A convenient method of synthesis of unsymmetrical urea derivatives

Article abstract of DOI:10.1021/op020055g

A method for the preparation of unsymmetrical urea derivatives that may contain functional groups such as hydroxyl, amine, amide, and carboxyl is described. The method consists of a one-pot modified Curtius rearrangement starting with appropriate aromatic acid chloride and carried out in a nonaqueous system.

Full text of DOI:10.1021/op020055g

Organic Process Research & Development 2002, 6, 759−761
Articles
A Convenient Method of Synthesis of Unsymmetrical Urea Derivatives
Graz˘yna Groszek*
Faculty of Chemistry, Rzeszo´w UniVersity of Technology, W Pola 2, 35-959 Rzeszo´w, Poland
Abstract:
problem of this process is the hydrolysis of isocyanates. A
A method for the preparation of unsymmetrical urea derivatives
that may contain functional groups such as hydroxyl, amine,
amide, and carboxyl is described. The method consists of a one-
pot modified Curtius rearrangement starting with appropriate
aromatic acid chloride and carried out in a nonaqueous system
trace of water favored formation of urethanes, byproducts
that are very hard to remove. Furthermore, during incomplete
conversion of acid chloride to azide, undesired amide can
be formed in the last step.
An advantage of the method reported herein is the wide
range of its applications to the synthesis of a variety of urea
derivatives containing different functional moieties, for
example, hydroxyl, carboxyl, amine, or amide groups.
Introduction
Unsymmetrical ureas are known to be active herbicides
and pharmaceuticals. Another application of this kind of
chemical derivative is in supramolecular chemistry as recep-
tors for anions1 and for studying intramolecular hydrogen
bonding in investigations aimed at developing molecular
receptors and peptide conformational templates.2
Results and Discussion
The method involves the reaction of aromatic acid
chloride 1 with sodium azide in toluene with TEBA-Cl as a
phase-transfer catalyst (PTC). In the next step, the solid was
filtered off and then heated to complete rearrangement to
isocyanate 2. Finally, a suitable amine derivative was added
(Scheme 1).
Product 3 was obtained in high-yield owing to nonaqueous
conditions and to the presence of PTC catalyst. The substitu-
tion of chlorine by azide anion occurred according to the
mechanism proposed by Ma¸kosza6 at the phase boundary
between solid and liquid phases. Sodium azide was insoluble
in organic phase; therefore, a transition zone was formed
between solid and organic phases, where the substitution
reaction takes place. The diagram below illustrates the
proposed mechanism of the reaction.
Typical methods for the preparation of ureas consist of
the addition of an appropriate amine to an isocyanate or the
reaction of an amine with carbamoyl halides. In both cases,
phosgene is used as a supporting substrate. An alternative,
phosgene-free process for the synthesis of unsymmetrical
ureas is the reductive carbonylation of nitro derivatives
catalyzed by metal compounds of groups VII-X metals,3
where the yield can be as high as 73%. Some nontransition
elements such as selenium, sulfur, or tellurium have also been
found to catalyze this reaction.4 Unfortunately, in the latter
case, small, but detectable, amounts of the toxic catalysts
have been found to be present in the final product.3
Combinatorial solid-phase organic synthesis (SPOS) is a
powerful tool for preparing libraries of drug-like organic
molecules. Unsymmetrical ureas are examples of chemicals
obtained by using this method.5 However, although the
compounds were synthesized in high purity and good yield,
SPOS runs only on a small scale.
We have developed an operationally simple, high-yield
modification of the Curtius rearrangement for the synthesis
of unsymmetrical ureas. In its original embodiment, a serious
The Curtius rearrangement was monitored with the use
of IR by observing the disappearance of the azide group
bands (at 2138 cm-1) and the appearance of the characteristic
isocyanate band at 2255 cm-1. Table 1 below summarizes
the results for various aliphatic amines.
* To whom correspondence should be addressed. E-mail: ggroszek@
prz.rzeszow.pl.
(1) Hughes, M. P.; Smith, B. D. J. Org. Chem. 1997, 62, 4492-4499.
(2) Nowick, J. S.; Powell, N. E.; Martinez, E. J.; Smith, E. M.; Noronha, G. J.
Org. Chem. 1992, 57, 3763-3765.
(3) Tafesh, A. M.; Weiguny, J. Chem. ReV. 1996, 96, 2035-2052.
