Iodide-Catalyzed Synthesis of Secondary Thiocarbamates from Isocyanides and Thiosulfonates

Article abstract of DOI:10.1021/acs.orglett.6b01023

A new method for the synthesis of secondary thiocarbamates from readily available isocyanides and thiosulfonates with broad functional group tolerance is reported. The reaction proceeds under mild reaction conditions in isopropanol and is catalyzed by inexpensive sodium iodide.

Full text of DOI:10.1021/acs.orglett.6b01023

Letter
pubs.acs.org/OrgLett
Iodide-Catalyzed Synthesis of Secondary Thiocarbamates from
Isocyanides and Thiosulfonates
Pieter Mampuys,† Yanping Zhu,† Sergey Sergeyev,† Eelco Ruijter,*,‡ Romano V. A. Orru,‡
Sabine Van Doorslaer,§ and Bert U. W. Maes*,†
†Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium
‡Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute for Molecules, Medicines and Systems (AIMMS),
VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
§Biophysics and Biomedical Physics (BIMEF), Department of Physics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp,
Belgium
S
* Supporting Information
ABSTRACT: A new method for the synthesis of secondary
thiocarbamates from readily available isocyanides and thiosul-
fonates with broad functional group tolerance is reported. The
reaction proceeds under mild reaction conditions in
isopropanol and is catalyzed by inexpensive sodium iodide.
hiocarbamates constitute an important class of biologically
active compounds with various applications, including their
secondary thiocarbamates with a broad scope.11 In continuation
of our interest in isocyanide chemistry,12 and based on our
previously reported method for isothiourea synthesis,12d we
envisioned that thiocarbamates could be synthesized by reaction
of isocyanides with thiosulfonates,13 two compound classes
which generally show low to moderate toxicity (Scheme 2).14
T
use as herbicides (Thiobencarb, Orbencarb, and Molinate),
pesticides, antifertility agents, and antivirals.1 Secondary
thiocarbamates are hitherto far less explored than the tertiary
ones. Among the classical approaches toward secondary
thiocarbamates, the two-step reaction of phosgene with a
primary amine and a thiol (or the reverse) (Scheme 1, route 1)
Scheme 2. New Approach toward Secondary Thiocarbamates
Scheme 1. Classical Approaches toward Secondary
Thiocarbamates
Isocyanides have emerged as very useful C1 building blocks in
modern organic chemistry15 and are readily obtained commer-
cially or through synthesis, from the corresponding amine by
formylation and subsequent dehydration or via the Hofmann
isocyanide synthesis.16 Thiosulfonates can generally be synthe-
sized from the corresponding sodium sulfinates by sulfenylation
or from disulfides by selective oxidation.17 S-Methyl methane-
thiosulfonate and S-phenyl benzenethiosulfonate are commercial
reagents.
We started our optimization with the reaction of S-phenyl
benzenethiosulfonate (1a) and tert-butyl isocyanide (2a) to give
S-phenyl tert-butylthiocarbamate (3a) (section 3 Supporting
Information, SI). When we applied the reaction conditions of our
previously developed isothiourea synthesis (CuI catalyst, 75 °C,
2-MeTHF, 20 h, 4 Å MS) on the model system, only 28% of 3a
is the most commonly applied synthetic route.2,3 Other
phosgene derived C1-reagents such as di-tert-butyl dicarbonate4
and carbonyldiimidazole5 have also been used. Carbon
monoxide (CO) can be considered a promising replacement of
phosgene, as it allows the direct introduction of the C1-
fragment.6 Thiocarboxylation via the reaction of primary amine,
CO, and S8 via a Se-catalyzed,7 base- or solvent-mediated8
reaction yields a thiocarbamate salt which upon S-alkylation gives
the target compounds (route 2).9
In general, the reported routes toward secondary thiocarba-
mates share disadvantages such as the use of hazardous reagents
