1
254
E. Vickerstaffe et al.
LETTER
Spectroscopic Data for 3
Pale brown solid (19.7 mg, 99%); mp 109–110 °C (lit. 108 °C);
A.; Rossi, R. Synthesis 2004, 2419. (c) Miura, M. Angew.
Chem. Int. Ed. 2004, 43, 2201.
1
5
R = 0.51 [EtOAc–hexane (1:9)]. IR n = 2913 (CH), 1606 (C=C),
(4) (a) Okamoto, K.; Akiyama, R.; Kobayashi, S. Org. Lett.
2004, 6, 1987. (b) Akiyama, R.; Kobayashi, S. J. Am. Chem.
Soc. 2003, 125, 3412. (c) Djakovitch, L.; Koehler, K. J.
Mol. Catal. A: Chem. 1999, 142, 275. (d) Trost, B. M.;
Keinan, E. J. Am. Chem. Soc. 1978, 100, 7779. (e) FibreCat
1001 is available from Johnson Matthey. (f) Polymer-
supported Pd(PPh ) is available from Biotage AB.
f
max
–
1
+
1
1
499 (C=C), 1250 (CO) cm . HRMS: m/z calcd for C H O [M] :
14 14
1
98.1044; found: 198.1047. H NMR (400 MHz, CDCl ): d = 7.50
3
(
d, 2 H, J = 9 Hz, ArH), 7.44 (d, 2 H, J = 8 Hz, ArH), 7.22 (d, 2 H,
J = 8 Hz, ArH), 6.96 (d, 2 H, J = 9 Hz, ArH), 3.84 (s, 3 H, OCH ),
3
1
3
2
1
.38 (s, 3 H, ArCH3). C NMR (125 MHz, CDCl ): d = 158.9 (C),
3
38.0 (C), 136.3 (C), 133.7 (C), 129.4 (CH), 127.9 (CH), 126.6
3
4
(
[
CH), 114.1 (CH), 55.3 (CH ), 21.0 (CH ). MS (EI+): m/z = 198
(5) (a) Ramarao, C.; Ley, S. V.; Smith, S. C.; Shirley, I. M.;
DeAlmeida, N. Chem. Commun. 2002, 1132. (b) Ley, S. V.;
Ramarao, C.; Gordon, R. S.; Holmes, A. B.; Morrison, A. J.;
McConvey, I.; Shirley, I. M.; Smith, S. C.; Smith, M. D.
3
3
+
M] . HPLC: t = 6.46 min (98%; 254 nm).
R
General Microwave Procedure for Suzuki Couplings
A solution of the aryl halide in degassed DMF (1 mL, 0.1 M) and
the boronic acid in degassed DMF (1 mL, 0.2 M) were added to a
sealed microwave tube containing MP-Carbonate (200 mg) and
Pd(OAc) EnCat (6.3 mg, 2.5 mol%). Then, H O (100 mL) and a so-
Chem. Commun. 2002, 1134. (c) Pd(OAc) EnCat™ is
available from Sigma Aldrich.
2
(6) Standard solution-phase conditions employed for Suzuki
coupling reaction: To a solution of 4-iodoanisole (1 mmol)
and 4-tolylboronic acid (2 mmol) in DMF (10 mL) was
added Na CO (0.4 mmol), H O (2 mL) and
2
2
lution of Et N in DMF (60 mL, 0.35 M) were added to the reaction
3
vessel and the reaction mixture was irradiated at a set temperature
of 120 °C for 15 min with stirring using a Biotage Emrys micro-
wave reactor. The reaction mixture was filtered and the resins
washed with DMF (3 ꢀ 3 mL). The organic filtrates were combined
and the solvent removed in vacuo. The residue was then redissolved
in DMF (2.5 mL) and incubated with PS-DEAM (179 mg, 0.3
mmol) for 4 h at r.t., with high-speed vortexing (800 rpm). The re-
action mixture was filtered and the resin washed with DMF (3 ꢀ 3
mL). The organic filtrates were combined and the solvent removed
in vacuo to yield the biaryl products.
2
3
2
Pd(OAc) EnCat™ (5 mol%, based on palladium content).
2
The reaction mixture was stirred at 85 °C for 18 h.
