A general Synthesis of Unsymmetrical Tetrasubstituted Ureas

Full text of DOI:10.1021/jo962245t

J . Org. Chem. 1997, 62, 4155-4158
4155
Notes
Sch em e 1
A Gen er a l Syn th esis of Un sym m etr ica l
Tetr a su bstitu ted Ur ea s
Alan R. Katritzky,* David P. M. Pleynet, and
Baozhen Yang
Center for Heterocyclic Compounds, Department of
Chemistry, University of Florida, Gainesville, Florida
32611-7200
the only reported synthesis of unsymmetrical26 tetrasub-
stituted ureas is by reaction of carbamoyl chloride
(prepared from the interaction of a secondary amine and
phosgene) with a secondary amine.28 Moreover, this
method, used more recently by Voss29 and Somlo,29
suffers from several drawbacks. An excess of amine and/
or the use of an acid scavenger (such as pyridine or
triethylamine) is required, and the carbamoyl chloride
intermediate can be both unstable and difficult to isolate
when needed. Moreover, the production of hydrochloric
acid prevents the application of this method when acid-
sensitive functionalities are present. We now report that
1,1′-carbonylbisbenzotriazole (2) is a safe, mild, and
versatile reagent for the synthesis of unsymmetrical
tetrasubstituted ureas. It can also be used to make di-
and trisubstituted ureas.
Received December 3, 1996
In tr od u ction
Substituted ureas have been the subject of much
attention and synthetic effort due to their applications
which range widely including the dyeing of hair and
cellulose fibers, serving as antioxidants in gasoline for
automobiles, as additives in detergents to prevent carbon
deposits, and acting as corrosion inhibitors.1 Their
biological activities as plant growth regulators, pesticides,
herbicides, tranquillizing, and anticonvulsant medicinal
preparations are also important.1 Recently, unsym-
metrical substituted ureas have been shown to be potent
HIV-1 protease inhibitors.2,3
Resu lts a n d Discu ssion
Although numerous methods are available for the
preparation of symmetrical and unsymmetrical di- or
trisubstituted ureas in good to excellent yields,4 until now
1,1′-Carbonylbisbenzotriazole (2) has previously been
described30 and utilized for the dehydration of aldoxime
amides to nitriles.31 A simplified high-yielding method
(90%) to prepare 2 involves vigourous stirring for 3 days
of 2 equiv of benzotriazole with phosgene (Scheme 1).
This allows complete evolvement of the HCl byproduct.
Attempts using 4 equiv of benzotriazole (in order to
neutralize the HCl formed) gave lower yields, and the
isolation of 2 proved less effective. The NMR spectra of
2 showed that it was essentially 1,1′-carbonylbisbenzo-
triazole (2) although traces of the isomers containing one
and two benzotriazol-2-yl groups were detected by NMR
on the crude product. A one-pot reaction of reagent 2
successively with 1 mol each of the two amines, aniline
and n-octylamine, produced the expected unsymmetrical
disubstituted urea 4a in high yield (85%, Table 1, Scheme
2).
(1) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russ. Chem.
Rev. (Engl. Transl.) 1985, 54, 249.
(2) Kempf, D. J .; Marsh, K. C.; Paul, D. A.; Knigge, M. F.; Norbeck,
D. W.; Kohlbrenner, W. E.; Codacovi, L.; Vasavanonda, S; Bryant, P.;
Wang, X. C.; Wideburg, N. E.; Clement, J . J .; Plattner, J . J .; Erickson,
J . Antimicrob. Agents Chemother. 1991, 35, 2209.
(3) Getman, D. P.; DeCrescenzo, G. A.; Heintz, R. M.; Reed, K. L.;
Talley, J . J .; Bryant, M. L.; Clare, M.; Houseman, K. A.; Marr, J . J .;
