2596
J. Mahdi et al. / Tetrahedron Letters 52 (2011) 2594–2596
In the first step, the 2-chloro derivatives of benzoic acid (2) and
Supplementary data
phenylacetic acid (4) were acylated to the corresponding acid chlo-
rides 3 and 5 in the presence of cyanuric chloride (1), pyridine and
DCM using microwave radiation for 15 min at 50 °C (Scheme 1).
After the reaction mixture was completed (as determined by
GC/MS), the mixture cooled to 30 °C, and AlCl3 or FeCl3 (2 M equiv)
was added directly to the reaction mixture, which was then irradi-
ated in the microwave for 5 min at 30 °C at 250 psi (powermax on).
It should be noted that when AlCl3 or FeCl3 was added to the acid
chloride and spun conventionally with the use of a vortex mixer, it
took 20–25 min for the AlCl3 to completely dissolve. Hence, the use
of microwave heating significantly decreased the time needed for
the reaction to take place. Finally, after the formation of the alu-
mina complex, benzene, toluene, or anisole was added and the
resulting mixture was irradiated in the microwave at 70 °C for
15 min to give desired ketones 6 and 7, respectively. These last
two steps are shown in Scheme 2.
As shown in Table 1, using AlCl3 as catalyst, the benzophenones
(entries 1–10) were formed in yields ranging between 98% and
55%, whereas the acetophenones (entries 11–15) were formed in
yields ranging between 98% and 58%. The structures of the ketones
are listed in Table 1, and were supported by GC/MS, 1H NMR, 13C
NMR and IR spectroscopy. Some of the reactions listed in the table
were run using FeCl3 a more environmentally friendly catalyst than
AlCl3. As shown, the FeCl3 catalyzed reactions gave pure ketones in
similar yields (93–51%); however, dissimilar to FeCl3 catalyzed
reactions, in AlCl3 catalyzed reactions crude mixtures containing
an unknown impurity was obtained, which then had to be purified
by column chromatography. The products were identified on the
basis of 1H NMR, 13C NMR, and GC/MS.
Supplementary data associated with this article can be found, in
Reference and notes
1. See for example: Rais, A.; Ankati, H.; Biehl, E. Trends Heterocycl. Chem. 2009, 14,
17–19.
2. Kangani, C. O.; Day, B. W. Org. Lett. 2008, 10, 2645–2648.
3. Paglainni, G.; Cignarella, G.; Testa, E. Farmaco 1965, 20, 686–695.
4. Pfirmann, R.. Eur. Pat. Appl. 1994, 13pp. EP 600317 A1 19940608.
5. Himmler, T.; Kraatz, U.; Kraemer, W.; Stroech, K. Eur. Pat. Appl. 1991, 27 pp. EP
461483 A2 19911218.
6. Begunov, R. S.; Brodskii, I. I.; Kuntasov, A. M. Russ. 2009, 11pp. RU 2365579 C1
20090827.
7. Pepin, R.; Schmitz, C.; Lacroix, G. B.; Dellis, P.; Veyrat, C. Braz. Pedido PI 1990,
174 pp. BR 8904477 A 19900417.
8. Preparation of (2-chloro-4-nitrophenyl)(p-tolyl)methanone (6a). Method A (using
AlCl3): 2-Chloro-4-nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride
(368 mg, 2 mmol) in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol)
and irradiated in the microwave for 15 min at 50 °C. Then, the resulting mixture
was treated with AlCl3 (400 mg, 3.01 mmol) and irradiated in the microwave for
5 min at 30 °C. Finally, 3 mL of toluene was added to the solution and irradiated
in the microwave for 15 min at 70 °C. Then the reaction mixture was poured
onto the ice and filter from Celite. The filtrate was washed with water followed
by brine solution. The separated organic layer was dried on Na2SO4 and
concentrated under reduced pressure to give crude product, which is purified by
column chromatography (98:2 heptane/ethyl acetate) to give the pure white
color product 6a (269.5 mg, 91% yield). Method B (using FeCl3): 2-Chloro-4-
nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride (368 mg, 2 mmol)
in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol) and irradiated in
the microwave for 15 min at 50 °C. Then, the resulting mixture was treated with
FeCl3 (324 mg, 2.0 mmol) and irradiated in the microwave for 5 min at 30 °C.
Finally, 3 mL of toluene was added to the solution and irradiated in the
microwave for 15 min at 70 °C. Then the reaction mixture was filtered from
Celite. The filtrate was washed with sodium thiosulphate followed by brine
solution. The separated organic layer was dried on Na2SO4 and concentrated
In conclusion we have developed a one-pot, 3-step microwave-
assisted reaction for the preparation of novel, titled ketones in
good to excellent yields. A typical example for the preparation of
6a is given.8 The experimental details and physical properties of
the various ketones are listed in the Supplementary data.
under reduced pressure to give pure product 6a (269.5 mg, 93% yield). Mp 110–
1
112 °C (lit.
111.2 °C). 1H NMR (500 MHz, CDCl3): d 2.39 (s, 3H), 7.26 (d,
J = 7.45 Hz, 2H), 7.54 (d, J = 7.45 Hz, 1H), 7.61 (d, J = 6.85 Hz, 2H), 8.26 (dd,
J = 6.85, 2.7 Hz, 1H), 8.30 (d, J = 7.4 Hz, 1H); 13C NMR (500 Hz, CDCl3): d 21.4
(CH3), 122.0 (CH), 125.1 (CH), 129.6 (CH), 129.7 (CH), 130.15 (CH), 132.2 (C),
144.6 (C), 146.2 (C), 148.9 (C), 193.5 (CO); IR (cmÀ1): 638.3, 740.8, 801.5, 836.3,
863.0, 1000.7, 1025.9, 1052.5, 1005.1, 1133.9, 1158.3, 1180.7, 1272.5, 1294.3,
1315.8, 1349.1, 1403.2, 1449.5, 1461.2, 1528.8, 1573.3, 1595.7, 1607.9, 1673.9,
3087.5; GC/MS: 275 [M+]; HRMS: calcd for C14H10ClNO3: 275.0349. Found:
275.0467.
Acknowledgment
This work was sponsored in part by the Welch Grant N-118,
Houston, Texas.