An Efficient Direct Access to Carbamates from Alcohols and TosMIC Mediated by Iodine in DMSO

Article abstract of DOI:10.1055/s-0037-1610229

A new approach for the synthesis of carbamates from alcohols and TosMIC promoted by iodine/DMSO system is reported. This method offers a one-step, direct and practical strategy for the rapid construction of carbamates under mild conditions. The reaction proceeds via sequential oxidation of isocyanide to isocyanate and nucleophilic addition of alcohols to isocyanate to afford the carbamates in high yields.

Full text of DOI:10.1055/s-0037-1610229

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
N. Pogaku et al.
Letter
Synlett
An Efficient Direct Access to Carbamates from Alcohols and
TosMIC Mediated by Iodine in DMSO
Naresh Pogakua,b
Palakodety Radha Krishnaa
Y. Lakshmi Prapurna*a
H
I2 (0.6 equiv)
O
N
Ts
R
OH
N
C
R
DMSO, rt
Ts
TosMIC
O
R = alkyl, aryl,
heteroaryl, etc.
15–20 min
carbamates
37 examples
78–94% yield
a D-207, Discovery Laboratory, Organic and Biomolecular
Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, India,
.
Mild reaction conditions
.
.
Easily available starting materials
Shorter reaction times
CSIR-IICT communication number: IICT/Pubs./2018/234
b Academy of Scientific and Innovative Research (AcSIR),
New Delhi 110025, India
Received: 14.06.2018
Accepted: 10.07.2018
Published online: 02.08.2018
DOI: 10.1055/s-0037-1610229; Art ID: st-2018-v0364-l
Encouraged by this result, we investigated the reaction
of alcohols with TosMIC in the presence of iodine in DMSO
as reaction conditions. To our delight, the reaction under-
went smoothly at room temperature to furnish carbamates
in high yields.
The literature review reveals very few reports are
known for the direct synthesis of carbamates from isocya-
nides.13 The previous report by Ganem and co-workers for
the synthesis of carbamates employing TosMIC involves a
two-step process that requires low reaction temperature
conditions.14 Herein, we describe an efficient new strategy
to carbamates from alcohols and TosMIC promoted by
Abstract A new approach for the synthesis of carbamates from alco-
hols and TosMIC promoted by iodine/DMSO system is reported. This
method offers a one-step, direct and practical strategy for the rapid
construction of carbamates under mild conditions. The reaction pro-
ceeds via sequential oxidation of isocyanide to isocyanate and nucleo-
philic addition of alcohols to isocyanate to afford the carbamates in
high yields.
Key words alcohols, TosMIC, carbamate, iodine, DMSO, isocyanate
Carbamates are important functional groups with wide
applications in agricultural chemistry, medicinal chemistry,
and polyurethane synthesis.1,2 The classical approaches to
carbamates are condensation of aniline with phosgene and
its derivatives,3 and reaction of alcohol with isocyanates
generated in situ via Hofmann,4 Curtius,5 Lossen,6 and
Schmidt7 rearrangement reactions. However, these reac-
tions are limited by the high reactivity and toxicity of start-
ing materials and requirement of metal catalysts. Owing to
their significance, there is a continuous and strong interest
in the development of new efficient methods for the syn-
thesis of carbamates. Consequently, alternative routes to
carbamates employing CO2 as a C1 building block have been
established.8,9 Even though, the replacement of phosgene
with CO2 has emerged as a significant improvement, the re-
quirement of harsh reaction conditions due to thermody-
namic stability of CO2 is the major drawback associated
with these reports. Thus, the development of a general and
practical method for easy access to carbamates is highly de-
sirable.
