Novel synthesis of ureas: Application of t-butylureas

Article abstract of DOI:10.1248/cpb.58.82

Otherwise inaccessible tropolonylureas were prepared by reaction of t-butylurea with appropriate amines, with elimination of t-butylamine. This method is also generally applicable for urea synthesis.

Full text of DOI:10.1248/cpb.58.82

82
Chem. Pharm. Bull. 58(1) 82—86 (2010)
Vol. 58, No. 1
Novel Synthesis of Ureas: Application of t-Butylureas
Ai ITO, Hideaki MURATAKE, and Koichi SHUDO*
Research Foundation Itsuu Laboratory; 2–28–10 Tamagawa, Setagaya-ku, Tokyo 158–0094, Japan.
Received September 28, 2009; accepted October 30, 2009; published online November 4, 2009
Otherwise inaccessible tropolonylureas were prepared by reaction of t-butylurea with appropriate amines,
with elimination of t-butylamine. This method is also generally applicable for urea synthesis.
Key words urea; t-butylurea; isocyanate; tropolone; substitution
Urea is an important pharmacophore which is present in leaving the hydroxy group intact. However, when 1 was
various pharmaceutical drugs and agrochemicals. For exam- treated with 1 eq of t-butyl isocyanate at reflux for 51 h in
ple, terguride1) is a dopamine agonist, many sulfonylureas2,3) tetrahydrofuran (THF), N,Nꢀ-di(5-tropolonyl)urea (2) was
are used as therapeutics for diabetes, sorafenib4,5) is used unexpectedly obtained as a major product instead of N-t-
to treat renal cell carcinoma, N-(3,4-dichlorophenyl)-Nꢀ,Nꢀ- butyl-Nꢀ-(5-tropolonyl)urea (3). In order to obtain 3, an ex-
dimethylurea (diuron)6) is a herbicide, and N-(2-chloro-4- cess amount of t-butyl isocyanate and a shorter reaction time
pyridyl)-Nꢀ-phenylurea (forchlorofenuron)7) is a plant growth are required, suggesting that 3 may serve as an intermediate
regulator.8) Such compounds may be prepared by conven- in the formation of 2. Indeed, when isolated 3 was treated
tional methods,9,10) i.e., reaction of an amine with an iso- with 1 in toluene at 120 °C for 14 h, 2 was smoothly gener-
cyanate (or in situ-formed isocyanate generated by Curtius ated in a good yield of 82% (Chart 1).
rearrangement of acid azide),11—14) reaction of an amine and
When N-adamantyl-Nꢀ-tropolonylurea was prepared and
a carbamate,15—18) or reaction of an amine and phosgene or reacted with 1 under similar conditions, 2 was obtained in a
its equivalents.19—21) The last method is convenient, but lower yield of 36%. The main reason for this may be that the
sometimes encounters difficulties when the amine or inter- adamantylamine is not readily removed during the reaction,
mediate is reactive. In some cases, none of these methods because of its high boiling point. Therefore, the t-butylamine
can be easily applied.
may be the best leaving alkylamine in terms of both bulki-
We have been investigating the structural and medicinal ness (high eliminability) and high volatility. This method for
chemistry of tropolone (2-hydroxy-2,4,6-cycloheptatrien-1- urea preparation, utilizing t-butylurea, should be available
one),22) which is a nonbenzenoid aromatic compound having not only for 5-tropolonyureas, but also for general prepara-
a flat seven-membered ring. The tropolone fragment can tion of ureas (vide infra).
be used as a pharmacophore instead of benzoic acid, phenol
Reaction of 3 with a variety of primary and secondary
or other heteroaromatic moieties,23) and its derivatives, e.g., amines (e.g., aromatic, heterocyclic, aliphatic amines) in
thujaplicins and colchicines, possess antibacterial, antifungal, toluene at 120 °C afforded the desired ureas in good yield
antiviral, and antitumor properties.24,25) Some tropolone (Table 1, entries 1—19). A hindered amine, 2,6-dimethylani-
derivatives show significant retinoid activity.23) Therefore, line, reacted with 3 to give 4a (entry 1). The reaction pro-
we set out to synthesize various tropolonylureas from 5- ceeded well with amines that are nucleophilic (e.g., entries 2,
aminotropolone (1).26,27) When we attempted to extend 4, 6) or weakly nucleophilic (e.g., entries 3, 5, 8, 9, 11). As
tropolone chemistry, we found that compounds such as N,Nꢀ- expected, 3 reacted with piperazine, a bidentate amine, to af-
di(5-tropolonyl)urea (2) were not readily accessible from 1, ford N-piperazinyl-Nꢀ-(5-tropolonyl)urea (4l) in 72% yield,
since we could not obtain 5-tropolonyl isocyanate by conven- leaving one amino group intact (entry 12). Ureas 4m—p
tional methods (e.g., using phosgene equivalents). Fortu- were also readily obtained by the reaction of 3 with other
nately, we found a method to prepare compound 2 (Chart 1), aliphatic secondary amines (entries 13—16). The method
and this method can also be applied to general synthesis of was also extended to more complex tropolonylureas (entries
urea compounds, as described below.
