Efficient carbamate synthesis via a three-component coupling of an amine, CO2, and alkyl halides in the presence of Cs2CO3 and tetrabutylammonium iodide

Full text of DOI:10.1021/jo001140u

J . Org. Chem. 2001, 66, 1035-1037
1035
formation of tertiary amines,5b usually accompany these
carbamations.
Efficien t Ca r ba m a te Syn th esis via a
Th r ee-Com p on en t Cou p lin g of a n Am in e,
CO2, a n d Alk yl Ha lid es in th e P r esen ce of
Cs2CO3 a n d Tetr a bu tyla m m on iu m Iod id e
Under our developed conditions, carbamations were
smooth and convenient to generate the desired carbam-
ates efficiently. For instance, carbamate 2 was found to
exclusively form in high yield through the three-
component coupling of amine 1, CO2, and 1-bromobutane
by applying a similar procedure to our carbonylation
protocol.6a In this conversion, the reaction mixture was
saturated with CO2 by bubbling the gas continuously in
the presence of Cs2CO3 at room temperature while N,N-
dimethylformamide proved to be the solvent of choice.
Interestingly, tetrabutylammonium iodide (TBAI) was
found to be a crucial additive in averting direct N-
alkylations and overalkylation of the produced carbam-
ate.8 Thus, this procedure is highly chemoselective,
convenient, and efficient, which overcomes the common
problems encountered utilizing similar methods (vide
supra).
Ralph N. Salvatore, Seung Il Shin, Advait S. Nagle, and
Kyung Woon J ung*
Department of Chemistry, University of South Florida,
4202 E. Fowler Avenue, Tampa, Florida 33620-5250 and
Drug Discovery Program, H. Lee Moffitt Cancer Center &
Research Institute, Tampa, Florida 33612-9497
kjung@chuma.cas.usf.edu
Received J uly 26, 2000
The carbamation of amines has frequently been uti-
lized in the synthesis of organic carbamates,1 which hold
unique applications in the field of pharmaceuticals2 and
agriculture.3 Organic carbamates have also played an
important role in the area of synthetic organic chemistry
primarily as key intermediates or as novel protecting
groups.4 However, the scope of existing methodologies5
for carbamate formation are limited by the need for
specialized reagents, and operational complexity due to
the use of either toxic or cumbersome reagents such as
phosgene. Because of the toxicity of these materials, we
have undertaken a significant effort for the development
of more efficient and safer protocols. Recently, we re-
ported a cesium base-promoted carbonylation method,
which successfully allows for the efficient coupling of
various alcohols with halides in the presence of cesium
carbonate, tetrabutylammonium iodide (TBAI), and car-
bon dioxide.6 Analogous to this route, we applied this
carbonate technology to the synthesis of carbamates,
envisioning high yields under mild reaction conditions.
Although there have been several examples with regards
to carbamate formation utilizing carbon dioxide alkyla-
tion, these precedented conditions lack in practicality
mainly because they require severe reaction conditions.7
Furthermore, N-alkylation reactions, resulting in the
Sch em e 1
As shown in Table 1, numerous substrates were exam-
ined and found to be suitable to the newly developed
techniques. Various amines with primary alkyl chains
were efficiently united with benzyl chloride in high yields
(entries 1-4). As depicted in entry 5, cyclooctylamine 7,
a relatively bulky amine, underwent consolidation easily
to provide the desired carbamate in good yield while
secondary amine 8 (i.e., 4-benzylpiperazine, entry 6)
required longer reaction time. Likewise, treatment of an
unreactive bromide such as 10 with numerous primary
amines afforded the desired carbamates in less than 8 h
(entries 7-11). Interestingly, tryptamine 14 was found
to carbonylate at the primary amine selectively, leaving
the secondary amine intact.
Using the conditions described above, we next inves-
tigated carbamate formation using aromatic and other
heterocyclic amines. As summarized in Table 2, aromatic
amines underwent facile carbamation in high yields
using two different reactive electrophiles (entries 1 and
2). As expected, the secondary aromatic amine, N-
ethylaniline 17, reacted slowly to afford the carbamate
in 78% yield after a 22 h time period (entry 3). Hetero-
cyclic amines including 2- and 3-aminopyridines were
noticed to react in a similar fashion with bromide 10
(entries 4 and 5). Subsequently, with the introduction of
an electron-withdrawing substituent on the aromatic ring
(i.e., carbonyl or nitro group), the amine was rendered
less nucleophilic; hence, the reactions were sluggish and
* To whom correspondence should be addressed. Phone: 813-974-
7306; Fax: 813-974-1733.
(1) For a comprehensive review on organic carbamates, see Adams,
P.; Baron, F. A. Chem. Rev. 1965, 65, 567.
