A simple direct phosgeneless route to N-heteroaryl unsymmetrical ureas

Article abstract of DOI:10.1039/c1gc15984d

A new simple approach to the synthesis of unsymmetrical ureas HetNC(O)NRR′ (HetNH = pyrrole, indole, carbazole; R, R′ = H, alkyl, aryl) has been explored, which involves the direct reaction of the N-phenoxycarbonyl derivatives of pyrrole, indole and carba

Full text of DOI:10.1039/c1gc15984d

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PAPER
A simple direct phosgeneless route to N-heteroaryl unsymmetrical ureas
Marianna Carafa,a Valentina Melea and Eugenio Quaranta*a,b,c
Received 9th August 2011, Accepted 11th October 2011
DOI: 10.1039/c1gc15984d
A new simple approach to the synthesis of unsymmetrical ureas HetNC(O)NRR¢ (HetNH =
pyrrole, indole, carbazole; R, R¢ = H, alkyl, aryl) has been explored, which involves the direct
reaction of the N-phenoxycarbonyl derivatives of pyrrole, indole and carbazole, HetNCO2Ph,
with amines. The aminolysis reaction can be catalyzed by the amidine base DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene) under usually very mild conditions and provides a
straightforward convenient entry into the target products through a route which avoids the
traditional protocols based on multistep procedures and toxic phosgene or phosgene-derivatives.
Introduction
The search for new direct eco-friendly synthetic routes is a major
challenge for modern chemistry.1 Despite the efforts currently
devoted to redesign the synthesis of many classes of products
according to strategies more sustainable from the environmental
point of view, HetNC(O)NRR¢ carboxamides of N-heteroarenes
as pyrrole, indole and carbazole provide an example of chemicals
which are still manufactured through traditional multistep
methods based on risky and/or harmful starting materials.
These particular unsymmetrical ureas,2,3 wherein one of the
Scheme 1 Classic phosgene-based synthetic routes to unsymmetrical
ureas HetNC(O)NRR¢.
ureidic N atoms is also part of a heteroaromatic ring,4 are widely
used as synthetic intermediates,5,6 find practical application
in several fields,7 and usually exhibit biological activity or
interesting pharmacological properties.8,9
to the heterocyclic salt HetNM, which may depend on the
nature of cation M and, therefore, necessitate the empirical
characterization of the experimental conditions privileging N-
over C-functionalization.12
The classic methods of synthesis of these compounds start
from derivatives of phosgene4,10 or directly from COCl2,5,8
a
A relatively more recent method (Scheme 2) used CO2 as the
source of carbonyl group and was based on the activation of car-
boxylic acid HetNCO2H (HetNH = pyrrole, indole) to anhydride
[HetNC(O)]2O.13 However, the activation step requires the use of
a stoichiometric amount of a coupling reagent as EDCI·HCl (1-
[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride),
usually manufactured from phosgene.14 Moreover, the synthetic
route is atomically uneconomical, as it implies a multistep
procedure and needs 2 mol of HetNH (for preforming the
anhydride) per mol of product.
toxic and harmful species, the utilization of which in chem-
ical synthesis finds, nowadays, larger and larger constraints
due to governmental policies for environmental protection.11
The preliminary formation of a N-heteroaryl metal salt,
HetNM, is often required. Usually, HetNC(O)NHR ureas
are prepared by reaction of HetNM (M = Li, K, MgX)
salts with isocyanates (Scheme 1(a)).10a,b,d N,N-Disubstituted
ureas HetNC(O)NRR¢4,5,8 have been often obtained by reaction
of HetNM salts with N,N-disubstituted carbamoyl chlorides
(Scheme 1(b)).4 A major additional problem of these approaches
(Scheme 1) is also the regioselectivity of the electrophilic attack
aDipartimento di Chimica, Universita` degli Studi di Bari “Aldo Moro”,
Campus Universitario, Via E. Orabona, 4, 70126, Bari, Italy.
E-mail: quaranta@chimica.uniba.it; Fax: (+39)-080-544-2129
bICCOM-CNR, Dipartimento di Chimica, Campus Universitario, Via E.
Orabona, 4, 70126, Bari, Italy
cUdRBA1, Consorzio “INCA”, Via Delle Industrie, 21/8, 30175,
Marghera (VE), Italy
Scheme 2 Synthesis of unsymmetrical ureas HetNC(O)NRR¢ via
HetNCO2H activation.
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In the last few years many efforts have been addressed to
develop a fully phosgene-free chemistry and the study of safe
non-toxic active carbonyl species which can serve as substitutes
for phosgene or phosgene-derivatives has been drawing growing
attention.15–18 In this regard, carbonic acid diesters have been
shown to play an important role15a,16–18 as these compounds are
currently manufactured, even on the industrial scale, through
phosgene-free routes.19,20 As a part of our studies in this field,16,17
we have recently reported on the direct carbonylation of N-
heteroaromatics HetNH, such as pyrrole, indole and carbazole,
with organic carbonates for the phosgeneless synthesis of
carbonyl derivatives HetNCO2R,17b,d usually obtained through
phosgenation methods.21 The carbonylation reaction can be cat-
alyzed by superbases as DBU (1,8-diazabicyclo[5.4.0]undec-7-
ene) or phosphazenes. Notably, the DBU-promoted reaction of
HetNH (pyrrole, indole, carbazole) with diphenyl carbonate was
shown to be an excellent new method for the selective high-yield
synthesis of the N-phenoxycarbonyl derivatives HetNCO2Ph
1–3 [eqn (1)].17d Herein, with the intent of designing a fully
phosgene-free green approach to the synthesis of unsymmetrical
ureas HetNC(O)NRR¢ (R, R¢ = H, alkyl, aryl), we have explored
the potential of compounds 1–3 as carbonylating agents of
amines [eqn (2)]. Under usually mild conditions, the direct reac-
tion of 1–3 with amines provided a straightforward phosgeneless
access into N-heteroaryl unsymmetrical ureas HetNC(O)NRR¢
(Fig. 1) through a convenient route which is an eco-friendly
alternative to the classic methods described above.
1 was quantitatively converted into 4 within a short time (1 h).
The formation of 4 was very selective (>99%). The attack of the
amine to the substrate caused the selective expulsion of phenoxy
group with formation of 4, which, under the working conditions,
did not react further with the amine to generate the symmetrical
urea (RNH)2CO (R = benzyl). Accordingly, the IR spectrum of
the reaction mixture in the range 1800–1600 cm-1 showed one
only absorption at 1701 cm-1 due to 4.
