Cs2CO3-promoted efficient carbonate and carbamate synthesis on solid phase

Article abstract of DOI:10.1021/ol006212i

Mild and efficient preparation of alkyl carbonates and carbamates on solid supports is described herein. Alcohols or amines were coupled with Merrifield's resin through a CO₂ linker in the presence of cesium carbonate and tetrabutylammonium iodide (TBAI).

Full text of DOI:10.1021/ol006212i

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2797-2800
Cs2CO -Promoted Efficient Carbonate
and Carbamate Synthesis on Solid
Phase
3
Ralph N. Salvatore, Vincent L. Flanders, Dang Ha, and Kyung Woon Jung*
Department of Chemistry (SCA 400), UniVersity of South Florida, and Drug DiscoVery
Program, H. Lee Moffitt Cancer Center & Research Institute, 4202 East Fowler
AVenue, Tampa, Florida 33620-5250
kjung@chuma.cas.usf.edu
Received June 15, 2000
ABSTRACT
Mild and efficient preparation of alkyl carbonates and carbamates on solid supports is described herein. Alcohols or amines were coupled
with Merrifield’s resin through a CO linker in the presence of cesium carbonate and tetrabutylammonium iodide (TBAI).
2
Organic reactions on solid phases have played an important
role in combinatorial and medicinal chemistry.1 Preparation
of small molecule libraries on polymer supports has emerged
as a powerful method for the development of new lead
compounds in the field of drug discovery.2 The synthetic
targets include peptidomimetics,3 oligonucleotides,4 and
oligosaccharides.5 Because of new interesting structural
features, artificial biomolecules containing new scaffoldings
have become popular synthetic targets. In this Letter, we
describe an efficient and practical solid-phase synthesis of
carbonates and carbamates that can be utilized as a frame-
work in further syntheses.6
The carbonate and carbamate linkers are usually prepared
by utilizing haloformates or carbonate exchange.7 These
methods are often costly, and the employed reagents are
toxic; therefore, alternative approaches are in demand.
Recently, we reported a highly efficient cesium base-
promoted solution-phase synthesis of alkyl carbonates that
(5) For recent reviews on oligosaccharides, see: (a) Frechet, J. M.;
Schuerch, C. Carbohydr. Res. 1972, 22, 399. (b) St. Hilaire, P. M.; Meldal,
M. Angew. Chem., Int. Ed. 2000, 39, 1162. (c) Osborn, H. M. I.; Khan, T.
H. Tetrahedron 1999, 4, 481. (d) Danishefsky, S. J.; Bilodeau, M. T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1380. (e) Sofia, M. J. In Combinatorial
Chemistry and Molecular DiVersity in Drug DiscoVery; Gordon, E. M.,
Kerwin, J. F., Jr., Eds.; Wiley-Liss; New York, 1998; pp 243-269.
(6) For carbonate scaffoldings, see: (a) Mertes, M. P.; Coats, E. A. J.
Med. Chem. 1969, 12, 154. (b) Jones, D. S.; Tittensor, J. R. Chem. Commun.
1969, 1240. (c) Tittensor, J. R. J. Chem Soc. 1971, 2656. For carbamate
scaffoldings, see: (d) Cho, C. Y.; Moran, E. J.; Chery, S. R.; Stevens, J.
C.; Fodor, S. P. A.; Adams, C. L.; Sundaram, A.; Jacobs, J. W.; Schultz, P.
G. Science 1993, 261, 1303. (e) Paikoff, S. J.; Wilson, T. E.; Cho, C. Y.;
Schultz, P. G. Tetrahedron Lett. 1996, 37, 5653.
(7) For a recent review on linkers for solid-phase organic synthesis,
see: (a) James, I. W. Tetrahedron 1999, 55, 4855. For selective examples,
see: (b) Ohlmeyer, M. H. J.; Swanson, R. N.; Dillard, L. W.; Reader, J.
C.; Asouline, G.; Kobayashi, R.; Wigler, M.; Still, W. C. Proc. Natl. Acad.
Sci. U.S.A. 1993, 90, 10922. (c) Greenburg, M. M.; Matray, T. J.; Kahl, J.
D.; Yoo, D. J.; McMinn, D. L. J. Org. Chem. 1998, 63, 4062. (d) Alsina,
J.; Rabanal, F.; Chiva, C.; Giralt, E.; Albericio, F. Tetrahedron 1998, 54,
10125. (e) Veerman, J. J. N.; Rutjes, F. P. J. T.; van Maarseveen, J. H.;
Hiemstra, H. Tetrahedron Lett. 1999, 40, 6079. (f) Raju, B.; Kogan, T. P.
Tetrahedron Lett. 1997, 38, 3373.
(1) (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Gallop, M. A. J.
Med. Chem. 1994, 37, 1385. (b) Thompson, L. A.; Ellman, J. A. Chem.
ReV. 1996, 96, 555. (c) Fruchtel, J. S.; Jung, G. Angew. Chem. 1996, 108,
19. (d) Balkenhohl, F. O.; Bussche-Hunnefeld, C. v. d.; Lansky, A.; Zechel,
C. Angew. Chem. 1996, 108, 2437. (e) Hermkens, P. H. H.; Ottenheijm, H.
C. J.; Rees, D. Tetrahedron 1997, 53, 5643. (f) Wilson, S. R.; Czarnik, A.
W. Combinatorial Chemistry; Wiley-Interscience: New York, 1997, and
references therein.
(2) (a) See refs 1a and 1b. (b) Gordon, E. M.; Gallop, M. A.; Patel, D.
V. Acc. Chem. Res. 1996, 29, 144. (c) Patel, D. V.; Gordon, E. M. Drug
DiscoVery Today 1996, 1, 134.
(3) For reviews on solid-phase peptide synthesis and its derivatives,
see: (a) Atherton, E.; Sheppard, R. C. Solid-phase peptide synthesis; a
practical approach; IRL Press: Oxford, 1989. (b) Stewart, J. M.; Young,
J. D. Solid-Phase Peptide Synthesis, 2nd ed.; Pierce Chemical Co.:
Rockford, IL, 1984. (c) Jung, G.; Beck-Sickinger, A. G. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 367. (d) Pavia, M. R.; Sawyer, T. K.; Moos, W. H.
Bioorg. Med. Chem. Lett. 1993, 3, 387. (e) Gallop, M. A.; Barrett, R. W.;
Dower, W. J.; Foder, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37,
1233.
(4) For reviews on solid-phase oligonucleotide synthesis, see: (a)
Beaucage, S. L.; Iyer, R. P. Tetrahedron 1992, 48, 2223. (b) Montserrat,
F. X.; Eritja, A. G.; Pedroso, E. Tetrahedron 1994, 50, 2617.
10.1021/ol006212i CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/04/2000

