Propargylation/ cyclization sequence

SCHEME 8 Furocoumarin formation through a propargylation/cyclization sequence. 

In their total synthesis of isolaurallene (66), Crimmins and co-workers [85] relied on the anti-selective S -substitution of a propargylic sulfonate with LiCuBr2 (cf. Schemes 18.21 and 18.22) instead of the enyne cyclization sequence, which had turned out to be unsatisfactory in terms of stereocontrol (Scheme 18.26). 

Cyclizations. Cyclization of hydroxylated propargyl sulfones may involve isomerization to the corresponding allenyl sulfones which should behave as Michael acceptors. Access to the indolizidine skeleton by an intramolecular Michael reaction of 5-tosyl-4-pentenamide and subsequent alkylation at nitrogen and carbon is quite efficient. A synthesis of resorcinols from dimethyl acetonedicarboxylate and alkyl alkynoates involves a Michael reaction-Dieckmann cyclization sequence. 

Previously, Olivi etal. [50] had shown that a consecutive amine propargylation-Sonogashira sequence proceeds very efficiently in the sense of a three-component coupling- cyclization to furnish the benzofuran 27 or the aniline 28 upon applying the standard Sonogashira catalyst system (Scheme 12.18). 

Similar to the cycloaddition of allyl cations30, allenyl cations have been found to undergo cycloadditions with alkenes to afford bicyclic compounds31. The allenyl cations were generated from propargyl chlorides by treatment with Lewis acids. This reaction sequence proceeds via the cyclization 34 -------> 3532, in spite of the fact that... 

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

A possible mechanism for the observed transformation includes the sequence outlined in Scheme 2.327 (i) propargyl (A) - allene (B) tautomerization, (ii) 8jt-cyclization (C), (iii) N-0 cleavage (diradical D), (iv) diradical recombination (cyclopropanone derivative E), and (v) one or two step cyclizations of the azadienyl cyclopropanone into azepinone F. The occurrence of cyclopropanones (type E), as intermediates, is supported by the formation, in some cases, of isoindoles (type I) (789) as minor products (Scheme 2.327) (139, 850, 851). 

Treatment of the propargylic alcohol 144, readily prepared from condensation between benzophenone (143) and the lithium acetylide 101, with thionyl chloride promoted a sequence of reactions with an initial formation of the chlorosulfite 145 followed by an SNi reaction to produce in situ the chlorinated and the benzannulated enyne-allene 146 (Scheme 20.30) [62], A spontaneous Schmittel cyclization then generated the biradical 147, which in turn underwent a radical-radical coupling to form the formal [4+ 2]-cycloaddition product 148 and subsequently, after a prototropic rearrangement, 149. The chloride 149 is prone to hydrolysis to give the corresponding 11 H-bcnzo h fluoren-ll-ol 150 in 85% overall yield from 144. Several other llff-benzo[fc]fluoren-ll-ols were likewise synthesized from benzophenone derivatives. 

A tandem sequence of double [2,3]-sigmatropic rearrangement-six-electron electro-cyclization-4 + 2-cycloaddition has been shown to convert acyclic ene-bis(propargyl alcohols) such as (71), via the corresponding bis-sulfenic ethers such as (72), into anthracene (with an intermolecular final cycloaddition) or phenanthrene or related (with an intramolecular cycloaddition) skeletons. The sequence is illustrated in Scheme 12 for synthesis of a steroid skeleton, estra-l,3,5(10)-trien-17-one (73).81... 

Butenolides,1 Addition of the Schwartz reagent to a protected propargylic alcohol (2) followed by carbonylation provides an acyl zirconocene complex (3). This is not isolated but treated in situ with iodine to provide an intermediate (a) that cyclizes to a 3,5-disubstituted butenolide (4). Optically active substrates undergo this sequence with no loss of optical purity. 

The silver-catalyzed cycloisomerization of allenic carboxylic acids to butenolides was also reported by Marshall and co-workers.329 Starting from the enantiomerically enriched propargyl mesylate 390, palladium-catalyzed hydroxycarbonylation led to the chiral allenecarboxylates 391 which afforded the butenolides 392 upon treatment with silver nitrate (Scheme 114). Unfortunately, partial racemization could not be avoided in this two-step sequence. In a related study, Ma and Shi330 have shown that the combination of Pd(PPh3)4 and Ag2C03 promotes the cyclization of allenecarboxylates to the corresponding butenolides, accompanied by the introduction of aryl or alkenyl groups at C3. 

Mechanistically, this new insertion-CI-Diels-Alder hetero domino sequence can be rationalized as follows (Scheme 64) After the oxidative addition of the aryl halide 115 or 118 to the in situ generated Pd(0) species the arylpalladium halide 120 intramolecularly coordinates and inserts into the tethered triple bond via a syn-carbopaUadation to furnish cyclized vinylpalladium species 121 with a p-acceptor substitution in a stereospecific fashion. Transmetallation of the in situ generated copper acetylide 122 gives rise to the diorganylpalladium complex 123 that readily undergoes a reductive elimination and liberates the electron poor vinylpropargylallyl ether 124. The triethylamine catalyzed propargyl-allene isomerization furnishes the... 

Scheme 47). In the synthesis of 9-acetoxyfukinanolide (140), the propargyl ester derived from the precursor 138 underwent successful cyclization to yield the lactone 139 [95] (Scheme 48). A retroaldol-aldol sequence on the hydroxy lactone derivative resulted in the epimerization at the quaternary diastereogenic center leading to the natural configuration. The allylic propiolate 141 reacted with tribu-tylstannane to produce the Z-a-stannylmethylene-y-butyrolactone 142, which served as an intermediate in the stereoselective synthesis of gadain (143) [96] (Scheme 49). 

This section covers cyclizations to the pyrrole nucleus catalyzed by other metals (Ti, Mn, Ru, Pd, Pt, Zn, In). Dembinski and co-workers used zinc(II) chloride as ligand-free catalyst for the microwave-assisted cyclization of homopropargyl azides 26 to afford substituted pyrroles 27 (Scheme 8) [62]. A similar methodology for the synthesis of 2,4,5-trisubstituted pyrroles was described by Driver et al. employing substituted 1-azidobuta-l,3-dienes in a cyclization reaction using catalytic amounts of zinc(ll) iodide [63]. A three-component zinc-catalyzed one-pot cyclization of aromatic and aliphatic propargylic acetates, silyl enol ethers, and primary amines to substituted pyrroles has been described by Zhan et al. The reaction sequence includes propargylation of the silyl enol ether, amination, 5-exo-(7ig-cyclization, and isomerization [64]. Hiroya and co-workers have shown... 

Metal-catalyzed cyclization/conjugate addition sequences involving substituted propargyl epoxides have also been employed in the synthesis of highly functionalized furans. These reactions are generally catalyzed by... 

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