A high yielding one-pot, novel synthesis of carbamate esters from alcohols using Mitsunobu's reagent

Article abstract of DOI:10.1016/j.tetlet.2003.08.018

A novel process for the one-step conversion of primary alcohols into carbamates as protected amines has been developed using Mitsunobu's reagent in the presence of gaseous carbon dioxide. Thus, carbamate esters of the different amines were prepared in very good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2003.08.018

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7637–7639
A high yielding one-pot, novel synthesis of carbamate esters
from alcohols using Mitsunobu’s reagentꢀ
Devdutt Chaturvedi, Atul Kumar and S. Ray*
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 9 July 2003; revised 25 July 2003; accepted 8 August 2003
Abstract—A novel process for the one-step conversion of primary alcohols into carbamates as protected amines has been
developed using Mitsunobu’s reagent in the presence of gaseous carbon dioxide. Thus, carbamate esters of the different amines
were prepared in very good to excellent yields.
© 2003 Elsevier Ltd. All rights reserved.
Organic carbamates, initially encountered largely as
agrochemicals1 and in peptide chemistry as protecting
groups2 or linkers in combinatorial synthesis3 are
rapidly emerging as pharmaceuticals4 mainly in the
form of prodrugs. To satisfy the demand, their synthe-
sis has changed from the use of harmful chemicals like
phosgene and its derivatives directly or indirectly, to the
use of chloroformates5 or isocyanates,6 to abundantly
available cheap and safe reagents like CO2. The prepa-
ration of carbamates using CO2 has been reported
electrochemically,7 supercritically,8 in combination with
metals and non metal species,9 macrocyclic
polyethers,10 and various phase transfer catalysts.11 Uti-
lization of sterically hindered strong bases or cesium
carbonate has been proposed to enhance the reactivity
of carbamate anions towards O-alkylation.12 Recently
we have reported13 an efficient, high yielding, one-pot
carbamate ester synthesis from alcoholic tosylates using
carbon dioxide and tetra-n-butylammonium iodide.
report as a guide, we attempted16 the synthesis of
carbamates by mild carboxylation of alkyl amines with
CO2 and an alcohol in the presence of Mitsunobu’s
reagent.
We assumed that the unstable carbamic acid generated
from alkylamine and CO2 would react with the Mit-
sunobu complex formed from Ph3P and diethyl azodi-
carboxylate, to furnish the stabilized ionic species which
in turn would undergo O-alkylation giving rise to the
formation of carbamate esters as shown in Scheme 1.
Thus, the alkylamine was taken in a suitable solvent
and a stream of CO2 was rapidly passed through it for
its conversion to substituted carbamic acid. The Mit-
We report here the synthesis of N-alkyl carbamates in
good to excellent yields, by mild carboxylation of alkyl-
amines with CO2 followed by O-alkylation with an
alcohol in the presence of Mitsunobu’s reagent (i.e.
diethyl azodicarboxylate and triphenylphosphine). The
use of Mitsunobu’s reagent in ether formation is well
known.14 Its use for the synthesis of carbonate esters
has also been reported by Hoffmann.15 Taking this last
Keywords: diethyl azodicarboxylate (DEAD); triphenylphosphine;
Mitsunobu’s reagent; carbon dioxide; N-alkylcarbamates.
ꢀ CDRI Communication No. 6398.
* Corresponding author. Tel.: +91-522-2212411-18, extn 4334; fax:
Scheme 1. Proposed mechanism of formation of carbamate
+91-522-2223405,
2223938;
e-mail:
ddccdri@yahoo.co.in;
atulcdri@yahoo.com; suprabhatray@yahoo.co.in
ester.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.018

