Selective and environmentally friendly methodologies based on the use of electrochemistry for fine chemical preparation: An efficient synthesis of N,N′-disubstituted ureas

Article abstract of DOI:10.1021/jo034750d

A novel efficient synthesis of N,N′-disubstituted ureas has been developed. Aromatic and aliphatic primary amines undergo oxidative carbonylation under atmospheric pressure of carbon monoxide using Pd(II) catalyst in combination with its anodic recycling at a graphite electrode.

Full text of DOI:10.1021/jo034750d

Selective a n d En vir on m en ta lly F r ien d ly
Meth od ologies Ba sed on th e Use of
Electr och em istr y for F in e Ch em ica l
P r ep a r a tion : An Efficien t Syn th esis of
N,N′-Disu bstitu ted Ur ea s
The reaction with a Pd catalyst implies the use of a
reoxidant reagent in stoichiometric amount to transform
Pd(0) (that results from the reaction) into Pd(II) (the
reactive species of the catalyst); usually, high pressures
of CO and O
2
are necessary, sometimes in combination
1
5
with I
2
;
alternatively, CO, O , and copper salts can be
2
used.16
Isabella Chiarotto and Marta Feroci*
Electrochemistry has also been used as reoxidizing
system: recently Deng and co-workers have applied
electrochemistry to the synthesis of symmetrical dialkyl
Universit a` degli Studi “La Sapienza”, Dipartimento di
Ingegneria Chimica, dei Materiali, delle Materie Prime e
Metallurgia, via Castro Laurenziano, 7 I-00161 Rome, Italy
ureas using Pd(PPh
3
)
2
Cl
2
2
as catalyst and Cu(OAc) as co-
catalyst, instead of high pressure of CO/O
2
. In this case,
marta.feroci@uniroma1.it
Received J une 3, 2003
2
it is proved that Cu(OAc) “acted as not only an electron
transfer agent but also a catalyst”.17
In all these syntheses of ureas, a side reaction of either
double carbonylation to oxamides takes place or the
formation of isocyanates probably by amine-elimination
reaction from urea. It is therefore important to find a
synthesis with high selectivity to minimize the side
reactions.
Abstr a ct: A novel efficient synthesis of N,N′-disubstituted
ureas has been developed. Aromatic and aliphatic primary
amines undergo oxidative carbonylation under atmospheric
pressure of carbon monoxide using Pd(II) catalyst in com-
bination with its anodic recycling at a graphite electrode.
In the course of our studies aimed at the use of elec-
trochemistry as a selective and environmentally friendly
tool in organic synthesis, we have developed a new
methodology for palladium(II) catalyst recycling by means
of its anodic oxidation at a graphite electrode in the
absence of any other cocatalyst or stoichimetric oxidant.
This methodology was applied to the synthesis of methyl
acetylencarboxylates starting from alkynes, carbon mon-
oxide, and methanol18 and oxazolidin-2-ones starting from
2-amino-1-alkanols and carbon monoxide, obtaining these
heterocyclic compounds in very good yields. In this
paper, we want to extend this new procedure in order to
obtain an efficient synthesis of N,N′-disubstituted ureas
starting from amines and carbon monoxide.
The advantage of the anodic recycling at a graphite
electrode of Pd(II) is that it proceeds efficiently under
atmospheric pressure of carbon monoxide and avoids the
Substituted ureas have been of recent interest due to
the appearance of this functionality in drug candidates
