope of the reaction was then investigated.
A variety of N,N′-disubstituted and N,N,N′-trisubstituted
thioureas were synthesized by using this method (Scheme
2).
To investigate the mechanism of the thionation and ami-
nation of isocyanides, several experiments were per-
formed. First, cyclohexyl isocyanide (1a, R = Cy) was
stirred separately with amine 2a (R1 = CH2C6H4-4-Me,
R2 = H) and with sulfur. In both cases, isocyanide 1a was
The mild reaction conditions allowed the thionation and
amination of isocyanides to be carried out in the presence
Biographical Sketches█
Dr. Ali Al-Mourabit (left) was born Ludmila Ermolenko (middle) grad- Thanh Binh Nguyen (right) was
in 1958 at Beni Chiker, Nador, Mor- uated MS in chemistry from the born in Hanoi, Vietnam in 1982. He
roco and received his education in or- Lomonosov University (Moscow, obtained his BS degree from Univer-
ganic
chemistry
and
natural Russia) in 1975. She received her sity of Natural Sciences, Hochiminh
substances in France. He obtained his PhD degree from the École Normale city in 2004. He subsequently re-
Ph.D in 1989 from Paris XI Universi- Supérieur de Cachan (France) under ceived his MS (2005, Pr. J. Mortier)
ty under the supervision of Dr. P. the supervision of J. Delaire on the and PhD (2008, Dr. G. Dujardin)
Potier at the Institut de Chimie des photocatalyzed aerobic oxidation of from University of Maine, Le Mans,
Substances Naturelles. After an alkanes in the presence of decatung- France. From 2009 to 2011, he was a
Alexander von Humboldt postdoctor- states. In 1997, she was appointed at postdoctoral fellow at the Institut de
al fellowship in Germany in organic CNRS as a postdoctoral fellow and Chimie des Substances Naturelles
synthesis, he began his academic ca- then as a research engineer. She (ICSN) with Dr. F. Guéritte and Dr.
reer as a researcher (Chargé de Re- worked successively on new method- Qian Wang Zhu. He then joined the
cherche) at the CNRS-ICSN (Gif- ologies for the stereoselective syn- group of Dr. A. Al-Mourabit - Centre
sur-Yvette, France). At present, he is thesis of L-hexoses and 2-deoxy-2- National de la Recherche Scien-
head of the marine natural products amino hexoses and the synthesis of tifique as a researcher (Chargé de Re-
chemistry group and the coordinator inhibitors of AGEs involved in the cherche) at the same Institute in
of Natural Substances and Medicinal complications of diabetes (Pierre October 2011. His current research
Chemistry at the ICSN. He founded Potier’s group). In 2007, she joined interests include medicinal chemis-
the BioChiMar network that is under the group of Dr. A. Al-Mourabit at try, synthesis of marine natural prod-
his leadership since 2009. His current the ICSN. Her current research inter- ucts, new methods for carbon–
research interests include bioactive ests involve synthetic methodology, nitrogen bond formation involving
natural products isolation, biomimet- biomimetic synthesis of marine me- elemental sulfur, iron/sulfur catalysis
ic synthesis, medicinal chemistry and tabolites, and mechanistic studies of and green chemistry.
green chemistry.
the secondary metabolite formation.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3172–3179

3174
T. B. Nguyen et al.
FEATURE ARTICLE
shown to be inert towards amine 2a and elemental sulfur this step can occur in a stepwise manner to give isothiocy-
without the addition of a catalyst at the usual reaction tem- anate which is trapped by free amine in the reaction medi-
perature.12,17 Consequently, the formation of thiourea by um, leading to thiourea 3.
the present method could be initiated with the activation
An alternative nitrilium pathway would be initiated by a
nucleophilic addition of the isocyanide 1 to elemental sul-
fur leading to nitrilium 5. Trapping of intermediate 5 by
of elemental sulfur by the aliphatic amine,9 as presented in
Scheme 3. Aliphatic amine 2 reacts with cyclic S8 to yield
a zwitterionic ammonium polysulfide chain 4. The chain
amine 2 and subsequent transformation leads to thiourea
length of this zwitterion 4 can vary in a wide range de-
3.18
pending on the temperature and concentration, as well as
To demonstrate the synthetic utility of our method, we ap-
the sulfur-to-amine ratio. The zwitterion form 4 can be in
plied the present reaction conditions to both m- and p-am-
equilibrium with its neutral form 4′. Having a negatively
inobenzylamine (Scheme 4). The reactions proceeded
charged sulfur terminus which is very nucleophilic due to
smoothly at room temperature and selectively afforded
both the anionic and alpha effects of the polysulfane
the aminobenzyl-substituted thioureas in excellent yields.
