PAPER
Preparation of N,N-Dimethyl-N¢-Arylureas
807
mmol) in anhyd toluene (5 mL) was heated at reflux (110 °C) with
an oil bath, under stirring. After 24 h, GC and H NMR analyses
Acknowledgment
1
This work was supported by the Ministero dell’Università e della
Ricerca Scientifica e Tecnologica (MURST) and the National
Research Council (CNR), Italy, National Project ‘New synthetic
methodologies for industrial intermediates and products’ and by the
University of Turin.
showed that the two reagents were unchanged and no trace of 8e
was present.
Reaction between N,N-Dimethylcarbamoyl Chloride (5) and
3-(Trifluoromethyl)aniline (7, Ar = 3-F3CC6H4) in Anhydrous
Hexane under Reflux or at 60 or 65 °C
1. As described above, N,N-dimethylcarbamoyl chloride (5) was
prepared starting from S-methyl N,N-dimethylthiocarbamate (3;
2.38 g, 20 mmol) and Cl2 (0.71 g, 10 mmol) in anhyd hexane (10
mL). According to procedure A, 5 was then reacted with 3-(trifluo-
romethyl)aniline (7, Ar = 3-F3CC6H4; 1.61 g, 10 mmol), in the pres-
ence of Na2CO3 (2.12 g, 20 mmol) and NaI (0.06 g, 0.4 mmol). The
mixture was heated to reflux (69 °C) with an oil bath and the
References
(1) Professor Emeritus, University of Turin, Italy.
(2) Kirk-Othmer: Encyclopedia of Chemical Technology, 3rd
ed., Vol. 12; Grayson, M.; Eckroth, D., Eds.; John Wiley &
Sons: New York, 1980, 319–324.
(3) For reviews on the synthesis and applications of substituted
ureas, see: (a) Petersen, U. In Houben–Weyl, 4th ed., Vol.
E4; Hagemann, H., Ed.; Thieme: Stuttgart, 1983, 334–367;
and references cited therein. (b) Vishnyakova, T. P.;
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249. (c) Petersen, H. In Ullmann’s Encyclopedia of
Industrial Chemistry, 5th ed., Vol. A27; Elvers, B.;
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(e) Bigi, F.; Maggi, R.; Sartori, G. Green Chem. 2000, 2,
140. (f) Sartori, G.; Maggi, R. In Science of Synthesis, Vol.
18; Knight, J. G., Ed.; Thieme: Stuttgart, 2005, 665–758.
(4) For recent references on synthesis and applications of
substituted ureas, see: Artuso, E.; Degani, I.; Fochi, R.;
Magistris, C. Synthesis 2007, 3497; and references cited
therein.
(5) (a) Todd, C. W. E. I., (du Pont de Nemours & Co., USA); US
2655445, 1953; Chem. Abstr. 1954, 48, 5057. (b) Searle, N.
E. E. I., (du Pont de Nemours & Co., USA); US 2764478,
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(6) (a) Scherer, O.; Hörlein, G.; Schönowsky, H., (Hoechst
Aktiengesellschaft Germany); US 3937726, 1976; Chem.
Abstr. 1976, 85, 192415. (b) Spatz, D. M.; Cross, B.,
(American Cyanamid Co., USA); US 4289903, 1981; Chem.
Abstr. 1982, 96, 6442. (c) Sumitomo Chemical Co., Ltd.,
Japan; JP 56156253, 1981; Chem. Abstr. 1982, 96, 122456.
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1
progress of the reaction was monitored by GC, GC-MS, and H
NMR analyses. Fluometuron (8e) and 1,1,5,5-tetramethyl-3-[3-(tri-
fluoromethyl)phenyl]biuret (15) began to form slowly and both sep-
arated from the reaction mixture as colorless solids, immediately
1
after being formed (GC, GC-MS, and H NMR analyses). Only
traces of compound 15 dissolved in the solvent. After 16 h, 3-(tri-
fluoromethyl)aniline (7, Ar = 3-F3CC6H4) disappeared while part of
the starting N,N-dimethylcarbamoyl chloride (5) was still present in
the hexane soln. The mixture was worked up as described in proce-
dure A. The crude residue consisted of only two products, 8e and
15, which were separated by column chromatography (silica gel,
CH2Cl2–EtOAc, 4:1). This gave pure fluometuron (8e) and pure
1,1,5,5-tetramethyl-3-[3-(trifluoromethyl)phenyl]biuret (15). (GC-
MS analysis of the collected hexane solns showed the presence of
5, dimethyl disulfide {4; m/z = 94 [M+]}, tetramethylurea {m/z =
116 [M+]}, 15 (traces), and other byproducts.)
