W(CO)6-catalyzed oxidative carbonylation of primary amines to n,n'-disubstituted ureas in single or biphasic solvent systems. Optimization and functional group compatibility studies

Article abstract of DOI:10.1021/jo000364+

Primary amines undergo carbonylation to N,N'-disubstituted ureas using W(CO)₆ as the catalyst, I₂ as the oxidant, and CO as the carbonyl source. Preparation of various N,N'-disubstituted ureas from aliphatic primary amines, RNH₂ (R = n-Pr, n-Bu, i-Pr, sec-Bu, or t-Bu), was achieved in good to excellent yields. Studies of functional group compatibility using a series of substituted benzylamines demonstrated broad tolerance of functionality during the carbonylation reaction. Preparation of various N,N'-disubstituted ureas from substituted benzylamines, R-C₆H₄CH₂NH₂ (R = H, p-OCH₃, p-CO₂H, p-CO₂Et, p-CH₂OH, p-SCH₃, p-vinyl, p-Cl, p-Br, m-I, p-NH₂, p-NO₂, or p-CN), was achieved in good yields. For many substituted benzylamines, yields of ureas were higher when a two-phase CH₂Cl₂/H₂O solvent system was used.

Full text of DOI:10.1021/jo000364+

5216
J . Org. Chem. 2000, 65, 5216-5222
W(CO)6-Ca ta lyzed Oxid a tive Ca r bon yla tion of P r im a r y Am in es to
N,N′-Disu bstitu ted Ur ea s in Sin gle or Bip h a sic Solven t System s.
Op tim iza tion a n d F u n ction a l Gr ou p Com p a tibility Stu d ies
J ennifer E. McCusker, A. Denise Main, Kirsten S. J ohnson, Cara A. Grasso, and
Lisa McElwee-White*
Department of Chemistry, University of Florida, Gainesville, Florida 32611
lmwhite@chem.ufl.edu
Received March 14, 2000
Primary amines undergo carbonylation to N,N′-disubstituted ureas using W(CO)6 as the catalyst,
I2 as the oxidant, and CO as the carbonyl source. Preparation of various N,N′-disubstituted ureas
from aliphatic primary amines, RNH2 (R ) n-Pr, n-Bu, i-Pr, sec-Bu, or t-Bu), was achieved in good
to excellent yields. Studies of functional group compatibility using a series of substituted
benzylamines demonstrated broad tolerance of functionality during the carbonylation reaction.
Preparation of various N,N′-disubstituted ureas from substituted benzylamines, R-C6H4CH2NH2
(R ) H, p-OCH3, p-CO2H, p-CO2Et, p-CH2OH, p-SCH3, p-vinyl, p-Cl, p-Br, m-I, p-NH2, p-NO2, or
p-CN), was achieved in good yields. For many substituted benzylamines, yields of ureas were higher
when a two-phase CH2Cl2/H2O solvent system was used.
In tr od u ction
while phosgene derivatives can be expensive to use on a
large scale. Additional impetus for replacement of phos-
gene derivatives comes from the standpoint of atom
economy10 by which using CO to install a carbonyl moiety
into a urea would be preferable to a method using a
typical phosgene derivative such as 1,1-carbonyldiimid-
azole. The direct metal-catalyzed conversion of amines
and CO to ureas provides an alternative to phosgene and
its derivatives.
Although catalytic carbonylation has been investigated
over many years,11-13 the topic remains of interest.
Oxidative conversion of primary amines into ureas has
been reported for transition metal catalysts involving
Ni,14 Co,15 Mn,16,17 Ru18 and, most commonly, Pd.19-21
Main group elements such as sulfur22,23 and selenium24-26
can also serve as catalysts. However, neither the transi-
Substituted ureas have been of recent interest due to
appearance of this functionality in drug candidates such
as HIV protease inhibitors,1,2 FKBP12 inhibitors,3 CCK-B
receptor antagonists4,5 and endothelin antagonists.6 In
addition, ureas have found widespread use as agricul-
tural chemicals, resin precursors, dyes, and additives to
petroleum compounds and polymers.7 Among the numer-
ous methods for synthesis of N,N′-disubstituted ureas are
the reactions of primary amines with isocyanates, phos-
gene, or phosgene derivatives.8,9 Yields are usually good
to excellent for these reactions, but other aspects can be
problematic. Phosgene itself is highly toxic and corrosive
(1) Lam, P. Y. S.; J adhav, P. K.; Eyermann, C. J .; Hodge, C. N.; Ru,
Y.; Bacheler, L. T.; Meek, J . L.; Otto, M. J .; Rayner, M. M.; Wong, Y.
N.; Chang, C. H.; Weber, P. C.; J ackson, D. A.; Sharpe, T. R.; Erickson-
Viitanen, S. Science 1994, 263, 380-384.
(2) Lam, P. Y. S.; Ru, Y.; J adhav, P. K.; Aldrich, P. E.; DeLucca, G.
V.; Eyermann, C. J .; Chang, C. H.; Emmett, G.; Holler, E. R.; Daneker,
W. F.; Li, L. Z.; Confalone, P. N.; McHugh, R. J .; Han, Q.; Li, R. H.;
Markwalder, J . A.; Seitz, S. P.; Sharpe, T. R.; Bacheler, L. T.; Rayner,
M. M.; Klabe, R. M.; Shum, L. Y.; Winslow, D. L.; Kornhauser, D. M.;
J ackson, D. A.; Erickson-Viitanen, S.; Hodge, C. N. J . Med. Chem.
1996, 39, 3514-3525.
