A tandem oxidation/cyclization reaction of γ-(arylmethyl)oxy-α-diazobutyrate derivatives was investigated. While oxidative cleavage of the PMB ether was only observed upon treatment of an α-diazo-β-ketoester with DDQ, oxidation of α-diazo esters with an sp 3 carbon at the β-position was accompanied by intramolecular attack of the diazo carbon atom and expulsion of the nitrogen gas to give 2,3-dihydrofurans in modest to good yields when an electron-withdrawing group was substituted at the

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... ion. Substrates bearing no electron-withdrawing β-substituent were found to give rearranged products, albeit in modest yields. A benzofuran derivative could also be obtained, although a hydroquinone adduct was formed as a byproduct. INTRODUCTION Since the preparation of ethyl diazoacetate in 1883, diazo compounds have frequently been used in organic synthesis due to their high versatility and synthetic utility. 1 These compounds have long been recognized as 1,3-dipoles, cycloaddition of which with dipolarophiles provides pyrazoline derivatives. 2 Carbene species can be generated by expulsion of nitrogen gas upon exposure to heat or light, 3 whereas transition metal-catalyzed diazo decomposition produces metal carbenoids, which can participate in a wide variety of reactions such as cyclopropanation, X−H insertion, and ylide formation. 4 It is also well known that diazo compounds undergo both electrophilic and nucleophilic reactions; the electrophilic capability of the terminal nitrogen atom allows reaction with highly reactive carbon nucleophiles, 5 and the negatively polarized diazo carbon atom is sufficiently nucleophilic to react with electrophiles such as proton, aldehydes and imines. 6 While α-diazo carbonyl compounds are easily deprotonated under basic conditions, their inherent nucle- † Dedicated to Professor Kiyoshi Tomioka on the occasion of his 70th birthday ophilicity comparable to that of silyl enol ethers 7 allows reaction with carbonyl compounds with the aid of an appropriate Lewis acid. Roskamp reaction, in which Lewis acid-catalyzed generation of diazonium intermediates from α-diazo esters and aldehydes is followed by an expulsion of nitrogen and subsequent 1,2-hydride shift to provide β-ketoesters, is representative of this type of transformation (Scheme 1). 8 It Scheme 1. Lewis acid-catalyzed reactions of aldehydes with α-diazoacetates has also been reported that the use of some Lewis acids in the reaction with aromatic aldehydes led to the preferential formation of α-formyl ester via 1,2-aryl migration, 9 whereas epoxide formation via Darzenstype reaction occurred by the action of MeReO 3 or La(OTf) 3 . 10 In 2009, Doyle and Zhou developed an intramolecular variant of the Lewis acid-catalyzed reaction in which either Zn(OTf) 2 or BF 3 ·OEt 2 was employed for the activation of iminodiazoacetates and elimination occurred instead of rearrangement to give indoles in quantitative yields (Scheme 2). 11 Scheme 2. Lewis acid-catalyzed cyclization of iminodiazoacetates During the course of our studies on second-generation synthesis of zaragozic acids, 12 we found that our attempt to remove the PMB protecting group in α-diazo ester 1 with DDQ 13,14 met with failure but resulted in the formation of 2,3-dihydrofuran 2 in 64% yield even in the presence of pH 7 phosphate buffer (Scheme 3). This result clearly revealed that the oxidative generation of oxocarbenium ions can trigger the cyclization of diazo compounds, and that intramolecular attack of the diazo carbon atom proceeded faster than hydrolysis of oxocarbenium ion 3 to provide diazonium intermediate 4. In this paper, we document the scope and limitations of the tandem oxidation/cyclization reaction using α-diazo esters as substrates. 15 R CO 2 Me H N 2 CO 2 Me N LA Zn(OTf) 2 or BF 3 ·OEt 2 R Scheme 3. Unexpected 2,3-dihydrofuran formation from α-diazo ester 1 RESULTS AND DISCUSSION Since the nucleophilicity of the diazo carbon atom can be regulated by adjacent substituents, α-diazoβ-ketoester 5 and α-diazo ester 6a were chosen as substrates for optimization of the reaction parameters due their ease of preparation (Scheme 4). α-Diazo-β-ketoester 5 was obtained by a two-step sequence involving coupling of aldehyde 7 16 with tert-butyl diazoacetate according to the Wenkert procedure 17 (47% yield) and oxidation with IBX 18 in the presence of pyridine (81% yield). On the other hand, the synthesis of α-diazo ester 6a commenced with mono-alkylation of commercially available L-(+)-glycerate (9) 19 with PMBI via the stannylene acetal, 20 affording PMB ether 10 in 57% yield. After oxidation of the remaining secondary alcohol with IBX (84% yield), α-diazo ester functionality was installed as with 7 and subsequent protection of the resultant alcohol with HMDS completed the preparation of α-diazo ester 6a in 42% yield in two steps. Scheme 4. Preparation of diazo compounds 5 and 6a With substrates 5 and 6a in hand, we then proceeded to investigate the cyclization reaction. We initially explored the reaction of α-diazo-β-ketoester 5, but exposure of 5 to DDQ in CH 2 Cl 2 resulted, after aque-N PMBO CHO 7 N 2 CHCO 2 t-Bu LDA, THF, -78 °C 47% IBX, pyridine DMSO/THF (1:1) 81% PMBO 8 OH N 2 CO 2 t-Bu PMBO 5 O N 2 CO 2 t-Bu RO CO 2 Me OH Bu 2 SnO, PhH reflux, then CsF PMBI, DMF 57% 9: R = H 10: R = PMB IBX, AcOEt, reflux 84% PMBO CO 2 Me O 11 1. N 2 CHCO 2 t-Bu LDA, THF, -78 °C 2. HMDS imidazole, THF 42% PMBO CO 2 Me TMSO 6a N 2 CO 2 t-Bu ous workup, only in cleavage of the PMB ether, leaving the diazo group intact (Scheme 5). This result suggested that the diazo carbon stabilized by two electron-withdrawing groups did not possess sufficient nucleophilicity to participate in the projected intramolecular addition reactions. Scheme 5. Oxidation of α-diazo-β-ketoester 5 with DDQ On the other hand, the desired five-membered ring formation could be achieved by the use of more nucleophilic α-diazo ester 6a instead of 5 as a substrate, providing 2,3-dihydrofuran 14a in 79% yield (Table 1, entry 1). Encouraged by this result, oxidants other than DDQ were next screened for their ability to promote the tandem reaction. It was found that o-chloranil and 2,3-dichloro-1,4,5,8-naphthalenetetrone (DClNTO) 21 furnished cyclization product 14a, albeit in low yields (entries 2 and 4), whereas a complex mixture was obtained by the use of p-chloranil, tritylium tetrafluoroborate, and tropylium tetrafluoroborate (entries 3, 5 and 6). We were concerned that the cyclization would compete with hydrolysis by adventitious water, but a beneficial effect was not observed with 4 Å MS (entry 7). While LiClO 4 was 7 DDQ 4 Å MS CH 2 Cl 2 20 3 73 8 DDQ LiClO 4 CH 2 Cl 2 20 3 69 9 DDQ Na 2 CO 3 CH 2 Cl 2 20 3 71 a The reaction was carried out on a 50-mg scale.