chain, the zwitterion form 4 can attack the carbenoid car-
bon atom of the isocyanide 1 to yield the thiourea 3 in a
concerted fashion with concomitant extrusion of the cy-
clic polysulfane with one less sulfur atom. Alternatively,
In summary, we have developed the first thionation and
amination of isocyanides using elemental sulfur and ali-
phatic amines at room temperature. This reaction provides
R2
R2
H
H
r.t. to 50 °C
solvent-free or
PhMe (0.1 mL)
R1
N C
N
R3
N
N
+
+
S
R3
R1
S
3
1a–e
2a–p
(1 mmol)
(1.2 equiv) (1.2 equiv)
Cl
H
H
N
H
H
H
H
N
H
N
H
N
N
N
N
N
N
S
Cl
S
S
S
3aa, r.t., 3 h, 97%
3ab, r.t., 1 h, 77%
3ac, r.t., 3 h, 97%
3ad, r.t., 2 h, 90%
Me
H
H
H
H
H
N
N
Ph
H
H
N
N
Ph
N
N
N
N
Ph
Bn
S
Ph
S
S
S
3ae, 40 °C, 1 h, 99%
3af, 50 °C, 16 h, 97%
3ag, 50 °C, 16 h, 68%
3ah, 40 °C, 5 h, 97%
H
H
Bn
H
H
N
N
OH
H
( )4
N
N
N
N
N
N
Bn
S
S
S
S
3ai, 40 °C, 6 h, 70%
3aj, 40 °C, 1 h, 95%
3ak, r.t., 16 h, 85%
3al, r.t., 3 h, 97%
H
N
H
H
H
H
H
N
N
N
N
N
Ph
N
H
S
S
S
3am, r.t., 2 h, 97%
3an, r.t., 1 h, 97%
3ao, r.t., 8 h, 95%
Cl
H
H
N
H
N
N
H
H
N
N
N
H
Bn
Ph
N
N
t-Bu
S
Bn
t-Bu
S
S
S
3bk, r.t., 16 h, 90%
3bp, r.t., 2 h, 93%
3cb, r.t., 2 h, 94%
3ck, r.t., 16 h, 97%
H
H
Me
H
N
H
N
N
H
H
N
Ph
Ph
N
N
EtO2C
N
N
Ph
Ph
Bn
S
t-Bu
S
S
S
3cp, r.t., 1 h, 90%
3dh, r.t., 0.5 h, 93%
3ek, r.t., 16 h, 85%
3ep, r.t., 1 h, 90%
Scheme 2 Thioureas from isocyanides, sulfur and amines
Synthesis 2014, 46, 3172–3179
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Thioureas from Isocyanides, Aliphatic Amines and Elemental Sulfur
3175
sulfur activated by amine pathways
R1
H
N
R1
C
S8
R1
2
N
R2
N
SH
R1 (S)n
S
( )
S n–3
R1
N
1
S
N
S
R1
R1
S
R1 (S)n
H
4'
S
H
stepwise pathway
C
4
N
R2
R1
C
N
concerted pathway
N
S
R2
R1 (S)n–1
H
1
R2
( )
S
S n–3
S
C N
R1
H
N
S
N
S
R1
R1
R1
N
R2
R1
S
H
C
NH
R1
N
R2
S
Sn
3
R1
H
N
R1
2
nitrilium pathway
N
R1
N
R2
NH
S
S–
R1
R2
C
(
)
6
S
S8
N
R2
– S7
S
1
5
3
Scheme 3 Proposed mechanism
tored by TLC on precoated silica gel (Kieselgel 60 F254) plates.
The spots were visualized under UV light (254 nm) or with vanillin
stain (green spots). Flash column chromatography was conducted
using silica gel (230–400 mesh) with different mixtures of solvents
as the mobile phase (CH2Cl2–MeOH or EtOAc–heptane).
R2
R2
R1
C
N
R1
r.t.
H
N
H
+
S
+
N
H2N
t-Bu
t-Bu
S
Thioureas 3 from Isocyanides 1, Sulfur and Amines 2; General
Procedure
(1.2 equiv)
(1 mmol)
(1.2 equiv)
2q, R1 = H, R2 = NH2
2r, R1 = NH2, R2 = H
3cq, R1 = H, R2 = NH2, 1 h, 92%
3cr, R1 = NH2, R2 = H, 3 h, 90%
1c
A 10-mL test tube equipped with a magnetic stir bar was charged
with an isocyanide 1 (1 mmol, 1 equiv), elemental sulfur (38.4 mg,
1.2 mmol, 1.2 equiv) and an amine 2 (1.2 mmol, 1.2 equiv). The re-
sulting mixture was stirred for the indicated time at the indicated
temperature (see Schemes 2 and 4). Toluene (0.1 mL) can be added
if necessary to facilitate the stirring. The crude mixture (oily or sol-
id) was purified by silica gel column chromatography (eluent: ap-
propriate mixtures of heptane–EtOAc, heptane–CH2Cl2 or CH2Cl2–
MeOH).
Scheme 4 Chemoselective formation of thioureas from aminoben-
zylamines 2q and 2r
an efficient and convenient multicomponent approach to
unsymmetrical thioureas in a total atom-economical man-
ner. Considering the mild reaction conditions and high
functional group tolerance of the present reaction, as well
as the widely known applications of thiourea moieties in
medicinal chemistry and asymmetric synthesis, this meth-
od could be very useful for the direct transformation of
available isocyanide natural products19 or building
blocks15 into a wide range of thioureas for structure–
activity relationship studies.
1-Cyclohexyl-3-(4-methylbenzyl)thiourea (3aa)
Eluent: heptane–EtOAc, 3:1.
Yield: 254 mg (97%); white solid; mp 108 °C.
