Intramolecular C—O bond formation

Metal-catalyzed intramolecular C—O bond formation has proven to be a crucial tactic in benzofuran synthesis. Willis et al. demonstrated that a-(t -haloaryl) ketones could act as benzofuran precursors via an enolization/palladium-catalysed intramolecular O-arylation reaction with a DPEPhos-derived palladium catalyst system (Scheme 24.29, disconnection D-1 and Scheme 24.30) [109]. 

Although only a few examples have been reported, palladium-catalyzed C—O bond formation has proved useful in the synthesis of isocoumarins. Wang and Shen utilized an intramolecular C—O bond formation in tandem with an intermolecular Stille reaction to produce isocoumarin products such as 66 in excellent yields from gem-dibromovinylarene substrates such as 65 (Scheme 24.37) [129], The Stille reaction was postulated to occur first with the E-alkenyl bromide before the intramolecular C—O bond-forming cyclization and ensuing elimination of methyl bromide. Tadd et al. reported a palladium-catalyzed carbonylative isocoumarin synthesis, beginning with the same a-(o-haloaryl) ketone substrates as those used previously in benzofuran synthesis (Scheme 24.30) [130]. 

Scheme 13. Intramolecular ipso SnAr C-O bond formation.

Unimolecular cyclizations involving C-N bond formation include intramolecular alkylations and acylations were applied for a variety of azocines, while macrocyclic O-alkylations and ketalizations are the most reliable methods for oxocine core synthesis through C-O bond formation. Other types of unimolecular cyclizations are scarce and erratic, and they usually depend on stereochemistry of the open-chain precursors and require tuning of the functional groups involved. 

Intramolecular palladium-catalyzed cyclization reactions have also been used to synthesize pyrazole derivatives. iV-Aryl-iV-(o-bromobenzyl)hydrazines 494 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2//-indazoles 495 (Equation 101) <20000L519>. Palladium-catalyzed intramolecular C-N bond formation of iV-acetamino-2-(2-bromo)arylindolines 496, followed by hydrolysis and air oxidation in the presence of aluminium oxide, allowed the preparation of indolo[l,2-3]indazoles 498 via intermediate 497 (Scheme 58) <2002TL3577>. 3-Substituted pyrazoles have been prepared from the intramolecular cyclization of A -tosyl-iV-(l-aryl/ vinyl-1-propyn-3-yl)hydrazine and then exposme of the reaction mixture of the cyclization to potassium /i //-butoxide <1997SL959>. iV-Aryl-iV -(o-bromobenzyl)hydrazines 499 or [A -aryl-A -(t>-bromobenzyl)hydrazinato-A ]-triphenyl-phosphonium bromides 501 participated in a palladium-catalyzed intramolecular amination reaction to give 1-phenyl-l//-indazoles 500 (Scheme 59) <2001TL2937>. 

Buchwald et al. demonstrated that the intramolecular palladium-catalyzed C—O bond formation was an attractive means to assemble the oxygen heterocycles 557 (Scheme 170).243 They applied this methodology to the synthesis of MKC-242 (560), a benzodioxane antidepressant (Scheme 171).243b... 

The initial studies on Pd-catalyzed C—O bond formation were conducted as intramolecular reactions to form oxygen heterocycles (Eq. 1). It is known that copper complexes will catalyze these transformations, and copper acetylide is particularly valuable for these... 

A direct and easy palladium-catalyzed C-H bond oxidative cyclization for the synthesis of polycyclic aromatic hydrocarbons (PAHs) was reported. The intramolecular palladium-catalyzed direct oxidative C-H bond functionalization for the C-O bond formation was demonstrated, which... 

Various other acetylenic substrates can also be used for the synthesis of furans by intramolecular gold-catalyzed C-O bond formation. Thus, acetylenic diols gave a variety of monosubstituted, disubstituted, or trisubstituted fiirans by dehydrative cyclization in the presence of 2 mol% Au[P(r-Bu)2(o-biphenyl)]Cl/AgOTf or AuCl at 0 °C (Scheme 4-8In the latter case, the catalyst loading can be decreased to 0.05 mol% by scavenging water with activated molecular sieves and conducting the reaction in refluxing THF. 

Intramolecular Pd(0)-catalyzed Stille reaction of organotin reagents with electrophiles leading to C—C o-bond formation in synthesis of heterocycles, particularly, macrocyclic lactones 99JCS(P1)1235. 

The authors also used this transformation to investigate the overall stereochemical course, and in particular the pathway of oxidative intermolecular aminopalladation. Within this detailed mechanism, they arrived at the conclusion of an overall sequence of syn-aminopalladation and anti-C-O bond formation to explain the observed product stereochemistry for aminoacetoxylation of an internal alkene. This final result matches with the observed stereochemistry from related intramolecular cases [87]. 

C—O Bond Formation Trapping of ArLi intermediates can be achieved with trimethyl borate or triisopropyl borate [41]. The intermediate hthium borate complexes, when treated with water, afford oxidizable boronates. With fluorodimethoxyborane, spontaneous elimination of flnoride leads directly to boronates, which are precursors of phenols by oxidation. Chemoselective metal-heteroatom exchange or deprotonation generates carbanions in the presence of dialkyl peroxides, and intramolecular trapping provides an efficient route to dihydrobenzofuranes and dihydrobenzopyrans [42]. 

A route to /3-keto-macrolides, based on some earlier work of Eschenmoser, involves an intramolecular C—S rather than C—O bond formation (Scheme 11). High dilution conditions are necessary, with yields varying between 25 and 58% this approach may be expedient with polyfunctional molecules as a variety of functional groups (e.g. olefins, acetylenes, esters, ketones, acetals) are unaffected by the reagents used. Diplodialide A has been prepared by this route. 

The first synthesis and structural characterisation of a cyclic pyr-anopterin monophosphate (cPMP) analogue, namely cyclic phosphate (14) has been reported by Berkessel et al. Key steps of this 13-step synthesis involved (1) acylation of c /t/jo-lithiated 2-halopyrazines (13) (2) ring-closing by intramolecular nucleophilic aromatic substitution and C-O bond formation, and (3) introduction of the phosphoric diester moiety (Scheme 5). 

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