Arylboronic acid-catalyzed direct condensation of carboxylic acids with ureas

Article abstract of DOI:10.1055/s-2004-825615

The first example of the catalytic direct condensation of carboxylic acids with ureas to give N-acylureas, N,N′-diacyl-2-imidazolidones, and poly(N,N′-diacyl-2-imidazolidone)s is described. Arylboronic acids bearing electron-withdrawing substituents are highly effective as catalysts for this condensation. Furthermore, a new and efficient one-pot procedure for the conversion of carboxylic acids and urea to nitriles via N-acylurea intermediates was accomplished by using arylboronic acid and rhenium(VII) oxo complexes as hybrid catalysts.

Full text of DOI:10.1055/s-2004-825615

LETTER
1355
Arylboronic Acid-Catalyzed Direct Condensation of Carboxylic Acids with
Ureas
Arylboronic
Ac
o
id-Catalyzed
s
D
irect Co
h
ndensation
i
k
oxylic Acidsatsu Maki,a Kazuaki Ishihara,*a Hisashi Yamamoto*b
a
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Fax +81(52)7893222; E-mail: ishihara@cc.nagoya-u.ac.jp
b
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA
E-mail: yamamoto@uchicago.edu
Received 5 March 2004
Dedicated to Professor Clayton H. Heathcock
activation of carboxylic acids by the addition to
carbodiimides16 and the monoacylation of sodium ureas
with alk-1-en-2-yl esters17 are also convenient routes to
N-acylureas.
Abstract: The first example of the catalytic direct condensation of
carboxylic acids with ureas to give N-acylureas, N,N¢-diacyl-2-imi-
dazolidones, and poly(N,N¢-diacyl-2-imidazolidone)s is described.
Arylboronic acids bearing electron-withdrawing substituents are
highly effective as catalysts for this condensation. Furthermore, a
new and efficient one-pot procedure for the conversion of carboxy-
lic acids and urea to nitriles via N-acylurea intermediates was ac-
complished by using arylboronic acid and rhenium(VII) oxo
complexes as hybrid catalysts.
However, these methods are environmentally undesirable.
The use of stoichiometric amounts of condensing reagents
or large excess amounts of substrates should be avoided to
promote atom efficiency in synthesis and to avoid the gen-
eration of environmental waste. We recently found that
arylboronic acids bearing electron-withdrawing substitu-
ents at the aryl group, such as 3,4,5-trifluorophenylboron-
ic acid (1) and 3,5-bis(trifluoromethyl)phenylboronic acid
(2), are highly effective catalysts for direct amide conden-
sation with equimolar amounts of amines and carboxylic
acids (Scheme 1).18 An active (acyloxy)boron complex 3
is generated in situ by the condensation of arylboronic ac-
ids with carboxylic acids. Amides are then produced by
the nucleophilic attack of amines to 3. In this paper, we
describe a direct condensation of carboxylic acids with
urea derivatives, which are less nucleophilic than amines,
catalyzed by 1 or 2 to give N-acylureas. To the best of our
knowledge, this is the first example of the catalytic syn-
thesis of N-acylurea.
Key words: acylations, catalysis, condensation, green chemistry,
nitriles
N-Acylureas and N-acylcarbamates play important roles
in phytochemistry1 as well as in medicinal chemistry.2
These compounds are also interesting as new functional
materials. For example, polymerizable N-acryloyl ureas
and carbamates are useful as materials that contain func-
tional side chains.3 Poly(N,N¢-diacylurea)s prepared by
the polycondensation of N,N¢-bis(trimethylsilyl)-2-imida-
zolidone with a,w-dicarboxylic acid dichlorides are useful
as semicrystalline materials, and are soluble in acidic sol-
vents.4 Optically active N-acylureas are efficient chiral
auxiliaries for the synthesis of optically pure cyclic car-
boxylic acid derivatives.5 Over the past decade, urea de-
rivatives bearing electron-withdrawing groups have been
used as chiral or achiral organocatalysts for several reac-
tions: e. g., the radical allylation reaction of sulfoxides,6
Claisen rearrangement of 6-methoxy allyl vinyl ether,7
Diels–Alder reactions,8 nucleophilic addition of TMSCN
and ketene silyl acetals to nitrones and aldehydes,9 enan-
tioselective Michael reaction of malonates to nitroole-
fins,10 and enantioselective Strecker and Mannich
reactions.11
F
F3C
F
B(OH)2
B(OH)2
F
F3C
1
2
HNR1R2
–1 or 2
O
R
NR1R2
H
1 or 2
O
O
B
RCO2H
N-Acylureas are classically prepared by acylating ureas
with anhydrides or acyl chlorides in the presence of acids
or bases.12 It is also known that direct condensation of car-
boxylic acids with ureas can occur in the presence of ex-
cess strong acids such as chlorosulfonic acid.13 The
condensation of amines with acylisocyanates14 or S-allyl
N-acylmonothiocarbamates15 leads to N-acylureas. The
–H2O
R
O
Ar
O
R
O
O=C(NH2)2
3
N
NH2
–1 or 2
H
Scheme 1
We first investigated the catalytic activities of several
arylboronic acids (5 mol%), which promote the model re-
action of 4-phenylbutyric acid (1 equiv) with urea (1.1
equiv) in toluene at azeotropic reflux with the removal of
water for 26 hours (Table 1). As expected, commercially
SYNLETT 2004, No. 8, pp 1355–1358
Advanced online publication: 18.05.2004
DOI: 10.1055/s-2004-825615; Art ID: Y01604ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
7.
2
0
0
4