Mueller, R. A.; Vazquez, M. L.; Shieh, H.-S.; Stallings, W. C.; Stegeman,
R. A. J . Med. Chem. 1993, 36, 288.
(4) The most important of the wide variety of methods to prepare
mono-, di-, and trisubstituted ureas1,5 mostly fall into three main
groups. In the first place, primary amines are reacted with carbonyl
insertion compounds such as phosgene,5 trisphosgene,6 various
carbonates,7-9 S,S-dimethyl thiocarbonate,10 and N,N′-carbonyldiimi-
dazole.11 The second class comprises the reactions of primary amines
with NCO equivalent compounds like carbamates,12-14 formamides (in
the presence of a ruthenium catalyst),15 and most importantly isocy-
anates.5,16 Thirdly, ureas have been prepared by the catalyzed carbo-
nylation of amines using carbon monoxide17-20 or carbon dioxide21,22
in the presence of metal complexes, selenium,17 phosphorus com-
pounds,23,24 and N,N′-dicyclohexylcarbodiimide.25
Trisubstituted ureas were synthesized by one-pot reac-
tions of 2 successively with a primary amine and a
(5) Petersen, U. In Methoden der Organishen Chemie, Houben-Weyl,
E4; G. Thieme Verlag: New York, 1983; p 334.
(6) Majer, P.; Randad, R. S. J . Org. Chem. 1994, 59, 1937.
(7) Takeda, K.; Ogura, H. Synth. Commun. 1982, 12, 213.
(8) Izdebski, J .; Pawlak, D. Synthesis 1989, 423.
(21) Morimoto, Y.; Fujiwara, Y.; Taniguchi, H.; Hori, Y.; Nagano,
Y. Tetrahedron Lett. 1986, 27, 1809.
(22) Fournier, J .; Bruneau, C.; Dixneuf, P. H.; Le´colier, S. J . Org.
Chem. 1991, 56, 4456.
(9) Freer, R.; McKillop, A. Synth. Commun. 1996, 26, 331.
(10) Leung, M.-k.; Lai, J .-L.; Lau, K-H.; Yu, H.-h.; Hsiao, H.-J . J .
Org. Chem. 1996, 61, 4175.
(11) Staab, H. A. Liebigs Ann. Chem. 1957, 609, 75.
(12) Basha, A. Tetrahedron Lett. 1988, 29, 2525.
(13) Kno¨lker, H.-J .; Braxmeier, T.; Schlechtingen, G. Synlett 1996,
502.
(14) Lamothe, M.; Perez, M.; Colovray-Gotteland, V.; Halazy, S.
Synlett 1996, 507.
(23) Yamazaki, N.; Higashi, F.; Iguchi, T. Tetrahedron Lett. 1974,
1191.
(24) Yamazaki, N.; Iguchi, T.; Higashi, F. Tetrahedron 1975, 31,
3031.
(25) Ogura, H.; Takeda, K.; Tokue, R.; Kobayashi, T. Synthesis 1978,
394.
(26) Nudelman and co-workers27 reported the carbonylation of
lithium amides in an atmosphere of carbon dioxide to afford sym-
metrical tetrasubstituted ureas in average to good yields.
(27) Nudelman, N. S.; Lewkowicz, E. S.; Pe´rez, D. G. Synthesis 1990,
917.
(15) Kotachi, S.; Tsuji, Y.; Kondo, T.; Watanabe, Y. J . Chem. Soc.,
Chem. Commun. 1990, 549.
(16) Reichen, W. Helv. Chim. Acta 1977, 60, 498.
(17) Sonoda, N.; Yasuhara, T.; Kondo, K.; Ikeda, T.; Tsutsumi, S.
J . Am. Chem. Soc. 1971, 93, 691.
(18) Tsuji, Y.; Takeuchi, R.; Watanabe, Y. J . Organomet. Chem.
1985, 290, 249.
(19) Giannoccaro, P. J . Organomet. Chem. 1987, 336, 271.
(20) Pri-Bar, I.; Alper, H. Can. J . Chem. 1990, 68, 1544.
(28) Hammerich, H. Ber. Dtsch. Chem. Ges. 1892, 25, 1819.
(29) (a) Voss, J . Liebigs Ann. Chem. 1971, 746, 92 and references
therein. (b) Somlo, T. Ger. Offen. 2,206,365; Chem. Abstr. 1992, 77,
151532r.
(30) Staab, H. A.; Seel, G. Liebigs Ann. Chem. 1958, 612, 187.
(31) Katritzky, A. R.; Zhang, G.-F.; Fan W.-Q. Org. Prep. Proc. Int.
1993, 25, 315.
