Expeditious method for synthesis of symmetrical 1,3-disubstituted ureas and thioureas

Article abstract of DOI:10.1081/SCC-200061656

Symmetrical 1,3-disubstituted ureas and symmetrical thioureas have been synthesized from corresponding isocyanates, diisocyanates, and isothiocyanates by a new versatile, simple, and quick method in the presence of tertiary amines at room temperature. The method under discussion has several advantages over the existing techniques, as it is simple to carry out, does not require complicated equipment, has a simple workup, and does not use expensive chemicals. Moreover, the yields are almost quantitative. This method has potential in commercial applications. Copyright Taylor & Francis, Inc.

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Expeditious Method for
Synthesis of Symmetrical
1,3‐Disubstituted Ureas and
Thioureas
Shahnaz Perveen a , Syed M. Abdul Hai a , Rashid A.
Khan a , Khalid Mohammed Khan b , Nighat Afza a
Tahira B. Sarfaraz a
a PCSIR Laboratories Complex Karachi, Karachi,
Pakistan
&
b H.E.J. Research Institute of Chemistry,
International Center for Chemical Sciences,
University of Karachi, Karachi, Pakistan
Version of record first published: 16 Aug 2006.
To cite this article: Shahnaz Perveen , Syed M. Abdul Hai , Rashid A. Khan , Khalid
Mohammed Khan , Nighat Afza & Tahira B. Sarfaraz (2005): Expeditious Method
for Synthesis of Symmetrical 1,3‐Disubstituted Ureas and Thioureas, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:12, 1663-1674
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Synthetic Communicationsw, 35: 1663–1674, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200061656
Expeditious Method for Synthesis of
Symmetrical 1,3-Disubstituted Ureas and
Thioureas
Shahnaz Perveen, Syed M. Abdul Hai, and Rashid A. Khan
PCSIR Laboratories Complex Karachi, Karachi, Pakistan
Khalid Mohammed Khan
H.E.J. Research Institute of Chemistry, International Center for Chemical
Sciences, University of Karachi, Karachi, Pakistan
Nighat Afza and Tahira B. Sarfaraz
PCSIR Laboratories Complex Karachi, Karachi, Pakistan
Abstract: Symmetrical 1,3-disubstituted ureas and symmetrical thioureas have been
synthesized from corresponding isocyanates, diisocyanates, and isothiocyanates by a
new versatile, simple, and quick method in the presence of tertiary amines at room
temperature. The method under discussion has several advantages over the existing
techniques, as it is simple to carry out, does not require complicated equipment, has
a simple workup, and does not use expensive chemicals. Moreover, the yields are
almost quantitative. This method has potential in commercial applications.
Keywords: 1,3-Disubstituted ureas, diisocynates, isocyanates, tertiary amines,
thioisocyanates
INTRODUCTION
During recent years much attention has been paid to the synthesis and appli-
cation of symmetrical substituted ureas. These are essential components of
drug candidates including HIV protease inhibitors, CCK-B receptor antagonists,
Received in the USA February 14, 2005
Address correspondence to Shahnaz Perveen, PCSIR Laboratories Complex
Karachi, Off University Road, Karachi 75280, Pakistan. Fax: þ92-21-8141847;
E-mail: dr_shahnaz_perveen@yahoo.com
1663

