Pd-catalyzed heteroannulation

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 popular Pd-catalyzed method for the production of furans and benzofurans involves reactions of alkynols. Acyclic alkynols are converted into furans, while benzene substituted alkynols are transformed into benzofurans. The use of this strategy is widespread for the synthesis of benzofurans however, it is occasionally used for the syntheses of furans. For example, intramolecular alkoxylation of alkyne 189 proceeds via an alkenylpalladium complex and subsequent carbonylation to form furan 190 [156, 157]. In addition, 3 -hydroxyalkyl-benzo[/)J furans were 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 [158]. In a related series of experiments, Qing demonstrated that alkynes 191 could be efficiently converted into furans 192 [159]. 

Pyrrolopyrazine is a core structure that has drawn some attention from the pharmaceutical industry, both as a surrogate structure for indole or azaindole and as a novel kinase inhibitor [120]. The synthesis of 6,7-diphenylpyrrolopyrazines (238) was achieved via a Pd-catalyzed heteroannulation of 237, utilizing both conventional and microwave heating conditions. The reaction proceeded under microwave irradiation conditions to yield the desired products in modest yield [121]. 

As part of their study on gastric (H+/K+)-ATPase inhibitors, Kang et al. developed a simple and convenient synthetic approach to 1,2,3-trisubstituted pyrrolo[3,2-c]quinolines by means of Pd-catalyzed heteroannulation of 4-amino-3-iodoquinoline derivatives with internal alkynes [76]. The following scheme shows an example of a reaction using 4-arylamino-3-iodoquinoline derivative 180 with alkyne 181 to provide 1-arylpyrrolo [3,2-c]quinoline 182, illustrating the possibility of introducing diverse substituents to 1-arylpyrrolo[3,2-c]quinolines. In addition, a Pd-catalyzed domino hydroarylation/ cyclization process was reported to form substituted quinolines [77]. Thus, 3-arylquino-lines were prepared in 56-74% yield when 3,3-diethyl-l-phenyl-1-propyne and aryl iodide were refluxed in ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate [(bmim)BF4 ],in the presence of HCO2H, EtjN, and palladium catalyst. Meanwhile,... 

Starting from 2-ethynylaniline, some 2-aryl- and 2-cycloalkenyl-indoles have been prepared in the solution phase by coupling and subsequent cyclization utilizing Pd-catalyzed reactions [157, 158]. Adaptation of the reaction sequence to the solid phase was first reported in ref [152]. Since the authors introduced only one point of diversity in their synthesis, a later publication -with three independently variable residues is discussed here [159]. Interestingly, Pd-catalyzed heteroannulation of terminal alkynes has been similarly used for the solid-phase synthesis of benzofurans utilizing ortho-hydroxy aryl iodides [160]. 

Some synthetic approaches to pyrazines relied on metal-assisted reactions. A synthesis of 6-substituted 5H-pyrrolol2,3-bJpyrazines via Pd-catalyzed heteroannulation from W-(3-chloropyrazin-2-yl)methanesulfonamide and alkynes was developed <04TL8087>, and 3- and 5-substituted 2(l//)-pyrazinones were prepared by Suzuki and Heck reactions using 3,5-dichloro-2(l//)-pyrazinones <04TL1885>. An improved synthesis of 6-substituted-5//-pyrrolo 2,3-iiJ-pyrazines via microwave-assisted Pd-catalyzed heteroannulation was developed <04TL8631>, and the reaction of a-diazo-P-keto esters with Boc amino acid amides in the presence of a Rh catalyst gave, after air oxidation, pyrazin-6-ones 111, which were then converted into tetrasubstituted pyrazines 112 <04OL4627>. 

Internal Alkynes. Several applications of the Larock synthesis of indoles have been published where heterocycles are used as substrate. f " In the Larock method for indol construction, Pd-catalyzed heteroannulation of internal alkynes using ort/to-iodoanilines are used. Similarly, Pd-catalyzed heteroannulation of internal alkynes using ortho-amino-iodopyridine substrates produces azaindoles (Scheme 103). The method provides a convenient access to a structurally diverse range of 5-, 6-, and 7-azaindoles, 304, 305, and... 

The synthesis of 11-methoxymacroline 350 (239) required 6-methoxy-D-tryptophan 359, which was prepared by Larock s Pd-catalyzed heteroannulation of iodoaniline 360 and the propargyl compound 361 (prepared in turn from the Schollkopf chiral auxiliary derived from L-valine), followed by removal of the chiral auxiliary, and N(l)-methylation (Scheme 28). The 6-methoxy-D-tryptophan 359 was then transformed into the pentacyclic sarpagine derivative 362, via the 11-methoxytetracyclic ketone 354, following the same protocol as that employed in the A -methylsarpagine synthesis (vide... 

Several 2,3-disubstituted pyrrolo[2,3-fe]pyridines (7-azaindoles) 24 have been obtained with high regioselectivity by Pd-catalyzed heteroannulation of alkynes with 2-amino-3-iodopyridine derivatives under the experimental conditions shown in Scheme 14 (1998TL627). The easy manipulation of substituents was also demonstrated. 

G. Raffa, M. Rusch, G. Bahne, N. Monteiro, A Pd-catalyzed heteroannulation approach to 2,3-disubstituted furo[3,2-c]coumarins, Org. Lett. 

---