Pyrrole, 2-chloro-, synthesis

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. ... 

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... 

Pyridinium bromide perbromide efficiently brominates pyrroles already substituted by electron-withdrawing substituents and also gives a high yield of 3-bromoindole in its reaction with indole. In conjunction with sulfuryl chloride, it has been used in the synthesis of 3-bromo-2-chloro-, 2-bromo-3-chloro- and 2,3-dibromo-indole (81SC253). 3-Methylindole reacts with A-bromosuccinimide in acetic acid to give the 2-bromo derivative which reacts further with an excess of A-bromosuccinimide to yield 2,6-dibromo-3-methylindole (B-70MI30500, 72HC(25-2)127) whilst in aqueous or alcoholic media, 3-bromo-3-methylox-indole is produced (cf. Scheme 15). All of these reactions proceed via the 3-bromo-3A-indolium cation, but the course of the reaction depends not only upon the orientation or... 

A Diels-Alder reaction of N-(carbomethoxy)pyrrole and phenylsulfonyl 6-chloro-3-pyridyI acetylene was used similarly in a total synthesis of epibatidine, an alkaloid heralded for its high analgesic potency [536]. 

Recently, the synthesis of 5-aryl-2-oxopyrrole derivative 210 as synthon for the highly substituted pyrrole 211 as starting compound for fused heterocycle 212 was published [56], Diethyl 6-bcnzyl-5-phenyl-6//-thieno[2,3-/ ]pyrrolc-2,4-dicarboxylatc 212 was prepared from ethyl l-benzyl-5-chloro-4-formyl-2-phcnyl-l //-pyrrolc-3-carboxylate 211 and ethyl 2-sulfanylacetate in refluxing ethanol (Scheme 41). 

Our interest in expanding the acylative pyrrole annulation approach to additional heterocyclic systems has led to an efficient synthesis of pyrrolo[3,2-c]pyridin-2-ones and pyrido[3,4-6]pyrrolizidin-l-ones starting from 4-chloro-N-benzyl-2(l//)-pyridinone and amino acid salts.811 Over the years pyrrolo[3,2-c]pyridines (5-azaindoles)41 have been of interest for applications as elements in new drug design, nucleotide analogues,42 and biochemical tools. However, available synthetic routes to multifunctionalized members from this class of heterocyclic structures are limited.41 43... 

Recently, 4-chloro-3-formylcoumarin and amino derivatives have been used in the synthesis of 2-functionalized [l]benzopyrano[4,3-fo]pyrrol-4(lfT)-one derivatives via the Fischer-Fink reaction [7]. Although this new synthesis requires neither protection nor harsh conditions, there are still... 

The 3-chloro-l,7-dimethylpyridazino[3,4-(7][l,3]oxazine-4,5-dione (149) was prepared in a four-step synthesis starting with (Z)-methyl-3-(3,6-dichloro-l-methyl-4-oxo-l,4-dihydropyridazin-5-yl)-2-methylacrylate (146) which is converted with sodium azide into the 6-azido compound (147). Heating in o-dichlorobenzene at 150°C results in cyclization to methyl 3-chloro-l,6-dimethyl-4-oxo-1,4-dihydro(7//)pyrrolo[2,3-c]pyridazine-5-carboxylate (148) via a nitrene intermediate. Ozonolysis effects ring-enlargement of the pyrrole ring into the 3-chloro-l,7-dimethylpyridazino[3,4-d][l,3]oxazine-4,5-dione (149) (Scheme 26) <79JHC1213>. 

Efficient preparation of dicarboxylic acid 1275 <2001J(P1)1039> was the starting point of the novel, convenient synthesis of a known, central nervous system active 8-chloro-4//,6//-pyrrolo[l,2- r][4,IJbenzoxazepine 1276 (Equation 281). In the two-step synthesis the dicarboxylic acid 1275 was reduced to the diol, then this was treated with silica gel. Silica is acidic enough to promote elimination of water under mild conditions. In this way, compound 1276 could be prepared conveniently while the known methods (use of P2O5 or other strong acid) initiate serious side reactions of the pyrrole moiety. 

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