Solution-Phase Parallel Synthesis of Carbamates Using Polymer-Bound N-Hydroxysuccinimide

Article abstract of DOI:10.1021/ol026756f

(Matrix Presented) A convenient method for the synthesis of carbamates using polymer-supported N-hydroxysuccinimide is described. Various carbamates were synthesized in highly pure form without the need for chromatographic purification. This new "catch an

Full text of DOI:10.1021/ol026756f

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3923-3926
Solution-Phase Parallel Synthesis of
Carbamates Using Polymer-Bound
N-Hydroxysuccinimide
Hirokazu Sumiyoshi, Takafumi Shimizu, Miho Katoh, Yoshiyasu Baba, and
Mikiko Sodeoka*
Institute of Multidisciplinary Research for AdVanced Materials, Tohoku UniVersity,
Katahira, Aoba, Sendai, 980-8577 Japan, and PRESTO, Japan Science and
Technology Corporation (JST)
sodeoka@tagen.tohoku.ac.jp
Received August 20, 2002
ABSTRACT
A convenient method for the synthesis of carbamates using polymer-supported N-hydroxysuccinimide is described. Various carbamates were
synthesized in highly pure form without the need for chromatographic purification. This new “catch and release”-type solid-phase synthesis
should be useful for combinatorial synthesis of various carbamates.
The carbamate group has reasonable chemical and biological
stability, and has been used as a protecting group for the
amino group.1,2 It is also found in various pharmaceuticals
and agrochemicals,3 and a number of procedures for the
synthesis of the carbamate group have been reported.4
Combinatorial chemistry is now becoming a powerful
approach in the search for biologically active compounds,
and an efficient method for the parallel synthesis of a variety
of pure carbamates is required for library synthesis. This
would be particularly useful for preparing focused libraries,
i.e., groups of compounds having a wide variety of residues
connected to a specific “core”, 5 for lead optimization, since
carbamate would be a good functional group to connect the
two parts. Polymer-supported reagents would be useful for
this purpose, because both spent and unreacted reagent can
be removed by simple filtration. Several syntheses of the
carbamate group using polymer-supported reagents have been
reported, in which chloroformates were required for the
preparation of the reagents.6 Only a few chloroformates such
as Fmoc-Cl and Boc-Cl are commercially available. Thus,
these previous methods are useful only for preparation of
Fmoc- or Boc-protected amines or amino acids. From the
viewpoint of library synthesis, synthetic protocols that enable
the use of alcohols are preferred. Here we report a new “catch
and release”-type method for the efficient synthesis of
(1) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
3rd ed.; Wiley and Sons: New York, 1999; pp 503-550 and references
therein.
(2) Henklein, P.; Heyne, H. U.; Halatsch, W. R.; Niedrich, H. Synthesis
1987, 166-167.
(3) (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.
(5) (a) Sodeoka, M.; Sampe, R.; Kojima, S.; Baba, Y.; Usui, T.; Ueda,
K.; Osada, H. J. Med. Chem. 2001, 44, 3216-3222. (b) Sodeoka, M.; Baba,
Y. J. Synth. Org. Chem., Jpn. 2001, 59, 1095-1102.
(4) (a) Sandler, S. R.; Karo, W. In Organic Functional Group Prepara-
tions; Academic Press: New York, 1971; Vol. II, pp 223-245. (b) Ghosh,
A. K.; Duong, T. T.; McKee, S. P.; Thompson, W. J. Tetrahedron Lett.
1992, 33, 2781-2784. (c) Morpurgo, M.; Bayer, E. A.; Wilchek, M. J.
Biochem. Biophys. Methods 1999, 38, 17-28. (d) Ghosh, A. K.; McKee,
S. P.; Duong, T. T.; Thompson, W. J. J. Chem. Soc., Chem. Commun. 1992,
1308-1310.
(6) (a) Dendrinos, K. G.; Kalivretenos, A. G. J. Chem. Soc., Perkin Trans.
1 1998, 1463-1464. (b) Barrett, A. G.; Cramp, S. M.; Roberts, R. S.; Zecri,
F. J. Org. Lett. 2000, 2, 261-264. (c) Chinchilla, R.; Dodsworth, D. J.;
Na´jera, C.; Soriano, J. M. Tetrahedron Lett. 2001, 42, 7579-7581. (d)
Chinchilla, R.; Dodsworth, D. J.; Na´jera, C.; Soriano, J. M. Bioorg. Med.
Chem. Lett. 2002, 12, 1817-1820. (e) Phoon, C. W.; Sim, M. M. Synlett
2001, 5, 697-699.
10.1021/ol026756f CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/09/2002

