Synthesis of Methyl Carbamates
Conclusions
2
for the reported time (Tables 1-3); after cooling, CO was
slowly vented by bubbling it into MeOH (5 mL). The content
of the cell was washed with additional MeOH, and the
combined methanolic solutions were analyzed by GC and GC-
MS. The purification and characterization data of compounds
The study of the reaction of primary aliphatic amines
with DMC in the presence of CO
2
shows that the pressure
of CO affects both the reaction conversion and the
2
5
a and 5d are indicated as specific examples.
selectivity. The first (conversion) plausibly reflects op-
posing effects on (i) the acid/base equilibrium between
the reactant amine and CO
favored at a high CO
solubility of RNHCO
b), which on the other hand may be favored by a low
pressure of CO . Overall, at 130 °C, conversion shows a
Methyl N-Benzyl Carbamate 5a. Under the conditions
2
of entry 4 in Table 1 (130 °C, 42 bar of CO ), 5a was obtained
in a 51% yield by GC (conversion 68%). It was then purified
by FCC on silica gel (Merck F60; eluant, diethyl ether and
petroleum ether in a 1:4 v/v; R ) 0.3) and isolated as a white
solid (mp 59-61 °C), in a 41% yield. H NMR (CDCl
2
(Scheme 1, a), which is
pressure, and (ii) the reactivity/
2
-
+
2
RNH
3
with/in DMC (Scheme 1,
f
1
3
) δ: 3.70
(
3H, s), 4.37 (2H, d, J ) 6.1 Hz), 5.01 (1H, s broad), 7.20-7.40
2
+
+
(
5H, m); GC-MS m/z: 165 (M , 70%), 150 ([M - Me] , 100),
maximum at about 40 bar. Selectivity toward methyl
carbamates 5 increases continuously from 5 to 200 bar,
because the competitive N-methylation of amines 2 is
+
+
1
33 ([M - OMe - H] , 21) 106 ([M - COOMe] , 51), 91
+
(
[C
Methyl N-(2-Amino)benzyl Carbamate 5d. Under the
conditions of entry 3 in Table 3 (130 °C, 90 bar of CO ), 5d
was obtained in a 58% amount by GC (conversion 80%). It was
then purified by FCC on Al (Macheray-Nagel; eluant, CH
Cl , MeOH, aq NH 9:1:0.1 v/v/v; R ) 0.4) and isolated as a
7 7
H ] , 75), 79 (42), 65 (20), 51 (19).
2
hindered by the increase of the CO pressure.
2
The use of cosolvents does not significantly improve
the reaction outcome, though it provides useful informa-
tion on the nature and on the reactivity of the nucleo-
O
2 3
2
-
2
3
f
-
+
yellow viscous oil, in a 57% yield. GC-MS (70 eV) m/z: 180
philic species involved (RNH
The reaction of bifunctional amines 2d-i with DMC/
CO proceeds with an unusual chemoselectivity: only
aliphatic amino groups undergo methoxycarbonylation,
while alcohols and/or aromatic NH groups do not react
at all. This result is not otherwise achievable with
conventional procedures using ClCO Me as a methoxy-
2
and RNHCO
2
3
RNH ).
+
+
+
(
M , 100%), 165 ([M - Me] , 17), 147 ([M - OMe - 2H] , 16)
+
+
1
21 ([M - COOMe] , 97), 106 ([M - NHCOOMe] , 45), 94 (29),
1
2
7
3
7 (22). H NMR (CDCl , Figure 1a) δ: 3.69 (3H, s), 4.29 (2H,
13
d, J ) 6.2 Hz), 4.97 (1H, s broad), 6.60-7.20 (4H, m). C NMR
(DMSO-d , Figure 1b) δ: 157.1, 145.9, 128.5, 127.7, 122.4,
115.7, 114.6, 51.4, 40.8. IR (cm ) (KBr): 3363 (NH, stretch-
ing), 2949, 1703 (CO, stretching), 1529, 1460, 1263.
Other methyl carbamates 5 were purified by FCC; their
physical and spectroscopic data are reported in Supporting
Information.
2
6
-
1
2
carbonylating reagent. Overall, although the reaction is
quite energy intensive and yields are sometimes moder-
ate, the method offers an ecofriendly and viable alterna-
tive for the preparation of methyl carbamates.
Reactions with Cosolvents. Table 2. Reactions were run
using the above-described procedure on the condition that
initial solutions of amines in DMC were also added with a
volume (2-4 mL) of a cosolvent (DMSO, DMF, MeOH, DME,
and CyH).
Experimental Section
SAFETY WARNING: Operators of high pressure equip-
Reactions of Amines 2a-e and 2h-i with Methyl
ment should take proper precautions to minimize the risks of
Chloroformate. Scheme 11. A procedure of methoxycarbo-
2
8
26
personal injury.
nylation of amines with ClCO
2
Me was used. In a 10-mL flask,
the amine (0.5 g) was dissolved in toluene (3 mL) and an
aqueous solution of K CO (1.7 M, 3 mL) was added. The
resulting biphasic system was vigorously stirred and cooled
to 0 °C. Then, ClCO Me (in a 1.2 molar excess with respect to
Reactions of Aliphatic Amines 2 with DMC in Super-
critical CO . A stainless steel (AISI 316), jacketed autoclave
2
2
3
of 90 mL equipped with two valves, a manometer, and two
sapphire windows (fixed on the head and the bottom cover)
was used as the reactor. In a typical experiment, the autoclave
was charged with a solution of the amine in DMC (compounds
2
the amine) was slowly dropped to the mixture. After 30 min,
diethyl ether (2 × 5 mL) was added to extract the organic
phase. The combined ethereal solutions were dried over
2
a-c: 1.04 M, 10 mL; compounds 2d-i: 0.5 M, 8 mL), and
by using an automatic syringe pump (ISCO model 260 D), CO
was inlet at a pressure approximately half of the desired value
2 4
Na SO and filtered. When necessary, products were purified
2
by FCC or directly characterized by NMR and GC-MS.
Spectroscopic data are reported in Supporting Information.
(
in the range of 5-200 bar; see Tables 1-3). The reactor was
electrically heated at 130 °C, while the reaction mixture was
magnetically stirred. Then, the final pressure was reached by
Acknowledgment. MIUR is gratefully acknowl-
edged for financial support.
slowly adding further CO
2
. The reaction was allowed to proceed
Supporting Information Available: Isolation methods
(
27) Only for the reaction of the p-aminophenethylamine (2f) with
2
1
13
and characterization data ( H and C NMR, GC-MS, and IR
spectra) of methyl carbamates 5a-m and of methyl carbonates
9a,b. This material is available free of charge via the Internet
at http://pubs.acs.org.
ClCO
Me, the selective formation of the carbamate 5f was reported,
though a very low temperature (-78 °C) was necessary. Prugh, J. D.;
Birchenough, L. A.; Egbertson, M. S. Synth. Commun. 1992, 16, 2357-
6
0.
(
28) Jessop, P. G.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996,
1
18, 344-355.
JO0477796
J. Org. Chem, Vol. 70, No. 7, 2005 2777