(4) Yang, Y.; Lu, S. Tetrahedron Lett. 1999, 40, 4845-4846.
(5) Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hahn, P. J.
Tetrahedron Lett. 1996, 37, 7193-7196. Estep, K. G.; Neipp, C. E.;
Stephens Stramiello, L. M.; Adam, M. D.; Allen, M. P.; Robinson, S.;
Roskamp, E. J. J. Org. Chem. 1998, 63, 5300-5301.
In the case of urea derivatives with an amino group in
the side chain, we have found it necessary to protect one
(6) Ma¸kosza, M. Pure Appl. Chem. 1975, 43, 439.
10.1021/op020055g CCC: $22.00 © 2002 American Chemical Society
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759

Scheme 1
sodium azide (0.088 mol) was stirred vigorously at room
temperature for 24 h. Then, the reaction mixture was filtered,
and from the filtrate one-fourth of the volume of solvent
was distilled off. The residue was kept at 90 °C for ca. 22 h
until the reaction was complete as determined by IR. After
the mixture cooled to room temperature, the amine (0.033
mol) was added. The agitation was continued for 30 min,
before the excess of amine and solvent was removed using
a rotary evaporator. The crude urea derivative was crystal-
lized or recrystallized.
amino group using a BOC group, followed by deprotection
in the last step (Scheme 2).
1
1-tert-Butyl-3-(4-methoxyphenyl)urea (3c): H NMR
The protection of one amino group in 1,3-diaminopropane
was carried out using the method described by Krapcho and
Kuel.9 To characterize compound 6, we employed the
deprotection procedure described by Nudelman et al.10 The
reason for this was that free amine 6 was unstable under
standard conditions; hence, it had to be characterized in the
form of hydrochloride. Unfortunately, the original Nudelman
procedure failed in our case. Compound 6 could not be
isolated as a monohydrochloride. We found it necessary to
obtain amine 6 as a solid by using an excess of acetyl
chloride and methanol (see Experimental Section). Possibly
this modification resulted in the formation of a multihydro-
chloride of amine 6, involving more than one N-H group.
The synthesis of urea derivatives with carboxylic or amide
groups or both was performed according to the procedure
described by Paal and Zitelmann11 (shown in Scheme 3).
During the synthesis of compounds 7a-b, it was neces-
sary to change the order of addition of reagents (isocyanate
derivative was added to the solution of amino acid sodium
salt).
(CDCl3) 1.3 (s, 9H, 3 × CH3); 3.7 (s, 3H, OCH3); 5.1 (s,
1H, NH); 6.8, 7.2 (2m, 5H arom and N-H). 13C NMR
(CDCl3) 29.3 (C-9); 50.4 (C-8); 55.5 (C-10); 114.4, 123.3
(C-2, C-6 and C-3, C-5); 131.9 (C-1); 156.0, 156.1 (C-7 and
C-4). IR (KBr), ν (cm-1) 1511 (N-CdO); 1558 (C-H
arom); 1600 (N-H amide); 1648 (CdO); 2965 (C-H); 3338
(N-H). UV (ethanol), (nm) λmax ) 245 (ꢀ ) 19654) for c
) 0.1036 mg/10 cm3. HR-EIMS (70 eV), m/z: calcd for
C12H18N2O2 222.13683, found 222.13746. Anal. Calcd for
C12H18N2O2 [%] C 64.84, H 8.1, N 12.60; found 64.84, 8.18,
and 12.40, respectively.
1-(2-Hydroxyethyl)-3-(4-methoxyphenyl)urea (3d): 1H
NMR (DMSO-d6) 3.1 (q, J ) 5.6, 2H, N-CH2); 3.4 (m,
2H, CH2-O); 3.7 (s, 3H, O-CH3); 4.7 (br s, 1H, OH);
6.1 (t, J ) 5.2, 2H, NH); 7.8, 7.3 (2m, 4H arom); 8.3 (s,
1H, NH). 13C NMR 41.8 (C-8); 55.1 (C-10); 60.1 (C-9);
113.8, 119.2 (C-2, C-6 and C-3, C-5); 133.7 (C-1); 153.8,
155.5 (C-7 and C-4). IR (KBr), ν (cm-1) 1529 (N-CdO);
1583 (C-H arom); 1611 (N-H amide); 1631 (CdO);
2937 (C-H); 3309 (N-H); 3517 (OH). UV (ethanol),
(nm) λmax ) 243 (ꢀ ) 34223), c ) 0.192 mg/10 cm3.