(3) Dragovich, P. S.; Barker, J . E.; French, J .; Imbacuan, M.; Kalish,
V. J .; Kissinger, C. R.; Knighton, D. R.; Lewis, C. T.; Moomaw, E. W.;
Parge, H. E.; Pelletier, L. A. K.; Prins, T. J .; Showalter, R. E.; Tatlock,
J . H.; Tucker, K. D.; Villafranca, J . E. J . Med. Chem. 1996, 39, 1872-
1884.
(4) Semple, G.; Ryder, H.; Rooker, D. P.; Batt, A. R.; Kendrick, D.
A.; Szelke, M.; Ohta, M.; Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata,
K. J . Med. Chem. 1997, 40, 331-341.
(5) Castro, J . L.; Ball, R. G.; Broughton, H. B.; Russell, M. G. N.;
Rathbone, D.; Watt, A. P.; Baker, R.; Chapman, K. L.; Fletcher, A. E.;
Patel, S.; Smith, A. J .; Marshall, G. R.; Ryecroft, W.; Matassa, V. G.
J . Med. Chem. 1996, 39, 842-849.
(6) vonGeldern, T. W.; Kester, J . A.; Bal, R.; WuWong, J . R.; Chiou,
W.; Dixon, D. B.; Opgenorth, T. J . J . Med. Chem. 1996, 39, 968-981.
(7) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russ. Chem.
Rev. (Engl. Transl.) 1985, 54, 249-261.
(8) Hegarty, A. F.; Drennan, L. J . in Comprehensive Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O.,
Rees, C. W., Eds.; Pergamon: Oxford, 1995; Vol. 6, pp 499-526.
(9) Guichard, G.; Semetey, V.; Didierjean, C.; Aubry, A.; Briand, J .
P.; Rodriguez, M. J . Org. Chem. 1999, 64, 8702-8705.
(10) Trost, B. M. Angew. Chem.-Int. Edit. Engl. 1995, 34, 259-281.
(11) Colquhoun, H. M.; Thompson, D. J .; Twigg, M. V. Carbonyla-
tion: Direct Synthesis of Carbonyl Compounds; Plenum: New York,
1991.
(12) Sheldon, R. A. Chemicals from Synthesis Gas; Dordrecht:
Boston, 1983.
(13) Wender, I.; Pino, P. Organic Syntheses via Metal Carbonyls;
Wiley-Interscience: New York, 1968.
(14) Giannoccaro, P.; Nobile, C. F.; Mastrorilli, P.; Ravasio, N. J .
Organomet. Chem. 1991, 419, 251-258.
(15) Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. J . Mol. Catal.
1990, 60, 41-48.
(16) Dombek, B. D.; Angelici, R. J . J . Organomet. Chem. 1977, 134,
203-217.
(17) Calderazzo, F. Inorg. Chem. 1965, 4, 293-296.
(18) Mulla, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. J . Mol.
Catal. A-Chem. 1997, 122, 103-109.
(19) Pri-Bar, I.; Alper, H. Can. J . Chem.-Rev. Can. Chim. 1990, 68,
1544-1547.
(20) Dahlen, G. M.; Sen, A. Macromolecules 1993, 26, 1784-1786.
(21) Gupte, S. P.; Chaudhari, R. V. J . Catal. 1988, 114, 246-258.
(22) Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F. J . Org.
Chem. 1961, 26, 3306-3308.
(23) Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F.; Bolze,
C. J . Org. Chem. 1961, 26, 3309-3312.
(24) Sonoda, N.; Yasuhara, T.; Kondo, K.; Ikeda, T.; Tsutsumi, S.
J . Am. Chem. Soc. 1971, 93, 6344.
(25) Yoshida, T.; Kambe, N.; Murai, S.; Sonoda, N. Bull. Chem. Soc.
J pn. 1987, 60, 1793-1799.
10.1021/jo000364+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/02/2000

Oxidative Carbonylation of Primary Amines
J . Org. Chem., Vol. 65, No. 17, 2000 5217
Ta ble 1. Oxid a tive Ca r bon yla tion of n -P r op yla m in e
Ta ble 2. Op tim iza tion of th e Ca ta lytic Ca r bon yla tion of
w ith Gr ou p 6 Meta l Ca r bon yls
n -P r op yla m in e
catalyst
yielda,b (%)
W(CO)6 (mol %)
K2CO3 (equiv)
T (°C)
yielda,b (%)
W(CO)6
Mo(CO)6
Cr(CO)6
67
50
30
1.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
1.5
2.0
1.0
24
24
90
90
90
54
67
72
90
31
55
a
Isolated yield of di-n-propylurea calculated per equivalent of
b
n-propylamine. Values are ( 5%. Reaction conditions: n-propyl-
amine (14.2 mmol), W(CO)6 (0.28 mmol), I2 (7.1 mmol), K2CO3 (14.2
mmol), CH2Cl2 (40 mL), room temperature., 80 atm CO, 18 h.
110
a
Isolated yield of di-n-propylurea calculated per equivalent of
b
n-propylamine. Values are ( 5%. Reaction conditions: n-propyl-
amine (14.2 mmol), I2 (7.1 mmol), CH2Cl2 (40 mL), 80 atm CO, 18
h.
tion metal- nor the main group-catalyzed reactions are
ideal. The transition metal-catalyzed reactions generally
require high temperatures and pressures. In addition,
yields for aliphatic amines are generally much lower than
those for aromatic cases. Among the main group cata-
lysts, selenium-catalyzed carbonylation reactions can
produce high yields of ureas under mild conditions.
However, generation of hydrogen selenide as a byproduct
and the need for stoichiometric or excess selenium for
certain substrates25,26 are problematic.