18, 19). The reaction of 3 with bioactive substances, such as
histamine and pindolol, provided the corresponding ureas 4r
and 4s derivatized from the aliphatic amines, respectively, in
Results and Discussion
5-Aminotropolone (1) reacts with various isocyanates, high yield. The reactions of N-t-butyl-Nꢀ-phenylurea (5) and
such as phenyl, substituted phenyl, and aliphatic isocyanates, N-t-butyl-Nꢀ-(3-pyridyl)urea (7) with amines are illustrated
Chart 1
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: kshudo@itsuu.or.jp

January 2010
83
Table 1. Reaction of t-Butylureas (3, 5, 7) with Various Amines
Time
(h)
Yield
(%)
Time
(h)
Yield
(%)
Entry t-Butylurea
Amine
Product
Entry t-Butylurea
Amine
Product
1
2
3
3
3
3
5.5
6
4a
4b
4c
71
90
61
14
15
16
3
3
3
3.5
2
4n
4o
4p
45
62
84
6
4
4
5
6
7
3
3
3
3
5
5
3
4d
4e
4f
73
91
78
86
17
18
19
3
3
3
3
24
4
4q
4r
4s
61
84
91
12
4g
8
9
3
3
3
3
1.5
3
4h
4i
96
93
80
78
20
5
5
5
23
2
6a
6b
6c
38
76
87
21a)
22
10
11
7
4j
20
18
4k
12
13
3
3
5
3
4l
72
77
23
24
7
7
19
4
8a
8b
65
63
4m
a) See Experimental.
likely.31—34) The presence of amine is necessary for the reac-
tion to proceed. The amine may catalyze elimination of the t-
butylamine to afford the isocyanate. Or, nucleophilic attack
of the amine on the carbonyl group and subsequent removal
of t-butylamine may occur. In any case, the formed t-butyl-
amine (bp 44—46 °C) is highly volatile, and can be easily re-
moved from the reaction medium. t-Butylamine evaporated
from the reaction medium can be easily detected with pH test
paper.
Chart 2
Conclusion
in entries 20—24.
A simple and versatile method for the preparation of ureas,
Possible reaction pathways include a stepwise reaction in- based on reaction of t-butylureas with amines, was devel-
volving an isocyanate intermediate formed by elimination of oped. This method is especially useful for synthesizing urea
t-butylamine, and/or direct nucleophilic substitution of the t- compounds for which corresponding isocyanates or their pre-
butylamine by amine (RꢀRꢁNH) (Chart 2). It was reported cursors are not available.
that N-alkyl-Nꢀ-phenylureas can be prepared from N,Nꢀ-
diphenylurea by treatment with aliphatic amines, though this
Experimental
General Procedures Melting points were determined on a Yanagimoto
micro-melting point apparatus (hot plate) without correction. Mass spectra
were recorded on a Hitachi M-80B spectrometer at an ionizing voltage of
reaction lacks versatility, and the reaction mechanism has not
been established.28—30) In the present reaction, the t-butyl-
ureas are stable at toluene reflux temperature, and simple
70 eV, and figures in parentheses indicate the relative intensities. IR spectra
thermal dissociation to the isocyanate intermediate is un- were measured on a Shimadzu IR-460 spectrophotometer. 1H- and 13C-NMR

84
Vol. 58, No. 1
292.0659). MS m/z: 292 (Mꢅ, 10), 163 (52), 155 (54), 137 (40), 135 (45),
129 (100), 127 (39).
spectra were obtained on a Varian Mercury 300 at 300 MHz and at 75 MHz,
respectively. Chemical shifts are recorded in ppm, and coupling constants (J)
in Hz. Chemical shifts were calculated on the basis of tetramethylsilane
(0 ppm for 1H-NMR in CDCl3), (CH3)2SO (2.49 ppm for 1H-NMR in
DMSO-d6), (CH3)2SO (39.5 ppm for 13C-NMR in DMSO-d6), or CH3OH
N-Methyl-N-phenyl-Nꢀ-(5-tropolonyl)urea (4d) Ocher prisms
(AcOEt), mp 134—136 °C. 1H-NMR (DMSO-d6) d: 8.37 (1H, br s, NH),
7.46 (2H, dd, Jꢃ11.1, 1.5 Hz), 7.41 (2H, dd, Jꢃ7.2, 7.2 Hz), 7.33 (2H, dd,
Jꢃ7.2, 1.2 Hz), 7.25 (1H, tt, Jꢃ7.2, 1.2 Hz), 7.14 (2H, dd, Jꢃ11.1, 1.5 Hz),
3.25 (3H, s, OMe). 13C-NMR (DMSO-d6) d: 168.8, 154.7, 143.5, 139.9,
130.1, 129.1, 126.2, 125.9, 124.0, 39.7. IR (KBr) cmꢄ1: 3400, 3225, 1684,
1543, 1496, 1445, 1363, 1262. HR-MS m/z: 270.1015 (Calcd for
C15H14N2O3: 270.1004). MS m/z: 270 (Mꢅ, 27), 163 (29), 134 (82), 106
(100).
1
(3.30 ppm for H-NMR in CD3OD). Fuji Davison BW 300 or Merck alu-
minum oxide 90 was used for flash chromatography, and TLC was carried
out on Merck Silica gel 60 PF254
.
