Convenient method for the preparation of carbamates, carbonates, and thiocarbonates

Article abstract of DOI:10.1021/ol7024108

(Chemical Equation Presented) A convenient, rapid, and efficient method for the preparation of carbamates from amines with 1-alkoxycarbonyl-3-nitro-1,2,4- triazole transfer reagents is reported. Reactions of newly synthesized stable crystalline reagents with alkyl amines were completed in a few minutes without any additional base, and highly pure carbamates were obtained without chromatographic purification. These highly active reagents are also useful for the selective protection of nucleobases and preparation of carbonates and thiocarbonates.

Full text of DOI:10.1021/ol7024108

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5231-5234
Convenient Method for the Preparation
of Carbamates, Carbonates, and
Thiocarbonates
Mamoru Shimizu and Mikiko Sodeoka*
RIKEN (The Institute of Physical and Chemical Research), 2-1 Hirosawa,
Wako, 351-0198, Japan
sodeoka@riken.jp
Received October 3, 2007
ABSTRACT
A convenient, rapid, and efficient method for the preparation of carbamates from amines with 1-alkoxycarbonyl-3-nitro-1,2,4-triazole transfer
reagents is reported. Reactions of newly synthesized stable crystalline reagents with alkyl amines were completed in a few minutes without
any additional base, and highly pure carbamates were obtained without chromatographic purification. These highly active reagents are also
useful for the selective protection of nucleobases and preparation of carbonates and thiocarbonates.
Carbamates, carbonates, and thiocarbonates have been used
as protecting groups for amines, alcohols, and thiols,
respectively,1 and these functional groups are also found in
various pharmaceuticals and agrochemicals.2 Alkyl chloro-
formates are the most frequently used reagents for the
preparation of these functional groups. However, many
commonly used alkyl chloroformates are hazardous liquids
and are susceptible to thermolysis and hydrolysis, requiring
careful handling and storage. Furthermore, addition of base
and a long reaction time are usually necessary for completion
of the reaction. Although many other active carbonate-type
reagents, such as alkyl N-hydroxysuccinimidyl carbonates,
and alkyloxycarbonylammonium-type reagents, such as imi-
dazolium and tetrazolium salts,3 have been used for carbam-
ate formation, these reagents also have drawbacks in terms
of reactivity and difficulty of separation of the product from
the co-product. Selective protection of less reactive amines,
such as the amino groups of nucleobases, is problematic in
some cases. Thus, development of a more practical and
convenient method for such reactions is still desirable. Herein
we report novel 1-alkoxycarbonyl-3-nitro-1,2,4-triazole re-
agents which are useful for the preparation of carbamates,
carbonates, and thiocarbonates.
To achieve rapid and clean reaction, the nature of the
leaving group is important. It should have a highly electron-
withdrawing nature in order to increase the electrophilicity
of the carbonyl carbon, and the nucleophilicity should be
low to avoid side reactions. It should also be easily separable
from the product. With these requirements in mind, we
focused on 3-nitro-1,2,4-triazole (NT).4 Although NT shows
nucleophilicity, we anticipated that it could be easily
excluded from the reaction system because NT is almost
insoluble in CH2Cl2 or CHCl3. Sulfonyl NT5 and phospho-
nium NT6 derivatives are used as condensing reagents.
(1) Wuts, P. G. M.; Greene, T. W. Greene’s ProtectiVe Groups in
Organic Synthesis, 4th ed.; Wiley: New Jersey, 2007; pp 279-298, 416-
418, 684-686, 706-771 and references therein.
(2) (a) Wu, T.; Huang, J.; Arrington, N. D.; Dill, G. M. J. Agric. Food
Chem. 1987, 35, 817-823. (b) Kato, T.; Suzuki, K.; Takahashi, J.;
Kamoshita, K. J. Pesticide Sci. 1984, 9, 489-495.
(4) (a) Katritsky, A. R., Ed. Physical Methods in Heterocyclic Chemistry;
Academic Press: New York, 1963; Vol. 1. (b) Brown, E. J. Aust. J. Chem.
1969, 22, 2251-2254.
(3) (a) Vilkas, E. Bull. Chem. Soc. Fr. 1978, 11-37. (b) Watkins, B. E.;
Rapoport, H. J. Org. Chem. 1982, 47, 4471-4477.
10.1021/ol7024108 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/15/2007