1664
S. Perveen et al.
and endothelin antagonists.[1] Recently oligoureas have also been introduced as
scaffolds for the creation of artificial b sheets[2] and as peptide backbone
mimetics.[3] The symmetrical substituted ureas are found in natural
products[4] and act as useful intermediates in the synthesis of different
chemicals.[5,6] The traditional synthetic approaches to symmetrical ureas are
well documented and standard procedures involve the reactions of amines
with phosgene and its derivatives,[7] isocyanates,[8] or carbamates.[8,3b]
A
report describes synthesis by phenyl diisocyanate in hot pyridine without indi-
cating its mechanism and conversion into urea.[9] A synthesis of 1,3-disubsti-
tuted ureas is reported through a reaction of carbonic acid ester with an
amine in the presence of catalyst.[10] Several homogenous Pd,[11,12] Ru,[13]
Co,[14] Mn,[15] Se,[16,17] and W[18,19] catalysts were also used for the
oxidative carbonylation of amine into ureas. Very recently, two procedures
have appeared in print: one is by oxidative carbonylation in the presence[20]
of Pd/ZrO4-SO24 2, but in a majority of cases the actual product was
accompanied with a measurable amount of undesired by-products and results
are quoted by GC-MS, whereas the other report is a two-step synthesis of dis-
ubstituted ureas through reaction of substituted carbamates with an amine.[21]
During the total synthesis of a natural product, we discovered that tertiary
amines could promote the reaction of isocyanate to symmetrical ureas without
generating intermediate primary amines. Thus, we used three amines as reac-
tion promoters including triethyl amine, pyridine, and 2,6-lutidine for
synthesis of different ureas. Herein we describe a general one-step procedure
for the preparation of symmetrical substituted ureas and thioureas from the
corresponding isocyanates and isothiocyanates in almost quantitative yields.
RESULTS AND DISCUSSION
Reaction of phenylisocyanate in 1,4-dioxane/water or pyridine/water gives
1,3-diphenylurea,[21] but the reaction is very slow and takes about 12 to
16 h. In this communication, we report a simple, economical, efficient, high-
yielding, one-pot synthesis of symmetrical disubstituted ureas, cyclic ureas,
and thioureas from the corresponding isocyanates, diisocyanates, and isothio-
cyanates in 1,4-dioxane in the presence of different tertiary amines. It was
found that excellent yields for the synthesis of symmetrical disubstituted ureas
and thioureas were obtained in the presence of triethyl amine (Scheme 1).
Scheme 1.

1,3-Disubstituted Ureas and Thioureas
1665
Other amines used in this investigation were pyridine and 2,6-lutidine, but
they were found to be less effective (Table 1). When the reaction was
carried out in 1,4-dioxane, the tertiary amines acted as promoters; the
reaction proceeded very vigorously and was completed in 5–30 min. Isocya-
nates react more rapidly than isothiocyanates and the reaction was completed
in 1–3 min. In a typical reaction, 0.3 mol of isocyanate/diisocyanate or iso-
thiocyanate is treated with 2 mol of tertiary amines in the presence or
absence of 1,4-dioxane at room temperature, and progress of the reactions
was monitored through TLC. After the completion of the reactions, the
reaction mixture was poured into ice-cold water with continuous stirring.
The solid was filtered, which afforded pure desired product.
The rate enhancement of the reactions indicated that the reactions are
promoted by tertiary amines (see the mechanism in Scheme 4). The same
type of reactions are also observed when isocyanates are treated with tertiary
amines in the absence of 1,4-dioxane. The latter result gave very strong
evidence that the tertiary amines are acting as reaction promoters. Reagent-
grade tertiary amines were used, which contain moisture that was responsible
for the transformation. Under anhydrous conditions, cyclic diamide was
formed. If we look at our proposed mechanisms, it seems that the final
product, that is, the urea derivatives, cannot be obtained without some
moisture and in the end the intermediate will be easily converted to the
product during aqueous workup. A report[22] describes the synthesis of several
aromatic and carbohydrate-based ureas and thioureas. According to their
mechanism (Scheme 2), the reaction was initiated by water and an anhydride-
type intermediate was formed. This anhydride was then converted into substi-
tuted symmetrical disubstituted urea. Interestingly, this report does not show
the role of tertiary amine in the proposed mechanism. If the reaction was
initiated by water, then the amine was formed (Scheme 3) instead of symmetrical
disubstituted ureas. Schemes 2 and 3 indicated that these were amine-free mech-
anisms. In our case, the requirement of tertiary amines and presence of inherent
moisture supports our proposed mechanism (Scheme 4).
CONCLUSION
The described procedure serves as an excellent method for preparing sym-
metrical 1,3-disubstituted ureas and thioureas. It is an efficient, one-step
Scheme 2.