IR (neat): 3228, 3048, 2929, 2853, 1539, 1515, 1447, 1340, 1254,
1230, 1059, 811 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.16 (dd, J = 15.3, 7.8 Hz, 4 H),
6.35 (br s, 1 H), 5.95 (br s, 1 H), 4.55 (br s, 2 H), 3.87 (br s, 1 H),
2.32 (s, 3 H), 1.93 (m, 2 H), 1.61 (m, 3 H), 1.33 (m, 2 H), 1.13 (m,
3 H).
13C NMR (75 MHz, CDCl3): δ = 180.4, 137.7, 129.4, 127.6, 53.4,
48.2, 32.8, 25.5, 24.7, 21.4.
Commercially available starting materials were purchased from
1
Sigma-Aldrich and used without further purification. H and 13C
NMR spectra were acquired using a Bruker (300 MHz) spectrome-
ter. CDCl3 was used as the solvent. Chemical shifts are reported in
ppm with internal reference to residual CHCl3 at 7.24 ppm. Cou-
pling constants are reported in Hz. Reaction progress was moni-
HRMS-ESI+: m/z [M + H]+ calcd for C15H23N2S: 263.1582; found:
263.1578.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3172–3179

3176
T. B. Nguyen et al.
FEATURE ARTICLE
1-(4-Chlorobenzyl)-3-cyclohexylthiourea (3ab)20
Eluent: heptane–EtOAc, 3:1.
HRMS-ESI+: m/z [M + H]+ calcd for C16H25N2S: 277.1738; found:
277.1725.
Yield: 218 mg (77%); white solid; mp 115 °C.
1-Benzhydryl-3-cyclohexylthiourea (3ag)
IR (neat): 3238, 3050, 2930, 2853, 1539, 1488, 1449, 1318, 1235,
1061, 1012, 813, 797 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.26 (m, 4 H), 6.42 (s, 1 H), 6.05
(s, 1 H), 4.62 (s, 2 H), 3.83 (s, 1 H), 1.93 (m, 2 H), 1.65 (m, 3 H),
1.30 (m, 2 H), 1.18 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 180.8, 135.8, 133.8, 129.3, 53.3,
47.8, 32.8, 25.5, 24.6.
Eluent: heptane–EtOAc, 3:1.
Yield: 221 mg (68%); white solid; mp 193 °C.
IR (neat): 3375, 3211, 2922, 2850, 1540, 1511, 1448, 1254, 1225,
760, 701 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.33 (m, 10 H), 6.39 (m, 1 H), 5.91
(s, 1 H), 5.51 (s, 1 H), 4.08 (s, 1 H), 1.86 (s, 2 H), 1.50 (m, 3 H), 1.34
(m, 2 H), 1.05 (m, 3 H).
1-(2-Chlorobenzyl)-3-cyclohexylthiourea (3ac)
Eluent: heptane–EtOAc, 3:1.
13C NMR (75 MHz, CDCl3): δ = 180.0, 140.1, 129.4, 128.9, 127.5,
62.6, 53.6, 32.4, 25.3, 24.4.
HRMS-ESI+: m/z [M + H]+ calcd for C20H25N2S: 325.1738; found:
Yield: 274 mg (97%); pale yellow solid; mp 140 °C.
325.1720.
IR (neat): 3203, 3060, 2930, 2854, 1550, 1489, 1410, 1371, 1317,
1236, 1086, 1012, 933, 826, 797 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.43 (m, 2 H), 7.27 (m, 2 H), 6.34
(s, 1 H), 5.93 (s, 1 H), 4.78 (s, 2 H), 3.81 (s, 1 H), 1.99 (m, 2 H), 1.68
(m, 3 H), 1.35 (m, 2 H), 1.17 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 180.6, 134.7, 133.3, 130.1, 129.6,
129.2, 127.2, 53.2, 46.0, 32.7, 25.4, 24.9.
HRMS-ESI+: m/z [M + H]+ calcd for C14H20ClN2S: 283.1036;
1-Benzyl-3-cyclohexyl-1-methylthiourea (3ah)
Eluent: heptane–EtOAc, 3:1.
Yield: 254 mg (97%); white solid; mp 90 °C.
IR (neat): 3279, 3055, 2932, 2855, 1538, 1488, 1452, 1409, 1370,
1317, 1236, 1086, 1062, 1012, 826, 797 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.13 (m, 5 H), 5.31 (d, J = 7.5 Hz,
1 H), 5.03 (s, 2 H), 4.34 (m, 1 H), 3.15 (s, 3 H), 2.06 (m, 2 H), 1.64
(m, 3 H), 1.41 (m, 2 H), 1.15 (m, 3 H).
found: 283.1044.
1-Cyclohexyl-3-(pyridin-3-ylmethyl)thiourea (3ad)21
The product was obtained by washing the solid, crude mixture with
toluene.
13C NMR (75 MHz, CDCl3): δ = 181.2, 136.6, 129.0, 127.8, 127.2,
56.7, 54.4, 37.8, 33.4, 25.8, 25.0.
HRMS-ESI+: m/z [M + H]+ calcd for C15H23N2S: 263.1582; found:
Yield: 224 mg (90%); pale yellow solid; mp 215 °C.
263.1567.
IR (neat): 3295, 3210, 3062, 2930, 2854, 1555, 1489, 1410, 1372,
1344, 1317, 1237, 1087, 1062, 1012, 974, 934, 826, 797, 694 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.41 (d, J = 4.5 Hz, 1 H), 7.84 (s,
1 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.14 (t,
J = 8.1 Hz, 1 H), 4.63 (s, 2 H), 3.90 (m, 1 H), 1.86 (m, 2 H), 1.52
(m, 2 H), 1.51 (m, 1 H), 1.17 (m, 5 H).