However, to our knowledge, there is no report on the use
of carbonyl NT reagents for alkoxycarbonyl transfer reac-
tions.
First, we examined the synthesis of 1-benzyloxy-
carbonyl-3-nitro-1,2,4-triazole (1a, Z-NT). Reaction of
benzyl chloroformate (Z-Cl) with the sodium salt of NT
in THF proceeded smoothly. Pure Z-NT was obtained as
pale yellow prisms by simple filtration and subsequent
recrystallization in 95% yield (Table 1, entry 1). The struc-
50%, probably due to the formation of nonreactive
(R)-1-phenylethylamine hydrochloride. Reaction of Z-OSu
with 2 was also initially rapid at the beginning (5 min,
83% yield) but then slowed down (30 min, 87%; 1 h, 91%;
15.5 h, 97%), and a long reaction time was needed
for completion. In contrast, reaction of 1a reached com-
pletion in less than 5 min, and concurrent precipitation of
NT was observed, suggesting that 1a has sufficient
electrophilicity, and precipitation of NT appeared to drive
the reaction efficiently to completion as we had
hoped. Furthermore, the insoluble NT was easily removed
by simple filtration, and 7a with >99% purity was ob-
tained in quantitative yield without any further purifi-
cation.
Table 1. Synthesis of 1a-d
With this promising result in hand, NT reagents based on
other useful protecting groups, Troc-NT (1b), Fmoc-NT (1c),
and Teoc-NT (1d), were similarly synthesized from the
corresponding chloroformates (Table 1, entries 2-4).7,8 The
products 1b-d were obtained in excellent yields as crystal-
line solids.9
entry
R
product
yield (%)
1
2
3
4
benzyl
1a: Z-NT
95
92
95
96
2,2,2-trichloroethyl
9-fluorenylmethyl
2-(trimethylsilyl)ethyl
1b: Troc-NT
1c: Fmoc-NT
1d: Teoc-NT
Reactions of these NT reagents 1a-d with primary and
secondary amines and amino alcohols are summarized
in Table 2. The reactions of the amines 2-6 with 1 equiv
of 1a-d in CH2Cl2 proceeded quickly to give the corre-
sponding carbamates in >95% yield.10 The purity of
the reaction products was determined by 1H and 13C
NMR analyses.11 In many cases, highly pure (>99%)
carbamates were isolated by simple filtration and evapor-
ture of Z-NT was confirmed by X-ray crystallographic
analysis (Figure 1). Crystalline Z-NT is nonhygroscopic and
(5) (a) Jones, S. S.; Rayner, B.; Reese, C. B.; Ubasawa, A.; Ubasawa,
M. Tetrahedron 1980, 36, 3075-3085. (b) Ivanova, E. M.; Khalimskaya,
L. M.; Romanenko, V. P.; Zarytova, V. F. Tetrahedron Lett. 1982, 23,
5447-5450. (c) Chandrasegaran, S.; Murakami, A.; Kan, L. J. Org. Chem.
1984, 49, 4951-4957.
(6) (a) Shimizu, M.; Wada, T.; Oka, N.; Saigo, K. J. Org. Chem. 2004,
69, 5261-5268. (b) Oka, N.; Shimizu, M.; Saigo, K.; Wada, T. Tetrahedron
2006, 62, 3667-3673.
(7) Hamley, P. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, UK, 1995; pp 4107-4110 and
references therein.
Figure 1. X-ray structure of 1a.
(8) Sekine, M.; Tobe, M.; Nagayama, T.; Wada, T. Lett. Org. Chem.
2004, 1, 179-182.
(9) For X-ray crystallographic structures of 1b and 1d, see Supporting
Information.
(10) Reactions in CH3CN or THF were also investigated. Though NT
did not precipitate, 2 was smoothly reacted with 1a and obtained 7a in
96% yield (CH3CN, 15 min) and 94% yield (THF, 15 min) after washing
with 5% NaHCO3.
thermally stable, and it was stored at 4 °C for more than 2
years without any problem.
Next, to compare the reactivity of 1a with that of the
known reagents, benzyl chloroformate (Z-Cl) and benzyl
succinimidyl carbonate (Z-OSu), (R)-1-phenylethylamine
(2) (1 equiv) was allowed to react with Z-Cl, Z-OSu, or
1a in CDCl3 at room temperature (Scheme 1), with 1H NMR
(11) See Supporting Information.
(12) The compounds 1a and 1b were almost insoluble to MeOH at rt in
the absence of base, but methyl carbonate formations were observed at
elevated temperature.
(13) Iyer, R. P. In Current Protocols in Nucleic Acid Chemistry;
Beaucage, S. L., Bergstrom, D. E., Glick, G. D., Jones, R. A., Eds.; John
Wiley & Sons Inc.; New York, 2000; Vol. 1, pp 2.1.1-2.1.17.
(14) Wada, T.; Ohkubo, A.; Mochizuki, A.; Sekine, M. Tetrahedron Lett.
2001, 42, 1069-1072.
Scheme 1. Reaction of 2 with Z-NT, Z-Cl, and Z-OSu
(15) (a) Hayakawa, Y.; Kato, H.; Uchiyama, M.; Kajino, H.; Noyori, R.
J. Org. Chem. 1986, 51, 2400-2402. (b) Sakakura, A.; Hayakawa, Y.;
Harada, H.; Hirose, M.; Noyori, R. Tetrahedron Lett. 1999, 40, 4359-
4362.
(16) Zhou, X. X.; Ugi, I.; Chattopadhyaya, J. Acta Chem. Scand. 1985,
B39, 761-765.
(17) Schneiderwind, R. G. K.; Ugi, I. Z. Naturforsch., B: Chem. Sci.
1981, 36B, 1173-1175.
(18) (a) Dreef-Tromp, C. M.; Hoogerhout, P.; van der Marel,
G. A.; van Boom, J. H. Tetrahedron Lett. 1990, 31, 427-430.
(b) Dreef-Tromp, C. M.; van Dam, E. M. A.; van den Elst, H.;
van der Marel, G. A.; van Boom, J. H. Nucleic Acids Res. 1990, 18, 6491-
6495.
monitoring. The reaction with Z-Cl was rapid initially (<5
min) but stopped when the yield of 7a reached approximately
5232
Org. Lett., Vol. 9, No. 25, 2007

