of diarylmethanes via VNS reaction of nucleophiles of type
1 in which the electron-withdrawing group comprises one
of the aryl groups. The new method described below is
ideally suited for the synthesis of functionalized diaryl-
methanes in which only one of the aryl groups is introduced
in the VNS reaction.
Scheme 2. Three-Component VNSAr-SNAr Coupling Reaction
We now report that the anion 2 can be arylated by the
reaction with substituted ortho-halonitroarenes. The process
not only is efficient but also uniquely combines two different
sequential modes of aromatic nucleophilic substitution.
Reaction of ethyl 2-chloropropionate (4a) with nitroben-
zene in the presence of NaH gave the usual dark blue-colored
solution of the intermediate anion 2 (Scheme 1). Addition
of 2,4-dinitrofluorobenzene (5a) in DMF resulted in rapid
decolorization of the solution. The desired diarylmethane 3a
1
was isolated in 77% yield (Scheme 2).11 The H NMR
spectrum clearly indicated the presence of both a 1,4-
disubstituted and 1,2,4-trisubstituted aryl group.12 This is
consistent with the expected para-selective VNS reaction
followed by SNAr process.
To explore the scope of the reaction, a number of simple
esters 4a-c were combined with nitrobenzene and different
SNAr electrophiles 5a-d under the reaction conditions
described above. The results shown in Table 1 clearly
Diarylmethanes are extremely useful synthetic intermedi-
ates,7 and the diarylmethyl motif is found in many pharma-
cologically important agents.8 A versatile route to this
important scaffold incorporating several points of diversity
is potentially useful. The diarylmethyl group is also embed-
ded within many important drugs, e.g., 3-arylindole deriva-
tives. Makosza9 and Katritzky10 have described the synthesis
Table 1. Yields of Product Diarylmethyl Sulfones 8a-h
R1
R3
R4
yield (%)
a
b
c
d
e
f
Cl
Cl
Cl
Cl
CF3
CF3
CF3
CF3
NO2
NO2
CN
CF3
NO2
NO2
CN
NO2
CF3
NO2
NO2
NO2
CF3
NO2
NO2
74
75
74
75
79
81
78
78
(3) Kabachnik, M. I.; Lobanov, D. I.; Matveeva, A. G.; Kovsheva, O.
E.; Terekhova, M. I.; Petrov, E. S.; Petrovskii, P. V.; Matrosov, E. I. IzV.
Akad. Nauk SSSR, Ser. Khim. 1991, 1598-1604.
(4) Olstead, W. N.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3299-
3305;
(5) Gurjar, M.; Reddy, D. S.; Murugaiah, A.; Murugaiah, S. Synthesis
2000, 1659-1661. Selvakumar, N.; Reddy, B. Y.; Kumar, G. S.; Iqbal, J.
Tetrahedron Lett. 2001, 42, 8395-8398.
g
h
CF3
(6) Bluhm, A. L.; Sousa, J. A.; Weinstein, J. J. Org. Chem. 1964, 29,
636-640. Borsche, W.; Fiedler, A. Chem. Ber. 1913, 46, 2117-2131.
Wrobel, Z.; Wojciechowski, K. Pol. J. Chem. 1992, 66, 1125-1129. Cheng,
X.-M.; Lee, C.; Klutchko, S.; Winters, T.; Reynolds, E. E.; Welch, K. M.;
Flynn, M. A.; Doherty, A. M. Bioorg. Med. Chem. Lett. 1996, 6, 2999-
3002.
(7) For examples: (a) Itami, K.; Mineno, M.; Kamei, T.; Yoshida, J.
