A practical synthesis of carbamates using an 'in-situ' generated polymer-supported chloroformate

Article abstract of DOI:10.1016/j.tetlet.2004.07.124

A versatile method for the synthesis of carbamates from an 'in-situ' generated polymer-supported chloroformate resin is presented. BTC (bis-trichloromethyl carbonate) is used as phosgene equivalent to afford a supported chloroformate, which, by sequential 'one-pot' reaction with a variety of alcohols and amines, furnishes the corresponding carbamates in high yields and purities. A versatile method for the synthesis of carbamates from an 'in-situ' generated polymer-supported chloroformate resin is presented. BTC (bis-trichloromethyl carbonate) is used as phosgene equivalent to afford a supported chloroformate, which, by sequential 'one-pot' reaction with a variety of alcohols and amines, furnishes the corresponding carbamates in high yields and purities.

Full text of DOI:10.1016/j.tetlet.2004.07.124

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6831–6834
A practical synthesis of carbamates using an Ôin-situÕ
generated polymer-supported chloroformate
a,b
David Mormeneo, Amadeu Llebaria and Antonio Delgado
b
a,b,
*
a
Universidad de Barcelona, Facultad de Farmacia, Undad de Qu ı´ mica Farmac e´ utica (Unidad Asociada al CSIC),
Avda. Juan XXIII, s/n, 08028 Barcelona, Spain
b
Research Unit on Bioactive Molecules (RUBAM), Departament de Qu ı´ mica Org a` nica Biol o` gica, Institut dÕInvestigacions Qu ı´ miques i
Ambientals de Barcelona (IIQABC.S.I.C), Jordi Girona 18-26, 08034 Barcelona, Spain
Received 21 June 2004; revised 22 July 2004; accepted 27July 2004
Abstract—A versatile method for the synthesis of carbamates from an Ôin-situÕ generated polymer-supported chloroformate resin is
presented. BTC (bis-trichloromethyl carbonate) is used as phosgene equivalent to afford a supported chloroformate, which, by
sequential Ôone-potÕ reaction with a variety of alcohols and amines, furnishes the corresponding carbamates in high yields and
purities.
ꢀ
2004 Elsevier Ltd. All rights reserved.
Carbamate is a widespread functional group in organic
synthesis. In general, carbamates are found as protect-
ing groups for the amino function, especially in the
Since the number of commercially available chlorofor-
mates is rather limited and preparation of individual
chloroformates may be cumbersome, these results
prompted us to develop a more versatile procedure for
the generation of carbamates 3, based on the Ôin-situÕ
1
chemistry of peptides and peptidomimetics. Moreover,
carbamates also play an important role in drug design,
2
3
10
as hydrolytically resistant ester or phosphate surro-
gates. In this context, we are currently exploring the
development of combinatorial libraries of phospholipid
analogues in which the more robust carbamate group is
used as phosphodiester surrogate. Based on these pre-
mises, we wish to report on an efficient synthetic proto-
col for the solution-phase parallel synthesis of
carbamates by means of a polymer supported Ôin-situÕ
generation of a supported chloroformate (4) followed
by sequential reaction with the required alcohols and
amines. Among the commercially available safer phos-
gene equivalents, we found that reaction of resin 1 with
1
1,12
bis-trichloromethyl carbonate (BTC)
sequential treatment of the putative chloroformate 4
followed by
with excess (5equiv) isobutyl alcohol and benzylamine
afforded carbamate 3e in comparable yield to that found
4
,5
13,14
generated chloroformate.
in the above two-step procedure.
This method also
proved efficient for other amines, as indicated in Table 2.
In all cases, with the exception of the aniline derivative
shown in entry 9, the corresponding carbamates 3e–m
were obtained in good overall yields. Interestingly,
chloroformate 4 reacts chemoselectively with amino
alcohols, as shown in entries 5 and 6.
Our approach relies on the nitrophenol resin 1, easily
6
prepared from an inexpensive polystyrene-type resin,
7
,8
as described in the literature. To check the feasibility
of this strategy, we first reacted resin 1 with a series of
commercially available chloroformates to afford inter-
mediate carbonates 2a–d. Gratifyingly, carbamates 3a–e
were obtained in good isolated yields upon treatment
of the above carbonates with different amines, as shown
The intermediate chloroformate 4 was also challenged
against a series of alcohols (Table 3) and the intermedi-
ate carbonates 2a,e–i were next reacted with benzyl-
amine to afford the corresponding carbamates 3n–s in
good yields.
5
,9
in Table 1.
Keywords: Supported reagents; Solid phase; Carbamates; Phosgene
equivalent; Parallel synthesis.
*
Corresponding author. Tel.: +34 934 006 108; fax: +34 932 045 904;
e-mail addresses: adelgado@cid.csic.es; antonio.delgado@ub.edu
The method is straightforward, since excess alcohol and
coupling reagents can be removed by simple filtration of
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.124