utilized nontoxic reagents under mild conditions.8 As a
complementary approach, this protocol has been extended
to solid-phase synthesis of both carbonates and carbamates,
which is the theme of the current report.
unreactive alcohols and chiral templates particularly prone
to racemization. (Table 2).11 Using secondary alcohols such
In the presence of cesium carbonate and tetrabutylammo-
nium iodide (TBAI), various alcohols and amines were
ligated to Merrifield resin 1 via a CO2 bridge to exclusively
produce carbonates 2 and carbamates 3, respectively (Scheme
1). Carbon dioxide was supplied by bubbling it into the
Table 2. Solid-Phase Synthesis of Carbonates Using Secondary
Alcohols and Chiral Templates
Scheme 1
reaction suspension, where N,N-dimethylformamide was the
choice of solvent. In our solution-phase carbonylations and
carbamations, the desired conversions were achieved at
ambient temperatures, whereas the solid-phase syntheses
required elevated reaction temperatures, still allowing for
clean transformations.
as cyclohexanol 7 and 3,3-dimethyl-2-butanol 8, similar
trends were observed to deliver the resin-bound carbonates
in excellent yields (entries 1 and 2). Subsequently, using
chiral alcohols containing a small degree of sterics, such as
menthol 9, the desired chiral carbonate formed in high yield
(entry 3). As depicted in entries 4-6, R-hydroxy esters and
lactones encompassing lactate 10, phenyllactate 11, and
γ-butyrolactone 12 underwent carbonylations to deliver their
corresponding carbonates in moderate yields without any loss
of stereochemical sense.12
In a comparative study (Table 1), 1-decanol (entry 1),
benzyl alcohol (entry 3), and p-nitrobenzyl alcohol (entry
Table 1. Conditions for Solid-Phase Synthesis of Carbonates at
Various Temperatures
Carbonylations were also successful upon switching reac-
tion partners, as illustrated in Table 3. Using the polymeric
Wang resin 13 and various bromides, unsymmetrical carbon-
ates formed smoothly in high yields, making this method
complementary to the aforementioned route (Table 3).13
Table 3. Solid-Phase Synthesis of Carbonates Using Wang
Resin and Bromides
5) smoothly conjugated with CO2 at room temperature to
give the intermediate carbonate anion in DMF. Upon addition
of polystyrene resin 1, carbonate-bound resin 2 was obtained
in moderate yields over a 24 h time period. On the other
hand, after screening several reaction temperatures including
reflux temperature, the optimum reaction temperature was
found to be 60 °C, which offered shortened reaction times
and increased yields significantly (entries 2, 4, and 6,
respectively).9
Under these conditions,10 we applied our technology to
solid-phase carbonate synthesis using sterically crowded
(8) For our cesium-promoted carbonylations, see: (a) Kim, S.-I.; Chu,
F.; Dueno, E. E.; Jung, K. W. J. Org. Chem. 1999, 64, 4578. (b) Chu, F.
Dueno, E. E.; Jung, K. W. Tetrahedron Lett. 1999, 40, 1847.
2798
Org. Lett., Vol. 2, No. 18, 2000