carbamates that should find application not only for protec-
tion of the amino group but also for the synthesis of
carbamate libraries.
THF at 23 °C, affording the desired products (Table 1).
Various amines, including a secondary amine and an
We have reported that polymer-supported N-hydroxysuc-
cinimide (NHS) 2 can easily be prepared from commercially
available PS-thiophenol resin 1 and N-hydroxymaleimide,
and we showed that it is useful for the synthesis of various
amides.7 Thus, we planned to use this PS-NHS resin 2 for
the synthesis of carbamate libraries. Figure 1 illustrates the
Table 1. Synthesis of Carbamates Using Fmoc-Cl
a Reaction time ) 1 h. b Reaction time ) 7 h.
Figure 1. General scheme for the synthesis of carbamates using
polymer-bound N-hydroxysuccinimide.
aromatic amine, were cleanly converted to the corresponding
Fmoc derivatives in good chemical yields. The purity of the
product obtained by the simple filtration, washing, and
evaporation was confirmed to be >95% by 1H NMR analysis.
Next, preparation of polymer-supported NHS-carbonates
using various alcohols was examined. Efficient parallel
synthesis of carbamates in four-step sequences from 1 was
achieved by using a semi-automated apparatus, Quest210
(Argonaut). The PS-NHS resin 2 was first prepared from
the PS-thiophenol resin 1 and N-hydroxymaleimide in a
reaction vessel with a filter, basically according to the
reported procedure.7 It was then treated with BTC (2.0 equiv)
and pyridine (1.0 equiv) in dichloromethane (CH2Cl2) at 23
°C for 2 h. After removal of excess reagents by filtration,
the resin was washed with CH2Cl2. The resulting resin was
stirred with an alcohol (3.0 equiv with respect to the NHS
group) and pyridine (1.0 equiv) in CH2Cl2 at 23 °C for 3 h
and then washed with CH2Cl2 to give the polymer-supported
carbonate 4. Loading of the alcohol was estimated from the
recovery of the alcohol.11 It was found that 43-75% of the
thiophenol groups of resin 1 were converted to NHS-
carbonate groups. It is possible that a cross-linked disuccin-
imidyl carbonate was partially formed on the resin, in
addition to the chloroformate 3.
idea behind our column-chromatography-free carbamate
synthesis. Namely, treatment of 2 with bistrichloromethyl
carbonate (BTC)8,9 would afford the polymer-supported
chloroformate 3. Further treatment of 3 with an alcohol is
expected to give the polymer-supported NHS-carbonate 4.
Pure carbamate should be obtained by the reaction of 4 with
an amine, followed by filtration and evaporation of the
filtrate.
To examine the stability and reactivity of 4, and to
compare our procedure with the published protocols,5 first
the polymer-supported Fmoc carbonate resin 4a was prepared
by the reaction of 2 (1.00 mmol/g)10 with Fmoc-Cl (1.5
equiv) in the presence of pyridine (1.5 equiv) in THF (23
°C, 2 h). Filtration and washing afforded 4a (0.83 mmol/
g),10 which was sufficiently stable for storage at ambient
temperature. The amines (0.6 equiv) were stirred with 4a in
(7) Katoh, M.; Sodeoka, M. Bioorg. Med. Chem. Lett. 1999, 9, 881-
884.
(8) Cotarca, L.; Delogu, P.; Nardelli, A.; Sunjic, V. Synthesis 1996, 553-
576.
(9) Konakahara, T.; Ozaki, T.; Sato, K.; Gold, B. Synthesis 1993, 103-
106.
(10) Reaction with N-hydroxymaleimide or Fmoc-Cl was assumed to
be almost quantitative, and the loading of resin 2 or 4a was estimated from
the original loading of the thiophenol group and the weight of the recovered
resin 2 or 4a.
(11) After the reaction with alcohol, all filtrates were combined and
concentrated, and diphenylmethane (3.0 equiv with respect to the NHS
group) was added to this mixture as an internal standard. Recovery of the
1
alcohol was quantified by H NMR analysis.
3924
Org. Lett., Vol. 4, No. 22, 2002

