LETTER
Hindered Aryl Malononitriles
3169
aryl halides proceeded with only slightly lower yields.
Problems only arose in cases where the substituents are
base sensitive, e.g. with 4-bromobenzonitrile or 4-bromo-
acetophenone (entries 10 and 11). The procedure is also
applicable for heteroaromatic bromides such as 2-bromo-
pyridine (entry 12), while chloro arenes did not react
under these conditions (see entry 9). However, with a
more activating ligand such as the secondary diada-
mantylphosphine which was found to be very effective for
various coupling reactions of aryl chlorides,11 good to
medium yields were obtained (entries 13 and 14), while 2-
chloropyridine gave only 23% yield (result not shown).
References and Notes
(1) (a) Cederbaum, F.; Brunner, H. G.; Boeger, M. WO 9216510
A1, 1992; Chem. Abstr. 1993, 118, 38935. (b) Krueger, B.
W.; Fischer, R.; Bertram, H. J.; Bretschneider, T.; Boehm,
S.; Krebs, A.; Schenke, T.; Santel, H. J.; Luerssen, K. DE
4109208, 1992; Chem. Abstr. 1993, 118, 22227.
(c) Muehlebach, M.; Glock, J.; Maetzke, T.; Stoller, A. WO
9947525 A1, 1999; Chem. Abstr. 1999, 131, 228720.
(d) Muehlebach, M.; Glock, J.; Maetzke, T.; Stoller, A. WO
2000047585A1, 2000; Chem. Abstr. 2000, 133, 164053.
(e) Maetzke, T.; Mutti, R.; Szczepanski, H. WO 2000078881
A2, 2000; Chem. Abstr. 2000, 134, 56699.
(2) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Chem. Eur. J. 2004, 10, 5607; and references therein.
(3) Cristau, H.-J.; Vogel, R.; Taillefer, M.; Gadras, A.
Tetrahedron Lett. 2000, 41, 8457.
(4) Uno, M.; Seto, K.; Takahashi, S. J. Chem. Soc., Chem.
Commun. 1984, 932.
(5) This method indeed worked well in our hands for the
preparation of 2 using substrate 1b (58% yield), but failed
completely when the technically more suitable bromide 1a
was used.
(6) Gao, C.; Tao, X.; Qian, Y.; Huang, J. Synlett 2003, 1716.
(7) Gao, C.; Tao, X.; Qian, Y.; Huang, J. Chem. Commun. 2003,
1414.
(8) (a) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
(b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J.
Am. Chem. Soc. 2000, 122, 1360.
In conclusion, we have developed a convenient and
general protocol, which allows the preparation of a wide
variety of substituted aryl malononitriles starting from the
corresponding aryl bromides or even aryl chlorides.
Compared to most other methodologies, good yields are
obtained at much lower catalyst loadings with reasonable
reaction times. The catalyst is easy to prepare from
relatively cheap palladium chloride and the readily
available PCy3 ligand. The reaction using aryl bromide 1a
was carried out on a 100 kg scale, demonstrating that the
method is easy to scale up for technical applications.
Acknowledgment
(9) Standard Experiment.
Malononitrile (181 mg, 2.75 mmol), t-BuONa (720 mg, 7.5
mmol) and xylene (13 mL) were stirred in a Schlenk tube
under argon at r.t. for 1 h. Aryl halide (2.5 mmol) and a
mixture of PdCl2 (2.5 mmol) and PCy3 (17.5 mmol) in xylene
(2 mL) were added and the reaction mixture was stirred at
the required temperature. For the experiments described in
Table 2, the product was extracted with NaOH solution and
after acidification with HCl, was isolated by filtration. The
1H NMR spectra of all products were in agreement with the
proposed structures.
We thank Roman Portmann and Marcel Uebelhart (Solvias) for
careful experimental work.
(10) Zapf, A.; Beller, M. Chem. Eur. J. 2000, 6, 1830.
(11) Schnyder, A.; Aemmer, T.; Indolese, A. F.; Pittelkow, U.;
Studer, M. Adv. Synth. Catal. 2002, 344, 495.
Synlett 2006, No. 18, 3167–3169 © Thieme Stuttgart · New York