Low-temperature synthesis of tetraalkylureas from secondary amines and carbon dioxide

Article abstract of DOI:10.1021/jo026369j

The reaction of dialkylamines with CO₂ giving tetraalkylureas can be performed at 60°C. The reaction requires CCl₄, is weakly promoted by DMAN or PPh₃, and is not promoted by a Pd catalyst. A two-step procedure, in which dialkylammonium dialkylcarbamate is produced in situ and then reacted with CCl₄ and free dialkylamine, gave greater yields of urea than a simple single-stage procedure.

Full text of DOI:10.1021/jo026369j

amount of triphenylphosphine in CCl4/MeCN solvent (eq
1).16 The highest yield of urea was 7 turnovers (mol of
urea per mol of Pd). We initially chose to investigate this
system to determine whether the catalytic efficiency
could be increased and whether the reaction could be
performed with a substoichiometric quantity of the
phosphine.
Low -Tem p er a tu r e Syn th esis of
Tetr a a lk ylu r ea s fr om Secon d a r y Am in es
a n d Ca r bon Dioxid e
Chih-Cheng Tai, Melissa J . Huck, Erin P. McKoon,
Tiffany Woo, and Philip G. J essop*
Department of Chemistry, University of California-Davis,
Davis, California 95616
jessop@chem.ucdavis.edu
Received August 29, 2002
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. All chemicals were obtained from
commercial sources and used directly without further purifica-
tion. The CO2 was industrial grade obtained from Praxair. Most
of the experiments were carried out under air, except as noted.
THF and toluene were dried and distilled from sodium/ben-
zophenone ketyl, and MeCN and DMSO were dried by stirring
with Na2SO4. The yield of tetraalkylurea was calculated by 1H
NMR integration relative to CH2Cl2 as an internal standard.
The identification of the product was confirmed by comparison
of the 1H NMR spectrum to that of the commercially available
tetraalkylurea (1,1,3,3-tetraethylurea, 1,1,3,3-tetrabutylurea, or
bis(pentamethylene)urea) and published spectra17-19 and by
checking that no new peaks or line broadening were observed
in the spectrum of a mixture of the obtained product and the
commercially available sample.
Sin gle-Step Meth od for th e P r ep a r a tion of Tetr a eth yl-
u r ea . Experiments were carried out by combining 10 mL of
solvent with 2 mmol of NHR2 and 1 mmol of DMAN in a 35 mL
glass vial with a stir bar, under the pressure of CO2 indicated
in the tables, and then heating to 60 °C for 24 h.
Tw o-Step Meth od for th e P r ep a r a tion of Tetr a a lk yl-
u r ea . In the first step of this procedure, 10 mL of solvent, 1
mmol of HNR2, and 1 mmol base (if used) and a stir bar were
placed into a 35 mL glass vial and stirred under 1 bar of CO2 at
room temperature for 1 h. Subsequently, the vial was opened to
air and 1 mL of CCl4 and another 1 mmol of HNR2 were added.
The vial was heated and stirred, with an empty balloon on the
top of the vial, at 60 °C for 23 h, except as noted.
Abstr a ct: The reaction of dialkylamines with CO2 giving
tetraalkylureas can be performed at 60 °C. The reaction
requires CCl4, is weakly promoted by DMAN or PPh3, and
is not promoted by a Pd catalyst. A two-step procedure, in
which dialkylammonium dialkylcarbamate is produced in
situ and then reacted with CCl4 and free dialkylamine, gave
greater yields of urea than a simple single-stage procedure.
