Synthesis of carbamates and ureas using Zr(IV)-catalyzed exchange processes

Article abstract of DOI:10.1021/ol0702728

Equation presented Zirconium(IV)-catalyzed exchange processes have been developed to prepare both carbamates and ureas from dialkyl arbonates and carbamates employing 2-hydroxypyridine (HYP) and 4-methyl-2-hydroxyquinoline (MeHYQ) as catalytic additives, respectively A microwave acceleration effect was observed in Zr(IV)-catalyzed carbamate-urea exchange.

Full text of DOI:10.1021/ol0702728

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1517-1520
Synthesis of Carbamates and Ureas
Using Zr(IV)-Catalyzed Exchange
Processes
Chong Han and John A. Porco, Jr*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment,
Boston UniVersity, 590 Commonwealth AVenue, Boston, Massachusetts 02215
porco@bu.edu
Received February 2, 2007
ABSTRACT
Zirconium(IV)-catalyzed exchange processes have been developed to prepare both carbamates and ureas from dialkyl carbonates and carbamates
employing 2-hydroxypyridine (HYP) and 4-methyl-2-hydroxyquinoline (MeHYQ) as catalytic additives, respectively. A microwave acceleration
effect was observed in Zr(IV)-catalyzed carbamate−urea exchange.
Carbamate and urea functional groups play important roles
in organic, medicinal, supramolecular, and material chem-
istry.1 For example, recent reports have cited examples of
ureas as potent HIV-1 protease inhibitors,2 p38 MAP kinase
inhibitors for the treatment of inflammatory diseases,3 and
peptidomimetics with increased metabolic stability. Although
a number of methodologies, including oxidative carbonyla-
tion of amines,4 have been developed, the standard prepara-
tion of carbamates and ureas generally involves use of toxic
and highly reactive phosgene,5 phosgene derivatives,6 or
isocyanates.7
Recently, dialkyl carbonates8 have emerged as environ-
mentally friendly and nontoxic substitutes for phosgene and
phosgene derivatives in alkoxycarbonylation reactions. For
instance, metal-catalyzed carbamate syntheses using dim-
ethylcarbonate and amines have been reported.9 Related
syntheses of ureas from O-alkyl carbamates and amines have
also been accomplished in the presence of stoichiometric
amounts of mediators.10 Direct conversion of carbamates to
ureas obviates the need for intermediate deprotection and
activation steps. On the basis of our previous work concern-
(7) Ozaki, S. Chem. ReV. 1972, 72, 457.
(1) (a) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russ. Chem.
ReV. (Engl. Transl.) 1985, 54, 249. (b) Gabriele, B.; Salerno, G.; Mancuso,
R.; Costa, M. J. Org. Chem. 2004, 69, 4741 and references therein.
(2) (a) Han, Q.; Chang, C.-H.; Li, R.; Ru, Y.; Jadhav, P. K.; Lam, P. Y.
S. J. Med. Chem. 1998, 41, 2019 and references therein. (b) Guichou, J.-
F.; Viaud, J.; Mettling, C.; Subra, G.; Lin, Y.-L.; Chavanieu, A. J. Med.
Chem. 2006, 49, 900.
(3) Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.;
Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C.;
Pav, S.; Proto, A.; Swinamer, A.; Tong, L.; Torcellini, C. J. Med. Chem.
2002, 45, 2994 and references therein.
(4) McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C. A.;
McElwee-White L. J. Org. Chem. 2000, 65, 5216 and references therein.
(5) Babad, H.; Zeiler, A. G. Chem. ReV. 1973, 73, 75.
(6) For a review on the use of phosgene substitutes, see: Biggi, F.; Maggi,
R.; Sartori, G. Green Chem. 2000, 2, 140.
(8) For recent reviews on the chemistry of dialkyl carbonates, see: (a)
Shaikh, A.-A. G.; Sivaram, S. Chem. ReV. 1996, 96, 951. (b) Parrish, J. P.;
Salvatore, R. N.; Jung, K. W. Tetrahedron 2000, 56, 8207. For a review
on the chemistry of dimethylcarbonate, see: (c) Tundo, P.; Selva, M. Acc.
Chem. Res. 2002, 35, 706.
(9) Pb(NO3)2: (a) Baba, T.; Fujiwara, M.; Oosaku, A.; Kobayashi, A.;
Deleon, R. G.; Ono, Y. Appl. Catal., A 2002, 227, 1. Yb(OTf)3: (b) Curini,
M.; Epifano, F.; Maltese, F.; Rosati, O. Tetrahedron Lett. 2002, 43, 4895.
Sc(OTf)3 and La(OTf)3: (c) Distaso, M.; Quaranta, E. Tetrahedron 2004,
60, 1531.
(10) SiRnCl4-n: (a) Chong, P. Y.; Janicki, S. Z.; Petillo, P. A. J. Org.
Chem. 1998, 63, 8515. γ-Al2O3: (b) Vauthey, I.; Valot, F.; Gozzi, C.; Fache,
F.; Lemaire, M. Tetrahedron Lett. 2000, 41, 6347. SiI2H2: (c) Gastaldi, S.;
Weinreb, S. M.; Stien D. J. Org. Chem. 2000, 65, 3239. AlMe3: (d) Lee,
S.-H.; Matsushita, H.; Clapham, B.; Janda, K. D. Tetrahedron 2004, 60,
3439.
10.1021/ol0702728 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/15/2007

