J. Org. Chem. 2000, 65, 1697-1701
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Catalysis of a Diels-Alder Reaction by Amidinium Ions Tilmann Schuster, Markus Kurz, and Michael W. Go¨bel*,† Institut fu¨ r Organische Chemie der J. W. Goethe-Universita¨ t Frankfurt, Marie-Curie-Strasse 11, D-60439 Frankfurt am Main, Germany Received August 30, 1999
Amidines and guanidines are important functional groups in molecular recognition and hostguest chemistry. Here it is shown that lipophilic amidinium ions catalyze a cycloaddition reaction representing the key step of the Quinkert-Dane estrone synthesis. Hydrogen-bond-mediated association with the organic cation leads to an electrophilic activation of the dienophile and to enhanced rates of the Diels-Alder reaction. The observed effects are similar to those expected from mild Lewis acids. In competition experiments, amidinium catalysis favors the reaction of the less electron deficient dienophile. Introduction Among synthetic receptor molecules based on amidinium and guanidinium ions, good catalysts for phosphoryl transfer reactions can be found.1,2 Their mode of action is to increase substrate electrophilicity by forming hydrogen bonded ion pairs. It has been shown earlier that organic cations may also associate with neutral carbonyl compounds.3 The enhanced guest electrophilicity in those complexes should accelerate reactions with nucleophiles and cycloadditions.4 Lewis acids are common catalysts for Diels-Alder reactions. In lithium perchlorate promoted cycloadditions, again the Lewis acidity of the cation is exploited.5 In rare cases, even weaker electrophiles are sufficient for catalysis: Diels-Alder reactions have been accelerated by complexing dienophiles to hydrogen-bond-forming receptors.6 Since amidinium ions are good hydrogen bond donors, they might catalyze cycloadditions in a similar way. In contrast to lithium perchlorate, the shape of amidinium salts can be easily optimized for certain applications, e.g. by introduction of chirality.7 Here we present two examples of amidinium-catalyzed [4 + 2] cycloadditions. The first reaction constitutes a simple case in which rac-3 is formed from maleic anhydride 1 and diene 2 (Scheme 1).8 A more Phone: +49 69 798 29222. Fax: +49 69 798 29464. E-mail:
[email protected]. (1) (a) Jubian, V.; Dixon, R. P.; Hamilton, A. D. J. Am. Chem. Soc. 1992, 114, 1120. (b) Jubian, V.; Veronese, A.; Dixon, R. P.; Hamilton, A. D. Angew. Chem. 1995, 107, 1343; Angew. Chem., Int. Ed. Engl. 1995, 34, 1237. (c) Smith, J.; Ariga, K.; Anslyn, E. V. J. Am. Chem. Soc. 1993, 115, 362. (d) Oost, T.; Filippazzi, A.; Kalesse M. Liebigs Ann. Recl. 1997, 1005. (e) Oost, T.; Kalesse, M. Tetrahedron 1997, 53, 8421. (2) (a) Muche, M.-S.; Go¨bel, M. W. Angew. Chem. 1996, 108, 2263; Angew. Chem., Int. Ed. Engl. 1996, 35, 2126. (b) Muche, M.-S.; P. Kamalaprija, P.; Go¨bel, M. W. Tetrahedron Lett. 1997, 38, 2923. (3) Bell, D. A.; Anslyn, E. V. J. Org. Chem. 1994, 59, 512. (4) Raposo, C.; Almaraz, M.; Crego, M.; Mussons, M. L.; Pe´rez, N.; Caballero, M. C.; Mora´n, J. R. Tetrahedron Lett. 1994, 35, 7065. (5) (a) Pindur, U.; Lutz, G.; Otto, C. Chem. Rev. 1993, 93, 741. (b) Flohr, A.; Waldmann, H. J. Prakt. Chem. 1995, 337, 609. (6) Kelly, T. R.; Meghani, P.; Ekkundi, V. S. Tetrahedron Lett. 1990, 31, 3381. (7) (a) Lehr, S.; Schu¨tz, K.; Bauch, M.; Go¨bel, M. W. Angew. Chem. 1994, 106, 1041; Angew. Chem., Int. Ed. Engl. 1994, 33, 984. (b) Schuster, T.; Go¨bel, M. W. Synlett 1999, 966. (8) (a) Dane, E.; Ho¨ss, O.; Bindseil, A. W.; Schmitt, J. Liebigs Ann. Chem. 1937, 532, 39. (b) Bachmann, W.; Controulis, J. J. Am. Chem. Soc. 1951, 73, 2636. †
Scheme 1
complex behavior is observed in the cycloaddition of 2 and diketone 5.9 This reaction leads to rac-8, a key intermediate in the Quinkert-Dane synthesis of estrone (Scheme 2).10 Results and Discussion To favor the association of amidinium groups and dienophiles, less polar solvents and noncoordinating counterions are essential. Structure 12 was chosen instead of simpler amidines to guarantee sufficient solubility of the salts (Scheme 3). Starting from palmitoyl amide 10,11 we prepared the amidinium tetrafluoroborate 12a via O-alkylation (11; 86%) and ammonolysis (46%). Anion exchange then produced the tetraaryl borate salts 12b-d.12 While all three compounds are soluble in CH2Cl2, a strong tendency for ion pairing was seen in 12b. The 1H NMR signal of the a methylene group (δ ) 2.33 (9) Dane, E.; Schmitt, J.; Rautenstrauch, C. Liebigs Ann. Chem. 1937, 532, 29. (10) Quinkert, G.; Del Grosso, M.; Do¨ring, A.; Do¨ring, W.; Schenkel, R. I.; Bauch, M.; Dambacher, G. T.; Bats, J. W.; Zimmermann, G.; Du¨rner, G. Helv. Chim. Acta 1995, 78, 1345 (and references cited herein). (11) Krafft, F.; Stauffer, B. Ber. Dtsch. Chem. Ges. 1882, 15, 1728. (12) Sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate: (a) Iwamoto, H.; Sonoda, T.; Kobayashi, H. Tetrahedron Lett. 1983, 24, 4703. (b) Nishida, H.; Takada, N.; Yoshimura, M.; Sonoda, T.; Kobayashi, H. Bull. Chem. Soc. Jpn. 1984, 57, 2600.