Disuccinimidyl carbonate is also known to react with
alcohol, but only a half of the NHS groups on the resin could
be converted to NHS-carbonate, if disuccinimidyl carbonate
were formed. The resulting NHS-carbonates 4b-g were
stirred with 4-phenylbutylamine (0.7 equiv with respect to
the carbonate) in CH2Cl2 at 23 °C. The solution phase was
separated, and the resin was washed with CH2Cl2. The
combined solution was concentrated to give the desired
carbamate in good chemical yield, except for the tertiary
alcohols (Table 2). It is likely that polymer-supported NHS-
Table 3. Synthesis of Carbamates Using Various Amines
Table 2. Synthesis of Carbamates Using Various Alcohols
a Reaction time ) 3 h. b Reaction time ) 12 h. c Reaction time ) 24 h.
a Conditions: 23 °C, 10 h, vigorous shaking using a shaker for the last
step. b Conditions: 23 °C, 3 h. c Conditions: 40 °C, 24 h.
carbonate of the tertiary alcohol is sterically hindered, and
approach of the amine to the carbonyl carbon might be
difficult.
due to its poor nucleophilicity. It is also noteworthy that the
reaction with the amino alcohols proceeded without dif-
ficulty, and no O-acylation was observed in any case (entries
10-12). In the case of the reaction of amines with low
solubility in CH2Cl2 (entries 1, 5, and 11), vigorous shaking
was required for the completion of the reaction.
Finally, the NHS-resin was found to be recyclable. Three
successive cycles were run using the same resin in the same
reaction vessel. Namely, the reactions of 1 with N-hydroxy-
maleimide, BTC, 1-decanol, and 1-phenylethylamine were
carried out in a manner similar to that shown in Table 3,
entry 2. After the isolation of the carbamate, the resin that
Reactions of the polymer-supported NHS-carbonate 4b
with various amines were also examined. As shown in Table
3, the reaction proceeded smoothly to give the desired
carbamate in highly pure form (>95%) without any purifica-
tion. No significant amount of the starting amine or byprod-
uct was observed in the solution phase. The purity of the
product was confirmed by HPLC and/or 1H NMR. Not only
aliphatic amines, but also aromatic amines (except for
p-nitroaniline) reacted smoothly to give the corresponding
carbamates. No reaction occurred for p-nitroaniline, probably
Org. Lett., Vol. 4, No. 22, 2002
3925

remained in the reaction vessel was retreated with BTC and
1-decanol in the same sequence to give the carbonate resin
4b. This recycled resin was used for the second reaction with
1-phenylethylamine. After the second reaction, the resin was
retreated with BTC, 1-decanol, and the amine again. Load-
ings of the alcohol in each cycle, as estimated from the
consumption of the alcohol, were 53, 58, and 45%, respec-
tively. The yields of the carbamate were 84, 74, and 87% in
the first, second, and third cycles, respectively.
the ability to prepare carbamates in highly pure form without
any time-consuming purification step such as column chro-
matography. The whole procedure is suitable for automation.
Since alcohols can be used in this method,12 it should be
useful for the synthesis of carbamate libraries.13 Furthermore,
this methodology is useful not only for protection of the
amino group in small molecules and for combinatorial
chemistry but also for the selective labeling of small
molecules or proteins4b with biotin, a chromophore, a
photoreactive group, a radiolabel, and so on.
In conclusion, a new method for the facile preparation of
various carbamates by utilizing polymer-supported NHS 2
has been developed. The major advantage of this method is
Acknowledgment. We thank Argonaut Technologies for
the generous gift of the PS-thiophenol resin. This work was
supported in part by a grant from Uehara Memorial Founda-
tion, The Naito Foundation, Suzuken Memorial Foundation,
and Hoh-ansha Foundation, as well as a Grant-in-Aid for
Creative Scientific Research (No. 13NP0401), a Grant-in-
Aid for Scientific Research from the Japan Society for the
Promotion of Science, and a Grant-in-Aid for Scientific
Research on Priority Areas (A) from The Ministry of
Education, Culture, Sports, Science and Technology.
(12) Recently, solid-phase synthesis of carbamates using a large excess
of alcohols and amines was reported. However, it requires an acid cleavage
step to obtain the final product. See: Fernandez-Forner, D.; Huerta, J. M.;
Ferrer, M.; Casals, G.; Ryder, H.; Giralt, E.; Albericio, F. Tetrahedron Lett.
2002, 43, 3543-3546.
(13) General Procedure. PS-Thiophenol resin 1 (200 mg, 1.14 mmol/
g) was placed in the reaction vessel of a Quest machine and first treated
with tri-n-butylphosphine to reduce the oxidized thiophenols. The resin was
treated with N-hydroxymaleimide (0.296 mmol) and diisopropylethylamine
(DIPEA) (0.091 mmol) in THF/DMF (2:1, 5 mL) to afford the PS-NHS
resin 2. This resin was then suspended in CH2Cl2 (3 mL), and a solution of
BTC (0.456 mmol) in CH2Cl2 (2 mL) and pyridine (0.228 mmol) were
added. The reaction mixture was stirred at 23 °C for 2 h; then, the liquid
phase was separated, and the resin was washed with CH2Cl2. The resin
was treated with an alcohol (0.684 mmol) and pyridine (0.288 mmol) at 23
°C for 2 h to give the carbonate resin 4. Finally, this resin 4 was treated
with an amine (0.7 equiv with respect to the carbonate) in CH2Cl2 (5 mL)
at 23 °C until all the amine was consumed. The desired carbamate was
obtained by simple filtration, washing with CH2Cl2, and evaporation of the
solvent.
Supporting Information Available: Experimental details
and spectral data for carbamates. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL026756F
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Org. Lett., Vol. 4, No. 22, 2002