Carbon dioxide fixation offers the potential of replacing
syntheses based upon toxic carbon monoxide or phosgene
while simultaneously taking advantage of the abundance
of waste CO2. Literature studies describe a range of
reactions of CO2, including dialkylureas from primary
amines and CO2.1-12 Unfortunately, the preparation of
tetraalkylureas from CO2 and secondary amines has been
more difficult.2,13 Fichter et al. found that the tendency
of the carbamates of ammonia and primary amines to
be dehydrated to the corresponding ureas was not
observed with the carbamates of secondary amines.1,2,14
The transformation has been achieved but with both
catalysis and elevated temperatures (120-250 °C).10,15 At
moderate temperatures (i.e., below 100 °C), the only
published synthesis using CO2 required large concentra-
tions of PdCl2(MeCN)2 catalyst and a stoichiometric
Isola tion of Tetr a a lk ylu r ea . Although the yield data in the
tables are spectroscopic yields, the isolated yields were also
determined. For example, isolation of tetrabutylurea from the
product mixture was achieved by evaporating the volatiles under
vacuum, adding 3 M HCl(aq) to the residue, and extracting several
times with ether. Removal of the ether from the dried extract
gave the product, tetrabutylurea, in 62% yield, as confirmed
gravimetrically and by 1H NMR spectroscopy. For bis(penta-
methylene)urea and tetraethylurea (both prepared in MeCN),
the isolated yields were 71 and 35%, respectively.
(1) Fichter, F.; Becker, B. Ber. 1912, 44, 3481-3485.
(2) Werner, E. A. J . Chem. Soc. 1920, 117, 1046-1053.
(3) Hayashi, T.; Kuyama, M. Nat. Sci. Rept. Ochanomizu Univ.
(Tokyo) 1951, 2, 79-86.
(4) Yamazaki, N.; Higashi, F.; Iguchi, T. Tetrahedron Lett. 1974,
1191-1194.
(5) Yamazaki, N.; Yamaguchi, M. Synthesis 1979, 355-356.
(6) Ogura, H.; Takeda, K.; Tokue, R.; Kobayashi, T. Synthesis 1978,
394-396.
(7) Sasaki, Y.; Kagawa, H. Kogai Shigen Kenkyusho Iho 1989, 18,
13-18.
Resu lts a n d Discu ssion
(8) Fournier, J .; Bruneau, C.; Dixneuf, P. H.; Lecolier, S. J . Org.
Chem. 1991, 56, 4456-4458.
During an evaluation of the Pd-catalyzed synthesis of
tetraalkylureas from dialkylamines and CO2 (eq 1), we
compared single-step and two-step procedures. In the
(9) Bruneau, C.; Dixneuf, P. H. J . Mol. Catal. 1992, 74, 97-107.
(10) Nomura, R.; Hasegawa, Y.; Ishimoto, M.; Toyosaki, T.; Matsuda,
H. J . Org. Chem. 1992, 57, 7339-7342.
(11) Kubota, Y.; Kodaka, M.; Tomohiro, T.; Okuno, H. Y. J . Chem.
Soc., Perkin Trans. 1 1993, 5-6.
(12) Cooper, C. F.; Falcone, S. J . Synth. Commun. 1995, 25, 2467-
(16) Morimoto, Y.; Fujiwara, Y.; Taniguchi, H.; Hori, Y.; Nagano,
Y. Tetrahedron Lett. 1986, 27, 1809-1810.
(17) The Sadtler Standard Spectra; Sadtler Research Laborato-
ries: Philadelphia, 1980.
(18) Nudelman, N. S.; Lewkowicz, E. S.; Pe´rez, D. G. Synthesis 1990,
917-920.
(19) Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.-I.; Murahashi,
S.-I. Bull. Chem. Soc. J pn. 1996, 69, 2079-2090.
2474.
(13) Haruki, E. In Organic and Bio-organic Chemistry of Carbon
Dioxide; Inoue, S., Yamazaki, N., Eds.; Kodansha, Ltd.: Tokyo, 1982;
pp 5-78.
(14) Fichter, F.; Becker, B. Ber. 1912, 44, 3473-3480.
(15) Farlow, M. W.; Adkins, H. J . Am. Chem. Soc. 1935, 57, 2222-
2223.
