Metal free oxidative coupling of aryl formamides with alcohols for the synthesis of carbamates

Article abstract of DOI:10.1039/c4ob00066h

A direct transformation of N-aryl formamides to the corresponding carbamates via the formation of isocyanate intermediates is achieved in good yields using hypervalent iodine as an oxidant. This journal is

Full text of DOI:10.1039/c4ob00066h

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Metal free oxidative coupling of aryl formamides
with alcohols for the synthesis of carbamates†
Cite this: Org. Biomol. Chem., 2014,
12, 2172
N. Veera Reddy, K. Rajendra Prasad, P. Sudhir Reddy, M. Lakshmi Kantam and
K. Rajender Reddy*
Received 9th January 2014,
Accepted 13th February 2014
DOI: 10.1039/c4ob00066h
www.rsc.org/obc
A direct transformation of N-aryl formamides to the corresponding
carbamates via the formation of isocyanate intermediates is
achieved in good yields using hypervalent iodine as an oxidant.
Scheme 1 Carbamate synthesis via isocyanate intermediate from
N-aryl formamides.
Organic carbamates are synthetically highly useful compounds
having widespread utility in areas such as pharmaceuticals,1
agrochemicals,2 and polymers3 and as valuable protecting
groups in peptide chemistry.4 Typically, carbamates are syn-
thesized by reacting suitable alcohols with isocyanates, which
in turn are prepared from phosgene.5 However, to overcome
the issues associated with phosgene chemistry, considerable
attention has been paid in the recent past to developing
efficient and safer methodologies for carbamate synthesis.6
As a result many methods have been made available for
their synthesis, including oxidative and reductive carbonyl-
ation of amines and nitroaromatics,7 the utilization of CO2,8
application of metal catalyzed cross couplings of isocyanate
anions and the various rearrangement reactions.9
In recent years oxidative couplings involving C–H bond acti-
vations have been recognized as useful strategies in synthetic
organic chemistry and the importance of these approaches
are well documented in several recent reviews.10 Though the
formamides are traditionally used as solvents and also as a
source of CO, Me2N, Me2NCO, and oxygen for various organic
transformations,11 the synthetic utility of these formamides in
coupling reactions under oxidative conditions was exploited
only in recent investigations. For example, it has been shown
that formamide can act as a source of amide or amine in ami-
dation reactions.12 Similarly, direct synthesis of α-ketoamides
was achieved from methyl ketones and dialkylformamides
using tert-butylhydroperoxide (TBHP) as an oxidant and
nBu4NI as a catalyst.13
Our group has been working on oxidative couplings using
metal and non-metal catalysts over the last couple of years.14
During these investigations, we have shown the direct coupling
of formamides with phenols and β-keto esters under oxidative
conditions.15 While the method allowed accessing the phenol
carbamates, the substrate scope was limited to 2-carbonyl sub-
stituted derivatives. Moreover use of formamide in large excess
as both solvent and reagent further limits the application of
this useful reaction. In order to expand the scope of the forma-
mides especially with aromatic formamides, we explored
the other possibilities. Since hypervalent iodine compounds
are extensively used for carbamate synthesis in Hofmann-type
rearrangements, where the isocyanate is the key intermedi-
ate,16 we have chosen these oxidants for the present
work. Moreover, we anticipated that a direct transformation of
formamides to isocyanates could be much more useful
for making carbamates (Scheme 1). Although the possibility
of direct conversion of N-arylformamides to corresponding
carbamates using lead(IV) acetate was reported by Leardini and
co-workers,17 to the best of our knowledge hypervalent iodine
reagents were not utilized for this direct transformation.
First, we have investigated the formation of carbamate
between N-phenyl formamide and n-butanol under different
reaction conditions, and results are summarized in Table 1.
The use of (diacetoxyiodo)benzene as an oxidant resulted in
a maximum yield of 25% in dichloroethane at an elevated
temperature (Table 1, entry 4). Inferior results are observed
when the reaction is carried out with other solvents
and copper catalysts (see other entries in Table 1). However, a
sharp rise in yield (82%) was observed when [bis(trifluoroace-
toxy)iodo]benzene was used as an oxidant (Table 1, entry 8).
