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J. Org. Chem. 2001, 66, 6650-6653
Carbon-Carbon Bond Formation of Alkenylphosphonates by Aldehyde Insertion into Zirconacycle Phosphonates Abed Al Aziz Quntar and Morris Srebnik*,† Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Hebrew University in Jerusalem, Jerusalem 91120, Israel
[email protected] Received April 24, 2001
Ethyl 1-butynylphosphonate reacts with Cp2ZrCl2/2n-BuLi to give a three-membered zirconacycle that readily inserts aldehydes. Hydrolysis of the intermediate five-membered zirconacycles leads to two products, 4 and 5. In the major product, 5, the aldehyde inserts into C2 of the zirconacycle, while in the minor product, 4, the aldehyde inserts into C1. Products 5 are obtained in 38-75% isolated yields. Products 4 are obtained in approximately 1-12%. Essentially, only compounds 5 are produced with ortho-substituted aldehydes. The regio- and stereochemistry of 4 and 5 were determined by 3JPH, 2JPC2, and 3JPC3 coupling constants. Vinylphosphonates are an important group of compounds that have found use in organic transformations.1 The double bond in vinylphosphonates can be converted to aziridines,2 epoxidized,3 and C-glycosylated.4 It reacts with organocuprate reagents that can be further transformed.5 Vinylphosphonates are also useful reagents for the synthesis of biologically active compounds or as investigative reagents.6 The synthesis of vinylphosphonates is varied. However, the synthesis of vinylphosphonates by addition of organometallic reagents to 1-alkynylphosphonates though attractive has not received much attention and includes syn-addition of organocuprates,7 reaction of R-stannylated phosphonates with aldehydes to give E/Z mixtures of 1,2-disubstituted vinylphosphonates,8 anti hydrotelluration,9 Heck reactions using aryldiazonium salts,10 R-lithiation of β-oxy or β-thio vinylphos† Affiliated with the David R. Bloom Center for Pharmaceutics at the Hebrew University in Jerusalem. (1) For a recent review, see: (a) Minam I, T.; Motoyoshiya, J. Synthesis 1992, 333. Afarinkia, K.; Binch, H. M.; Modi, C. Tetrahedron Lett. 1998, 39, 7419. (2) Kim, D. Y.; Rhie, D. Y. Tetrahedron 1997, 53, 13603. (3) Cristau, H.-J.; Mbiana, X. Y.; Geze, A.; Beziat, Y.; Gasc, M.-B. J. Organomet. Chem. 1998, 571, 189. (4) Junker, H.-D.; Fessner, W.-D. Tetrahedron Lett. 1998, 39, 269. (5) Afarinkia, K.; Binch, H. M.; Modi, C. Tetrahedron Lett. 1998, 39, 7419. (6) As intermediates in drugs or biological investigative compounds: (a) Harnden, M. R.; Parkin, A.; Parratt, M. J.; Perkin, R. M. J. Med. Chem. 1993, 36, 1343. (b) Smeyers, Y. G.; Romero-Sanchez, F. J.; Hernandez-Laguna, A.; Fernandez-Ibanez, N.; Galvez-Ruano, E.; Arias-Perez, S. J. Pharm. Sci. 1987, 76, 753. (c) Megati, S.; Phadtare, S.; Zemlicka, J. J. Org. Chem. 1992, 57, 2320. (d) Lazrek, H. B.; Rochdi, A.; Khaider, H.; Barascut, J. L.; Imbach, J. L.; Balzarini, J.; Witvrouw, M.; Pannecouque, C.; De Clerq, E. Tetrahedron 1998, 54, 3807. (e) Smith, P. W.; Chamiec, A. J.; Chung-G.; Cobley, K. N.; Duncan, K.; Howes, P. D.; Whittington, A. R.; Wood, M. R. J. Antibiot. Tokyo 1995, 48, 73. Agrochemicals: (f) Chance, L. H.; Moreau, J. P. U.S. Patent 3910886, 1975. (7) Cristau, H.-J.; Mbianda, X. Y.; Beziat, Y.; Gasc, M.-B. J. Organomet. Chem. 1977, 529, 301. (b) Gil, J. M.; Oh, D. Y. J. Org. Chem. 1999, 64, 2950. (8) Mimouni, N.; About-Jaudet, E.; Collignon, N. Synth. Commun. 1991, 21, 2341. (9) Jang, W. B.; Oh, D. Y.; Lee, C.-W. Tetrahedron Lett. 2000, 41, 51. (10) Brunner, H.; Le Cousturier de Courcy, N.; Geneˆt, J.-P. Synlett 2000, 210.
