Annulation reactions internal alkynes

Related to the Heck reaction is the Larock annulation of internal alkynes, which is a general route to heterocyclic and carbocyclic systems. Especially attractive is the construction of the pharmaceutically important indole ring system via palladium-catalyzed coupling of 2-iodo-aniline and the corresponding V-methyl, acetyl, and tosyl derivatives with a wide variety of internal alkynes. The catalytic process appears to involve arylpalladium formation, regioselective addition to the carbon-carbon triple bond, and subsequent intramolecular palladium displacement.- ... 

The rhodium-catalyzed annulation of internal alkynes with naphthylcarbamates was found to afford either benzoindole or benzoquinoline derivatives depending upon the additives used in the reaction (Scheme 3.91) [94]. The key component in this chemistry was copper acetate. In the presence of this copper salt (0.5equiv), benzoindoles were preferentially formed in high yield. If the copper salt was never added to the reaction mixture, benzoquinolines were formed in high yield. This chemoselective reaction is an attractive approach to the synthesis of these compounds due to the operational simplicity of the process and the ease in which either substrate could be selected. 

Pyrrole derivatives are prepared by the coupling and annulation of o-iodoa-nilines with internal alkynes[291]. The 4-amino-5-iodopyrimidine 428 reacts with the TMS-substituted propargyl alcohol 429 to form the heterocondensed pyrrole 430, and the TMS is removed[292]. Similarly, the tryptophane 434 is obtained by the reaction of o-iodoaniline (431) with the internal alkyne 432 and deprotection of the coupled product 433(293]. As an alternative method, the 2,3-disubstituted indole 436 is obtained directly by the coupling of the o-alky-nyltrifluoroacetanilide 435 with aryl and alkenyl halides or triflates(294]. 

An efficient synthesis of functionalized carbazoles was developed by the palladium-catalyzed annulation of a variety of internal alkynes. This reaction involves arylpalladation of the alkyne, followed by intramolecular Heck olefination, and double bond isomerization. The iodoindole 588 reacts with the alkyne 589 in the presence of a catalytic amount of palladium(O) to give substituted carbazoles 590. In this reaction two new C-C bonds are formed in a single step. Higher reaction temperatures were necessary due to the low reactivity of the iodoindole (566) (Scheme 5.29). 

The insertion of alkynes into arylpalladium complexes might also be accompanied by the insertion of carbon monoxide into the resulting vinylpalladium intermediate. The carbonylative annulation of TV-protected 2-iodoanilines and internal alkynes under an ambient pressure of carbon monoxide resulted in the formation of 2-quinolones (4.14.), The protection of the nitrogen atom in the aniline is crucial to the success of the reaction. 

Abstract Palladium readily catalyzes the cross-coupling of functionally substituted aryl or vinylic halides and alkynes to afford a wide variety of heterocycles and carbocycles in one efficient step. Terminal alkynes presumably initially generate aryl (vinylic) alkynes, which under the reaction conditions are rapidly cyclized by the palladium or copper salts employed in the first step to produce the final product. Internal alkynes apparently react by carbo-palladation of the alkyne and subsequent intramolecular nucleophilic substitution of the palladium moiety to generate the observed products. A variety of other closely related processes have also been reported, including the simultaneous annulation of alkynes and car-... 

Internal alkynes will also readily undergo palladium-catalyzed annulation by functionally substituted aromatic or vinylic halides to afford a wide range of heterocycles and carbocycles. However, the mechanism here appears to be quite different from the mechanism for the annulation of terminal alkynes. In this case, it appears that the reaction usually involves (1) oxidative addition of the organic halide to Pd(0) to produce an organopalladium(II) intermediate, (2) subsequent insertion of the alkyne to produce a vinylic palladium intermediate, (3) cyclization to afford a palladacycle, and (4) reductive elimination to produce the cyclic product and regenerate the Pd(0) catalyst (Eq. 28). 

Rhodium(lll)-catalyzed redox—neutral coupling of N-phenoxyacet-amides and alkynes led to benzo[l)]furan derivatives (13AGE6033). Furo[2,3-l)]pyran-6-one derivatives were prepared via rhodium(II)-catalyzed reactions of diazo compounds and ethynyl compounds (13T9294). Copper-mediated oxidative annulation of phenols and unactivated internal alkynes afforded benzo[l ]furan derivatives (13CS3706). E t-kaurane maoecrystalV was produced via C-H functionalization (13JA14552). Rhodium-catalyzed intramolecular C-H... 

Disubstituted isocoumarins arise from the copper(II)-catalyzed addition of o-halobenzoic acids to active internal alkynes (13JOC1660), rhodium(III)-mediated oxidative coupling ofbenzoic acids with disubsti-tuted alkynes (13T4454), palladium(II)-catalyzed tandem annulation reaction of o-alkynylbenzoates with methyl vinyl ketone (13T8626), and nickel(II)-promoted t-butyl isocyanide insertion in 2-(o-bromophenyl)-1-ethanones followed by hydrolysis (Scheme 69) (13SC3262). 