Previous approaches
(a) Classical Method
O
R1X
· Hazardous reagent
· Stability Issues
R
R1
R
N C O
N
X
X = NH2 or OH
H
(b) Rousseaux (2018)9d
i) CO2 (balloon), DBU
H
NH2
ii) DMSO, TFAA, –60 °C
N
OR
R
R
iii) Et3N, then HOR
O
O
(c) Zhang (2017)13
Ar
(d) Ganem (2014)14
H2O (5 equiv)
Ag2O (50 mol%), O2 (balloon)
NC
R
OH
RO
NHAr
PhCl, 100 °C, 24–48 h
step 1
step 2
OH
DMSO (1.0 equiv)
TFAA (0.6 equiv)
R
O
C
TsCH2NHCO2R
Ts
NC
Ts
N
CH2Cl2,
heat, 16 h
–78 °C to rt
This work
OH
p-Toluenesulfonylmethyl isocyanide (TosMIC) is a multi-
purpose reagent and is renowned for its diversity in organic
synthesis.10 In continuation of our long-standing interest in
TosMIC chemistry,11 recently, we reported a iodine-cata-
lyzed synthesis of sulfones in which TosMIC was utilized as
a sulfonylating agent.12
H
I2
O
R
N
Ts
R
Ts
NC
DMSO, rt
15–20 min
O
Scheme 1 Previous work and our approach for the synthesis of carba-
mates
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
N. Pogaku et al.
Letter
Synlett
iodine in DMSO (Scheme 1). The major advantages of the
present method are readily available starting conditions,
operational simplicity, single-step process, and lesser reac-
tion times. Moreover, the mild reaction conditions make
the present reaction as a better substitute for CO2-based
methods for the synthesis of carbamates. The present work
led to a simple approach for the rapid and eco-friendly syn-
thesis of carbamates, for which most of the methods re-
quire harsh reaction conditions and longer reaction times.
We commenced our studies with methanol (1) and
TosMIC (2) promoted by iodine in DMSO (Table 1). Pleasing-
ly, the reaction provided the corresponding carbamates
within 20 min. Further, the optimum amount of iodine
loading was found to be 0.6 equiv. After extensive screening
of various solvents and catalysts the iodine/DMSO was
found to be a suitable choice of catalytic system to furnish
the desired carbamate in high yield. No product formation
was observed when the reactions were performed with
t-butyl and cyclohexyl isocyanides demonstrating the
unique reactivity of TosMIC.
yields. For example, the primary alcohols from methanol to
decanol (1a–g) provided the desired carbamate (3a–g) in
high yields. The substituted aliphatic alcohols with groups
like ethoxy, chloro, bromo, and phenyl groups (1h–k) were
compatible under the reaction conditions to generate 3h–k
in 78–93% yields. Further, the cyclohexanemethanol (1l)
took part in the reaction effectively to give the carbamate 3l
in 91% yield. The alkenyl and propargyl alcohols 1m–p were
feasible with the reaction conditions delivering the expect-
ed products 3m–p in 88–94% yields. The secondary alco-
hols, isopropyl alcohol 1q, cyclohexyl alcohol 1r, and men-
thol 1s reacted smoothly with TosMIC to furnish carba-
mates 3q–s in 92–94% yields. Notably, the tertiary alcohol,
H
I2
O
N
Ts
Ts
NC
R
OH
R
DMSO, rt
15–20 min
O
1
2
3a–k
O
O
O
R
R
O
N
Ts
O
N
Ts
H
H
O
N
Ts
With the optimal conditions established, a variety of
aliphatic alcohols were evaluated (Scheme 2). A wide range
of alcohols including 1°, 2°, and 3° alcohols, aryl and
heteroaryl alcohols were well tolerated under standard
conditions to give the corresponding carbamates in high
H
3a, R = CH3, 93%
3b, R = C2H5, 90%
3c, R = C4H9, 91%
3d, R = C7H15, 91%
3e, R = C8H17, 94%
3f, R = C9H19, 90%
3g, R = C10H21, 94%
3h, R = OC2H5, 88%
