Arynes alkylation

These reactions follow first-order kinetics and proceed with racemisalion if the reaction site is an optically active centre. For alkyl halides nucleophilic substitution proceeds easily primary halides favour Sn2 mechanisms and tertiary halides favour S 1 mechanisms. Aryl halides undergo nucleophilic substitution with difficulty and sometimes involve aryne intermediates. 

This is clearly an elimination/addition mechanism [in contrast to the addition/elimination of SN2 (aromatic)] and formally parallels, in its genesis, the elimination reactions of simple alkyl halides that we shall consider subsequently (p. 246). Direct evidence in support of the aryne pathway is provided by the fact that the halides (98), (99) and (100),... 

The first clue to the existence of the SrnI mechanism came from product studies both in aliphatic and aromatic cases. It was noticed that in the reaction of benzyl and substituted benzyl chlorides with the 2-nitropropane anion, oxygen alkylation, yielding the oxime and then the aldehyde, occurs exclusively in the case of benzyl chloride and 3-nitrobenzyl chloride, whereas, with 4-nitrobenzyl chloride, the yield of aldehyde is only 6% and the carbon-alkylated (104) product is obtained in 92% yield (Kornblum, 1975). This was interpreted as the result of a competition between 8, 2 (O-alkylation) and S l (C-alkylation) reactions. In the aromatic case, it was observed that the reaction of 5- and 6-halopseudocumenes with KNHj in liquid ammonia (Kim and Bunnett, 1970) forms the 5- and 6-pseudocumi-dines in a ratio which is the same whether the starting compound is the 5- or 6-isomer in the case of the chloro- and bromo-derivatives, as expected from an aryne mechanism (Scheme 9), whereas much more non-rearranged... 

It has been shown that, in the presence of lithium diethylamide at —70 °C, bromoben-zoic acids form arynes which may react with arylacetonitriles to yield, predominantly, 2-cyanobenzoic acids. The reaction of alkyl and aryl isocyanides with benzyne may yield benzamide derivatives, showing their ability to act as charge-reversed equivalents to isocyanates. The generation and cyclization of a benzyne-tethered alkyllithium have been reported, and lead to a convenient synthetic route for 4-substituted indans. ... 

The reactive zwitterions arising from the nucleophilic attack of imines 479 on the benzyne generated in situ from 2-(trimethylsilyl)phenyl triflate 478 proved to be an appropriate molecular scaffold for the capture of CO2 with sufficient electrophilicity to yield 2-aryl-3,l-benzoxazin+-ones 480 (Equation 53). Both substituents of the C=N bond affected the course of the reaction considerably the best yields were achieved by using imines with electron-rich or neutral aryl groups on the carbon, and benzyl or nonbranched chain alkyl substituents on the nitrogen atom. With substituted derivatives of 478, the unsymmetrically substituted arynes led to regioisomeric products <2006JA9308>. 

A mild and efficient process for the acyl-alkylation of arynes to give ortho-substituted arenes has been reported (Scheme 63)." The transformation results in the formation of two new C-C bonds by the net insertion of an arene unit into the a,/3-single bond of a /3-keto ester. 

Metal alkyls of late transition metals readily undergo decomposition by /3-hydrogen elimination.31 In principle, it should therefore be possible to prepare aryne complexes of dw metals by thermolysis of appropriately substituted late transition-metal aryl complexes. However, in practice this... 

Support for this mechanism is found in the reactions of 74 (R = H) (which can be isolated) with 3-hexyne, acetone, acetonitrile, and selenium to give products expected of an aryne complex.55 Cyclometallation of other zirco-nium-benzyne complexes with alkyl-substituted Cps has been observed in a few other cases.2... 

Zbiral, E. Arynes as electrophilic reagents. I. Reaction with alkyl phosphoranes. Monatsh. Chem. 1964, 95, 1759-1780. 

Some typical reactions of stannylanionoids which result in the formation of a C-Sn bond are shown in Table 4-1. Primary and secondary alkyl halides react mainly by substitution, but tertiary alkyl halides give mainly elimination. Aryl halides can also give arynes through elimination reactions. 

On the other hand, arynic reactions are also of interest in the synthesis of benzocyclenones substituted on the aromatic ring by an alkyl group in the ortho position of the carbonyl group. In these syntheses, ortho alkyl bromobenzenes must be used and arynic condensation intermediaries are of the 108 type ... 

A major route to arynes and hetarynes proceeds by dehydrohalogenating molecules which are deactivated with respect to substitution by an SnAt mechanism. Frequently employed bases are amide and alkylamide ions, alkyl and aryl lithium reagents and tew-butoxide ion. In spite of various claims this approach has not been used successfully to generate a 5-membered hetaryne.68,7S)... 

The second synthesis of cephalotaxine was reported by Semmelhack and co-workers (24), also in 1972. Their convergent strategy involved the alkylation of spirocycle 49, prepared in several steps from p)nTolidone 45, with p-nitrobenzenesulfonate ester 50, prepared from piperonal in 45-55% overall yield as shown in Scheme 2. The resulting key intermediate, 51a (X = Cl), was converted to ( )-cephalotaxinone (22), initially through an aryne intermediate. Route I, Scheme 3, in 15% yield. Cephalotaxinone was then converted to ( )-cephalotaxine (1) upon reduction with diisobutyl-aluminum hydride. The Semmelhack group expended considerable effort studying the conditions of the nucleophilic aromatic substitution (i.e., 51a-c... 

The indolizidinedione derivatives (322), easily available from l-alkyl-3,4-dihydroisoquinolines and oxalyl chloride, react with arynes to give 13-substituted 8-oxo-protoberberines (323), probably through the mechanism outlined in Scheme 73. This chemistry has been exploited in the total synthesis of the alkaloid (+ )-corydaline <86JOC278i>. 

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