1,3,4-Oxadiazoles are ac ommon motif in pharmaceuticalc hemistry,b ut few convenient methods for their modification exist. Af ast, convenient, high yielding and general a-substitution of 1,3,4-oxadiazolesh as been developed using am etalation-electrophilict rapping protocol both in batch and under continuousf low conditions in contradiction to previous reports which suggest that a-metalation of this ring system results in ring fragmentation. In batch, lithiation is accomplished at an industrially convenientt emperature, À30 8C, with subsequentt rapping giving isolated yields of up to 91 %. Under continuousf low conditions, metalationi s carriedo ut at room temperature, and subsequent in flow electrophilic trapping gave up to quantitativei solated yields. Notably,l ithiation in batch at room temperature results only in ring fragmentation and we propose that the superior mixingi nf low allows interception and exploitation of an unstablei ntermediate before decomposition can occur.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

(4) indicates that they are in fact best represented by structure l a rather than structures of type lb. Similar considerations also appear to hold for an isothiazole derivative 2a (5) and for a benzo-1,2-thioxole derivative 2b (6). However, it is of interest to examine related compounds in which the central atom is incapable of valency shell expansion to determine to what extent their properties approach those of the 6a-thiathiophthenes 1. These should possibly exhibit valencytautomerism which has been proposed (7) to explain the properties of the thiathiophthenes. A suitable compound for examination is 7-acetyl-3-methyl-2,I-benzisoxazole (3a), which has a structure of the required potential symmetry for n.m.r. examination and possesses similar electronic and structural features to some benzo-1,2-dithiolium derivatives (8) of the thiathiophthene system.2-Nitroisophthaloyl chloride (4a) reacted with ethyl ethoxymagnesiummalonate to provide the tetracarboxylic ester 46. This was not isolated but provided, after acid hydrolysis, 2,6-diacetylnitrobenzene (4c). This method is reported to be the most satisfactory for the preparation of o-nitroacetophenones (9). When the nitro compound was reduced, using stannous chloride in hydrochloric acid, 7-acetyl-3-methyl-2, I-benzisoxazole (3a) and 2,6-diacetylaniline (4d) were S-S-S S-S SR UR R J&AR L R1 = H; R2 = Me; Z = NMe b R1, R2 = CH:C(OMe)-CH:CH; Z = 0 obtained after separation by chromatography. 2,6-Diacetylaniline (4d) was obtained as the sole product when the reaction was performed at a higher temperature.Although the 'H n.m.r. spectrum of the 2,lbenzisoxazole 3a in deuterochloroform solution at 0" to 20" gave only one peak, indicating that Can. J. Chem. Downloaded from www.nrcresearchpress.com by 54.245.55.244 on 05/12/18For personal use only.

A variety of anthracenes react with dibenzoylethylene and diacetylethylene to give substituted bicyclooctadienes as Diels–Alder adducts. Treatment of these with phosphorus pentasulfide gives derivatives of benzenonaphtho[c]thiophenes, which are thiophene analogues of triptycene. Reaction of the anthracenes with dibenzoylacetylene gave substituted bicyclooctatrienes, which on treatment with phosphorus pentasulfide gave inseparable mixtures of the benzenonaphtho[c]thiophenes and benzenonaphtho[c]-furans. Attempted retro Diels–Alder reactions of the thiophenes were unsuccessful.

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1H-Tetrazoles occupy an important role in modern medicinal chemistry, but few methods for their modification exist. Many extant protocols require the use of a difficult to remove N-alkyl-protecting group, precluding the products from use as carboxylate bioisosteres, the major role of tetrazoles in pharmaceuticals. We herein report a convenient, protecting-group-free lithiation-substitution protocol for benzylic tetrazoles. Metalation with n-BuLi at 0 °C followed by electrophilic trapping gave a range of α-functionalized benzyltetrazoles in up to 91% yield.