We previously reported preliminary studies on the
catalytic oxidative carbonylation of primary amines to
ureas using either [(CO)2W(NPh)I2]2 or W(CO)6 as the
precatalyst and I2 as the oxidant.27,28 The W(CO)6/I2
catalyst system also works for the conversion of second-
ary amines to tetrasubstituted ureas29 and the prepara-
tion of cyclic ureas directly from primary and secondary
R,ω-diamines.30 We now report more extensive optimiza-
tion studies on oxidative carbonylation of aliphatic
primary amines to N,N′-disubstituted ureas using the
W(CO)6/I2 oxidative carbonylation system (eq 1). The
product ureas can be obtained in good to excellent yields.
Additionally, studies of functional group compatibility
using a series of substituted benzylamines demonstrate
broad tolerance of substrate functionality during the
carbonylation reaction.
lined 300-mL Parr high-pressure vessel pressurized with
80 atm CO and stirred at room temperature for 18 h
produced di-n-propylurea in a 67% yield with respect to
amine. Based on the results with W(CO)6, the congeneric
metal carbonyl compounds, Mo(CO)6 and Cr(CO)6, were
also examined as catalysts. For comparison purposes, the
experiments were all run under identical conditions
instead of being individually optimized for each metal.
Using Mo(CO)6 as the catalyst, di-n-propylurea was
produced in a 50% yield, while with Cr(CO)6 the urea
yield decreased further to 30%. Because second row
transition metal catalysts are generally more active than
their third row analogues, it had been expected that Mo-
(CO)6 would be an improvement over W(CO)6. However,
it is possible that the molybdenum intermediates were
not sufficiently robust for the reaction conditions and side
reactions became more significant. Following these ex-
periments, further optimization studies involved W(CO)6
as the catalyst.
Once W(CO)6 had been established as the preferred
catalyst, other variables were examined. Lowering the
amount of W(CO)6 to only 1 mol % resulted in a reduced
isolated yield of 54% and observation of unreacted
starting material under the conditions specified in Table
2. Subsequent experiments utilized 2 mol % W(CO)6 to
obtain complete reaction within a reasonable period of
time. Furthermore, increasing the temperature from
room temperature to 90 °C improved the yield marginally
to 72%. More significant improvement was obtained at
90 °C by increasing the amount of K2CO3 to 1.5 equiv
with respect to amine, which raised the yield of di-n-
propylurea to 90%. Further increases in the amount of
base caused the yields to decrease, most likely because
the additional insoluble K2CO3 caused stirring problems
in the reactor. Raising the temperature to 110 °C resulted
in formation of a brown oil and a decrease in yield to 55%.
The choice of solvent also turned out to be significant,
as seen in Table 3. Among the single solvents, chlorinated
solvents such as CH2Cl2 or CHCl3 gave the best yields of
di-n-propylurea at room temperature, as well as the
cleanest crude products. The remainder of the solvents
in Table 3 resulted in decreased urea yields. Surprisingly,
changing the solvent to methanol resulted in a change
in the carbonylation product. In the presence of methanol,
primary amines were carbonylated to the corresponding
formamides, instead of the expected ureas or carbamates.
Although CH2Cl2 was the best single solvent for the
n-propylamine case, solubility problems were encoun-
tered when CH2Cl2 was used as solvent for various
substituted benzylamines (vide infra), for which either
the amine starting material or the hydroiodide salt was
insoluble. Note that the stoichiometry of oxidative car-
Resu lts a n d Discu ssion
Op tim iza tion of Rea ction Con d ition s. In the initial
report on W(CO)6-catalyzed oxidative carbonylation of
aliphatic primary amines to 1,3-disubstituted ureas,28 we
reported conversion of n-butylamine to di-n-butylurea in
80% yield based on amine. This was a promising but
unoptimized result. The system has subsequently been
more thoroughly explored. Variables such as catalyst,
temperature, solvent, CO pressure and quantity of added
base have now been examined and the results are
described below.
As seen in Table 1, the initial carbonylation of n-
propylamine in the presence of 2 mol % W(CO)6, 0.5 equiv
of I2, and 1.0 equiv K2CO3 in 40 mL CH2Cl2 in a glass-
(26) Yoshida, T.; Kambe, N.; Murai, S.; Sonoda, N. Tetrahedron Lett.
1986, 27, 3037-3040.
(27) McCusker, J . E.; Abboud, K. A.; McElwee-White, L. Organo-
metallics 1997, 16, 3863-3866.
(28) McCusker, J . E.; Logan, J .; McElwee-White, L. Organometallics
1998, 17, 4037-4041.
(29) McCusker, J . E.; Qian, F.; McElwee-White, L. J . Mol. Catal.
A-Chem. in press.
(30) McCusker, J . E.; Grasso, C. A.; Main, A. D.; McElwee-White,
L. Organic Lett. 1999, 1, 961-964.

5218 J . Org. Chem., Vol. 65, No. 17, 2000
McCusker et al.
Ta ble 3. Com p a r ison of Solven ts in th e Oxid a tive
Ta ble 4. Va r ia tion of CO P r essu r e in th e Oxid a tive
Ca r bon yla tion of n -P r op yla m in e
Ca r bon yla tion of n -P r op yla m in e
solvent
yielda,b (%)
pressure (atm)
yielda,b (%)
CH2Cl2/H2Oc
CH2Cl2
CHCl3
toluene
ethyl acetate
THF
CH3CN
ether
water
73
62
51
48
43
41
36
32
32
28
15
14
12
20
40
60
80
63
68
75
90
a
Isolated yield of di-n-propylurea calculated per equivalent of
b
n-propylamine. Values are ( 5%. Reaction conditions: n-propy-
lamine (14.2 mmol), W(CO)6 (0.28 mmol), I2 (7.1 mmol), K2CO3
(21.3 mmol), CH2Cl2 40 mL, 90 °C, 24 h.
