Efficient and selective N-alkylation of carbamates in the presence of Cs2CO3 and TBAI

Article abstract of DOI:10.1016/S0040-4039(01)00019-3

Mild and selective N-alkylation of carbamates was carried out in the presence of cesium carbonate, tetrabutylammonium iodide (TBAI), and a halide. This protocol was highly selective and efficient, offering aliphatic and aromatic N-alkyl carbamates exclusively in high yields.

Full text of DOI:10.1016/S0040-4039(01)00019-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1799–1801
Efficient and selective N-alkylation of carbamates in the
presence of Cs2CO3 and TBAI
Ralph N. Salvatore,a Seung Il Shin,a Vincent L. Flandersa and Kyung Woon Junga,b,
*
aDepartment of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL 33620-5250, USA
bDrug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612-9497, USA
Received 12 December 2000; accepted 3 January 2001
Abstract—Mild and selective N-alkylation of carbamates was carried out in the presence of cesium carbonate, tetra-
butylammonium iodide (TBAI), and a halide. This protocol was highly selective and efficient, offering aliphatic and aromatic
N-alkyl carbamates exclusively in high yields. © 2001 Published by Elsevier Science Ltd.
The carbamate moiety is an important structural ele-
ment in numerous biologically active compounds1 and
has played a crucial role in the area of synthetic organic
chemistry primarily as a novel protecting group.2
Therefore, functionalization of organic carbamates
offers great potential in the generation of large combi-
natorial libraries for rapid screening3 and drug design.4
During our efforts towards efficient syntheses of carba-
mate peptidomimetic analog 2, we found that direct
N-alkylation methods of carbamate 1 proved problem-
atic since they employ harsh reaction conditions, such
as the use of a strong base which commonly causes
hydrolysis or epimerization.2 Furthermore, other alky-
lation methods use toxic5 or expensive exotic reagents6
to carry out the desired transformation. Thus, these
methods lack in generality, prompting us to embark on
a selective N-alkylation protocol suited for carbamates
under mild reaction conditions, which circumvent these
shortcomings.
Recently, we reported a cesium base mediated chemose-
lective procedure for the mono-N-alkylation of a pri-
mary amine7 as well as a synthetic methodology for
carbamate formation using a three component coupling
of an amine, CO2, and an alkyl halide in the presence of
a cesium base.8 In a continuing study, as illustrated in
Scheme 1, subsequent alkylations of carbamates pro-
gressed smoothly using cesium carbonate and tetra-
butylammonium
iodide
(TBAI)
at
ambient
temperatures, to give the corresponding N-alkylated
products exclusively using N,N-dimethylformamide as
the solvent.
As delineated in Table 1, the newly developed
techniques9 were applicable with various mixed alkyl
carbamates. Benzyl carbamates 6 and 7 reacted quickly
with benzyl chloride offering N,N-dibenzyl carbamates
in high yields. Aliphatic phenethylamine carbamates 8
and 9 proved facile, whereas the TIPS carbamate 10, a
R2
O
O
R2
O
O
H
N
H
N
"N-Alkylation"
R'X
Bn2N
O
Bn2N
O
O
N
H
N
H
OR
O
N
N
OR
R8
O
R1
O
R8
R'
R'
O
R1
1
2
R''
N
H
N
Cs2CO3, TBAI
DMF, 23 °C
R'
O
+ R''X
R
R'
R
O
O
3
4
5
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00019-3

1800
R. N. Sal6atore et al. / Tetrahedron Letters 42 (2001) 1799–1801
Table 1.
O
O
Cs2CO3, TBAI
DMF, 23 °C
+
BnCl
R
R'
R
R'
N
Bn
O
N
H
O
H
N
O
O
Ph
OBn
Ph
Ph
N
H
OBn
N
H
OMe
O
(8, 8 h, 91%)
(7, 5 h, 92%)
O Ph
(6, 5 h, 96%)
H
N
H
N
O
Ph
TIPS
O
O
MeO
(9, 3 h, 90%)
(10, 12 h, 75%)
H
N
H
N
H
N
O
Ph
OBn
O
OBn
S
O
(13, 6 h, 88%)
N
H
O
O
(11, 7 h, 91%)
(12, 6 h, 93%)
H
N
H
N
Ph
O
O
Ph
O
O
(14)
(15)
Table 2.
O
O
Cs2CO3, TBAI
+
Ar
R'
Ar
R'
BnCl
N
H
O
N
Bn
O
DMF, 23 °C
entry
1
yield
98%
aromatic carbamate
H
time
5 h
(16)
N
O
Ph
O
H
N
OBn
(17)
(18)
2
3
5 h
6 h
96%
93%
O
O
H
N
Ph
O
Me
H
N
O
Ph
N
(19)
4
6 h
88%
O
H
N
O
Ph
(20)
(21)
93%
90%
5
6
6 h
6 h
O
O
O2N
H
N
OBn
O
O2N
NO2
H
N
Ph
(22)
(23)
93%
7
8
6 h
6 h
O
O
H
N
O
Ph
96%
O

