Alkyl Carbonates: Efficient Three Component Coupling of Aliphatic Alcohols, CO2, and Alkyl Halides in the Presence of Cs2CO3

Full text of DOI:10.1021/jo990520g

4578
J . Org. Chem. 1999, 64, 4578-4579
Sch em e 1
Alk yl Ca r bon a tes: Efficien t Th r ee
Com p on en t Cou p lin g of Alip h a tic Alcoh ols,
CO2, a n d Alk yl Ha lid es in th e P r esen ce of
Cs2CO3
Seok-In Kim, Feixia Chu, Eric E. Dueno, and
Kyung Woon J ung*
Department of Chemistry, University of South Florida,
4202 East Fowler Avenue, Tampa, Florida 33620-5250, and
Drug Discovery Program, H. Lee Moffitt Cancer Center &
Research Institute, Tampa, Florida 33612-9497
Sch em e 2
Received March 24, 1999
Organic carbonates1 have been utilized ubiquitously in
industry2 as well as in biological and medicinal fields,3 and
aliphatic carbonates, in particular, have exhibited promise
in medical applications.4 Nonetheless, the lack of facile
synthetic methodologies has hampered further studies,5
prompting us to develop efficient procedures for the prepara-
tion of alkyl carbonates via carbon dioxide alkylation.6 As
representatively shown in the Scheme 1, our previously
reported method exploited the cesium base promoted O-
alkylation, allowing primary and secondary alcohols to
couple efficiently with various primary alkyl bromides,
where cesium carbonate was utilized as both a base and a
carbon dioxide source.7 Complementary to this technology,
alternative conditions have also been examined to offer a
general protocol for unsymmetrical carbonates, where CO2
gas was employed in the presence of Cs2CO3 utilized only
as a base.
Unlike other alkali equivalents, cesium alkoxides such as
3 can react with carbon dioxide or bicarbonate to yield alkyl
carbonates (e.g., 4) presumably because alkoxides conjugated
with cesium are considered to constitute “naked anions”,
exhibiting enhanced nucleophilicities.8 Since carbon dioxide
was generated in situ from cesium carbonate upon heating
(i.e., 93 °C), the concentration of CO2 was anticipated to be
low, thereby retarding the alkylation process. In our con-
tinuous efforts to avert these impediments, we envisioned
that an additional source of CO2 gas would facilitate the
carbonic acid formation, and the preliminary results are
elaborated upon hereafter.
(1) For comprehensive reviews on organic carbonates, see: (a) Hegarty,
A. F. In Comprehensive Organic Chemistry; Sutherland, I. O., Ed.; Perga-
mon: London, 1979; Vol. 2, p 1067. (b) Shaikh, A.-A. G.; Sivaram, S. Chem.
Rev. 1996, 96, 951.
(2) (a) Taylor, L. D.; Waller, D. P. U.S. Pat. 5,243,052, 1993. (b) Kolliker,
H.-P.; Staub, A.; Hindermann, P. U.S. Pat. 3,689,510, 1972. (c) Ishida, N.;
Sakamoto, T.; Hasegawa, H. U.S. Pat. 5,370,809, 1994. (d) Ishida, N.;
Hasegawa, H.; Sasaki, U.; Ishikawa, T. U.S. Pat. 5,391,311, 1995. (e)
Pacheco, M. A.; Marshall, C. L. Energy Fuels 1997, 11, 2. (f) Yamaguchi, I.;
Tanaka, H.; Osakada, K.; Yamamoto, T. Macromolecules 1998, 31, 30. (g)
Ho¨cker, H.; Keul, H. Makromol. Chem., Macromol. Symp. 1992, 54/ 55, 9.
(h) J ackson, W. J ., J r.; Darnell, W. R. U.S. Pat. 4, 350, 805, 1982.
(3) (a) Buzzolini, M. G. U.S. Pat. 3,931,275, 1976. (b) Hodge, E. B. U.S.