Larock s group studied the application of palladium catalysts in the ear-bonylative annulation of internal allqmes with 2-iodobenzyl alcohols. Seven- and eight-membered ring lactones were synthesized and the scope and limitations of the process were examined. With a lower reaction temperature, non-alkyne-inserted phthalides were produced. 

N-Annulation of a,(3-enone with internal alkyne To a MeOH solution (0.2 mL) of 2-methyl-5-methylenenonan-4-one (33.7 mg, 0.20 mmol) and 4-octyne (44.1 mg, 0.40 mmol) were added [Cp RhCl2]2 (3.1 mg, 0.005 mmol) and Cu(OAc)2 H2O (79.9 mg, 0.40 mmol), NH4OAC (30.8 mg, 0.40 mmol), and the reaction mixture was stirred at 130°C under a nitrogen atmosphere for 6h. After cooling to room temperature, the solvent was removed in vacuo, and the resulting erude mixture was subject to flash column chromatography (n-hexane ethyl acetate = 90 1) to afford 3-butyl-2-isobutyl-5,6-dipropylpyridine (51.8 mg, 0.188 mmol) in 94% yield. 

The reaction of phenylphosphine oxides (197) with internal alkynes, mediated by AcOAg, has been found to proceed as a dehydrogenative annulation, involving C-H... 

Annulation reactions between unactivated alkynes and a range of heteroatom-containing substrates have facilitated the preparation of a host of heterocycles. For example, the preparation of isoquinolones was achieved through a rhodium-catalyzed annulation of internal acetylenes with 0-methyl hydroxamates (Scheme 3.78 and Example 3.12) [81]. The reaction conditions were quite mild, and most reactions were complete within 16 h. The overall process was redox neutral and used a catalytic amount of cesium acetate to promote the reaction. Additionally, the process was not appreciably sensitive to the electronic composition of the 0-methyl hydroxamates. One of the more attractive aspects of this chemistry was the observation that the rhodium-catalyzed reaction... 

In 2009, Fagnou et al. discovered a Rh(III)-catalyzed synthesis of substituted isoquinolines 45 by oxidative annulation between N-tBu aromatic aldimines and internal alkynes [28a]. The -Bu leaving group was eliminated as isobutene in the reaction process and avoided the generation of a mixture of isoquinolines. However, the substrate scope was limited to aldimines, and a stoichiometric amount of Cu(0Ac)2-H20 was used as an external oxidant. Mechanistic studies omitted the ort/zo-alkenylation/64 -electrocyclization/oxidation pathway, and intermediate H2 was crucial for the C-N reductive elimination to proceed (Eq. (5.44)). At the same time, Satoh and Miura groups also exploited a Rh(III)-catalyzed oxidative cyclization of N-H benzophenone imine and internal alkynes to give isoquinolines [28b]. Both aromatic and aliphatic alkynes were agreeable for this protocol, but a stoichiometric amount of the Cu(II) salt was required. 

In 2008, Jones et cd. disclosed a stoichiometric Rh(III)-mediated reaction of JV-benzylidenemethylamine with dimethyl acetylenedicarboxylate to give the corresponding isoquinolinium salt [52a]. Inspired by this work, in 2012 we developed a Rh(III)-catalyzed one-pot synthesis of isoquinolinium salts 104 from benzaldehydes, primary amines, and internal alkynes by C-H activation and annulation [52b]. This was the first report for the synthesis of isoquinohnium salts by catalytic C-H activation. It is noteworthy that the current procedure was successfully apphed to the total synthesis of isoquinolinone alkaloid oxy-chelerythrine 105 (Eq. (5.99)). In 2013, our group and Huang independently found that various isoquinohnium salts could be synthesized from aryl ketimines, 2-phenyl pyridines, and alkynes under similar reaction conditions, as shown in Eqs. (5.100)-(5.102) [52c-e]. 

Shortly after, the same group reported a Rh(III)-catalyzed oxidative annulation of benzyl alcohols with internal alkynes for the synthesis of isochromenes (Scheme 6.16a) [28]. Interestingly, a,a-dimethylallyl alcohol also underwent the oxidative annulation reaction to give the corresponding products in good yields... 

Recently, Ackermann and coworkers reported aliphatic hydroxyl-directed oxidative annulation reactions of benzyl alcohols with alkynes to form isochromene derivatives (Eq. (7.11)) [16]. This C-H/O-H functionalization process performed smoothly by using [RuCl2(/ -cymene)]2 (5 mol%)/AgPFg (20 mol%) as catalyst and Cu(OAc)2 H2O (20 mol%) as oxidant under an atmosphere of air. Various tertiary benzylic alcohols, a,a-dimethylallyl alcohol, and diverse internal alkynes are appropriate substrates for this transformation. The reaction occurred with moderate to high regioselectivity for unsymmetrical alkylarylacetylene, and an irreversible C-H metalation step is involved in the catalytic cycle. 

Matsunaga, Kanai, and coworkers developed a Cp Co -catalyzed redox-neutral annulation reaction of an Af-carbamoyl-indole bearing a morpholinyl group and an internal alkyne to afford a pyrrololndolone derivative (Scheme 10.12) [32]. The annulation reaction employs a catalytic system consisting of a cationic... 

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