Reaction of 5-Aminotropolone (1) with 1 eq of t-Butyl Isocyanate
A
solution of 5-aminotropolone (1, 206 mg, 1.50 mmol) and t-butyl isocyanate
(171 ml, 1.50 mmol) in THF (10 ml) was refluxed for 51 h, then cooled to
room temperature, and the solvent was evaporated in vacuo. The residue was
washed with MeOH to give N,Nꢀ-di(5-tropolonyl)urea (2, 96 mg, 43%) as
N-(8-Quinolyl)-Nꢀ-(5-tropolonyl)urea (4e) Yellow needles (MeOH),
1
mp 246—248 °C. H-NMR (DMSO-d6) d: 10.1 (1H, br s, NH), 9.78 (1H,
1
dark brown powder, mp 258—260 °C (dec.). H-NMR (DMSO-d6) d: 9.06
br s, NH), 8.93 (1H, dd, Jꢃ4.4, 1.8 Hz), 8.53 (1H, dd, Jꢃ6.0, 3.0 Hz), 8.40
(1H, dd, Jꢃ8.6, 1.8 Hz), 7.69 (2H, dd, Jꢃ11.0, 1.2 Hz), 7.64 (1H, dd, Jꢃ8.6,
4.4 Hz), 7.59—7.52 (2H, m), 7.26 (2H, dd, Jꢃ11.0, 1.2 Hz). 13C-NMR
(DMSO-d6) d: 168.6, 152.1, 148.2, 139.6, 137.5, 136.5, 135.3, 127.7, 127.2,
127.0, 125.0, 122.0, 120.0, 114.4. IR (KBr) cmꢄ1: 3315, 3215, 3080, 1712,
1571, 1548, 1525, 1458, 1356. HR-MS m/z: 307.0962 (Calcd for
C17H13N3O3: 307.0956). MS m/z: 307 (Mꢅ, 1), 170 (53), 163 (27), 144
(100).
(2H, br s, NHꢂ2), 7.55 (4H, d, Jꢃ12.0 Hz), 7.21 (4H, d, Jꢃ12.0 Hz). IR
(KBr) cmꢄ1: 3195, 1612, 1548, 1448, 1419, 1262. MS m/z: 163 (Mꢅꢄ137,
67), 137 (65), 135 (59), 109 (90), 80 (57), 52 (100). The filtrate was evapo-
rated to give a residue (184 mg) which consisted of three compounds, N-t-
butyl-Nꢀ-(5-tropolonyl)urea (3), N,Nꢀ-di(t-butyl)urea, and 1 in a ratio of ca.
1 : 0.7 : 0.5 estimated by the 1H-NMR integration of the respective NH
groups.
Reaction of 1 with 3 eq of t-Butyl Isocyanate A solution of 1 (411 mg,
3.00 mmol) and t-butyl isocyanate (1.06 ml, 9.00 mmol) in THF (10 ml) was
refluxed for 3 h, then cooled to room temperature and the solvent was evapo-
rated in vacuo. The residue was flash-chromatographed [silica gel,
MeOH–CH2Cl2 (1 : 9)] to give 3 (466 mg, 66%) as brown scales (MeOH–
hexane), mp 207—210 °C. 1H-NMR (DMSO-d6) d: 8.50 (1H, br s, NH),
7.51 (2H, dd, Jꢃ11.0, 1.5 Hz), 7.17 (2H, dd, Jꢃ11.0, 1.5 Hz), 6.13 (1H, br s,
NH), 1.27 (9H, s, t-Bu). 13C-NMR (DMSO-d6) d: 168.0, 153.8, 140.9,
126.3, 125.2, 49.7, 28.9. IR (KBr) cmꢄ1: 3350, 3170, 3005, 1640, 1560,
1446, 1359, 1260. HR-MS m/z: 236.1163 (Calcd for C12H16N2O3:
236.1160). MS m/z: 236 (Mꢅ, 9), 163 (13), 137 (100).
Reaction of N-t-Butyl-Nꢀ-(5-tropolonyl)urea (3) with 1 A solution of
3 (253 mg, 1.07 mmol) and 1 (293 mg, 2.14 mmol) in toluene (10 ml) was
heated at 120 °C for 14 h, then cooled to room temperature and the solvent
was evaporated in vacuo. The residue was washed with MeOH to give 2
(264 mg, 82%).
N-(5-Indolyl)-Nꢀ-(5-tropolonyl)urea (4f) Ocher needles (MeOH), mp
238—240 °C. 1H-NMR (DMSO-d6) d: 10.9 (1H, br s, indole NH), 8.82 (1H,
br s, NH), 8.54 (1H, br s, NH), 7.66 (1H, d, Jꢃ2.1 Hz), 7.59 (2H, d,
Jꢃ12.0 Hz), 7.32—7.26 (2H, m), 7.21 (2H, d, Jꢃ12.0 Hz), 7.07 (1H, dd,
Jꢃ8.9, 2.1 Hz), 6.38—6.32 (1H, m). IR (KBr) cmꢄ1: 3265, 1628, 1613,
1562, 1535, 1448, 1353. HR-MS m/z: 295.0942 (Calcd for C16H13N3O3:
295.0956). MS m/z: 295 (Mꢅ, 20), 164 (20), 163 (82), 137 (100).
N-(3-Coumarinyl)-Nꢀ-(5-tropolonyl)urea (4g) Ocher powder (MeOH),
1
mp 288—290 °C (dec.). H-NMR (DMSO-d6) d: 9.66 (1H, br s, NH), 8.89
(1H, br s, NH), 8.43 (1H, s), 7.67 (1H, d, Jꢃ7.8 Hz), 7.56 (2H, d,
Jꢃ12.0 Hz), 7.47 (1H, dd, Jꢃ7.8, 7.8 Hz), 7.39 (1H, d, Jꢃ7.8 Hz), 7.32 (1H,
dd, Jꢃ7.8, 7.8 Hz), 7.20 (2H, d, Jꢃ12.0 Hz). IR (KBr) cmꢄ1: 3340, 1674,
1555, 1449. HR-MS m/z: 324.0731 (Calcd for C17H12N2O5: 324.0745). MS
m/z: 324 (Mꢅ, 5), 187 (76), 161 (100).