10.1021/jo026369j CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/19/2002
9070
J . Org. Chem. 2002, 67, 9070-9072

TABLE 1. Con ver sion of Dieth yla m in e a n d CO2 to
Tetr a eth ylu r ea
TABLE 2. Effect of Ad d ed Ba ses on th e Syn th esis of
Tetr a eth ylu r ea a
[PdCl2(MeCN)2]
(mmol)
PPh3
(mmol)
urea yieldb
(%)
urea yieldb
entry
procedurea
base
NHEt2:base
(%)
1
2
3
4
5
0
0.3
0
0.3
0.3
0
B
B
A
B
B
44
17
11
45
34
no extra base added
DMAN
na
2:1
20:1
2:1
20:1
2:1
20:1
2:1
34
55
43
36
32
30
22
36
25
0.1
0.1
0.1
0
NEt2Ph
NPh3
a
Procedures. (A) One-Step Procedure: 10 mL of THF with 2
mmol of NHEt2, 1 mL of CCl4, under 1 bar of CO2 as indicated,
heat to 60 °C for 24 h. (B) Two-Step Procedure: (step 1) 10 mL of
THF with 1 mmol of NHEt2 under 1 bar of CO2 for 1 h at rt; (step
2) remove CO2, heat to 60 °C, add 1 mL of CCl4 and 1 mmol of
NEt3
20:1
a
Procedure: (step 1) 10 mL of solvent with 1 mmol of NHEt2
and 1 or 0.1 mmol of base (where used), under 1 atm of CO2 for 1
h at room temperature; (step 2) remove CO2, heat at 60 °C, add 1
b
NHR2 stirring for 23 h. Percentage of theoretical yield, as
determined spectroscopically.
b
mL of CCl4 and 1 mmol of NHEt2 stirring for 23 h. Percentage
of theoretical yield, as determined spectroscopically.
single-step procedure, the dialkylamine, CCl4, Pd catalyst
precursor, and PPh3 were heated together in solvent
under 1 bar of CO2 for 60 °C for 1 day. In the two-step
procedure (eq 2, where base ) NHR2), 1 mmol of the
dialkylamine in the presence of the Pd complex and PPh3
was exposed to CO2 for 1 h to convert the amine to the
carbamate, after which the CO2 source was removed and
the carbamate was reacted with a second mmol of
dialkylamine and excess CCl4. The carbamate was ob-
served after the first step by 1H NMR spectroscopy.
Compared to the single-step procedure, the two-step
procedure gave greater yields of tetraalkylurea (entries
3 and 4 in Table 1).
TABLE 3. Con ver sion of Dia lk yla m in e a n d CO2 to
Tetr a a lk ylu r ea in th e P r esen ce of DMAN
T
CO2
t
urea yieldb
(%)
entry
amine
procedurea (°C) (bar) solvent (h)
1
2
3
4
5
6
7
8
9
NHEt2
NHEt2
NHEt2
NHEt2
NHEt2
NHEt2
NHEt2
NHEt2
NHEt2
A
A
B
B
B
B
B
B
B
B
B
B
B
B
60
60
rt
1
THF
24
24
24
24
2
33
0
20
0
50 THF
1
0
1
1
1
1
1
1
1
1
1
1
THF
THF
THF
THF
THF
MeCN 24
DMSO 24
toluene 24
THF
THF
MeCN 24
THF 24
60
60
60
60
60
60
60
70
60
60
60
14
55
62
64
0
32
34
53
72
99
24
72
10 NHEt2
11 NHEt2
12 piperidine
13 piperidine
14 NHBu2
24
24
a
Note that these experiments were performed in THF
solvent, rather than acetonitrile, because all attempts to
use the Pd catalyst for this reaction in acetonitrile
resulted in the formation of not only urea but also
significant quantities of an unidentified salt.
Procedures: (A) One-Step Procedure: 10 mL of solvent with
2 mmol of NHR2, 1 mL of CCl4, and 1 mmol of DMAN, under the
pressure of CO2 as indicated, heat for 24 h. (B) Two-Step
Procedure: (step 1) 10 mL of solvent with 1 mmol of NHR2 and 1
mmol of DMAN, under 1 bar of CO2 for 1 h at room temperature;
(step 2) remove CO2, heat at the temperature indicated, add 1 mL
b
The effect of the amount of phosphine and Pd catalyst
on the urea synthesis was measured using the two-step
procedure in THF. First, we noted that the Pd catalyst
has no beneficial effect (compare runs 2 and 5 and runs
4 and 1). However, the yield of tetraalkylurea is improved
in the presence of PPh3 (compare runs 1 and 5 and runs
2 and 4). Therefore, it is not necessary to add the Pd
catalyst, but the phosphine alone has some weak ability
to promote the reaction. The Pd catalyst was omitted in
all subsequent experiments, giving the added advantage
that the occurrence of N,N-diethylformamide as a minor
byproduct, as observed by both Morimoto16 and ourselves
when using the published method, is suppressed.
