Efficient and clean synthesis of N-alkyl carbamates by transcarboxylation and O-alkylation coupled reactions using a DBU-CO2 zwitterionic carbamic complex in aprotic polar media

Article abstract of DOI:10.1016/S0040-4039(02)00697-4

N-Alkyl carbamates were obtained with good to excellent yields by clean and mild transcarboxylation of several amines with the previously synthesized DBU-CO₂ complex and subsequent O-alkylation. Transcarboxylation was found to be selective, as

Full text of DOI:10.1016/S0040-4039(02)00697-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4091–4093
Efficient and clean synthesis of N-alkyl carbamates by
transcarboxylation and O-alkylation coupled reactions using a
DBU–CO zwitterionic carbamic complex in aprotic polar media
2
Eduardo R. P e´ rez, Michele Odnicki da Silva, Vanessa C. Costa, Ubirajara P. Rodrigues-Filho and
Douglas W. Franco*
Instituto de Qu ´ı mica de S a˜ o Carlos, Cx. P. 780 CEP 13560-970, Universidade de S a˜ o Paulo, S a˜ o Paulo, Brazil
Received 31 January 2002; accepted 29 March 2002
Abstract—N-Alkyl carbamates were obtained with good to excellent yields by clean and mild transcarboxylation of several amines
with the previously synthesized DBU–CO complex and subsequent O-alkylation. Transcarboxylation was found to be selective,
2
as only carbamate was formed from 1-hydroxy-2-aminobutanol. © 2002 Published by Elsevier Science Ltd.
N-Alkyl carbamates represent an important class of
organic compounds, mainly employed in agriculture
We report here the synthesis of N-alkyl ethyl carba-
mates, with good to excellent yields, by mild transcar-
boxylation of several amines (Table 1, entries 1–5) with
(
pesticides, fungicides), pharmacology (medicinal drugs)
1
and as valuable intermediates in synthesis. Also,
organic carbamates have been found useful as protec2-
tive groups for the amine function in peptide synthesis.
a DBU–CO complex followed by the O-alkylation of
2
8
the N-alkyl carbamate intermediates with ethyl iodide.
An exploratory experiment was carried out using 1,6-
dibromohexane for the O-alkylation of the model N-
cyclohexyl carbamate intermediate to check the
compatibility of our method with different alkyl
halides. Hence, the corresponding N-cyclohexyl bromo-
hexyl carbamate was obtained with 80% yield (GC).
Classical procedures for the preparation of N-alkyl
carbamates are based on the reaction of either amines
3
4
with chloroformates, or alcohols with isocyanates.
Chloroformates and isocyanates are toxic and polluting
reagents and require careful handling. On the other
hand, the uncatalyzed reaction of primary or secondary
amines with carbon dioxide, and subsequent alkylation
In our experiments, DBU was found to be an efficient
catalyst for the activation of the carbon dioxide
molecule through nucleophilic attack on the weak elec-
trophilic carbon center of the CO2 molecule. The
5
usually leads to mainly N-alkylation products.
Recently, some attractive procedures for carbamates
synthesis have been reported which proposed the use of
carbon dioxide, as a clean and abundant raw material.
Utilization of sterically hindered strong organic bases
resulted DBU–CO carbamic complex was able to trans-
2
carboxylate several amines (entries 1–5) to provide the
N-alkyl carbamates intermediates as ‘‘naked anions’’
which, conjugated with protonated DBU, were con-
verted to the corresponding N-alkyl carbamates esters
by subsequent O-alkylation (Scheme 1).
or cesium carbonate has been proposed to enhance the6
reactivity of the carbamate anion toward O-alkylation.
Use of amidines such as the diazabicycloundecene
(
DBU) for carbonylation with carbon dioxide was
7
About 75% (w/w) of the employed DBU was recovered
as a free base, from the first catalytic cycle shown in
Scheme 1, which has been reutilized once again for the
synthesis of N-cyclohexyl ethyl carbamate (entry 1)
with reproducible yield and purity. Carbamate interme-
diates, isolated from the reaction mixtures (entries 1
and 4), were unambiguously characterized (NMR, mass
spectrometry) and subsequently transformed in the
related N-alkyl ethyl carbamates.
described in the synthesis of dihydroquinazolines.
Keywords: carbon dioxide; DBU–CO ; transcarboxylation; N-alkyl
carbamates.
*
2
Corresponding author. Fax: 55 16 273 9976; e-mail: douglas@
iqsc.sc.usp.br
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00697-4

4
092
E. R. P e´ rez et al. / Tetrahedron Letters 43 (2002) 4091–4093
Table 1.
9
proton transfer, despite the reported pK (23.9) value
a
for DBU in acetonitrile being greater than those for
investigated alcohols (e.g. pK of ethanol is 17.0). On
a
the other hand, alcohols used in our experiments were
not strong enough as nucleophiles to displace the CO2
molecule from the DBU–CO complex.
2
The most important features of the protocol described
here are the following:
i. The suitability of DBU as a trap for fixation and
storage of CO in the form of a reactive DBU–CO
Scheme 1.
2
2
adduct, which is useful for transcarboxylation of
several amines.
ii. The cleanness and mildness of the procedure that
The reactivity of the DBU–CO2 complex has been
investigated towards aliphatic primary (C –C ) alco-
hols. Consequently, with the selective amine transcar-
boxylation observed for aminoalcohols (entry 3),
carbonate formation was unsuccessful even with DBU–
1
5
employs CO as a trouble-free starting material for
2
the preparation of important synthetic intermediates
CO excess (5 equiv.) for 24 h (Scheme 2). In all the
2
cases, starting alcohols and DBU–CO complex were
2
almost quantitatively recovered. Similar results were
obtained when the reactions were carried out using
DBU (5 equiv.) as base under pressurized CO (10 atm)
2
even with heating (60°C) for reaction times up to 48 h.
Under the above conditions, the formation of the
DBU–CO adduct occurs rather than thermodynamic
Scheme 2.
2

