A novel and efficient method for the Pd-catalysed oxidative carbonylation of amines to symmetrically and unsymmetrically substituted ureas.

Article abstract of DOI:10.1039/b211740a

A new method for the Pd-catalysed oxidative carbonylation of amines to symmetrically and unsymmetrically substituted ureas with unprecedented catalytic efficiencies for this kind of reaction has been developed.

Full text of DOI:10.1039/b211740a

A novel and efficient method for the Pd-catalysed oxidative
carbonylation of amines to symmetrically and unsymmetrically
substituted ureas
a
b
b
c
Bartolo Gabriele,* Raffaella Mancuso, Giuseppe Salerno* and Mirco Costa
a
Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy.
E-mail: b.gabriele@unical.it; Fax: 39 0984 492044; Tel: 39 0984 492130
Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy
Dipartimento di Chimica Organica e Industriale, Parco Area delle Scienze 17/A, Università di Parma,
b
c
43100 Parma, Italy
Received (in Cambridge, UK) 27th November 2002, Accepted 13th January 2003
First published as an Advance Article on the web 24th January 2003
A new method for the Pd-catalysed oxidative carbonylation
of amines to symmetrically and unsymmetrically substituted
ureas with unprecedented catalytic efficiencies for this kind
of reaction has been developed.
The development of new synthetic protocols for the production
Scheme 1 Mechanism of formation of ureas 2.
of ureas has recently attracted great interest in view of their
1
many important applications. The classical syntheses of ureas
Formation of 2 can be rationalized as depicted in Scheme 1,
involving the formation of carbamoylpalladium species I as the
key intermediate (anionic iodide ligands are omitted for
clarity).
The use of a coordinating aprotic solvent of low polarity, such
as DME, was essential for the success of the reaction. In fact,
very low yields and catalytic efficiencies were obtained
working in polar protic or polar aprotic solvents, such as MeOH
or N,N-dimethylacetamide (DMA), under the above conditions.
We interpret this result as follows. As shown in Scheme 1, in the
course of the process 1 acts as nitrogen nucleophile, and
substrate carbonylation is accompanied by the formation of 2
have been based on the use of dangerous reagents, such as
phosgene or isocyanates. In recent years, however, alternative
routes have been developed via the use of a variety of carbonyl
1
derivatives, CO
2
, or CO. Particularly attractive, also from the
standpoint of atom economy, is the oxidative carbonylation
2
methodology, which employs amines, carbon monoxide and
oxygen as starting materials and produces only H
2
O as co-
product.3
We wish to report here a new method for the Pd-catalysed
oxidative carbonylation of amines to symmetrically and
unsymmetrically substituted ureas [eqns. (1) and (2), re-
spectively], which is characterized by unprecedented catalytic
efficiencies for this kind of reaction.
4
b
mol of HI and 1 mol of Pd(0). As we have already reported,
reoxidation of Pd(0) under our conditions occurs through
oxidative addition by I , generated by oxidation of HI by
2
oxygen. Clearly, in the presence of a basic substrate such as 1,
acid–base equilibrium (3) takes place, which lowers the
concentration of both HI [thus hindering Pd(0) reoxidation] and
free 1. As a consequence, the overall carbonylation process
tends to be inhibited. This is particularly important in polar
5
solvents, where equilibrium (3) is strongly shifted to the right.
Carbonylations of primary aliphatic amines 1 [eqn. (1), R =
alkyl] were carried out in 1,2-dimethoxyethane (DME) (1 mmol
of 1/mL of DME) at 100 °C and under a 4+1+10 mixture of
However, it is very well known that basicity of amines is
significantly reduced in low-polar aprotic solvents with respect
5
to polar solvents. Therefore, in a low-polar solvent the catalytic
CO+air+CO
2
(60 atm total pressure at 25 °C) in the presence of
in conjunction
with KI. Some representative results are shown in Table 1, runs
–3. As shown in the Table, excellent yields in the correspond-
ing ureas 2 were obtained, with turnover numbers as high as
400 mol of 2 per mol of Pd used.† Butylamine 1a (R = n-Bu,
cycle can run effectively even in the presence of a basic
a very simple catalytic system consisting of PdI
2
4
Table 1 Synthesis of ureas 2 by Pd-catalysed oxidative carbonylation of
primary amines 1a
1
Yield of
2 (%)b
Mol of
2/mol of PdI
2
2
Run
1
R
1/PdI
2
t/h
run 1) was more reactive than sterically demanding tert-
butylamine 1b (R = t-Bu, run 2), and somewhat less reactive
1
2
3
1a
1b
1c
1c
1d
1e
n-Bu
t-Bu
2
5000
2000
5000
5000
1000
3000
15
15
4
4
16
15
96 (99)
90 (98)
94
78
87
98
2400
900
2350
1950
435
than benzylamine 1c (R = CH
absence of CO , less satisfactory results were obtained
compare run 4 with run 3).