amine 6 were slower than those of the other amines, the
carbamates 11a-d were obtained in excellent yield.
Table 2. Synthesis of Carbamates Using Various Amines
Next, the reactions of aromatic amines were also inves-
tigated (Table 3). In contrast to aliphatic amines, aromatic
Table 3. Reactions of 1a-d with Aromatic Amines
1
additive
(equiv)
yield
(%)
entry (equiv)
R1
time
product
1
1a (2)
1b (1)
1c (2)
1d (2)
1b (2)
H
15 min Et3N (5) 12a
15 min Et3N (2) 12b
87
97
68
94
83
2a
3
H
H
H
24 h
60 min Et3N (5) 12d
13b
12c
4
5
PhS 20 h
a Washing with 5% NaHCO3 is sufficient purification.
amines were less reactive, and the reaction did not go to
completion under the conditions described above. However,
the addition of Et3N was found to be effective to promote
the reactions. With 2 equiv of 1a or 1d in the presence of
Et3N (5 equiv), the reactions were completed within 15 min,
and the carbamates 12a and 12d were obtained in excellent
yield after chromatographic purification (entries 1 and 4).
In the case of the reaction with Troc-NT, 1 equiv of 1b and
Et3N (2 equiv) was sufficient, and highly pure 12b was
obtained by simple extraction with 5% NaHCO3 (entry 2).
Reaction with the Fmoc-NT (1c) in the presence of Et3N
was found to be problematic because the Fmoc group can
be decomposed under basic conditions. The reaction of
aniline with 1c in the absence of base was slow, and the
yield of 12c was only 68% even after 24 h (entry 3).
a Method A: yield after filtration.11 Method B: yield after washing with
5% NaHCO3.11 Method C: in CH2Cl2/5% NaHCO3 (1:1), yield after
separation.11 b Containing a small amount of NT (<10%).11 c Reaction
time: 30 min.
Protection of the exocyclic amino group of nucleobases
is very important for the efficient synthesis of oligonucle-
otides and many other biologically important nucleic acid
derivatives. Carbamates are attractive protecting groups for
nucleobases, but protection using chloroformates is trouble-
some in some cases, and many reagents for the introduction
of carbamate protecting groups into nucleobases have been
actively investigated to overcome this problem.3,13 The choice
of appropriate protecting groups is sometimes crucial to
successful synthesis of oligonucleotides. Protecting groups
which can be cleaved under neutral conditions should be
useful for the synthesis of various base-sensitive oligonucle-
otide derivatives.14-18 Among them, fluoride ion labile
protecting groups such as 2-(trimethylsilyl)ethoxycarbonyl
(Teoc)19 are expected to be particularly useful. As far as we
know, however, introduction of the Teoc group at 2-NH2 of
ation of the solvent (method A). In some cases, a
small amount of NT (<10%) contaminated the filtrate and
decreased the purity of the carbamate. For such cases,
aqueous workup with 5% NaHCO3 was effective (method
B), affording highly pure (>99%) carbamates without
column chromatographic purification. The recovered NT was
also highly pure and could be recycled. In the case of entries
4 and 16, the reaction did not go to completion and only
about 80% yield of the carbamate was obtained even after a
prolonged reaction time. In these cases, a biphasic system
(CH2Cl2/5% NaHCO3 (1:1)) was effective (method C), and
the reaction was completed within 5 min. Simple phase
separation and evaporation afforded highly pure (>99%)
carbamates. It is also noteworthy that the reaction of the
amino alcohols proceeded without problem, and no carbonate
formation or cyclic carbamate formation was observed in
any case (entries 13-20).12 Even though an excess amount
of 1 (5 equiv) was used, no carbonate was formed under
these conditions. Although the reactions of the propanol
(19) (a) Kozyukov, V. P.; Sheludyakov, V. D.; Mironov, V. F. J. Gen.
Chem. USSR 1968, 38, 1133-1138. (b) Carpino, L. A.; Tsao, J.-H.;
Ringsdorf, H.; Fell, E.; Hettrich, G. Chem. Commun. 1978, 358-359. (c)
Campbell, A. L.; Pilipauskas, D. R.; Khanna, I. K.; Rhodes, R. A.
Tetrahedron Lett. 1987, 28, 2331-2334.
Org. Lett., Vol. 9, No. 25, 2007
5233

