Catalytic oxidative carbonylation of primary and secondary α,ω-diamines to cyclic ureas

Article abstract of DOI:10.1021/ol990690f

(matrix presented) Primary and secondary diamines can be catalytically carbonylated to cyclic ureas using W(CO)₆ as the catalyst, I₂ as the oxidant, and CO as the carbonyl source. Preparation of five-, six-, and seven-membered cyclic ureas from the diamines RNHCH₂(CH₂)_nCH₂NHR (n = 0-2; R = H, Me) and RNHCH₂CH₂NHR (R = Et, i-Pr, Bz) was achieved in moderate to good yields.

Full text of DOI:10.1021/ol990690f

ORGANIC
LETTERS
1
999
Vol. 1, No. 7
61-964
Catalytic Oxidative Carbonylation of
Primary and Secondary r,ω-Diamines to
Cyclic Ureas
9
Jennifer E. McCusker, Cara A. Grasso, Andrea D. Main, and Lisa McElwee-White*
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
lmwhite@chem.ufl.edu
Received May 26, 1999
ABSTRACT
Primary and secondary diamines can be catalytically carbonylated to cyclic ureas using W(CO)
the carbonyl source. Preparation of five-, six-, and seven-membered cyclic ureas from the diamines RNHCH
Me) and RNHCH CH NHR (R ) Et, i-Pr, Bz) was achieved in moderate to good yields.
6
as the catalyst, I
2
as the oxidant, and CO as
CH NHR (n ) 0−2; R ) H,
2
(CH
2
)
n
2
2
2
Cyclic ureas have interesting pharmacological properties
which have led to their use as inhibitors of a broad set of
retroviral proteases, including HIV protease. In addition,
Due to the facile closure of five-membered rings, the
conversion of ethylenediamine to 2-imidazolidinone has
served as a test case for many of these methods. Phosgene
itself is ineffective for this substrate, producing the five-
1
they have also found use as chiral auxiliaries for asymmetric
2
9
synthesis.
membered cyclic urea in only 13% yield. However, when
Several synthetic routes from diamines to the correspond-
ing cyclic ureas have been described. Most of these rely on
the related aromatic phenylenediamine is reacted with
phosgene, the cyclic urea is produced in a 50% yield.
3
4b
nucleophilic reactions of the amines with phosgene and
related compounds. Methods that convert primary diamines
to the corresponding cyclic ureas have utilized carbonyl
Phosgene derivatives, such as S,S-dimethyl dithiocarbonate,
can be used to carbonylate ethylenediamine to the five-
5
membered cyclic urea in 80% yield. Furthermore, disuc-
4
5
sources including phosgene, phosgene derivatives, dialkyl
cinimido carbonate (DSC) serves to carbonylate ethylene-
6
7
8
2
6
carbonates, carbonyl sulfide, carbonyl selenide, and urea.
diamine to 2-imidazolidinone in a 90% yield. Urea itself
can be transaminated in the presence of water at 200 °C to
(
1) Hodge, C. N.; Lam P. Y. S.; Eyermann, C. J.; Jadhav, P. K.; Ru, Y.;
produce five-membered cyclic ureas from the corresponding
Fernandez, C. H.; De Lucca, G. V.; Chang, C.; Kaltenbach, R. F.; Holler,
E. R.; Woerner, F.; Daneker, W. F.; Emmett, G.; Calabrese, J. C.; Aldrich,
P. E. J. Am. Chem. Soc. 1998, 120, 4570-4581 and references therein.
2
diamines in about 85% yield.
While there are several synthetic routes to prepare the
parent cyclic ureas directly from primary diamines, the
general difficulties associated with synthesis of tetrasubsti-
(2) (a) Sankhavasi, W.; Yamamoto, M.; Kohmoto, S.; Yamada, K. Bull.
Chem. Soc. Jpn. 1991, 64, 1425-1427. (b) Cardillo, G.; D’Amico, A.;
Orena, A.; Sandri, S. J. Org. Chem. 1988, 53, 2354-2356. (c) Davies, S.