Inorganic and Physical Chemistry Division, CSIR–Indian Institute of Chemical
Technology, Tarnaka, Hyderabad – 500 607, India. E-mail: rajender@iict.res.in,
rajenderkallu@yahoo.com; Fax: (+91) 040-27160921
†Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, 1H, 13C, IR and mass spectra. See DOI: 10.1039/
c4ob00066h
2172 | Org. Biomol. Chem., 2014, 12, 2172–2175
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 1 Optimization studies of N-aryl carbamate synthesis for the
reaction between N-phenyl formamide and n-butanola
Table 2 Direct synthesis of N-aryl carbamates (3) from N-aryl forma-
mides (1) and alcohols (2)a
Isolated
yield [%]
Entry
Oxidant
Solvent
Temp./°C
1
2
3
4
5
6
7
8
Phl(OAc)2
Phl(OAc)2
Phl(OAc)2
Phl(OAc)2
TBHP, Cu(OAc)2
H2O2, Cu(OAc)2
Phl(OCOCF3)2
Phl(OCOCF3)2
DCM
DCM
THF
DCE
DCE
DCE
DCE
DCE
rt
NR
15
NR
25
5
NR
40
82
40
60
60
60
60
rt
60
a Reaction conditions: N-phenyl formamide (1 mmol), n-butanol
(5 mmol), dichloroethane (3 mL, solvent), oxidant (1 mmol), 60 °C, MS
4 Å, N2, 1 h.
Moreover, a drop in yields is also observed when the reac-
tion is carried out either taking lower amounts of alcohols or
in the absence of molecular sieves. Performing the reactions
for longer reaction times does not improve the yield; in con-
trast we observed some decomposition of the product.
With these optimizations, we looked at the scope of the
reaction with different N-aryl formamides and alcohols
(Table 2).18 First we have screened with n-butanol with
different formamides and found that both electron donating
and withdrawing groups on the phenyl group work very well
for this reaction, providing the carbamate product in 65–82%
yield (Table 2, 3a–3e). However, a small decrease in yield was
observed for the electron withdrawing substrate with respect to
donating analogues. Similarly, substitution at ortho-position
with ethyl- and benzyl- groups on aryl formamide has little
influence on yields of the product (Table 2, 3f and 3g).
Further investigations were carried out with different alco-
hols and formamides, and results are shown in Table 2. Vari-
ation of alcohols viz. n-propanol, iso-propanol, iso-butanol,
tert-butanol and cyclo-pentanol provided the corresponding
carbamates in good yields (Table 2, 3h–3r). Then we looked at
other alcohols such as 2-methoxyethanol and 2-phenylethanol,
and invariably we observed moderate to good yields of the
desired carbamate products (Table 2, 3s–3x). Finally to expand
the scope of alcohols, formamides are treated with phenols
and benzyl alcohols. In the case of benzyl alcohols, a moderate
yield of the carbamate products (Table 2, 3y and 3z) are iso-
lated. On the other hand, no product was observed with
simple phenol.
Based on previously reported mechanistic studies of aryl
carbamates using lead(IV) acetate,17 we propose that the isocya-
nate formation is the key step in this reaction also (Scheme 1).
Further, isocyanate formation could also be possible from ami-
doiodane intermediates, which are proposed in Hofmann
rearrangement of amides using hypervalent iodine reagents
(see ESI† for mechanism).16b Moreover, GC-MS analysis of the
a Reaction conditions: N-arylformamide (1) (1 mmol), alcohol (2)
(5 mmol), dichloroethane (3 mL, solvent), oxidant (1 mmol), 60 °C, MS
4 Å, N2, 1 h.
reaction mixture in the absence of alcohols clearly reveals the
formation of isocyanate intermediates.
Conclusions
In summary, we have reported a mild and efficient procedure
for the synthesis of N-aryl carbamates by a direct transform-
ation of N-aryl formamides. Two important features: (i) accessi-
bility of the formamides from the commercially available
amines by various catalytic procedures and (ii) the direct trans-
formation of formamides to carbamates via isocyanate for-
mation, may provide the present reaction
a synthetic
advantage over Hofmann type rearrangements, where amides
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 2172–2175 | 2173

View Article Online
Communication
Organic & Biomolecular Chemistry
are often used. Moreover, isocyanate intermediate from forma-
mides can be readily utilized for various organic transform-
ations, which we are currently investigating in our laboratory.
and M. H. Baghersad, Adv. Synth. Catal., 2011, 353, 2599;
(c) X. Yang, Y. Zhang and D. Ma, Adv. Synth. Catal., 2012,
354, 2443.
10 For selected reviews on C–H bond functionalizations, see:
(a) K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069;
(b) S. I. Murahashi and D. Zhang, Chem. Soc. Rev., 2008, 37,
1490; (c) C. J. Li, Acc. Chem. Res., 2009, 42, 335;
(d) C. J. Scheuermann, Chem.–Asian J., 2010, 5, 436;
(e) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111,
1215; (f) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev.,
2011, 111, 1780; (g) M. Klussmann and D. Sureshkumar,
Synthesis, 2011, 353; (h) S. Y. Zhang, F. M. Zhang and
Y. Q. Tu, Chem. Soc. Rev., 2011, 40, 1937;
(i) A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew.