1,1-Dibenzyl-3-cyclohexylthiourea (3ai)
Eluent: heptane–EtOAc, 4:1.
Yield: 237 mg (70%); white solid; mp 113 °C.
IR (neat): 3375, 3215, 2922, 2850, 1542, 1511, 1448, 1257, 1229,
1088, 759, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.34 (m, 10 H), 5.38 (m, 1 H), 4.99
(s, 4 H), 4.33 (s, 1 H), 1.94 (s, 2 H), 1.49 (m, 3 H), 1.36 (m, 2 H),
1.00 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 180.4, 156.5, 148.6, 137.2, 122.6,
53.1, 49.6, 32.5, 25.7, 24.3.
1-Cyclohexyl-3-(1-phenylethyl)thiourea (3ae)
13C NMR (75 MHz, CDCl3): δ = 181.6, 136.0, 128.9, 127.9, 127.1,
54.3, 54.1, 32.5, 25.4, 24.4.
HRMS-ESI+: m/z [M + H]+ calcd for C21H27N2S: 339.1895; found:
Eluent: heptane–EtOAc, 3:1.
Yield: 259 mg (99%); white solid; mp 130 °C.
IR (neat): 3375, 3218, 2925, 2853, 1542, 1513, 1494, 1446, 1256,
1228, 760, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.33 (m, 5 H), 6.43 (m, 1 H), 5.52
(s, 1 H), 4.83 (s, 1 H), 3.99 (s, 1 H), 1.93 (s, 1 H), 1.67 (m, 1 H), 1.50
(m, 5 H), 1.27 (s, 3 H), 1.09 (m, 2 H), 0.87 (s, 1 H).
339.1882.
N-Cyclohexylazepane-1-carbothioamide (3aj)
Eluent: heptane–EtOAc, 3:1.
Yield: 228 mg (95%); white solid; mp 110 °C.
13C NMR (75 MHz, CDCl3): δ = 179.4, 142.0, 129.3, 127.9, 125.8,
54.0, 53.2, 32.6, 32.2, 25.3, 24.3, 24.1, 23.6.
IR (neat): 3292, 3206, 3061, 2929, 2855, 1553, 1551, 1539, 1410,
1369, 1344, 1317, 1238, 1087, 1013, 974, 797, 693, 658 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.21 (d, J = 7.1 Hz, 1 H), 4.33 (m,
1 H), 3.76 (s, 4 H), 2.07 (m, 2 H), 1.63 (m, 11 H), 1.40 (m, 2 H),
1.16 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 179.6, 54.0, 50.5, 33.3, 27.6, 26.8,
25.6, 25.0.
HRMS-ESI+: m/z [M + H]+ calcd for C15H23N2S: 263.1582; found:
263.1591.
1-Cyclohexyl-3-(2-phenylpropan-2-yl)thiourea (3af)
Eluent: heptane–EtOAc, 3:1.
Yield: 268 mg (97%); white solid; mp 128 °C.
HRMS-ESI+: m/z [M + H]+ calcd for C13H25N2S: 241.1738; found:
IR (neat): 3372, 3218, 2928, 2850, 1539, 1515, 1447, 1254, 1227,
757, 701 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.42 (m, 5 H), 6.53 (s, 1 H), 4.95
(s, 1 H), 4.03 (s, 1 H), 1.65 (s, 8 H), 1.37 (m, 1 H), 1.22 (m, 4 H),
1.00 (m, 1 H), 0.76 (s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 178.7, 144.0, 129.6, 128.5, 125.6,
57.5, 53.7, 32.0, 29.9, 25.3, 23.7.
241.1753.
N-Cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carbothioamide
(3ak)
Eluent: heptane–EtOAc, 3:1.
Yield: 233 mg (85%); white solid; mp 126 °C.
IR (neat): 3362, 3256, 2949, 1733, 1535, 1491, 1455, 1340, 1218,
1193, 1092, 1019, 953, 742, 690 cm–1.
Synthesis 2014, 46, 3172–3179
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Thioureas from Isocyanides, Aliphatic Amines and Elemental Sulfur
3177
1H NMR (300 MHz, CDCl3): δ = 7.22 (m, 4 H), 5.34 (m, 1 H), 4.92
(s, 2 H), 4.43 (s, 1 H), 3.96 (t, J = 6.0 Hz, 2 H), 2.97 (t, J = 6.0 Hz,
2 H), 2.15 (s, 2 H), 1.72 (m, 3 H), 1.45 (m, 2 H), 1.22 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 180.0, 135.4, 133.0, 127.8, 127.2,
126.8, 126.6, 54.2, 49.3, 45.5, 33.4, 29.1, 25.6, 25.2.
IR (neat): 3253, 3062, 2918, 1540, 1493, 1458, 1421, 1380, 1337,
1294, 1251, 1197, 1184, 1108, 1061, 746, 702 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.59 (m, 5 H), 7.23 (m, 4 H), 5.73
(m, 1 H), 4.97 (s, 4 H), 4.01 (t, J = 6.0 Hz, 2 H), 2.98 (t, J = 6.0 Hz,
2 H).
HRMS-ESI+: m/z [M + H]+ calcd for C16H23N2S: 275.1582; found:
275.1566.