G.; Mortlock, A. A. Tetrahedron Lett. 1991, 32, 4791-4794.
10
tuted ureas render direct synthesis of N,N′-disubstituted
(
3) Hegarty, A. F.; Drennan, L. J. In ComprehensiVe Organic Functional
cyclic ureas from secondary diamines more challenging. As
Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W.,
Eds.; Pergamon: Oxford, 1995; Vol. 6, pp 499-526.
(4) (a) Birkofer, L.; Kuhlthau, H. P.; Ritter, A. Chem. Ber. 1960, 93,
(7) Ulrich, H.; Tucker, B.; Richter, R. J. Org. Chem. 1978, 43, 1544.
(8) Kondo, K.; Yokoyama, S.; Miyoshi, N.; Murai, S.; Sonoda, N. Angew.
Chem., Intl. Ed. Engl. 1979, 18, 692.
(9) Boon, W. R. J. Chem. Soc. 1947, 307-318.
(10) Katritzky, A. R.; Pleynet, D. P. M.; Yang, B. J. Org. Chem. 1997,
62, 4155-4158.
2
1
810-2813. (b) Hayward, R. J.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans.
1975, 212-219. (c) Maclaren, J. A. Aust. J. Chem. 1977, 30, 455-457.
(5) Leung, M.; Lai, J.; Lau, K.; Yu, H.; Hsiao, H. J. Org. Chem. 1996,
6
1, 4175-4179.
(6) Takeda, K.; Ogura, H. Synth. Comm. 1982, 12, 213-217.
1
0.1021/ol990690f CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/03/1999

a result, N,N′-disubstituted cyclic ureas are often prepared
by deprotonation and alkylation of their unsubstituted
analogues.11
Catalytic oxidative carbonylation of diamine substrates
would provide an alternative route to cyclic ureas in which
CO could be used as the carbonyl source. Oxidative
carbonylation of primary amines to acyclic ureas has been
report the catalytic oxidative carbonylation of R,ω-diamines
to cyclic ureas. Both primary and secondary diamines are
substrates for the reaction, with secondary diamines being
converted directly to the corresponding N,N′-disubstituted
cyclic ureas. To our knowledge, this simple procedure is the
first example of a transition metal-catalyzed method to
convert both primary and secondary diamines to cyclic ureas
using carbon monoxide as the carbonyl source.
1
2
13
14
reported to be catalyzed by complexes of Ni, Co, W,
15
16
17
Mn, Ru, and Pd. However, the transition metal-catalyzed
reactions generally require high temperatures and pressures,
and yields tend to be much lower for aliphatic amines than
When the primary diamines H
0-2) were reacted with CO (100 atm) in the presence of
catalytic amounts of W(CO) and nearly stoichiometric I
2 2 2 n 2 2
NCH (CH ) CH NH (n )
6
2
,
1
8
for aromatic ones. Main group elements such as sulfur and
the diamines were converted to the corresponding cyclic
selenium19 can also serve as catalysts.
22
ureas (eq 1). Note that the reactions were run at room
The formation of cyclic ureas by catalytic carbonylation
has been much less well explored than the acyclic cases.
Catalytic carbonylation of diamines with carbon monoxide
to form cyclic ureas in high yields has been reported to
proceed in the presence of elemental selenium; however, the
reaction generates hydrogen selenide as a byproduct and
certain substrates such as 2-(2-aminoethylaniline) only form
the cyclic urea in the presence of stoichiometric or excess
temperature, in contrast to the 100-200 °C ranges that are
typical for catalytic oxidative carbonylation. The yields are
1
9
selenium. Prior reports of transition metal-catalyzed car-
bonylation of diamines cite cyclic ureas only as very minor
significantly improved by addition of excess K
2 3
CO to
scavenge the byproduct HI. Because the competitive forma-
or side products. As an example, Mn
carbonylation of the diamines H N(CH NH
) yielded no cyclic products when n ) 2, 4, or 6 and only
2
(CO)10-catalyzed
1
7c
tion of oligomers is favored by high concentrations of
diamine, it was necessary to employ high dilution conditions.