7638
D. Chatur6edi et al. / Tetrahedron Letters 44 (2003) 7637–7639
Table 1. Conversion of the primary alcohols into carbamates of general formula I
Entry no.
R
R1
R2
n
Time (h)
Yields (%)
1
2
3
4
5
6
7
8
Phenyl
Phenyl
Phenyl
Phenyl
n-Octyl
n-Hexyl
n-Butyl
n-Propyl
i-Propyl
n-Propyl
Ethyl
n-C4H9
n-C6H13
n-C3H7
H
H
n-C3H7
n-C3H7
H
H
H
H
H
H
H
H
1
2
1
2
3
1
1
2
2.5
2
3
3
2
2.5
2.5
3
1
1
90
95
81
85
98
92
89
90
92
90
86
96
n-C3H7
n-C6H13
3-Methoxybenzyl
n-Butyl
Cyclohexyl
n-Hexyl
i-Amyl
n-Hexyl
Cyclohexyl
9
2.5
2.5
3
10
11
12
1
1
2-Naphthyloxy
3
All the products were characterized by IR, NMR, and mass spectral data.
Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1998, 39,
7404–7410.
4. (a) Sasse, A.; Stark, H.; Ligneau, X.; Elz, S.; Reidemeis-
ter, S.; Ganellin, C. R.; Schwartz, J. C.; Schunack, W.
Bioorg. Med. Chem. 2000, 8, 1139–1149; (b) Karki, R. G.;
Kulkarni, V. M. Bioorg. Med. Chem. 2001, 9, 3153–3160;
(c) Yu, D.; Huiyuan, G. Bioorg. Med. Chem. Lett. 2002,
12, 857–859.
Scheme 2. Reagents and conditions: (a) dry DMSO, DEAD/
Ph3P, CO2 bubbling, 90–100°C.
5. Satchell, D. P. N.; Satchell, R. S. Chem. Soc. Rev. 1975,
4, 231–250.
6. Raucher, S.; Jones, D. S. Synth. Commun. 1985, 15,
1025–1031.
7. (a) Casedei, M. A.; Inesi, A.; Moracci, F. M.; Rossi, L.
Chem. Commun. 1996, 2575–2576; (b) Casadei, M. A.;
Moracci, F. M.; Zappia, G.; Inesi, A.; Rossi, L. J. Org.
Chem. 1997, 62, 6754–6759; (c) Feroci, M.; Inesi, A.;
Rossi, L. Tetrahedron Lett. 2000, 41, 963–966.
8. Yoshida, M. A.; Hara, N.; Okuyama, S. Chem. Commun.
2000, 2, 151–152.
sunobu’s reagent generated from triphenylphosphine
and diethyl azodicarboxylate in dry dimethylsulfoxide
(DMSO) was then added to it followed by addition of
the alcohol.
The carbamate esters thus prepared from aliphatic
amines are given in Table 1. We tried several solvents
like n-heptane, n-hexane, DMSO, dimethylformamide
and hexamethylphosphoric triamide of which dry
DMSO proved to be the most suitable, in a tempera-
ture range of 90–100°C. The overall reaction is shown
in Scheme 2.
9. Mahe, R.; Sasaki, Y.; Bruneau, C.; Dixneuf, P. H. J. Org.
Chem. 1989, 54, 1518.
10. Aresta, M.; Quaranta, E. Tetrahedron 1992, 48, 1515–
1530.
11. (a) Inesi, A.; Muccinate, V.; Rossi, L. J. Org. Chem.
1998, 63, 1337–1338; (b) Salvatore, R. N.; Shin, S. I.;
Nagle, A. S.; Jung, K. W. J. Org. Chem. 2001, 66,
1035–1037.
Acknowledgements
One of the authors (D.C.) thanks the CSIR New Delhi
for financial support in the form of Senior Research
Fellowship.
12. Salvatore, R. N.; Ledger, J. A.; Jung, K. W. Tetrahedron
Lett. 2001, 42, 6023–6025.
13. Chaturvedi, D.; Kumar, A.; Ray, S. Synth. Commun.
2002, 32, 2651–2655.
14. Mitsunobu, O. Synthesis 1981, 1–28.
References
15. Hoffmann, W. A. J. Org. Chem. 1982, 47, 5209–5210.
16. Typical experimental procedure: 2-phenylethyl n-butyl
carbamate.
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602; (b) Mateen, A.; Chapalamadugu, S.; Kashar, B.;
Bathi, A. R.; Chaudry, G. R. Biol. Degrad. Biorem.
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2. (a) Kocienski, P. J. Protecting Groups; Thieme Verlag:
Stuttgart, 1994; (b) Greene, T. W.; Wuts, P. G. M.
Protecting Groups in Organic Synthesis, 3rd ed.; John
Wiley and Sons: New York, 1999; pp. 503–550.
n-Butylamine (0.83 ml, 9 mmol) in dry DMSO (60 ml)
was reacted with dried CO2 gas rapidly bubbled into it at
90°C for 0.5 h. To the reaction mixture triphenylphos-
phine (2.2 g, 9 mmol) was added and then diethyl azodi-
carboxylate (1.33 ml, 9 mmol) was added slowly in 2–3
small portions. Next, 2-phenylethyl alcohol (1 ml, 9
mmol) was added. The reaction was continued till com-
pletion (3.5 h). The reaction mixture was poured into
distilled water (80 ml) and extracted with ethyl acetate
thrice. The organic layer was separated and dried over
3. (a) Mayer, J. P.; Lewis, G. S.; Curtius, M. J.; Zhang, J.
Tetrahedron Lett. 1997, 38, 8445–8448; (b) Buchstaller,
H. P. Tetrahedron 1998, 54, 3465–3470; (c) Holte, P. T.;

D. Chatur6edi et al. / Tetrahedron Letters 44 (2003) 7637–7639
7639
anhydrous sodium sulfate, and then concentrated to
give 2-phenylethyl n-butyl carbamate. (1.68 g, 91%), as
an oil. IR (neat, cm−1): 1684 (O-CO-NH, carbamate
linkage), 1H NMR (CDCl3): l=0.89–0.96 (t, 3H, J=
6.5 Hz, CH3), 1.28–1.34 (m, 2H, CH2CH3), 1.54–1.59
(m, 2H, CH2CH2CH3), 2.83–2.88 (t, 2H, J=6.7 Hz,
PhCH2), 2.94–2.96 (m, 2H, O-CONHCH2), 4.40–4.45 (t,
2H, J=7 Hz, CH2-O-CO-NH), 7.08–7.21 (m, 5H, Ar-H
of phenyl ring), 7.7 (bs, 1H, NH6 ). Mass: m/z 221
(91%). Analysis: C13H19NO2, calcd: C, 70.56%; H,
8.65%; N, 6.33%; obsd: C, 70.89%; H, 8.18%; N,
6.14%.