Pat. 4,751,239, 1988. (c) Ghiron, C.; Rossi, T.; Thomas, R. J . Tetrahedron
Lett. 1997, 38, 3569. (d) Kole, H. K.; Akamatsu, M.; Ye, B.; Yan, X.; Barford,
D.; Roller, P. P.; Burke, T. R., J r. Biochem. Biophys. Res. Commun. 1995,
209, 817. (e) Avramova, P.; Dryanovska, L.; Ilarionov, Y. Pharm. 1983, 38,
443. (f) Avramova, P.; Dryanovska, L.; Ilarionov, Y. Pharm. 1977, 32, 575.
(4) (a) Kawaguchi, T.; Nakano, M.; J uni, K.; Inoue, S.; Yoshida, Y. Chem.
Pharm. Bull. 1983, 31, 1400. (b) Acemoglu, M.; Bantle, S.; Mindt, T.;
Nimmerfall, F. Macromolecules 1995, 28, 3030. (c) Zhu, K. J .; Hendren, R.
W.; J ensen, K.; Pitt, C. G. Macromolecules 1991, 24, 1736.
When the reaction mixture was saturated with carbon
dioxide by bubbling the gas continuously, carbonylation of
alcohol 1 was complete at ambient temperature, rendering
exclusively the desired mixed carbonate 2 through the three
component coupling of cesium alkoxide 3, CO2, and alkyl
bromide as mechanistically illustrated in Scheme 2. The
addition of tetrabutylammonium iodide (TBAI) accelerated
the reactions significantly while N,N-dimethylformamide
was the solvent of choice. More importantly, cesium carbon-
ate played the most critical role in the three way couplings
since the use of different bases including other alkali
carbonates and amine bases proved inefficient. It is strongly
believed that the cesium alkoxides constitute weakly coor-
dinated species, enhancing the nucleophilicities enough to
effect the nucleophilic attack to the relatively inert carbon
dioxide at room temperature, which is not the case with
other alkali alkoxides.7,8 These superior procedures were
facile, allowing for moderate reaction conditions such as
lower temperatures, shorter reaction times, and substrate
versatilities better than those in the aforementioned meth-
odology. Some representative examples are discussed below.
(5) For alcoholysis of phosgene or its derivatives, see: (a) Eckert, H.;
Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894. (b) Burk, R. M.;
Roof, M. B. Tetrahedron Lett. 1993, 34, 395. (c) Keohan, F. L.; Freelin, R.
G.; Riffle, J . S.; Yilgo¨r, I.; McGrath, J . E. J . Polym. Sci. Polym. Chem. Ed.
1984, 22, 679. For organic carbonate exchange, see: (d) Grynkiewicz, G.;
J urczak, J .; Zamojski, A. Tetrahedron 1975, 31, 1411. (e) Shaikh, A.-A. G.;
Sivaram, S. Ind. Eng. Chem. Res. 1992, 31, 1167. (f) Bertolini, G.; Pavich,
G.; Vergani, B. J . Org. Chem. 1998, 63, 6031. For inorganic carbonate
alkylation, see: (g) Cella, J . A.; Bacon, S. W. J . Org. Chem. 1984, 49, 1122.
(h) Bosworth, N.; Magnus, P.; Moore, R. J . Chem. Soc., Perkin Trans. 1
1973, 2694. (i) Lissel, M.; Dehmlow, E. V. Chem. Ber. 1981, 114, 1210.
(6) Carbon dioxide has been an attractive reagent because it is environ-
mentally safe and economically inexpensive. For some examples of using
carbon dioxide in carbonate formation, see: (a) McGhee, W.; Riley, D. J .
Org. Chem. 1995, 60, 6205. (b) Kuran, W.; Pasynkiewicz, S.; Skupinska, J .
Makromol. Chem. 1977, 178, 47. (c) Tsuda, T.; Chujo, Y.; Saegusa, T. J .
Am. Chem. Soc. 1980, 102, 431. (d) Bongini, A.; Cardillo, G.; Orena, M.;
Porzi, G.; Sandri, S. J . Org. Chem. 1982, 47, 4626. (e) Frevel, L. K. U.S.