N-(2-Benzothiazolyl)-Nꢀ-(5-tropolonyl)urea (4h) Pale yellow powder
1
(MeOH), mp 257—260 °C (dec.). H-NMR (DMSO-d6) d: 11.4—10.0 (1H,
Preparation of N-(1-Adamantyl)-Nꢀ-(5-tropolonyl)urea A solution of
1 (206 mg, 1.50 mmol) and 1-adamantyl isocyanate (531 mg, 3.00 mmol)
in THF (10 ml) was refluxed for 28 h, then cooled to room temperature and
the solvent was evaporated in vacuo. The residue was flash-chro-
matographed [silica gel, CH2Cl2–1,2-dimethoxyethane (20 : 1)] to give N-(1-
adamantyl)-Nꢀ-(5-tropolonyl)urea (168 mg, 36%) as brown scales (MeOH),
mp 214—216 °C and 230—235 °C (dec.). 1H-NMR (DMSO-d6) d: 8.51
(1H, br s, NH), 7.50 (2H, d, Jꢃ12.3 Hz), 7.17 (2H, d, Jꢃ12.3 Hz), 6.01 (1H,
br s, NH), 2.06—1.98 (3H, m), 1.94—1.89 (6H, m), 1.64—1.59 (6H, m). IR
(KBr) cmꢄ1: 3370, 2905, 1664, 1529, 1447. HR-MS m/z: 314.1617 (Calcd
for C18H22N2O3: 314.1629). MS m/z: 314 (Mꢅ, 0.3), 163 (20), 151 (17), 135
(17), 107 (15), 94 (100).
Tropolonylureas 4a—s; General Procedure A solution of 3 (0.5
mmol) and amine (1—3 eq) in toluene (5 ml) was heated at 120 °C. The re-
action was monitored by NMR (or TLC). When the reaction reached com-
pletion, the solvent was evaporated in vacuo. The residue was washed with
MeOH (or CH2Cl2, ether, or H2O), and the crude product was collected by
filtration. If necessary, the residue was purified by flash chromatography (sil-
ica gel or aluminum oxide).
br s, NH), 9.37 (1H, br s, NH), 7.89 (1H, br d, Jꢃ7.8 Hz), ca. 7.65—7.58
(1H, m), 7.64 (2H, d, Jꢃ12.3 Hz), 7.39 (1H, ddd, Jꢃ7.8, 7.8, 1.2 Hz),
7.27—7.20 (1H, m), 7.24 (2H, d, Jꢃ12.3 Hz). IR (KBr) cmꢄ1: 3350, 3265,
2990, 1710, 1552, 1444, 1350. HR-MS m/z: 313.0509 (Calcd for
C15H11N3O3S: 313.0520). MS m/z: 313 (Mꢅ, 0.6), 176 (100), 163 (33), 150
(91).
N-(5-Bromo-2-pyridyl)-Nꢀ-(5-tropolonyl)urea (4i) Dark brown pow-
der (MeOH), mp 240—242 °C. 1H-NMR (DMSO-d6) d: 10.0 (1H, br s, NH),
9.61 (1H, br s, NH), 8.39 (1H, d, Jꢃ2.4 Hz), 7.49 (1H, dd, Jꢃ8.7, 2.4 Hz),
7.61 (2H, d, Jꢃ12.3 Hz), 7.61 (1H, d, Jꢃ8.7 Hz), 7.22 (2H, d, Jꢃ12.3 Hz).
HR-MS m/z: 336.9872, 334.9919 (Calcd for C13H10BrN3O3: 336.9886,
334.9905). MS m/z: 337, 335 (Mꢅ, 19, 20), 200 (51), 198 (51), 174 (96),
172 (100).
N-(2-Chloro-5-pyridyl)-Nꢀ-(5-tropolonyl)urea (4j) Ocher needles
1
(MeOH), mp 248—250 °C (dec.). H-NMR (DMSO-d6) d: 9.41 (1H, br s,
NH), 9.29 (1H, br s, NH), 8.50 (1H, d, Jꢃ2.7 Hz), 7.98 (1H, dd, Jꢃ8.7,
2.7 Hz), 7.54 (2H, d, Jꢃ12.3 Hz), 7.42 (1H, d, Jꢃ8.7 Hz), 7.17 (2H, d,
Jꢃ12.3 Hz). HR-MS m/z: 293.0370, 291.0404 (Calcd for C13H10ClN3O3:
293.0380, 291.0410). MS m/z: 293, 291 (Mꢅ, 1, 4), 163 (49), 154 (100).
N-Pyrazinyl-Nꢀ-(5-tropolonyl)urea (4k) Brown powder (MeOH), mp
N-(2,6-Dimethylphenyl)-Nꢀ-(5-tropolonyl)urea (4a) Dark brown
1
1
scales (MeOH), mp 258—260 °C. H-NMR (DMSO-d6) d: 9.01 (1H, br s,
258—260 °C. H-NMR (DMSO-d6) d: 9.77 (1H, br s, NH), 9.68 (1H, br s,
NH), 7.87 (1H, br s, NH), 7.59 (2H, d, Jꢃ12.3 Hz), 7.20 (2H, d, Jꢃ12.3 Hz),
7.01 (3H, s), 2.19 (6H, s, Meꢂ2). HR-MS m/z: 284.1163 (Calcd for
C16H16N2O3: 284.1160). MS m/z: 284 (Mꢅ, 4), 163 (53), 135 (49), 121
(100).
