entry 7). Further experiments will be pursued to probe this
apparent microwave effect.
MeHYQ-catalyzed carbamate-urea exchange conditions in
an attempt to prepare tetra-substituted ureas. This result
indicates that an isocyanate intermediate19,20 is likely gener-
ated in situ from the carbamate, which is consistent with
literature precedents on carbamate decomposition.10a,21 We
believe that the greater reactivity of MeHYQ versus HYP
for carbamate-urea exchange is likely due to the higher
basicity of the conjugate base of MeHYQ, which facilitates
isocyanate formation by deprotonation of the carbamate.22
In conclusion, zirconium(IV)-catalyzed exchange processes
have been developed to prepare both carbamates and ureas
from dialkyl carbonates and carbamates employing 2-hy-
droxypyridine (HYP) and 4-methyl-2-hydroxyquinoline (Me-
HYQ), respectively, as catalytic additives. Mechanistic
studies and application of the exchange processes to the
synthesis of complex carbamates and ureas are currently
underway and will be reported in due course.
The scope and limitations of urea formation using car-
bamate-urea exchange were evaluated under microwave
irradiation using 10 mol % of Zr(Ot-Bu)4 and 20 mol % of
MeHYQ as catalyst (Table 4). In general, reactions to prepare
mono-, di-, and trisubstituted ureas were completed in 15
min at temperatures varying from 60 to 140 °C depending
on the specific substrate. During reaction optimization, we
found that the reactions were best performed without solvent;
however, a minimum amount of solvent (chlorobenzene,
1.0-2.0 M) was employed in some cases to aid in dissolving
substrates. Based on observed reaction temperature differ-
ences, the reactivity of a number of synthetically useful
carbamate protecting groups was found to decrease in the
following order: Troc > Alloc > methyl carbamate, ethyl
carbamate, Cbz > Boc (Table 4, entry 1).17 The relatively
high reactivity of the Troc carbamate18 identifies it as a
desirable precursor for the synthesis of complex ureas via
exchange processes (Table 4, entries 5-8) including 20
(entry 7), a recently reported inhibitor of human cyclophilin
A with potent anti-HIV activity.2b Of note is the chemose-
lective addition of amines to the Troc carbamate versus tert-
butyl and ethyl esters, respectively (Table 4, entries 5 and
6). However, utilizing HYP as an additive or under conven-
tional heating, a lower selectivity for urea formation was
observed in the case of entry 6 (Table 4).
Acknowledgment. Financial support from the National
Institutes of Health (NIGMS CMLD initiative, P50 GM-
067041), Merck Research Laboratories, and Bristol-Myers
Squibb (Unrestricted Grant in Synthetic Organic Chemistry,
J.A.P, Jr.) is gratefully acknowledged. We thank CEM Corp.
(Matthews, NC) for assistance with microwave instrumenta-
tion.
Supporting Information Available: Experimental pro-
cedures and characterization. This material is available free
In comparison to the stepwise protocol, a one-pot urea
synthesis sequence was also developed (Table 4, entry 4) in
which carbamate 6 was prepared in situ from amine and
carbonate and condensed with a second amine in the same
reaction vessel without purification. A one-pot synthesis of
cyclic ureas by condensation of diamines and diethyl
carbonate was also found to be workable (Table 4, entries 9
and 10). It should be noted that carbamates derived from
secondary amines were found to be inert under Zr(IV)-
OL0702728
(19) For representative metal isocyanate complexes, see: Fe: (a) King,
R. B.; Bisnette, M. B. Inorg. Chem. 1966, 5, 306. (b) Drapier, J.; Hoornaerts,
M. T.; Hubert, A. J.; Teyssie´, P. J. Mol. Catal. 1981, 11, 53. Ir: (c) Collman,
J. P.; Kubota, M.; Vastine, F. D.; Sun, J. Y.; Kang, J. W. J. Am. Chem.
Soc. 1968, 90, 5430. Rh: (d) Hasegawa, S.; Itoh, K.; Ishii, Y. Inorg. Chem.
1974, 13, 2675. Zr: (e) Anderson, S. J.; Brown, D. S.; Finney, K. J. J.
Chem. Soc., Dalton Trans. 1979, 152.
(20) For zirconium-catalyzed condensation of isocyanates and alcohols,
see: Blank, W. J.; He, Z. A.; Hessell, E. T. Prog. Org. Coat. 1999, 35, 19.
(21) For dealcoholysis of carbamates to isocyanates, see: (a) Uriz, P.;
Serra, M.; Salagre, P.; Castillon, S.; Claver, C.; Fernandez, E. Tetrahedron
Lett. 2002, 43, 1673. (b) Gallou, I.; Eriksson, M.; Zeng, X.; Senanayake,
C.; Farina, V. J. Org. Chem. 2005, 70, 6960.
(17) Troc ) 2,2,2-trichloroethyloxycarbonyl, Alloc ) allyloxycarbonyl,
Cbz ) benzyloxycarbonyl, Boc ) tert-butoxycarbonyl.
(18) For urea synthesis via high-pressure-promoted condensation of Troc
carbamates and amines, see: Azad, S.; Kumanoto, K.; Uegaki, K.; Ichikawa,
Y.; Kotsuki, H. Tetrahedron Lett. 2006, 47, 587.
(22) pKa (DMSO): HYP, 17.0; HYQ, 20.7; NH2CO2Et, 24.6. Bordwell,
F. G. Acc. Chem. Res. 1988, 21, 456.
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Org. Lett., Vol. 9, No. 8, 2007