(7) MP-Carbonate was obtained from Sigma-Aldrich with a
reported loading of 2.5–3.5 mmol/g.
(8) Lan, P.; Berta, D.; Porco, J. A.; South, M. S.; Parlow, J. J. J.
Org. Chem. 2003, 68, 9678.
(9) (a) Hall, D. G.; Tailor, J.; Gravel, M. Angew. Chem. Int. Ed.
1999, 38, 3064. (b) Bolton, G. L.; Booth, R. J.; Cresswell,
M. W.; Hodges, J. C.; Warmus, J. S.; Wilson, M. W.;
Kennedy, R. M. WO 9742230, 1997. (c) N,N-Diethanol-
aminomethyl polystyrene (PS-DEAM) was obtained from
Biotage AB.
Acknowledgment
(
10) Although the water present could be removed using
anhydrous molecular sieves, a more reliable and pragmatic
procedure proved to be co-evaporation prior to redissolution
in DMF.
GlaxoSmithKline is gratefully acknowleged for generous financial
support of this work. The European Community is thanked for a
Marie Curie Industry Host Fellowship (to A.-L. V.; contract number
HPMI-CT-2001-00118).
(
11) (a) Wang, Y.; Sauer, D. R. Org. Lett. 2004, 6, 2793. For
recent reviews of microwave chemistry, see: (b) Kappe, C.
O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2006. (c) Kappe, C. O.
Angew. Chem. Int. Ed. 2004, 43, 6250. (d) Lidströmm, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57,
9225. (e) Perreux, L.; Loupy, A. Tetrahedron 2001, 57,
9199. (f) Microwave reactions were performed using an
References and Notes
(
1) Recent reviews include: (a) Suzuki, A. Chem. Commun.
005, 38, 4759. (b) Miyaura, N. In Metal-Catalyzed Cross-
2
Coupling Reactions, 2nd ed., Vol. 1; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004, 41–123.
®
(c) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
Emrys synthesiser available from Biotage AB.
M. Chem. Rev. 2002, 102, 1359. (d) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633. (e) Littke, A. F.;
Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176.
(12) Microwave temperatures were measured externally to the
reactor vial using the IR sensor fitted to the Emrys®
synthesiser. It is extremely unlikely that these values
accurately reflect the significantly higher localised
temperatures attained at the catalyst metal surface under
microwave irradiation.
(13) Palladium residue levels were determined using inductively
coupled plasma optical emission spectroscopy performed on
4¢-methoxy-4-methylbiphenyl(3) for both thermal and
microwave reactions and indicated residual palladium levels
(
2) For example: (a) Murray, T. K.; Whalley, K.; Robinson, C.
S.; Ward, M. A.; Hicks, C. A.; Lodge, D.; Vandergriff, J. L.;
Baumbarger, P.; Siuda, E.; Gates, M.; Ogden, A. M.;
Skolnick, P.; Zimmerman, D. M.; Nisenbaum, E. S.;
Bleakman, D.; O’Neill, M. J. J. Pharmacol. Exp. Ther. 2003,
306, 752. (b) Faghih, R.; Dwight, W.; Pan, J. B.; Fox, G. B.;
Krueger, K. M.; Esbenshade, T. A.; McVey, J. M.; Marsh,
K.; Bennani, Y. L.; Hancock, A. A. Bioorg. Med. Chem.
Lett. 2003, 13, 1325. (c) Hajduk, P. J.; Bures, M.;
in 3 corresponding to Pd leaching from Pd(OAc) EnCat™ to
2
be 2.1% and 1.7%, respectively.
(14) High-speed vortexing was performed using a DESYRE -
®
Praetgaard, J.; Fesik, S. W. J. Med. Chem. 2000, 43, 3443.
3) (a) O’Brien, C. J.; Kantchev, E. A. B.; Hadei, N.; Valente,
C.; Chass, G. A.; Lough, A.; Hopkinson, A. C.; Organ, M.
G. Chem. Eur. J. 2006, 12, 4743. (b) Bellina, F.; Carpita,
(
MIX vortexer, available from Zinsser Analytic GmbH.
(15) Tamura, Y.; Chun, M. W.; Inoue, K.; Minamikawa, J.
Synthesis 1978, 822.
Synlett 2007, No. 8, 1251–1254 © Thieme Stuttgart · New York