1356
T. Maki et al.
LETTER
available 1 and 2 were highly effective catalysts for the
present reaction (entries 3 and 4). N-Monoacylureas were
produced selectively. On the other hand, N,N¢-diacylureas
were not produced in a detectable amount. Phenylboronic
acid was less active than arylboronic acids bearing elec-
tron-withdrawing substituents (entry 2). No reaction oc-
curred in the absence of any catalysts under the same
conditions as in the other catalytic reactions (entry 1). A
less polar solvent like toluene was suitable for the conden-
sation catalyzed by a Lewis acid such as 1 or 2.
Table 2 Direct Condensation of Urea Derivatives with Carboxylic
Acids Catalyzed by 2a
O
O
O
O
2 (5 or 10 mol%)
+
R
N
NH2
R
OH
R1HN
(1.1 equiv)
NHR2
toluene
azeotropic
reflux, 9–24 h
H
Entry Carboxylic acid
Urea derivative
Yield (%) of
N-acylureab
1
2
82
85
CO2H
O
Table 1 Direct Condensation of Urea with 4-Phenylbutyric Acida
H2N
H2N
NH2
O
O
O
O
O
O
CO2H
Catalyst
Ph
CO2H
O
(5 mol%)
N
NH2
N
H
Ph
Ph
Ph
Ph
+
H
toluene
azeotropic
reflux, 26 h
H2N
NH2
3
78
84
74
85
Ph
Ph
Ph
CO2H
(1.1 equiv)
Ph
H2N
H2N
H2N
HN
N
H
Entry
Catalyst
Yield (%)b
4c
5c
6d
CO2H
1
2
3
4
None
<1
22
88
92
N
H
PhB(OH)2
1
2
CO2H
N
H
O
Ph
Ph
Ph
CO2H
a Unless otherwise noted, in the presence of 0.1 mmol of ArB(OH)2,
a mixed solution of 2 mmol of 4-phenylbutyric acid and 2.2 mmol of
urea in 10 mL of toluene was heated at azeotropic reflux with the re-
moval of water.
NH
7c,e
80
72
O
CO2H
CO2H
b Isolated yield by column chromatography on silica gel.
HN
O
8e
The applicability of the present protocol to a large-scale
process was then investigated (Scheme 2). Complete de-
hydrative condensation of urea (110 mmol) and 4-phenyl-
butyric acid (100 mmol) was observed in the presence of
5 mol% of 2, and the corresponding monoacylurea was
isolated in 84% yield by washing with water and hexane.
S
H2N
NH2
a Unless otherwise noted, in the presence of 0.1 mmol of 2, a mixed
solution of 2 mmol of carboxylic acid and 2.2 mmol of urea in 10 mL
of toluene was heated at azeotropic reflux with the removal of water.
b Isolated yield by column chromatography on silica gel.
c 10 mol% of 2 was used.
O
O
d Mesitylene was used in place of toluene.
CO2H
O
e Xylene was used in place of toluene.
2 (5 mol%)
N
NH2
+
H
H2N
NH2
toluene
(250 mL)
Ph
Although 2-oxazolidone and thiourea were less reactive
than 2-imidazolidone and urea, respectively, their con-
densations proceeded smoothly at azeotropic reflux in
xylenes (entries 7 and 8).
Ph
azeotropic
reflux, 1 day
100 mmol
110 mmol
84% yield
Scheme 2
Recently, we found that rhenium(VII) oxo complexes are
extremely active as catalysts for the dehydration of prima-
ry amides to nitriles.20 We envisaged that a fragmentation
reaction of N-monoacylureas to nitriles might proceed
through a cyclic intermediate 4 in the presence of rheni-
um(VII) oxo complexes (Scheme 3).
To explore the generality and scope of 2-catalyzed con-
densation, the reaction was examined with various struc-
turally diverse carboxylic acids and urea derivatives
(Table 2). In most cases, the reactions proceeded cleanly,
and the desired N-monoacylureas were obtained in good
yields. The catalyst was useful for not only straight-chain
but also a-branched carboxylic acids with ureas. Alkyl-
ureas like benzylurea, 1-phenylethylurea,19 and 2-imida-
zolidone were more suitable reactants than urea itself
because of the better solubility of alkylureas in toluene.
In fact, N-(4-phenylbutyryl)urea was transformed to 4-
phenylbutyronitrile via 4-phenylbutyramide as an inter-
mediate by heating in mesitylene at azeotropic reflux in
the presence of 10 mol% of perrhenic acid (Scheme 4).21
Synlett 2004, No. 8, 1355–1358 © Thieme Stuttgart · New York