HR-LSIMS(+) calcd 211.10827 [for C10H15N2O3) (M +
H)+], found 211.10676. Anal. Calcd for C10H14N2O3 [%] C
57.13, H 6.71, N 13.32; found 57.10, 6.71, and 13.34,
respectively.
Formation of compound 7a was always accompanied by
formation of a byproduct (1,3-bis(4-methoxyphenyl)urea).
The problem did not occur during synthesis of compound
7b.
Experimental Section
Melting points were determined on a Boe¨tuis apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded
on Tesla BS 587 A (80 MHz) or Varian Gemini (200 MHz)
instruments. Chemical shifts are expressed in ppm (δ)
referred to TMS, coupling constants (J) are in Hz. IR and
UV spectra were recorded on Perkin-Elmer Paragon 1000
and Hewlett-Packard 8453 instruments, respectively. Mass
spectra were obtained on an AMD-604 spectrometer. Mi-
croanalyses were performed on Fisons EA-1108 apparatus.
TLC plates were silica gel 60 F254 Merck, and silica gel
Merck 70-230 mesh were used for column chromatography.
Solvents were distilled and dried if required; other
materials were commercial.
Synthesis of 1-(3-Aminopropyl)-3-(4-methoxyphenyl)-
urea (6). Monoprotected 1,3-diaminopropane by BOC group
was obtained as described by Krapcho et al.9 in the form of
oil (56% yield based on dicarbonate). H NMR confirmed
the structure of compound 4.
1
The monoprotected diamine 4 (1.5 equiv) was added to
isocyanate 2, and the precipitate was filtrated off and dried
in air, affording compounds 5 (86% yield) which was then
submitted to further transformation.
To the stirred solution of compound 5 (0.3 g, 0.93 mmol)
in acetone (10 cm3) were added methanol (1.2 cm3, 25 mmol)
and acetyl chloride (1.1 cm3, 15.5 mmol) at 0 °C (ice +
water bath). After 30 min the reaction mixture was warmed
to room temperature; the precipitate was filtered off and dried
in air, affording compound 6 (0.19 g, 85% yield), mp 156-
158 °C.
1H NMR (DMSO-d6) 1.7 (m, 2H, N-CH2); 2.8 (m, 2H,
N-CH2); 3.2 (m, 2H, CH2); 3.7 (s, 3H, O-CH3); 6.8 and
7.3 (2m, 4H arom). 13C NMR 28.0 (C-9); 35.9, 36.6 (C-8
and C-10); 55.1 (C-11); 113.7, 119.3 (C-2, C-6 and C-3,
C-5); 133.6 (C-1); 153.8, 155.9 (C-7 and C-4). IR (KBr), ν
(cm-1) 1572 (N-CdO); 1511 (C-H arom); 1632 (CdO);
The General Procedure for Synthesis of Unsym-
metrical Ureas (3). A solution of the appropriate acid
chloride (0.022 mol) in anhydrous toluene (40 cm3), contain-
ing benzyltriethylammonium chloride (3 × 10-3 mol) and
(7) Ozaki, S.; Nagoya, T. Bull. Chem. Soc. Jpn. 1957, 30, 444-449.
(8) Gerhard W. Ber. 1884, 17, 3039.
(9) Krapcho, A. P.; Kuel, C. S. Synth. Commun. 1990, 20, 2559-2564.
(10) Nudelman, A.; Bechor, Y.; Falb, E.; Fischer, B.; Wexler, B. A. Synth.
Commun. 1998, 28, 471-474.
(11) Paal, C.; Zitelmann, G. Chem. Ber. 1903, 36, 3338.
760
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Table 1. Characterization of urea derivatives 3
product
R1
R2
R3
yield [%]
mp [°C]
61-63 (crude)
88-89 (acetone-hexane)
128-130 (acetone-hexane)
134-135 (acetone)
literature mp [°C]
3a
3b
3c
3d
OCH3
H
OCH3
OCH3
C2H5
C2H5
H
C2H5
C2H5
C(CH3)3
CH2CH2OH
93
85
84
96
61.5-62a
85b
-
H
-
a Reference 7. b Reference 8.