Depending on the solvent properties and/or expensiveness of
amine reactant, the use of solventless conditions, or a large excess
of amine, may be poorly attractive from the synthetic point of
view or not practicable at all. Therefore, the aminolysis reaction
was studied also in ethereal solvents (diethyl ether or THF),22
using a modest excess of amine. In diethyl ether, at ambient
temperature, the reaction of 1 with a slight excess (ª10 mol%) of
PhCH2NH2 afforded 4 in practically quantitative yield (Entry
2, Table 1). However, under the used conditions, the conversion
rate, while being satisfactory soon after mixing the reactants,
became excessively slow in the long run (entry 2, Table 1) and
the full conversion of the substrate required a markedly longer
time.
The above behavior may reflect the fact that aminolysis of
carbamates is usually catalyzed by amine itself, since a second
molecule of amine can act as a catalyst of the process.23 We
have, therefore, investigated the effect of a base organo-catalyst
and focused the attention on the strong amidine superbase
DBU. Under experimental conditions otherwise analogous to
those used in entry 2 (Table 1), the presence of 1 equivalent of
the amidine superbase enhanced markedly the conversion rate
(entry 3, Table 1). The aminolysis reaction was promoted also
by markedly lower loadings of DBU, but less effectively, unless
the working temperature was increased. Accordingly, at 338 K,
in the presence of 10 mol% of DBU, 1 converted quantitatively
to 4 within only 2 h (entry 4, Table 1).
(1)
(2)
Table 2 summarizes the results obtained with a few other
amines. Like benzylamine, at ambient temperature also ally-
lamine reacted easily with 1 (RNH2/1 ª 1.14 mol/mol), in
THF and in the presence of 1 equivalent of DBU, to afford
1-allylaminocarbonyl pyrrole (5) (entry 1, Table 2).
The behavior of a few representative secondary aliphatic
amines was also studied. In ethereal solvents (diethyl ether, THF)
the DBU-promoted aminolysis of 1 with a cyclic secondary
amine such as morpholine proceeded smoothly under very
mild conditions and produced the relevant unsymmetrical urea
6 selectively (≥99%) with quantitative yield (entries 2 and 3,
Table 2). In comparison, a sterically encumbered secondary
acyclic amine, such as dibenzylamine, was, by far, much less
reactive. For instance, under conditions similar to those used
for morpholine in entry 3 (Table 2), dibenzylamine exhibited
very poor reactivity towards 1 (entry 4, Table 1). Even at 393 K,
the DBU-assisted aminolysis of 1 with a very modest excess of
(PhCH2)2NH (ª10 mol% vs. 1), in THF, required prohibitively
long reaction times (entries 5 and 6, Table 2). Much higher
conversion rates, which depended on the used catalyst load (10–
100 mol%), were observed at higher temperature (423 K) under
solventless conditions, using the amine in larger excess with
respect to the substrate (entry 7 and entry 8, Table 2). In the
range 393–423 K (entries 5–8, Table 2) the selectivity towards
1-dibenzylaminocarbonyl pyrrole (7) was moderate (ª75–85%)
Fig. 1 Synthesized unsymmetrical ureas.
Results and discussion
A preliminary study concerned the reaction of a primary
aliphatic amine such as benzylamine with 1-phenoxycarbonyl
pyrrole (1), which was selected as the reference substrate
(Table 1). At 293 K, in the absence of any catalyst, 1 reacted
promptly with an excess of benzylamine, used both as reactant
and solvent, to afford 1-benzylaminocarbonyl pyrrole (4) and
phenol: under the used solventless conditions (entry 1, Table 1),
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Table 1 Aminolysis of C4H4NCO2Ph (1) with PhCH2NH2, under different experimental conditions. The catalytic role of DBU
Entry
PhCH2NH2 (mmol)
1 (mmol)
DBU (mol%)a
Solvent
T/K
t/h
Conversionb [%]
4 [%]c
1
2
3
4
5.95
0.66
1.24
1.11
1.07
0.59
1.10
1.08
—
—
100
9.9
—
293
293
293
338
1
100
86
Diethyl etherd
Diethyl etherg
THFd
36e
2
ª100
ª100
ª100
>99f
87
2
90
a Relative to 1. b Of 1 (by GC). c Isolated yield (based on 1), unless otherwise specified. d 1 mL. e See also main text. f Selectivity to 4. g 2 mL.
Table 2 Aminolysis of C4H4NCO2Ph (1) to C4H4NC(O)NRR¢ (R, R¢ = H, alkyl, aryl) ureas by aliphatic or aromatic amines
Entry
amine (mmol)
1 (mmol)
DBU (mol%)a
Solventb
T/K
t/h
Conversionc [%]
Urea: [%]d
1
2
3
4
5
6
7
8
CH2 CHCH2NH2 (0.94)
O(CH2CH2)2NH (0.63)
O(CH2CH2)2NH (1.20)
(PhCH2)2NH (1.20)
(PhCH2)2NH (1.20)
(PhCH2)2NH (0.62)
(PhCH2)2NH (2.47)
(PhCH2)2NH (2.47)
(PhCH2)2NH (2.34)
PhNH2 (5.49)
PhNH2 (5.49)
PhNH2 (2.47)
PhNMeH (2.40)
PhNMeH (2.49)
0.82
0.55
1.08
1.09
1.09
0.57
0.82
0.82
0.74
0.55
0.55
0.82
0.81
0.83
0.85
101
103
9.9
9.8
9.8
99.4
10.0
102
202
—
104
103
108
102
10.2
THF
diethyl ether
THF
THF
THF
THF
—
—
293
293
338
338
393
393
423
423
293
293
293
293
293
338
373
2
2
2
6
285
166
18
5
60
18
48
12
38
8
100
100
100
ª 0
5: 87
6: >99e
6: 93
7: f
100g
99i
7: h
7: h
99
7: h
100
100j
ª0
7: h
9
—
—
7: 81
10
11
12
13
14
15
8: f
diethyl ether
99
8: 81
8: 83
9: 89
9: 88
9: 97e
—
—
—
—
ª100
ª100
100
99
PhNMeH (2.77)
48
a Relative to 1. b 1 mL, when solvent (diethyl ether, THF) was used. c Of 1 (by GC). d Isolated yield (based on 1) of C4H4NC(O)NRR¢, unless otherwise
specified. e Selectivity. f The product formed in trace amounts. g After 8 days the conversion of 1 was close to 80%. h Not isolated. i After 4 days the
conversion of 1 was close to 75%. j After 1 day the conversion of 1 was close to 70%.
because of side-formation of other species, such as, for instance,
phenyl N,N-dibenzylcarbamate (the major by-product)24 and
very minor amounts of 1,1¢-carbonyldipyrrole.17d The formation
of significant amounts of (PhCH2)2NCO2Ph demonstrates that,
at these temperatures, the substitution of pyrryl moiety can
seriously compete with that of phenoxy group. Higher selectivity
to the target product 7 may be favored by markedly lower
reaction temperatures. To overcome the consequent drawback
due to the lower conversion rate a higher catalyst load was
used. Accordingly, at 293 K, under solventless conditions, urea 7
was obtained selectively (ª99%) and quantitatively within a still
reasonable reaction time (60 h) by reacting 1 with (PhCH2)2NH
(amine/1 ª 3 mol/mol) in the presence 2 equivalent of DBU
(entry 9, Table 2).