such as HIV protease inhibitors; in addition, ureas have
found widespread use as agricultural chemicals, resin
1
,2
precursors, dyes, and additives to petroleum compounds
and polymers.3
For these reasons, many efforts have been made to find
new efficient syntheses of ureas to replace the classical
4
reactions of amines with phosgene or related compounds
1
9
5
6
(
isocyanates, carbonyldiimidazole, or disuccinimmide
7
carbonate ).
The synthesis of symmetrical ureas from amines can
be accomplished by oxidative carbonylation of amines by
means of carbon monoxide and a transition-metal cata-
8
9
10
11
12
13
14
lyst (W, Ni, Mn, Co, Rh, Ru, and Pd ). Among
them, the most commonly used is Pd.
2
use of copper or halide ions and high pressure of O gas,
which also implies the formation of water and causes
undesired side reactions;17 this way, the performances
of the catalysts should be enhanced.
(
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.
(8) McCusker, J . E.; Grasso, C. A.; Main, A. D.; McElwee-White, L.
Org. Lett. 1999, 1, 961-964. McCusker, J . E.; Qian, F.; McElwee-White,
L. J . Mol. Catal. A.: Chem. 2000, 159, 11-17. McCusker, J . E.; Main,
A. D.; J ohnson, K. S.; Grasso, C. A.; McElwee-White, L. J . Org. Chem.
2000, 65, 5216-5222.
1
996, 39, 3514-3525.
(9) Giannoccaro, P.; Nobile, C. F.; Mastrorilli, C.; Ravasio, J . J .
Organomet. Chem. 1991, 419, 251-258.
(
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-
(10) Srivastva, S. C.; Shrimal, A. K.; Srivastva, A. J . Organomet.
Chem. 1991, 414, 65-69.
(11) Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. J . Mol. Catal.
1990, 60, 41-48.
1
884.
(
4) For use of phosgene and its derivatives, see: Hegarty, A. F.;
(12) Mulla, S. A. R.; Gupte, S. P.; Chaudhari, R. V. J . Mol. Catal.
1991, 67, L7-L10.
Drennan, L. J . In Comprehensive Organic Funcional Group Transfor-
mations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Perga-
mon: Oxford, 1995; Vol. 6, pp 499-526. Guichard, G.; Semetery, V.;
Didierjean, C.; Aubry, A.; Briand, J . P.; Rodriguez, M. J . Org. Chem.
(13) Mulla, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. J . Mol.
Catal. A.: Chem. 1997, 122, 103-109.
(14) Valli, V. L. K.; Alper, H. Organometallics 1995, 14, 80-82.
Gupte, S. P.; Chaudhari, R. V. J . Catal. 1988, 114, 246-258.
(15) Pri-Bar, I.; Alper, H. Can. J . Chem. 1990, 68, 1544-1547. Shi,
F.; Deng, Y.; SiMa, T.; Yang, H. Tetrahedron Lett. 2001, 42, 2161-
2163.
1
999, 64, 8702-8705. Majer, P.; Randal, R. S. J . Org. Chem. 1994,
5
9, 1937-1938. Scialdone, M. A.; Shuey, S. W.; Soper, P.; Hamuro, Y.;
Burns, D. M. J . Org. Chem. 1998, 63, 4802-4807.
(
5) Satchell, R. S.; Satchell, D. P. N. Chem. Soc. Rev. 1975, 4, 231-
50.
6) Zhang, X.; Rodrigues, J .; Evans, L.; Hinckle, B.; Ballantyne, L.;
Pena, M. J . Org. Chem. 1997, 62, 6420-6423.
7) Takeda, K.; Akagi, Y.; Saiki, A.; Tsukahara, T.; Ogura, H.
Tetrahedron Lett. 1983, 24, 4569-4572.
2
(16) Giannoccaro, P. J . Organomet. Chem. 1987, 336, 271-278.
(17) Yang, H.; Deng, Y.; Shi, F. J . Mol. Catal. A.: Chem. 2001, 176,
73-78.
(18) Chiarotto, I.; Carelli, I. Synth. Commun. 2002, 32, 881-886.
(19) Chiarotto, I.; Feroci, M. Tetrahedron Lett. 2001, 42, 3451-3453.
(
(
1
0.1021/jo034750d CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/15/2003
J . Org. Chem. 2003, 68, 7137-7139
7137