(CO, phosgene, isocyanate).10 Consequently, there is consid-
erable interest for efficient and mild methods to synthesize
Received: April 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01023
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
was obtained.12d Clearly, completely different reaction con-
ditions and a different reaction mechanism are required for
efficient thiocarbamate synthesis. The use of an alcohol as solvent
proved to be essential for efficient thiocarbamate formation
(Table 1, entries 2−5), with the corresponding alkyl
benzenethiosulfonate reagents (1). Weakly electron-withdraw-
ing (1b−c) and electron-donating (1d−i) substituents were
tolerated well, and the corresponding S-aryl tert-butylthio-
carbamates were obtained in high yield (3a−3i). While a
hydroxyl group is tolerated (3e), an amino group proved to be
incompatible (3g). However, carbamate or amide protection
delivered the corresponding thiocarbamates 3h and 3i in good to
excellent yields. Especially 3i is interesting, as it shows that ortho-
substitution is tolerated. Good yields were also observed with S-
aryl benzenethiosulfonates bearing strong electron-withdrawing
substituents such as a trifluoromethyl and alkoxycarbonyl group
(3j−l). Also in this case ortho-substitution in the thiosulfonate
reagent does not hamper the reaction. Only with extreme
functionalities as exemplified by a nitro group a lower yield was
obtained (3m−n). S-Alkyl benzenethiosulfonates (1o−s),
including challenging ones such as the cysteine derived 1r,
were well tolerated and gave the corresponding S-alkyl tert-
butylthiocarbamates in high yield (3o−s). S-Aryl/alkyl meth-
anethiosulfonates could also be used as coupling partners to give
the same thiocarbamates (3a, 3c−d, 3f, 3n, 3o, 3r). In this case,
the volatile byproduct isopropyl methanesulfinate (4b) is readily
removed in vacuo, greatly simplifying the workup. Simple
filtration over a silica plug is then sufficient to purify the
thiocarbamate. For certain thiocarbamates a higher yield was
obtained when the sodium methanethiosulfinate derived reagent
was used (3n and 3r). This offers one the choice between an easy
workup or the recovery of the isopropyl sulfinate byproduct and
its recycling by selecting respectively the methane- or the
benzenethiosulfonate reagent.
Next, the scope of the reaction with respect to the isocyanide
reagent was investigated with 1a as thiosulfonate (Scheme 4).
Besides 2a, other tertiary isocyanides were well tolerated, even
the bulky adamantyl isocyanide (5a−c). We were pleased to find
that our new protocol is also compatible with secondary and
primary isocyanides (5d−k). In addition, different functional
groups were tolerated in the isocyanide, such as ether (5k, 5n) or
ester (5b, 5i, 5j) groups. Notably, the reaction of methyl
isocyanoacetate (2i), featuring an acidic methylene functionality,
delivers the desired thiocarbamate in good yield (5i).
Unfortunately, when TosMIC (2l) was used, 5l was not formed.
Gratifyingly, our method tolerates aromatic isocyanides, which is
a
Table 1. Summary of Reaction Optimization
b
b
entry
solvent
catalyst
yield 3a (%)
yield 4a (%)
1
2
3
4
5
6
7
isopropanol
isopropanol
2-MeTHF
toluene
−
19
20
c
c
NaI
NaI
NaI
NaI
NaBr
NaCl
I2
93 (97)
93 (95)
12
0
0
0
1,4-dioxane
isopropanol
isopropanol
isopropanol
18
34
25
46
0
33
27
46
d
8
a
Reaction conditions: S-Phenyl benzenethiosulfonate (1a, 0.5 mmol),
tert-butyl isocyanide (2a, 0.6 mmol), catalyst (5 mol %), solvent (0.5
b
mL), 30 °C, 4 h, air. 1H NMR yield using 1,3,5-trimethoxybenzene as
c
d
internal standard. Isolated yield. I2 (2.5 mol %) was added to the
reaction.
benzenesulfinate as the byproduct (Scheme 2). As alkyl sulfinates
(4) can be transformed into sodium sulfinates by basic hydrolysis
(section 4 SI), the byproduct can be recycled into 1.