3i, R = Cl, 80%
3j, R = Br, 78%
3l, 91%
3k, R = Ph, 93%
O
O
O
Table 1 Optimization of Reaction Conditionsa
O
N
Ts
O
N
H
Ts
R
O
N
Ts
H
H
H
I2
3p, 91%
O
N
Ts
3m, R = H, 94%
3n, R = C3H7, 93%
3o, R = Ph, 88%
3q, 92%
Ts
NC
CH3 OH
CH3
DMSO, rt
15–20 min
O
O
1
2
3
O
O
O
O
N
Ts
H
Entry Isonitrile
Catalyst (equiv) Solvent
Time (h) Yield (%)b
N
Ts
O
N
H
Ts
3t, 82%
H
1
2
t-BuNC
c-C6H11NC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
TosMIC
I2 (1.0)
I2 (1.0)
I2(1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3OH
THF
24
24
0
0
3r, 94%
3s, 93%
O
O
3
0.3
93
93
93
80
0
O
N
Ts
4
I2(1.5)
0.3
0.3
0.3
H
O
N
Ts
H
R
5
I2(0.6)
R2
Ts
R1
3u, R = H, 92%
3v, R = CH3, 90%
3w, R = OMe, 89%
3x, R = OBn, 90%
3y, R = F, 91%
O
3af, R1 = CH3, R2 = H, 86%
3ag, R1 = Cl, R2 = H, 84%
3ah, R1 = Cl, R2 = Cl, 84%
6
I2(0.4)
O
N
7
NaI (0.6)
KI (0.6)
TBAI (0.6)
CuI (0.6)
NIS (0.6)
I2(0.6)
24
H
8
24
24
24
0
3z, R = Cl, 92%
3ad, R = OPh, 92%
3ae, R = CN, 85%
R
9
0
3aa, R = Br, 89%
3ab, R = NO2, 81%
3ac, R = Ph, 88%
10
11
12
13
14
15
16
0
O
0.3
76
0
O
N
Ts
H
O
24
24
24
O
3aj, 86%
O
N
Ts
I2(0.6)
trace
trace
46
0
O
N
Ts
H
H
O
I2(0.6)
CH3CN
DMF
3ak, 83%
3ai, 87%
I2(0.6)
0.3
24
Scheme 2 Synthesis of tosylmethyl carbamates from alcohols and
I2(0.6)
DMSO–H2O
TosMIC. a Reaction conditions: alcohol 1 (1.0 equiv), TosMIC (2, 1 equiv),
and I2 (0.6 equiv) in DMSO (2 mL) at room temperature for 15–20 min.
b Yields refer to isolated products purified by column chromatography.
a Reaction conditions: CH3OH (1, 1.0 equiv), TosMIC (2, 1.0 equiv), and
catalyst in solvent.
b Yields refer to isolated products purified by column chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
N. Pogaku et al.
Letter
Synlett
t-butanol 1t also proved to be a suitable reaction partner to
deliver the carbamate 3t in 82% yield, which often resulted
in products with less yields due to steric crowding. Various
aryl alcohols bearing substituents on the aromatic ring like
alkyl, alkoxy, benzyloxy, halo, nitro, and phenyl groups
(1u–aj) were compatible under standard conditions and
afforded the carbamates 3u–aj in 81–92% yields. Similarly,
the reaction of heteroaryl alcohol 1ak with TosMIC gave the
desired carbamate 3ak in 83% yield.
After successful evaluation of scope of the reaction, we
turned our attention toward the reaction mechanism. The
addition of TEMPO to the reaction of methanol and TosMIC
under the reaction conditions did not hamper the reaction,
thus ruling out the possibility of radical mechanism. The
plausible mechanism for the synthesis of carbamates is
shown in Scheme 3. Based on the literature reports, initially
the oxidation of TosMIC to p-toluenesulfonylmethyl isocya-
nide (TsCH2N=C=O) takes place via oxidation of isonitrile di-
halide formed in situ by DMSO.15 Next, the formation of
carbamates takes place by the nucleophilic addition of alco-
hol to the isocyanate.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610229.
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References and Notes
(1) (a) For a comprehensive review on organic carbamates, see:
Adams, P.; Baron, F. A. Chem. Rev. 1965, 65, 567. (b) Aresta, M.;
Quaranta, F. In Proceedings of the International Conference on
Carbon Dioxide Utilization, Bari, Italy, 1993; Department of
Chemistry, University of Bari: Bari, 1993, 63–77; and references
cited therein. (c) Babad, H.; Zeiler, A. G. Chem. Rev. 1973, 73, 75.
