Pd-P(t-Bu)3-Catalyzed Consecutive
Cross-Coupling of p-Phenylenedizinc Compound
with Two Different Electrophiles Leading to
Unsymmetrically 1,4-Disubstituted Benzenes
Takahiro Kawamoto, Shogo Ejiri, Kana Kobayashi,
Shunsuke Odo, Yasushi Nishihara, and Kentaro Takagi*
Department of Chemistry, Faculty of Science, Okayama
FIGURE 1. Synthesis of p-disubstituted benzenes.
UniVersity, Tsushima, Okayama 700-8530, Japan
partners provides 1 with an unsymmetrical structure, in which
the greater the difference in reactivity between the two leaving
groups X1 and X2, the higher the degree of selectivity in the
transformation of 2 to the desired product. Thus, in such
reactions, the synthetic equivalents of 3b (possessing X1 ) I or
Br and X2 ) B, Zn, Mg, or Sn2) or 3c (possessing X1 ) I and
X2 ) Br or OTf3) have been generally employed, whereas those
of 3a have been little utilized, presumably because of the
difficulty in preparing 2 with two different kinds of elec-
trofuges.4 Hereupon, it is noted that, even if the electrofuges
are the same, i.e., X1 ) X2, the chemoselective coupling on
one site is essentially possible; the reactivity of the singly
coupled product 4 is no longer the same as that of the starting
material. Thus far, the transformations using the synthetic
equivalents of 3a have been carried out using B or Sn derivatives
along with the catalysis by Pd, thus affording unsymmetrical
terphenyls in the low yields of 13-33% by the consecutive
treatment with two kinds of aryl iodides.1f,h,n We envisaged that
the efficiency of the transformations might be improved by
making use of the more positively charged X1, causing a greater
difference between the reactivities of 2 and 4. As a metal, we
were interested in Zn (EN: B ) 2.0; Sn ) 1.8; Zn ) 1.7). We
previously reported that the reaction between iodobenzenes and
zinc powder smoothly takes place in N,N,N′,N′-tetramethylurea
(TMU) to afford the corresponding arylzinc compounds in good
ReceiVed September 26, 2007
Pd-P(t-Bu)3 was found to be a chemoselectiVe catalyst for
the reaction of p-phenylenedizinc compound with equimolar
amounts of carbon electrophiles to afford the single cross-
coupling products in good yields, effectively suppressing the
formation of double cross-coupling products. The subsequent
additions of other electrophiles to the resulting solutions
caused the second cross-coupling of the incipient products
to take place, achieving a novel and efficient one-pot
synthesis of unsymmetrically 1,4-disubstituted benzenes. The
origin of the observed high chemoselectivity was speculated.
As a synthetic method of disubstituted benzenes 1, the cross-
coupling reaction between phenylene-supplying reagents 2,
synthetic equivalents of 3a-c, and their electronically matching
counterparts is useful, since the products are entirely free from
contamination by any regioisomers (Figure 1).1 In the reaction,
the consecutive treatment of 2 with two kinds of coupling
(2) X1, X2 ) B, Br: (a) Shimada, S.; Yamazaki, O.; Tanaka, T.; Rao,
M. L. N.; Suzuki, Y.; Tanaka, M. Angew. Chem., Int. Ed. 2003, 42, 1845-
1848. (b) Simoni, D.; Giannini, G.; Baraldi, P. G.; Romagnoli, R.; Roberti,
M.; Rondanin, R.; Baruchello, R.; Grisolia, G.; Rossi, M.; Mirizzi, D.;
Invidiata, F. P.; Grimaudo, S.; Tolomeo, M. Tetrahedron Lett. 2003, 44,
3005-3008. X1, X2 ) Zn, Br or I: (c) Amatore, C.; Jutand, A.; Negri, S.;
Fauvarque, J.-F. J. Organomet. Chem. 1990, 390, 389-398. (d) Krasovskiy,
A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 6040-6044. X1, X2 ) Li, Br: (e) Banwell, M. G.; Flynn, B. L.;
Hamel, E.; Hockless, D. C. R. Chem. Commun. 1997, 207-208. X1, X2 )
Mg, Br or I: (f) Yang, X.; Rotter, T.; Piazza, C.; Knochel, P Org. Lett.
2003, 5, 1229-1231. (g) Krasovskiy, A.; Knochel, P. Angew. Chem. Int.
Ed. 2004, 43, 3333-3336. X1, X2 ) Bi, Br: (h) Rasmussen, L. K.; Begtrup,
M.; Ruhland, T. J. Org. Chem. 2006, 71, 1230-1232.
