H. R. Chobanian et al. / Tetrahedron Letters 47 (2006) 3303–3305
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4. Meligres, P.; Waters, M. S.; Fleitz, F.; Askin, D. Tetra-
hedron Lett. 1999, 40, 8193.
5. Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005,
70, 1508.
6. Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271.
7. Sundermeier, M.; Zapf, A.; Beller, M.; Sans, J. Tetra-
hedron Lett. 2001, 42, 6707.
8. Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984.
9. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685.
suggesting that the oxidative insertion step may be rate-
limiting for less reactive chlorides. The cyanation of
3-chloropyridine (entry 2) also worked well under these
conditions (76% isolated yield in 30 min), while a previ-
ously described attempt using KCN, Pd(OAc)2, DPPPE
and TMEDA7 led to 48% isolated yield of 3-cyanopyri-
dine after 16 h of heating. This new catalyst system is
also amenable to thermal conditions, and comparable
yields of products were obtained after 1 h of heating at
120 °C, underlying ‘unprecedented activity’ of this cata-
lyst system previously reported by Buchwald.9 Not sur-
prisingly, these conditions can also be applied to the
conversion of aryl bromides to aryl cyanides (entry 7,
81% yield under microwave-assisted conditions and
94% under thermal conditions).
10. General experimental conditions:
Microwave: 1 (500 mg, 2.2 mmol), (79 mg, 009 mmol), S-
Phos (89 mg, 0.2 mmol), Zn(CN)2 (300 mg, 2.5 mmol)
were dissolved in 10 mL 99:1 v/v DMF/H2O in a 20 mL
microwave vial. The solution was degassed with N2 for
10 min before being capped and heated in the microwave
reactor for 30 min at 150 °C. Once complete, the reaction
was diluted with 1 N NaOH (40 mL) and EtOAc
(100 mL). The EtOAc layer was removed, dried over
MgSO4, filtered, and concentrated giving rise to an oil.
The oil was purified via silica gel chromatography (5–40%
EtOAc/hexanes) and concentrated under reduced pressure
to yield 462 mg (97%) of 2 as a white solid.
Thermal: 1 (500 mg, 2.2 mmol), Pd2(dba)3 (79 mg, 009
mmol), S-Phos (89 mg, 0.2 mmol), Zn(CN)2 (300 mg,
2.5 mmol) were dissolved in 20 mL 99:1 v/v DMF/H2O.
The solution was degassed with N2 for 10 min before being
heated to 120 °C for 1 h. Once complete, the reaction was
purified as described above.
In summary, we have shown that palladium-catalyzed
cyanation of aryl chlorides can be performed readily by
use of the commercially available S-Phos ligand under
either microwave-assisted or thermal conditions.10–12
The reaction is general for a variety of substrates and
can also be applied to aryl bromides.
References and notes
1. Merck Summer Research Intern, University of Montana,
Missoula, MT.
2. (a) Schareina, T.; Zapf, A.; Beller, M. J. Organomet.
Chem. 2004, 689, 4576; (b) Sundermeier, M.; Zapf, A.;
Mutyala, S.; Baumann, W.; Sans, J.; Weiss, S.; Beller, M.
Chem. Eur. J. 2003, 9, 1828.
11. S-Phos ligand was purchased from Strem Chemicals Inc.,
7 Mulliken Way, Dexter Industrial Park, Newburyport,
MA 01950.
12. The catalyst loading for the microwave was lowered to
1 mol % Pd2(dba)3 and 2 mol % S-Phos for the conversion
of 1 to 2 without any significant change in yield or reaction
time.
3. Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837.