13C NMR (75 MHz, CDCl3): δ = 181.6, 138.2, 135.3, 132.9, 128.7,
128.2, 127.9, 127.8, 127.3, 126.8, 126.5, 50.5, 49.8, 45.8, 29.0.
1-Cyclohexyl-3-(4-hydroxybutyl)thiourea (3al)
Eluent: CH2Cl2–MeOH, 93:7.
1-Benzyl-3-phenethylthiourea (3bp)24
Eluent: heptane–EtOAc, 3:1.
Yield: 223 mg (97%); pale yellow solid; mp 106 °C.
Yield: 251 mg (93%); white solid; mp 127 °C.
IR (neat): 3411, 3283, 3209, 3061, 2929, 2854, 1552, 1489, 1410,
1369, 1349, 1318, 1238, 1087, 1013, 798, 695 cm–1.
IR (neat): 3365, 3256, 2952, 1537, 1491, 1382, 1343, 1292, 1215,
1195, 1185, 773, 749, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.70 (s, 1 H), 6.37 (s, 1 H), 3.89
(s, 1 H), 3.61 (m, 2 H), 3.44 (s, 3 H), 1.94 (m, 2 H), 1.62 (m, 7 H),
1.22 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 179.7, 61.8, 53.0, 44.1, 32.9, 29.6,
25.8, 25.5, 24.9.
HRMS-ESI+: m/z [M + H]+ calcd for C11H23N2OS: 231.1531;
found: 231.1545.
1H NMR (300 MHz, CDCl3): δ = 7.29 (m, 8 H), 7.13 (m, 2 H), 6.34
(m, 1 H), 5.92 (s, 1 H), 4.52 (s, 2 H), 3.74 (m, 2 H), 2.88 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 181.9, 138.3, 136.7, 128.9, 128.8,
128.7, 128.0, 127.5, 126.8, 48.2, 45.8, 35.1.
1-(4-Chlorobenzyl)-3-(2,4,4-trimethylpentan-2-yl)thiourea
(3cb)
Eluent: heptane–EtOAc, 3:1.
Yield: 294 mg (94%); white solid; mp 111 °C.
1-Cyclohexyl-3-[2-(phenylamino)ethyl]thiourea (3am)
Eluent: heptane–EtOAc, 1:1.
IR (neat): 3259, 2949, 1535, 1493, 1380, 1341, 1242, 1194, 1182,
1107, 1062, 743, 703 cm–1.
Yield: 269 mg (97%); white solid; mp 102 °C.
1H NMR (300 MHz, CDCl3): δ = 7.27 (m, 4 H), 6.11 (s, 1 H), 6.02
(s, 1 H), 4.74 (d, J = 5.4 Hz, 2 H), 1.71 (s, 2 H), 1.41 (s, 6 H), 0.99
(s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 181.2, 136.1, 133.5, 129.0, 128.9,
57.2, 52.3, 49.0, 31.7, 31.5, 30.7.
HRMS-ESI+: m/z [M + H]+ calcd for C16H26ClN2S: 313.1505;
found: 313.1523.
IR (neat): 3295, 3211, 3061, 2928, 2855, 1555, 1488, 1343, 1315,
1254, 1236, 1086, 1061, 796 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.18 (t, J = 7.6 Hz, 2 H), 6.74 (t,
J = 7.6 Hz, 1 H), 6.65 (br s, 1 H), 6.63 (d, J = 7.1 Hz, 2 H), 6.39 (m,
1 H), 4.21 (s, 1 H), 3.69 (s, 3 H), 3.29 (m, 2 H), 1.91 (m, 2 H), 1.63
(m, 3 H), 1.31 (m, 2 H), 1.08 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 180.7, 147.7, 129.9, 118.2, 113.1,
53.0, 44.0, 32.7, 25.4, 24.7.
HRMS-ESI+: m/z [M + H]+ calcd for C15H24N3S: 278.1691; found:
N-(2,4,4-Trimethylpentan-2-yl)-3,4-dihydroisoquinoline-
2(1H)-carbothioamide (3ck)
Eluent: heptane–EtOAc, 3:1.
278.1677.
1-Allyl-3-cyclohexylthiourea (3an)22
Yield: 295 mg (97%); white solid; mp 90 °C.
Eluent: heptane–EtOAc, 3:1.
IR (neat): 3249, 2925, 1537, 1494, 1376, 1339, 1315, 1196, 1186,
1060, 745, 700 cm–1.
Yield: 192 mg (97%); white solid; mp 82 °C.
1H NMR (300 MHz, CDCl3): δ = 7.25 (m, 4 H), 5.44 (s, 1 H), 4.91
(s, 2 H), 3.94 (t, J = 6.0 Hz, 2 H), 2.96 (t, J = 6.0 Hz, 2 H), 2.11 (s,
2 H), 1.68 (s, 6 H), 1.05 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 180.0, 135.4, 133.5, 127.8, 127.2,
126.7, 126.5, 58.4, 51.5, 48.9, 45.3, 31.8, 31.1, 30.1, 29.2.
HRMS-ESI+: m/z [M + H]+ calcd for C18H29N2S: 305.2051; found:
305.2068.