Reaction of 13 with lipophilic primary bromides 14 and 15
gave rise to the exclusive synthesis of carbonate resin 2 in
excellent yields (entries 1 and 2). Using a reactive bromide
such as benzyl bromide 16, the desired carbonate was
generated in 91% yield (entry 3). In comparison, regardless
of electron-withdrawing or -donating substituents at the
4-position of benzyl bromide, the carbonate formations were
highly efficient (entries 4 and 5).
carbamate analogue of tryptamine 21 formed in 60% yield
after the same duration. Saturated primary alkylamines,
encompassing 2-methoxyethylamine 22 and tetrahydrofufu-
rylamine 23, exhibited similar reactivities using the same
conditions, and cycloalkylamines 24 and 25 were also found
to couple with 1 efficiently. With chiral auxiliaries in mind,
methylbenzylamine 26 and aminoester 27 were examined,
and the desired resin-bound organic carbamates formed
exclusively in good yields. In addition, various secondary
amines also proved to be facile and pragmatic (28-31).15
Since aromatic amines and nitrogen heterocycles are
extensively used as building blocks in numerous syntheses,
we next directed our attention toward the formation of
aromatic carbamates on a solid support (Table 5). Using our
As shown in Table 4, the newly developed techniques were
applicable with various amines, also offering efficient
Table 4. Solid-Phase Synthesis of Carbamates Using
Merrifield Resin with Primary and Secondary Amines
Table 5. Solid-Phase Synthesis of Carbamates Using Aromatic
Amines and Merrifield Resin
carbamate synthesis.14 Allylic amines 19 and 20 gave
polymer-bound carbamates in high yields, whereas the
(9) Infrared spectra of all resin-bound carbonates were taken as KBr
pellets and showed the indicative carbonyl stretching band in the appropriate
locations for carbonates. The yield for the reactions were calculated on the
basis of resin loading from gravimetric analysis after drying in vacuo over
a 24 h time period. For a similar calculation, see the Supporting Information
from the following reference: Hunt, J. A.; Roush, W. R. J. Am. Chem.
Soc. 1996, 118, 9998.
cesium base-promoted carbamate methodology, aniline 32
reacted smoothly under the standard conditions with complete
conversion. Comparatively, its electron rich derivatives 33
and 34 and electron deficient anilines 35 and 36 all reacted
efficiently. In addition, 2- and 3-aminopyridines reacted
smoothly, offering moderate yields (entries 6 and 7).
Likewise, a secondary aromatic amine, N-ethylaniline 39,
led to the corresponding carbamate in 86% yield.15
(10) Representative experimental procedure for carbonates: Benzyl
alcohol (0.61 mL, 6 mmol, 3 equiv) was dissolved in anhydrous N,N-
dimethylforamide (20 mL) to make a clear solution. Into the solution were
consecutively added cesium carbonate (1.95 g, 6 mmol) and tetrabutylam-
monium iodide (2.22 g, 6 mmol, 3 equiv). The suspension was stirred at
room temperature while passing carbon dioxide gas through the solution
for 1 h before Merrifield’s peptide resin (1 g, 2 mmol) was added to the
solution. Carbon dioxide gas was continuously bubbled through the solution,
and the reaction was allowed to proceed overnight at 60 °C. The mixture
was then cooled to room temperature and diluted with water. The resin
was washed successively with MeOH/H2O, H2O, 0.2 N HCl, H2O, THF,
CH2Cl2, and MeOH. After drying under vacuum for 24 h, 1.22 g of resin
was obtained (97% yield): IR (KBr pellet) 3061, 3020, 2918, 2851, 1945,
(12) The stereochemistry of the products was confirmed by spectroscopi-
cally comparing the products with the authentic samples. Also, the resulting
carbonates were converted to the starting alcohols by cleavage with TFA/
CH2Cl2, and the optical rotations of the produced products were compared
with starting materials as well as those reported. If any sterochemical sense
was lost, it was to a negligible extent.
(13) Carbonate products using Wang resin 13 were verified using infrared
analysis (KBr pellet) showing the absence of the hydroxyl band. Also, the
products were cleaved from the resin using triethylamine (10 equiv) in
methanol, to yield the appropriate corresponding alcohols cleanly, which
were compared to authentic samples by proton NMR analysis.
1870, 1816, 1744, 1605, 1499, 1448, 1361, 763, 698, 546 cm-1
.
(11) Under basic conditions, R-hydroxy esters and lactones racemize
easily; therefore, 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.
Org. Lett., Vol. 2, No. 18, 2000
2799