Chem., Int. Ed., 2011, 50, 11062; ( j) L. Shi and W. Xia,
Chem. Soc. Rev., 2012, 41, 7687; (k) C. Zhang, C. Tang and
N. Jiao, Chem. Soc. Rev., 2012, 41, 3464; (l) J. Yamaguchi,
A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012,
51, 8960; (m) Y. Xi, H. Yia and A. Lei, Org. Biomol. Chem.,
2013, 11, 2387.
Acknowledgements
N.V.R. and K.R.P. thank the Council of Scientific and Indus-
trial Research (CSIR) for the award of research fellowships.
K.R.R. thanks CSIR for financial support under network
project CSC-0123.
Notes and references
1 (a) S. Ray, S. R. Pathak and D. Chaturvedi, Drugs Future,
2005, 30, 161; (b) D. K. Hutchinson, Curr. Top. Med. Chem.,
2003, 3, 1021; (c) W. Li, J. Li, Y. Wu, J. Wu, R. Hotchandani,
K. Cunningham, I. McFadyen, J. Bard, P. Morgan,
F. Schlerman, X. Xu, S. Tam, S. J. Goldman, C. Williams,
J. Sypek and T. S. Mansour, J. Med. Chem., 2009, 52, 1799.
2 (a) T. T. Wu, J. Huang, N. D. Arrington and G. M. Dill,
11 J. Muzart, Tetrahedron, 2009, 65, 8313–8323, and references
therein.
J. Agric. Food Chem., 1987, 35, 817; (b) R. J. Kuhr 12 (a) Z. Liu, J. Chang, S. Chen, E. Shi, Y. Xu and X. Wan,
and H. W. Dorough, Carabamate Insecticides: Chemistry,
Biochemistry and Toxicology, CRS, Cleveland, OH, 1976;
(c) The Pesticide Manual, ed. C. Thomlin, British Crop
Protection Council Publications, Thornton Heath, UK,
10th edn, 1994.
3 (a) B. S. Lee, B. C. Chun, Y. C. Chung, K. I. Sul and
J. W. Cho, Macromolecules, 2001, 34, 6431; (b) P. Król, Prog.
Mater. Sci., 2007, 52, 915.
Angew. Chem., Int. Ed., 2012, 51, 3231; (b) K. Xu, Y. Hu,
S. Zhang, Z. Zha and Z. Wang, Chem.–Eur. J., 2012, 18,
9793; (c) T. He, H. Li, P. Li and L. Wang, Chem. Commun.,
2011, 47, 8946.
13 W. P. Mai, H. H. Wang, Z. C. Li, J. W. Yuan, Y. M. Xiao,
L. R. Yang, P. Mao and L. B. Yu, Chem. Commun., 2012, 48,
10117.
14 (a) R. A. Kumar, G. Saidulu, B. Sridhar, S. T. Liu and
K. R. Reddy, J. Org. Chem., 2013, 78, 10240; (b) P. S. Kumar,
G. S. Kumar, R. A. Kumar, N. V. Reddy and K. R. Reddy,
Eur. J. Org. Chem., 2013, 1218; (c) G. S. Kumar, R. A. Kumar,
P. S. Kumar, N. V. Reddy, K. V. Kumar, M. L. Kantam,
S. Prabhakar and K. R. Reddy, Chem. Commun., 2013, 49,
6686; (d) G. S. Kumar, B. Pieber, K. R. Reddy and
C. O. Kappe, Chem.–Eur. J., 2012, 18, 6124; (e) R. A. Kumar,
G. Saidulu, K. R. Prasad, G. S. Kumar, B. Sridhar and
K. R. Reddy, Adv. Synth. Catal., 2012, 354, 2985;
(f) R. A. Kumar, C. U. Maheswari, S. Ghantasala, C. Jyothi
and K. R. Reddy, Adv. Synth. Catal., 2011, 353, 401;
(g) C. U. Maheswari, G. S. Kumar, M. Venkateshwar,
R. A. Kumar, M. L. Kantam and K. R. Reddy, Adv. Synth.
Catal., 2010, 352, 341; (h) K. R. Reddy, M. Venkateshwar,
C. U. Maheswari and S. Prashanthi, Synth. Commun., 2009,
40, 186; (i) K. R. Reddy, C. U. Maheswari, M. Venkateshwar
and M. L. Kantam, Eur. J. Org. Chem., 2008, 3619.