S0022-3263(96)02245-1 CCC: $14.00 © 1997 American Chemical Society

4156 J . Org. Chem., Vol. 62, No. 12, 1997
Notes
Ta ble 1. P r ep a r a tion of Ur ea s by Su ccessive Tr ea tm en ts
w ith (i) R1NHR2 a n d (ii) R3NHR4
three secondary amines, pyrrolidine, N-methylaniline,
and diphenylamine, to prepare the desired tetrasubsti-
tuted unsymmetrical ureas 4c, 4d , and 4e in yields of
82%, 80%, and 71%, respectively. Reactions of carbamoyl
3a with piperidine and N-n-butyl-N-methylamine af-
forded ureas 4f and 4g in good yields (71% and 80%,
respectively). However, the interaction of carbamoyl 3a
with N-methylbenzylamine, diphenylamine, and N-me-
thylaniline provided the corresponding ureas 4h , 4i, and
4j in lower yields (25%, 51%, and 57%, respectively).
Similar reactions between carbamoyl 3b and dipheny-
lamine or N-methylaniline afforded ureas 4k and 4l in
yields of 47% and 51%, respectively. Especially the
preparations of ureas 4i and 4k illustrate the efficiency
of this method to produce ureas as evidenced by the
reported low reactivity of diphenylamine, e.g. toward
isocyanates.1 The use of diphenylcarbamoyl chloride was
previously required to prepare a N,N-diphenyl-substi-
tuted urea.32 The low yield of formation of 4h can be
explained by the difficult purification of 4h (compound
not UV-active and need to use phosphomolybdic acid
(PMA) as a stain). The range of unsymmetrical tetra-
substituted ureas prepared (aromatic, aliphatic, bicyclic)
shows that this method can accommodate a wide variety
of amines.
product
R1
R2
R3
R4
yield (%)
4a
4b
4b
4c
4d
4e
4f
4g
4h
4i
phenyl
phenyl
phenyl
n-butyl
n-butyl
n-butyl
H
H
H
n-octyl
H
85a
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)4-
phenyl methyl
phenyl phenyl
-(CH2)5-
n-butyl methyl
benzyl
phenyl phenyl
phenyl methyl
16a
70b
methyl
methyl
methyl
82c,d
80c,d
71c,d
71c,d
80c,d
25c,d
51c,d
57c,d
47c,d
51c,d
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
methyl
4j
4k
4l
-(CH2)2N(CH3)(CH2)2- phenyl phenyl
-(CH2)2N(CH3)(CH2)2- phenyl methyl
a
b
One-pot procedure carried out at room temperature. One-
pot procedure carried out at room temperature after addition of
the primary amine and heated under reflux after addition of the
secondary amine. c Two-pot procedure: yield from corresponding
d
compound 3. Heated under reflux and use of the sodium salt of
the amine.
Sch em e 2
In conclusion, the present work shows that unsym-
metrical tetrasubstituted ureas in particular can be
efficiently prepared from 1,1′-carbonylbisbenzotriazole
(2). The application of this method should provide a safe
and versatile route to these ureas which are difficult to
obtain by other methods.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points are uncorrected. 1H
NMR spectra were recorded at 300 MHz with tetramethylsilane
(TMS) as an internal reference. 13C NMR spectra were recorded
at 75 MHz, using the middle peak of CDCl3 (δ ) 77.0 ppm) as
the reference. The 1H and 13C broad signals reported for
compounds 3a -c and 3f,g are due to the relation to the NMR
time scale of the rate of the s-cis to s-trans interconversions
about the N-CO bonds. All reagents were purchased from
chemical suppliers and used without further purification unless
otherwise indicated. Tetrahydrofuran (THF) was distilled from
sodium/benzophenone prior to use. Hexanes used in elution
systems for purification by column chromatography were in the
boiling range of 40-60 °C. HRMS spectra were obtained by
using the positive FAB method unless otherwise indicated.
