We report herein that the cyclialkylation reactions involving (4-halo-1-alkenyl)metals 1 are widely applicable to the synthesis of 1-monoorganyl-, and 1,2-diorganylcyclobutenes and related heterofunctional cyclobutenes containing a metal group or iodine at an alkenyl carbon center. These latter compounds can be readily converted to 1,2-diorganylcyclobutenes via cross-coupling involving organometals, such as those containing Li 2 and Zn(Pd) 3 (Schemes 1-3). Recent developments of novel procedures for the preparation of stereo-and regiodefined (4-halo-1-alkenyl)metals and the corresponding iodides (1) via Zr-promoted alkene-alkyne coupling 4 and those of 4-iodo-3-buten-1-ols (3), 5,6 readily convertible to 1, via treatment of 5-lithio-2,3-dihydrofuran with organocoppers or organolithiums have made it possible to achieve the reported general synthesis of cyclobutenes via cyclialkylation.Synthetic methods permitting direct synthesis of cyclobutenes 7 that are not substituted with alkylidene, benzo, or heteroatom groups, such as oxo, from acyclic precursors are relatively rare. 8-13 Representative earlier methods include (i) photocyclization of 1,3-butadienes, 8 (ii) photocycloaddition of alkynes with enones, 9 (iii) treatment of 1,4-dichloro-1-butenes with Mg, 10 (iv) baseinduced extrusion of SO 2 from sulfones, 11 (v) Lewis acidcatalyzed cycloaddition of alkynes with alkenes, 12 and (vi) condensation of propiolic esters with olefins catalyzed by CpFe(CO) 2 BF 4 . 13 Unfortunately, these reactions either give relatively low yields of cyclobutenes often produced along with other significant byproducts or appear to be of limited scope. Although the McMurry olefination 14a is promising, 1,2-diphenylcyclobutene appears to be the only reported example. 14 In short, none has been demonstrated to be general, high-yielding, and selective. We previously reported two related but discrete cyclialkylation routes to cyclobutenes. 1 One involves a σ-type cyclialkylation of (4-halo-1-alkenyl)lithiums related to the Parham synthesis of benzocyclobutenes. 15 The other proceeds via a novel π-type cyclization of (4-halo-1-(trimethylsilyl)-1-alkenyl)metals. Although the potential synthetic utility of these reactions has already been indicated by their application to the synthesis of grandisol 1a and sterpurene, 16 the scopes of these reactions as reported in our previous papers 1 were rather limited. (1) (a) Negishi, E.; Boardman, L. D.; Tour, J. M.; Sawada, H.; Rand, C. L. J. Am. Chem. Soc. 1983, 105, 6344. (b) Boardman, L. D.; Bagheri, V.; Sawada, H.; Negishi, E. J. Am. Chem. Soc 1984, 106, 6105. (c) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A. J. Am. Chem. Soc. 1985, 107, 2568. (d) Negishi, E.; Boardman, L. D.; Sawada, H.; Bagheri, V.; Stoll, A. T.; Tour, J. M.; Rand, C. L.

Linear [6.6.6] tricyclic moieties whose center ring is made of two atoms of differing size (here primarily thioxanth-9-ones and phenoxathiins) monosubstituted meta to the sulfur by C(O)NHMe include potent and selective inhibitors of monoamine oxidase A. Similarities with effects on SAR of acylamide and of diazapentacyclic substitution on such rings, including positional variables, the requirement for monomethylation (primary and dialkylated amides are inactive and higher monoalkylated amides show little or no potency), and that sulfur is optimally in sulfone form, suggest that binding to the enzyme occurs similarly in each series. No significantly greater rise in blood pressure was found in rats given sufficient 8 to inhibit most brain and liver MAO A and then followed by oral tyramine than was found on administration of tyramine to controls. This is in contrast to a large blood pressure rise in rats pretreated with phenelzine followed by tyramine, and in accord with the belief that an inhibitor selective for MAO A which is reversibly bound to the enzyme and therefore displaced by any ingested tyramine will not lead to the "cheese effect" (hypertension during treatment with MAO inhibitors usually caused by ingestion of foods containing tyramine).

It is believed that a monoamine oxidase (MAO) inhibitor specific for MAO A, which is reversibly bound to this enzyme and displaceable by tyramine, will be an antidepressant which will not cause a rise in blood pressure when tyramine-containing foods are ingested. Some linear tricyclic compounds with a larger and a smaller group forming the central ring and with a lipophilic group ortho to the larger group (here mostly the SO2 function of phenoxathiin 10,10-dioxide) are reported to have the sought properties. Potency appears to require short length and relatively small cross section for the substituent. The 1-ethyl (13), 1-vinyl (22), 1-trifluoromethyl (27), and 1-iodo (76) phenoxathiin dioxides had the best profiles. Structure-activity relationships, syntheses, and a possible rationale for the selectivity of these compounds and related tricyclics are given. Compound 13 was selected for further development. A summary of pharmacological data for 13 is given.

Five unique fluorinated analogs, 8a‐c and 15a,b, of the monoamine oxidase‐A inhibitor 3‐iso‐propoxyphenoxathiin 10,10‐dioxide (II) were prepared via oxidation of the corresponding phenoxathiins 7 and 14. 3‐Fluoro‐7‐isopropoxy‐ 7a, 2‐fluoro‐3‐isopropoxy‐ 7b, and 2,7‐difluoro‐3‐isopropoxyphenoxathiin (7c) were prepared by a modification of the Mauthner synthesis which involved cyclization of the corresponding 2‐hydroxy‐4‐isopropoxythiophenols 4 with the appropriate 2‐halonitrobenzenes 5 in the presence of potassium tert‐butoxide. Preparation of 2,8‐difluoro‐3‐isopropoxyphenoxathiin (14b) from 4b and 2,4‐difluoronitrobenzene (5c) employing similar methods failed, leading instead to a novel macrocycle 9. Attempts to obtain 2‐fluoro‐7‐isopropoxyphenoxathün (14a) and the 2,8‐difluoro analog 14b via trifluoroacetic acid deprotection of intermediate thio‐protected 2‐nitrophenyl 2‐thiophenyl ethers 11a and c followed by cyclization of the resulting thiols were also unsuccessful. Deprotection of 11a with trifluoroacetic acid produced only complex product mixtures, while similar deprotection of 11c and treatment of the resulting crude product with potassium tert‐butoxide in refluxing dimethylformamide produced the 2,7‐difluorophenoxathiin analog 7c, a result consistent with a Smiles rearrangement of the intermediate thiol 12 prior to ring closure. The phenoxathiins 14 were ultimately prepared by a modification of a relatively unexploited phenoxathiin synthesis involving the intramolecular radical substitution at sulfur of 2‐aminophenyl 2‐thiophenyl ethers 13 containing para‐methoxybenzyl and methoxymethylthio‐protecting groups.

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Convenient and General Synthesis of 1-Monoorganyl-and 1,2-Diorganylcyclobutenes via Cyclialkylation.-Two different approaches to the title compounds (cf. (II) and (VI)) are reported. The preparation of the starting materials (I) follows a published procedure. -(NEGISHI, E.; LIU, F.; CHOUEIRY, D.; MOHAMUD, M. M.; SILVEIRA, A. JUN.; REEVES, M.;