NH), 9.00 (1H, d, Jꢃ1.2 Hz), 8.32 (1H, dd, Jꢃ2.7, 1.2 Hz), 8.27 (1H, d,
Jꢃ2.7 Hz), 7.61 (2H, d, Jꢃ12.0 Hz), 7.23 (2H, d, Jꢃ12.0 Hz). IR (KBr)
cmꢄ1: 3025, 1695, 1604, 1549, 1503, 1451, 1419, 1399, 1362. HR-MS m/z:
258.0752 (Calcd for C12H10N4O3: 258.0752). MS m/z: 258 (Mꢅ, 28), 163
(41), 137 (55), 121 (58), 109 (100), 95 (86).
1-(5-Tropolonylcarbamoyl)piperazine (4l) Pale yellow powder
(CH2Cl2–MeOH), mp 232—235 °C (dec). 1H-NMR (DMSO-d6) d: 8.61
(1H, br s, NH), 7.44 (2H, d, Jꢃ12.0 Hz), 7.14 (2H, d, Jꢃ12.0 Hz), 3.34 (4H,
t, Jꢃ5.1 Hz), 2.67 (4H, t, Jꢃ5.1 Hz). HR-MS m/z: 249.1124 (Calcd for
C12H15N3O3: 249.1112). MS m/z: 249 (Mꢅ, 1), 163 (100), 135 (71), 107
(50), 86 (39), 79 (34), 52 (58), 44 (94).
N-(4-Methylphenyl)-Nꢀ-(5-tropolonyl)urea (4b) Pale yellow needles
1
(MeOH), mp 260—262 °C (dec.). H-NMR (DMSO-d6) d: 8.85 (1H, br s,
NH), 8.68 (1H, br s, NH), 7.56 (2H, d, Jꢃ12.3 Hz), 7.32 (2 H, d, Jꢃ8.7 Hz),
7.20 (2H, d, Jꢃ12.3 Hz), 7.08 (2H, d, Jꢃ8.7 Hz), 2.23 (3H, s, Me). IR (KBr)
cmꢄ1: 3300, 3210, 1683, 1605, 1544, 1449, 1425, 1355. HR-MS m/z:
270.0997 (Calcd for C15H14N2O3: 270.1004). MS m/z: 270 (Mꢅ, 21), 163
(19), 137 (77), 109 (100).
N-(3,4-Difluorophenyl)-Nꢀ-(5-tropolonyl)urea (4c) Ocher needles
(MeOH), mp 259—261 °C (dec.). H-NMR (DMSO-d6) d: 9.01 (1H, br s,
NH), 8.95 (1H, br s, NH), 7.64 (1H, ddd, Jꢃ13.3, 7.5, 2.4 Hz), 7.54 (2H, d,
Jꢃ12.0 Hz), 7.34 (1H, ddd, Jꢃ10.0, 9.0, 9.0 Hz), 7.20 (2H, d, Jꢃ12.0 Hz),
7.15—7.10 (1H, m). HR-MS m/z: 292.0646 (Calcd for C14H10F2N2O3:
4-(2-Hydoxyethyl)-1-(5-tropolonylcarbamoyl)piperazine (4m) Yellow
prisms, mp 93—95 °C, then solidify and melt at 200—202 °C. 1H-NMR
(CDCl3) d: 7.43 (2H, dd, Jꢃ10.8, 1.8 Hz), 7.30 (2H, dd, Jꢃ10.8, 1.8 Hz),
6.40 (1H, br s), 3.68 (2H, t, Jꢃ5.1 Hz), 3.54 (4H, t, Jꢃ5.1 Hz), 2.62 (2H, t,
Jꢃ5.1 Hz), 2.59 (4H, t, Jꢃ5.1 Hz). HR-MS m/z: 293.1344 (Calcd for
1

January 2010
85
C14H19N3O4: 293.1374). MS m/z: 293 (Mꢅ, 4), 163 (59), 135 (55), 99 (100).
4-Methyl-1-(5-tropolonylcarbamoyl)homopiperazine (4n) Yellow
powder, mp 105—107 and 175—177 °C. H-NMR (CDCl3) d: 7.46 (2H, d,
Jꢃ12.3 Hz), 7.30 (2H, d, Jꢃ12.3 Hz), 6.33 (1H, br s, NH), 3.72—3.62 (2H,
m), 3.60 (2H, t, Jꢃ6.0 Hz), 2.74—2.66 (2H, m), 2.66—2.58 (2H, m), 2.41
(3H, s, Me), 2.00 (2H, m). HR-MS m/z: 277.1430 (Calcd for C14H19N3O3:
277.1425). MS m/z: 277 (Mꢅ, 5), 163 (54), 135 (47), 114 (22), 107 (38), 58
(100).
dd, Jꢃ8.7, 7.5 Hz), 6.95 (1H, tt, Jꢃ7.5, 1.2 Hz), 6.87 (1H, s), 3.45 (2H, t,
Jꢃ6.9 Hz), 2.79 (2H, t, Jꢃ6.9 Hz). IR (KBr) cmꢄ1: 3360, 1640, 1554, 1305.
HR-MS m/z: 230.1155 (Calcd for C12H14N4O: 230.1167). MS m/z: 230 (Mꢅ,
4), 138 (25), 119 (73), 82 (100).
1
Preparation of N-t-Butyl-Nꢀ-(3-pyridyl)urea (7) A solution of 3-
aminopyridine (376 mg, 4.00 mmol) and t-butyl isocyanate (1.42 ml,
12.0 mmol) in THF (5 ml) was refluxed for 7 h under Ar. The reaction mix-
ture was evaporated in vacuo, and the residue was taken up in H2O then ex-
tracted with ether. The organic layer was washed with brine, dried over
Na2SO3 and evaporated in vacuo to give 7 (212 mg, 27%) as colorless nee-
4-(5-Tropolonylcarbamoyl)morpholine (4o) Pale yellow powder
1
(MeOH), mp 213—215 °C. H-NMR (CDCl3) d: 7.43 (2H, d, Jꢃ12.3 Hz),
1
dles (AcOEt–hexane), mp 141—143 °C (lit.,38) mp 145—147 °C). H-NMR
7.29 (2H, d, Jꢃ12.3 Hz), 6.43 (1H, br s, NH), 3.76 (4H, t, Jꢃ4.5 Hz), 3.50
(4H, t, Jꢃ4.5 Hz) HR-MS m/z: 250.0951 (Calcd for C12H14N2O4: 250.0953).