Other bases were also tested for their ability to
promote the reaction in the absence of Pd and PPh3.
Although the promoting effect is moderate, the greatest
effect was found with DMAN (1,8-dimethylaminonaph-
thalene, Table 2). Other amines did not affect the yield
significantly, probably because they are no stronger than
diethylamine as bases. The combination of the two-step
procedure with the use of DMAN gave tetraethylurea
yields of 55-64% (Table 3). The corresponding reaction
of CO2 with piperidine and dibutylamine gave bis-
(pentamethylene)urea and 1,1,3,3-tetrabutylurea in high
yield.
of CCl4 and 1 mmol of NHR2 stirring for 23 h. Percentage of
theoretical yield, as determined spectroscopically.
The two-step procedure was designed to ensure that a
fair concentration of free dialkylamine (neither carbox-
ylated nor protonated) was present in solution during the
reaction. Tests of the single-step procedure showed that
at very high CO2 pressures, under which conversion of
the amine to the carbamate salt would be expected to be
complete, no urea was formed (Table 3, compare entries
1 and 2).
The conversion of dimethylamine to tetramethylurea
in CCl4 as an undesired side reaction was noticed by
White et al.,20 although they did not recognize that CO2
from the air was the carbonyl source. That the reaction
is indeed a fixation of CO2 has now been demonstrated
by performing the reaction under nitrogen using degassed
reagents and solvent. For this experiment, the two-step
procedure (Table 3, entry 4) was followed, with the
exception that no CO2 was present. Neither tetraethyl-
urea nor diethylformamide was produced.
(20) White, E. H.; Ryan, T. J .; Hahn, B. S.; Erickson, R. H. J . Org.
Chem. 1984, 49, 4860-4866.
J . Org. Chem, Vol. 67, No. 25, 2002 9071

The tetraethylurea yield was affected by reaction
temperature and solvent. Although the temperature
effect (entries 3, 6, and 11) is not yet understood, the
greater yield at 60 °C compared to that at 70 °C may be
related to the fact that the decomposition temperature
of the carbamate salt is 62-63 °C.21 Among the solvents
tested, acetonitrile allows the best yield of urea and only
gave the undesired salt if the Pd catalyst was present.
THF also gave fair results, but the yield was significantly
lower in DMSO and toluene.
Other halide sources are not nearly as effective as CCl4
for the urea synthesis. After testing CBr4, CH2Cl2, CHCl3,
MeI, HCl (as [NH2Et2]Cl), CCl3C(O)CCl3, and tert-butyl-
iodide as alternative halide sources, only CBr4 was found
to be effective, producing urea at a yield of 38% but with
a large amount of an unidentified product. In the absence
of any halide source, no tetraethylurea was produced. The
role of the halide source is not yet known, but CCl4 in
combination with Lewis bases is known to react with
carbonyl compounds to give CCl3-subsituted alcohols.22
One could then speculate that such a reaction on dieth-
ylcarbamic acid would generate a CCl3-substituted in-
termediate that would be more reactive to nucleophilic
attack by amine.
Con clu sion s
The reaction of dialkylamines with CO2 giving tetra-
alkylureas requires CCl4, is weakly promoted by DMAN
or PPh3, and is not promoted by a Pd catalyst. The use
of a two-step procedure, in which dialkylammonium dial-
kylcarbamate is produced in situ and then reacted with
CCl4 and free dialkylamine, gave greater yields of urea
than mixing all reagents together at the same time.
Ack n ow led gm en t. We gratefully acknowledge sup-
port from the Division of Chemical Sciences, Office of
Basic Energy Sciences, Office of Science, U. S. Depart-
ment of Energy (Grant DE-FG03-99ER14986). This
support does not constitute an endorsement by DOE of
the views expressed in this article.
J O026369J
(21) Schroth, W.; Scha¨dler, H.-D.; Andersch, J . Z. Chem. 1989, 29,
129-135.
(22) Villieras, J .; Bacquet, C.; Normant, J . F. J . Organomet. Chem.
1975, 97, 325-354.
9072 J . Org. Chem., Vol. 67, No. 25, 2002