P r ep a r a tion of 1,1′-Ca r bon ylbisben zotr ia zole (2). Ben-
zotriazole (5.96 g, 50 mmol) was dissolved in dry THF (200 mL)
under a dry atmosphere of nitrogen, and phosgene (12.95 mL,
1.93 M solution in toluene) was added dropwise. The reaction
was stirred vigourously for 72 h, and the solvent was removed
under reduced pressure. The solid obtained was washed with
copious amounts of diethyl ether (5 × 100 mL) and dried to give
2 as a white solid (5.90 g, 90%): mp 182-184 °C (lit.30 mp 183-
185 °C); 1H NMR δ 8.26-8.21 (m, 4H), 7.81-7.75 (m, 2H), 7.65-
7.59 (m, 2H); 13C NMR δ 145.6, 144.7, 132.4, 130.7, 126.7, 120.8,
113.3. Anal. Calcd for C13H8N6O: C, 59.09; H, 3.05; N, 31.80.
Found: C, 59.09; H, 2.93; N, 31.89.
Ta ble 2. P r ep a r a tion of Ca r ba m oyl Ben zotr ia zoles 3
Accor d in g to Sch em e 2
product
R1
-(CH2)2O(CH2)2-
-(CH2)2N(CH3)(CH2)2-
R2
yield (%)
3a
3b
3c
3d
3e
3f
74a
73a
65a
23b
40b
50c
76c
n-butyl
methyl
phenyl
methyl
benzyl
methyl
phenyl
phenyl
benzyl
benzyl
3g
a
b
Room temperature. Heated under reflux and use of the
sodium salt of the amine. c Heated under reflux.
secondary amine: the second step now required more
forceful conditions (reflux) than for the reaction of a
primary amine with the carbamoylbenzotriazole inter-
mediate 3. The yield of 4b was improved from 16% at
room temperature to 70% by carrying out the reaction
under reflux. Attempts to reverse the order of addition,
i.e. to react 2 first with the secondary amine and then
with a primary amine did not give satisfactory yields of
trisubstituted ureas in one-pot procedures. However,
secondary amines were reacted with 2 to form carbam-
oylbenzotriazoles 3a -g in good yields (Scheme 2, Table
2). The reaction conditions and the yields of 3 obtained
were significantly affected by the steric hindrance ema-
nating from the substituents of the secondary amine. The
procedure succeeded at room temperature in good yields
for cyclic, aliphatic, and aromatic amines whereas harsher
conditions were required and lower yields obtained from
congested secondary amines.
P r oced u r e for th e P r ep a r a tion of N-P h en yl-N′-n -octyl-
u r ea (4a ). Compound 2 (1.06 g, 4 mmol) was dissolved in dry
THF (40 mL) under a dry atmosphere of nitrogen, and aniline
(0.37 mL, 4 mmol) was added. The reaction mixture was stirred
at room temperature for 27 h, octylamine (0.65 mL, 4 mmol)
was then added, and the resulting reaction mixture was stirred
at room temperature for 27 h before being extracted with diethyl
ether (3 × 40 mL). The ethereal extracts were successively
washed with 2 N HCl (2 × 20 mL), 2 N NaOH (2 × 20 mL), and
The carbamoylbenzotriazoles 3a -g were used to pre-
pare the ten diverse unsymmetrical tetrasubstituted
ureas 4c-l (Table 1). Carbamoyl 3c was reacted with
(32) Helsley, G. C.; Franko, B. V.; Welstead, W. J .; Lunsford, C. D.
J . Med. Chem. 1968, 11, 1034.

Notes
J . Org. Chem., Vol. 62, No. 12, 1997 4157
saturated NaCl (30 mL), dried with MgSO4, and filtered.
Removal of the solvent under reduced pressure gave 4a as a
white powder (840 mg, 85%): mp 74-75 °C (lit.33 mp 74-74.5
°C); 1H NMR δ 7.61 (br s, 1H), 7.29-7.18 (m, 4H), 7.01-6.95
(m, 1H), 5.76 (br s, 1H), 3.17-3.11 (m, 2H), 1.43-1.39 (m, 2H),
1.28-1.22 (m, 10H), 0.86 (t, J ) 7 Hz, 3H); 13C NMR δ 156.7,
139.1, 129.0, 123.0, 120.3, 40.3, 31.8, 30.2, 29.3, 29.2, 26.9, 22.6,
14.0. Anal. Calcd for C15H24N2O: C, 72.54; H, 9.74; N, 11.28.
Found: C, 72.38; H, 9.73; N, 11.25.