IR (neat): 3379, 3218, 2922, 2846, 1537, 1513, 1445, 1256, 1225,
758, 701 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.34 (s, 1 H), 6.06 (s, 1 H), 5.88
(m, 1 H), 5.05–5.25 (m, 2 H), 4.07 (m, 3 H), 1.99 (m, 2 H), 1.66 (m,
3 H), 1.38, 1.18 (2 × m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 180.4, 133.7, 117.4, 53.2, 47.1,
33.2, 25.7, 24.9.
1-Phenethyl-3-(2,4,4-trimethylpentan-2-yl)thiourea (3cp)
1-Cyclohexyl-3-prop-2-ynylthiourea (3ao)
Reaction was performed in toluene (0.2 mL). Eluent: heptane–
CH2Cl2, 1:1 to 0:1.
Eluent: heptane–EtOAc, 3:1.
Yield: 263 mg (90%); amorphous solid.
Yield: 274 mg (95%; ~90% purity); amorphous solid.
IR (neat): 3379, 3215, 2928, 2849, 1539, 1505, 1446, 1356, 1254,
1230, 888, 765, 701 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.32, 7.23 (2 × m, 5 H), 6.01 (s, 1
H), 5.57 (s, 1 H), 3.87 (m, 2 H), 2.94 (t, J = 6.7 Hz, 2 H), 1.45 (s, 2
H), 1.26 (s, 6 H), 0.92 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 180.9, 138.4, 128.9, 128.6, 127.0,
56.5, 52.1, 46.7, 35.0, 31.6, 31.2, 30.2.
HRMS-ESI+: m/z [M + H]+ calcd for C17H29N2S: 293.2051; found:
IR (neat): 3256, 3056, 2119, 1628, 1613, 1537, 1449, 1364, 1340,
1220, 1152, 1063, 890 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.09 (br s, 1 H), 6.01 (br s, 1 H),
13C NMR (75 MHz, CDCl3): δ = 180.8, 79.0, 72.9, 53.3, 34.3, 32.9,
25.5, 24.8.
HRMS-ESI+: m/z [M + H]+ calcd for C10H17N2S: 197.1112; found:
197.1102.
293.2065.
N-Benzyl-3,4-dihydroisoquinoline-2(1H)-carbothioamide
(3bk)23
Ethyl 2-(3-Benzyl-3-methylthioureido)acetate (3dh)
Eluent: heptane–EtOAc, 2:1.
Eluent: heptane–EtOAc, 3:1.
Yield: 248 mg (93%); white solid; mp 70 °C.
Yield: 254 mg (90%); white solid; mp 134 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3172–3179

3178
T. B. Nguyen et al.
FEATURE ARTICLE
IR (neat): 3365, 3263, 2952, 1535, 1490, 1429, 1377, 1341, 1290,
1194, 1184, 747, 704 cm–1.
HRMS-ESI+: m/z [M + H]+ calcd for C16H28N3S: 294.2004; found:
294.1995.
1H NMR (300 MHz, CDCl3): δ = 7.25 (m, 5 H), 6.05 (s, 1 H), 5.01
(s, 2 H), 4.37 (d, J = 4.5 Hz, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 3.10 (s,
3 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 182.3, 170.3, 136.4, 128.8, 127.8,
127.4, 61.7, 57.1, 47.9, 37.5, 14.3.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
HRMS-ESI+: m/z [M + H]+ calcd for C13H19N2O2S: 267.1167;
found: 267.1179.
References
(1) For selected examples, see: (a) Anzini, M.; Chelini, A.;
Mancini, A.; Cappelli, A.; Frosini, M.; Ricci, L.; Valoti, M.;
Magistretti, J.; Castelli, L.; Giordani, A.; Makovec, F.;
Vomero, S. J. Med. Chem. 2010, 53, 734. (b) Lee, J.; Lee, J.;
Kang, M.; Shin, M.; Kim, J.; Kang, S.; Lim, J.; Choi, H.;
Suh, Y.; Park, H.; Oh, U.; Kim, H.; Park, Y.; Ha, H.; Kim,
Y.; Toth, A.; Wang, Y.; Tran, R.; Pearce, L. V.; Lundberg,
D. J.; Blumberg, P. M. J. Med. Chem. 2003, 46, 3116.
(c) Touati-Jallabe, Y.; Bojnik, E.; Legrand, B.;
N-Phenyl-3,4-dihydroisoquinoline-2(1H)-carbothioamide (3ek)
Eluent: heptane–EtOAc, 3:1.
Yield: 228 mg (85%); pale yellow solid; mp 143 °C.
IR (neat): 3372, 3191, 1593, 1539, 1491, 1450, 1351, 1314, 1246,
1176, 1160, 1109, 1065, 997 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.31–7.12 (m, 10 H), 4.94 (s, 2 H),
4.02 (t, J = 6.0 Hz, 2 H), 2.98 (t, J = 6.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 182.2, 139.9, 134.9, 132.8, 128.9,
128.1, 127.2, 126.7, 126.5, 125.6, 124.7, 51.0, 47.1, 28.8.
Mauchauffée, E.; Chung, N. N.; Schiller, P. W.; Benyhe, S.;
Averlant-Petit, M.-C.; Martinez, J.; Hernandez, J.-F. J. Med.
Chem. 2013, 56, 5964. (d) Van Daele, I.; Munier-Lehmann,
H.; Froeyen, M.; Balzarini, J.; Van Calenbergh, S. J. Med.