1H NMR (DMSO-d6) 2.5 (dd, J ) 15.9, J ) 5.6, 1H,
Scheme 2
CH2); 2.67 (dd, J ) 15.9, J ) 5.6, 1H, CH2); 3.68 (s, 3H,
O-CH3); 4.4 (dt, J ) 8.5, J ) 5.2, 1H, CH); 6.4 (d, J )8.5,
1H, NH); 6.8 and 7.3 (2m, 4H arom); 6.9, 7.4 (2s, 2H, NH2);
8.7 (s, 1H, NH); 12.5 (s, 1H, COOH). 13C NMR
37.2 (C-9); 48. 9 (C-8); 55.1 (C-12); 113.9, 119.1 (C-2, C-6
and C-3, C-5); 133.5 (C-1); 153.9, 154.9 (C-7 and C-4);
171.8, 173.5 (C-10 and C-11). IR (KBr), ν (cm-1) 1514
(N-CdO); 1570, 1591 (C-H arom and amide); 1672, 1720,
and 1739 (3 × CdO); 3169 and 3282 (N-H amide); 3391
(N-H). UV (ethanol), (nm) λmax ) 245 (ꢀ ) 32946), for c
) 0.052 mg/10 cm3. HR-LSIMS(+) calcd 282.10900 [for
C12H16N3O5) (M + H)+], found 282.10821. Anal. Calcd for
C12H15N3O5 [%] C 51.24, H 5.38, N 14.94; found 51.40, 5.25,
and 14.84, respectively.
Scheme 3a
Synthesis of 2-[3-(4-Methoxyphenyl)ureido]-3-meth-
ylpentanoic Acid (7b). Compound 7b was obtained accord-
ing to the procedure described above. The product was
isolated as an oil via extraction with methylene chloride (3
× 100 cm3) and then, after evaporation of solvent, crystal-
lized from benzene-petroleum ether (40/60) affording acid
7b (83% yield).
For analysis the products were recrystallized from etha-
nol-water, mp 107-110 °C.
1H NMR (DMSO-d6) 0. 9 (m, 6H, 2 × CH3); 1.5 (m,
1H, CH); 1.4, 1.8 (2m, 2H, CH2); 3.7 (s, 3H, O-CH3); 4.2
(dd, J ) 8.7, J ) 3.8, 1H, N-CH); 6.3 (d, J ) 8.7, 1H,
NH); 6.8 and 7.3 (m, 4H, arom); 8.4 (s, 1H, NH), 12.5
(s,1H, COOH). 13C NMR 11.4, 15.7 (C-12 and C-11);
24.6 (C-10); 37.1 (C-9); 55.1, 56.4 (C-11 and C-8); 113.9,
119.0 (C-2, C-6 and C-3, C-5); 133.3 (C-1); 153.9, 155.0
(C-7 and C-4); 173.7 (C-13). IR (KBr), ν (cm-1) 1513, 1539
(N-CdO and C-H arom); 1614, 1646, and 1696 (2 ×
CdO and N-H amide); 2963 (OH); 3284, 3408 (N-H and
COOH). HR-LSIMS(+) calcd 281.15272 [(for C14H21N2O4)
(M + H)+], found 281.15013. Anal. Calcd for C14H20N2O4
[%] C 59.99, H 7.19, N 9.99; found 59.95, 7.21, and 10.00,
respectively.
a i) NaOH aq; ii) p-CH3OPhNCO; iii) H2SO4 aq
3002 (N-H); 3303, 3342 (2 × N-H). UV (ethanol),
(nm) λmax ) 234.0 (ꢀ ) 20007) for c ) 0.0896 mg/10 cm3.
HR-LSIMS(+) calcd 224.13990 [(for C11H18N3O2)]; found
224.13863.
Synthesis of 2-[3-(4-Methoxyphenyl)ureido]succinamic
Acid (7a). To the stirred aqueous solution of sodium hy-
droxide (8%, 10.12 cm3, 0.022 mol) was added L-asparagine
(2.97 g, 0.022 mol) at room temperature; then while the
mixture was externally cooled (ice + water), 4-methoxyphen-
ylisocyanate (0.022 mol) in acetone (10 cm3) was added.
The precipitate was filtered off and discarded. The filtrate
was treated with sulfuric acid (5% aq) to pH ∼4 (litmus),
and then the precipitate was filtered off, washed with water,
and dried in air, affording product 7a (3.81 g, 61% yield).
For analysis, the product was crystallized from DMSO-
water, mp 186-190 °C.
Received for review June 7, 2002.
OP020055G
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