10.1021/jo991372x CCC: $19.00 © 2000 American Chemical Society Published on Web 02/24/2000
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J. Org. Chem., Vol. 65, No. 6, 2000 Scheme 2
Schuster et al. Table 1. Diels-Alder Experiments with Maleic Anhydride 1 catalyst (no. of equiv)
ratioa rac-3:rac-4
acceleration
yielda after 4 h (%)
no catalyst 12d (1) 13 (0.5) 13 (1) 13 (2)
6:1 14:1 11:1 13:1 17:1
1 2.5 1.7 2.6 3.9
63b 82 74 82 88
a The yields and ratios were determined by HPLC. b 88% yield after 24 h.
Scheme 3
in DMSO-d6) is shifted to 0.95 ppm in CDCl3. We attribute this shift to a ring current effect from a tightly bound tetraphenyl borate ion. In compound 12c the effect was reduced (δ ) 1.43) and completely absent in compound 12d (δ ) 2.33, CDCl3). All kinetical studies, therefore, used the latter salt.13 The 2-(benzylamino)pyridinium salt 13 may be seen as a heterocyclic analogue of an amidinium ion.14 Compared to 12a-d, its acidity is distinctly increased. The reaction of maleic anhydride 1 with diene 2 (CH2Cl2, 7 °C, 24 h) produced 75% of rac-3 together with 13% of the exo isomer rac-4 (Scheme 1).15 Reaction rates and (13) In our initial experiments, isolated yields of rac-8 and rac-9 were determined instead of reaction rates. In accordance with their tendency of ion pairing, 12b led to the lowest and 12d to the best yields. The tetrafluoroborate salt 12a was not sufficiently soluble to be tested. (14) Sprinzak, Y. Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 91. (15) Andreev, V. M.; Segal, G. M.; Kucherov, V. F. Bull. Acad. Sci. USSR Div. Chem. Sci. 1961, 1374.
yields were determined by HPLC using 2-methoxy-6methylnaphthalene (14) as internal standard (k2 ) 2.5 × 10-6 mM-1 s-1).16 In 1H NMR titrations with amidinium salt 12d (CDCl3, 7 °C), a low-field shift of the NH signals was seen upon addition of maleic anhydride. However, the association must be weak since the shift remained small and could not be saturated. Electron-poor anhydrides have been shown previously to possess the lowest affinities toward organic cations within a series of carbonyl compounds.3 In consequence, the amidinium salts 12d and 13 did not induce large rate effects (Table 1). The ratio of the endo and exo isomers rac-3:rac-4 was shifted in favor of endo. Enolization of diketone 5 would form a cyclopentadienone derivative with antiaromatic properties. As a result, 5 prefers the keto form, a rare exception within the class of 1,2-dicarbonyl compounds. In contrast to maleic anhydride, diketone 5 readily associates with amidinium salt 12d. Ka could be determined by 1H NMR titration (37 ( 6 M-1; CDCl3, 7 °C). The stability constant for the complex 13‚5 was estimated in the same way (70 ( 20 M-1; CDCl3, 7 °C). Further evidence for association came from the mass spectra of 13 when 100 equiv of diketone 5 was added. In the presence of an equimolar mixture of maleic anhydride and diketone, only the complex 13‚5 could be detected. Accordingly, ESI-MS permits to select good binding partners within a mixture or small library of weakly coordinating guest molecules. The Diels-Alder reaction of diene 2 and diketone 5 (Scheme 2) is complicated by the existence of constitutional isomers and by the slow tautomerization to the final keto enols. In addition, special care is necessary to avoid artifacts: glass surfaces and silica gel are good catalysts and influence both rates and product ratios.17 All reactions therefore were run in polyethylene vials (CH2Cl2, 7 °C). Analytical samples, quenched in acetonitrile and stored in liquid nitrogen, proved to be sufficiently stable. They were analyzed without further workup by HPLC, again using naphthalene 14 as internal standard. Pure samples of diene 2, 14, product rac8, and isomeric product rac-9 were prepared according to published procedures and applied to the calibration of the HPLC system. In the absence of catalysts, the reaction produced rac-8 and rac-9 (ratio < 0.1:1) slowly and in low yield (