Chem. 2007, 50, 5281. (e) Verlinden, B. K.; Niemand, J.;
Snyman, J.; Sharma, S. K.; Beattie, R. J.; Woster, P. M.;
Birkholtz, L.-M. J. Med. Chem. 2011, 54, 6624. (f) Sharma,
S. K.; Wu, Y.; Steinbergs, N.; Crowley, M. L.; Hanson, A.
S.; Casero, R. A. Jr.; Woster, P. M. J. Med. Chem. 2010, 53,
5197. (g) Kim, H. S.; Jin, M.; Kang, S.; Lim, J.; Tran, P.;
Hoang, V.; Ann, J.; Ha, T.; Pearce, L. V.; Pavlyukovets, V.
A.; Blumberg, P. M.; Lee, J. Bioorg. Med. Chem. Lett. 2014,
24, 2685.
HRMS-ESI+: m/z [M + H]+ calcd for C16H17N2S: 269.1112; found:
269.1129.
1-Phenethyl-3-phenylthiourea (3ep)24
Eluent: heptane–EtOAc, 3:1.
Yield: 231 mg (90%); pale yellow solid; mp 106 °C (Lit.23 106 °C).
IR (neat): 3375, 3188, 1591, 1537, 1491, 1450, 1351, 1316, 1248,
1176, 1160, 1108, 1069, 999 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.05 (br s, 1 H), 7.41–7.21 (m, 6
H), 7.17–7.14 (m, 2 H), 7.03–7.01 (m, 2 H), 6.03 (br s, 1 H), 3.91 (t,
J = 6.8 Hz, 2 H), 2.93 (t, J = 6.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 180.1, 138.5, 136.1, 130.0, 128.8,
128.7, 127.0, 126.6, 125.0, 46.2, 34.8.
HRMS-ESI+: m/z [M + H]+ calcd for C15H17N2S: 257.1112; found:
(2) For recent examples, see: (a) For amidines: Biswas, K.;
Greaney, M. F. Org. Lett. 2011, 13, 4946. (b) For
benzothiazoles: Zhao, J.; Huang, H.; Wu, W.; Chen, H.;
Jiang, H. Org. Lett. 2013, 15, 2604. (c) For thiazoles: Kim,
S. K.; Kim, J. H.; Park, Y. C.; Kim, J. W.; Yum, E. K.
Tetrahedron 2013, 69, 10990. (d) For pyrimidines:
Dotsenko, F.; Krivokolysko, P. Chem. Heterocycl. Compd.
2013, 49, 440. (e) For aminotetrazoles: Batey, R. A.; Powell,
D. A. Org. Lett. 2000, 2, 3237. (f) For 2-amino-4H-1,3-
thiazines: Huang, S.; Pan, Y.; Zhu, Y.; Wu, A. Org. Lett.
2005, 7, 3797.
(3) For representative examples, see: (a) Jordan, B. J.; Pollier,
M. A.; Miller, L. A.; Tiernan, C.; Clavier, G.; Audebert, P.;
Rotello, V. M. Org. Lett. 2007, 9, 2835. (b) Osorio-Planes,
L.; Rodríguez-Escrich, C.; Pericàs, M. A. Org. Lett. 2014,
16, 1704. (c) Vonlanthen, M.; Finney, N. S. J. Org. Chem.
2013, 78, 3980. (d) Wu, Z.; An, Z.; Chen, X.; Chen, P. Org.
Lett. 2013, 15, 1456. (e) Boyle, E. M.; Comby, S.; Molloy,
J. K.; Gunnlaugsson, T. J. Org. Chem. 2013, 78, 8312.
(f) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
10012.
257.1098.
1-(3-Aminobenzyl)-3-(2,4,4-trimethylpentan-2-yl)thiourea
(3cq)
Eluent: heptane–EtOAc, 1:1.
Yield: 270 mg (92%); pale yellow solid; mp 125 °C.
IR (neat): 3255, 2945, 1535, 1496, 1451, 1376, 1341, 1193, 1151,
1110, 745, 701 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.11 (m, 1 H), 6.64 (m, 3 H), 6.02
(s, 2 H), 4.59 (s, 2 H), 3.61 (s, 2 H), 1.74 (s, 2 H), 1.42 (s, 6 H), 0.99
(s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 180.9, 147.1, 138.6, 129.9, 117.8,
114.7, 114.3, 57.0, 51.9, 49.6, 31.7, 31.4, 30.3.
HRMS-ESI+: m/z [M + H]+ calcd for C16H28N3S: 294.2004; found:
294.2015.
(4) Schroeder, D. C. Chem. Rev. 1955, 55, 181.
(5) Kumamoto, K.; Misawa, Y.; Tokita, S.; Kubo, Y.; Kotsuki,
H. Tetrahedron Lett. 2002, 43, 1035.
(6) Matsumura, T.; Nakada, M. Tetrahedron Lett. 2014, 55,
1412.
1-(4-Aminobenzyl)-3-(2,4,4-trimethylpentan-2-yl)thiourea
(3cr)
Eluent: heptane–EtOAc, 1:1.
Yield: 264 mg (90%); yellow solid; mp 90 °C.
