C. Faustino, L. Garc ´ı a-R ´ı o, J. R. Leis, F. Norberto
FULL PAPER
nitrosating agent N
2
O
3
, while the organic layer became yellow due
of the nitroso substrate. Ionic strength was kept constant at 1.0 m
to the formation of the nitroso compound. This method has the
advantage of preventing the hydrolysis of the nitroso derivative by
withdrawing it in the organic phase as soon as it is formed. The
reaction was monitored by TLC with diethyl ether/hexane (8:2) as
the eluent. After 2 h, the reaction mixture was carefully neutralized
with 5% sodium bisulfite solution. The organic layer was separated,
washed thoroughly with water, and dried with anhydrous sodium
sulfate. After concentration to dryness, the residue was purified by
4
by addition of NaClO . Reactions were monitored by recording the
change in absorbance at 260Ϫ270 nm due to the disappearance of
the nitroso compound. Absorbance/time data always fitted the
first-order integrated rate equation, thus affording the observed
pseudo-first-order rate constants, kobs. The pH in the 3Ϫ11 range
was controlled by use of buffers of the desired pH, while for pH Ͻ
3 and pH Ͼ 11 hydrochloric acid or sodium hydroxide solutions of
the appropriate concentration were used. The pH values of buffer
solutions and of the final reaction mixtures were measured with a
flash chromatography with hexane/diethyl ether (8:2) as the eluent,
1
and BMNU (1) was obtained as a yellow oil (yield 2.6%). H NMR Radiometer M82 pH-meter fitted with GK2401C combined glass
(
CDCl
3
): δ ϭ 3.32 (s, 3 H, N(NO)CH
3
], 7.49 (t, 2 H, 3,5-phenyl- electrodes. For pH Ͻ 3 and pH Ͼ 11 titration procedures were
employed. All reagents and solvents used in the preparation of
MS (EI): m/z ϭ 207.1 [M ], 206.0 [M Ϫ H], 177.1 [M Ϫ NO]. solutions for kinetic studies were of the highest purity grade com-
IR (CHCl
): ν˜ max ϭ 1708.5 (urea CO), 1680.6 (benzoyl CO), 1458.7 mercially available. Sodium hydroxide and hydrochloric acid solu-
NO) cmϪ1.
H), 7.59 (t, 1 H, 4-phenyl-H), 7.78 (d, 2 H, 2,6-phenyl-H) ppm.
ϩ
ϩ
ϩ
3
(
tions were prepared by dilution of commercial Merck Titrisol solu-
tions. The identities of reaction products were confirmed by the
UV spectra of the reaction mixtures on completion and in some
cases also by TLC and comparison with authentic samples, with
diethyl ether/hexane (8:2) and ethyl acetate/methanol (9:1) as el-
uents. The presence of nitrite in the final reaction mixtures was
detected by a modification of Shinn’s method.[
NЈ-Benzoyl-N,NЈ-dimethyl-N-nitrosourea (2): Nitrosation of N-ben-
zoyl-N,NЈ-dimethylurea by the above method afforded BDMNU
(
H, NCH
7
1
2) as a yellow oil (yield 4.7%). H NMR (CDCl
3
): δ ϭ 2.83 (s, 3
3
), 3.58 [s, 3 H, N(NO)CH
3
], 7.35 (t, 2 H, 3,5-phenyl-H),
.42 (t, 1 H, 4-phenyl-H), 7.51 (d, 2 H, 2,6-phenyl-H) ppm. MS
17]
ϩ
ϩ
(
3 3
EI): m/z ϭ 205.9 [M Ϫ CH ], 190.9 [M Ϫ NO]. IR (CHCl ):
ν˜ max ϭ 1720.1 (urea CO), 1683.0 (benzoyl CO), 1453.6 (NO) cmϪ1.
Benzoylureas: N-Benzoyl-NЈ-methylurea was obtained by conden-
sation of methylamine and benzoyl isocyanate, while N-benzoyl-
N,NЈ-dimethylurea was prepared by acylation of N,NЈ-dimeth-
ylurea with benzoyl chloride, by standard literature pro-
Acknowledgments
Financial support from the Xunta de Galicia (PGIDT03-
PXIC20905PN and PGIDIT04TMT209003PR) and the Ministerio
de Ciencia y Tecnolog ´ı a (Project BQU2002-01184 and HP03-34) is
gratefully acknowledged.
[
15,16]
cedures.
N-Benzoyl-NЈ-methylurea: Benzoyl isocyanate (1.50 mL, 11 mmol)
was slowly added at 0 °C, with stirring, to a solution of methyl-
amine in THF (2.0 m, 10 mL, 20 mmol). After 2 h, the reaction
solvents were evaporated to dryness and the crude product was
recrystallized from chloroform/n-hexane to afford N-benzoyl-NЈ-
methylurea as colorless crystals (yield 68.0%), m.p. 168.7Ϫ169.5
[
1] [1a]
Cancer Chemotherapy and Biotherapy (Eds.: B. A. Chabner,
D. L. Longo), 2nd ed., Lippincott-Raven Pub., Philadelphia,
[1b]
1
996.
C. T. Gnewuch, G. Sosnovsky, Chem. Rev. 1997, 97,
8
29Ϫ1013.