CCl4
hexane
acetone
benzene
Although the carbonylation of n-propylamine at room
temperature in the two-phase CH2Cl2/H2O solvent system
had originally resulted in 73% yield (Table 3), repeating
the reaction at 90 °C resulted in a 85% yield which was
comparable to the 90% yield achieved in CH2Cl2. There-
fore, the optimal conditions for the carbonylation of
n-propylamine were determined to be 2 mol % W(CO)6,
stoichiometric amounts of amine and I2, and 1.5 equiv of
K2CO3 per equiv amine reacted in CH2Cl2 at 90 °C under
80 atm CO pressure. A series of primary amines was
reacted under these conditions to give the corresponding
N,N′-disubstituted ureas, as seen in Table 5. The ureas
were formed in good to high yields, ranging from 90%
for N,N′-di-n-propylurea to 53% for N,N′-di-i-propylurea.
In the case of N,N′-di-n-propylurea, approximately 5%
of the starting material can be recovered at the end of
the reaction, so that virtually all of the material can be
accounted for. The yields are generally lower if the amine
bears secondary or tertiary alkyl substituents. Only a few
percent of starting material was recovered for the more
highly branched ureas, suggesting that the higher degree
of substitution results in undesired side reactions. For
comparison, the amines in Table 5 were also run in the
CH2Cl2/H2O solvent system. Analogous to the decrease
in yield of the n-propyl urea in the two-phase system at
90 °C, the other primary amines also suffered a decrease
in yield when carbonylated in the mixed solvent system.
It is noteworthy that aniline is unreactive under the
reaction conditions, considering aromatic amines are
generally better substrates than their aliphatic analogues
for the formation of ureas under transition metal-
catalyzed carbonylation conditions.31,32 The nucleophilic-
ity of the amine is apparently critical in these reactions.
Similar reactivity is observed in the related carbonylation
of amines using [(CO)2W(NPh)I2]2, in which the first C-N
bond is formed by nucleophilic attack of amine on a
carbonyl.28
a
Isolated yield of di-n-propylurea calculated per equivalent of
b
n-propylamine. Values are ( 5%. Reaction conditions: n-propy-
lamine (14.2 mmol), W(CO)6 (0.28 mmol), I2 (7.1 mmol), K2CO3
(21.3 mmol), solvent 40 mL, room temperature, 80 atm CO, 24 h.
c The solvent was CH2Cl2 (35 mL) plus H2O (5 mL). Other
conditions are as in footnote a.
bonylation of amines to ureas dictates that two equiv of
the amine hydroiodide (RNH3I) will be produced per
equiv of urea (eq 2). In the absence of added base, these
amine salts are observed in the reaction mixtures. The
presence of K2CO3 as a sacrificial base increases the
product yield by regenerating the free amine from the
salt and returning it to the substrate pool. However,
insolubility of the amine salts will hinder this deproto-
nation since the K2CO3 and the salt will coexist as
immiscible solids. To circumvent the inability of solid K2-
CO3 to deprotonate insoluble amine salts, the two-phase
solvent system CH2Cl2/H2O was investigated. Due to the
solubility of the hydroiodide salts in basic water, they
could be deprotonated and shuttled back into the meth-
ylene chloride layer as the free amine. An added advan-
tage was that the base is soluble in the water layer and
stirring problems associated with solid K2CO3 were
eliminated.
For both n-propylamine (Table 3) and many of the
substituted benzylamines used in the functional group
compatibility studies (vide infra), room-temperature
yields increased when the solubility problems were
resolved with the two-phase CH2Cl2/H2O solvent system.
Although there are several examples of two-phase car-
bonylation reactions in the literature, a biphasic system
for the carbonylation of amines is to the best of our
knowledge unprecedented. In fact, carbonylation of amines
in aqueous medium has only been reported for conversion
of amines to formamides with a water-soluble ruthenium
carbonyl catalyst.31
F u n ction a l Gr ou p Com p a tibility
To explore applications of this reaction in organic
synthesis, a study of functional group tolerance was
undertaken. Various substituted benzylamines (eq 3)
were reacted with CO under similar carbonylation condi-
tions, as seen in Table 6. Substituted benzylamines were
A study of carbonylation yields as a function of CO
pressure was performed as described in Table 4. At 20
atm CO and 90 °C, the yield of di-n-propylurea was 63%,
while at 80 atm the urea yield was 90%. Increases above
80 atm did not result in further improvements in yield.
(32) Wilkinson, G.; Stone, F. A.; Abel, E. W. Comprehensive Orga-
nometallic Chemistry; Pergamon Press: New York, 1982; Vol. 8, p 174
and references therein.
(31) Khan, M. M. T.; Halligudi, S. B.; Shukla, S.; Abdi, S. H. R. J .
Mol. Catal. 1989, 51, 129-135.

Oxidative Carbonylation of Primary Amines
J . Org. Chem., Vol. 65, No. 17, 2000 5219
Ta ble 5. Oxid a tive Ca r bon yla tion of P r im a r y Am in es to Ur ea s u n d er Op tim ized Con d ition s
a
b
Isolated yield of urea calculated per equivalent of amine. Values are ( 5%. Reaction conditions: amine (14.2 mmol), W(CO)6 (0.28
mmol), I2 (7.1 mmol), K2CO3 (21.3 mmol), CH2Cl2 (40 mL), 90 °C, 80 atm CO, 24 h. c The solvent was CH2Cl2 (35 mL) plus H2O (5 mL).