Under those conditions wherein benzylamine reacted readily
with 1 in the absence of DBU (entry 1, Table 1), a primary
aromatic amine such as aniline was practically inert towards
1 (entry 10, Table 2). The presence of DBU (1 equivalent
vs. 1) in the reaction mixture promoted the aminolysis of
1 with formation of 1-phenylaminocarbonyl pyrrole (8) even
at ambient temperature (entries 11 and 12, Table 2). Under
solventless conditions (entry 12, Table 2) the conversion rate was
more satisfactory than in diethyl ether (entry 11, Table 2). The
aminolysis reaction was promoted also by catalytic amounts of
DBU, but, in this case, the quantitative conversion of 1 required a
longer reaction time at ambient temperature. At 393 K (DBU =
10 mol% vs. 1; PhNH2/1 = 3 mol/mol), the conversion was
faster, but less selective because of major formation of N,N¢-
diphenylurea, which, under the working conditions, formed by
further reaction of 8 with aniline.10a The analysis of the reaction
mixture showed also the side-formation of trace amounts of
1,1¢-carbonyldipyrrole.17d
The synthetic protocol followed for aniline was extended
also to N-methyl aniline (entries 13–15, Table 2) for the
synthesis of 1-(N-methyl-N-phenylaminocarbonyl) pyrrole (9).
The aminolysis reaction was selective (>96%) and, for in-
stance, even at the highest temperature investigated (373 K;
entry 15, Table 2), the side-formation of MePhNCO2Ph was
modest.
We have also explored the compatibility of the synthetic
approach with the presence of a few functional groups in the
molecule of amine and studied the ureidization of functionalized
amines, such as the methyl ester of L-leucine, which we have
used in the form of chlorohydrate salt, and a few amino alcohols
(Table 3).
At 293 K, the salt L-Me2CHCH2CH(CO2Me)NH3Cl (L-
RNH3Cl) was poorly reactive towards 1 (entry 1, Table 3)
because of poor nucleophilicity of quaternary N atom. A
negligible conversion to urea 10 was observed also when the
substrate and the salt were reacted at ambient temperature
in the presence of 1 equivalent (vs the salt) of the amidine
base (entry 2, Table 3), which, under the working conditions,
acted mainly as a proton scavenger [eqn (3)]25 rather than as
the catalyst. The aminolysis of 1 by the chlorohydrate salt
required a larger amount of the amidine base and, under very
mild temperature conditions (293–333 K), was achieved more
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Table 3 Aminolysis of C4H4NCO2Ph (1) with functionalized amines
Entry
amine reactanta (mmol)
1 (mmol)
DBU (mol%)b
THF (mL)
T/K
t/h
Conversionc[%]
Urea: [%]d
e
1
2
3
4
5
6
7
8
L-RNH3Cl (0.65)
L-RNH3Cl (0.65)
L-RNH3Cl (0.68)
L-RNH3Cl (0.76)
H2NCH2CH2OH (16.6)
H2NCH2CH2OH (0.89)
H2NCH2CH2OH (0.63)
H2NCH2CH2OH (0.64)
H2NCH2CH(Ph)OH (0.99)
H2NCH2CH(Ph)OH (0.79)
H2NCH2CH(Ph)OH (0.67)
0.49
0.49
0.55
0.60
0.75
0.56
0.58
0.56
0.60
0.64
0.58
—
1
3
3
3
—
1
1
1
1
1
1
293
293
293
333
293
293
293
293
293
293
293
46
24
44
16
1
2
36
1
10: e
131f
246h
229i
—
<10
ª100
ª100
100
10: g
10: 84
10: 87
11: ª100j
11: ª100j
11: 85
11: 81
12: 91
12: 80
12: 78
—
—
11.8
—
10.4
100.5
ª100
k
100
100
ª100
100
9
10
11
2
2
0.25
a R is Me2CHCH2CH(CO2Me). b Relative to 1. c Of 1 (by GC). d Isolated yield (based on 1), unless otherwise specified. e No reaction was observed.
f Corresponding to 1 equivalent of DBU with respect to the chlorohydrate salt. g Not isolated. h Corresponding to 1.97 equivalents of DBU with
respect to the chlorohydrate salt. i Corresponding to 1.81 equivalents of DBU with respect to the chlorohydrate salt. j Selectivity to 11. k After 36 h
the conversion was nearly quantitative and addition of more AE (0.011 mL, 0.20 mmol) caused the fast conversion of the residual amounts of 1.
effectively by working in the presence of ª2 equivalents of DBU
(vs the salt; entry 3 and entry 4, Table 3).28
Me2CHCH2CH(CO2Me)NH3Cl + DBU ꢀ DBU·HCl +
(3)
Me2CHCH2CH(CO2Me)NH2
In principle, the reaction of 1 with aminoalcohols H2N-R-OH
may effect not only the functionalization of H2N-moiety but also
that of OH group with formation of carbamate C4H4NC(O)O-
R-NH2. Elsewhere, in fact, we have reported that 1 can react
with alcohols through a transesterification reaction.17d Methanol
reacted easily with 1, even at ambient temperature, to give 1-
methoxycarbonyl pyrrole, C4H4NCO2Me, but more sterically
Scheme 3 Possible routes to C4H4NC(O)NHCH2CHRO(O)CNC4H4.
crowded alcohols, as PhCH2OH or t-BuOH, required the use of
higher temperatures and/or a catalyst as DBU. In the presence
293 K, in THF. Under the above conditions most of substrate
of DBU the transesterification process was less selective, as
(ª90%) reacted within the first 4–5 h, but the conversion of
the amidine base can also cause the defunctionalization of the
the residual amounts of 1 required a longer time. The use of a
heteroaromatic ring with formation of pyrrole and carbonic acid
higher H2N-R-OH/1 molar ratio (60–65 mol%; entry 6 and 9 in
diesters (ROC(O)OPh, (RO)2CO).17b,d
Table 3) or of solventless conditions (entry 5, Table 3) allowed to
We have found that, in THF, in the presence of DBU (10-100
overcome the above drawback and to conjugate high selectivity
mol% vs. 1), 1 reacted smoothly with aminoalcohols H2N-R-OH
(ª100%) towards 11 or 12 with more satisfactory conversion rate.