6832
D. Mormeneo et al. / Tetrahedron Letters 45 (2004) 6831–6834
Table 1.
O
NO2
OH
OH
ClCOOR (4 equiv)
O
O
1 2
R R NH (5 equiv)
DMAP (0.25 equiv)
R1
OH
O
OR
N
R
OR
CHCl3, rt, 20 h
2
DIPEA (6 equiv)
CHCl3, rt, 20 h.
1
2a-d
3a-e
a
Yield (%)
Entry
1
Chloroformate
Carbonate
Amine
Carbamate
OCOCl
2a
NH2
3a
3b
95
97
H
N
2
OCOCl
2b
N
H
3
4
5
OCOCl
2c
2d
2d
3c
75
99
80
NH2
b
3d
HO
NH2
HO
NH2
3e
a
Isolated yields.
Reaction was run in THF due to low solubility of amino alcohol.
b
Table 2.
OH
5 equiv)
BTC (1.3 equiv)
pyr (7.5 equiv)
O
1 2
O
O
R R NH (5 equiv)
2
R1
(
OH
O
Cl
O
O
N
R
O
CH2Cl2
rt, 2h
pyr (7.5 equiv),
CH Cl , rt, 2.5 h
CHCl , rt, 20 h
2
3
1
4
2d
3e-m
2
2
a
Entry
1
Amine
Carbamate
Yield
NH2
3e
88
75
89
2
3
NH2
3f
3g
N
H
N
4
5
3h
3i
69
99
H
H N
2
OH
OH
6
7
3j
94
81
NH2
NH2
3k
N
H
8
9
3l
88
40
OCH3
3m
H N
2
a
1
Yields were calculated from the HNMR crude in the presence of dimethyl terephthalate as internal standard.
1
5
the resin, whereas excess amine can be efficiently
removed from the final product by aqueous acidic wash-
ings. In all cases, the resulting carbamates showed
homogeneous chromatographic (HPLC) and spectro-