4 (a) T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, Wiley, New York, 3rd edn, 1999,
pp. 503–550; (b) P. Adams and F. A. Baron, Chem. Rev.,
1965, 65, 567.
5 (a) H. Babad and A. G. Zeiler, Chem. Rev., 1973, 73, 75;
(b) D. Chaturvedi, N. Mishra and V. Mishra, Curr. Org.
Synth., 2007, 4, 308; (c) R. A. Batey, V. Santhakumar,
C. Y. Ishii and S. D. Taylor, Tetrahedron Lett., 1998, 39, 6267.
6 D. Chaturvedi, Tetrahedron, 2012, 68, 15–45 and references
therein.
7 (a) F. Shi and Y. Deng, Chem. Commun., 2001, 443;
(b) H. Alper and F. W. Hartstock, J. Chem. Soc., Chem.
Commun., 1985, 1141; (c) T. W. Leung and B. D. Dombek,
J. Chem. Soc., Chem. Commun., 1992, 205; (d) Y. Watanabe,
Y. Tsuji and R. Takeuchi, Bull. Chem. Soc. Jpn., 1984, 57,
3011; (e) F. Paul, Coord. Chem. Rev., 2000, 203, 269.
8 (a) D. B. Dell’ Amico, F. Calderazzo, L. Labella, F. Marchetti
and G. Pampaloni, Chem. Rev., 2003, 103, 3857; 15 G. S. Kumar, C. U. Maheswari, R. A. Kumar, M. L. Kantam
(b) M. Rohr, C. Geyer, R. Wandeler, M. S. Schneider, and K. R. Reddy, Angew. Chem., Int. Ed., 2011, 50, 11748.
E. F. Murphy and A. Baiker, Green Chem., 2001, 3, 123; 16 (a) N. Okamoto, Y. Miwa, H. Minami, K. Takeda and
(c) R. N. Salvatore, S. I. Shin, A. S. Nagle and K. W. Jung,
J. Org. Chem., 2001, 66, 1035; (d) P. Tascedda and
E. Dunach, Chem. Commun., 2000, 449.
R. Yanada, Angew. Chem., Int. Ed., 2009, 48, 9693;
(b) A. Yoshimura, M. W. Luedtke and V. V. Zhdankin,
J. Org. Chem., 2012, 77, 2087; (c) E. Hernandez, J. M. Velez
and C. P. Vlaar, Tetrahedron Lett., 2007, 48, 8972.
9 (a) E. V. Vinogradova, N. H. Park, B. P. Fors and
S. L. Buchwald, Org. Lett., 2013, 15, 1394; (b) E. Kianmehr 17 R. Leardini and G. Zanardi, Synthesis, 1982, 225.
2174 | Org. Biomol. Chem., 2014, 12, 2172–2175
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
18 General procedure for the synthesis of N-aryl carbamates:
in a reaction vessel 1 mmol of N-aryl formamide was dis-
solved in 3 mL of dichloroethane solvent, and slowly added
the [bis(trifluoroacetoxy)iodo]benzene (oxidant, 1 mmol) to
the solution with stirring over a period of 2 minutes in the
presence of molecular sieves (4 Å) under a nitrogen atmos-
phere. Then 5 mmol of alcohol was added to the above
reaction mixture and the temperature was increased to
60 °C and stirred for one hour. The reaction was monitored
by thin layer chromatography. After completion of the reac-
tion, the resulting solution was cooled to room tempera-
ture. The reaction mixture was then filtered through a
silica gel bed using ethyl acetate and the filtrate was con-
centrated under reduced pressure. The residue was purified
by column chromatography on silica gel using a petroleum
ether/ethyl acetate mixture used as an eluent to afford the
corresponding products. The products were confirmed by
1H, 13C NMR, IR and mass spectroscopic analysis. Butyl
phenylcarbamate: (compound 3a): (Isolated yield = 82%):
IR cm−1: 3372, 2940, 1725, 1532, 1297, 1078, 745, 632.
1H NMR δ (500 MHz, CDCl3): 7.38 (d, J = 7.6 Hz, 2H), 7.30
(t, J = 7.4 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 6.74 (br, 1H), 4.16
(t, J = 6.7 Hz, 2H), 1.67–1.61 (m, J = 7.1 Hz, 2H), 1.43–1.37
(m, J = 7.6 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR
δ (75 MHz, CDCl3): 153.7, 137.9, 128.9, 123.2, 118.5, 65.0,
30.8, 19.0, 13.6. MS (ESI): m/z = 216 (M + Na)+, HRMS: ESI
(M + H)+ m/z calcd for C11H16O2N (M + H)+ = 194.11810,
found = 194.11717.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 2172–2175 | 2175