MS m/z: 250 (Mꢅ, 26), 163 (56), 135 (58), 114 (81), 107 (45), 70 (100).
N-[2-(Dimethylamino)ethyl]-N-methyl-Nꢀ-(5-tropolonyl)urea (4p)
(DMSO-d6) d: 8.28 (1H, d, Jꢃ2.4 Hz), 8.19 (1H, dd, Jꢃ4.7, 1.5 Hz), 8.05
(1H, ddd, Jꢃ8.4, 2.4, 1.5 Hz), 7.44 (1H, br s, NH), 7.21 (1H, dd, Jꢃ8.4,
4.7 Hz), 5.19 (1H, br s, NH), 1.37 (9H, s, t-Bu). MS m/z: 193 (Mꢅ, 16), 136
(6), 120 (44), 94 (98), 59 (100).
1
Ocher powder, mp 108—110 °C. H-NMR (CDCl3) d: 11.0 (1H, br s, NH),
N-(3-Pyridyl)-Nꢀ-(5-tropolonyl)urea (8a) Dark brown granules
(EtOH), 212—213 °C. 1H-NMR (DMSO-d6) d: 9.04 (1H, br s, NH), 9.00
(1H, br s, NH), 8.60 (1H, d, Jꢃ2.4 Hz), 8.19 (1H, dd, Jꢃ4.7, 1.2 Hz), 7.91
(1H, ddd, Jꢃ8.4, 2.4, 1.2 Hz), 7.56 (2H, d, Jꢃ12.6 Hz), 7.31 (1H, dd, Jꢃ8.4,
4.7 Hz), 7.22 (2H, d, Jꢃ12.6 Hz). 13C-NMR (DMSO-d6) d: 168.7, 152.5,
143.0, 140.1, 139.2, 135.9, 127.9, 125.3, 124.8, 123.5. HR-MS m/z:
257.0803 (Calcd for C13H11N3O3: 257.0800). MS m/z: 257 (Mꢅ, 16), 214
(9), 163 (99), 137 (100).
7.39 (2H, d, Jꢃ12.6 Hz), 7.30 (2H, d, Jꢃ12.6 Hz), 3.38 (2H, t, Jꢃ4.2 Hz),
2.99 (3H, s, Me), 2.63 (2H, t, Jꢃ4.2 Hz), 2.42 (6H, s, Meꢂ2). HR-MS m/z:
265.1414 (Calcd for C13H19N3O3: 265.1425). MS m/z: 265 (Mꢅ, 1.4), 163
(15), 135 (16), 107 (13), 79 (19), 58 (100).
N-[3-(4-Morpholinopropyl)]-Nꢀ-(5-tropolonyl)urea (4q) Ocher pow-
der, mp 186—188 °C. 1H-NMR (CD3OD) d: 7.62 (2H, dd, Jꢃ11.1, 1.5 Hz),
7.30 (2H, dd, Jꢃ11.1, 1.5 Hz), 3.69 (4H, t, Jꢃ4.5 Hz), 3.24 (2H, t,
Jꢃ6.9 Hz), 2.48 (4H, t, Jꢃ4.5 Hz), 2.43 (2H, t, Jꢃ7.5 Hz), 1.74 (2H, tt,
Jꢃ7.5, 6.9 Hz). HR-MS m/z: 307.1544 (Calcd for C15H21N3O4: 307.1531).
MS m/z: 307 (Mꢅ, 0.2), 171 (15), 163 (41), 135 (39), 100 (100).
N-(3-Pyridyl)-Nꢀ-p-tolylurea (8b) Colorless prisms (from EtOH–H2O),
1
mp 188—189 °C. (lit.,39) 180 °C). H-NMR (DMSO-d6) d: 8.76 (1H, br s,
NH), 8.65 (1H, br s, NH), 8.57 (1H, d, Jꢃ2.7 Hz), 8.16 (1H, dd, Jꢃ4.7,
1.2 Hz), 7.96 (1H, ddd, Jꢃ8.6, 2.7, 1.2 Hz), 7.33 (2H, d, Jꢃ8.4 Hz), 7.29
(1H, dd, Jꢃ8.6, 4.7 Hz), 7.08 (2H, d, Jꢃ8.4 Hz), 2.23 (3H, s, Me). MS m/z:
227 (Mꢅ, 35), 120 (20), 107 (87), 106 (80), 94 (100).
N-[2-(4-1H-Imidazolyl)ethyl]-Nꢀ-(5-tropolonyl)urea (4r) Yellow pow-
der (AcOEt), mp 190—192 °C. 1H-NMR (CD3OD) d: 7.60 (1H, d,
Jꢃ1.2 Hz), 7.57 (2H, dd, Jꢃ10.8, 1.5 Hz), 7.27 (2H, dd, Jꢃ10.8, 1.5 Hz),
6.87 (1H, d, Jꢃ1.2 Hz), 3.45 (2H, t, Jꢃ6.6 Hz), 2.80 (2H, t, Jꢃ6.6 Hz). IR
(KBr) cmꢄ1: 3210, 1664, 1504, 1432, 1344. MS m/z: 163 (Mꢅ, ꢄ111, 52),
137 (15), 135 (50), 107 (43), 82 (100).