Other conditions are as in footnote b.
chosen as model substrates for the compatibility study
because the benzene ring provides a rigid backbone which
separates the functional group from the reacting amine.
The possibility of intramolecular interaction is eliminated
in these substrates. This first screen of functional groups
addresses interference by simple binding of the catalyst
to the functional group or competitive reaction of the
functional group by oxidation or carbonylation. More
complex substrates, such as conformationally flexible
amino alcohols in which carbonylation could lead to
different types of products, are the subject of further
investigation33 and will not be discussed here.
Upon addition of water to the reaction mixtures, the
yields of the ureas increased to 77%, 77%, and 70%
respectively.
In experiments with ether and thioether compounds
in CH2Cl2, the p-methoxybenzylamine 1e was carbony-
lated to urea 2e in 47% yield, while p-methylthiobenzyl-
amine 1f was carbonylated to urea 2f in 24% yield. Under
these conditions, the major products were the hydro-
iodide salts. The solubility problem was again circum-
vented by addition of H2O to the solvent system resulting
in the ureas forming in 70% and 81% yields, respec-
tively.
Initial studies with the parent benzylamine established
that N,N′-dibenzylurea was formed in 63% yield upon
reaction under the optimized reaction conditions for
n-propylamine (Table 6, CH2Cl2). As discussed above, the
low yields of ureas for many of the substituted benzyl-
amines were attributed to the insolubility of their respec-
tive hydroiodide salts in CH2Cl2. As shown in Table 6, it
was found that yields for many of the substituted ureas
were significantly higher when the 7:1 CH2Cl2/H2O
solvent system was used (Procedure C, Experimental
Section).
The effects of aryl halides were examined first. The
p-chloro-, p-bromo-, and m-iodobenzylamines 1b-d pro-
duced their respective N,N′-disubstituted ureas 2b-d in
surprisingly low 35%, 30%, and 39% yields when the
reaction was run in CH2Cl2. Although side reactions
resulting from oxidative addition of the aryl halide bonds
to the W complex were considered,34,35 the main products
of the reactions turned out to be the amine hydroiodides.
The hydroxymethyl compound 1g produced urea 2g
with yields of 5% in CH2Cl2 and 58% in CH2Cl2/H2O.
Remarkably, the carbonylation reaction was completely
selective for the amine over the alcohol, within the limits
of detection. None of the corresponding carbamate or
carbonate could be observed in the reaction mixtures.
This experiment suggests that the carbonylation of
amines could be carried out in the presence of unpro-
tected hydroxyl groups. In contrast, thiol 1h failed to form
the corresponding urea, undoubtedly due to the sensitiv-
ity of thiols to oxidation.
The ester-substituted benzylamine 1i was also suc-
cessfully carbonylated to the urea 2i in 36% yield in CH2-
Cl2 with 55% yield obtained in CH2Cl2/H2O. The carbox-
ylic acid analogue 1j is insoluble in CH2Cl2, which
hindered efforts to explore the tolerance of the catalyst
(34) Buffin, B. P.; Poss, M. J .; Arif, A. M.; Richmond, T. G. Inorg.
Chem. 1993, 32, 3805-3806.
(35) Poss, M. J .; Arif, A. M.; Richmond, T. G. Organometallics 1988,
7, 1669-1670.
(33) McElwee-White, L.; Main, A. D.; Vieta, R. S. unpublished
results.

5220 J . Org. Chem., Vol. 65, No. 17, 2000
McCusker et al.
Ta ble 6. Ca ta lytic Ca r bon yla tion of P r im a r y Am in es to
Ur ea s
corresponding urea 2j in 37% yield from the CH2Cl2/H2O
system.
Compatibility of the catalyst system with terminal
alkenes was then examined. The olefin 1k was reacted
under the carbonylation conditions to form the urea 2k
in a 41% yield in CH2Cl2. Although we anticipated
possible problems with reactivity at the double bond,
there were no identifiable products in which the double
bond had been perturbed. The low yields could, however,
be indicative of unidentified side reactions. Unlike the
previously described reactions of substituted benzyl-
amines, higher yields were obtained when the reaction
using CH2Cl2 as the solvent was diluted to 0.03 M in
substrate and conducted at room temperature.
In addition, p-nitrobenzylamine (1l) was successfully
carbonylated to urea 2l in a 45% yield in CH2Cl2 with
76% yield obtained in CH2Cl2/H2O. The cyano-substituted
benzylamine 1m was also carbonylated to its respective
urea (2m ) in 37% yield in CH2Cl2 and 68% yield in CH2-
Cl2/H2O. Note that the possibility of the nitrile moiety
serving as a ligand for the catalyst did not interfere with
the reaction.
Further functional group studies included the reaction
of the p-aminobenzylamine 1n under the carbonylation
conditions. If both the aliphatic and aromatic amines
were to participate in the carbonylation reaction, oligo-
meric products would be formed. Primary aromatic
amines, such as aniline were unreactive under the
carbonylation conditions, so formation of the simple urea
2n was expected to dominate. However the reaction
mixture was quite complex and urea 2n was only isolated
in 28% yield. In this case, addition of water to the solvent
system decreased the yield to 14%.
The apparent participation of the aromatic amine in
the reactions of 1n result brought up the question of
intramolecular carbonylation of the o-amino benzylamine
1o to form 3,4-dihydro-2(1H)-quinazolinone (eq 4). Al-
though aromatic amines are apparently not nucleophilic
enough to initiate the reaction, they could be sufficiently
nucleophilic to complete the cyclization following initial
reaction of the aliphatic amine. In fact, under the
carbonylation conditions 1n did form the cyclic urea,
albeit in low yields (17% yield in CH2Cl2 and 20% yield
in CH2Cl2/H2O). The results from 1n and 1o suggest that
differentiation between aliphatic and aromatic amines
is not sufficiently good to obtain selective reactivity in
the presence of both.
