NaIO4-oxidized carbonylation of amines to ureas

Article abstract of DOI:10.1039/b819891h

Oxidative carbonylation of amines using NaIO₄ as the oxidant and NaI as a promoter affords good to excellent yields of ureas from primary amines in the absence of transition metal catalysts. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b819891h

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NaIO4-oxidized carbonylation of amines to ureasw
Phillip A. Shelton, Yue Zhang, Thi Hoang Ha Nguyen and Lisa McElwee-White*
Received (in College Park, MD, USA) 10th November 2008, Accepted 9th December 2008
First published as an Advance Article on the web 15th January 2009
DOI: 10.1039/b819891h
Oxidative carbonylation of amines using NaIO4 as the oxidant
and NaI as a promoter affords good to excellent yields of ureas
from primary amines in the absence of transition metal catalysts.
mixture or not (eqn (1)). In fact, the W(CO)6-catalyzed version
of this reaction afforded the urea in only 3% higher yield than
the experiments in which no metal carbonyl had been added
(84% vs. 81%). Low to negligible yields of the urea were
formed when every other oxidant was reacted in the absence of
the metal catalyst. These results led us to carry out optimization
studies on the NaIO4-oxidized carbonylation reaction with the
goal of developing conditions that did not require the addition
of a metal catalyst.
In addition to being common functional groups in pharma-
ceutical compounds,1–4 ureas are also frequently found in
agricultural products and dyes.5–7 Traditional methods to
synthesize ureas are generally based on reactions of amines
with phosgene or phosgene derivatives, such as carbodiimidazole
(CDI), triphosgene or S,S-dimethyl dithiocarbonate (DMDTC).8,9
These reactions can produce a variety of symmetrical or
unsymmetrical ureas in excellent yields. However, phosgene
is toxic and phosgene derivatives are undesirable from the
standpoint of expense, waste minimization10 and atom
economy.11
ð1Þ
Control experiments were performed with 4-methoxybenzylamine
as substrate, H2O–CH2Cl2 as solvent and K2CO3 as base.
Initial experiments addressed the need for the presence of both
the NaIO4 oxidant and the NaI promoter. When NaI was used
in the absence of oxidant, no urea was produced under CO
pressures of 45 atm. Analogously, an experiment with only
NaIO4 as oxidant but no iodide promoter yielded similar
results, confirming that both components must be present in
the reaction mixture.
Transition metal-catalyzed oxidative carbonylation of
amines12,13 provides an alternative to phosgene and phosgene
derivatives. Many metals including Pd, Ru, Rh, Au, Co, Ni
and W have been employed as catalysts in the carbonylation
reaction.12,13 However, there are also problems with metal
catalysts including the expense of noble metal complexes and
the possibility of heavy metal contamination in the products.
Sulfur14–16 and selenium17–19 catalyzed systems are also
known and avoid some of the drawbacks associated with
metal catalysis. These systems, however, produce the volatile
and toxic byproducts, H2S and SeH2, respectively.
Control experiments were carried out to investigate the
possibility that iron or ruthenium carbonyl present in trace
amounts in the carbon monoxide26 could be catalyzing
this reaction. When authentic Fe(CO)5 or Ru3(CO)12
(4.0 ꢀ 10ꢁ5 mol, 2 mol%) was added to a reaction of
4-methoxybenzylamine under the standard conditions, the
yield of urea was similar to that obtained in the absence of
the metal carbonyl complex (68% and 62%, respectively). In
efforts to minimize the possibility of contamination of the CO
by Fe or Ru carbonyl, the reaction was repeated with CO
from an aluminium cylinder.26 Fe(CO)5 is known to be a
contaminant in CO from steel cylinders, however, the use of
aluminium tanks minimizes the content of Fe(CO)5 in the CO.
Using NaIO4–NaI and K2CO3 as base, but with CO from the
aluminium cylinder, 80% yield of bis(4-methoxybenzyl) urea
was obtained. Together, these control experiments rule out
catalysis by adventitious metal carbonyls.
Additional methods that avoid the presence of metal
catalysts while addressing toxicity and waste stream issues
would be advantageous. We now report oxidative carbonylation
of amines to ureas without the addition of metal catalysts in a
system using sodium periodate as the oxidant and iodide as the
promoter.
In conjunction with our previous work on W(CO)6-catalyzed
carbonylation of ureas as methodology for synthesis of
complex targets,20–23 we investigated carbonylation of amines
using various combinations of oxidants, promoters and
bases.24 Among the oxidants studied were NaIO4, 30%
H2O2, I2–FeCl3, I2, 4-methylmorpholine N-oxide and O2.
Extensive control experiments established that the W(CO)6
catalyst was necessary to obtain high yields of the urea
products, with one exception.25 When the oxidant was NaIO4
and iodide ion was present as a promoter, 4-methoxybenzylamine
was converted to the corresponding urea in excellent yield,
whether the W(CO)6 catalyst was added to the reaction
In an additional reaction, I2 was used as a cooxidant–iodide
source in place of the NaI. This reaction did, in fact, yield
complete conversion of the starting material but afforded a
1 : 1.7 ratio of urea to formamide (eqn (2)). When the solvent
is CH2Cl2 without the addition of water as a cosolvent, only
trace amounts of the urea can be detected in the 1H NMR
spectra. Failure of the reaction under these conditions is
probably due to insolubility of NaIO4 and NaI. These
experiments have established that NaIO4, a base and a source
Department of Chemistry and Center for Catalysis, University of
Florida, Gainesville, FL 32611-7200, USA.
E-mail: lmwhite@chem.ufl.edu; Tel: +1 (0)352-392-8768
w Electronic supplementary information (ESI) available: Experimental
procedures for carbonylation of amines. See DOI: 10.1039/b819891h
ꢂc
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Chem. Commun., 2009, 947–949 | 947