1666
S. Perveen et al.
Scheme 3.
method. The requirement of moisture supports the proposed mechanism for
the transformation.
EXPERIMENTAL
1H NMR spectra were recorded in CD3OD, CDCl3, and DMSO-d6 on a Bruker
Aspect AM-300 operating at 300 MHz using TMS as an internal standard. The
solvent was CD3OD unless otherwise mentioned. Chemical shifts are given in
ppm. IR spectra were recorded in KBr on a SHIMADZU IR-460 and Bruker
vector 22 spectrometer (wave numbers in cm21). Mass spectra (EIMS) were
measured on Finnigan MAT-1 12 instrument. High-resolution EIMS were
recorded in Jeol JMS HX-110 spectrometer.
General Procedure for the Synthesis of Ureas and Thioureas
To a mixture of 0.3 mol of isocyanate/diisocyanate or isothiocyanate in 20 to
25 mL of 1,4-dioxane was added 2 mol of tertiary amines at room temperature
and progress of reaction was monitored via TLC. After completion of reaction
(times for individual reactions are shown in Table 1), the reaction mixture was
poured into ice-cold water with continuous stirring, and the solid was filtered
and crystallized by appropriate solvent to afford the desired product.
Elemental analyses were performed by a Perkin Elmer analyzer.
Scheme 4.

Table 1. Results of syntheses of symmetrical 1,3-disubstituted ureas and thioureas
%Yield
Substrates
Products
TEA
98a
Py.
85c
Lut.
80c
M.P. (8C)
240
97b
80d
80d
152–153
99a
83c
82c
166–168
147–148
98b
84d
80d
(continued)

Table 1. Continued
%Yield
Substrates
Products
TEA
96a
Py.
85c
Lut.
84c
M.P. (8C)
CH222ðCH2Þ422CH2
252–253
j
j
N55C55O O55C55N
H2C55CH–CH2–N55C55O
11
98.5a
99a
90c
80c
86c
80c
91–93
310
97a
80c
70c
225–227

98a
88c
84c
245–248
99a
88c
78c
286–288
H3C–CH2–N55C55O
21
98.5a
82c
78c
112–113
142–143
H3C–CH2–N55C55S
23
99b
85d
80d
TEA ¼ triethylamine, Py. ¼ pyridine, lut. ¼ 2,6-Lutidine.
a
ꢀ3 min.
b
ꢀ10 min.
c
ꢀ15–20 min.
d
ꢀ25–30 min.