The results for a series of primary diamines are shown in
Table 1. Preparation of the five-, six-, and seven-membered
cyclic ureas was achieved in moderate to good yields. The
highest isolated yield was obtained for the six-membered
cyclic urea, while only trace amounts of the eight-membered
2
)
2 n
2
(n ) 2-4 and
6
6
% of the six-membered urea when n ) 3.1 Carbonylation
5b
of ethylenediamine catalyzed by Ni(CO)
4
yielded 2-imida-
20
zolidinone as a minor product in 10% yield. In addition to
the catalytic cases involving CO, there is also a report of
carbonylation of both primary and secondary diamines to
cyclic ureas in moderate to good yields using CO
carbonyl source and Ph SbO/P
10 as catalyst.21
We recently reported the catalytic oxidative carbonylation
2 2
of primary amines to ureas using either [(CO) W(NPh)I ]
2
as the
3
4
S
Table 1. Catalytic Carbonylation of Primary R,ω-Diamines to
Cyclic Ureas
2
6 2
or W(CO) as the catalyst and I
as the oxidant.1 We now
4b
(11) See, for example: Nugiel, D. A.; Jacobs, K.; Worley, T.; Patel,
M.; Kaltenbach, R. F.; Meyer, D. T.; Jadhav, P. K.; DeLucca, G. V.; Smyser,
T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J. Med.
Chem. 1996, 39, 2156-2169.
(12) Giannocaro, P.; Nobile, C. F.; Mastrorilli, P.; Ravasio, N. J.
Organomet. Chem. 1991, 419, 251-258.
13) Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. J. Mol. Catal.
990, 60, 41-48.
14) (a) McCusker, J. E.; Abboud, K. A.; McElwee-White, L. Organo-
(
1
(
metallics 1997, 16, 3863-3866. (b) McCusker, J. E.; Logan, J.; McElwee-
White, L. Organometallics 1998, 17, 4037-4041.
(
15) (a) Calderazzo, F. Inorg. Chem. 1965, 4, 293-296. (b) Dombek,
B. D.; Angelici, R. J. J. Organomet. Chem. 1977, 134, 203-217.
16) Mulla, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. J. Mol.
Catal. A. 1997, 122, 103-109.
(
(
17) (a) Pri-Bar, I.; Alper, H. Can. J. Chem. 1990, 68, 1544-1547. (b)
Gupte, S. P.; Chaudhari, R. V. J. Catalysis 1988, 114, 246-258. (c) Dahlen,
G. M.; Sen, A. Macromolecules 1993, 26, 1784-1786.
(18) (a) Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F.; Bolze,
C. J. Org. Chem. 1961, 26, 3309-3312. (b) Franz, R. A.; Applegath, F.;
Morriss, F. V.; Baiocchi, F. J. Org. Chem. 1961, 26, 3306-3308. (c) Franz,
R. A.; Applegath, F.; J. Org. Chem. 1961, 26, 3304-3305.
(19) (a) Sonoda, N.; Yasuhara, T.; Kondo, K.; Ikeda, T.; Tsutsumi, S. J.
Am. Chem. Soc. 1971, 93, 6344. (b) Yoshida, T.; Kambe, N.; Murai, S.;
Sonoda, N. Bull. Soc. Chem. Jpn. 1987, 60, 1793-1799. (c) Yoshida, T.;
Kambe, N.; Murai, S.; Sonoda, N. Tetrahedron Lett. 1986, 27, 3037-3040.
(
20) Martin, W. E.; Farona, M. F. J. Organomet. Chem. 1981, 206, 393-
3
97.
21) Nomura, R.; Hasegawa, Y.; Ishimoto, M.; Toyosaki, T.; Matsuda,
H. J. Org. Chem. 1992, 57, 7339-7342.
a
(
Isolated yield per equivalent of starting diamine.