(2) Barthelemy, J . Lyon Pharm. 1986, 37 (6), 297.
(3) (a) Tai-The, W.; Huang, J .; Arrington, N. D.; Dill, G. M. J . Agric.
Food Chem. 1987, 35, 817. (b) Kato, T.; Suzuki, K.; Takahashi, J .;
Kamoshita, K. J . Pesticide Sci. 1984, 9, 489. (c) Picardi, P. La Chimica
e l’Industria 1986, 68, 108. (d) Rivetti, F.; Romano, U.; Sasselli, M.
U.S. Patent 4514339, ECS 1985.
(4) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J . W. Wiley and Sons: New York, 1999; pp 503-
550 and references therein.
(5) For traditional synthetic methods for carbamate formation, see
(a) Babad, H.; Zeiler, A. G. Chem Rev. 1973, 73, 75. (b) Butcher, K. J .
Synlett 1994, 825. (c) Sasaki, Y.; Dixneuf, P. J . Org. Chem. 1987, 52,
314. (d) Ohta, A.; Inagawa, Y.; Mitsugi, C. J . Heterocycl. Chem. 1985,
22, 1643. (e) Parra, V. G.; Sanchez, F.; Torres, T. Synthesis 1985, 282.
(f) Tartar, A.; Gesquiere, J . C. J . Org. Chem. 1979, 44, 5000. (g) Sasaki,
Y.; Dixneuf, P. H. J . Org. Chem. 1987, 52, 314. (h) Raucher, S.; J ones,
D. S. Synth. Commun. 1985, 15, 1025.
(6) For our cesium-promoted carbonate formation, see (a) Kim,
S.-I.; Chu, F.; Dueno, E. E.; J ung, K. W. J . Org. Chem. 1999, 64, 4578.
(b) Chu, F.; Dueno, E. E.; J ung, K. W. Tetrahedron Lett. 1999, 40, 1847.
For our cesium-promoted carbonate and carbamate synthesis on solid
phase, see (c) Salvatore, R. N.; Flanders, V. L.; Ha, D.; J ung, K. W.
Org. Lett. 2000, 2, 2797.
(7) (a) Yamazaki, N.; Iguchi, T.; Higashi, F. Tetrahedron, 1975, 31,
3031. (b) Yoshida, Y.; Inoue, S. J . Chem. Soc., Perkin Trans. 1 1979,
3146. (c) Casadei, M. A.; Moracci, F. M.; Zappia, G. J . Org. Chem. 1997,
62, 6754. (d) Aresta, M.; Quaranta, E. Tetrahedron 1992, 48, 1515. (e)
McGhee, W.; Riley, D.; Christ, K.; Pan, Y.; Parnas, B. J . Org. Chem.
1995, 60, 2820.
(8) In a similar fashion, tetrabutylammonium bromide (TBABr) and
various other onium salts have been utilized in supercritical carbon
dioxide for the selective formation of urethanes. See: Yoshida, M.;
Hara, N.; Okuyama, S. Chem. Commun. 2000, 151.
10.1021/jo001140u CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/06/2001

1036 J . Org. Chem., Vol. 66, No. 3, 2001
Notes
Ta ble 1. Ca r ba m a te F or m a tion Usin g Alip h a tic Am in es,
Ha lid es, a n d CO2 in th e P r esen ce of Cs2CO3 a n d TBAl
Sch em e 2
Sch em e 3
2, 4, and 6).9 Therefore, allowing the reaction to proceed
at room temperature for longer duration (e.g., 5 days),
the starting amine was found to be consumed. These
optimal conditions gave rise to the exclusive formation
of the desired products in excellent yields (entries 1, 3,
and 5) without any concomitant formation of side prod-
ucts.
Keeping peptidomimetic synthesis in mind, we directed
our attention toward carbamate formation using amino
acids and their derivatives. As depicted in Scheme 2,
amino acids and esters were smoothly converted to the
corresponding carbamates in excellent yields. For ex-
ample, when phenylalanine 23 was subjected to the
standard conditions, carbamation was accompanied along
with the anticipated esterification. Also, valine ester 25
reacted efficiently to afford 26 in high yield without any
degree of saponification.