54 (broad signal), 37-36 (broad signal). Anal. Calcd for C14
12N4O: C, 67.65; H, 5.30; N, 21.04. Found: C, 67.54; H, 5.31;
N, 20.96.
-
H
Gen er a l P r oced u r e for th e P r ep a r a tion of Ur ea s 4c-l
a n d Ca r ba m oylben zotr ia zoles 3d ,e. To a secondary amine
(1.2 equiv) dissolved in dry THF under a dry atmosphere of
nitrogen was added sodium hydride (60% solution in mineral
oil), and the resulting mixture was added via canula to a solution
of the corresponding compounds 3 or 2 (for 3f and 3g) in dry
THF. The reaction mixture was heated under reflux for 1 day
for 3d , 4i, and 4j, 1.5 days for 4g,h , 4c-e, and 4k ,l, 3 days for
3e, and 4 days for 4f before being extracted with diethyl ether.
The ethereal extracts were successively washed with 2 N NaOH
and saturated NaCl, dried with MgSO4, and filtered. Removal
of the solvent under reduced pressure gave oils which were
purified by column chromatography unless otherwise indicated.
Compounds 3d and 3e were purified by column chromatography
without any prior workup.
N-n -Bu tyl-N-m eth yl-N′,N′-tetr a m eth ylen eu r ea (4c): pale
yellow oil (Kugelrohr distillation, 750 mg, 82%); 1H NMR δ 3.34
(t, J ) 6 Hz, 4H), 3.17 (t, J ) 7.5 Hz, 8H), 2.81 (s, 3H), 1.81 (t,
J ) 6 Hz, 4H), 1.54 (quintet, J ) 8 Hz, 2H), 1.35-1.26 (m, 2H),
0.93 (t, J ) 7.5 Hz, 3H); 13C NMR δ 163.2, 49.7, 48.2, 35.8, 29.7,
25.3, 19.9, 13.7; HRMS calcd for C10H20N2O 185.1653 (M + 1),
found 185.1648 (M + 1).
N-n -Bu tyl-N,N′-d im eth yl-N′-p h en ylu r ea (4d ): pale yellow
oil (eluent diethyl ether/hexane (30:70), 525 mg, 80%); 1H NMR
δ 7.34-7.28 (m, 2H), 7.12-7.05 (m, 3H), 3.19-3.11 (m, 5H), 2.58
(s, 3H), 1.42-1.35 (m, 2H), 1.26-1.18 (m, 2H), 0.87 (t, J ) 7
Hz, 3H); 13C NMR δ 161.8, 147.1, 129.3, 124.1, 123.7, 49.6, 39.6,
35.9, 29.2, 20.0, 13.7; HRMS calcd for C13H20N2O 221.1653 (M
+ 1), found 221.1650 (M + 1).
N-n -Bu tyl-N-m eth yl-N′,N′-d ip h en ylu r ea (4e): pale yellow
oil (eluent diethyl ether/hexane (50:50), 600 mg, 71%): 1H NMR
δ 7.29 (t, J ) 7.7 Hz, 4H), 7.10 (t, J ) 7.5 Hz, 2H), 7.02 (d, J )
7.5 Hz, 4H), 3.23 (t, J ) 7.5 Hz, 2H), 2.76 (s, 3H), 1.49-1.41 (m,
2H), 1.27 (sextet, J ) 7.5 Hz, 2H), 0.90 (t, J ) 7.5 Hz, 3H); 13C
NMR δ 160.5, 145.0, 129.1, 124.8, 124.4, 49.7, 35.8, 29.3, 20.0,
13.8. Anal. Calcd for C18H22N2O: C, 76.56; H, 7.85; N, 9.92.
Found: C, 76.95; H, 8.21; N, 10.15.