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of iodide are required to carry out metal-free urea synthesis
under these conditions.
Several primary amines have been subjected to the
NaIO4–NaI carbonylation conditions (Table 1). Unhindered
alkylamines form the urea readily under these conditions
(entries 1 and 2). Sterically hindered tert-butylamine gives
low yields (entry 4) but moderately hindered isopropyl amine
still gives excellent results (entry 3). With the exception of
tert-butylamine, yields compare favorably to those obtained
using Pd27 or W23 catalysts.
ð2Þ
Various 4-substituted benzylamines were subjected to the
reaction conditions (eqn (3)). Again, excellent yields were
obtained when optimized conditions were used (Table 2). When
DMAP is used as the base, yields are higher than those obtained
with W(CO)6 as catalyst.23 Pd catalysts produce higher yields in
the reported cases,27,29 but the literature data are limited. Little
substituent effect was observed except that more electronegative
halide derivatives give slightly lower yields (entries 6–9).
Interestingly, when a weaker base, K2CO3, is used, proton
acidities do become relevant (column 4).
Optimization studies using 4-methoxybenzylamine (1) led to
the following conditions: 1.5 equiv. of 4-(dimethylamino)
pyridine (DMAP) as base, 0.8 equiv. of NaIO4 as oxidant
and 0.5 equiv. of NaI as promoter under 45 atm of CO
pressure. After 8 hours, urea 2 was obtained as an off-white
powder in 81% yield. Increased temperature, pressure or time
resulted in lower yield.
Optimization experiments revealed that at pressures as low as
20 atm, the urea was formed as the major product. When the
experiment was conducted at 1 atm, no urea was produced but
4-methoxybenzonitrile was formed in 42% yield. Precedent for
this oxidation reaction is found in the transformation of
benzylamines to benzonitriles upon treatment with the
Dess–Martin periodinane.28 To test if the nitrile was an inter-
mediate in urea formation, two equiv. of 4-methoxybenzonitrile
were subjected to the same reaction conditions that converted
4-methoxybenzylamine to urea. This yielded no urea, leading to
the conclusion that the nitrile is not an intermediate.
ð3Þ
In an effort to extend these results to aromatic amines, aniline
was also subjected to metal-free carbonylation conditions, but
oxidation occurred in preference to carbonylation, yielding
hydroquinone as the major product. This result is consistent
Table 1 Carbonylation of amines with NaIO4–NaI
% Yielda,b
% Yielda,c
% Yielda,d
(NaIO4–NaI)
Entry
RNH2 R =
(Pd(0)-catalyzed)27
(W(CO)6-catalyzed)23
1
2
3
4
n-Bu
i-Bu
i-Pr
96
—
—
89
78
—
27
62
94
96
91
20
t-Bu
a
b
Isolated yield per equivalent of amine. Conditions: 20.0 mmol amine, 0.2 mmol PdI2, 0.02 mmol KI, 20 mL DME, 100 1C, 16 atm CO, 4 atm
c
air, 40 atm CO2, 15 h. Conditions: 3.6 mmol amine, 0.071 mmol W(CO)6, 1.8 mmol I2, 5.0 mmol K2CO3, 15 mL H2O–15 mL CH2Cl2, 70 1C,
