Arylations indolizine

Ten years later R. Fischer et al. (Bayer) discovered 2-aryl-indolizine-2,4-diones with herbicidal and miticidal activity [59] and reported compound 3 (Fig. 9.5) to inhibit plastidic ACC of grasses [6]. 

Indolizines were arylated under similar conditions selectively in the 3-position (6.90.). A detailed mechanistic study of the transformation revealed that in this reaction the arylpalladium species, formed in the first step of the catalytic cycle, is attached to the indolizine core in an electrophilic substitution step, which is followed by reductive elimination. The presence of alternate routes such as Heck-type insertion, oxidative addition of the C-H bond, or transmetalation were excluded on the basis of experimental evidence.121... 

A Michael-type addition reaction of substituted ethylenes (39) with 2-phenylindolizines yields 3-substituted indolizines (40) <66AC(R)752). Arylation occurs on treatment of an indolizine with the salt (41) (67TL4321) or with diphenylcyclopropenone (68TL5537), yielding the tetrafluoroborate (42). 

Vilsmeier reaction, 4, 1051 Furo[3,2-6]pyrroles MO calculations, 6, 979 synthesis, 4, 1069 6, 1009 Furo[3,4-a]pyrrolo[2,1,5-cd]indolizine nomenclature, 1, 22 Furopyrylium salts, 4, 993-995 Furoquinolines biosynthesis, 4, 992 occurrence, 4, 988 pharmacology, 4, 992 reactions, 4, 988 synthesis, 4, 989 Furo[3,2-c]quinolines, 4, 991 Furo[3,4-fe]quinoxaline, 1,3-diphenyl-synthesis, 4, 993 Furoquinoxalines, 4, 992 Furo[2,3-6]quinoxalines synthesis, 4, 992 Furosemide toxicity, 1, 136 Furospinulosin UV spectra, 4, 587 Furospongin-I mass spectrometry, 4, 583 Furo[3,4-d][l,2,3]triazole, 2,6-dihydro-synthesis, 6, 996 Furo[3,4 -d][ 1,2,3]triazoles synthesis, 6, 996 Furoxan, 4-amino-3-aryl-tautomerism, 6, 404 Furoxan, 4-amino-3-methyl-synthesis, 4, 414 Furoxan, 4-aryl-3-methyl-rearrangement, 6, 408 Furoxan, 3-aryl-4-nitro-synthesis, 6, 414 Furoxan, 4-benzoyl-3-methyl-oxime... 

Indolizines are obtained in good yield when compounds of type 80 are treated with 25% hydrazine hydrate at room temperature92 [Eq. (16)]. The R1 and R2 may be methyl or aryl groups, but the yields are low if R2 is not an aryl group. 

Not surprisingly, azo derivatives of indolizines are readily prepared since the aryl diazonium ion is a good electrophile. Many compounds of this type (e.g., 129188) have been synthesized,183 188,189 some of which are used as dyes.190... 

Substituted indolizines 18 are formed in Chichibabin reactions of l-[alkyl(aryl)carbonylmethyl]-2-alkylpyridinium halides 17 (Scheme 11) <1972AJC1003>. Various modifications of this method are used for the preparation of many other pyrrolo[l,2-< ]azines and pyrrolo[l,2- ]azoles. Indolizines can also be made by intramolecular Michael additions, e.g., by the cyclization of 2-acylpyridine 19 (Scheme 12). 

Park C-H, Ryabova V, Seregin IV, Sromek AW, Gevorgyan V (2004) Palladium-catalyzed arylation and heteroarylation of indolizines. Org Lett 6 1159-1162... 

Palladium-catalyzed direct (hetero)arylations of indolizines proceeded in a highly efficient and regioselective manner (Scheme 9.42) [103], Mechanistic studies strongly supported an electrophilic substitution-type mechanism for this transformation. 

Scheme 9.42 Palladium-catalyzed regioselective direct arylation of the indolizine 148...

Treatment of triazolopyiidine 132b with phenylacetylene in the presence of Rh(Il) acetate smoothly produced a mixture of cyclopropene 135 and indolizine 136. Cyclopropene 135 does not undergo further isomerization into indolizine 136 under these conditions (07AGE4757). However, the selectivity of the trans-annulation (136 over 135) could be dramatically improved by using rhodium(II) heptafluorobutyrate as catalyst. Thus, trans-annulation of 132b with a series of aryl and alkenyl alkynes proceed highly chemoselectively to produce indolizines 136. Electron-rich, electron-deficient and sterically hindered aryl alkynes are nearly equally effective (Scheme 31). 

Novel 2-acyl-6-aryl substituted indolizines were obtained starting from 4-acyl-p)rrrole-2-carbaldehyde and a, (3-unsaturated esters, in the presence of K2CO3 in DMF, with pelds between 42 and 68% after 8-12 h at 50°C [26]. 

Park S, Kim I. Electron-withdrawing group effect in aryl gliopu of allyl bromides for the successful s)mthesis of indolizines via a novel [3+3] annulation approach. Tetrahedron. 2015, 71 1982-1991. 