1670
S. Perveen et al.
1,3-Diphenylurea (2). Crystallization by diethyl ether or ethanol gave needle-
like crystals. Rf ¼ 0.40 (CHCl3–MeOH; 9.5:0.5); mp 2408C. IR nmax (KBr):
3285, 3194, 3036, 1647, 1597, 1555, 1312 cm21; UV lmax 254.3 ( [ 289.7),
262.9 ( [ 285), 275.5 ( [ 314.7), 283.57 ( [ 333.6), 1H NMR (CD3OD): d
7.1–7.75 (m, 10H), 7.43 (brs, 2H); HREIMS: m/z (rel. int.) ¼ 212.0947 [Mþ,
C13H12N2O requires 212.2533] (22), 120 (2), 119 (5), 93 (100), 77 (11), 66
(10), 65 (13). Anal. calcd. for C13H12N2O: C, 73.56; H, 5.70; N, 13.20.
Found: C, 73.54; H, 5.68; N, 13.18.
1,3-Diphenylthiourea (4). Recrystallization by hot ethanol gave leaflets.
Rf ¼ 0.9 (CHCl3–MeOH; 9.5:0.5); mp 152–1538C. IR nmax (KBr): 3206,
3011, 1595, 1549, 1342, 1238 cm21; UV lmax 259.46 ( [ 327.6), 287.59
( [ 430.5), 293.33 ( [ 457.6); 1H NMR (CD3OD): d 8.99 (brs, 2H),
7.23–7.75 (m, 10H); HREIMS: m/z (rel. int.) ¼ 228.0719 [Mþ, C13H12N2S
requires 228.3179] (100), 194 (100), 135 (84), 119 (37), 93 (100), 77 (100).
Anal. calcd. for C13H12N2S: C, 68.39; H, 5.30; N, 12.27. Found: C, 68.41;
H, 5.32; N, 12.25.
1,3-Dibenzylurea (6). The compound on crystallization from ethanol gave
needle-like crystals. Rf ¼ 0.40 (CHCl3–MeOH; 9.5:0.5); mp 166–1688C.
1
IR nmax (KBr): 3350, 3020, 1660, 1600, 1410 cm21; H NMR (CD3OD): d
7.0 (m, 10H), 5.78 (brs, 2H), 3.90 (d, 4H, J ¼ 16.0 Hz); HREIMS: m/z (rel.
int.) ¼ 240.1264 [Mþ, C15H16N2O requires 240.3075] (30), 163 (20), 149
(100), 133 (65). Anal. calcd. for C15H16N2O: C, 74.97; H, 6.71; N, 11.66.
Found: C, 74.95; H, 6.72; N, 11.67.
1,3-Dibenzylthiourea (8). The solid was crystallized from ethanol and gave
leaflets or plates. Rf ¼ 0.90 (CHCl3–MeOH; 9.5:0.5); mp 147–1488C. IR
nmax (KBr): 3110, 3010, 1610, 1550, 1340 cm21 1H NMR (CD3OD): d
;
7.10 (m, 10H), 5.69 (brs, 2H), 3.92 (d, 4H, J ¼ 16.1 Hz); HREIMS: m/z
(rel. int.) ¼ 256.1036 [Mþ, C15H16N2S requires 256.3721] (29), 179 (15),
165 (100), 149 (76). Anal. calcd. for C15H16N2S: C, 70.28; H, 6.29; N,
10.93. Found: C, 70.23; H, 6.27; N, 10.99.
Octahydro-2H-1,3-diazonin-2-one (10). Rf ¼ 0.60 (CHCl3–MeOH;
9.5:0.5); mp 252–2538C. IR nmax (KBr): 3335, 2932, 2856, 1626, 1574,
1
1477, 1254 cm21; H NMR (DMSO-d6): d 5.74 (t, 2H, J ¼ 5.88 Hz), 2.94
(q, 4H, J ¼ 5.88 Hz), 1.33 (m, 4H), 1.22 (m, 4H); HREIMS: m/z (rel.
int.) ¼ 142.1106 [Mþ, C7H14N2O requires 142.2023] (4), 113 (5), 100 (23),
99 (22), 86 (58), 85 (62), 83 (93), 70 (15). Anal. calcd. for C7H14N2O: C,
59.13; H, 9.92; N, 19.70. Found: C, 59.16; H, 9.91; N, 19.69.
1,3-Diallylurea (12). Recrystallization from ethanol afforded crystals of
compound 12. Rf ¼ 0.40 (CHCl3–MeOH; 9.5:0.5); mp 90–938C. IR nmax
1
(KBr): 3200, 3015, 2930, 1620, 1540, 1330 cm21; H NMR (CD3OD): d