80 atm CO, 24 h. Conditions: 2.0 mmol amine, 1.0 mmol NaI, 1.6 mmol NaIO4, 3.0 mmol DMAP, 15 mL H2O–15 mL CH2Cl2, room
temperature, 45 atm CO, 8 h.
d
Table 2 Carbonylation of 4-substituted benzylamines
% Yielda
(Pd(0)-catalyzed)
% Yielda,b
% Yielda,c
(NaIO4–NaI K2CO3)
% Yielda,d
(NaIO4–NaI DMAP)
Entry
X
(W(CO)6-catalyzed)23
1
2
3
4
5
6
7
8
9
–OMe
–CH3
–H
—
70
—
73
55
76
—
77
77
—
81
61
46
10
1
27
21
7
81
78
88
9929,e
9427,f
—
–COORg
–NO2
–I
85h
79h
87h
78
—
—
–Br
–Cl
–F
—
8729,e
—
72
72
0
a
b
Isolated yield per equivalent of amine. Conditions: 3.6 mmol amine, 0.071 mmol W(CO)6, 1.8 mmol I2, 5.0 mmol K2CO3, 15 mL H2O–15 mL
c
CH2Cl2, 70 1C, 80 atm CO, 24 h. Conditions: 2.0 mmol amine, 1.0 mmol NaI, 1.6 mmol NaIO4, 3.0 mmol K2CO3, 15 mL H2O–15 mL CH2Cl2,
room temperature, 45 atm CO, 16 h. Conditions: 2.0 mmol amine, 1.0 mmol NaI, 1.6 mmol NaIO4, 3.0 mmol DMAP, 15 mL H2O–15 mL
e
CH2Cl2, room temperature, 45 atm CO, 8 h. Conditions: 22.0 mmol amine, 0.0044 mmol Pd(aniline)(NHC) catalyst, 6.0 mL DMF, 31.6 atm CO,
d
f
8.0 atm O2, 150 1C, 1 h. Conditions: 20.0 mmol amine, 0.2 mmol PdI2, 0.02 mmol KI, 20 mL DME, 100 1C, 16 atm CO, 4 atm air, 40 atm CO2,
15 h. For the W(CO)6-catalyzed reaction, R = Et; for the NaIO4–NaI conditions, R = Me. One extra equiv. of base was added since the amine
was added as the HCl salt.
g
h
ꢂc
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948 | Chem. Commun., 2009, 947–949

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with similar observations by Srivastava et al.30 during studies on
oxidation of aromatic amines using periodate.
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In conclusion, conversion of amines to ureas using mild and
atom economical conditions has been realized in the absence
of a transition metal catalyst. These transformations take
place at room temperature under CO pressures as low as
20 atm. High yields of urea have been obtained for unhindered
primary alkyl amines and benzylamines. The reaction is
sensitive to steric hindrance in the alkyl substituent, as
evidenced by lower yields from tert-butylamine. The mechanism
of this reaction is still under study but preliminary results
suggest that a hypervalent iodine species could be responsible
for the reactivity. Further research on this reaction is
underway.
We thank the donors of the American Chemical Society
Petroleum Research Fund for support of this work through
the Green Chemistry Institute. T.H.H.N. thanks the Ecole
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National Superieure de Chimie de Clermont Ferrand
´
(ENSCCF) and the US/France REU Program funded by
NSF for support of her internship at the University of Florida.
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M. Kokka and L. McElwee-White, J. Org. Chem., 2002, 67, 4086.
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ureas and oxidant studies, PhD dissertation, University of Florida,
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 947–949 | 949