LETTER
Arylboronic Acid-Catalyzed Direct Condensation of Carboxylic Acids
1357
We applied the present system to the direct polycondensa-
tion of a,w-dicarboxylic acids with 2-imidazolidone. For
example, poly[N,N¢-(1,10-decanedicarboxyl)-2-imida-
zolidone]4 was directly synthesized from 1,10-decanedi-
carboxylic acid with 2-imidazolidone in the presence of 5
mol% of 2 (Scheme 7). Heating the reaction mixture at
azeotropic reflux in mesitylene for 1 day gave the corre-
sponding poly(acylurea) in 95% yield.22 The average de-
O
O
cat. HOReO3
O
Re
RCN
O
O
R
R
NH2
mesitylene
azeotropic reflux
H
R
N
O
O
O
O
O
cat. HOReO3
Re
O
O
1
N
NH2
mesitylene
azeotropic reflux
H
gree of polymerization (DP), 34, was determined by H
H
R
N
N
H
NMR analysis. The number-average molecular weight
(Mn) and the weight-average molecular weight (Mw) were
estimated to be 8100 and 22000, respectively, from GPC
for elution by chloroform.23 It was ascertained that no
polycondensation occurred under the same conditions
with Scheme 7 in the absence of 2.
4
Scheme 3
O
O
CN
HOReO3 (10 mol%)
mesitylene
N
NH2
H
O
HO2C(CH2)10CO2H
+
azeotropic reflux, 20 h
Ph
84% yield
HN
NH
Ph
O
O
O
Scheme 4
2 (5 mol%)
95% yield
DP = 34
Mn = 8100
Mw = 22000
H
(
)
10
HO
N
N
mesitylene
azeotropic reflux, 1 day
Furthermore, we succeeded in a one-pot synthesis of ni-
triles from the corresponding carboxylic acids and urea in
n
the presence of catalytic amounts of 2 and perrhenic acid. Scheme 7
Thus, 4-phenylbutyronitrile and adamantylnitrile were
obtained in good yields (Scheme 5). This means that we
In summary, we have demonstrated that arylboronic acids
bearing electron-withdrawing substituents are practical
and green catalysts for the direct condensation of carbox-
ylic acids with ureas, which are less reactive than amines.
The present method can be applied to direct polyconden-
sation and is suitable for large-scale operations.
can use urea as a synthetic equivalent of ammonia.
2 (10 mol%)
HOReO3 (10 mol%)
(H2N)2C=O (3 equiv)
CO2H
CN
mesitylene
Ph
azeotropic reflux, 1 day
Ph
83% yield
Acknowledgment
2 (30 mol%)
HOReO3 (10 mol%)
(H2N)2C=O (3 equiv)
This work was supported by SORST, Japan Science and Technolo-
gy (JST), General Sekiyu Research & Development Encourage-
ment & Assistance Foundation, and JSPS.KAKENHI(15205021).
CO2H
CN
mesitylene
azeotropic reflux, 1 day
76% yield
References
Scheme 5
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O
O
CO2H
O
2 (5 mol%)
N
N
+
HN
NH
mesitylene
azeotropic
reflux, 23 h
Ph
(2 equiv)
Ph
Ph
94% yield
Scheme 6
Synlett 2004, No. 8, 1355–1358 © Thieme Stuttgart · New York