References
1) Stephens D. N., Löschmann P. A., Lanzinger C., Wachtel H., Mont-
gomery A. M. J., Herberg L. J., Behav. Pharmacol., 1, 521—530
(1990).
2) Lebovitz H. E., Feinglos M. N., Diabetes Care, 1, 189—198 (1978).
3) Feinglos M. N., Lebovitz H. E., Nature (London), 276, 184—185
(1978).
4) Wilhelm S. M., Carter C., Tang L., Wilkie D., McNabola A., Rong H.,
Chen C., Zhang X., Vincent P., McHugh M., Cao Y., Shujath J.,
Gawlak S., Eveleigh D., Rowley B., Liu L., Adnane L., Lynch M., Au-
clair D., Taylor I., Gedrich R., Voznesensky A., Riedl B., Post L. E.,
Bollag G., Trail P. A., Cancer Res., 64, 7099—7109 (2004).
5) Kane R. C., Farrell A. T., Saber H., Tang S., Williams G., Jee J. M.,
Liang C., Booth B., Chidambaram N., Morse D., Sridhara R., Garvey
P., Justice R., Pazdur R., Clin. Cancer Res., 12, 7271—7278 (2006).
6) Tixier C., Sancelme M., Bonnemoy F., Cuer A., Veschambre H., Envi-
ron. Toxicol. Chem., 20, 1381—1389 (2001).
7) Okamoto T., Shudo K., Takahashi S., Kawachi E., Isogai Y., Chem.
Pharm. Bull., 29, 3748—3750 (1981).
8) Review: Shudo K., Yakugaku Zasshi, 114, 577—588 (1994).
9) Sandler S. R., Karo W., “Organic Functional Group Preparations,” Vol.
II, Chap. 6, ed. by Blomquist A. T., Academic Press, New York, 1971,
pp. 134—165.
10) Review: Bigi F., Maggi R., Sartori G., Green Chem., 2, 140—148
(2000).
11) Ozaki S., Chem. Rev., 72, 457—496 (1972).
12) Overman L. E., Taylor G. F., Petty C. B., Jessup P. J., J. Org. Chem.,
43, 2164—2167 (1978).
13) Knölker H.-J., Braxmeier T., Schlechtingen G., Synlett, 1996, 502—
504 (1996).
14) Knölker H.-J., Braxmeier T., Schlechtingen G., Angew. Chem., Int. Ed.
Engl., 34, 2497—2500 (1995).
15) Izdebski J., Pawlak D., Synthesis, 1989, 423—425 (1989).
16) Lamothe M., Perez M., Colovray-Gotteland V., Halazy S., Synlett,
1996, 507—508 (1996).
17) Matsumura Y., Satoh Y., Onomura O., Maki T., J. Org. Chem., 65,
1549—1551 (2000).
18) Gallou I., Erikosson M., Zeng X., Senanayake C., Farina V., J. Org.
Chem., 70, 6960—6963 (2005).
19) Nowick J. S., Powell N. A., Nguyen T. M., Noronha G., J. Org. Chem.,
57, 7364—7366 (1992).
N-[2-Hydroxy-3-(4-1H-indolyloxy)propyl]-N-(2-propyl)-Nꢀ-(5-
tropolonyl)urea (4s) Light brown prisms (MeOH–AcOEt–hexane), mp
163—165 °C. 1H-NMR (CD3OD) d: 7.46 (2H, dd, Jꢃ10.4, 1.5 Hz), 7.27
(2H, dd, Jꢃ10.4, 1.5 Hz), 7.11 (1H, d, Jꢃ3.3 Hz), 7.40—6.97 (2H, m),
6.55—6.49 (1H, m), 6.51 (1H, d, Jꢃ3.3 Hz), 4.46 (1H, qq, Jꢃ6.9, 6.9 Hz),
4.30—4.14 (1H, m), 4.20 (1H, dd, Jꢃ9.3, 4.8 Hz), 4.09 (1H, dd, Jꢃ9.3,
6.9 Hz), 3.67 (1H, dd, Jꢃ16.1, 1.8 Hz), 3.51 (1H, dd, Jꢃ16.1, 8.4 Hz), 1.26
(3H, d, Jꢃ6.9 Hz), 1.21 (3H, d, Jꢃ6.9 Hz). IR (KBr) cmꢄ1: 3230, 1672,
1564, 1500, 1436, 1352, 1209, 1080. MS m/z: 248 (Mꢅ, ꢄ163, 9), 204 (5),
163 (16), 133 (89), 104 (24), 72 (100).
Phenylureas (6a—c) and 3-pyridylureas (8a—b) were obtained by a pro-
cedure similar to that described for tropolonylureas (4).
Preparation of N-t-Butyl-Nꢀ-phenylurea (5) A solution of t-butyl-
amine (1.06 ml, 10.0 mmol) and phenyl isocyanate (1.08 ml, 10.0 mmol) in
benzene (10 ml) was stirred for 2 h at room temperature, and the resulting
precipitate was collected by filtration to afford 5 (1.14 g, 59%) as colorless
prisms (benzene), mp 167—169 °C (lit.,35) 165 °C). 1H-NMR (DMSO-d6) d:
8.18 (1H, br s, NH), 7.32 (2H, d, Jꢃ7.5 Hz), 7.18 (2H, dd, Jꢃ7.5, 7.5 Hz),
6.85 (1H, t, Jꢃ7.5 Hz), 5.94 (1H, br s, NH), 1.27 (9H, s, t-Bu). MS m/z: 192
(Mꢅ, 42), 135 (16), 94 (75).
