Benzyne with pyridine

The reaction of benzyne with pyridine has been studied only at 690°C (benzyne generated from phthalic anhydride).96 The main condensable products in order of decreasing abundance were naphthalene, phenyl-pyridines (three isomers), bipyridyls, and quinoline. It is necessary to consider two modes of 1,4-cycloaddition, followed by rearomatization, to account for the formation of naphthalene (Eq. 4) and quinoline (Eq. 5), respectively. 

Lester Friedman and Frauds M. Logullo prepared substituted benzynes by diazotizing substituted anthranilic acid. This is a mild, room-temperature reaction which permits simultaneous reactions of the benzynes with suitable acceptors to prepare halogen. —NO , — ClL. and —OCH3 derivatives. They have also prepared new heterocyclic arynes, such as 3-pyridine from 3-amino-isonicotinic add. 

Neutral borabenzene complexes with pyridine undergo interesting addition processes. For example, the reaction of 74 with dimethyl acetylenedicarboxylate leads to the [4+2] adduct 27, a new borabarrelene derivative, via a Diels-Alder reaction in 90% isolated yield (Scheme 2) <2006OL2875>. Similarly, trapping of the borabenzene ring of 74 with in r(/ -generated benzyne affords the novel benzoborabarrelene 75 in 23% yield. The X-ray crystal stmcture of... 

From the addition reactions of phthalic anhydride with pyridine, naphthalene was formed in much greater quantity than quinoline isoquinoline was either totally absent or present in only minute amounts. These facts indicated (a) if there were much 1,2-addition of benzyne, it occurred predominantly at the 1,2 and 3,4 atoms in pyridine (b) 1,4-addition took place at carbon atoms in preference to a nitrogen and a carbon atom. Studies with other systems indicate that arynes have a decided preference for 1,4- over 1,2-addition. 

The major products from the reaction of arynes with thiophene and benzothiophene by addition and insertion are shown in Table 11. Benzyne from phthalic anhydride reacted with thiophene at 690° to give naphthalene and benzothiophene by 1,4-addition and loss of sulfur, and by 1,2-addition and loss of acetylene, respectively, as well as phenyl-thiophene by insertion (Fields and Meyerson, 1966d, 1967e) (Scheme 19). The ratio of naphthalene to benzothiophene was about 9 1, nearly the same preference for 1,4-over 1,2-addition as was inferred from the reaction of benzyne with dichlorobenzenes and pyridine at the same temperature, and again reflects the strong tendency of benzyne to act as a dienophile. 

Cycloaddition reactions were illustrated in CHEC-I by, for example, reactions of benzyne with pyridazine A -oxides and A -acetylimides (to give 2-hydroxy- and 2-acetylaminophenylpyridazines), inverse electron demand cycloaddition reactions of pyridazinecarboxylates with electron rich acetylenes (to give pyridines and benzenes) and dipolar cycloaddition reactions of a pyridazinone with... 

Biehl s group [97] has developed an efficient syntesis of benzo[4,5]thieno [2,3- ]pyridines and appropriate naphthyl-analogues by reaction of in situ generated benzyne with Barton esters. For example, when the acetone solution of anthranilic acid (58) was added dropwise to the refluxing mixture of the Barton ester 527 and isopentyl nitrite in dichloromethane, after an additional 3-h refluxing period, the respective benzo[4,5]thieno[2,3-A]pyridine (528) was obtained in 52% yield. Scheme 52. 

Whereas only one dehydrobenzene, benzyne, has been detected, two pyridynes are possible. Thus, the scheme we can write ab initio for the action of a nucleophile on the isomeric monosubstituted derivatives of pyridine involving 2,3- (26) and/or 3,4-pyridyne (31) is more complicated than that for the analogous reaction of the corresponding benzene derivative. The validity of this scheme can be checked using data available in the hterature on reactions of halogenopyridines with potassium amide and hthium piperidide involving pyridynes. 

Since the nitrogen in pyridine is electron attracting it seemed reasonable to predict that the trihalopyridynes would also show the increased electrophilic character necessary to form adducts with aromatic hydrocarbons under similar conditions to those employed with the tetra-halogeno-benzynes. The availability of pentachloropyridine suggested to us and others that the reaction with w-butyl-lithium should lead to the formation of tetrachloro-4-pyridyl-lithium 82 84>. This has been achieved and adducts obtained, although this system is complicated by the ease with which pentachloropyridine undergoes nucleophilic substitution by tetrachloro-4-pyridyl lithium. Adducts of the type (45) have been isolated in modest yield both in the trichloro- and tribromo- 58) series. 