P r oced u r e for th e P r ep a r a tion of N-P h en yl-N′,N′-(3-
oxa p en ta m eth ylen e)u r ea (4b). Compound 2 (1.06 g, 4 mmol)
was dissolved in dry THF (40 mL) under a dry atmosphere of
nitrogen, and aniline (0.37 mL, 4 mmol) was added. The reaction
mixture was stirred at room temperature for 24 h, and morpho-
line (0.35 mL, 4 mmol) was added. The resulting reaction
mixture was heated under reflux for 24 h, cooled, and extracted
with diethyl ether (3 × 40 mL), and the ethereal extracts were
successively washed with 2 N HCl (2 × 20 mL), 2 N NaOH (2 ×
20 mL), and saturated NaCl (30 mL), dried with MgSO4, and
filtered. Removal of the solvent under reduced pressure gave a
solid which was purified by column chromatography, eluting
with diethyl ether/hexane (70:30). Compound 4b was obtained
1
as a white powder (571 mg, 70%): mp 157-159 °C; H NMR δ
7.36-7.26 (m, 4H), 7.05 (t, J ) 7 Hz, 1H), 6.47 (br s, 1H), 3.71
(t, J ) 5 Hz, 4H), 3.46 (t, J ) 5 Hz, 4H); 13C NMR δ 155.2, 138.7,
128.9, 123.4, 120.2, 120.1, 66.5, 44.3. Anal. Calcd for C11H14
-
N2O2: C, 64.06; H, 6.84; N, 13.58. Found: C, 63.95; H, 7.03; N,
13.31.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca r ba m oyl-
ben zotr ia zoles 3a -c,f,g. Compound 2 was dissolved in dry
THF under a dry atmosphere of nitrogen, and the secondary
amine (1.1 equiv) added. The reaction mixture was stirred at
room temperature for 2 days for 3a and 3b and 1 day for 3c or
heated under reflux for 1 day for 3f and 3g. The crude reaction
mixtures were purified by column chromatography without prior
workup because compounds 3 were not stable to base washings.
1-(N ,N -(3-O x a p e n t a m e t h y le n e )c a r b a m o y l)b e n z o -
tr ia zole (3a ): white powder (eluent diethyl ether/hexane (50:
1
50), 680 mg, 74%): mp 102-103 °C; H NMR δ 8.10 (d, J ) 8
Hz, 1H), 8.00 (d, J ) 8 Hz, 1H), 7.64-7.59 (m, 1H), 7.49-7.43
(m, 1H), 3.95-3.88 (m, 8H); 13C NMR δ 149.4, 145.3, 133.1,
129.4, 125.3, 119.8, 113.5, 66.6, 48-46 (weak broad signal). Anal.
Calcd for C11H12N4O2: C, 56.89; H, 5.21; N, 24.12. Found: C,
57.12; H, 5.32; N, 24.15.
N ,N -P e n t a m e t h yle n e -N ′,N ′-(3-oxa p e n t a m e t h yle n e )-
u r ea (4f): white powder (Kugelrohr distillation, 700 mg, 71%):
mp 40-43 °C; 1H NMR δ 3.74-3.66 (m, 4H), 3.25-3.21 (m, 8H),
1.60-1.50 (m, 6H); 13C NMR δ 164.2, 66.6, 47.7, 47.4, 25.7, 24.6;
HRMS calcd for C10H18N2O2 199.1446 (M + 1), found 199.1447
(M + 1).
1-(N,N-(N-Meth yl-3-a za p en ta m eth ylen e)ca r ba m oyl)ben -
zotr ia zole (3b): off-white powder (eluent ethyl acetate/hexane
1
(90:10), 710 mg, 73%); mp 78-80 °C; H NMR δ 8.09 (d, J ) 8
N-n -Bu t yl-N-m et h yl-N′,N′-(3-oxa p en t a m et h ylen e)u r ea
1
Hz, 1H), 7.99 (d, J ) 8 Hz, 1H), 7.60 (t, J ) 8 Hz, 1H), 7.45 (t,
J ) 8 Hz, 1H), 3.94 (br s, 4H), 2.60 (t, J ) 4.5Hz, 4H), 2.38 (s,
3H); 13C NMR δ 149.3, 145.3, 133.1, 129.3, 125.1, 119.8, 113.5,
54.7, 48-46 (weak broad signal), 45.9. Anal. Calcd for
(4g): pale yellow oil (Kugelrohr distillation, 800 mg, 80%); H
NMR δ 3.69 (t, J ) 4.5 Hz, 4H), 3.22-3.16 (m, 6H), 2.83 (s, 3H),
1.53 (m, 2H), 1.30 (sextet, J ) 7.7 Hz, 2H), 0.92 (t, J ) 7.5 Hz,
3H); 13C NMR δ 164.5, 66.5, 128.6, 49.7, 47.3, 35.9, 29.4, 19.8,
13.7; HRMS calcd for C10H20N2O2 201.1603 (M + 1), found
201.1611 (M + 1).