Pat. 3,657,310, 1972. (f) Tsuda, T.; Chujo, Y.; Saegusa, T. J . Chem. Soc.,
Chem. Commun. 1976, 415. (g) Inoue, S.; Koinuma, H.; Tsuruta, T. Polym.
Lett. 1969, 7, 287. (h) Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J . Chem.
Soc., Chem. Commun. 1981, 465. (i) Fang, S.; Fujimoto, K. Appl. Catal. A:
Gen. 1996, 142, L1-L3. (j) Hori, Y.; Nahano, Y.; Nakao, J .; Fukuhara, T.;
Taniguchi, H. Chem. Express 1986, 1, 224. (k) Carlo, V.; Rino, D. Span Pat.
479,522, 1980. (l) Kao, J .-L.; Wheaton, G. A.; Shalit, H.; Sheng, M. N. U.S.
Pat. 4,247,465, 1981. (m) McGhee, W. D.; Talley, J . J . U.S. Pat. 5,302,717,
1994. (n) Oi, S.; Kuroda, Y.; Matsuno, S.; Inoue, Y. Chem. Soc. J pn. 1993,
985. (o) Casadei, M. A.; Cesa, S.; Feroci, M.; Inesi, A.; Rossi, L.; Moracci, F.
M. Tetrahedron 1997, 53, 167. (p) Sakakura, T.; Saito, Y.; Okano, M.; Choi,
J .-C.; Sako, T. J . Org. Chem. 1998, 63, 7095. (q) Darensbourg, D. J .;
Niezgoda, S. A.; Draper, J . D.; Reibenspies, J . H. J . Am. Chem. Soc. 1998,
120, 4690. (r) Cheng, M.; Lobkovsky, E. B.; Coates, G. W. J . Am. Chem.
Soc. 1998, 120, 11018.
(7) For our cesium promoted O-alkylations, see: (a) Dueno, E. E.; Chu,
F.; Kim, S.-I.; J ung, K. W. Tetrahedron Lett. 1999, 40, 1843. (b) Chu, F.;
Dueno, E. E.; J ung, K. W. Tetrahedron Lett. 1999, 40, 1847.
(8) Galli, C. Org. Prep. Proced. Int. 1992, 24, 287, and references therein.
10.1021/jo990520g CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/09/1999

Communications
J . Org. Chem., Vol. 64, No. 13, 1999 4579
Ta ble 1. Ca r bon a te F or m a tion Usin g Alcoh ols, Ha lid es,
a n d CO2 in th e P r esen ce of Cs2CO3
Ta ble 2. Ca r bon a te F or m a tion Usin g Ch ir a l Tem p la tes
desired carbonates in high yields. If any, stereochemical
sense was lost to a negligible extent.10 Using chiral tem-
plates, carbonate formation was efficient without any elimi-
nation or hydrolysis, where no or little racemization was
observed.
In summary, a three way coupling was performed using
alcohols, carbon dioxide, and halides, leading to the exclusive
synthesis of mixed alkyl carbonates, where the use of cesium
bases was crucial due to the inherently enhanced nucleo-
philicities of the corresponding cesium alkoxides generated
in situ from various aliphatic alcohols. Primary and second-
ary alcohols were easily incorporated into CO2, which then,
in turn, reacted with diverse halides including secondary
bromides, which are usually resistant to alkylations due to
eliminations. In addition, modification of the developed
conditions is currently under study to facilitate the carbonate
formation from tertiary substrates (i.e., trityl alcohol), which
were sluggish or resistant to react, leaving most starting
materials intact. Our procedures discussed herein were mild
enough to avert side reactions such as hydrolysis and trans-
esterification, common in various O-alkylation methods in
the presence of ester or its equivalent functionalities. Thus,
chiral substrates encompassing R-hydroxy esters, susceptible
to racemization, were also durable under the developed
conditions. Our synthetic methodology is facile, convenient,
and expeditious, and it is believed that this technology will
be used generally in the syntheses of various aforementioned
carbonates2-4 as well as in functional group manipulation
and protection.11
As delineated in Table 1, the newly developed techniques
were compatible with various substrates. Primary alcohol
1 was efficiently reacted with active halides (entries 1-3)
as well as unreactive secondary bromides (i.e., 2-bromo-
butane, entry 4) which required prolonged reaction time. The
secondary alcohol 5 was also converted exclusively to its
corresponding carbonates in high yields (entries 5-7).