Yield (8e): 1.72 g (74%, based on 7); mp 161.5–162.6 °C.
Yield (15): 0.39 g (13%, based on 7); mp 144.1–145.5 °C; 147.7–
148.6 °C (recrystallized from EtOH) (Lit.33 140 °C); spectral data
not reported before.
1H NMR (200 MHz, CDCl3): d = 2.90 (s, 6 H, 2 × CH3), 7.16–7.26
(m, 1 H, ArH), 7.26–7.31 (m, 1 H, ArH), 7.42–7.51 (m, 2 H, ArH).
13C NMR (50 MHz, CDCl3): d = 38.8 (CH3), 123.1, 123.2 (CH),
123.9, 124.0 (CH), 117.0, 122.4, 127.8, 133.2 (q, JC–F = 272 Hz,
CF3), 129.6 (CH), 131.4 (CH), 132.3, 132.9, 133.6, 134.2 (q, JC–F
32.8 Hz, C-CF3), 143.0 (C-N), 158.7 (CO).
=
MS (EI, 70 eV): m/z (%) = 303 (15) [M+], 188 (10), 72 (100).
(e) Haeberle, N.; Oeltze, H.; Brader, L., (Dow Chemical Co.,
USA); DE 3638753, 1988; Chem. Abstr. 1988, 109,
149091. (f) Haug, M.; Santel, H. J.; Schmidt, R. R.; Strang,
H., (Bayer AG, Germany); DE 3800269, 1989; Chem. Abstr.
1990, 112, 193779.
2. After the disappearance of 3-(trifluoromethyl)aniline (7, Ar = 3-
F3CC6H4), the above reaction mixture was refluxed for another 8 h,
until N,N-dimethylcarbamoyl chloride (5) had also disappeared.
The above workup afforded pure 8e and pure 15.
(7) (a) Ciba Geigy AG, Switzerland; GB 1407587, 1975; Chem.
Abstr. 1976, 84, 4711. (b) Lamuela, J., (Kemichrom S. L.,
Spain); ES 505400, 1982; Chem. Abstr. 1983, 98, 71722.
(c) Asahi Chemical Industry Co., Ltd., Japan; JP 57169454,
1982; Chem. Abstr. 1983, 98, 53444. (d)Sales Barquets, R.;
Perez Esteban, L.; Martin Recio, R.; Hervas Gayo, A.,
(Industria Espanola de Productos Organicos S. A., Spain);
ES 520096, 1984; Chem. Abstr. 1987, 107, 236251.
(e) Wang, X.; Mei, J.; Lu, S., (Faming Zhuanli Shenqing
Gongkai Shuomingshu); CN 1597663, 2005; Chem. Abstr.
2006, 144, 191981.
Yield (8e): 1.19 g (51%); mp 162.3–163.6 °C; yield (15): 1.15 g
(38%); mp 145.1–146.7 °C.
3. The reaction was carried out as described above (trial reaction 2)
with the only difference that the mixture was heated at 60 °C, in-
stead of at reflux. Also in this case, 3-(trifluoromethyl)aniline (7,
Ar = 3-F3CC6H4) disappeared after 16 h. The above workup afford-
ed pure 8e and pure 15.
Yield (8e): 2.19 g (94%); mp 162.7–163.9 °C; yield (15): 0.15 g
(5%); mp 144–145 °C.
4. The same reaction, carried out at 65 °C for 16 h, afforded pure 8e
and pure 15.
(8) (a) Schroth, W.; Andersch, J.; Schaedler, H.-D.; Spitzner, R.
Chem.-Ztg. 1989, 113, 261; Chem. Abstr. 1990, 112,
157600. (b) Ucb S. A., Belgium; WO 9706134, 1997; Chem.
Abstr. 1997, 126, 211920.
Yield (8e): 1.58 g (68%); mp 163.6–163.8 °C; yield (15): 0.45 g
(15%); mp 146–147 °C.
(9) (a) Goldhamer, D. L.; Onyszkewycz, M.; Wilson, A.
Tetrahedron Lett. 1968, 38, 4077. (b) CIBA Ltd.; GB
1152892, 1969; Chem. Abstr. 1969, 71, 123898. (c) Ihara
Chemical Industry Co., Ltd., Kumiai Chemical Industry Co.,
Synthesis 2009, No. 5, 801–808 © Thieme Stuttgart · New York