962
Org. Lett., Vol. 1, No. 7, 1999

ring compound could be detected in the reaction mixtures.
Failure to close the eight-membered ring was not surprising
as there are no reports in the literature of preparation of this
compound from 1,5-pentanediamine. In addition, (+)-(1R,2R)-
cyclic ureas was achieved. The highest isolated yield (52%)
was obtained for the six-membered ring. Note that yields
for closure of the N,N′-dimethyldiamines are comparable to
those of their primary counterparts. In addition, pure material
of the N,N′-dialkyl compounds in Table 2 can be obtained
by chromatography in contrast to the parent cyclic ureas of
Table 1 which were purified by sublimation due to their
insolubility.
1,2-diphenyl-1,2-ethanediamine was carbonylated to the
chiral 2-imidazolidinone in a 46% yield. All of the product
cyclic ureas are known compounds, and they were character-
ized by comparison to authentic samples purchased from
Aldrich or by comparison of their spectral data to literature
values.
To probe steric limitations on the ring closure reaction,
N,N′-diethyl, diisopropyl, and dibenzyl diamines were reacted
Reaction of secondary diamines under similar catalytic
oxidative carbonylation conditions resulted in conversion of
the diamines to the corresponding N,N′-disubstituted cyclic
23
under the standard conditions. The N,N′-disubstituted cyclic
ureas were formed in varying yields, as shown in Table 2.
As expected, 1,3-diethyl-2-imidazolidinone was produced in
2
3
ureas (eq 2). Once again it was necessary to employ high
4
6% yield, similar to the yield of 1,3-dimethyl-2-imidazo-
lidinone. Changing the substituents to benzyl groups dropped
the yield only slightly. However, the steric hindrance of the
bulky isopropyl groups dramatically reduced the yield of 1,3-
diisopropyl-2-imidazolidinone to only 10%. Attempts to
increase yields of the diisopropyl cyclic urea by raising the
reaction temperature to 90 °C did not result in meaningful
improvement (13% vs 10% at room temperature). In a test
case with one primary and one secondary amine terminus,
N-methylpropanediamine reacted under the oxidative car-
bonylation conditions to produce the corresponding N-methyl
cyclic urea in 31% yield, indicating that cyclization can
compete with acyclic urea formation through the more
reactive primary amines. Once again, all of the products listed
in Table 2 are known compounds and were characterized
by comparison to authentic samples purchased from Aldrich
or by comparison to literature data.
dilution conditions to minimize formation of oligomers. The
results for a series of secondary diamines are shown in Table
2.
3 2 2 n 2 3
Closure of the diamines CH NHCH (CH ) CH NHCH (n
)
0-2) to the corresponding five-, six-, and seven-membered
Table 2. Catalytic Carbonylation of Secondary R,ω-Diamines
to Cyclic Ureas
The diamines in Tables 1 and 2 lack functionality because
they are simple cases intended to illustrate the ring closure.
In conjunction with studies of the oxidative carbonylation
6 2
of primary amines to acyclic ureas with this W(CO) /I
(22) The following procedure is typical for primary diamines. Synthesis
of 2-Imidazolidinone. To a stirred solution of W(CO)6 (30 mg, 0.085 mmol)
in a 90 mL solution of CH2Cl2 in the glass liner of a Parr high-pressure
vessel were added 100 equiv of ethylenediamine (0.57 mL, 8.54 mmol),
2
7
10 equiv of K2CO3 (2.47 g, 17.9 mmol), and 90 equiv of iodine (1.95 g,
.68 mmol). The vessel was then charged with 100 atm of CO and left to
stir under pressure at room temperature for 24 h. The pressure was released,
and the maroon solution was filtered away from a red solid. The CH2Cl2
layer was concentrated and then taken up into methanol, while the red solid
was rinsed with methanol. Both methanol fractions were combined and
concentrated to obtain a yellow powder. The yellow powder was then
sublimed to obtain a white solid (0.29 g, 40% yield, TON ) 40). The solid
was identified as 2-imidazolidinone by comparison with an authentic sample.