(d) Rossi, L. In Science of Synthesis: Houben-Weyl Method of
Molecular Transformation;
2005, 461–648. (e) Ghosh, A. K.; Brindisi, M. J. Med. Chem. 2015,
58, 2895.
1
V8o.
l
Knight, J. C., Ed.; Thieme: Stuttgart,
(2) For selected examples, see: (a) Feroci, M.; Orsini, M.; Rossi, L.;
Sotgiu, G.; Inesi, A. J. Org. Chem. 2007, 72, 200; and references
cited therein. (b) Vijay Kumar, S.; Ma, D. J. Org. Chem. 2018, 83,
2706.
(3) For selected examples, see: (a) Engels, H.-W.; Pirkl, H.-G.;
Albers, R.; Albach, R. W.; Krause, J.; Hoffmann, A.; Casselmann,
H.; Dormish, J. Angew. Chem. Int. Ed. 2013, 52, 9422. (b) Six, C.;
Richter, F. Isocyanates, Organic, In Ullmann’s Encyclopedia of
Industrial Chemistry; Wiley-VCH: Weinheim, 2003. (c) Storace,
L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.; Fortunak, J. M.;
Giangiordano, M.; Haley, J. J. Jr.; Kamholz, K.; Li, H.-Y.; Ma, P.;
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Waltermire, R. E.; Wood, C. C. Org. Process Res. Dev. 2002, 6, 54.
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W.; Huang, X. Org. Synth. 2002, 78, 234.
I
I
DMSO
I2
Ts
NC
Ts
N C
O
O
ROH
C
R
Ts
N
Ts
N
O
H
(5) (a) Smith, P. A. S. Org. React. 1946, 3, 337. (b) Lebel, H.; Leogane,
O. Org. Lett. 2006, 8, 5717.
carbamate
tosylmethyl isocyanate
(6) (a) Yale, H. L. Chem. Rev. 1943, 33, 209. (b) Dubé, P.; Nathel, N. F.;
Vetelino, M.; Couturier, M.; Aboussafy, C. L.; Pichette, S.;
Jorgensen, M. L.; Hardink, M. Org. Lett. 2009, 11, 5622.
(7) Wolff, H. Org. React. 1946, 3, 307.
Scheme 3 A plausible reaction pathway
In conclusion, a simple and practical strategy has been
developed for the synthesis of carbamates from alcohols
and TosMIC by using simple, cheap, and nontoxic I2/DMSO
as reaction medium.16 The new approach is applicable to a
variety of alcohols and offers a direct access to a broad
range of carbamates. The carbamates were isolated in good
to high yields and even the less reactive tertiary alcohols
performed well under the reaction conditions. The mild re-
action conditions and easily available starting materials
make the reaction attractive for easy and rapid synthesis of
carbamates and valuable addition to TosMIC chemistry.
(8) (a) Yuan, G.; Qi, C.; Wu, W.; Jiang, H. Curr. Opin. Green Sustain.
Chem. 2017, 3, 22. (b) Liu, Q.; Wu, L.; Jackstell, R.; Beller, M. Nat.
Commun. 2015, 6, 5933. (c) Yang, Z.-Z.; He, L.-N.; Gao, J.; Liu, A.-
H.; Yu, B. Energy Environ. Sci. 2012, 5, 6602. (d) Quaranta, E.;
Aresta, M. The Chemistry of N–CO2 Bonds: Synthesis of Carbamic
Acids and their Derivatives, Isocyanates and Ureas, In Carbon
Dioxide as Chemical Feedstock; Aresta, M., Ed.; Wiley-VCH:
Weinheim, 2010, 121–167. (e) Dell’Amico, D. B.; Calderazzo, F.;
Labella, L.; Marchetti, F.; Pampaloni, G. Chem. Rev. 2003, 103,
3857.
(9) (a) Germain, N.; Müller, I.; Hanauer, M.; Paciello, R. A.;
Baumann, R.; Trapp, O.; Schaub, T. ChemSusChem 2016, 9, 1586.
