3 -chloro-4- pyrrole

Rearrangement of A-haloazoles to C-haloazoles is a typical reaction of /V-haloazoles capable of halogenation at a ring-carbon atom. A -Chloro-pyrrole 1, while heated with methanol, gives a mixture of pyrrole (30%), 2-chloropyrrole (—30%), 3-chloropyrrole (15-20%), and 2,5-dichloro-pyrrole (—10%) (82JOC1008). On the addition of the basic resin Amberlist A-21 to the reaction mixture the formation of 2-chloro-, 3-chloro-, and 2,5-dichloropyrrole sharply decreases (to 0.5-3%) (Scheme 26). 

Pyridazinones may undergo ring contraction to pyrroles, pyrazoles and indoles, the process being induced either by an acid or base. The structure of the final product is strongly dependent on the reaction conditions. For example, 4,5-dichloro-l-phenylpyridazin-6(lFT)-one rearranges thermally to 4-chloro-l-phenylpyrazole-5-carboxylic acid (12S), while in aqueous base the corresponding 4-hydroxy acid (126) is formed (Scheme 40). 

In the pyrrole series, ester groups a to nitrogen are more readily hydrolyzed by alkali, but those in a /3 position more readily by acid. A methoxycarbonyl group in the 2-positlon is meta directing thus bromination yields mainly 4-bromo-2-methoxycarbonylpyrrole. Free radical chlorination with f-butylhypochlorite gives the 5-chloro derivative. 

Pyrrole-3-carboxylic acid, l-benzoyl-5-chloro-2,4-dimethyl-ethyl ester chlorination, 4, 271... 

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield. ... 

Carbon tetrachloride was also found to react with pyrryl potassium to give 3-chloropyridine, however the mechanism is obscure and would justify further investigation. In a preparatively useful reaction, pyrrole and chloroform in the vapor phase at 500-550° gave 3-chloro-pyridine (33%) and a little 2-chloropyridine (2-5%). No interconversion of the isomers occurred under these conditions, though pyrolytic rearrangement of N-alkylpyrrole to 3-substituted pyridines is considered to involve 2-alkylpyrroles as intermediates. There is some independent evidence that dichlorocarbene is formed in the vapor phase decomposition of chloroform. ... 

Chlorpheniramine maleate 1 -(o-Chloro)-benzyl-2-di- ec-butyl-aminoacetyl-pyrrole Viminol... 

As with the pyrroles, N-chloroamides have been widely employed in indole chlorination [66JOC2627 80H( 14)867 81JOC2054]. Chloroindolen-ines may be isolated under controlled conditions [80H( 14)867 81JOC2054], 2-Phenyl-, l-methyl-2-phenyl-and 3-methyl-2-phenyl-indoles were converted by 1-chloroisatin (NCI) into the 3-chloro derivatives... 

Amino-7-chloro-2,3(l//,4//)-quinoxalinedione (116) and 2,5-dimethoxytetra-hydrofuran (117) gave 6-chloro-7-(pyrrol-l-yl)-2,3-(l//,4//)-quinoxaline-... 

In the frame of a medicinal project at J J Pharmaceutical Research and Development aimed at designing new potent and selective glycogen synthase kinase-3/i (GSK-3/3) inhibitors, the C-3 derivatization of the 1-methyl-4-[l-alkyl-lff-indol-3-yl]-lff-pyrrole-2,5-dione scaffold was explored [31]. Microwave-assisted Stille reaction of 3-chloro-l-methyl-4-[l-alkyl-lff-indol-3-yl]-lH-pyrrole-2,5-diones with (2,4-dimethoxy-5-pyrimidinyl)(tributyl) stannane at 200 °C yielded in 6 min the desired 3,4-diaryl-lff-pyrrole-2,5-diones in moderate yields (Scheme 12). 

CN 3-chloro-4-(2,5-dihydro-17/-pyrrol-1 -y I)-a-methy Ibenzeneacetic acid... 

Nitrobenzofurazan 240 and 4-chloro-7-nitrobenzofurazan 232 also condense with isocyanoacetates in the presence of the non-nucleophilic base l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give tricyclic pyrrole derivatives 241 in excellent yields (Scheme 60) <2005T11615>. 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

Among early reported Pd-catalyzed reactions, the Mori-Ban indole synthesis has proven to be very useful for pyrrole annulation. In 1977, based on their success of nickel-catalyzed indole synthesis from 2-chloro-fV-allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [122]. Compound 102, easily prepared from 2-bromo-lV-acetylaniline and methyl bromocrotonate, was adopted as the cyclization precursor. Treatment of 102 with Pd(OAc)2 (2 mol%), Ph3P (4 mol%) and NaHCQ3... 

Halogenated pyrroles can serve as the aryl halide in Stille couplings with organotin reagents. Scott has used this idea to prepare a series of 3-vinylpyrroles, which are important building blocks for the synthesis of vinyl-porphyrins, bile pigments, and indoles [77]. Although 3-chloro-and 3-bromopyrroles fail completely or fared poorly in this chemistry, 3-iodopyrroles 101 work extremely well to yield 3-vinylpyrroles 102. 

As will be seen in this chapter and in the rest of the book, the Heck reaction and its numerous variations represent a fantastically powerful set of tools available to the heterocyclic chemist. Although most Heck chemistry that involves pyrroles is intramolecular or entails synthesis of the pyrrole ring, a few intermolecular Heck reactions of pyrroles are known. Simple pyrroles (pyrrole, A-methylpyrrole, A-(phenylsulfonyl)pyrrole) react with 2-chloro-3,6-dialkylpyrazines under Heck conditions to give mixtures of C-2 and C-3 pyrrole-substituted pyrazines in low... 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other rc-sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines [22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[fc]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

Halopyrimidines also couple with stannanes of heterocycles such as furans [41], azaindoles [42], pyridines [43-46], thiazoles, pyrroles [46] and thiophenes [47], A representative example is the coupling of 3-tributylstannyl-7-azaindole 72 with 5-bromopyrimidine to furnish heterobiaryl 73 after acidic hydrolysis [42]. Moreover, a selective substitution at the 5-position was achieved when 4-chloro-5-iodopyrimidine 74 was allowed to react with 2-thienylstannane to provide thienylpyrimidine 75 [47]. 

Rearrangements of TV-chloro compounds in heterocyclic systems have been studied. TV-Chloroindole 51 gives62 the 3-chloro isomer 52. With pyrrole (53) there are two... 

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