Pyrrolo pyrazines reactions

Interesting constructs of molecules such as pyrrolo-pyridines, pyrrolo-quinolines, pyrrolo-pyrazines, pyrrolo-quinoxalines and pyrrolo-pyrimidines could be constructed by intramolecular Chichibain-type reaction. Davis and co-workers were the first to show the first of these examples, where p-methylazines react with nitriles to give the corresponding fused bicycle in the presence of excess base (2.5 equiv). For example, P-picoline reacts with benzonitrile in the presence of LDA to give the pyrrolo-pyridine adduct 61 in a 90% yield and traces of 62a. Under similar conditions and if... 

H,3H- Pyrrolo[l, 2-c]oxazole-l, 3-dione, 5,6,7,8-tetrahydro-IR spectra, 6, 978 [2.2](2,5)Pyrrolophane, N-aryl-rearrangements, 4, 209 Pyrrolophanes natural products, 7, 764 synthesis, 7, 771 Pyrrolophanes, N-aryl-synthesis, 7, 774 (2,4)Pyrrolophanes synthesis, 7, 771 Pyrrolo[3,4-c]pyran-4-ones synthesis, 4, 288 Pyrrolopyrans synthesis, 4, 525, 526 Pyrrolopyrazines synthesis, 4, 526 Pyrrolo[l, 2-a]pyrazines synthesis, 4, 516 Pyrrolo[2,3-6]pyrazines Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolo[3,4-c]pyrazole, 1,3a,6,6a-tetrahydro-structure, 6, 976 synthesis, 6, 1019 Pyrrolopyrazoles synthesis, 5, 164 Pyrrolo[l,2-6]pyrazoles synthesis, 6, 1002, 1006 Pyrrolo[3,4-c]pyrazoles reactions, 6, 1034 synthesis, 6, 989, 1043 Pyrrolo[3,4-c]pyrazolones synthesis, 6, 989 Pyrfolopyridazines synthesis, 4, 517 Pyrrolo[l, 2-6]pyridazines synthesis, 4, 297 6/7-Pyrrolo[2,3-d]pyridazines synthesis, 4, 291 2/f-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291 6/7-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291... 

Upon reaction of A -vinyliminophosphoranes (109) with aromatic isocyanates, vinylcarbodiimides (110) are formed, as shown in Scheme 47. Divi-nylcarbodiimides (111) can be obtained as side products (88CB271). With isonitriles the vinylcarbodiimides also afford pyrroles (112) via [4 + 1]-cycloaddition. Divinylcarbodiimide can also react via [4 -l- l]-cycloaddition with an isonitrile, whereupon an electrocyclic step of the initial diaza-1,3,5-trienes (113) follows. Finally, the pyrrolo[2,3-e]pyrazine 114 is obtained (88CB271). 

Replacement of a chloro group on the pyrazine by nucleophilic substitution with the anion of an activated methylene species is the major pathway in the synthesis of pyrrolo[2,3-3]pyrazines. The symmetrical pyrazine 250a undergoes reaction with malononitrile and K2CO3 in acetonitrile to form 251a (Scheme 24). Reaction of this intermediate with benzylamine in acetonitrile affords 252a <2001MC152>. 

Interest in the synthesis and reactions of pyrrolo[3,4- ]pyrazines is focused on two goals. The first is the development of analogs of zopiclone 256, a hypnotic agent <2001MI27>. Analogs of 256 are typically prepared from pyrazine-2,3-dicarboxylic anhydride (a furo[3,4- ]pyrazine) and a variety of aliphatic or aromatic amines <1996MI26, 1997MI28>. 

The reaction of 2-(3-chloropyrazin-2-yl)-Tphenylbutan-l-one with either primary amines or hydrazines, catalyzed by acid, at high temperatures provided the corresponding pyrrolo[2,3- ]pyrazine <2006T9919>. 