(H2N-R-OH/1 = 1.14–1.20 mol/mol) such as 2-aminoethanol
Table
4 shows a few examples of aminolysis of 1-
(AE) or ( )-2-amino-1-phenylethanol (Ph-AE) to give, under
very mild conditions (293 K), the corresponding ureas 11 and 12
with high yield (entries 8, 10 and 11, Table 3). However, variable
amounts of C4H4NC(O)NHCH2CHRO(O)CNC4H4 (17: R = H;
18: R = Ph) also formed under the working conditions (see also
Experimental).
phenoxycarbonyl indole (2) and 9-phenoxycarbonyl carbazole
(3). Under the working conditions (Table 4), the aminolysis
of 3 with morpholine proceeded more sluggishly. Moreover,
substrate 3 reacted with the investigated amines (allylamine,
morpholine) with moderate selectivity (ª70%) mainly because of
competitive defunctionalization of 3 and formation of carbazole
Scheme 3 shows two possible routes for the formation
of C4H4NC(O)NHCH2CHRO(O)CNC4H4, both of which,
in principle, may be operative. However, we note that in
no case we detected (by GC, GC-MS) the presence of
C4H4NCO2CHRCH2NH2 (R = H, Ph) in the reaction mixture.
This fact suggests that C4H4NCO2CHRCH2NH2, if it really
formed, did not accumulate in the reaction mixture, but reacted
fast to give C4H4NC(O)NHCH2CHRO(O)CNC4H4.
The selectivity towards the target products can be controlled
more easily by working in the absence of the amidine base and
suitably varying the H2N-R-OH/1 molar ratio. For instance,
only minor amounts of C4H4NC(O)NHCH2CH2O(O)CNC4H4
were detected in the reaction mixture when 1 was reacted with a
slight excess of AE (AE/1 = 1.09 mol/mol; entry 7, Table 3), at
Table 4 DBU-promoted aminolysis of HetNCO2Ph (2, 3) to
a
HetNC(O)NRR¢
Entry Amine (mmol)
HetNCO2Ph (mmol) Urea: [%]b
1
2
3
4
CH2 CHCH2NH2 (0.96) 2 (0.86)
CH2 CHCH2NH2 (0.96) 3 (0.86)
13: 92
14: 64
15: 92
16: 61
O(CH2CH2)2NH (0.80)
O(CH2CH2)2NH (0.80)
2 (0.71)
3 (0.71)
a Solvent: THF (1 mL); DBU: ª100 mol% vs. 2 or 3; temperature:
293 K; reaction time: 3 h, except in entry 4 (10 h). Under the working
conditions, the substrate (2 or 3) converted quantitatively or, if any, was
detected in trace amounts. b Isolated yield (based on HetNCO2Ph) of
HetNC(O)NRR¢.
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of wastes (salts, etc.) typical of phosgenation methods. It
provides a new solution for the synthesis of unsymmetrical ureas
HetNC(O)NRR¢ through a green route alternative to the current
conventional procedures.
Experimental
General methods
Scheme 4 Aminolysis of HetNCO2Ph.
All solvents were dried according to conventional methods
(P2O5; Na/benzophenone)29 and stored under N2. The carbonyl
derivatives 1–3 were obtained as previously reported.17d DBU
and the amines were commercial products (Fluka or Aldrich)
and were stored and manipulated under N2 to prevent any
significant contamination by atmospheric CO2 and moisture.
Ph-AE was purified by column chromatography (silica gel;
MeOH as eluent) and recrystallized from EtOH(minimum
amount)/diethyl ether/n-hexane before use. GC analyses were
performed with a HP 5890 Series II gas-chromatograph (cap-
illary column: Heliflex AT-5, 30 m ¥ 0.25 mm, 0.25 mm film
thickness). GC-MS analyses were carried out with a Shimadzu
GC-17A linked to a Shimadzu GC-MS QP5050 selective mass
detector (capillary column: Supelco MDN-5S, 30 m ¥ 0.25 mm,
0.25 mm film thickness). IR spectra were taken on a Shimadzu
FT-IR Prestige 21 spectrophotometer or recorded with a Perkin
Elmer FT-IR 1710 instrument. Polarimetric measurements were
carried out with a Perkin Elmer 343 Polarimeter. NMR spectra
were run with a Varian Inova 400 spectrometer or a Bruker
AM 500 instrument. Chemical shift are in d (ppm) vs. Me4Si.
Coupling constants are in Hz.
(Scheme 4, route (b)). In comparison, the analogous reactions
of 1 (see also Table 2) and 2 with the same amines were more
selective and only in the aminolysis of 2 with morpholine
(entry 3, Table 4) minor amounts of HetNH (indole) and
O(CH2CH2)2NCO2Ph were found in the reaction mixture. The
above features may reflect the importance of steric factors
(bulkiness of both the attacking amine and HetN group in
the substrate) in controlling not only the rate of the aminolysis
process, but also the direction of the substitution reaction.
Conclusion
The reaction of the N-phenoxycarbonyl derivatives of pyrrole,
indole and carbazole, HetNCO2Ph, with amines has been shown
to be a convenient method of synthesis of unsymmetrical ureas
HetNC(O)NRR¢ (HetNH = pyrrole, indole, carbazole). The
aminolysis reaction can be catalyzed by the amidine base DBU
under usually mild conditions and proceeded with good to
excellent selectivity depending on the working conditions (sub-
strate, amine, temperature). The protocol has been successfully
extended also to functionalized amines, such as amino esters
and amino alcohols.
Synthesis and characterization of unsymmetrical ureas
HetNC(O)NRR¢ (4–16)
The synthetic approach is simple, direct, efficient and allows
to gain access to the target products through a phosgene- and
halogen-free synthetic pathway (Scheme 5; as a comparison, see
also Scheme 1), whichis safeand obviates the large co-generation
The reactions were preferably conducted under N2 and carried
out in a ª20 mL glass reactor equipped with a Sovirel cap and a
Thorion stopcock.