ing Zr(IV)-catalyzed ester-amide exchange,11 we wished to
extend our methodology to the synthesis of carbamates and
ureas by reaction of amines with both dialkyl carbonates and
carbamates.
Table 2. Scope of Carbonate-Carbamate Exchangea
In line with our previous studies concerning the additive
acceleration effects in Zr(IV)-catalyzed ester-amide ex-
change,11a initial experiments focused on evaluation of
catalytic amounts of Zr(Ot-Bu)4 and a series of nucleophilic
additives in the reaction of N-Me benzylamine and dimeth-
ylcarbonate in the absence of solvent (Table 1). Among
Table 1. Optimization of Carbonate-Carbamate Exchangea,b
entry
conditions
conversion (%)c
1
2
3
4
5
6
7
8
9
none
7
69
75
47
58
79
87 (85)d
88
Zr(Ot-Bu)4 (5 mol %)
Zr(Ot-Bu)4 (5 mol %), HOAt (5 mol %)
Zr(Ot-Bu)4 (5 mol %), HOBt (5 mol %)
Zr(Ot-Bu)4 (5 mol %), MeHYQ (5 mol %)
Zr(Ot-Bu)4 (5 mol %), HYP (5 mol %)
Zr(Ot-Bu)4 (5 mol %), HYP (10 mol %)
Zr(Ot-Bu)4 (5 mol %), HYP (20 mol %)
HYP (10 mol %)
a Reaction conditions: amine (1.0 equiv), carbonate (1.5 equiv), Zr(Ot-
Bu)4 (5 mol %), HYP (10 mol %), neat, 80 °C, 12 h. b Isolated yield after
purification by silica gel chromatography. c 1.1 equiv of carbonate employed.
d Zr(Ot-Bu)4 (10 mol %), HYP (20 mol %) employed. e 3 equiv of carbonate
employed. f Reaction conducted at 100 °C.
17
a Reaction conditions: amine (1.0 equiv), dimethylcarbonate (1.1 equiv),
neat, 80 °C, 16 h. b HOAt ) 1-hydroxy-7-azabenzotriazole, HOBt )
1-hydroxybenzotriazole, MeHYQ ) 4-methyl-2-hydroxyquinoline, HYP )
2-hydroxypyridine. c Conversions based on 1H NMR analysis of the crude
reaction mixture. d Isolated yield indicated in parenthesis.
(12 h). Four different carbonates (Me, Et, Bn, allyl) examined
showed similar reactivities in reactions with benzylamine.
In terms of the amine scope, both aliphatic and aromatic
amines performed well. The reaction of 2-aminobenzylamine
with dimethylcarbonate was found to be chemoselective for
aliphatic versus aromatic amines (Table 2, entry 3). In
contrast, 2-aminobenzylamine has been shown to react with
methyl chloroformate to afford the corresponding bis-
carbamate without selectivity.14 Functional groups
additives evaluated,12 2-hydroxypyridine (HYP)13 was found
to be optimal. Control experiments without catalyst or with
10 mol % HYP showed low conversions (Table 1, entries 1
and 9). The effect of the ratio of metal to additive on catalyst
efficiency was also examined (Table 1, entries 6-8).
Increasing the ratio beyond 1:2 did not show noticeable
improvement on product conversions. Further optimization
to shorten the reaction time using microwave irradiation was
unsuccessful.
With effective conditions in hand, we next examined the
scope of Zr(IV)-catalyzed carbonate-carbamate exchange
(Table 2). In general, reactions were performed neat with
1.0 equiv of amine and 1.5 equiv of dialkyl carbonate in the
presence of 5 mol % Zr(Ot-Bu)4 and 10 mol % HYP at 80 °C
Table 3. Optimization of Carbamate-Urea Exchangea,b
entry
conditions
conversion (%)c
(11) (a) Han, C.; Lee, J. P.; Lobkovsky, E.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2005, 127, 10039 and references therein. For recent reports on Ti-
(IV)-catalyzed transamidation, see: (b) Eldred, S. E.; Stone, D. A.; Gellman,
S. H.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 3422. (c) Kissounko, D.
A.; Hoerter, J. M.; Guzei, I. A.; Cui, Q.; Gellman, S. H.; Stahl, S. S. J. Am.
Chem. Soc. 2007, 129, 1776.
(12) See Supporting Information for complete experimental details.
(13) For representative examples of metal complexes containing HYP
or HYP derivatives, see: Cu, Ni, and Co: (a) Parsons, S.; Winpenny, R.
E. P. Acc. Chem. Res. 1997, 30, 89. Pd: (b) Maity, S.; Roy, R.; Sinha, C.;
Sheen, W.-J.; Panneerselvam, K.; Lu, T.-H. J. Organomet. Chem. 2002,
650, 202. Au: (c) Thwaite, S. E.; Schier, A.; Schmidbaur, H. Inorg. Chim.
Acta 2004, 357, 1549. Ti and Zr: (d) Takashima, Y.; Nakayama, Y.;
Hashiguchi, M.; Hosoda, T.; Yasuda, H.; Hirao, T.; Harada, A. Polymer
2006, 47, 5762.
1
2
3
4
5
6
7d
none
3
74
62
86
95
13
99 (94)e
Zr(Ot-Bu)4 (10 mol %)
Zr(Ot-Bu)4 (10 mol %), HYP (20 mol %)
Zr(Ot-Bu)4 (10 mol %), HYQ (20 mol %)
Zr(Ot-Bu)4 (10 mol %), MeHYQ (20 mol %)
MeHYQ (20 mol %)
Zr(Ot-Bu)4 (10 mol %), MeHYQ (20 mol %)
a Reaction conditions: amine (1.1 equiv), urethane (1.0 equiv), neat,
100 °C, 12 h. b HYQ ) 2-hydroxyquinoline. c Conversions based on 1H
NMR analysis of the crude reaction mixture. d µW, 120 °C, 15 min.
e Isolated yield indicated in parenthesis.
1518
Org. Lett., Vol. 9, No. 8, 2007