TABLE 1. Electr och em ica l Syn th esis of N,N-Diben zylu r ea Usin g Differ en t P d (II) Com p lexes a s Ca ta lyst
reaction
time (h)
urea 2,
oxamide 3,
current
yield (%)
entry
catalyst
base
ligand
yielda (%)
yielda (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
NEt3
3
3
3
9
4
4
4
5
7
62
32
59
57
67
83
73
48
50
12
2
10
16
5
10
6
<1
6
81
68
73
85
90
86
81
99
77
TFPb
PPh3
dpppc
d
Pd2(dba)3
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2
PdCl2
a
Yields determined by HPLC, yields relative to starting 1. b TFP ) tri-2-furylphosphine. c dppp ) 1,3-bis(diphenylphosphino)propane.
d
Tris(dibenzylideneacetone)dipalladium(0).
TABLE 2. Electr och em ica l Syn th esis of Alip h a tic a n d
Ar om a tic Ur ea s Usin g P a lla d iu m Ca ta lysta
Aromatic and aliphatic primary amines undergo oxida-
tive carbonylation to give N,N′-disubstituted ureas; the
process is outlined in the following reaction (eq 1):
urea 2, oxamide current
amine
1, R
reaction yieldc 3, yield
c
yield
(%)
entry
catalystb time (h)
(%)
(%)
1
2
3
4
5
6
7
8
9
4-MeOPh
4-MeOPh
4-ClPh
4-ClPh
Ph
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
5
6
7
6
5
6
4
3
5
6
3
6
5
5
3
3
10
41
20
31
49
57
83
62
30
21
57
71
35
37
70
71
0
0
0
0
0
10
38
46
30
99
84
86
81
99
30
66
73
44
76
99
94
Ph
0
PhCH2
PhCH2
2-Py
10
12
0
0
0
0
1
1
3
The following general procedure was used: in a cell
with three separated compartments, kept at 50.0 ( 0.1
C, the electrolysis was carried out on a solution of amine
10 2-Py
1
1
1
1
1
1
2
3
4
5
C6H11
C6H11
C5H9
C5H9
Bu
°
(
(
0.50 mmol), in 30 mL of CH
3
CN containing n-Bu
0.20 mol L ) as supporting electrolyte, in the presence
(0.05 mmol) and NaOAc (2.00 mmol), under
4 4
NBF
-
1
of Pd(OAc)
atm of CO at +0.4 V vs SCE. A graphite electrode, of
2
16 Bu
0
2
0
1
a
General procedure: the same described in the text. b A,
2
apparent area of 3 cm , was used as working electrode.
The counter-electrode was a Pt wire, and the reference
was a saturated calomel electrode (SCE). The electrolysis
was stopped when the current reached the value recorded
at the end of the preelectrolysis.
Pd(PPh3)4; B, Pd(OAc)2. c Yields determined by HPLC, yields
relative to starting 1.
To test its applicability, this electrochemical syn-
thesis, using two different catalytic systems, a complex
of Pd(0), i.e., Pd(PPh ) , and a complex of Pd(II), i.e.,
Benzylamine was used as a model compound to study
the influence of catalyst and ligands. The effect of
different catalytic systems on the carbonylation of ben-
zylamine is presented in Table 1.
3
4
Pd(OAc) , were applied to a variety of primary aliphatic
2
and aromatic amines. The preparative results are sum-
marized in Table 2.22
Among the examinated catalytic systems, Pd
exhibited good selectivity to afford the urea in 67% and
oxamide in 5% yields, whereas the best yield in urea
2
(dba)
3
The yields in urea and the selectivity with respect to
the formation of oxamide (side product) depend both on
the structure of the starting amine and on the kind of
catalyst system: the aromatic amines seem less reactive
than the aliphatic ones, while the best catalyst seems to
be a complex of Pd(II). In all cases (except benzylamine,
entries 7 and 8), the selectivity was very high and
oxamide was formed only in a very small amount or it
was totally absent. It is to be underlined that in no case
isocyanate was evidenced, so only two products were
formed during the electrocatalytic carbonylation: diaryl
or dialkylurea and oxamide.
(
83%) was obtained using Pd(PPh
suggests that the palladium(0) complexes, such as
Pd(PPh and Pd (dba) , are good catalytic systems in
this transformation. From the electrochemical point of
view, the most efficient catalytic system was PdCl as it
3 4
) as catalyst. This
3
)
4
2
3
2
appears from the current yield (99%) and from the
selectivity of this reaction, but the reaction resulted very
slow. The use of a base is necessary to avoid the formation
+
+
of HPd(II)(L)
2
or of HPd(II) , which do not react in this
transformation.2 In the presence of PdCl
1
as catalyst,
2
The choice of solvent also appeared to be signifi-
cant; among the solvents used in the electrocarbonyla-
the use of NEt
electrocatalytic system; in fact, the current yield affords
7% in the presence of NEt , with respect to 99% in the
presence of AcONa.
3
, instead of AcONa, seems to decrease the
7
3
(21) Amatore, C.; J utand, A.; Meyer, G.; Carelli, I.; Chiarotto, I. Eur.
J . Inorg. Chem. 2000, 8, 1855-1859.
(22) Amines were purchased from commercial sources and were
purified prior to use. Standard of disubstituted ureas and oxamides
synthesized in this paper, are commercially available. The ureas and
oxamides were characterized by comparison of infrared, nuclear
magnetic resonance, and mass spectra with those for authentic
materials and literature data.
(
20) The working potential was slightly more positive than the
oxidation peak potential of Pd(0): Carelli, I.; Chiarotto, I.; Cacchi, S.;
Pace, P.; Amatore, C.; J utand, A.; Meyer, G. Eur. J . Org. Chem. 1999,
471-1473.
1
7
138 J . Org. Chem., Vol. 68, No. 18, 2003

tion, CH
3
CN gave the best yields of urea and easiness in
Ack n ow led gm en t. We thank Mr M. Di Pilato for
his contribution to the experimental part of this work.
This work was supported by research grants from
MURST (Cofin 2002) and CNR, Roma, Italy.
the electrolysis work up. Changing the solvent to THF
or DMF resulted in a change in the carbonylation
products and selectivity (no urea could be evidenced),
and further studies are in progress to understand the
influence of those solvents on the selectivity of the
product.23
In conclusion, the electrochemical methodology permits
a mild, selective and environmental friendly reoxidation
of Pd(0) into Pd(II) in oxidative carbonylation of amines
to ureas. The reaction is very selective (in most cases,
no side product is formed), and good yields in ureas are
obtained from aliphatic amines.
Su p p or tin g In for m a tion Ava ila ble: Spectral data of
ureas and oxamides. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O034750D
(23) The HPLC analysis of the electrolysis carried out in DMF
solvent showed the presence of both isocyanate and carbammic acid,
but no qualitative analysis was possible because carbammic acid can
be also produced, by hydrolysis of isocyanate, in the HPLC column.
J . Org. Chem, Vol. 68, No. 18, 2003 7139