(b) Heyn, R. H.; Jacobs, I.; Carr, R. H. CO2 Chemistry, In Advances
in Inorganic Chemistry;6V6o.
l
Aresta, M.; van Eldik, R., Eds.; Academic
Funding Information
Press: Boca Raton, FL, 2014, 83. (c) Shi, F.; Deng, Y.; SiMa, T.;
Peng, J.; Gu, Y.; Qiao, B. Angew. Chem. Int. Ed. 2003, 42, 3257.
(d) Ren, Y.; Rousseaux, S. A. L. J. Org. Chem. 2018, 83, 913.
(10) (a) Van Leusen, D.; Van Leusen, A. M. Org. React. 2001, 57, 417.
(b) Ramana Reddy, V. V. Synlett 2005, 363. (c) Kaur, T.; Wadhwa,
P.; Sharma, A. RSC Adv. 2011, 1, 100.
Dr. Y. Lakshmi Prapurna thanks Department of Science and Technology
(DST) for financial grant under Women Scientists Scheme-A (WOS-A),
Grant No. SR/WOS-A/CS-1034/2014 (G). The author N.P. acknowledg-
es UGC, New Delhi for fellowship support.
)(
(11) For selected examples, see: (a) Lingaswamy, K.; Mohan, D.;
Radha Krishna, P.; Lakshmi Prapurna, Y. Synlett 2016, 27, 1693.
(b) Lingaswamy, K.; Radha Krishna, P.; Lakshmi Prapurna, Y.
Synth. Commun. 2016, 46, 1275. (c) Lingaswamy, K.; Radha
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
N. Pogaku et al.
Letter
Synlett
Krishna, P.; Lakshmi Prapurna, Y. Adv. Synth. Catal. 2016, 358,
3863. (d) Naresh, P.; Radha Krishna, P.; Lakshmi Prapurna, Y.
Synth. Commun. 2017, 47, 1239.
aqueous Na2S2O3(2 × 20 mL) solution. Then the solution was
extracted with EtOAc (2 × 20 mL). The combined organic layers
were dried with anhydrous Na2SO4, and the solvent was
removed under reduced pressure. The resulting crude product
was purified by flash column chromatography on silica gel (elu-
ent: petroleum ether/ethyl acetate, 10:3) to afford 3a (0.22 g,
93% yield).
(12) Lingaswamy, K.; Radha Krishna, P.; Lakshmi Prapurna, Y. Org.
Lett. 2017, 19, 2580.
(13) Zhang, L.; Xiao, P.; Guan, X.; Huang, Z.; Zhang, J.; Bi, X. Org.
Biomol. Chem. 2017, 15, 1580.
(14) Le, H. V.; Ganem, B. Tetrahedron Lett. 2014, 55, 2003.
(15) Br2-DMSO: (a) Johnson, H. W. Jr.; Daughheter, P. H. Jr. J. Org.
Chem. 1964, 29, 246. Acid-DMSO: (b) Martin, D.; Weise, A.
Angew. Chem., Int. Ed. Engl. 1967, 6, 168.
(16) General Experimental Procedure (Scheme 2, 3a)
A mixture of alcohol 1 (0.032 g, 1.0 mmol), TosMIC (2, 0.19 g,
1.0 mmol), and iodine (0.15 g, 0.6 mmol) was stirred in DMSO
(2 mL) at room temperature for 15–20 min. After the reaction
was complete, the mixture was quenched with a cold saturated
Methyl (Tosylmethyl)carbamate (3a)
The general procedure was followed. White solid, mp 142–
144 °C. Yield 93% (0.22 g). 1H NMR (300 MHz, CDCl3): δ = 7.80
(d, J = 8.2 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 5.78 (s, 1 H), 4.56 (d,
J = 6.9 Hz, 2 H), 3.57 (s, 3 H), 2.45 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 155.7, 145.4, 133.7, 129.9, 128.9, 62.5, 52.9, 21.7.
ESI-MS: 266 [M + Na]+. HRMS: m/z calcd for C10H13O4NNaS [M +
Na]+: 266.0457; found: 266.0464.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D