Reaction of l-(3,4-dimethoxybenzyl)-9-hydroxy-l,2,3,4-tetrahydro-8//-pyrido[l,2-a]pyrazin-8-one with 37% formaldehyde solution gave a tetracyclic tetrahydroprotoberberine analogue in a Mannich-type reaction (78AJC187). Reactions of 2,3,4,4a,5,6-hexahydro-l//-pyrazino[l,2-a]-quinolines with 1 W-pyrrolo[2,3-h]pyridine in the presence of 37% aqueous CH20 and AcONa in AcOH, and with 3-dimethylaminomethyl-l //-pyrrolo[2,3-h]pyridine afforded 3-[(l//-pyrrolo[2,3-h]pyridin-3-yl)methyl] derivatives (94MIP6 96USP5576319). 

There is a paucity of functional group reactions associated with the pyrrolopyrazines. A few examples may be found within the references describing their syntheses. However, a reaction has been reported which describes the [4 + 2] cycloaddition of pyrrolopyrazines. Ring expansion of 2-phenyl-2//-pyrrolo[3,4-/ ]pyrazine (32) occurs through cyclocondensation of the trimethylsilyl ether (33) with, amongst other dienophiles, methyl acrylate, and a mixture of quinoxalines (34) is obtained in 38% yield (Scheme 2) <86JHC1641>. 

Two very simple precursors combine to produce 2-arylpyrrolo[2,3-6]pyrazines. The anion derived from 2-methylpyrazine (173) adds to a benzonitrile (e.g. (174)) to give the product (175) (Equation (59)). This reaction is not the favored pathway displacement of chlorine is preferred <89TL935> although a similar reaction without the chloro substituent does provide the pyrrolopyrazine as the major product <8iTLi2i9>. However, this reaction does not seem to have been investigated for additional examples. In another simple reaction, 2-aminopyrazine (176) reacts with ethyl chloro-acetoacetate to give ethyl 6-methyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylate (177) (Equation (60)) <89BSF467>. 

Depending on the reaction conditions, pyrrole amide 45 cyclizes either to pyrrolo[l,2- z]pyrazin-l-ones (46) or to a mixture of pyrrolo[2,3-c]pyridin-7-ones (47) and pyrrolo[3,2-c]pyridin-4-ones (48) [42], Isomers 47 and 48 are distinguishable by the lower chemical shift of the N—H proton (10.21 ppm) for 47 syn to the carbonyl) relative to that observed for 48 (9.08 ppm) and other spectral data. The cyclization leading to 47-48 is proposed to involve spiro intermediate 49. 

Butler has described that the treatment of l-ethoxycarbonylmethyl-2,3,4,5-tetraarylpyrazolium salts with base in the presence of DM AD (dimethyl acetylenedicarboxylate) affords l-(2 -amino-vinylpyrroles) and pyrrolo[l,2-a] pyrazines <93JCS(Pl)883> a mechanism has been proposed for this unexpected behavior. Reaction of l,3,4,5-tetraaryl-2-methylpyrazolium salts (141) with ethoxide base produces the fragmentation of the pyrazole ring with formation of 1,2-bisimines (142) the mechanism is represented in Scheme 2 <94JCR(S)12>. In both cases the structures of the resulting products were supported by x-ray determinations. 

Corbet J.P., Paris J.M. and Cotrel C. (1982) Une nouvelle reaction de cyclisation conduisant a des pyrrolo[l,2-a] pyrazines. Tetrahedron Lett. 23, 3565-6. 

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>. 

Two examples have been reported of rearrangements that lead to pyrrolo[l,2-a]pyrazines. The Schmidt reaction on the ketone 52 gave only one product, the 3-oxo compound 53, paralleling the behavior of the ketone 54, which gave only the corresponding 3-oxopyrido[l,2-a]pyrazine on treatment with hydrazoic acid. The 1,6-dioxo compound 56 was obtained on refluxing the fused imidazoline 55 in water. 

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