1358
T. Maki et al.
LETTER
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(21) A commercially available 65–70 wt% aq solution of
perrhenic acid was used.
(22) Procedure for the Direct Polycondensation of 1,10-
Decanedicarboxylic Acid with 2-Imidazolidone. A
reaction mixture of 1,10-decanedicarboxylic acid (4 mmol),
2-imidazolidone (4.08 mmol), and 2 (0.4 mmol) in
mesitylene (4 mL) was heated at azeotropic reflux with the
removal of H2O. After 1 d, the resulting solution was cooled
to ambient temperature and concentrated under reduced
pressure. The reaction mixture was cooled to precipitate
polymeric acylureas and diluted with toluene (ca 20 mL),
and the solvents were removed by filtration. The product
was dissolved in CHCl3, precipitated into MeOH, and dried
at 100 °C under reduced pressure to obtain the desired
poly(acylurea) in 95% yield. The DP value, n = 34, was
determined by 1H NMR analysis. 1H NMR (300 MHz,
CDCl3): d = 1.18–1.44 (m, 12n H, [O=C(CH2)2 (CH2)6
(CH2)2C=O)n], 1.56–1.75 (m, 4n H, [O=CCH2CH2
(CH2)6CH2CH2C=O)n], 2.33 (t, J = 8.4 Hz, 2 H, CH2CO2H),
2.91 [t, J = 7.8 Hz, 4n H, (O=CCH2 (CH2)8CH2C=O)n], 3.49
(t, J = 8.4 Hz, 2 H, HNCH2CH2N), 3.83 {s, 4n H,
[N(CH2)2N]n}, 3.95 (t, J = 8.4 Hz, 2 H, HNCH2CH2N).
(23) Two linear GPC columns of TSK-gel-SuperHZM-M (4.6
mmID × 15 cm) and TSK-gel-HZ2000 (4.6 mm ID × 15 cm)
were employed. The polymer was run at 20 mL (1 mg/mL) in
CHCl3 with a polystyrene standard.
Synlett 2004, No. 8, 1355–1358 © Thieme Stuttgart · New York