Con clu sion
In summary, aliphatic primary amines can be catalyti-
cally carbonylated to 1,3-disubstituted ureas in good to
high yields using the commercially available, inexpensive
and air stable W(CO)6 as the catalyst. The preference of
this catalyst for aliphatic amines is complementary to
the late transition metal catalysts, which are generally
more effective for aromatic amines than for aliphatic
ones. Not only does this system provide an alternative
to phosgene and phosgene derivatives, but it is also
compatible with a variety of functional groups, including
a
Isolated yield of urea calculated per equivalent of amine.
Values are ( 5%. b Reaction conditions: amine (7.1 mmol), W(CO)6
(0.14 mmol), I2 (3.5 mmol), K2CO3 (10.7 mmol), CH2Cl2 (20 mL),
70 °C, 80 atm CO, 24 h. c The solvent was CH2Cl2 (21 mL) plus
H2O (3 mL). Other conditions are as in footnote b.
to the presence of carboxylic acids. However, the solubil-
ity of 1j in basic H2O made it possible to obtain the

Oxidative Carbonylation of Primary Amines
J . Org. Chem., Vol. 65, No. 17, 2000 5221
P r ep a r a tion of N,N′-Diben zylu r ea 2a . Procedure A af-
forded 2a in 63% yield. Procedure C afforded 2a in 73% yield.
Urea 2a was identified by comparison with literature values.43
unprotected alcohols. Further work on these reactions is
currently underway.
P r ep a r a tion of N,N′-Bis(4-ch lor oben zyl)u r ea 2b. Pro-
cedure A afforded 2b in 35% yield. Procedure C afforded 2b
in 77% yield: 1H NMR (DMSO-d6) δ 7.37 (d, J ) 7.6 Hz, 4H),
7.26 (d, J ) 7.8 Hz, 4H), 6.56 (br s, 2H), 4.20 (d, J ) 5.4 Hz,
4H); 13C NMR (DMSO-d6) δ 158.0 (CdO), 140.1, 131.0, 128.8,
128.1, 42.3; IR (Nujol) 1567 cm-1; HRMS (FAB) calcd for
C15H15Cl2N2O (M + H+) 309.0561, found 309.0561.
Exp er im en ta l Section
Gen er a l Meth od s. Diethyl ether and tetrahydrofuran were
distilled from sodium/benzophenone. Aniline, benzene, toluene,
methylene chloride, chloroform, acetonitrile, and hexane were
distilled over calcium hydride. All other chemicals were
purchased in reagent grade and used with no further purifica-
tion unless stated otherwise. Authentic samples of the ureas
in Table 5 were prepared from the corresponding amines and
isocyanates7 or were purchased from Aldrich.
Amines 1f,36,37 1g,38 1h ,39 1i,40 1k ,41 and 1m 37 were synthe-
sized using literature procedures. Compounds 1a -e,j,l,n ,o
were purchased from Aldrich.
P r ep a r a tion of N,N′-Bis(4-br om oben zyl)u r ea 2c. Pro-
cedure A afforded 2c in 30% yield. Procedure C afforded 2c in
77% yield: 1H NMR (DMSO-d6) δ 7.50 (d, J ) 8.1 Hz, 4H),
7.20 (d, J ) 8.2 Hz, 4H), 6.53 (br s, 2H), 4.19 (d, J ) 5.9 Hz,
4H); 13C NMR (DMSO-d6) δ 158.0 (CdO), 140.5, 131.0, 129.2,
119.5, 42.3; IR (Nujol) 1561 cm-1; HRMS (FAB) calcd for
C
15H15Br2N2O (M + H+) 396.9551, found 396.9560.
Gen er a l P r oced u r e for th e Ca ta lytic Ca r bon yla tion
of P r im a r y Am in es w ith W(CO)6. To a stirred solution of
W(CO)6 (100 mg, 0.28 mmol) in 40 mL of CH2Cl2 in the glass
liner of a Parr high-pressure vessel was added 50 equiv of
n-propylamine (1.1 mL, 14 mmol), 75 equiv of K2CO3 (2.9 g,
21 mmol) and 25 equiv of iodine (1.8 g, 7.1 mmol). The vessel
was then charged with 80 atm of CO, and left to stir under
pressure for 18 h at 90 °C. After cooling to room temperature,
the pressure was released. The yellow solution was filtered
and washed with saturated Na2SO3 followed by 1 M HCl and
additional saturated Na2SO3. The resulting colorless solution
was then dried with Mg2SO4 and filtered. The solution was
concentrated and dried for 1-2 h to yield a white solid (0.92
g, 6.3 mmol, 90% yield). The solid was identified as di-n-
propylurea by comparison with an authentic sample. If neces-
sary, further purification of ureas obtained by this method
could be achieved by rinsing the solid with cold hexane,
followed by extraction into 25 mL ether or ethyl acetate and
filtration to remove any residual W(CO)6.
Gen er a l P r oced u r es for th e Ca ta lytic Ca r bon yla tion
of Ben zyla m in es w ith W(CO)6. P r oced u r e A. To a stirred
solution of W(CO)6 (49 mg, 0.14 mmol) in 20 mL of CH2Cl2 in
the glass liner of a Parr high-pressure vessel was added 50
equiv of p-methoxybenzylamine (1.0 mL, 7.1 mmol), 75 equiv
of K2CO3 (1.47 g, 10.7 mmol) and 25 equiv of iodine (0.89 g,
3.5 mmol). The vessel was then charged with 85 atm of CO,
heated to 70 °C and left to stir under pressure for 24 h. The
pressure was released and the maroon solution was filtered.