1,3-Disubstituted Ureas and Thioureas
1671
9.68 (brs, 2H), 5.93 (ddd, 2H, J ¼ 16.2, 11.6, 5.0 Hz), 5.76 (dd, 2H, J ¼ 16.2,
1.3 Hz), 5.05 (dd, 2H, J ¼ 11.6, 1.3 Hz), 4.16 (m, 4H); HREIMS: m/z (rel.
int.) ¼ 140.0945 [Mþ, C7H12N2O requires 140.1864] (10), 99 (100), 83
(56). Anal. calcd. for C7H12N2O: C, 59.98; H, 8.63; N, 19.98. Found: C,
60.00; H, 8.61; N, 19.86.
4,40-Dinitrocarbanilide (14). Recrystallization from ethanol gave yellow
needle-like crystals. Rf ¼ 0.45 (CHCl3–MeOH; 9.5:0 5); mp 3108C. IR
1
nmax (KBr): 3286, 3190, 1649, 1600, 1556, 1312 cm21; H NMR (CD3OD):
d 9.62 (brs, 2H), 8.13 (dd, 4H, J ¼ 8.1, 0.2 Hz), 8.22 (dd, 4H, J ¼ 8.1,
0.2 Hz); HREIMS: m/z (rel. int.) ¼ 302.0650 [Mþ, C13H10N4O5 requires
302.2484] (6), 257 (15), 181 (20), 162 (100), 123 (55). Anal. calcd.
for C13H10N4O5: C, 51.66; H, 3.33; N, 18.54. Found: C, 51.64; H, 3.35; N,
18.58.
2,20-Dinitrocarbanilide (16). Recrystallization from benzene gave pale
yellow crystals. Rf ¼ 0.69 (CHCl3–MeOH; 9.5:0.5); mp 225–2278C. IR
nmax (KBr): 3285, 3194, 1647, 1597, 1555, 1443, 1312 cm21 1H NMR
;
(CDCl3): d 8.82 (dd, 2H, J ¼ 8.0, 1.4 Hz), 8.33 (dd, 2H, J ¼ 8.2, 1.4 Hz),
7.66 (ddd, 2H, J ¼ 8.0, 7.3, 1.4 Hz), 7.38 (ddd, 2H, J ¼ 8.2, 7.3, 1.4 Hz);
HREIMS: m/z (rel. int.) ¼ 302.0655 [Mþ, C13H10N4O5 requires 302.2484]
(4), 257 (10), 181 (24), 164 (100), 123 (35). Anal. calcd. for C13H10N4O5:
C, 51.66; H, 3.33; N, 18.54. Found: C, 51.63; H, 3.29; N, 18.58.
3,30-Dichlorocarbanilide (18). Recrystallization by hot EtOH or hot AcOH
afforded needles of compound 18. mp 245–2488C. IR nmax (KBr): 3350, 3105,
1920, 1820, 1635, 1600, 1540, 1170cm21; 1H NMR (CD3OD): d 7.08 (ddd, 4H,
J ¼ 8.0, 2.1, 1.9 Hz), 7.03 (ddd, 2H, J ¼ 8.0, 2.2, 1.9 Hz), 6.94 (dd, 2H, J ¼ 2.2,
2.1 Hz); HREIMS: m/z (rel. int.) ¼ 281.0170 [Mþ, C13H10Cl2N2O requires
281.1434] (15), 245 (50), 154 (100), 127 (80). Anal. calcd. for C13H10Cl2N2O: C,
55.54;H,3.59;N, 9.96. Found:C,55.57;H,3.54;N,9.92.
4,40Dihydroxycarbanilide (20). Recrystallization from hot water gave fine
needles. mp 286–2888C. IR nmax (KBr): 3600, 3287, 3040, 1645, 1602,
1
1320 cm21; H NMR (DMSO-d6): d 10.19 (brs, 4H), 6.91 (dd, 4H, J ¼ 8.2,
0.3 Hz), 6.65 (dd, 4H, J ¼ 8.2, 0.3 Hz); HREIMS: m/z (rel.
int.) ¼ 244.0849 [Mþ, C13H12N2O3 requires 244.2521] (21), 277 (5), 151
(80), 136 (100), 93 (44). Anal. calcd. for C13H12N2O3: C, 63.93; H, 4.95;
N, 11.47. Found: C, 63.90; H, 4.90; N, 11.54.
1,3-Diethylurea (22). Crystallization was carried out with ethanol, which
gave needle-like crystals. Rf ¼ 0.54 (CHCl3-MeOH; 9.5:0.5), mp 112–
1
1138C. IR nmax (KBr): 3050, 2930, 1650, 1350 cm21; H NMR (CD3OD): d
3.95 (brs, 2H), 3.22 (9, 4H, J ¼ 7.1 Hz), 1.01 (t, 6H, J ¼ 7.1 Hz); HREIMS:
m/z (rel. int.) ¼ 116.0953 [Mþ, C5H12N2O requires 116.1641] (44), 101

1672
S. Perveen et al.
(100), 87 (60), 71 (26). Anal. calcd. for C5H12N2O: C, 51.70; H, 10.41; N,
24.12. Found: C, 51.73; H, 10.38; N, 24.09.
1,3-Diethylthiourea (24). Crystallization with ethanol gave crystals.
Rf ¼ 0.95 (CHCl3–MeOH; 9.5:0.5), mp 142–1438C. IR nmax (KBr): 3035,
1
2935, 1530, 1320 cm21; H NMR (CD3OD): d 3.90 (brs, 2H), 3.10 (q, 4H,
J ¼ 7.05Hz), 1.00 (t, 6H, J ¼ 7.05Hz); HREIMS: m/z (rel. int.) ¼ 132.0725
[Mþ, C5H12N2S requires 132.2287] (34), 117 (100), 103 (51), 88 (80), 87
(65). Anal. calcd. for C5H12N2S: C, 45.42; H, 9.15; N, 21.19. Found: C,
45.44; H, 9.11; N, 21.21.
ACKNOWLEDGMENTS
The authors are thankful to Chairman, PCSIR Pakistan, and Director General,
Karachi Laboratories, for providing necessary facilities and funding for this
research work.
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