Scheme 1
phontes,11 NaH-catalyzed olefination of benzenesulfinylmethylphosphonates,12 and addition of sodium organyl chalcogenolates.13 We have recently started to investigate the addition of organometallic reagents to 1-alkynylphosphonates. One such reaction is hydroboration. For instance, we have discovered that the hydroboration of 1-alkynylphosphonates with pinacolborane can be controlled to place boron on either C1 or C2 of the triple bond by proper use of base, catalyst, and reaction time.14 In conjunction with Suzuki coupling, we developed a highly stereospecific synthesis of vinylphosphonates (Scheme 1). Zirconacycles are very useful intermediates in organic transformations.15 Another very useful reaction of triple (11) Kouno. R.; Okauchi, T.; Nakamura, M.; Ichikawa, J.; Minami, T. J. Org. Chem. 1998, 63, 6239. (12) Shen, Y.; Jiang, G.-F. Synthesis 2000, 99. (13) Braga, A. L.; Alves, E. F.; Silveira, C. C.; Andrade de, L. H. Tetrahedron Lett. 2000, 41, 161. (14) Pergament, I.; Srebnik, M. Submitted. (15) (a) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124. (b) Negishi, E. In Comprehensive Organic Synthesis; Paquette, L. A., Ed.; Pergamon Press: New York, 1991; Vol. 5, p 1163.
10.1021/jo010424r CCC: $20.00 © 2001 American Chemical Society Published on Web 09/06/2001
C-C Bond Formation of Alkenylphosphonates
J. Org. Chem., Vol. 66, No. 20, 2001 6651
Scheme 2
Scheme 3
Table 1. Selected NMR Data and Yields of 4
bonds that we have begun to explore is zirconacycle formation of 1-alkynylphosphonates16 (eq 1).17
Thus, hydrolysis of the zirconacycles provided cisvinylphosphonates, and subsequent insertion reactions of the three-membered zirconacycles with different alkynes provided access to 1,3-butadienylphosphonates (Scheme 2).18 As a continuation of the study of metalation reactions of 1-alkynylphosphonates, we now report our results on the insertion of aldehydes into three-membered zirconacycles generated from 1-alkynylphosphonates to give the equivalent of Baylis-Hillman19 type carbon-carbon bond formation of alkenylphosphonates. Compounds such as 4 are readily converted to allenes by treatment with base under Horner-Wadsworth-Emmons conditions.20 When zirconacycles 1, prepared by reaction of diethylhexynylphosphonate and 2n-BuLi/Cp2ZrCl2, is treated with an aldehydes and the reaction hydrolyzed, two products are obtained, 4 and 5 (Scheme 3). The reaction was followed by 31P NMR of products 4 and 5 which absorbed in the 18-19.5 ppm range. The starting alkynylphosphonates absorb around -5 ppm. The reaction was accompanied by various amounts of cis-diethyl-1hexenylphosphonate which absorbed at 17.7 ppm. The major product, 5 (Table 2), occurs by insertion of the aldehydes into C2 of the zirconacycle, apparently due to steric factors. Evidence for this are the very low yields of 4 obtained with o-anisaldehyde (Table 1, entry h) and (16) Iorga, B.; Eymery, F.; Carmichael, D.; Savignac, P. Eur. J. Org. Chem. 2000, 3103. (17) Quntar, A. A. A.; Srebnik, M. Org. Lett. 2001, 3, 1379. (18) (a) Cristau, H.-J.; Mbianda, X. Y.; Beziat, Y.; Gasc, M.-B. J. Organomet. Chem. 1977, 529, 301. (b) Gil, J. M.; Oh, D. Y. J. Org. Chem. 1999, 64, 2950. (19) (a) Review: Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001. (b) Compounds similar to 5 are obtained from vinylphosphonates and LDA: (b) Nagaoka, Y.; Tomioka, K. J. Org. Chem. 1998, 63, 6428. (20) Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; John Wiley and Sons: New York, 1984.
entry
R
a b c d e f g h i
phenyl PhCHdCH 1,4-benzodioxane p-F-C6H4 1-naphthyl p-MeO-C6H4 C6H13 o-MeO-C6H4 2,4-dichloro-C6H3
isol. equiv of convna yield 3JPH 2JPC2 3JPC3 ald. (%) (%) (Hz) (Hz) (Hz) 1.2 1.2 1.2 2 2 2 2 2 2
98 98 95 75 65 65 95 96 70
10 11 9 11 12 7 8