Table 4. Urea Synthesis by Reaction of Amines and Carbamates or Carbonatesa
a Reaction conditions: amine (1.0 equiv), carbamate (1.1 equiv), Zr(Ot-Bu)4 (10 mol %), MeHYQ (20 mol %), neat, µW, temp, 15 min. For entries
9-10: amine (2.2 equiv), carbonate (1.0 equiv), Zr(Ot-Bu)4 (20 mol %), MeHYQ (40 mol %), chlorobenzene (1.0 M), µW, temp, 15 min. b Isolated yield
after purification by silica gel chromotagraphy. c Carbamate (1.5 equiv) employed. d Reaction performed in chlorobenzene (2.0 M). e Carbamate 6 was
prepared in situ without purification.
including acetonide (Table 2, entry 2), indole (entry 6), and
cyclic ketal (entry 7) were found to be tolerated under the
reaction conditions. For diamine substrates, cyclic urea
products were not observed (Table 2, entries 3 and 4).
We next explored urea formation through carbamate-urea
exchange. In contrast to the carbamate formation, additive
screening identified 4-methyl-2-hydroxyquinoline (Me-
HYQ)15 as an optimal additive in model reactions between
3,4-dimethoxyphenethylamine and N-ethyl urethane (Table
3). Control experiments without catalyst or with 20 mol %
MeHYQ showed low conversions (Table 3, entries 1 and
6). In contrast to carbamate formation, we found that urea
formation was significantly accelerated using microwave
irradiation.16 For instance, 12 h was required for the model
reaction to reach completion at 100 °C under conventional
heating, whereas only 15 min was needed if the reaction was
performed at 120 °C under microwave irradiation (Table 3,
(14) Selva, M.; Tundo, P.; Perosa, A.; Dall’Acqua, F. J. Org. Chem.
2005, 70, 2771.
(15) For examples of MeHYQ-containing metal complexes, see: Li: (a)
Liddle, S. T.; Clegg, W. J. Chem. Soc., Dalton Trans. 2002, 3923. Ru: (b)
Steed, J. W.; Tocher, D. A. J. Chem. Soc., Dalton Trans. 1992, 2765. (c)
Wilton-Ely, J. D. E. T.; Wang, M.; Honarkhah, S. J.; Tocher, D. A. Inorg.
Chim. Acta 2005, 358, 3218. Rh: (d) Kawamura, T.; Kachi, H.; Fujii, H.;
Kachi-Terajima, C.; Kawamura, Y.; Kanematsu, N.; Ebihara, M.; Sugimoto,
K.; Kuroda-Sowa, T.; Munakata, M. Bull. Chem. Soc. Jpn. 2000, 73, 657.
(16) (a) Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2004, 45, 7205. (b)
Bridgeman, E.; Tomkinson, N. C. O. Synlett 2006, 243. For recent reviews
on microwave-mediated synthesis, see: (c) Loupy, A.; Petit, A.; Hamelin,
J.; Texier-Boullet, F.; Jacquault, P.; Mathe´, D. Synthesis 1998, 1213. (d)
Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199. (e) Larhed, M.; Moberg,
C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (f) Kappe, C. O. Angew.
Chem., Int. Ed. 2004, 43, 6250.
Org. Lett., Vol. 9, No. 8, 2007
1519

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
of charge via the Internet at http://pubs.acs.org.
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.
1520
Org. Lett., Vol. 9, No. 8, 2007