N-Phenyl-Nꢀ-(5-tropolonyl)urea (6a) Brown scales (MeOH), mp
255—258 °C (dec.). 1H-NMR (DMSO-d6) d: 8.89 (1H, br s, NH), 8.79 (1H,
br s, NH), 7.56 (2H, d, Jꢃ12.3 Hz), 7.44 (2H, dd, Jꢃ7.8, 0.6 Hz), 7.28 (2H,
dd, Jꢃ7.8, 7.8 Hz), 7.21 (2H, d, Jꢃ12.3 Hz), 6.98 (1H, tt, Jꢃ7.8, 0.6 Hz).
HR-MS m/z: 256.0847 (Calcd for C14H12N2O3: 256.0847). MS m/z: 256
(Mꢅ, 14), 163 (96), 137 (70), 135 (86), 109 (100).
1-(Phenylcarbamoyl)piperazine (6b) In order to avoid the formation
of 1,4-bis(phenylcarbamoyl)piperazine (reaction of piperazine with one or
two36) equivalents of phenyl isocyanate gave this compound), an excess
amount of piperazine (15 eq) was used to afford 6b as white granules, mp
1
114—115 °C. H-NMR (CDCl3) d: 7.35 (2H, dd, Jꢃ7.2, 1.2 Hz), 7.31 (2H,
dd, Jꢃ7.2, 7.2 Hz), 7.04 (1H, tt, Jꢃ7.2, 1.2 Hz), 6.30 (1H, br s, NH), 3.47
(4H, t, Jꢃ5.1 Hz), 2.92 (4H, t, Jꢃ5.1 Hz). HR-MS m/z: 205.1206 (Calcd for
C11H15N3O: 205.1214). MS m/z: 205 (Mꢅ, 38), 137 (35), 119 (34), 85 (37),
69 (88), 56 (80), 44 (100).
1,4-Bis(phenylcarbamoyl)piperazine White solid, mp ꢆ300 °C (lit.,36)
1
320—321 °C). H-NMR (DMSO-d6) d: 8.56 (2H, br s, NH), 7.45 (4H, dd,
Jꢃ8.4, 0.9 Hz), 7.23 (4H, dd, Jꢃ8.4, 7.5 Hz), 6.93 (2H, tt, Jꢃ7.5, 0.9 Hz),
3.48 (8H, s). HR-MS m/z: 324.1588 (Calcd for C18H20N4O2: 324.1585). MS
m/z: 324 (Mꢅ, 3.5), 205 (88), 137 (59), 113 (34), 92 (50), 69 (100).
20) Kurita K., Matsumura T., Iwakura Y., J. Org. Chem., 41, 2070—2071
(1976).
21) Majer P., Randad R. S., J. Org. Chem., 59, 1937—1938 (1994).
N-[2-(4-1H-Imidazolyl)ethyl]-Nꢀ-phenylurea (6c) Colorless prisms
(AcOEt–MeOH–ether), 179—181 °C (lit.,37) 182—184 °C). 1H-NMR
(CD3OD) d: 7.59 (1H, d, Jꢃ1.2 Hz), 7.31 (2H, dd, Jꢃ8.7, 1.5 Hz), 7.22 (2H,

86
Vol. 58, No. 1
31) Mukaiyama T., Fujita Y., Bull. Chem. Soc. Jpn., 29, 54—57 (1956).
22) Ito A., Muratake H., Shudo K., J. Org. Chem., 74, 1275—1281 (2009).
23) Ebisawa M., Ohta K., Kawachi E., Fukasawa H., Hashimoto Y., 32) Ozaki S., Nagoya T., Bull. Chem. Soc. Jpn., 30, 444—449 (1957).
Kagechika H., Chem. Pharm. Bull., 49, 501—503 (2001).
24) Morita Y., Matsumura E., Okabe T., Shibata M., Sugiura M., Ohe T.,
Tsujibo H., Ishida N., Inamori Y., Biol. Pharm. Bull., 26, 1487—1490
(2003).
25) Zhao J., Curr. Med. Chem., 14, 2597—2621 (2007).
26) Nozoe T., Seto S., Ebine S., Ito S., J. Am. Chem. Soc., 73, 1895 (1951).
27) Nozoe T., Seto S., Proc. Jpn. Acad., 27, 188—189 (1951).
28) Furuya Y., Itoho K., Chem. Ind. (London), 1967, 359—360 (1967).
29) Ramadas K., Srinivasan N., Org. Prep. Proced. Int., 25, 600—601
(1993).
33) Stowell J. C., Padegimas S. J., J. Org. Chem., 39, 2448—2449 (1974).
34) Gulyaev N. D., Leonova T. V., Chimishkyan A. L., J. Org. Chem.
U.S.S.R. (Engl. Transl.), 19, 1909—1913 (1983).
35) Hughes M. P., Smith B. D., J. Org. Chem., 62, 4992—4499 (1997).
36) Rivett D. E., Wilshire J. F. K., Aust. J. Chem., 19, 869—875 (1966).
37) Battersby A. R., Nicoletti M., Staunton J., Vleggaar R., J. Chem. Soc.,
Perkin Trans. 1, 1980, 43—51 (1980).
38) Manley P. W., Quast U., J. Med. Chem., 35, 2327—2340 (1992).
39) Stanovnik B., Tiˇsler M., Golob V., Hvala I., Nikolicˇ O., J. Heterocycl.
Chem., 17, 733—736 (1980).
30) Yang Y., Lu S., Org. Prep. Proced. Int., 31, 559—561 (1999).