1-Benzylaminocarbonyl pyrrole (N-benzyl-1H-pyrrole-1-car-
boxamide) 4. To the solution of 1 (0.2021 g, 1.08 mmol) in
THF (1 mL), DBU (0.016 mL, 0.107 mmol) and the amine
(0.130 mL, 1.11 mmol) were added (entry 4, Table 1). The
reaction solution was stirred at 338 K for 2 h and, then,
cooled to room temperature. Product 4 was isolated by column
chromatography (silica gel; petroleum ether/diethyl ether (2 : 1
v/v)). Yield of 4: 194 mg, 90%. Found: C, 71.94; H, 6.09;
N, 14.00. Calc. for C12H12N2O: C, 71.98; H, 6.04; N, 13.98%;
n
max(Nujol)/cm-1 3321 s (NH), 1684vs (C O); dH (400 MHz;
CDCl3; 293 K) 4.57 (2 H, d, J = 5.9, CH2), 5.78 (1 H, br, NH),
6.25 (2 H, t, J = 2.2, Hb), 7.18 (2 H, t, J = 2.2, Ha ), 7.26–7.38 (5 H,
m, Ph); dC (100 MHz; CDCl3; 293 K) 44.91 (CH2), 111.99 (Cb),
118.38 (Ca ), 127.88 (Cortho), 127.91 (Cpara), 128.87 (Cmeta), 137.49
(Cipso), 150.87 (C O); m/z (EI) 200 (M+), 133 (M - C4H4NH),
104, 91, 67, 51, 39.
1-Allylaminocarbonyl pyrrole (N-(prop-2-en-1-yl)-1H-pyrrole-
1-carboxamide) 5. The reaction mixture, prepared by adding
DBU (0.125 mL, 0.84 mmol) and the amine (0.070 mL,
0.94 mmol) to the solution of 1 (0.1540 g, 0.82 mmol) in THF
(1 mL), was stirred at 293 K for 2 h. Product 5 was isolated
by column chromatography (silica gel; petroleum ether/diethyl
Scheme 5 Phosgeneless route to unsymmetrical ureas HetNC(O)-
NRR¢.
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ether (2 : 1 v/v)). Yield of 5: 107 mg, 87%. Found: C, 64.10;
H, 6.73; N, 18.59. Calc. for C8H10N2O: C, 63.99; H, 6.71; N,
18.65%; nmax(Nujol)/cm-1 3333 s (NH), 1682vs (C O); dH (500
(Cmeta), 136.76 (Cipso), 148.34 (C O); m/z (EI) 186 (M+), 119
(M - C4H4NH), 91, 67, 51, 39.
1-(N-Methyl-N-phenylaminocarbonyl) pyrrole (N-methyl-N-
3
3
4
MHz; CDCl3; 293 K) 4.00 (2 H, tt, JHCNH ª JHCCH = 5.8, J =
phenyl-1H-pyrrole-1-carboxyamide) 9. To the substrate
1
3
4
2
1.5, CH2), 5.18 (1 H, dq, Jcis = 10.3, J ª J = 1.4, Hcis), 5.24
(0.1509 g, 0.81 mmol), DBU (0.130 mL, 0.870 mmol) and the
amine (0.260 mL, 2.40 mmol) were added (entry 13, Table 2).
The reaction mixture was stirred at 293 K for 38 h and, then,
dissolved in diethyl ether (10 mL). The resulting solution was
washed with H2O (20 mL), HCl 0.17 M (35 mL), NaOH 1 M
(10 mL) and, again, with H2O. The organic phase was dried
on MgSO4 and evaporated in vacuo. Yield of 9: 144 mg, 89%.
Found: C, 71.93; H, 6.10; N, 13.97. Calc. for C12H12N2O: C,
71.98; H, 6.04; N, 13.99%; nmax(neat)/cm-1 1697vs and 1682vs
(poorly resolved, C O); dH (400 MHz; CDCl3; 293 K) 3.44 (3
H, s, CH3), 5.97 (2 H, t, J = 2.2, Hb), 6.74 (2 H, t, J = 2, Ha ),
7.06 (2 H, dm, Hortho), 7.21 (1 H, m, Hpara), 7.31 (2 H, m, Hmeta);
dC (100 MHz; CDCl3; 293 K) 40.11 (Me), 110.46 (Cb), 121.14
(Ca ), 125.45 (Cortho), 126.83 (Cpara), 129.81 (Cmeta), 144.48 (Cipso),
152.97 (C O); m/z (EI) 200 (M+), 134 (M - C4H4N), 119, 106,
77, 51, 39.
(1 H, dq, 3Jtrans = 17.2, 4J ª J = 1.4, Htrans), 5.76 (1 H, br, NH),
2
5.89 (1 H, m, HC CH2), 6.25 (2 H, t, J = 2.3, Hb), 7.19 (2 H, t,
J = 2.3, Ha ); dC (125 MHz; CDCl3; 293 K) 43.21 (CH2), 111.89
(Cb), 117.05 (CH = CH2) 118.35 (Ca ), 133.62 (HC = CH2),150.84
(C O); m/z (EI) 150 (M+), 135, 106, 94, 80, 67, 54, 41, 39.
1-Morpholinocarbonyl pyrrole (morpholin-4-yl(1H-pyrrol-1-
yl)methanone) 6. To the solution of 1 (0.2012 g, 1.08 mmol)
in THF (1 mL), DBU (0.016 mL, 0.107 mmol) and the amine
(0.105 mL, 1.20 mmol) were added. The reaction solution was
stirred at 338 K for 2 h, and, then, cooled to room temperature.
Product 6 was isolated by column chromatography (silica gel;
petroleum ether/diethyl ether (1 : 1 v/v)). Yield of 6: 180 mg,
93%. Found: C, 60.07; H, 6.80; N, 15.56. Calc. for C9H12N2O2:
C, 59.99; H, 6.71; N, 15.54%; nmax(Nujol)/cm-1 1682vs (C O);
d
H (500 MHz; CDCl3; 293 K) 3.60 (4 H, t, J = 4.8, NCH2), 3.72
(4 H, t, OCH2), 6.22 (2 H, t, J = 2.2, Hb), 6.98 (2 H, t, J = 2.3
Hz, Ha ); dC (125 MHz; CDCl3; 293 K) 46.98 (NCH2), 66.56
(OCH2), 110.98 (Cb), 120.33 (Ca ), 153.88 (C O); m/z (EI) 180
(M+), 149, 135, 122, 114 (M - C4H4N), 94, 80, 70, 66, 56, 42.