Interestingly, sodium iodide, an inexpensive inorganic salt used
as a nutrition additive, efficiently catalyzes the coupling between
1a and 2a while other sodium halide salts and I2 perform poorly
(Table 1, entries 1−2, 6−8). The transformation does not
require a transition metal catalyst and can be executed under air.
Moreover, a reaction temperature of 30 °C is sufficient to achieve
full conversion in 4 h affording 3a in 97% isolated yield. The
reaction was readily scaled to 10 mmol.
With the optimized conditions in hand [1a (1.0 mmol), 2a
(1.2 mmol), NaI (5 mol %), isopropanol (0.5 mL), 30 °C, 4 h,
air] we evaluated the scope of the reaction (Scheme 3). First, tert-
butylisocyanide (2a) was coupled with a variety of S-aryl
a
Scheme 3. S-Aryl/Alkyl Benzenethiosulfonate (1) Scope
a
Reaction conditions: S-Aryl/alkyl benzenethiosulfonate (1.0 mmol), tert-butyl isocyanide (2a, 1.2 mmol), NaI (5 mol %), isopropanol (0.5 mL), 30
b
c
d
e
f
°C, 4 h, air. S-Aryl/alkyl methanethiosulfonate (1.0 mmol), 40 °C, 6 h. 10 mmol scale. 50 °C, 15 h. 5 mmol scale. 27% of bis(2-
benzamidophenyl)disulfide was isolated. Up to 99% 4a.
g
B
DOI: 10.1021/acs.orglett.6b01023
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Isocyanide Scope
a
Reaction conditions: S-Phenyl benzenethiosulfonate (1a, 1.0 mmol), isocyanide (2, 1.2 mmol), NaI (5 mol %), isopropanol (0.5 mL), 30 °C, 4 h,
b
c
d
e
air. 15 h. S-Phenyl benzenethiosulfonate (1a, 1.0 mmol), diisocyanide (2, 0.5 mmol), NaI (10 mol %). 50 °C. Up to 90% 4a.
not self-evident because these compounds readily polymerize
(5m−o).15 Diisocyanides (2o−r) derived from industrially
important diamines (hexamethylenediamine, isophorone-
diamine, and 4,4′-diaminophenylmethane)18 used for polyur-
ethane synthesis were subsequently evaluated, and the desired
thiocarbamates were obtained in moderate to good yields (5p−
r). To illustrate the synthetic potential of our newly developed
transformation, S,S′-diphenyl hexane-1,6-diylbisthiocarbamate
(5p) was transformed in high yield into dialkyl hexane-1,6-
diylbiscarbamates (8a−b), which can be used for polyurethane
synthesis, by reaction with an alcohol using NEt3 as a base
(section 6, SI).18
Scheme 6. Proposed Mechanism for the Synthesis of 3a
Control reactions demonstrate that the choice of the
appropriate sulfenylating agent is essential for the thiocarbamate
synthesis as diphenyl disulfide 6a or thiophenol 7a does not lead
to the formation of 3a (Scheme 5). Performing the reaction in
Scheme 5. Control Experiments: Sulfenylating Agent
homolytic cleavage to yield the thiophenol radical C.20
Subsequently, C adds to isocyanide 2a furnishing radical E.
Reaction of E with benzenesulfinate radical D forms intermediate
F. Finally, alcoholysis of intermediate F with isopropanol
generates 3a and 4a. Intermediate D is formed via electron
transfer from benzene sulfinate A to the iodine radical, which is
plausible based on its low oxidation potential.21 Regeneration of
iodide justifies its role as a catalyst.