A method for synthesis of anthraquinones is by reaction of cyanophthalide carban-ions with benzynes [162], It is particularly useful for the access of 2 aza-l,3,8-trimeth-oxyanthraquinone because of the high regioselectivity imposed by the methoxy groups and the nitrogen atom of the pyridine. 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

O-Acyl derivatives of thiohydroxamic esters (Barton esters) react with benzynes to afford a tricyclic thiophene ring system thus the pyridine derivative 30 gives benzo[4,5]thieno[2,3-A pyridines 31 (Scheme 14) <2002JOC3409, CHEC-III(3.11.3.3)900>. 

Insertion of benzyne into tributyltin chloride forms an o-chlorophenyltin . In the presence of pyridine, neat, or in ethanol, Ph2SnBr2 and PhjSnBr react with allyl bromide and 3-bromocyclohex-l-ene to form the corresponding 1,2-addition products . The reaction is not general and, for example, allyl alcohols do not react. 

Based on our hypothesis that the acetylene was too flexible for 15/16 to function as a brake, we redesigned the system by deleting the acetylenic unit and connecting the pyridine directly to the triptycene as in 22. Unfortunately, the synthesis of 22 proved unsuccessful, because the reaction of the anthracene of 23 with benzyne then failed (Scheme 4). 

Alternatively, reduction of 176 with sodium borohydride (probably to a dihydropyridine, although this intermediate was not characterized) followed by thermolysis in acetic acid or acetic anhydride affords anthracene (93%) and pyridine or hydropyridines. These reaction sequences have been employed for the synthesis of overcrowded anthracene derivatives containing substituents with unfavorable peri interactions100 of particular interest is the conversion of 178 via its 1 2 adduct with benzyne into the pentaphenes 179 and 180. 

Katritzky and co-workers have demonstrated the 1,3-dipolar character of 3-oxidopyridinium betaines by cycloaddition of olefinic and acetylenic dipo-larophiles, including in some cases benzyne, across the 2- and 6-positions of the pyridine ring. Thus, 1 -phenylpyridinium 3-oxide (194) and benzyne afford the 1 1 adduct 196 (35%) 1-methylpyridinium 3-oxide (195) and benzyne give a 1 2 adduct (21%), which is formulated as 198 and its formation explained in terms of the mechanism outlined in Scheme 18 (cf. Scheme 12).103 Attempts to substantiate this mechanism were unsuccessful, since compounds 199 (R = CN, C02Me) analogous to the intermediate 1 1 adduct 197 failed to react with benzyne under similar conditions. 1,6-Dimethylpyridinium 3-oxide with benzyne gave a 1 2 adduct of the same type as 198.103... 

The reaction of pyridine 1-oxide (243) with benzyne has been studied under various conditions the highest yield (53%) of the major product, 3-o-hydroxy-phenylpyridine (246), was obtained when benzyne was generated by oxidation... 

Oxazole cycloadditions have been reported with alkyne dienophiles (tandem Diels-Alder addition and retro Diels-Alder loss of a nitrile leads on to furans), benzyne (the primary adduct can be isolated), and with typical alkene dienophiles and the adducts can be transformed into pyridines (8.14.1.4). 

Treatment of a series of benzynes 145 with the 2-selenoxo-2//-pyridine derivatives 146 under various conditions has been shown to lead to formation of the benzo[6]seleno[2,3-6]pyridines 147 in modest yields <04JHC13>. 

It has been reported that the furoindole (361) underwent Diels-Alder reactions with DMAD, N-phenylmaleimide and benzyne to give the expected products <84JOC45l8>. Treatment of 3-chloro-4-iodo-pyridine with t-butyllithium followed by addition of (361) led to a mixture of the isomeric Diels-Alder adducts (362) and (363) in 15% yield. Deoxygenation and desulfonylation of (362) and (363), gave a readily separable mixture of the pyridocarbazole alkaloids ellipticine (364), and isoellipticine (365), respectively (Scheme 14) <84JOC45l8,83TL5435>. 

To conclude this section, it is important to note that alkenes are not the only hydrocarbon dienophiles that are useful partners in the Diels-Alder reaction. Alkynes and even benzyne are quite useful. As a structure proof of an intermediate in Pandey s synthesis of epiboxidine, the methyl carbamate of pyrrole (34) reacted with dimethyl-2-butynoate (35),in the presence of aluminum chloride (see sec. 11.6.A for a discussion of Lewis acid catalysis) to give a 90% yield of azanorbomadiene (36). A benzyne derivative of pyridine was... 

The latter method, so commonly used for benzyne, is less used with pyridyne because the precursor is difficult to prepare and somewhat unstable. As an alternative, the use of 3-(3,3-dimethyltriazen-1 -yl)pyridine-4-carboxylic acid 718 has been recommended. It is readily prepared as shown, and is a shelf-stable crystalline solid. It decomposes in refluxing... 

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