Methyl 4-methyl-2-[(1H-pyrrol-1-ylcarbonyl)amino]pentano-
ate 10. To the mixture of 1 (0.1122 g, 0.60 mmol) and L-leucine
methylester hydrochloride (0.1377 g, 0.76 mmol), the solvent
(THF, 3 mL) and DBU (0.295 mL, 1.37 mmol) were added
(entry 4, Table 3). The resulting suspension was stirred at 333 K
for 16 h, cooled to room temperature and filtered to remove the
precipitate (mainly DBU·HCl). The solvent was evaporated and
the residue fractionated by flash chromatography on a silica gel
column with a petroleum ether/diethyl ether mixture (4 : 1 and,
then, 2 : 1 (v/v)). Yield of 10: 124 mg, 87%. The product can be
recrystallized at 253 K from diethyl ether/n-hexane. Found: C,
60.61; H, 7.70; N, 11.68. Calc. for C12H18N2O3: C, 60.49; H, 7.61;
N, 11.75%; nmax(Nujol)/cm-1 3325 s (NH), 1744vs (CO2Me),
1667vs (C O); dH (400 MHz; CDCl3; 293 K) 0.95 (3 H, d, 3J =
8, CH3), 0.97 (3 H, d, 3J = 8, CH3), 1.58–1.80 (3 H, overlapped
multiplets, CH2 and CHMe2), 3.76 (3 H, s, OMe), 4.68 (1 H,
1-Dibenzylaminocarbonyl pyrrole (N,N-dibenzyl-1H-pyrrole-
1-carboxamide) 7. To the mixture of 1 (0.139 g, 0.74 mmol) and
the amine (0.450 mL, 2.34 mmol), DBU (0.225 mL, 1.51 mmol)
was added (entry 9, Table 2). The reaction solution was stirred
at 293 K for 60 h and, then, dissolved in diethyl ether (25 mL).
The ethereal solution was washed with H2O (2 ¥ 25 mL), HCl
0.13 M (2 ¥ 25 mL), again with H2O, dried over MgSO4 and
evaporated in vacuo. Yield of 7: 174 mg, 81%. Product 7 can
be recrystallized at 253 K from diethyl ether/n-hexane. Found:
C, 78.63; H, 6.28; N, 9.61. Calc. for C19H18N2O: C, 78.59; H,
6.25; N, 9.64%; nmax(Nujol)/cm-1 1674vs (C O); dH (400 MHz;
CDCl3; 293 K) 4.58 (4 H, s, CH2), 6.21 (2 H, t, J = 2.2, Hb),
7.11 (2 H, t, J = 2.2, Ha ), 7.23 (4 H, dm, Hortho), 7.31 (2 H, m,
Hpara), 7.37 (4 H, m, Hmeta); dC (100 MHz; CDCl3; 293 K) 50.76
(CH2), 111.02 (Cb), 120.59 (Ca ), 127.73, 127.80, 128.88, 135.94
(Cipso) 155.14 (C O); m/z (EI) 290 (M+), 224 (M - C4H4N), 199
(M-PhCH2), 156, 132, 104, 91, 77, 65, 51, 39.
3
3
3
td, JHCCH = 5, JHCCH ª JHCNH = 8, CHCO2Me), 5.79 (1 H, br
3
d, JHCNH = 8, NH), 6.25 (2 H, t, J = 2, Hb), 7.19 (2 H, t, J =
2, Ha ); dC (100 MHz; CDCl3; 293 K) 21.91 (Me), 22.78 (Me),
24.83 (CHMe2), 41.79 (CH2), 51.99 (CHCO2Me), 52.57 (OMe),
112.11 (Cb), 118.42 (Ca ), 150.43 (C O), 173.38 (CO2Me); m/z
(EI) 238 (M+), 179 (M - CO2Me), 163, 138, 112, 88, 67, 55, 41.
1-Phenylaminocarbonyl pyrrole (N-phenyl-1H-pyrrole-1-
carboxamide) 8. To the substrate 1 (0.1525 g, 0.82 mmol),
DBU (0.125 mL, 0.837 mmol) and the amine (0.225 mL,
2.47 mmol) were added (entry 12, Table 2). The reaction
mixture was stirred at 293 K for 12 h and, then, dissolved in
diethyl ether (25 mL). The resulting solution was extracted with
H2O (2 ¥ 20 mL) and the organic solvent was evaporated. The
solid residue was washed with small volumes of H2O and dried
in vacuo. Yield of 8: 126 mg, 83%. Found: C, 70.93; H, 5.45;
N, 15.01. Calc. for C11H10N2O: C, 70.96; H, 5.41; N, 15.04%;
1-(2-Hydroxyethyl)aminocarbonyl pyrrole (N-(2-hydroxy-
ethyl)-1H-pyrrole-1-carboxamide) 11. To the solution of 1
(0.1053 g, 0.56 mmol) in THF (1 mL), DBU (0.010 mL,
0.067 mmol) and the amino alcohol (0.036 mL, 0.64 mmol)
were added (entry 8, Table 3). The reaction mixture was stirred
at 293 K for about 1 h and, after evaporating the solvent in
vacuo, was fractionated on a silica gel column using diethyl
ether as the eluent. Yield of 11: 70 mg, 81%.30 The product can
be recrystallized at 253 K from diethyl ether/n-hexane. Found:
C, 54.61; H, 6.60; N, 18.10. Calc. for C7H10N2O2: C, 54.54; H,
6.54; N, 18.16%; nmax(Nujol)/cm-1 3395 s and 3310 s, 1682vs
(C O), 1551vs; dH (400 MHz; CDCl3; 293 K) 2.67 (1 H, br s,
OH), 3.52 (2 H, q, 3J = 5, NCH2), 3.77 (2 H, t, 3J = 5, CH2O),
6.23 (2 H, t, J = 2, Hb), 6.26 (1 H, br, NH), 7.18 (2 H, t, J =
2.2, Ha ); dC (100 MHz; CDCl3; 293 K) 43.12 (NCH2), 61.65
n
max(Nujol)/cm-1 3335 s (NH), 1690vs (C O); dH (400 MHz;
CDCl3; 293 K) 6.31 (2 H, t, J = 2.2, Hb), 7.15 (1 H, m, Hpara),
7.26 (1 H, br, NH), 7.28 (2 H, t, J = 2.2, Ha ), 7.35 (2 H, m,
Hmeta), 7.48 (2 H, dm, Hortho); dC (100 MHz; CDCl3; 293 K)
112.51 (Cb), 118.53 (Ca ), 120.41 (Cortho), 124.91, (Cpara), 129.22
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(CH2OH), 112.00 (Cb), 118.39 (Ca ), 151.73 (C O); m/z (EI)
was fractionated on a silica gel column using a petroleum
154 (M+), 136 (M - H2O), 122 (M - MeOH), 106, 94, 80, 67, 56,
ether/diethyl ether (10 : 1 v/v) mixture as the eluent. Yield of
14: 137.4 mg, 64%. The product can be recrystallized (colorless
needles) at 253 K from diethyl ether(minimum amount)/n-
hexane. Found: C, 76.85; H, 5.7; N, 11.09. Calc. for C16H14N2O:
C, 76.78; H, 5.64; N, 11.19%; nmax(Nujol)/cm-1 3271 ms (NH),
1667vs (C O), 1528vs; dH (400 MHz; CDCl3; 293 K) 4.18 (2
41.