Primary aromatic amines [eqn. (1), R = Ar] were generally
less reactive than primary aliphatic amines. With aniline 1d (R
Ph), substrate to catalyst ratio was lowered to 1000 (run 5);
moreover, carbonylation of aniline gave better results working
in the absence of added CO . However, a more nucleophilic
primary aromatic amine such as 4-methoxyaniline 1e (R = p-
MeOC ) turned out to be more reactive than tert-butylamine
effect
2
Ph, run 3). Working in the
2
CH Ph
c
d
(
4
2
CH Ph
Ph
c
5
c
6
p-MeOC
H
6 4
1470
a
=
Unless otherwise noted, all reactions were carried out in DME (1 mmol of
1/mL of DME, 10–15 mmol scale based on 1) at 100 °C under 60 atm of a
4
1
2 2
+1+10 mixture of CO+air+CO in the presence of PdI in conjunction with
2
00 equiv. of KI. b Isolated yield (GLC yield) based on 1. Unless otherwise
c
noted, substrate conversion was practically quantitative in all cases. The
6 4
H
reaction was carried out under 20 atm of a 4+1 mixture of CO+air.
1
b (compare runs 6 and 2), with no significant CO
2
d
Substrate conversion was 86%.
observed in this case.
4
86
CHEM. COMMUN., 2003, 486–487
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substrate. DME appeared to be the solvent of choice for the
heated at 100 °C with stirring for the required time. In some cases (Table 1,
runs 4–6), the reaction was carried out by pressurizing only with CO (16
atm) and air (up to 20 atm). These conditions (16 atm of CO together with
present reaction, since it is an aprotic solvent of low polarity (e
6
=
7.54 at 25 °C, 6.09 at 80 °C), but sufficiently coordinating
5
total atm of air, considering that the autoclave was loaded under 1 atm of
to allow dissolution of the PdI
As we have seen, working in the presence of an excess of CO
40 atm) had a beneficial effect on carbonylation of primary
aliphatic amines (compare run 4 with run 3), analogous to what
we have already observed in the PdI –KI-catalysed oxidative
cyclization–methoxycarbonylation of (Z)-(2-en-4-ynyl)amines
2
–KI catalytic system.
air) corresponded to 76.2% of CO in air and were outside the explosion
limits for CO in air (ca. 16–70% at 18–20 °C and atmospheric pressure,
2
(
1
4.8–71.5% at 100 °C and atmospheric pressure. At higher total pressure,
the range of flammability decreases: for example, at 20 atm and 20 °C the
limits are ca. 20 and 60%. See: C. M. Bartish and G. M. Drissel, in Kirk–
2
rd
Othmer Encyclopedia of Chemical Technology, 3 edition, ed. M. Grayson,
7
D. Eckroth, G. J. Bushey, L. Campbell, A. Klingsberg and L. van Nes,
Wiley-Interscience, New York, 1978, vol 4, pp. 774–775). After cooling,
the autoclave was degassed and solvent removed by rotary evaporation.
Generally, some amount of crude product was already present in suspension
in the reaction mixture. Crude ureas 2a–d were purified by column
to pyrrol-2-acetic esters. This CO
that substrate basicity is further diminished in the presence of
CO through the formation of a carbamate species (Scheme 2).
The reaction did not occur in the absence of carbon monoxide,
which means that CO indeed acts as a promoter, as shown in
2
effect is related to the fact
2
2
2 3
chromatography on silica gel using as eluent: Et O (2a); CHCl (2b, 2c);
Scheme 2, and not as carbonylating agent. The fact that in the
case of aniline better results were obtained working in the
absence of CO (run 5) is in agreement with the lower
2
nucleophilicity and basicity of aniline as compared with
primary aliphatic amines.
THF (2d). Urea 2e was present in the reaction mixture as a white precipitate,
which was purified by washing with acetone to give the pure product as a
colorless solid.
‡ Ureas 4a and 4b were easily purified by column chromatography on silica
gel using hexane–AcOEt from 8+2 to 7+3 as eluent. All ureas synthesised
1
13
were fully characterized by IR, H NMR, C NMR spectroscopies and MS
spectrometry; elemental analyses were satisfactory.
1
For a review on recent progress in the synthesis of ureas, see: F. Bigi, R.
Maggi and G. Sartori, Green Chem., 2000, 2, 140.
Scheme 2 Carbon dioxide effect on carbonylation of 1.
Interestingly, secondary amines 3 were unreactive under the
above conditions. This result suggests the formation of
isocyanates 5 as the key intermediate of the process, with
carbamoylpalladium complex I formed in pre-equilibrium with
starting materials (Scheme 3). In agreement with this hypoth-
esis, isocyanates were detected in the reaction mixture in low-
conversion experiments.
2 For a general review on oxidative carbonylation, see: A. Klausener and J.
D. Jentsch, in Oxidative Carbonylation in Applied Homogeneous
Catalysis with Organometallic Compounds, ed. D. Cornils and W. A.
Herrmann, VCH, Weinheim, 1996, vol. 1, p. 169.