The solid collected on the filter paper was heated in CH2Cl2,
filtered, and both filtrates were combined. The combined CH2-
Cl2 layers were washed with a 1.0 M HCl solution followed by
washing with a saturated Na2SO3 solution. The resulting pale
yellow solution was then dried with Na2SO4 and filtered. The
solution was concentrated to yield a pale yellow solid, which
was then rinsed with 15 mL of ether. The urea was obtained
as a white solid (0.50 g, 1.7 mmol, 47% yield). The solid was
identified as N,N′-bis(4-methoxybenzyl)urea by comparison
with literature values.42 P r oced u r e B. Procedure B is identi-
cal to that of procedure A except the reaction was diluted to
0.03 M in substrate and run at room temperature. P r oced u r e
C. Procedure C is identical to that of procedure A except 21
mL of CH2Cl2 and 3 mL of H2O were employed as solvent. The
product urea precipitated out of the reaction mixture, was
filtered, washed with Et2O and collected.
P r ep a r a tion of N,N′-Bis(3-iod oben zyl)u r ea 2d . Proce-
dure A afforded 2d in 39% yield. Procedure C afforded 2d in
70% yield: 1H NMR (DMSO-d6) δ 7.60 (s, 2H), 7.56 (d, J )
7.7 Hz, 2H) 7.25 (d, J ) 7.5 Hz, 2H), 7.10 (t, 2H), 6.49 (t, 2H),
4.19 (d, J ) 5.9 Hz, 4H); 13C NMR (DMSO-d6) δ 158.0 (CdO),
143.8, 135.5, 135.2, 130.5, 126.4, 94.8, 42.2; IR (Nujol) 1584
cm-1; HRMS (FAB) calcd for C15H15I2N2O (M + H+) 492.9274,
found 492.9271.
P r epa r a tion of N,N′-Bis(4-m eth oxyben zyl)u r ea 2e. Pro-
cedure A afforded 2e in 47% yield. Procedure C afforded 2e in
70% yield. Literature reports on 2e42 do not contain spectral
data: 1H NMR (DMSO-d6) δ 7.15 (d, J ) 8.4 Hz, 4H), 6.85 (d,
J ) 8.2 Hz, 4H), 6.31 (br s, 2H), 4.13 (d, J ) 5.4 Hz, 4H), 3.71
(s, 6H); 13C NMR (DMSO-d6) δ 158.04 (CdO), 157.98, 132.8,
128.3, 113.6, 55.0, 42.4; IR (Nujol) 1578 cm-1; HRMS (FAB)
calcd for C17H21N2O3 (M + H+) 301.1552, found 301.1557.
P r ep a r a tion of N,N′-Bis(4-m eth ylth ioben zyl)u r ea 2f.
Procedure A afforded 2f in 24% yield. Procedure C afforded
2f in 81% yield: 1H NMR (DMSO-d6) δ 7.19 (m, 8H), 6.42 (br
t, 2H), 4.16 (d, J ) 6.0 Hz, 4H), 2.44 (s, 6H); 13C NMR (DMSO-
d6) δ 158.0 (CdO), 137.7, 135.9, 127.8, 126.1, 42.5, 15.0; IR
(Nujol) 1584 cm-1; HRMS (CI) calcd for C17H21N2OS2 (M + H+)
333.1095, found 333.1106.
P r ep a r a tion of N,N′-Bis(4-h yd r oxym eth ylben zyl)u r ea
2g. Procedure A afforded 2g in 5% yield. Procedure C afforded
2g in 58% yield: 1H NMR (DMSO-d6) 7.41 (m, 8H), 6.56 (t,
2H), 5.31 (t, 2H), 4.65 (d, J ) 5.4 Hz, 4H), 4.39 (d, J ) 6.0 Hz,
4H); 13C NMR (DMSO-d6) δ 158.0 (CdO), 140.8, 139.2, 126.8,
126.4, 62.7, 42.8; IR (Nujol) 3331, 1555 cm-1; HRMS (FAB)
calcd for C17H21N2O3 (M + H+) 301.1552, found 301.1533.
P r ep a r a tion of N,N′-Bis(eth yl 4-ca r boxylben zyl)u r ea
2i. Procedure A afforded 2i in 36% yield. Procedure C afforded
2i in 55% yield: 1H NMR (DMSO-d6) δ 7.91 (d, J ) 8.2 Hz,
4H), 7.38 (d, J ) 8.2 Hz, 4H), 6.65 (br t, 2H), 4.31 (s, 4H), 4.30
(qt, 4H), 1.32 (t, 6H); 13C NMR (DMSO-d6) δ 165.7, 158.1 (Cd
O), 146.7, 129.1, 128.2, 127.0, 60.6, 42.8, 14.2; IR (CH2Cl2)
1708, 1678 cm-1; HRMS (FAB) calcd for C21H25N2O5 (M + H+)
385.1763, found 385.1760.