R. N. Sal6atore et al. / Tetrahedron Letters 42 (2001) 1799–1801
1801
H
N
O
Ph
n-BuBr, Cs2CO3, TBAI
DMF, 23 °C, 10 h, 93%
N
O
Ph
O
O
Me
Me
N
18
24
H
N
O
Ph
n-BuBr, Cs2CO3, TBAI
DMF, 23 °C, 6 h, 82%
N
O
Ph
N
O
O
19
25
Scheme 2.
novel protecting group,10 also demonstrated to be prag-
matic. Various heterocyclic amines (11–13) were sub-
jected to similar conditions to produce the desired
alkylation products. However, much to our surprise
and disappointment, lipophilic carbamate 14 and steri-
cally hindered cyclooctyl carbamate 15 were resistant to
alkylations under the developed conditions, and the
unreacted starting materials were recovered.
References
1. Vauthey, I.; Valot, F.; Gozzi, C.; Fache, F.; Lemaire, M.
Tetrahedron Lett. 2000, 41, 6347.
2. 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 cited therein.
3. Warrass, R.; Weismuller, K.-H.; Jung, G. Tetrahedron
Lett. 1998, 39, 2715.
Next, our attention was directed towards N-alkylation
of aromatic carbamates. As exemplified in Table 2,
carbamates of aniline moieties reacted efficiently, giving
similar results to the aliphatic showcases (entries 1–3).
In addition, pyridine containing carbamates reacted
smoothly to offer the corresponding products in high
yields (e.g. entry 4). Comparatively, regardless of the
introduction of an electron withdrawing substituent,
which would render the carbamate less basic, nitrocar-
bamates (entries 5–7) or acetophenone carbamate 23
reacted expeditiously, affording the desired dialkyl car-
bamates respectively in outstanding yields. In all the
attempted examples, our conditions were highly
chemoselective and efficient, and no side products were
detected whatsoever.
4. (a) Li, Z.; Bitha, P.; Lang, Jr., S. A.; Lin, Y. Biol. Med.
Chem. Lett. 1997, 7, 2909; (b) Bundgaard, H. Drugs
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8. (a) Salvatore, R. N. Shin, S. I.; Nagle, A. S.; Jung, K. W.
J. Org. Chem. 2001, 66, 1035. For our solid phase car-
bamation protocol, see: (b) Salvatore, R. N.; Flanders,
V. L.; Ha, D.; Jung, K. W. Org. Lett. 2000, 2, 2797.
9. Representative experimental procedure: Under a nitrogen
atmosphere, carbamate 16 (0.11 g, 0.43 mmol) was dis-
solved in anhydrous DMF (5 mL), then Cs2CO3 (0.42 g,
1.29 mmol, 3 equiv.) and TBAI (0.48 g, 1.29 mmol, 3
equiv.) were added to the solution. After stirring for 30
minutes at ambient temperature, BnCl (0.17 g, 1.29
mmol, 3 equiv.) was added into the suspension. The
reaction mixture was stirred for 5 hours, poured into
water, and extracted with EtOAc (3×30 mL). The com-
bined organic layers were washed with water (2×30 mL),
brine (30 mL), and dried over anhydrous sodium sulfate.
Column chromatography (5:1 hexanes:EtOAc) gave the
To demonstrate prospects of mildness and substrate
versatility, N-alkylations were also successful using an
unreactive halide such as 1-bromobutane. As illustrated
in Scheme 2, carbamates 18 and 19 underwent facile
alkylations, implying this technology is compatible with
various alkyl bromides.
In conclusion, an efficient synthetic method was devel-
oped to prepare fully substituted carbamates. The
newly found alkylation conditions were mild and high
yielding to offer a general method with substrate ver-
satility. Furthermore, applications of this protocol to
the synthesis of carbamate peptidomimetics will be
reported in due course.
1
desired carbamate (0.15 g, 98%) as an oil. H NMR (360
MHz, CDCl3) l 1.83 (t, 2 H, J=6.7 Hz), 2.48 (t, 2 H,
J=7.1 Hz), 4.10 (t, 2 H, J= 5.8 Hz), 4.82 (s, 2 H),
7.00–7.27 (m, 15 H). 13C NMR (90 MHz, CDCl3) l 30.51,
31.94, 54.14, 64.93, 125.82, 126.42, 126.83, 127.21, 127.68,
128.31, 128.38, 128.76, 137.98, 141.22, 142.11, 155.73. IR
(thin film) 3389, 3085, 3062, 3028, 2952, 2858, 1948, 1876,
Acknowledgements
We gratefully acknowledge financial supports from the
H. Lee Moffitt Cancer Center & Research Institute and
the American Cancer Society (Institutional Research
Grant c032).
1803, 1702, 1597, 1496, 1404, 1275, 1223 cm−1
.
10. Lipshutz, B. H.; Papa, P.; Keith, J. M. J. Org. Chem.
1999, 64, 3792.
.