E. R. P e´ rez et al. / Tetrahedron Letters 43 (2002) 4091–4093
4093
and biologically interesting compounds (e.g. pyridine
and furfuryl derivatives).
6. (a) McGhee, W. C.; Pan, Y.; Riley, D. P. J. Chem. Soc.,
Chem. Commun. 1994, 699–700; (b) Casadei, M. A.; Inesi,
A.; Moracci, F. M.; Rossi, L. Chem. Commun. 1996,
In summary, we propose the utilization of the DBU–
2575–2576; (c) Inesi, A.; Mucciante, V.; Rossi, L. J. Org.
CO carbamic complex as an efficient, clean and selec-
2
Chem. 1998, 63, 1337–1338; (d) Salvatore, R. N.; Ledger,
J. A.; Jung, K. W. Tetrahedron Lett. 2001, 42, 6023–6025.
. Mizuno, T.; Okamoto, N.; Ito, T.; Miyata, T. Tetrahedron
Lett. 2000, 41, 1051–1053 and references therein.
. Representative experimental procedures: (a) DBU–CO2:
DBU (1.52 g, 10 mmol) was stirred in anhydrous acetoni-
trile (10 mL) under a continuous stream of carbon dioxide
tive transcarboxylating reagent for preparation of
N-alkyl carbamates. Furthermore, this procedure could
be used as a combinatorial chemistry approach for
simultaneous synthesis of several N-alkyl carbamates
from a diverse range of amines and alkyl halides.
7
8
Experimental and theoretical studies concerning the
(
30 mL/min) for 1 h at 5°C. Then, deposited solid was
capability of several hindered bases for CO coordina-
2
filtered off and washed with cold acetonitrile (3×5 mL) to
tion and transfer towards various nucleophiles are cur-
rently in progress at our Laboratory. Results from
these studies will be communicated elsewhere.
give DBU–CO as a white powder (1.57 g, 80%) with high
2
purity; mp 38–39°C dec. with a loss of 23% of mass (CO )
2
1
on TGA analysis; H NMR (200 MHz, D O) l 1.75–2.01
2
(
m, 3CH , C-5+C-6+C-8), 2.65 (t, CH , C-4), 3.15–3.25
2
2
Acknowledgements
(m, 2CH
2
, C-7+C-11), 3.51 (t, CH
2
, C-12), 4.60 (t, CH ,
2
13
C-10); C NMR (50.32 MHz, D O) l 19.5 (C-6), 23.9
2
We gratefully acknowledge financial support from
FAPESP. One of us, Eduardo R. P e´ rez is thankful for
a CAPES fellowship.
(C-5), 26.4 (C-7), 29.0 (C-11), 33.2 (C-12), 38.5 (C-4), 48.7
(C-8), 54.6 (C-10), 160.7 (C-1), 166.4 (C-3); (b) N-alkyl
carbamates: In a typical procedure, 2 mmol of amine
(
entry 4), were slowly added to the suspension of DBU–
CO (0.47 g, 2.4 mmol) in 10 mL of anhydrous acetoni-
2
References
trile, with stirring for 1.5 h at 5°C. Then, ethyl iodide (0.47
g, 3 mmol) was poured into the solution and the reaction
mixture was stirred at ambient temperature for an addi-
tional 6 h. Evaporation of the solvent and extraction with
ethyl ether (3×10 mL) or alternative column chromatogra-
1
. (a) The Agrochemicals Handbook, 2nd ed.; Royal Society
of Chemistry, 1987; (b) The Pesticide Manual, 10th ed.;
Royal Society of Chemistry, 1994; (c) Adams, P.; Baron,
F. A. Chem. Rev. (Washington, DC) 1965, 65, 567; (d)
Chong, P. Y.; Janicki, S. Z.; Petillo, P. A. J. Org. Chem.
phy (6:1 hexanes/EtOAc) gave the N-(2-furfuryl) ethyl
1
carbamate as a yellow oil. H NMR (200.13 MHz, CDCl )
3
1
998, 63, 8515–8521.
l 1.24 (t, 3H, methyl), 4.11 (q, 2H, methylene), 4.29 (d,
2
3
. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; John Wiley and Sons: New
York, 1991; pp. 315–348.
2
6
H, methylene), 5.05 (t, 1H, amino), 6.20 (d, 1H, 3-furyl),
.29 (dd, 1H, 4-furyl), 7.32 (d, 1H, 5-furyl). C NMR
13
(
50.32 MHz, D O) l 15.3, 37.9, 61.0, 107.0, 109.5, 142.1,
2
. Bergmann, M.; Zervas, L. Chem. Ber. 1932, 65, 1192–
1
51.6, 156.3. MS (70 eV) m/z 69, 81, 96 (100%), 140, 169
1
198.
+
−1
(
M ). IR (thin film on silicon wafer) cm 3336, 1679,
312.
4
5
. Osaki, S. Chem. Rev. 1972, 72, 475–496.
. (a) Aresta, M.; Quaranta, E. J. Chem. Soc., Dalton Trans.
992, 1893–1899; (b) Aresta, M.; Quaranta, E. J. Org.
Chem. 1998, 53, 4153–4154.
1
9
. Leffek, K.; Przuszynski, P.; Thanapaalasingham, K. Can.
J. Chem. 1989, 67, 590–595.
1