ORGANIC LETTERS
Reactivity of Quinoline- and Isoquinoline-Based Heteroaromatic Substrates in Palladium(0)-Catalyzed Benzylic Nucleophilic Substitution
2000 Vol. 2, No. 4 433-436
Jean-Yves Legros,* Gae1 lle Primault, Martial Toffano, Marie-Alix Rivie`re, and Jean-Claude Fiaud*,† Laboratoire de Catalyse Mole´ culaire associe´ au C.N.R.S., UPRESA 8075, Institut de Chimie Mole´ culaire d’Orsay, Baˆ timent 420, UniVersite´ de Paris-Sud, F91405 Orsay, France
[email protected] Received November 23, 1999
ABSTRACT
Quinolylmethyl, 1-(isoquinolyl)ethyl, and 1-(quinolyl)ethyl acetates reacted with dimethylmalonate anion in the presence of a Pd(0) catalyst to give products of nucleophilic substitution and/or byproducts, depending upon the substitution pattern. The observed side reactions were reduction in the case of primary acetates and elimination or elimination/Michael-type addition sequence for secondary substrates.
We described in recent years the formation of a benzylic carbon-carbon bond by the palladium(0)-catalyzed nucleophilic substitution of naphthylmethyl and 1-(1- or 2-naphthyl)ethyl acetates and carbonates by sodium dimethyl malonate (Scheme 1).1 This method has been extended to
Scheme 1
the formation of a carbon-nitrogen bond by using amines as nucleophiles.2 We report in this communication the substitution of N-heteroaromatic substrates 1-3 (Figure 1) derived from †
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10.1021/ol991274y CCC: $19.00 Published on Web 01/21/2000
© 2000 American Chemical Society
Figure 1. Structure of compounds 1-5.
quinoline and isoquinoline. We recently described the reactivity of 4-quinolylmethyl acetate 1c and other 4-quinolylmethyl esters in the palladium-catalyzed substitution by formate anion (formation of a carbon-hydrogen bond).3
Acetates 1 were prepared by reduction/acetylation of the commercialy available quinolinecarboxaldehydes. Acetates 2 and 3 were obtained similarly from the corresponding arylmethyl ketones 4 and 5. We recently developed a new preparation of compounds 4 and 5 from quinolyl and isoquinolyl derivatives (chlorides, bromides, or triflates) via palladium-catalyzed Stille and Heck coupling reactions.4 The secondary acetates 25 and 36 were also prepared in lower yields by literature methods. We first studied the reactivity of primary acetates 1 (Table 1). The nucleophile was preformed by mixing dimethyl-
(entries 5 and 6).8 It is worth noting that under the same reaction conditions reduction products (i.e., 1- and 2-methylnaphthalenes) were never detected from naphthylmethyl acetates.1a The substitution of secondary acetates 2 and 3 were next examined (Table 2). These substrates did not give reduction
Table 2. Substitution of Secondary Acetates 2 and 3a
Table 1. Substitution of Primary Acetates 1a
entry
substrate
solvent
product 6 (%)
product 7 (%)
1 2 3 4b 5 6
1a 1b 1c 1c 1b 1c
DMF DMF DMF DMF THF THF
6b (23) 6c (55) 6c (49) 6b (80) 6c (66)
7b (74) 7c (24) 7c (21)
a Isolated yields. b NaCH(CO CH ) (from NaH and dimethylmalonate) 2 3 2 as nucleophile.
malonate and potassium tert-butoxide. Substrate 1a was totally unreactive under the conditions described below (entry 1). At higher (100 °C) temperature, a slow degradation was observed but the expected substitution product 6a was never obtained. In contrast, acetates 1b and 1c displayed good reactivity with total consumption of the substrate in less than 4 h. The 1- and 2-naphthylmethyl acetates achieved 100% conversion in more than 5 h. However, in addition to the expected substitution products 6b and 6c,7 3- and 4-methylquinolines 7b and 7c, resulting from a formal reduction process, were obtained (entries 2 and 3). Sodium dimethylmalonate gave essentially the same result (entry 4), but the solvent was the source of this side reaction. Switching from DMF to THF allowed for a selective and high-yielding substitution reaction (1) (a) Legros, J. Y.; Fiaud, J. C. Tetrahedron Lett. 1992, 33, 25092510. (b) Legros, J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron 1995, 51, 3235-3246. (c) Legros, J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron: Asymmetry 1995, 6, 1899-1902. (2) Toffano, M.; Legros, J. Y.; Fiaud, J. C. Tetrahedron Lett. 1997, 38, 77-80. (3) (a) Boutros, A.; Legros, J. Y., Fiaud, J. C. Tetrahedron Lett. 1999, 40, 7329-7332. (b) Boutros, A.; Legros, J. Y., Fiaud, J. C. Tetrahedron, accepted for publication. (4) Legros, J. Y., Primault, G., Fiaud, J. C., unpublished work. (5) Taylor, R. J. Chem. Soc. B 1971, 2382-2387. (6) Glyde, E., Taylor, R. J. Chem. Soc., Perkin Trans. 2 1975, 17831791. (7) All new compounds were characterized by proton and carbon-13 NMR, IR, and either HRMS or elemental analysis. 434
entry
substrate
M
t (h)
substitution product (%)
elimination product (%)
1 2 3 4 5c 6d 7 8 9
2b 2b 2b 2c 2d 3b 3c 3c 3c
Na K Cs Na Na Na Na K Cs
10 8 8 24 24 24 24 24 24
8b (61) 8b (59) 8b (54) 8c (74) 8d (14) 9b (13)b 9c (78) 9c (44) 9c (60)
10b (3) 10b (7)b 10b (7) 10c (