P r ep a r a tion of N,N′-Bis(4-ca r boxylic a cid ben zyl)u r ea
2j. Procedure C was employed except that the product 2j did
not precipitate out until the reaction mixture was acidified
with 1 N HCl. Urea 2j was obtained in 37% yield: 1H NMR
(DMSO-d6) δ 12.89 (s, 2H), 7.88 (d, J ) 7.6 Hz, 4H), 7.35 (d, J
) 7.8 Hz, 4H), 6.62 (t, 2H), 4.29 (d, J ) 5.9 Hz, 4H); 13C NMR
(DMSO-d6) δ 167.2, 158.1 (NHCdO), 146.2, 129.3, 126.9, 109.4,
42.8; IR (Nujol) 1684, 1561 cm-1; MS (electrospray) for
(36) Ulman, A.; Willand, C. S.; Kohler, W.; Robello, D. R.; Williams,
D. J .; Handley, L. J . Am. Chem. Soc. 1990, 112, 7083-7090.
(37) McKay, A. F.; Garmaise, D. L.; Gaudry, R.; Baker, H. A.; Paris,
G. Y.; Kay, R. W.; J ust, G. E.; Schwartz, R. J . Am. Chem. Soc. 1959,
81, 4328-4337.
(38) Lee, T. R.; Niu, J . K.; Lawrence, D. S. J . Biol. Chem. 1995, 270,
5375-5380.
(39) Gubelmann, M.; Guibert, I., Fr. Patent, FR2685323, 1993.
(40) Blicke, F. F.; Lilienfeld, W. M. J . Am. Chem. Soc. 1943, 65,
2281-2284.
(41) Charreyre, M. T.; Razafindrakoto, V.; Veron, L.; Delair, T.;
Pichot, C. Macromol. Chem. Phys. 1994, 195, 2141-2152.
(42) Atanassova, I. A.; Petrov, J . S.; Mollov, N. M. Synth. Commun.
1989, 19, 147-153.
C
17H16N2O5 [M + H+] 329.3, calcd 329.3.
P r epar ation of N,N′-Bis(4-eth en ylben zyl)u r ea 2k. When
procedure A was employed, no product was isolated. The
viscous material obtained suggested the formation of oligo-
mers. Procedure B afforded a 69% yield of 2k . When procedure
C was employed, 2k was only isolated in 19% yield: 1H NMR
(DMSO-d6) δ 7.40 (d, J ) 7.9 Hz, 4H), 7.21 (d, J ) 7.9 Hz,
(43) Bigi, F.; Frullanti, B.; Maggi, R.; Sartori, G.; Zambonin, E. J .
Org. Chem. 1999, 64, 1004-1006.

5222 J . Org. Chem., Vol. 65, No. 17, 2000
McCusker et al.
4H), 6.70 (qt, 2H), 6.45 (br s, 2H), 5.78 (d, J ) 17.7 Hz, 2H),
5.21 (d, J ) 10.9 Hz, 2H), 4.21 (d, J ) 5.6 Hz, 4H); 13C NMR
(DMSO-d6) δ 158.1 (CdO), 140.7, 136.4, 135.5, 127.2, 126.0,
113.7, 42.7; IR (CH2Cl2) 1678 cm-1. Anal. Calcd for C19H20N2O:
C, 78.05; H, 6.89; N, 9.58. Found: C, 74.70; H, 6.95; N, 9.03.
P r ep a r a tion of N,N′-Bis(4-n itr oben zyl)u r ea 2l. Proce-
dure A afforded 2l in 45% yield. Procedure C afforded 2l in
76% yield: 1H NMR (DMSO-d6) δ 8.20 (d, J ) 8.5 Hz, 4H),
7.51 (d, J ) 8.5 Hz, 4H), 6.85 (br t, 2H), 4.34 (d, J ) 6.0 Hz,
4H); 13C NMR (DMSO-d6) δ 158.0 (CdO), 149.3, 146.2, 127.8,
123.4, 42.6; IR (Nujol) 1584, 1537 cm-1. Anal. Calcd for
C15H14N4O5: C, 54.54; H, 4.27; N, 16.96. Found: C, 54.07; H,
4.23; N, 16.66.
P r ep a r a tion of N,N′-Bis(4-cya n oben zyl)u r ea 2m . Pro-
cedure A afforded 2m in 37% yield. Procedure C afforded 2m
in 68% yield: 1H NMR (DMSO-d6) δ 7.80 (d, J ) 7.3 Hz, 4H),
7.44 (d, J ) 7.0 Hz, 4H), 6.79 (br s, 2H), 4.31 (d, J ) 4.9 Hz,
4H); 13C NMR (DMSO-d6) δ 158.0 (CdO), 147.1, 132.2, 127.7,
119.0, 109.2, 42.7; IR (CH2Cl2) 2214, 1678 cm-1; HRMS (FAB)
calcd for C17H15N4O (M + H+) 291.1246, found 291.1249.
P r ep a r a tion of N,N′-Bis(4-a m in oben zyl)u r ea 2n . When
procedure A was employed, the reaction formed a solid black
mass. Procedure B afforded the urea 2n in 28% yield after
recrystallization in EtOH. Procedure C afforded 2n in 14%
yield. The urea 2n was identified by comparison with literature
values.44
P r ep a r a t ion of 3,4-Dih yd r o-2(1H )-q u in a zolin on e 2o.
Procedure A afforded 2o in 17% yield. Procedure C afforded
2o in 20% yield. The urea 2o was identified by comparison
with literature values.44
Ack n ow led gm en t. We acknowledge the US/France
REU Site, funded by the National Science Foundation,
the CNRS, the French Ministry of Foreign Affairs, and
the French Ministry of National Education, Research,
and Technology. We would also like to acknowledge
partial funding from France Telecom and the Aquitaine
Regional Government.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
ureas 2b-d , 2f-g, and 2i-j. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O000364+
(44) Leung, M. K.; Lai, J . L.; Lau, K. H.; Yu, H. H.; Hsiao, H. J . J .
Org. Chem. 1996, 61, 4175-4179.