Menthol, a sterically crowded alcohol, underwent consolida-
tion smoothly to provide the desired carbonate in excellent
yield (entry 8). As depicted in entry 9, methyl mandelate 7
was subjected to the same conditions with 4-methoxy-
phenylmethyl chloride (MPMCl) to afford its MPM carbon-
ate, which could serve as a novel hydroxyl protecting group.
Any side reactions including elimination and hydrolysis were
not observed within our detection limits, permitting a wide
range of applications.
Subsequently, our attention was directed toward O-
alkylation of chiral alcohols, which are prone to racemization
under the known conditions.9 As demonstrated in Table 2,
R-hydroxy esters and lactones underwent facile carbonyl-
ation with no or little racemization, providing a new ap-
proach to hydroxyl protection. Alkylations of R-hydroxy
esters encompassing lactate 8, phenyllactate 9, and di-
methyl malate 10 were also efficient, resulting in the
exclusive formation of their corresponding carbonates with
>95% ee values (entries 1-4).10 Since pantolactone 11 is
resistant to most known protection methods,7 it is notewor-
thy that the three component couplings with carbon dioxide
and benzylic halides took place smoothly, delivering the
Ack n ow led gm en t. Financial support from the USF
Research Council is gratefully acknowledged, as is support
from the H. Lee Moffitt Cancer Center & Research Insti-
tute.
Su p p or tin g In for m a tion Ava ila ble: General experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O990520G
(9) Under basic conditions, R-hydroxy esters and lactones racemize easily,
so alkylations of such moieties are usually carried out under acidic
conditions. So far, silver catalyzed alkylations seem to be the most popular
alkylation method, which is a costly process. (a) McKenzie, A.; Wren, H. J .
Chem. Soc. 1919, 115, 602. (b) Bonner, W. A. J . Am. Chem. Soc. 1951, 73,
3126.
(10) The resulting carbonates were converted to the starting alcohols by
hydrogenolysis, and the optical rotations of the produced products were
compared with the values of the starting materials as well as those reported.
Using (R)-methoxyphenylacetic acid, the corresponding esters were prepared
from the decarbonylated alcohols, and the optical purities were measured
by their proton NMR analysis.
(11) For selective examples, see: (a) Sheehan, J . C.; Guziec, F. S., J r. J .
Am. Chem. Soc. 1972, 94, 6561. (b) Satyanarayana, G.; Sivaram, S. Synth.
Commun. 1990, 20, 3273. (c) Shute, R. E.; Rich, D. H. Synthesis 1987, 346.
(d) Ghosh, A. K.; McKee, S. P.; Duong, T. T.; Thompson, W. J . J . Chem.
Soc., Chem. Commun. 1992, 1308. (e) Iimori, T.; Shibazaki, T.; Ikegami, S.
Tetrahedron Lett. 1996, 37, 2267. (f) Paquet, A. Can. J . Chem. 1982, 60,
976. (g) Bruneau, C.; Darcel, C.; Dixneuf, P. H. Curr. Org. Chem. 1997, 1,
197. (h) Roush, W. R.; Blizzard, T. A. J . Org. Chem. 1984, 49, 4332. (i)
Greenberg, M. M.; Matray, T. J .; Kahl, J . D.; Yoo, D. J .; McMinn, D. L. J .
Org. Chem. 1998, 63, 4062. (j) Kim, S.; Chang, H. J . Chem. Soc., Chem.
Commun. 1983, 1357. (k) Renga, J . M. U.S. Pat. 4,612,386, 1986.