IR (neat): 3256, 2915, 1539, 1491, 1379, 1336, 1249, 1196, 1181,
1107, 1063, 745, 701 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.05 (d, J = 6.4 Hz, 2 H), 6.60 (d,
J = 6.4 Hz, 2 H), 6.00, 5.94 (2 × s, 2 H), 4.49 (s, 2 H), 3.76 (s, 2 H),
1.69 (s, 2 H), 1.36 (s, 6 H), 0.95 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 180.5, 146.4, 129.0, 115.4, 56.8,
51.8, 49.2, 31.6, 31.4, 30.3.
(7) (a) Vazquez, J.; Bernes, S.; Reyes, Y.; Moya, M.; Sharma,
P.; Alvarez, C.; Gutierrez, R. Synthesis 2004, 1955.
(b) Maddani, M. R.; Prabhu, K. R. J. Org. Chem. 2010, 75,
2327.
(8) Yin, B. L.; Liu, Z. G.; Zhang, J. C.; Li, Z. R. Synthesis 2010,
991.
(9) At the time of preparing this manuscript, elemental sulfur
(99.5–100.5% chemical purity) was commercially available
Synthesis 2014, 46, 3172–3179
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Thioureas from Isocyanides, Aliphatic Amines and Elemental Sulfur
3179
from Sigma-Aldrich for US$38.80/kg or US$1.24/mol
(13803-1KG-R).
selenium, see: (a) Fujiwara, S.-i.; Shin-Ike, T.; Sonoda, N.;
Aoki, M.; Okada, K.; Miyoshi, N.; Kambe, N. Tetrahedron
Lett. 1991, 32, 3503. With molybdenum catalysts, see:
(b) Adam, W.; Bargon, R. M.; Bosio, S. G.; Schenk, W. A.;
Stalke, D. J. Org. Chem. 2002, 67, 7037. (c) Byrne, J. J.;
Vallee, Y. A. Tetrahedron Lett. 1999, 40, 489. With rhodium
complexes, see: (d) Arisawa, M.; Ashikawa, M.; Suwa, A.;
Yamaguchi, M. Tetrahedron Lett. 2005, 46, 1727.
(17) We thank the reviewer for suggesting this alternative
mechanism.
(18) (a) Scheuer, P. J. Acc. Chem. Res. 1992, 25, 433. (b) Garson,
M. J.; Simpson, J. S. Nat. Prod. Rep. 2004, 21, 164.
(19) De Esch, I. J. P.; Mills, J. E. J.; Perkins, T. D. J.; Romeo, G.;
Hoffmann, M.; Wieland, K.; Leurs, R.; Menge, W. M. P. B.;
Nederkoorn, P. H. J.; Dean, P. M.; Timmerman, H. J. Med.
Chem. 2001, 44, 1666.
(10) (a) Davis, R. E.; Nakshbendi, H. F. J. Am. Chem. Soc. 1962,
84, 2085. (b) Hodgson, W. G.; Buckler, S. A.; Peters, G.
J. Am. Chem. Soc. 1963, 85, 543. (c) Thomson, J. W.;
Nagashima, K.; Macdonald, P. M.; Ozin, G. A. J. Am. Chem.
Soc. 2011, 133, 5036. (d) McMillan, F. H. J. Am. Chem. Soc.
1948, 70, 868. For a mechanistic study of the room
temperature reaction of sulfur with benzylamine, see:
(e) Sasaki, Y.; Olsen, F. P. Can. J. Chem. 1971, 49, 283.
(f) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Org.
Lett. 2012, 14, 4274.
(11) Nguyen, T. B.; Tran, M. Q.; Ermolenko, L.; Al-Mourabit, A.
Org. Lett. 2014, 16, 310.
(12) Lipp, M.; Dallacker, F.; Meier zu Köcker, I. Monatsh. Chem.
1959, 90, 41.
(13) Isothiocyanates have been reported to be formed by
refluxing a benzene solution of elemental sulfur and the
parent isocyanides; see: (a) Tanaka, S.; Uemura, S.; Okano,
M. Bull. Chem. Soc. Jpn. 1977, 50, 2785. (b) Boyer, J. H.;
Ramakrishnan, V. T. J. Org. Chem. 1972, 37, 1360.
(14) Zhu, T.; Xu, X.; Cao, J.; Wei, T.; Wang, S.; Ji, S. Adv. Synth.
Catal. 2014, 356, 509.
(15) Zajdlik, A.; Wang, Z.; Hickey, J. L.; Aman, A.; Schimmer,
A. D.; Yudin, A. K. Angew. Chem. Int. Ed. 2013, 52, 8411.
(16) Isocyanides have been found to react with S8 in the presence
of catalysts on heating to provide isothiocyanates; with
(20) Bourdais, J.; Omar, A. M. M. E. J. Heterocycl. Chem. 1980,
17, 555.
(21) Novak, L.; Hanania, M.; Kovacs, P.; Kovacs, C. E.;
Kolonits, P.; Szantay, C. Synth. Commun. 1999, 29, 1757.
(22) Lange, J. H. M.; Verhoog, S.; Sanders, H. J.; Van Loevezijn,
A.; Kruse, C. G. Tetrahedron Lett. 2011, 52, 3198.
(23) Omar, A. M. M. E.; Eshba, N. H. J. Pharm. Sci. 1984, 73,
1166.
(24) Mohanta, P. K.; Dhar, S.; Samal, S. K.; Ila, H.; Junjappa, H.
Tetrahedron 2000, 56, 629.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3172–3179