D. Mormeneo et al. / Tetrahedron Letters 45 (2004) 6831–6834
6833
Table 3.
NH2
BTC (1.3 equiv)
pyr (7.5 equiv)
O
O
O
ROH (5 equiv)
pyr (7.5 equiv),
(5 equiv)
OH
N
H
OR
O
Cl
O
OR
CH2Cl2
rt, 2h
CH Cl , rt, 20 h
2 2
CH Cl , rt, 2.5 h
1
4
2
2
2a,e-i
2n-s
a
Entry
1
Alcohol
Carbonate
Carbamate
Yield
OH
2a
3n
53
56
OH
2
2e
3o
OH
3
4
2f
3p
3q
66
70
2g
OH
OH
5
2h
2i
3r
3s
76
98
6
OH
a
1
Yields were calculated from the H NMR crude in the presence of dimethyl terephthalate as internal standard.
1
13
scopic ( H and C NMR) patterns, and no further puri-
fication was required.
References and notes
1
2
. Greene, T. W.; Wuts, P. G. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley, New York, 1999.
. Anastasi, C.; Vlieghe, P.; Hantz, O.; Schorr, O.; Panne-
couque, C.; Witvrouw, M.; De Clercq, E.; Clayette, P.;
Dereuddre-Bosquet, N.; Dormont, D. Bioorg. Med. Chem.
Lett. 2003, 13, 2459–2463.
Finally, the intrinsic Ôcatch and releaseÕ nature of this
methodology allows the recovery of the resin at the
end of the process. Interestingly, exploratory assays with
reused resin 1 showed no substantial loss of efficiency on
the synthesis of carbamates 3g–j (Table 2).
3
. Taguchi, M.; Sugimoto, K.; Goda, K.-I.; Akama, T.;
Yamamoto, K.; Suzuki, T.; Tomishima, Y.; Nishiguchi,
M.; Arai, K.; Takahashi, K.; Kobori, T. Bioorg. Med.
Chem. Lett. 2003, 13, 1963–1966.
In summary, a simple and straightforward procedure for
the solution-phase synthesis of carbamates in high yields
and purities from a nitrophenyl derived polymer-sup-
ported chloroformate is reported. The supported rea-
gent can be easily prepared from an inexpensive
4. For a conceptually similar approach from a rather
expensive PS-thiophenol resin, see: Sumiyoshi, H.; Shi-
mizu, T.; Katoh, M.; Baba, Y.; Sodeoka, M. Org. Lett.
2002, 4, 3923–3926.
6
commercial PS resin. The method allows the easy re-
moval (or recycling, if required) of the excess alcohols
5
. For solid phase synthesis of carbamates, see: (a) Fernan-
dez-Forner, D.; Huerta, J. M.; Ferrer, M.; Casals, G.;
Ryder, H.; Giralt, E.; Albericio, F. Tetrahedron Lett. 2002,
1
5
and amines at the end of each cycle. In addition, the
nitrophenyl resin can be reused with no significant loss
of efficiency. This method is suitable for application in
combinatorial synthesis, taking into account the wide
repertoire of commercially available alcohols and
amines as building blocks.
4
3, 3543–3546; For solution phase synthesis of carba-
mates from supported carbonates, see: (b) Chinchilla, R.;
Dodsworth, D. J.; Najera, C.; Soriano, J. M. Tetrahedron
Lett. 2001, 42, 7579–7581; (c) Chinchilla, R.; Dodsworth,
D. J.; Najera, C.; Soriano, J. M. Bioorg. Med. Chem. Lett.
2
002, 12, 1817–1820, For the use of supported carbamates
as protecting groups of amines, see Ref. 10c, and also; (d)
Burdick, D. J.; Struble, M. E.; Burnier, J. P. Tetrahedron
Lett. 1993, 34, 2589–2592; (e) Gouilleux, L.; Fehrentz, J.
A.; Winternitz, F.; Martinez, J. Tetrahedron Lett. 1996, 39,
Acknowledgements
7
031–7034; (f) Dressman, B. A.; Spangle, L. A.; Kaldor, S.
Financial support from Ministerio de Ciencia y Tec-
nolog ´ı a, Spain (Project MCYT BQU2002-03737), Fund-
aci o´ n Ram o´ n Areces, and Generalitat de Catalunya
W. Tetrahedron Lett. 1996, 37, 937–940; (g) Salvatore, R.
N.; Chu, F.; Nagle, A. S.; Kapxhiu, E. A.; Cross, R. M.;
Jung, K. W. Tetrahedron 2002, 58, 3329–3347; (h) Cantel,
S.; Boeglin, D.; Rolland, M.; Martinez, J.; Fehrentz, J.-A.
Tetrahedron Lett. 2003, 44, 4797–4799.
(
Projects 2001SGR00342 and 2001SGR00085) is
acknowledged. D.M. is also acknowledged to Ministerio
de Educaci o´ n, Cultura y Deporte (Spain) for a predoc-
toral fellowship.
6. CombiGel XE-305, macroreticular polystyrene-DVB, 50–
100 mesh (Aldrich: 49,477-1).