C
12H15N5O: C, 58.76; H, 6.16; N, 28.55. Found: C, 58.93; H,
6.25; N, 28.67.
1-(N-n -Bu tyl-N-m eth ylcar bam oyl)ben zotr iazole (3c): pale
yellow oil (eluent diethyl ether/hexane (50:50), 600 mg, 65%);
1H NMR δ 8.09 (d, J ) 8 Hz, 1H), 7.99 (d, J ) 8 Hz, 1H), 7.59
(t, J ) 8 Hz, 1H), 7.44 (t, J ) 8 Hz, 1H), 3.66 (t, J ) 9 Hz, 2H),
3.33 (br s, 3H), 1.82-1.72 (m, 2H), 1.41 (br s, 2H), 0.97 (br s,
3H); 13C NMR δ 150.3, 145.0, 133.0, 129.0, 124.9, 119.5, 113.5,
50.4 (broad signal), 37.7 (broad signal), 29.0 (broad signal), 19.7,
13.6. Anal. Calcd for C12H16N4O: C, 62.05; H, 6.94; N, 24.12.
Found: C, 62.01; H, 7.03; N, 24.10.
1-(N,N-Diben zylcar bam oyl)ben zotr iazole (3f): white pow-
der (eluent diethyl ether/hexane (50:50), 1.36 g, 50%); mp 114-
116 °C; 1H NMR δ 8.09 (d, J ) 4 Hz, 1H), 8.05 (d, J ) 4 Hz,
1H), 7.61 (t, J ) 7 Hz, 1H), 7.44 (t, J ) 7 Hz, 1H), 7.35 (br s,
10H), 4.86 (br s, 4H); 13C NMR δ 151.2, 145.3, 135.8, 133.4, 129.4,
128.8, 127.9, 125.2, 119.9, 113.6, 52 (weak broad signal). Anal.
Calcd for C21H18N4O: C, 73.65; H, 5.30; N, 16.37. Found: C,
73.28; H, 5.28; N, 16.43.
N-Ben zyl-N-m et h yl-N′,N′-(3-oxa p en t a m et h ylen e)u r ea
(4h ): pale yellow oil (eluent diethyl ether/hexane (50:50), 250
mg, 25%); 1H NMR δ 7.36-7.23 (m, 5H), 4.40 (s, 2H), 3.69 (t, J
) 4.5 Hz, 4H), 3.27 (t, J ) 4.5 Hz, 4H), 2.76 (s, 3H); 13C NMR δ
164.7, 137.5, 128.6, 127.9, 127.3, 66.6, 53.9, 47.4, 36.3; HRMS
(pos. CI) calcd for C13H18N2O2 235.1446 (M + 1), found 235.1416
(M + 1).
N,N-Dip h en yl-N′,N′-(3-oxa p en t a m et h ylen e)u r ea (4i):
white powder (eluent diethyl ether/hexane (50:50), 307 mg, 51%);
1
mp 107-109 °C; H NMR δ 7.31 (t, J ) 8 Hz, 4H), 7.13 (t, J )
7 Hz, 4H), 7.05 (d, J ) 8 Hz, 4H), 3.54 (t, J ) 5 Hz, 4H), 3.35 (t,
J ) 5 Hz, 4H); 13C NMR δ 159.7, 144.7, 129.2, 125.1, 124.9, 66.4,
45.9. Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92.
Found: C, 72.08; H, 6.56; N, 9.80.
N-Met h yl-N-p h en yl-N′,N′-(3-oxa p en t a m et h ylen e)u r ea
(4j): pale yellow oil (eluent diethyl ether/hexane (70:30), 270
mg, 57%); 1H NMR δ 7.37-7.31 (m, 2H), 7.15-7.10 (m, 3H),
3.49-3.46 (m, 4H), 3.24 (s, 3H), 3.24-3.18 (m, 4H); 13C NMR δ
160.9, 146.5, 129.4, 124.7, 123.8, 66.3, 46.0, 39.6; HRMS (pos.
