LETTER
Cross-Coupling Reactions of Pyridine Carboxylic Acid Chlorides with Alkylzinc Reagents
1093
Negishi cross-coupling products, respectively. Thus, the tinoyl chlorides with alkylzinc reagents in the presence of
present Pd(phen)Cl2 catalyst system achieved chemo- Pd(phen)Cl2 to afford pyridyl ketones with no formation
selective ketone formation between chloronicotinoyl of Negishi coupling product of 2-chloroazine moiety. This
chlorides and alkylzinc reagents.
catalyst system can be adapted to cross-coupling of vari-
ous pyridine carboxylic acid chlorides with alkylzinc re-
agents. Further explorations for applications of this
system are now in progress.
Furthermore, unsubstituted pyridine carboxylic acid chlo-
rides were also examined (Scheme 3). These acid chlo-
rides were commercially available as hydrochloric acid
salts 11a–c, so one equivalent excess of alkylzinc reagents
were needed in these cases. The reaction between nico-
tinoyl chloride hydrochloride (11a) and alkylzinc reagent
2 gave corresponding ketone 12a in high yield, however,
picolinoyl chloride hydrochloride (11b) and isonicotinoyl
chloride hydrochloride (11c) afforded moderate yields.
References and Notes
(1) (a) Dieter, R. K. Tetrahedron 1999, 55, 4177.
(b) Lawrence, N. J. J. Chem. Soc., Perkin Trans. 1 1988,
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(3) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1982, 22,
3815. (b) Balasubramaniam, S.; Aiden, I. S. Synthesis 2008,
3703.
O
O
Pd(phen)Cl2 (3 mol%)
PhCH2CH2ZnI (2)
Cl
Ph
MeCN, r.t., 2 h
HCl
N
N
(4) Handbook of Functionalized Organometallics; Knochel, P.,
Ed.; Wiley-VCH: New York, 2005.
11a 3-COCl
11b 2-COCl
11c 4-COCl
12a 75%
12b 44%
12c 42%
(5) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(b) Erdik, E. Organozinc Reagents in Organic Synthesis;
CRC Press: Boca Raton FL, 1996. (c) Organozinc
Reagents: A Practical Approach; Knochel, P.; Jones, P.,
Eds.; Oxford University Press: New York, 1999.
(d) Knochel, P.; Millot, N.; Rodriguez, A.; Tucker, C. E.
Org. React. 2001, 58, 417. (e) Knochel, P.; Calaza, M. I.;
Hupe, E. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
New York, 2004.
(6) (a) Ishino, Y.; Mihara, M.; Kageyama, M.; Nishiguchi, I.
Bull Chem. Soc. Jpn. 1998, 71, 2669. (b) Ishino, Y.;
Mihara, M.; Kageyama, M. Tetrahedron Lett. 2002, 43,
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J. Chem. Soc., Chem. Commun. 1977, 683. (c) Negishi, E.
Acc. Chem. Res. 1982, 15, 340.
Scheme 3
In the case of dicarboxylic acid dichlorides 13 and 15, cor-
responding ketones 14a and 16a were obtained in good
yields with small amount of isomerized products 14b and
16b, respectively (Scheme 4, Scheme 5). These isomer-
ized ketones 14b and 16b were presumably formed
through b-H elimination of alkylzinc reagent 2 followed
by alkene reinsertion preceding reductive elimination.21
Ph
Ph
N
Pd(phen)Cl2 (3 mol%)
Ph2CH2CH2ZnI (2)
O
O
Cl
Cl
14a 58%
N
MeCN, r.t., 2 h
O
O
Ph
13
Ph
(8) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller,
J. A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
(9) (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
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H.; Nakamura, T.; Tsubaki, K.; Yoshida, Z. Tetrahedron
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(13) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.;
Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189. (b) Mori,
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N
O
O
O
14b 6%
Scheme 4
Ph
O
O
Pd(phen)Cl2 (3 mol%)
Ph
O
N
Cl
Ph2CH2CH2ZnI (2)
Cl
16a 68%
MeCN, r.t., 2 h
N
O
15
Ph
Ph
N
O
16b 8%
Scheme 5
(15) Typical Procedure for Preparation of Alkylzinc
Reagents
In conclusion, we have developed an efficient and
chemoselective cross-coupling reaction of chloronico-
Under argon atmosphere, to a mixture of Zn metal (196 mg,
3.0 mmol) and DMI (0.43 mL, 4.0 mmol) in MeCN (3.0 mL)
Synlett 2009, No. 7, 1091–1094 © Thieme Stuttgart · New York