(23) The following procedure is typical for secondary diamines. Synthesis
of 1,3-Dimethyl-2-Imidazolidinone. To a stirred solution of W(CO)6 (30
mg, 0.085 mmol) in 90 mL of CH2Cl2 in the glass liner of a Parr high-
pressure vessel were added 150 equiv of N,N′-dimethylethylenediamine (1.36
mL, 12.8 mmol), 310 equiv of K2CO3 (3.63 g, 26.4 mmol), and 140
equiv of iodine (3.02 g, 11.9 mmol). The vessel was then charged with
1
00 atm of CO and left to stir under pressure at room temperature for 24
h. The pressure was released, and the yellow solution was filtered away
from a white solid and concentrated. The resulting pale yellow oil was
dissolved in ethyl acetate and chromatographed on silica with ethyl acetate
as eluent to obtain a colorless liquid (0.68 g, 47% yield, TON ) 70). The
liquid was identified as 1,3-dimethyl-2-imidazolidinone by comparison with
an authentic sample.
(
24) McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C. A.;
McElwee-White, L. Manuscript in preparation.
25) These initial studies were carried out with substituted benzyl amines
in which intramolecular reaction of the functional group with the amine
was not possible. Studies of more complex substrates are in progress.
(
a
Isolated yield per equivalent of starting diamine.
Org. Lett., Vol. 1, No. 7, 1999
963

system, we are carrying out studies of functional group
compatibility.24,25 The results indicate that oxidative carbo-
nylation of amines is tolerant of a wide variety of functional-
ity, including halides, esters, alkenes, and nitriles. A distin-
guishing feature is the tolerance of unprotected alcohols,
which would be problematic with phosgene derivatives.
In conclusion, we have developed a simple method to
catalytically convert R,ω-diamines and carbon monoxide to
cyclic ureas at room temperature in moderate yields using
the commercially available, inexpensive, and air-stable
6
W(CO) as catalyst. To our knowledge, this is the first
example of a transition metal-catalyzed procedure in which
both primary and secondary diamines can serve as substrates.
In the cases of the primary diamines, the yields of this
catalytic carbonylation reaction are moderate in comparison
to those obtained by some of the methods that utilize
phosgene derivatives. The yields from secondary diamines
are similar in magnitude but in some ways more favorable
because the direct conversion to the N,N′-disubstituted cyclic
ureas by this method can be compared to multistep sequences
in which conversion of the primary diamine to the corre-
sponding cyclic urea is followed by deprotonation and
alkylation. Such a sequence for preparation of protease
inhibitors is described in ref 11. The simplicity of this
method, the mild reaction conditions, the direct conversion
of secondary diamines to N,N′-disubstituted cyclic ureas, and
the functional group tolerance are positive features of this
carbonylation reaction.
The moderate yields of cyclic products can be attributed
to competition of the ring closure reaction with the formation
of acyclic oligomers. This problem has also been reported
2
c
for the reactions of phosgene equivalents with diamines.
The initial crude yields of material derived from oxidative
carbonylation of the diamines are approximately 85-90%,
similar to yields obtained for the oxidative carbonylation of
primary amines.24 However, purification results in loss of
approximately 50% of the crude product. Depending on the
method of purification, the remaining material is left behind
as residue in the sublimator or adheres to the top of the
column during chromatography. These properties are what
would be expected for oligomeric ureas. Thus, the moderate
yields do not appear to be the result of low amine conversion,
but rather the competitive formation of oligomers. Attempts
to minimize the amount of oligomerization by further diluting
the reaction mixtures merely slowed the reaction, rather than
increasing the yields of the cyclic ureas. As expected,
increasing the concentration of the reaction mixtures led to
decreased yields of the cyclic ureas while increasing the
yields of the residue.
Further work on these oxidative carbonylation reactions
is underway.
Acknowledgment. Support of this work was provided
by the Office of Naval Research.
OL990690F
964
Org. Lett., Vol. 1, No. 7, 1999