CI) calcd for C12H16N2O2 221.1290 (M + 1), found 221.1294 (M
+ 1).
N,N-Dip h en yl-N′,N′-(N-m et h yl-3-a za p en t a m et h ylen e)-
u r ea (4k ): white powder (eluent diethyl ether/ethyl acetate (30:
70), 330 mg, 47%): mp 89-91 °C; 1H NMR δ 7.29 (t, J ) 7.5
Hz, 4H), 7.11 (t, J ) 7 Hz, 2H), 7.04 (d, J ) 8 Hz, 4H), 3.38 (t,
1-(N-Ben zyl-N-m et h ylca r b a m oyl)b en zot r ia zole
(3g):
white powder (eluent diethyl ether/hexane (50:50), 1.53 g, 76%);
1
mp 54-57 °C; H NMR δ 8.11-8.04 (m, 2H), 7.61 (t, J ) 7 Hz,
1H), 7.48-7.38 (m, 6H), 4.89 (br s, 2H), 3.28 (br s, 3H); 13C NMR
δ 150.8, 145.2, 135.7, 133.2, 129.2, 128.7, 125.1, 119.7, 113.6,
(33) Mukaiyama, T.; Taguchi, T.; Nishi, M. Bull. Chem. Soc. J pn.
1971, 44, 2797.

4158 J . Org. Chem., Vol. 62, No. 12, 1997
Notes
J ) 5 Hz, 4H), 2.27-2.24 (m, 4H), 2.24 (s, 3H); 13C NMR δ 159.6,
129.4, 127.2, 126.6, 125.3, 120.0, 113.3. Anal. Calcd for
C
19H14N4O: C, 72.60; H, 4.49; N, 17.82. Found: C, 72.41; H,
144.8, 129.1, 125.0, 124.6, 54.5, 46.0, 45.4. Anal. Calcd for C18
21N3O: C, 73.19; H, 7.17; N, 14.23. Found: C, 72.83; H, 7.49;
N, 14.50.
-
4.37; N, 17.86.
H
1-(N-Met h yl-N-p h en ylca r b a m oyl)b en zot r ia zole
(3e):
white powder (eluent diethyl ether/hexane (20:80), 800 mg,
40%): mp 76-78 °C; 1H NMR δ 8.07-7.98 (m, 2H), 7.60 (t, J )
7.5 Hz, 1H), 7.43 (t, J ) 7 Hz, 8H), 7.34-7.16 (m, 5H); 13C NMR
δ 150.0, 144.9, 143.6, 132.7, 129.4, 129.1, 127.2, 125.8, 125.0,
119.7, 113.1. Anal. Calcd for C14H12N4O: C, 66.65; H, 4.79; N,
22.21. Found: C, 66.68; H, 4.91; N, 22.40.
N-Meth yl-N-p h en yl-N′,N′-(N-m eth yl-3-a za p en ta m eth yl-
en e)u r ea (4l): pale yellow oil (eluent dichloromethane/diethyl
ether/methanol/ethyl acetate (10:15:5:70), 290 mg, 51%); 1H
NMR δ 7.32 (t, J ) 7.5 Hz, 2H), 7.11-7.08 (m, 3H), 3.24-3.21
(m, 7H), 2.21-2.18 (m, 7H); 13C NMR δ 160.7, 146.6, 129.2,
124.3, 123.6, 54.3, 45.9, 45.4, 39.4. Anal. Calcd for C13H19N3O:
C, 66.92; H, 8.21; N, 18.01. Found: C, 66.55; H, 7.83; N, 17.88.
Su p p or tin g In for m a tion Ava ila ble: Spectra for 4c,d ,f-
h ,j (15 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
1-(N,N-Dip h en ylca r b a m oyl)b en zot r ia zole (3d ): white
powder (eluent diethyl ether/hexane (20:80), 570 mg, 23%); mp
103-105 °C; 1H NMR δ 8.07-7.99 (m, 2H), 7.63-7.57 (m, 1H),
7.45-7.20 (m, 11H); 13C NMR δ 150.1, 145.1, 142.8, 132.7, 129.5,
J O962245T