Heteroannulation

The mechanism of action of the cyanation reaction is considered to progress as follows an oxidative addition reaction occurs between the aryl halide and a palladium(O) species to form an arylpalladium halide complex which then undergoes a ligand exchange reaction with CuCN thus transforming to an arylpalladium cyanide. Reductive elimination of the arylpalladium cyanide then gives the aryl cyanide. 

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A variety of heteroannulated 1,2-diazepines 12 has been obtained by photoisomerization of the bicyclic /V-inunes 11, where R1, R2 represents part of a five-or six-mem bered heterocycle.143 The precursors of the imines, the AT ami no mesitylenesulfonates 10 (Ar = Mes), are prepared from the parent heterocycles by reaction with O-mesitylenesulfonylhydroxylamine.144... 

Table 4. Heteroannulated 1,5-Diazocines by the Condensation of Heterocyclic 1-Amino-2-carboxylic Acid Derivatives...

Scheme 7-10 A proposed reaction path of Pd-catalyzed carboylative heteroannulation ofo-iodothiophenol with allene...

A wide variety of heterocycles can be readily prepared by the heteroannulation of alkynes. For example, the palladium-catalyzed annulation of internal alkynes by 2-iodoanilines provides easy access to 2,3-disubstituted indoles by a process that involves initial reduction of Pd(OAc)2 to Pd(0), oxidative addition of the aryl halide to Pd(0), c/s-addition of the arylpalladium... 

Pyrazole iminophosphorane 620 reacts with phenyl isocyanate and several ArTADs in a three-component reaction to provide low yields of the corresponding heteroannulated pyrazoles 621 as the final products (Equation 93) <1994JOC3985>. 

A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel-Crafts heteroannulation of enaminone precursors <06SL749>. A lac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <06OL3573>. 

The Bohlmann-Rahtz synthesis of trisubstituted pyridines from /3-aminocrotonates and an ethynyl ketone has found application in the preparation of a variety of heterocycles based on the substituted pyridine motif. Bagley and coworkers have developed a microwave-assisted modification of this one-pot heteroannulation method that is best conducted in dimethyl sulfoxide at 170 °C for 20 min, providing the desired pyridines in 24—94% yield (Scheme 6.227) [406, 407]. Typically, 2 equivalents of the /3-aminocrotonates were employed. 

An enantioselective synthesis of 2-alkylidene-l,4-dioxanes is based on the Pd-catalysed heteroannulation of alkynyl carbonates to benzene-1,2-diol in the presence of chiral diphosphine ligands (Scheme 63) . 

Other allylic functionalizations have been reported. The catalytic heteroannulation of allylic benzylamines leads to heterocyclic products, whereas a stoichiometric version of this reaction leads to both allylic and aryl functionalization (Equation (189)).1S3 1S3a... 

Larock extended this Pd-catalyzed diene heteroannulation to other dienes and anilines [399], including functionalized dienes leading to, for example, ketotetrahydrocarbazoles [400]. Back has employed 1-sulfonyl-l,3-dienes in this 2-vinylindoline synthesis [401], and the use of 1,3-dienes in constructing indolines has been adapted to the solid phase by Wang [402]. Interestingly, Larock has shown that the electronically-related vinylcyclopropanes undergo a similar cyclization with o-iodoanilines to form 2-vinylindolines, e.g., 310 [403, 404]. Vinylcyclobutane also reacts in a comparable manner. 

The acyclic version of Larock s heteroannulation was successfully applied to the synthesis of highly substituted pyridines [166]. The annulation of rert-butylimine 210 with phenyl propargyl alcohol produced pyridine 211 regioselectively in excellent yield. The regiochemistry obtained was governed by steric effects. Furthermore, the choice of imines was crucial to the success of the heteroannulations. terr-Butylimine was the substrate of choice, since all other imines including methyl, isopropyl, allyl and benzyl imines failed completely to produce the desired heterocyclic products. 

The 5-, 6-, and 7-azaindoles were synthesized via the Pd-catalyzed heteroannulation of internal alkynes using orf/w-aminopyridine derivatives in an extention of Larock s indole synthesis [169], LiCl was found to be an essential component in order to obtain regioselectivity, reproducibility and improved yields. 

In 1985, Tsuji s group carried out a Pd-catalyzed reaction of propargyl carbonate with methyl acetoacetate as a soft carbonucleophile under neutral conditions to afford 4,5-dihydrofuran 109 [89-91]. The resulting unstable 109 readily isomerized to furan 110 under acidic conditions. In addition, they also reported formation of disubstituted furan 112 via a Pd-catalyzed heteroannulation of hydroxy propargylic carbonate 111 [92], Presumably, an allenylpalladium complex (c/. 114) was the key intermediate. 

Substituting the benzene ring with a double bond, Pd-catalyzed intramolecular alkoxylation of alkyne 122 also proceeded via an alkenyl palladium complex to form furan 123 instead of a benzofurans [99, 100]. In addition, 3-hydroxyalkylbenzo[fc]furans was prepared by Bishop et al via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis, [101]. 

Allenones have also been transformed into substituted furans via Pd-catalyzed heteroannulation. Ma and Zhang converted 1,2-dienyl ketones and organic halides to substituted furans under the agency of Pd(Ph3P)4 and Ag2C03. Addition of 10 mol% of Ag2C03 was crucial for the reaction of the organic halide. For example, allenone 134 and 5-bromopyrimidine were converted to pyrimidylfuran 135 in excellent yield [106]. 

The most unique feature of furan synthesis using palladium chemistry is heteroannulation. Enones, ynones and ynols all have been annulated into furans and benzofurans. More importantly, trapping the reactive Pd(II) intermediates at different stages with electrophiles offers unique opportunities to synthesize substituted furans and benzofurans. 

The reaction of 2-alkynylphenols with tertiary propargyl carbonates in the presence of a Pd(0) catalyst gave 2-substituted 3-allenylbenzo [bjfurans in moderate to high yields (Eq. 9.121) [93]. This heteroannulation is thought to proceed by a cr-allenylpal-ladium complex (Scheme 9.26). 

Scheme 9.26 Possible mechanism for heteroannulation promoted by cr-allenylpalladium intermediate.

This last section underlines once again the great synthetic potential of the iminophosphorane group, as predicted by Staudinger and Meyer after their first successful synthesis of the P = N double bond. Recently, iminophosphoranes have proved to be novel and versatile heteroannulation components in their reaction with two other components heterocumulenes and heteroarenes (C=X double bonds). 

Bagley MC, Chapaneri K, Dale JW, Xiong X, Bower J (2005) One-pot multistep Bohlmann-Rahtz heteroannulation reactions synthesis of dimethyl sulfomycinamate. J Org Chem 70 1389-1399... 

Tandem Enlargement of the Six-Membered Ring in Heteroannulated Tetrahydropyridines under the Action of Activated Alkynes - A General Method for the Synthesis of Condensed Azocines 116... 

The chemistry of heteroannulated azocines has not been explored in detail owing to the lack of efficient methods for their synthesis. The exception is azocinoindoles, which have been investigated extensively due to the host of alkaloids with an azocinoindole fragment in their structure. 

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