Org. Lett. 2002, 4, 3635-3638. (b) Hermanns, N.; Dahmen, S.; Bolm, C.;
Brase, S. Angew. Chem., Int. Ed. 2002, 41, 3692-3694. (c) Vanier, C.;
Lorge, F.; Wagner, A.; Mioskowski, C. Angew. Chem., Int. Ed. 2000, 39,
1679-1683.
indicate that the process is general and efficient. The
efficiency of the SNAr process is high, as the yields are close
to that expected for the protonation of the anion 2.2 The use
of activated arenes 5a-d allows the SNAr reaction to proceed
conveniently at ambient temperature, avoiding the need for
(10) Katritzky, A. R.; Toader, D. J. Org. Chem. 1997, 62, 4137-4141.
(11) General Procedure for the VNSAr-SNAr Reaction. Sodium
hydride (60% dispersion in oil) (0.813 g, 20.3 mmol) was added to
anhydrous DMF (5 mL) and the mixture flushed with nitrogen and cooled
to 0 °C. Chloroester 4 (8.13 mmol) and nitrobenzene (0.84 mL, 8.13 mmol)
were dissolved in anhydrous DMF (5 mL) and added dropwise to the sodium
hydride slurry. The reaction mixture was stirred at 0 °C for 30 min and
then allowed to warm to room temperature. The reaction mixture was then
cooled back to 0 °C using an ice-cooling bath. Aryl halide 5 (8.13 mmol)
in anhydrous DMF (2 mL) was then added, and the resulting mixture was
allowed to warm to room temperature and stirred for a further 2 h. The
reaction mixture was poured onto ice/hydrochloric acid (50 mL, 1 M
solution) and extracted with dichloromethane (3 × 30 mL). The combined
organic extracts were washed well with distilled water (5 × 50 mL) and
then saturated aqueous sodium bicarbonate solution (3 × 50 mL) and dried
(magnesium sulfate), and the solvent was removed under reduced pressure
to give the crude product, which was purified by column chromatography
(12) Other characterization data (e.g., 13C NMR, MS, IR) support the
product assignment.
(8) For examples: (a) Plobeck, N.; Delorme, D.; Wei, Z. Y.; Yang, H.;
Zhou, F.; Schwarz, P.; Gawell, L.; Gagnon, H.; Pelcman, B.; Schmidt, R.;
Yue, S. Y.; Walpole, C.; Brown, W.; Zhou, E.; Labarre, M.; Payza, K.;
St-Onge, S.; Kamassah, A.; Morin, P. E.; Projean, D.; Ducharme, J.; Roberts,
E. J. Med. Chem. 2000, 43, 3878-3894. (b) Hsin, L. W.; Dersch, C. M.;
Baumann, M. H.; Stafford, D.; Glowa, J. R.; Rothman, R. B.; Jacobson, A.
E.; Rice, K. C. J. Med. Chem. 2002, 45, 1321-1329. (c) Wai, J. S.;
Egbertson, M. S.; Payne, L. S.; Fisher, T. E.; Embrey, M. W.; Tran, L. O.;
Melamed, J. Y.; Langford, H. M.; Guare, J. P.; Zhuang, L. G.; Grey, V. E.;
Vacca, J. P.; Holloway, M. K.; Naylor-Olsen, A. M.; Hazuda, D. J.; Felock,
P. J.; Wolfe, A. L.; Stillmock, K. A.; Schleif, W. A.; Gabryelski, L. J.;
Young, S. D. J. Med. Chem. 2000, 43, 4923-4926. (d) Hewawasam, P.;
Gribkoff, V. K.; Pendri, Y.; Dworetzky, S. I.; Meanwell, N. A.; Martinez,
E.; Boissard, C. G.; Post-Munson, D. J.; Trojnacki, J. T.; Yeleswaram, K.;
Pajor, L. M.; Knipe, J.; Gao, Q.; Perrone, R.; Starrett, J. E. Bioorg. Med.
Chem. Lett. 2002, 12, 1023-1026.
(9) Makosza, M.; Surowiec, M.; Voskresensky, S. Synthesis 2000, 1237-
1240.
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Org. Lett., Vol. 6, No. 26, 2004