In conclusion, we have developed a novel, facile, and direct
approach toward secondary S-alkyl and S-aryl thiocarbamates
based on readily available isocyanides and thiosulfonates. The
reaction proceeds under very mild reaction conditions and uses
inexpensive NaI as a catalyst. Isopropanol is used both as a
reaction partner and as a green solvent.22 Our transition-metal-
free protocol shows a broad scope with respect to both
isocyanide and thiosulfonate reaction partners and is therefore
suitable for the synthesis of a broad range of secondary
thiocarbamates. Around 90% of the reaction products reported
in this study are hitherto unknown compounds, based on
Scifinder and Reaxys. In addition, the straightforward trans-
formation into industrially relevant carbamates illustrates the
synthetic potential of this new methodology.
dry isopropanol or under argon does not influence the yield, so
water and air could be excluded as the carbonyl oxygen source of
3a (Table S6). When NaI was replaced by PhSI (B),19 3a and 4a
were also obtained (Scheme S6) which suggests the involvement
of B in the reaction. In the presence of radical inhibitors
(TEMPO, Galvinoxyl, and BHT) low yields of 3a and 4a were
obtained pointing to a radical pathway (Table S6). Subsequently,
EPR experiments (section 5.3, SI) were executed on reactions
with DMPO added in order to trap short living radicals formed
during the reaction. This revealed the presence of a thiophenol
radical (C) and benzenesulfinate radical (D). Even when NaI was
omitted, D was still detected meaning that the background
reaction (Table 1, entry 1) is also radical in nature and does not
seem to involve a direct insertion reaction of isocyanide.13 Based
on these experiments, we propose a radical reaction mechanism
as outlined in Scheme 6. First, 1a reacts with sodium iodide
yielding benzenesulfinate (A) and PhSI (B). Then B undergoes
C
DOI: 10.1021/acs.orglett.6b01023
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) For selected synthetic methods towards tertiary thiocarbamates,
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I.; Hirashima, T. Tetrahedron 1993, 49, 2403. (c) Jacob, J.; Reynolds, K.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01023.
■
S
Optimization data, experimental procedures, character-
ization of new compounds and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(12) (a) Vlaar, T.; Cioc, R. C.; Mampuys, P.; Maes, B. U. W.; Orru, R.
V. A.; Ruijter, E. Angew. Chem., Int. Ed. 2012, 51, 13058. (b) Estevez, V.;
́
*E-mail: e.ruijter@vu.nl.
*E-mail: bert.maes@uantwerpen.be.
Notes
Van Baelen, G.; Lentferink, B. H.; Vlaar, T.; Janssen, E.; Maes, B. U. W.;
Orru, R. V. A.; Ruijter, E. ACS Catal. 2014, 4, 40. (c) Vlaar, T.;
Mampuys, P.; Helliwell, M.; Maes, B. U. W.; Orru, R. V. A.; Ruijter, E. J.
Org. Chem. 2013, 78, 6735. (d) Mampuys, P.; Zhu, Y.; Vlaar, T.; Ruijter,
E.; Orru, R. V. A.; Maes, B. U. W. Angew. Chem., Int. Ed. 2014, 53, 12849.
(13) Insertion of isocyanides into sulfenyl chlorides has been reported;
see: Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R.; Polo, C. Heterocycles
1990, 31, 1855. Based on their limited stability and high toxicity we did
not consider them as suitable reagents.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by the University of
Antwerp, the Research Foundation-Flanders (FWO) (PhD
fellowship to P.M.), the Hercules Foundation, and in part by The
Netherlands Organization for Scientific Research (NWO). The
research leading to these results has also received funding from
the Innovative Medicines Initiative (www.imi.europa.eu) Joint
Undertaking project CHEM21 under Grant Agreement No.
115360 (resources of which are composed of financial
contribution from the European Union’s Seventh Framework
Programme (FP7/2007-2013) and EFPIA companies’ in kind
contribution) and the European Union’s Horizon 2020 research
and innovation programme under the Marie Skłodowska-Curie
Grant Agreement 657883. We thank Heidi Seykens and Philippe
Franck (Univ. of Antwerp) for technical assistance.
(14) Health (H) rating of isocyanides (e.g., 2a: H = 2, 2h: H = 2, 2m: H
= 1) and thiosulfonates (e.g., 1a: H = 0, 1o: H = 1) shows low to
moderate toxicity; Scale from 0 (low) to 4 (high).
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D
DOI: 10.1021/acs.orglett.6b01023
Org. Lett. XXXX, XXX, XXX−XXX