To address issues of selectivity utilizing our solid-phase
protocol, the resulting carbonates and carbamates were
further verified by cleavage from the Merrifield resin using
two different conditions.16 As delineated in Scheme 2, resin-
detection limits. Furthermore, IR spectra of all cleaved resins
yielded only the corresponding polymer-supported benzyl
alcohol 42 exclusively (Scheme 3).
Scheme 3
Scheme 2
In summary, a one-step three-way coupling was performed
uniting Merrifield resin, carbon dioxide, and various alcohols
or amines, which led to the exclusive synthesis of mixed
alkyl carbonates or carbamates, respectively. Our reaction
conditions offered easy purification procedures and complete
conversions. Furthermore, isolation techniques allow for the
generation of large combinatorial libraries for rapid screening
in order to determine the pertinent activity of molecules
having new or interesting properties. The procedures dis-
cussed herein were mild enough to avert side reactions such
as hydrolysis or elimination commonly found using similar
methods. Chiral substrates encompassing R-hydroxy esters,
susceptible to racemization, survived the conditions. Our
solid-phase synthetic methodology provides alternative pro-
cedures for the preparation of carbonates and carbamates
efficiently as linkers on polymeric supports as well as
scaffoldings for novel artificial biomolecules.
bound octyl carbonate 40 was cleaved using LAH reduction
at room temperature to give n-octanol 41 after 7 h. However,
carbamate 43 required elevated temperatures, such as reflux,
which gave rise to the N-methylated amino alcohol 44 in
80% yield after 8 h.
Alternatively, hydrolytic cleavage of carbonate 45 or
carbamate 46 with TFA/CH2Cl2 (75:25, v/v) at room
temperature returned the starting alcohol 6 or amine 47 in
high yields. In all cases, crude NMR spectra exhibited clean
products and no other side products were noticed within our
(14) Representative experimental procedure for carbamates: 1,2,3,4-
Tetrahydroquinoline (0.67 g, 5 mmol, 2.5 equiv) was dissolved in N,N-
dimethylformamide (40 mL). Cesium carbonate (2.44 g, 7.5 mmol, 3.75
equiv) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 equiv) were
added to the solution under vigorous stirring. The temperature of reaction
was then raised to 60 °C, after which carbon dioxide was allowed to pass
into the stirred suspension at the same temperature for 10 h. Merrifield’s
resin (1 g, 2 mmol, 1 equiv) was added, and the reaction was continually
stirred at 60 °C for 12 h with constant carbon dioxide bubbling. The reaction
mass was then cooled to room temperature and filtered through a coarse
fritted filter disc. The resin was subsequently washed with 20 mL aliquots
of water, methanol/water (1:1, v/v), water, tetrahydrofuran, dichloromethane,
and methanol in the given order and then dried in vacuo for 24 h to yield
the desired carbamate (1.27 g, 95%) as a solid. IR (KBr pellet) 3440, 3075,
3045, 2920, 2850, 1900, 1875, 1740, 1695, 1590, 1560, 1505, 1450, 1395,
1320, 1250, 1220, 1170, 1115, 1010, 950, 905, 830, 820, 740, 695, 530
Acknowledgment. We acknowledge financial support
from the H. Lee Moffitt Cancer Center & Research Institute
and the American Cancer Society (IRG #032). We thank
Chemetall for generous supply of cesium bases.
Supporting Information Available: Additional experi-
mental procedures and method for determining yields are
illustrated for examples 11 and 29. This material is available
free of charge via the Internet at http://pubs.acs.org.
cm-1
.
(15) All carbamate products were verified by IR analysis, which indicated
the appropriate carbonyl stretching band as well as the corresponding amide
stretches.
(16) For similar cleavage examples, see: Ho, C. Y.; Kukla, M. J.
Tetrahedron Lett. 1997, 38, 2799.
OL006212I
2800
Org. Lett., Vol. 2, No. 18, 2000