guanosine and 2′-deoxyguanosine derivatives has not
been reported to date, though 6-N-{2-(trimethylsilyl)-
ethoxycarbonyl}adenosine and 4-N-{2-(trimethylsilyl)-
ethoxycarbonyl}cytidine derivatives and their 2′-deoxy
counterparts have been obtained (in good to moderate
yield).8 One reason for this may be the instability of Teoc-
Cl,8,19 and therefore, we decided to examine the reaction
of our new reagent Teoc-NT (1d) with nucleobases
(Table 4).
Table 5. Synthesis of Carbonates and Thiocarbonates of
Alcohols and Thiols
Table 4. Protection of Nucleobases with Teoc by Use of 1d
a Conditions: 1 (1 equiv), Et3N (2 equiv), yield after washing with 5%
NaHCO3. b Conditions: 1 (2 equiv), Et3N (5 equiv), yield after column
chromatography. c Reaction time: 1 h.
1 without problem to give the desired carbonates 21a, 21b,
and 21d in excellent yields (entries 4-6). Similarly, aromatic
and aliphatic thiols 18 and 19 also reacted with 1b to give
the desired thiocarbonates 22b and 23b in the presence of
Et3N (entries 7 and 8).
time
(h)
yield
(%)
entry
substrate
X
product
1
2
3a
14C
14A
14G
2
4
4
1
12
4
15C
15A
15G
quant
98
80
In conclusion, convenient methods for the preparation of
carbamates, carbonates, and thiocarbonates using the new
reagents 1a-d were developed. These reagents have the
following advantages: (1) they are highly stable and can be
stored for long periods without decomposition; (2) since they
are nonhygroscopic crystalline materials, they are easy to
handle and weigh accurately even on a milligram scale; (3)
the reactions can be carried out even in an open flask; (4)
the co-product NT can be recycled; (5) generally, carbamate
formation proceeds quickly (within 5 min) under neutral
conditions; (6) in most cases, highly pure carbamates were
obtained without tedious column chromatographic purifica-
tion.
In addition to Z-, Troc-, Fmoc-, and Teoc-NT, other
alkoxycarbonyl-NT derivatives should be similarly obtainable
and may be good alternatives to the existing reagents. New
reagents of this type should be especially useful for the
synthesis of various functionalized compounds that are
difficult to access by conventional methods.
a Et3N (10 equiv) was added in the reaction mixture.
Reaction of the cytidine derivative 14C with 1d (2 equiv)
proceeded smoothly in the absence of base, and the Teoc
group was cleanly introduced onto the 4-NH2 group to afford
15C in quantitative yield. Selective introduction of the Teoc
group at the 6-NH2 group of the adenosine derivative 14A
was also successful. Unfortunately, reaction of the guanosine
derivative 14G with 1d in the absence of base did not
proceed. However, we were pleased to find that reaction in
the presence of Et3N (10 equiv) at room temperature
proceeded smoothly to give the desired product having a
Teoc group on 2-NH2 of the guanosine derivative 15G in
good yield (Table 4, entry 3).
The mild fluoride ion assisted removal of the Teoc group
from the exocyclic amino functionality of nucleobases20 will
be of great value for the synthesis of base-labile nucleotide
analogues.
Finally, reactions of 1 with alcohols and thiols were
investigated (Table 5). As mentioned above, 1 did not
react with alcohols (Table 2, entries 13-20) in the absence
of base; however, the reaction of benzyl alcohol 16 with 1a,
1b, and 1d in the presence of Et3N proceeded smoothly to
afford the carbonates 20a, 20b, and 20d in excellent yields
(entries 1-3). Even the secondary alcohol 17 reacted with
Acknowledgment. We thank Dr. Daisuke Hashizume
(RIKEN) for obtaining X-ray crystallographic data. This
work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas from MEXT, and Special Project
Funding for Basic Science.
Supporting Information Available: Experimental details
and spectroscopic characterization of synthetic compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Protection of the base moiety of uridine is not necessary for the
amidite method, which is generally employed for the synthesis of oligori-
bonucleotides.
OL7024108
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Org. Lett., Vol. 9, No. 25, 2007