1-(2-Hydroxy-2-phenylethyl)aminocarbonyl pyrrole (N-(2-
hydroxy-2-phenylethyl)-1H-pyrrole-1-carboxamide) 12. To the
solution of 1 (0.1205 g, 0.64 mmol) and Ph-AE (0.1053 g,
0.79 mmol) in THF (1 mL), DBU (0.010 mL, 0.067 mmol)
was added (entry 10, Table 2). The reaction mixture was stirred
at 293 K for 2 h and, after evaporating the solvent in vacuo,
was fractionated on a silica gel column using a petroleum
ether/diethyl ether (1 : 1 v/v) mixture as the eluent. Yield of 12:
118.5 mg, 80%.31 The product can be recrystallized (colorless
plates) at 253 K from diethyl ether/n-hexane. Found: C, 67.90;
H, 6.20; N, 12.09. Calc. for C13H14N2O2: C, 67.81; H, 6.13; N,
12.16%; nmax(Nujol)/cm-1 3294 s, 1674vs (C O), 1558 ms; dH
(400 MHz; CDCl3; 293 K) 2.4 (1 H, very broad, OH), 3.42 (1
3
3
4
H, tt, JHCCH ª JHCNH = 6, J = 1.5, CH2), 5.25 (1 H, dq, Jcis
=
10.3, 2J ª J = 1.5 Hz, Hcis), 5.34 (1 H, dq, Jtrans = 17.2, 2J ª J =
1.5, Htrans), 5.77 (1 H, br, NH), 6.03 (1 H, m, CH), 7.33 (2 H,
m), 7.47 (2 H, m), 8.02 (4 H, overlapped dm); dC (100 MHz;
CDCl3; 293 K) 43.45 (CH2), 113.54, 117.43, 120.20, 122.29,
125.10, 126.95, 133.71, 138.27, 152.63 (C O); m/z (EI) 250
(M+), 167, 140, 115, 113, 83, 63, 56, 41.
4
4
1-Morpholinocarbonyl indole ((1H-indol-1-yl)(morpholin-4-
yl)methanone) 15. To the solution of 2 (0.1673 g, 0.71 mmol)
in THF (1 mL), DBU (0.105 mL, 0.703 mmol) and the amine
(0.070 mL, 0.80 mmol) were added. The reaction mixture was
stirred at 293 K for 3 h and, then, evaporated in vacuo. The
residue was fractionated on a silica gel column using a petroleum
ether/diethyl ether (1 : 1 v/v) mixture as the eluent. The fractions
containing the product were collected and the solvent was
evaporated. The product, which was contaminated by minor
amounts of O(CH2CH2)2NCO2Ph, was recrystallized at 253 K
from diethyl ether/n-hexane. Yield of 15: 149.3 mg, 92%. Found:
C, 67.90; H, 6.20; N, 12.10. Calc. for C13H14N2O2: C, 67.81; H,
6.13; N, 12.16%; nmax(Nujol)/cm-1 1682vs (C O); dH (400 MHz;
CDCl3; 293 K) 3.59 (4 H, t, J = 4.7, NCH2), 3.77 (4 H, t, J =
2
3
3
H, ddd, J = 13.9, JHCCH = 8.4, JHCNH = 4.4, CH2), 3.82 (1 H,
ddd, 2J = 13.9, 3JHCCH = 3.5, 3JHCNH = 7.3, CH2), 4.92 (1 H, dd,
3
3JHCCH = 3.5, JHCCH = 8.3, CH), 5.99 (1 H, br, NH), 6.25 (2 H,
t, J = 2, Hb), 7.16 (2 H, t, J = 2, Ha ), 7.26–7.40 (5 H, m, Ph);
dC (100 MHz; CDCl3; 293 K) 48.02 (NCH2), 73.27 (CHOH),
112.05 (Cb), 118.39 (Ca ), 125.78, 128.24, 128.71, 141.20 (Cipso),
151.49 (C O); m/z (EI) 230 (M+), 213 (M - OH), 181, 156,
144, 124, 107, 94, 80, 67, 51, 39.
1-Allylaminocarbonyl indole (N-(prop-2-en-1-yl)-1H-indole-1-
carboxamide) 13. To the solution of 2 (0.2042 g, 0.86 mmol)
in THF (1 mL), DBU (0.130 mL, 0.870 mmol) and the amine
(0.072 mL, 0.96 mmol) were added. The reaction mixture was
stirred at 293 K for 3 h and, then, evaporated in vacuo. The
residue was dissolved in diethyl ether and the solution extracted
with H2O. After drying over MgSO4, the ethereal solution was
evaporated in vacuo and the residue was fractionated on a silica
gel column using a petroleum ether/diethyl ether (3 : 1 v/v)
mixture as the eluent. Yield of 13: 158.6 mg, 92%. Product
13 can be recrystallized at 253 K from diethyl ether(minimum
amount)/n-hexane. Found: C, 71.90; H, 6.10; N, 13.90. Calc. for
C12H12N2O: C, 71.98; H, 6.04; N, 13.98%; nmax(Nujol)/cm-1 3356
ms (NH), 1682vs and 1666vs (poorly resolved, C O), 1535vs;
3
4
5 Hz, OCH2), 6.60 (1 H, dd, J = 3.7, J = 1, 3-H), 7.19 (1 H,
3
3
4
3
m, J5,4 = 7.7, J5,6 = 7.3, J5,7 = 1.1, 5-H), 7.29 (1 H, m, J6,5
=
3
4
3
7, J6,7 = 8.4, J6, 4 = 1.1, 6-H), 7.29 (1 H, d, J = 3.7, 2-H),
3
4
4
7.58 (1 H, dt, J4,5 = 7.7, J4, 6 ª J4, 3 = 1, H-4), 7.67 (1 H, dm,
3J7,6 = 8, 7-H); dC (100 MHz; CDCl3; 293 K) 47.05 (NCH2),
66.67 (OCH2), 106.27, 113.17, 121.12, 122.05, 123.75, 126.10,
129.59, 135.15, 154.27 (C O); m/z (EI) 230 (M+), 200, 144 (M
- N(CH2CH2)2O), 130, 114 (M - C8H6N), 103, 89, 70, 63, 42.