6834
D. Mormeneo et al. / Tetrahedron Letters 45 (2004) 6831–6834
7
. The use of resin 1 as precursor of a series of supported 11. Cotarca, L.; Delogu, P.; Nardelli, A. Synthesis 1996,
acylating reagents has been reported: (a) Chang, Y. T.;
Choi, J.; Ding, S.; Prieschl, E. E.; Baumruker, T.; Lee, J.
M.; Chung, S. K.; Schultz, P. G. J. Am. Chem. Soc. 2002,
553–576.
12. Konakahara, T.; Ozaki, T.; Sato, K.; Gold, B. Synthesis
1993, 103–106.
124, 1856–1857; (b) Parlow, J. J.; Normasell, J. E. Mol.
Diversity 1995, 1, 266–269.
. Synthesis of resin 1: Cohen, B. J.; Karoly-Hafeli, H.;
Patchornik, A. J. Org. Chem. 1984, 49, 922–924.
. Synthesis of carbamate 3e is representative: An agitated
suspension of nitrophenol resin 1 (200mg, 0.75mmol/g) in
13. Initial experiments showed, in some cases, a nonnegligible
formation of the corresponding symmetrical ureas. We
have attributed this side reaction to the incomplete
formation of carbonates 2 from chloroformate 4, which
depends on the intrinsic reactivity of the alcohol used. In
agreement with this assumption, ureas were not observed
from the sequential reaction of resin 1 with chloroformates
and amines (Table 1), a process that does not imply the
formation of chloroformate 4. The use of DMAP as
catalyst for the synthesis of carbonates 2 from chlorofor-
mate 4 was crucial to avoid the formation of the urea
byproducts.
8
9
anh. CHCl
DMAP (4.5mg, 0.037mmol) in CHCl
3
(1.0mL) was treated with a solution of
(0.5mL) and neat
3
DIPEA (160lL). After 15min agitation, a solution of
isobutyl chloroformate (78lL, 0.6mmol) in CHCl3
(
1.5mL) was added and the reaction mixture was agitated
for 20h at room temperature. The resin was next filtered
and successively washed with CHCl
3
(3 · 2mL), DMF
14. Synthesis of carbamate 3e is representative: A suspension
of nitrophenol resin 1 (200mg, 0.75mmol/g) in HPLC-
(3 · 2mL) and CHCl (3 · 2mL). The resin was next taken
up in CHCl
3
3
(3mL) and a solution of benzylamine
2 2
grade CH Cl (1.0mL) was treated with dry pyridine
(
81.5lL, 0.75mmol) in CHCl
3
(1.5mL) was added. After
agitation for 20h at room temperature, the resin was
(85lL, 1.05mmol) and agitated at room temperature for
10min. A solution of bis-trichloromethyl carbonate (BTC,
60mg, 0.20mmol) in CH Cl (0.5mL) was next added and
filtered and washed with CHCl (3 · 2mL). The combined
filtrates were washed with aqueous 1N HCl (3 · 1.5mL),
dried, and evaporated to furnish carbamate 3e (24.8mg,
3
2
2
the reaction mixture was agitated for 2.5h, filtered, and
washed with CH Cl
(5 · 3mL). The resin was suspended
in CH Cl (1.0mL) and treated with pyridine (85lL,
2
2
1
8
0%); H NMR (300MHz, CDCl ) d 0.92 (d, 6H,
3
2
2
J = 6.6Hz, CH
J = 6.6Hz, CH
3
), 1.91 (m, 1H, CH), 3.88 (d, 2H,
O), 4.37(d, 2H, J = 6Hz, CH N), 5.06
1.05mmol), DMAP (5mg), and a solution of the corre-
sponding alcohol (5equiv/mol) in CH Cl (1.0mL). After
2
2
3
2
2
1
(
(
br, 1H, NH), 7.27–7.36 (m, 5H, CH arom); C NMR
75MHz, CDCl ) 19.1, 28.1, 45.1, 71.3, 127.5, 127.6,
agitation at room temperature for 2.5h, the resin was
filtered and washed with CH Cl (5 · 3mL). The resin was
3
2
2
1
1
28.7, 138.7, 157.0; IR (film) 3335, 2961, 1698, 1558, 1521,
248.
2 2
next suspended in CH Cl (1.0mL), treated with a solution
2 2
of the amine (5equiv/mol) in CH Cl (1.0mL) and
1
0. For the synthesis of a polymer-supported chloroformate
from reaction of a hydroxymethyl resin with phosgene,
see: (a) Burdick, D. J.; Struble, M. E.; Burnier, J. P.
Tetrahedron Lett. 1993, 34, 2589–2592; For the use of
other polymer-supported active carbonate resins, see: (b)
Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36,
agitated for 20h at room temperature. The resin was next
filtered and washed with CH Cl (5 · 3mL). The com-
2
2
bined filtrates were washed with aqueous 1N HCl
(3 · 1.5mL), dried, and evaporated to furnish carbamate
3e (27.3mg, 88%). For NMR data, see Ref. 9.
15. In a single case, carbamate 3a (Table 1) was obtained in
comparable yield by using only 1.1equiv of the corre-
sponding amine. However, the generality of this modifi-
cation has to be confirmed. Usually, excess reagents are
recommended for parallel synthesis protocols.
1589–1592; (c) Rotella, D. P. J. Am Chem. Soc. 1996, 118,
1996, 118, 12246–12247; (d) Alsina, J.; Chiva, C.; Ortiz,
M.; Rabanal, F.; Giralt, E.; Albericio, F. Tetrahedron
Lett. 1997, 38, 883–886.