Ta ble 2. Ca r ba m a te F or m a tion Usin g Ar om a tic a n d
Heter ocyclic Am in es
Since the carbamation of amino acids and their deriva-
tives proved to be successful, the preparation of higher
order peptidomimetics such as trimer 31 was facile and
expeditious by applying our carbamation techniques as
outlined in Scheme 3. After amino bromide 28 was
prepared through our bromination techniques,10 it was
coupled with isoleucine methyl ester 27 and followed by
removal of dibenzyl moieties to afford the peptidomimetic
dimer 29, where the secondary bromide was rearranged
to the desired primary form via the corresponding aziri-
dinium salt during the alkylations.10 Subsequently, dimer
29 was conjugated with bromide 30 to synthesize trimer
31 cleanly. Using our developed protocol, racemizations
were not detected during any alkylations of these chiral
substrates while complications stemming from hydrolysis
were not observed to a noticeable extent.11
Ta ble 3. Ca r ba m a te F or m a tion Usin g Ar om a tic Am in es
Con ta in in g Electr on -With d r a w in g Gr ou p s w ith Bn Cl
entry
amine (ArNH2)
temp, °C
time
yield, %
1
2
3
4
5
6
20
20
21
21
22
22
23
70
23
70
23
70
5 d
24 h
5 d
24 h
5 d
24 h
81
70
87
60
96
65
In summary, a three-component coupling was per-
formed using amines, carbon dioxide, and halides, leading
to the efficient synthesis of carbamates, in the presence
of cesium carbonate and TBAI. Various aliphatic and
unreacted starting material was recovered along with the
carbamate (entries 6-8).
In a continuing study, we endeavored to optimize the
conditions for the aromatic amines containing electron-
withdrawing groups (Table 3). At higher temperatures
(70 °C), similar trends to the previous reactions (entries
6-8, Table 2) were noted. After 24 h, although yields
improved slightly, a complicated mixture of other side
products were accompanied with the carbamate (entries
(9) Various side products were detected by thin-layer chromatog-
raphy, but their structural elucidation was not carried out due to their
complicating patterns.
(10) Nagle, A. S.; Salvatore, R. N.; Chong, B. D.; J ung, K. W.
Tetrahedron Lett. 2000, 41, 3011.
(11) 1H NMR, 13C NMR, and 2D NMR analyses indicate the product
as a single isomer.

Notes
J . Org. Chem., Vol. 66, No. 3, 2001 1037
suspension. The reaction proceeded at an ambient temperature
with CO2 gas bubbling for 3 h, during which time the starting
material (benzylamine) was consumed. The reaction mixture was
then poured into water (30 mL) and extracted with EtOAc (3 ×
30 mL). The organic layer was washed with water (2 × 30 mL)
and brine (30 mL) and dried over anhydrous sodium sulfate.
Evaporation of solvent followed by flash column chromatography
(hexanes-EtOAc, 9:1 v/v) afforded the carbamate 2 (480 mg,
96%) as an oil. Data for 2: 1H NMR (360 MHz, CDCl3) δ 0.85 (t,
3 H, J ) 7.23 Hz) 1.32 (m, 2 H), 1.52 (m, 2 H), 4.02 (t, 2 H, J )
6.26 Hz), 4.28 (d, 2 H, J ) 4.71 Hz), 4.93 (bs, NH), 7.17-7.27
(m, 5 H). 13C NMR (90 MHz, CDCl3) δ 13.72, 19.03, 31.04, 44.99,
64.88, 127.40, 127.47,128.61, 138.59, 156.77. Anal. Calcd for
C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.31; H, 8.21;
N, 6.76.
aromatic amines containing electron-donating and elec-
tron-withdrawing groups were compatible while reactive,
unreactive, and secondary halides were examined to
demonstrate substrate versatility. These convenient and
safe procedures were superior when compared to known
methods since these methodologies avert common side
reactions such as the N-alkylation of the amine and
overalkylation of the carbamate. Furthermore, our tech-
nologies offer mild reaction conditions such as ambient
temperatures and short reaction times. Thus, chiral
substrates encompassing amino acids and amino acid
derivatives were resistant to racemization, and labile
functionalities including ester were tolerant. These tech-
niques are strongly believed to offer a general synthetic
method for various carbamates, offering a wide variety
of applications. Efficient synthesis of peptidomimetics
and preparation of combinatorial libraries will be re-
ported in due course.
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 Institute. This project was also supported in
part by the American Cancer Society’s Institutional
Research Grant #032. We thank Chemetall for generous
supply of cesium bases.
Exp er im en ta l Section
R ep r esen t a t ive E xp er im en t a l P r oced u r e. To benzyl-
amine 1 (200 mg, 1.9 mmol) in anhydrous N,N-dimethylforma-
mide (10 mL) were added cesium carbonate (1.8 g, 6.0 mmol, 3
equiv) and tetrabutylammonium iodide (2.1 g, 6.0 mmol, 3
equiv). Carbon dioxide gas (flow rate ≈ 25-30 mL/min) was
bubbled into the reaction mixture for 1 h, and then 1-bromobu-
tane (770 mg, 0.6 mL, 6.0 mmol, 3 equiv) was added into the
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O001140U