9-Morpholinocarbonyl carbazole ((9H-carbazol-9-yl)(morpho-
lin-4-yl)methanone) 16. To the solution of 3 (0.2028 g,
0.71 mmol) in THF (1 mL), DBU (0.105 mL, 0.703 mmol) and
the amine (0.070 mL, 0.80 mmol) were added. The reaction
mixture was reacted at 293 K for 10 h. After evaporating
the solvent in vacuo, diethyl ether was added. The resulting
solution was washed with H2O, dried on MgSO4 and fraction-
ated on a silica gel column using a petroleum ether/diethyl
ether (1 : 1 v/v) mixture as the eluent. The chromatographic
separation allowed to recover pure carbazole and a mixture
of O(CH2CH2)2NCO2Ph and the target urea, from which 16
was isolated (120.2 mg, 61%) by recrystallyzation at 253 K
from diethyl ether with n-hexane. Found: C, 72.90; H, 5.80;
N, 9.95. Calc. for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99%;
3
3
dH (400 MHz; CDCl3; 293 K) 4.09 (2 H, tt, JHCCH ª JHCNH
=
5.5, 4J = 1.5, CH2), 5.21 (1 H, dq, Jcis = 10.2, 2J ª J = 1.5, Hcis),
4
5.30 (1 H, dq, Jtrans = 17.2, 2J ª J = 1.5 Hz, Htrans), 5.65 (1 H, br,
4
NH), 5.96 (1 H, m, CH), 6.61 (1 H, dd, 3J = 3.7, 4J = 1.1, 3-H),
7.21 (1 H, m, 3J5,4 = 7.7, 3J5,6 = 7.3, 4J5,7 = 1.1, 5-H), 7.30 (1 H,
m, 3J6,5 = 7.3, 3J6,7 = 8.1, 4J6,4 = 1.5, 6-H), 7.44 (1 H, d, 3J = 3.7,
2-H), 7.58 (1 H, dt, 3J4,5 = 7.7, 4J4,6 ª J4,3 = 1.5, 4-H), 8.06 (1 H,
4
dm, 3J7,6 = 8, 7-H); dC (100 MHz; CDCl3; 293 K) 43.28 (CH2),
107.13, 114.01, 117.15, 121.22, 122.29, 123.96, 124.22, 130.17,
133.77, 135.03, 151.90 (C O); m/z (EI) 200 (M+), 130, 117, 89,
65, 63, 41, 39.
9-Allylaminocarbonyl carbazole (N-(prop-2-en-1-yl)-9H-
carbazole-9-carboxamide) 14. To the solution of 3 (0.2465 g,
0.86 mmol) in THF (1 mL), DBU (0.130 mL, 0.870 mmol) and
the amine (0.072 mL, 0.96 mmol) were added. The reaction
mixture was stirred at 293 K for 3 h and, then, evaporated
in vacuo. The residue was dissolved in diethyl ether and the
solution extracted with H2O. After drying over MgSO4, the
ethereal solution was evaporated in vacuo and the residue
n
max(Nujol)/cm-1 1666vs (C O); dH (400 MHz; CDCl3; 293 K)
3.60 (4 H, t, J = 4.8, NCH2), 3.78 (4 H, t, J = 5, OCH2), 7.31
(2 H, m), 7.46 (2 H, m), 7.65 (2 H, dm, J = 8.1), 8.02 (2 H,
dm, J = 7.7); dC (100 MHz; CDCl3; 293 K) 46.80 (NCH2), 66.84
(OCH2), 112.58, 120.24, 121.82, 124.48, 126.68, 138.44, 153.95
(C O); m/z (EI) 280 (M+), 194 (M - N(CH2CH2)2O), 180, 166
(M - OCN(CH2CH2)2O), 140, 114, 89, 70, 56, 42.
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Acknowledgements
Universita` degli Studi di Bari (Fondi di Ateneo) and Min-
istero dell’Istruzione, dell’Universita` e della Ricerca (PRIN
2008A7P7YJ_002) are acknowledged for financial support. The
Authors thank Dr C. Cardellicchio (ICCOM-CNR, Bari) for
polarimetric analyses.
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30 From the chromatographic separation we isolated an impure
fraction mainly containing the side-product 17 characterized as
C4H4NC(O)NHCH2CH2O(O)CNC4H4 on the basis of the NMR
and mass spectra. dH (400 MHz; CDCl3; 293 K) 3.77 (2 H, q, J =
5, NCH2), 4.54 (2 H, t, J = 5, CH2O), 6.24 (1 H, br unresolved
t, NH), 6.25 (2 H, t, J = 2, Hb ), 6.26 (2 H, t, J = 2, Hb), 7.18
(2 H, t, J = 2, Ha,ureidic), 7.25 (2 H, t, J = 2, Ha,carbamic); dC (100 MHz;
CDCl3; 293 K) 40.52 (NCH2), 65.79 (CH2O), 112.26 (Cb,ureidic), 113.05
(Cb,carbamic), 118.39 (Ca,ureidic), 120.09 (Ca,carbamic), 150.89 (C(O)O), 151.19
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224 | Green Chem., 2012, 14, 217–225
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(C O); m/z (EI) 247 (M+), 180 (M - C4H5N), 137, 111, 94, 80, 67,
42.
31 From the chromatographic separation we collected an impure
fraction mainly containing the side-product 18 characterized as
C4H4NC(O)NHCH2CH(Ph)O(O)CNC4H4 on the basis of the NMR
and mass spectra. dH (400 MHz; CDCl3; 293 K) 3.90–3.96 (2 H, m,
NCH2), 5.95 (1 H, br unresolved t, NH), 6.07 (1 H, dd, J = 4, 8,
OCH), 6.24 (2 H, t, J = 2 Hb,ureidic), 6.25 (2 H, t, J = 2, Hb,carbamic),
7.13 (2 H, t, J = 2, Ha,ureidic), 7.28 (2 H, t, J = 2, Ha,carbamic), 7.34–7.46
(5 H, m, Ph); dC (100 MHz; CDCl3; 293 K) 45.98 (NCH2), 77.88
(CH), 112.15 (Cb,ureidic), 113.01 (Cb,carbamic), 118.38 (Ca,ureidic), 120.15
(Ca,carbamic),126.36, 129.05, 129.18, 136.36 (Cipso), 150.10 (C(O)O),
150.87 (C O); m/z (EI) 323 (M+), 281, 256, 213, 184, 170, 156,
146, 128, 104, 94, 77, 68, 51, 39.
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The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 217–225 | 225
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