Base-induced cyclization of 1-benzyloxy-2,2,4,4-tetramethylpentan-3-ones: intramolecular nucleophilic addition of an anion of a benzyl ether to the carbonyl moiety without the Wittig rearrangement or protophilic decomposition

摘要

Ar OR ndash; O H Ar Rcent; Rcent; + ArCH2O ndash; ndash; R Ar Ondash; O O R2 R1 R1 O HO R2 trans-2 R1 O HO R2 cis-2 :B 1a R1 = m-MeO, R2 = Me b R1 = H, R2 = Me c R1 = p-MeO, R2 = Me d R1 = p-Br, R2 = Me e R1 = m-MeO, R2 = H O Ar O But ndash; O But O Li Ar ndash; trans-2 cis-2 + T-1 T-2 Base-induced cyclization of 1-benzyloxy-2,2,4,4-tetramethylpentan-3-ones: intramolecular nucleophilic addition of an anion of a benzyl ether to the carbonyl moiety without the Wittig rearrangement or protophilic decomposition Masakatsu Matsumoto,* Nobuko Watanabe, Akio Ishikawa and Hiroyuki Murakami Department of Materials Science, Kanagawa University, Tsuchiya, Hiratsuka, Kanagawa 259-12, Japan Alkyl benzyl ethers bearing a carbonyl moiety in the alkyl chain (1) cyclize effectively, without the Wittig rearrangement or protophilic decomposition, to give hydroxytetrahydrofurans (trans-2) on treatment with ButOK in DMSO at room temperature, whereas LDAndash;THF induces the cyclization of 1 to afford predominantly the stereoisomer cis-2.The a-carbanion of an alkyl benzyl ether is unstable and undergoes protophilic cleavage (elimination)1,2 or Wittig rearrangement3 ndash;5 even at low temperature (Scheme 1), so that little is known of its nucleophilic addition or substitution reactions, although extensive studies have been made on the rearrangement and the decomposition.6 We report here that (i) the a-carbanion of an alkyl benzyl ether is able to add effectively to a carbonyl moiety in the alkyl chain via intramolecular nucleophilic addition without Wittig rearrangement or protophilic decomposition, and (ii) the addition is sterically controlled by the basendash;solvent system used. When benzyl ether 1a (1.1 g, 4.0 mmol) was treated with ButOK (8.0 mmol) in DMSO (12 ml) under N2 at room temperature for 4 h, 1a was exclusively transformed into tetrahydrofuran trans-2a (91), which was isolated as a colourless oil in 88 yield after chromatographic purification (SiO2) (Table 1, entry 1).The structure of trans-2a was determined by 1H NMR, NOESY, IR and mass spectral analysis.dagger; A combination of base and solvent, e.g. ButOKndash;THF or MeONandash;DMSO, was ineffective for the cyclization of 1a. On the other hand, after treatment of 1a with LDAndash;THF at room temperature for 2 h, the cyclization took place smoothly to afford a stereoisomer cis-2a as colourless crystals (mp 83.0ndash;83.5 deg;C) together with a small amount of trans-2a (cis : trans = 82 : 18) (94) (entry 2). When the cyclization was carried out at 0 deg;C, the stereoselectivity was somewhat improved (cis : trans = 91 : 9) (entry 3).The reaction of 1a with LDAndash;THF proceeded sluggishly at 278 deg;C. The other benzyl ethers 1bndash;d also underwent base-induced cyclization to afford the corresponding tetrahydrofurans 2bndash;d with similar stereoselectivities, as shown in Table 1. It is noteworthy that even benzyl ether 1c bearing an electron-donating substituent at the para-position underwent cyclization in LDAndash;THF, even though ButOKndash;DMSO was ineffective (entries 6 and 7).The present results showed that (i) an alkyl benzyl ether is probably stable enough to undergo nucleophilic reaction without Wittig rearrangement or decomposition, so long as an electrophile such as a carbonyl moiety exists in a favourable situation, and (ii) the stereoselectivity of cyclization is tightly controlled by the basendash;solvent system used. The stereoselectivity can probably be rationalized as follows: for the ButOKndash; DMSO system, a naked anion of 1 attacks the carbonyl via transition state T-1, in which interaction between the aryl and tert-butyl groups is minimized, thus giving the sterically less congested isomer trans-2 (Scheme 2).On the other hand, in the Scheme 1 Table 1 Base-induced cyclization of alkyl benzyl ethers 1 Conversion Ratio Entry Systema t/hb ()c trans : cisd 1 1a A 4 91 2a 100 : 0 2 1a B 2 94 2a 80 : 82 3 1a B 2e 95 2a 9 : 91 4 1b A 4 92 2b 100 : 0 5 1b B 2 99 2b 9 : 91 6 1c A 4 0 mdash; mdash; 7 1c B 5f 86 2c 12 : 88 8 1d A 4 99 2d 100 : 0 9 1d B 2 96 2d 10 : 90 10 1e A 4 72 2e 93 : 7 11 1e B 5f 63g 2e 13 : 87 a A: 1 (4.0 mmol), ButOK (8.0 mmol), DMSO (12 ml).B: 1 (4.0 mmol), LDA (8.0 mmol), THF (12 ml). b Carried out at room temp. unless stated otherwise. c No product other than 2 was observed, unless stated otherwide. d Determined via 1H NMR analysis of the crude product. e Reaction performed at 0 deg;C. f Reaction performed at 278 deg;C for 2 h and then at room temp.for 3 h. g trans-2e (5.5), cis-2e (31) and 1e (37) recovered after chromatography. Scheme 2 Chem. Commun., 1997 2395MeO O But O 3 MeO O 4 MeO OH But O But 5 LDAndash;THF system a lithium ion might coordinate the carbonyl oxygen and the benzyl a-carbanion in transition state T-2 to afford cis-2 predominantly, even though the repulsive interaction between the aryl and tert-butyl moieties is thermodynamically unfavourable.This rationalization is consistent with the effect of temperature on the stereoselectivity in the cyclization of 1a using LDAndash;THF. It is noteworthy that 18-crown-6 promoted the trans-selective cyclization of 1a with ButOK in THF to give trans-2a exclusively (room temp. for 4.5 h; 87). Since the substrate 1 lacks a b-hydrogen on the alkyl chain, it is not susceptible to protophilic decomposition to form a terminal alkene (Scheme 1), but it should undergo 1,2-Wittig rearrangement.Thus, we examined the reaction of benzyl ether 3 as a representative ether bearing b-hydrogens on the alkyl chain. Treatment of 3 with LDA in THF (278 deg;C to room temp.) gave the expected cyclization product 4 in high yield,Dagger; while the use of ButOKndash;DMSO induced almost no reaction. Thus, intramolecular nucleophilic addition of the a-carbanion of an alkyl benzyl ether to the carbonyl of the alkyl site takes place effectively even if it bears b-hydrogens. In addition, we should note that benzyl ether 1e bearing an isobutyryl moiety also gave the corresponding cyclization product 2e on treatment with a base even though 1e possesses an acidic proton adjacent to the carbonyl moiety (entries 10 and 11). Both isomeric hydroxytetrahydrofurans trans- and cis-2a were easily dehydrated to give dihydrofuran 5, which is a key intermediate for the synthesis of a dioxetane used as a highly efficient chemiluminescent substrate7sect; in high yield upon treatment with SOCl2 and pyridine at room temperature.The other furans 2 obtained here were similarly dehydrated to give the corresponding dihydrofurans. The present results show that the a-carbanion of an alkyl benzyl ether such as 1 or 3 undergoes nucleophilic addition to a carbonyl moiety existing in the same molecule without Wittig rearrangement or protophilic decomposition. Furthermore, the present cyclization should form a facile entry to sterically crowded cyclic enol ethers.The authors gratefully acknowledge financial assistance in the form of a Grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of the Japanese Government. Footnotes and References * E-mail: matsumo@info.kanagawa-u.ac.jp dagger; All products obtained here gave satisfactory NMR, IR and mass spectral data. Dagger; A single isomer, with stereochemistry tentatively assigned as cis-4 was isolated in 90 yield. sect; Previously, the dihydrofuran 5 had been synthesized by the McMurry reaction of 3-oxo-2,2,4,4-tetramethylpentyl 3-methoxybenzoate using Ti0 (ref. 7). However, this method is expensive and not suitable for large-scale synthesis. 1 M. Maercker, Angew. Chem., Int. Ed. Engl., 1987, 26, 972. 2 M. Matsushita, Y. Nagaoka, H. Hioki, Y. Fukuyama and M. Kodama, Chemistry Lett., 1996, 1039. 3 U. Sch�ollkopf, Angew. Chem., Int. Ed. Engl., 1970, 9, 763. 4 T. Nakai and K. Mikami, Chem. Rev., 1986, 86, 885. 5 J. A. Marshall, in Comprehensive Organic Synthesis, ed. G. Pattenden, Pergamon, Oxford, 1991, vol. 3, p. 975. 6 J.-F. Biellmann and J.-B. Ducep, Org. React., 1982, 27, 1. 7 M. Matsumoto, N. Watanabe, N. C. Kasuga, H. Hamada and K. Tadokoro, Tetrahedron Lett., 1997, 38, 2863. Received in Cambridge, UK, 19th Seember 1997; 7/06802F 2396 Chem. Commun., 1997