Until very recently, no examples of a transition metal-catalyzed cycloisomerization of allenylpyridines into indolizines had been reported. A well-known instability of these seemingly versatile precursors prevented any significant use in the construction of the indolizine nucleus. The only precedent of this transformation was documented by Gevorgyan and coworkers. Thus, 1,3-disubstituted alkyl- and aryl-indohzines 316 were synthesized via the Cu(I)-catalyzed 5-endo-trigcydLzaiion of the corresponding disubstituted allenylpyridines 315, whereas the cycloisomerization of gem-disubstituted allene failed to produce the expected monosubstituted indolizine (Scheme 9.109) [290]. 

Direct arylations of indolizines 40 using aryl bromide 41 as electrophile was reported by Gevorgyan. These transformations proceeded selectively at position C-3 (42) and sensitive functionalities were tolerated (Scheme 9). Detailed mechanistic studies strongly supported an electrophilic aromatic substitution-type mechanism to be operative. Additionally, Gevorgyan developed a palladium-catalyzed direet arylation of 1,2,3-triazole 43 using aryl bromide 44 as electrophiles (Scheme 8). Experimental and theorical studies suggested that reactions are likely to proceed via electrophilic aromatic substitution-type mechanism. 

Gevorgyan et al. were the first to develop a synthetically useful protocol for the C3-arylation of indolizines with aryl and heteroaryl bromides. In the presence of a PdCl2(PPh3)2-KOAc catalyst system and phenyl bromide, indolizine (132) was C3-phenylated to afford 133 in 71% yield (Scheme 10.44). The arylation study provided the groundwork for a subsequent sp -sp coupling method of indolizine with differentially substituted alkynyl bromides whereby product 135 could be isolated in 62% yield. ... 

In both methodologies, the authors implicate an electrophilic substitution mechanism analogous to that proposed by Miura in the arylation of azole compounds the most electron-rich C3 position of the indolizine attacks an aryl/alkynylpalladium... 

In a later study, Zhao reported the arylation of indolizines with aryltrifluoroborate salts and used this same Pd(OAc)2/AgOAc catalyst system to affect C3-alkynylation with phenylpropiolic acids via a decarboxylative pathway. ... 

Abstract The chapter is devoted to the synthesis and application of indolizines bearing fluorine atoms, perfluorinated aUcyl (aryl) groups, and COCF3 fragments. 

Indolizine has also been reported to participate in C-H functionalization reactions with aryl halides (eq 2) ... 

The title compound was employed as a catalyst in the direct benzylation of thiazoles (eq 2), thiophenes, indolizines, im-idazopyridines, oxazoles, and furans. The Csp -Csp arylation was successful on a wide range of electron-rich and deficient... 

Low yields were obtained in the absence of pivalic acid however, employing greater than 30% pivalic acid did not further improve yields or reactivity. Substrates that performed well included C3-substituted benzothiophenes, C2-substituted thiophenes, pyrroles, imidazole, triazole, imidazopyridine, thiazole, and oxazoles, which could be efficiently arylated with aryl bromides. Unfortunately, benzofuran produced low yields (29% with 2-bromotoluene), and furans encountered issues with diarylation, which could be minimized by using more sterically hindered aryl bromides. Arylation of indolizines could be achieved, albeit electron-deficient aryl bromides required longer reaction times (16-24 h). Heterocyclic aryl bromides, such as 3-bromopyridine, could also be employed with thiazole. Problematic aryl halides included cyano, nitro, acetyl, pyridyl functionalities, and N-heterocyclic V-oxides. Other coupling partners, such as aryl tri-flates and aryl chlorides, performed poorly under the reaction conditions. Unsuitable heterocycles included unprotected imidazoles, 2-aminothiazole, isoxazole, benzothiazole, and benzoxa-zole, which failed to produce arylated products. 

Mamedov VA, Saifina DF, Gubaidulhn AT, Saifina AF, Rizvanov IKh, Ganieva VR (2009b) A novel rearrangement in the system 3-[aryl(chloro)methyl]quinoxalin-2(17/)-one-a-picoline as a simple and efficient route to indolizin-2-ylbenzimidazoles. Russ Chem BuU, Int Ed 58 (9) 1986-1990. doi 10.1007/sl 1172-009-0271-4... 

A highly related method showed that pyrrole ring formation from 50 to produce indolizines 52 is promoted efficiently by various transition-metal catalysts, such as platinum(II) [17], indium(lll) [17], copper(I) [18,19], gold(I) [18], and silver(I) [18] (Scheme 19.11). It should be noted that these reactions were reported independently by the three research groups at nearly the same time [17-19]. The palladium-catalyzed two-component reaction of alkynylpyridines 53 with aryl halides is a convenient strategy for the synthesis of highly substituted fused pyrroles 55 [20]. 

Pyridinopropargyl phosphates 77 were converted to 1,3-disubstituted indolizines 78 in the presence of copper catalysts (Scheme 27.28) [37]. The reaction involves a 3,3-phosphatyloxy rearrangement. The phosphatyloxy group in the indolizine 78 can be substituted to aryl and alkyl groups by Kumada cross-coupling. 

---