(3) See for example: X1, X2 ) I, Br or Cl: (a) Pena, M. A.; Perez, I.;
Sestelo, J. P.; Sarandeses, L. A. Chem. Commun. 2002, 2246-2247. (b)
Duan, X.-F.; Li, X.-H.; Li, F.-Y.; Huang, C.-H. Synthesis 2004, 2614-
2616. References 1p and 2b. X1, X2 ) OTf or I, Br or Cl (c) Ohe, T.;
Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-2208. (d) Rottla¨nder,
M.; Palmer, N.; Knochel, P. Synlett 1996, 573-575. (e) Fu¨rstner, A.; Leitner,
A. Angew. Chem., Int. Ed. 2003, 42, 308-311. (f) Cho, C.-H.; Kim, I.-S.;
Park, K. Tetrahedron 2004, 60, 4589-4599. (g) Cho, C.-H.; Park, H.; Park,
M.-A.; Ryoo, T.-Y.; Lee, Y.-S.; Park, K. Eur. J. Org. Chem. 2005, 3177-
3181.
(1) See for example: X1, X2 ) Cl, Cl: (a) Mao, L. S.; Sakurai, H.;
Hirao, T. Synthesis 2004, 2535-2539. X1, X2 ) Br, Br: (b) Wu, C.-J. J.;
Xue, C.; Kuo, Y.-M.; Luo, F.-T. Tetrahedron 2005, 61, 4735-4741. (c)
Dong, C.-G.; Hu, Q.-S. J. Am. Chem. Soc. 2005, 127, 10006-10007. (d)
Uozumi, Y.; Kikuchi, M. Synlett 2005, 1775-1778. X1, X2 ) I, I: (e)
Sinclair, D. J.; Sherburn, M. S. J. Org. Chem. 2005, 70, 3730-3733. X1,
X2 ) B, B: (f) Todd, M. H.; Balasubramanian, S.; Abell, C. Tetrahedron
Lett. 1997, 38, 6781-6784. (g) Ba¨hr, A.; Felber, B.; Schneider, K.;
Diederich, F. HelV. Chim. Acta 2000, 83, 1346-1376. (h) Iovine, P. M.;
Kellett, M. A.; Redmore, N. P.; Therien, M. J. J. Am. Chem. Soc. 2000,
122, 8717-8727. (i) Chaumeil, H.; Le Drian, C.; Defoin, A. Synthesis 2002,
757-760. (j) Thiemann, T.; Umeno, K.; Wang, J.; Tabuchi, Y.; Arima, K.;
Watanabe, M.; Tanaka, Y.; Gorohmaru, H.; Mataka, S. J. Chem. Soc., Perkin
Trans. 1 2002, 2090-2110. (k) Perret-Aebi, L.-E.; von Zelewsky, A. Synlett
2002, 773-774. (l) Kalai, T.; Balog, M.; Jeko, J.; Hubbell, W. L.; Hideg,
K. Synthesis 2002, 2365-2372. (m) Mandolesi, S. D.; Vaillard, S. E.;
Podesta, J. C.; Rossi, R. A. Organometallics 2002, 21, 4886-4888. (n)
Havelkova, M.; Dvorak, D.; Hocek, M. Tetrahedron 2002, 58, 7431-7435.
X1, X2 ) Sn, Sn: (o) Siesel, D. A.; Staley, S. W. J. Org. Chem. 1993, 58,
7870-7875. (p) Bao, Z.; Chan, W. K.; Yu, L. J. Am. Chem. Soc. 1995,
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232. (r) Corsico, E. F.; Rossi, R. A. J. Org. Chem. 2002, 67, 3311-3316.
Reference 1m.
(4) X1, X2 ) Si, Sn: (a) Nitschke, J. R.; Zu¨rcher, S.; Tilley, T. D. J.
Am. Chem. Soc. 2000, 122, 10345-10352. X1, X2 ) Mg, B prepared
successively: (b) Christophersen, C.; Begtrup, M.; Ebdrup, S.; Petersen,
H.; Vedso, P. J. Org. Chem. 2003, 68, 9513-9516. X1, X2 ) Mn, Mn
prepared successively: (c) Rieke, R. D.; Kim, S.-H.; Wu, X. J. Org. Chem.
1997, 62, 6921-6927. X1, X2 ) Mg, Mg prepared successively: ref 2f.
10.1021/jo702103r CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/17/2008
J. Org. Chem. 2008, 73, 1601-1604
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