[2] [2a]
C. Hansch, A. Leo, C. Schmidt, P. Y. C. Jow, J. Med. Chem.
°
C, in good agreement with literature values.[15] 1H NMR (CDCl
δ ϭ 2.95 (d, 3 H, NHCH ), 7.49 (t, 2 H, 3,5-phenyl-H), 7.59 (t, 1
H, 4-phenyl-H), 7.98 (d, 2 H, 2,6-phenyl-H), 8.67 (br. s, 1 H,
3
):
1980, 23, 1095Ϫ1101.
McLaughlin, J. Med. Chem. 1980, 23, 798Ϫ805.
3] [3a]
[2b]
J. W. Lown, A. V. Joshua, L. W.
3
[
N. Buckley, T. P. Brent, J. Am. Chem. Soc. 1988, 110,
520Ϫ7529. [ A. Naghipur, M. G. Ikonomou, P. Kebarle, J.
3b]
7
NHCH
3
), 9.57 (br. s, 1 H, PhCONH) ppm. MS (EI): m/z ϭ 178.2
[
3c]
ϩ
ϩ
W. Lown, J. Am. Chem. Soc. 1990, 112, 3178Ϫ3187.
Buckley, J. Am. Chem. Soc. 1987, 109, 7918Ϫ7920.
N.
[
M ], 104.9 [PhCO ]. IR (KBr): ν˜ max ϭ 1707.0 (urea CO), 1683.0
Ϫ1
(benzoyl CO) cm .
[4]
R. L. Wurdeman, K. M. Church, B. Gold, J. Am. Chem. Soc.
1989, 111, 6408Ϫ6412.
N-Benzoyl-N,NЈ-dimethylurea: Benzoyl chloride (1.2 mL, 10 mmol)
was added to N,NЈ-dimethylurea (0.88 g, 10 mmol) dissolved in an-
hydrous pyridine (10 mL). The reaction mixture was heated at re-
flux for 3 h and was then poured into cold HCl solution (1.0 m,
[
[
5]
6]
J. K. Snyder, L. M. Stock, J. Org. Chem. 1980, 45, 1990Ϫ1999.
J. W. Lown, S. M. S. Chauhan, J. Org. Chem. 1981, 46,
5309Ϫ5321.
[7] [7a]
E. R. Garrett, S. Goto, Chem. Pharm. Bull. 1973, 21,
100mL). The precipitate was recrystallized from chloroform/hexane
[7b]
1811Ϫ1823.
E. R. Garrett, S. Goto, J. F. Stubbins, J. Pharm.
to afford N-benzoyl-N,NЈ-dimethylurea as colorless crystals (yield
Sci. 1965, 54, 119Ϫ123.
6
9.3%), m.p. 97.4Ϫ99.3 °C, again in good agreement with literature
[8] [8a]
S. M. Hecht, J. W. Kozarich, J. Org. Chem. 1973, 38,
[
15] 1
[8b]
values.
H NMR (CDCl
3
): δ ϭ 2.93 (s, 3 H, PhCONCH
3
), 3.18
1821Ϫ1824.
S. M. Hecht, J. W. Kozarich, Tetrahedron Lett.
(
d, 3 H, NHCH
NHCH ). MS (EI): m/z ϭ 191.9 [M ], 105.1 [PhCO ]. IR (KBr):
ν˜ max ϭ 1707.0 (urea CO), 1629.0 (benzoyl CO) cm
3
), 7.46 (m, 5 H, phenyl-H), 9.04 (br. s, 1 H,
1972, 5147Ϫ5150.
ϩ
ϩ
[9] [9a] K. Yoshida, K. Yano, Bull. Chem. Soc., Jpn. 1982, 55,
3
2200Ϫ2203. [ K. Yoshida, K. Yano, K. Nagamatsu, J. Chem.
9b]
Ϫ1
.
Soc., Perkin Trans. 2 1985, 437Ϫ442.
[
10]
11]
12]
Kinetics: Most kinetics were recorded with Milton Roy Spectronic
000 Diode Array and Shimadzu UV-2100 spectrophotometers fit-
S. Amado, L. Garc ´ı a-R ´ı o, J. R. Leis, A. R ´ı os, J. Chem. Soc.,
Perkin Trans. 2 1996, 2235Ϫ2239.
3
[
[
W. M. Jones, D. L. Muck, T. K. Tandy Jr., J. Am. Chem. Soc.
ted with multiple thermostatted cell carriers. Kinetic runs were trig-
gered by injection of a small aliquot of a stock solution of the
nitrosourea in dioxane into the reaction medium, ensuring an in
situ nitrosourea concentration of 1.0 ϫ 10Ϫ4 m and a final dioxane
concentration of 1% (v/v). The faster reactions (pH Ն 11) were
monitored with an Applied Photophysics DX17MV sequential
stopped-flow spectrophotometer. All experiments were carried out
at 25 °C under pseudo-first order conditions, with a large deficit
1
966, 88, 68Ϫ74.
G. Hallett, D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2
980, 1372Ϫ1375.
1
[13]
[14]
J. Casado, A. Castro, F. M. Lorenzo, F. Meijide, M. Mosquera,
Bull. Soc. Chim. Fr. 1985, 597Ϫ601.
M. Isobe, Bull. Chem. Soc., Jpn. 1984, 57, 601Ϫ602.
C. G. Newton, W. D. Ollis, D. E. Wright, J. Chem. Soc., Perkin
Trans. 1 1984, 75Ϫ84.
[15]
160
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