3
For some recent examples of synthesis of ureas by the amine oxidative
carbonylation approach, see: F. Qian, J. E. McCusker, Y. Zhang, A. D.
Main, M. Chlebowski, M. Kokka and L. McElwee-White, J. Org. Chem.,
2
2
002, 67, 4086; T. Kihlberg, F. Karimi and B. Langström, J. Org. Chem.,
002, 67, 3687; H. Z. Yang, Y. Q. Deng and F. Shi, J. Mol. Catal. A:
Chem., 2001, 176, 73; F. Shi, Y. Deng, T. SiMa and H. Yang,
Tetrahedron Lett., 2001, 42, 2161; J. E. McCusker, F. Qian and L.
McElwee-White, J. Mol. Catal. A: Chem., 2000, 159, 11; J. E. McCusker,
A. D. Main, K S. Johnson, C. A. Grasso and L. McElwee-White, J. Org.
Chem., 2000, 65, 5216; J. E. McCusker, C. A. Grasso, A. D. Main and L.
McElwee-White, Org. Lett., 1999, 1, 961; J. E. McCusker, J. Logan and
L. McElwee-White, Organometallics, 1998, 17, 4037.
Scheme 3 Detailed mechanism of formation of ureas 2.
Formation of 5 as intermediates also suggested the possibility
to synthesise unsymmetrically substituted ureas by carrying out
the carbonylation of a primary amine in the presence of a
suitable excess of a secondary amine. Indeed, by reacting
4 The use of PdI2 in conjunction with an excess of KI (corresponding to
K PdI + KI in excess) in oxidative carbonylation reactions was disclosed
BuNH
presence of PdI
.67 mmol) in DME (21 mL) at 90 °C under 60 atm of a 4+1+10
mixture of CO+air+CO for 15 h, mixed urea 4a [eqn. (2), R, RA
Bu] was obtained as the main reaction product (75% isolated
yield), symmetrically substituted urea 2a being formed in only
7% yield. Analogously, the reaction of 1a and morpholine 3b
eqn. (2), R = Bu, RA = –(CH O(CH –] carried out under
2
1a (8.3 mmol) and Bu
2
NH 3a (12.5 mmol) in the
2
4
2
3
2
(3.0 mg, 8.3 3 10 mmol) and KI (277 mg,
by us some years ago: (a) B. Gabriele, M. Costa, G. Salerno and G. P.
Chiusoli, J. Chem. Soc., Chem. Commun., 1992, 1007; (b) B. Gabriele,
M. Costa, G. Salerno and G. P. Chiusoli, J. Chem. Soc., Perkin Trans. 1,
1
2
1
994, 83. The beneficial effect of iodide anions on oxidative carbonyla-
=
tion of amines has also been noted by other authors; see, for example: (c)
S. A. R. Mulla, C. V. Rode, A. A. Kelkar and S. P. Gupte, J. Mol. Catal.
A: Chem., 1997, 122, 103 and references therein.
R. G. Pearson and D. C. Vogelsong, J. Am. Chem. Soc., 1958, 80,
1038.
6 G. Goldoni, L. Marcheselli, G. Pistoni, L. Tassi and S. Fanali, J. Chem.
Soc., Faraday Trans., 1992, 88, 2003.
1
[
2
)
2
2 2
)
5
the same conditions but at 100 °C rather than 90 °C, led to
mixed urea 4b and symmetrically substituted urea 2a in 71%
and 13% isolated yield, respectively.‡
In conclusion, we have developed a new and efficient
protocol for the production of symmetrically substituted and
unsymmetrically substituted ureas (2 and 4, respectively) by
direct Pd-catalysed oxidative carbonylation of amines, with
unprecedented catalytic efficiencies for this kind of reaction. To
our knowledge, the formation of trisubstituted ureas by direct
Pd-catalysed oxidative carbonylation of primary and secondary
amines is also unprecedented. Ureas are a very important class
7 B. Gabriele, G. Salerno, A. Fazio and F. B. Campana, Chem. Commun.,
2
002, 1408.
8
For recent examples on pharmacological activity of ureas, see: T. B.
Lowinger, B. Riedl, J. Dumas and R. A. Smith, Curr. Pharm. Design,
2
002, 8, 2269; K. Matsuno, T. Nakajima, M. Ichimura, N. A. Giese, J. C.
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of carbonyl compounds, which have been shown to possess a
marked pharmacological activity.8
This work was supported by the Ministero dell’Università e
della Ricerca Scientifica e Tecnologica (Progetto d’Interesse
Nazionale PIN MM03027791).
Notes and references
†
Representative experimental procedure: a 250 mL stainless steel auto-
clave was charged in the presence of air with PdI (1.1–5.4 mg, 3.0 3
–1.5 3 10 mmol), KI (100 mmol per mmol of PdI ) and 1 (15 mmol)
dissolved in DME (15 mL). The autoclave was pressurized with stirring at
rt with CO (40 atm), CO (up to 56 atm) and air (up to 60 atm) and then
2
23
22
10
2
2
CHEM. COMMUN., 2003, 486–487
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