Reductive-cyclization -dione

Derivatives of pyrido[2,3-f>]pyrazine were prepared from pyridyl-substituted AAs. Reductive cyclization afforded 115 (79CZ387), whereas cyclization with potassium carbonate gave the dione 116 (87TL6363). 

The synthesis of 3,7-dimethylimidazo[4,5- ]quinazoline-6,8(5//,7//)-dione and imidazo[4,5- ]qui-nazoline-6,8(5/7,7/7)-dione, the 1-methyl and 1,9-dimethylated versions (155) of //n-benzoxanthine, respectively, has been achieved using an approach (Equation (75)) based upon an imidazole ring assembly on 7-chloro-3-methyl-6-nitroquinazoline-2,4(l//,3//)-dione, effected by treatment with NH3 or MeNH2 followed by reductive cyclization in HC02H <84JHC79l>. In this same investigation, the 9-(formylamino)-/m-benzoxanthine derivatives (156) were obtained from 7-hydrazino-6-nitro-quinazoline-2,4(l//,3//)-dione precursors. 

Amino-l,3-dimethylimidazo[4,5-g]quinoxaline-2,4-dione (63) was obtained in 54% yield by the reductive cyclization of nitrohydrazine 62 (84JHC791). 

Aromatization of 9-(2-nitrophenyl)tetrahydroacridine 1,8-dione 356 (R = 2-NO2-C6H4, R1 = H) with active Mn02 afforded 363 (R = 2-NO2-C6H4), which on reductive cyclization with Fe/HCl gave 3,3,7,7-tetramethyl-l,3,4,5,5fl,6,7,8-octahydroquino[2,3,4-fc/]acridine (05SC1781). 

Cycloaddition and cyclization routes were used to access certain 1,3-diazines. The 4+2 cycloaddition reaction of 4-(N-allyl-N-aryl)amino-l,3-diaza-l,3-butadienes with vinyl-, isopropenyl-, and chloroketene led to pyrimidinone-fused pyrimidinones <97T13841>. Cis-cyclopenta[d]pyrimidines were derived from cis-2-amino-l-cyclopentanecarboxylates by cyclization with KOCN and KSCN <97JHC1211>. 2-Thioxopyrido[3, 2 4,5]thieno[3,2-r/]pyrimidin-4(3//)-ones 19 were prepared by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-/)]pyridines and isothiocyanates <97JHC937>. Thiazolyl-benzimidazoles derived from 2-cyanomethyl-l//-benzimidazole and 2,3-dihydrothiazole-2-(3//)-thiones were cyclized to the corresponding thiazolo[4,5-r/]pyrimidines <97PHA346>. Reductive cyclization of 6-cyanomethyl-5-nitropyrimidines afforded 7-alkyl-5//-pyrrolo[3,2-r/]pyrimidines and 6-amino-7,7-dialkyl-7//-pyrrolo[3,2-rf]pyrimidines <97T391>. 7-Methyl-5-alkyl-2-vinyl-pyrazolo[3,4-r/]pyrimidine-4,6(5//,7//)-diones arose from cyclization and alkylation of... 

The intramolecular reductive aldol reaction of keto-enones was successfully conducted under conditions similar to those described above, employing a cationic Rh complex and PI13P (Scheme 20) [34]. The keto-enone 63 was cyclized in the presence of added K2CO3 to give the ketone-aldol 64 in 72% yield with exclusive ds-selectivity. Dione-enone derivatives, for example 68 and 70, were efficiently cyclized to furnish bicyclic aldol products 69 and 71, respectively, wherein three stereogenic centers of the bicyclic product form stereoselectivity through the intermediacy of a Rh-enolate. 

Chiu et al. developed a catalytic reductive aldol cyclization of alkyne-diones such as 115 and 117 using [Ph3PCuH]6 (10mol%) as catalyst and polymethylhydrosiloxane PMHS (200 mol %) as terminal reductant. The... 

Scheme 22.6 Catalytic hydrogen-mediated reductive aldol cyclization of enone-diones.

In the latter compounds, the cross-conjugated dienone is replaced by a fu-ran ring conjugated to an E double bond. Biosynthetically, it is not known if these compounds arise from 1,4-dione precursors such as 138 by a Paal-Knorr type cyclization (Scheme 2) or from the a-angelica lactones 134 by reduction of the lactone carbonyl followed by loss of water. 

The key intermediates 692 required for the thermal cyclization were prepared from the readily available indole-2,3-diones 693. The condensation of 693 with 3-methyl-4-phenylbut-3-en-2-one (694) afforded the 3-hydroxy derivatives 695. The dehydration of 695, followed by selective reduction of the 3,1 -double bond of compounds 696, provided the 3-alkyl derivative 697. Finally, the compounds 697 were transformed to the 3-(l,3-butadienyl)indoles 692 by reaction with an excess of ethyl chloroformate (Scheme 5.62). 

Condensation of Ar Ar -dilkyl-6-methyl-5-nitrouracils with benzaldehyde produces a 6-styryl derivative. Reduction of the nitro group leads to spontaneous cyclization to the corresponding Ar Ar -dialkyl-6-phenyl-pyrrolo[3,2-i7 pyr-imidin-2,4-diones <2006BMCL3642>. 

The requisite hydroxylamine function for such cyclizations can also be generated from a precursor having a nitro group. This novel route has provided access to hitherto unknown l-hydroxy-6-allyl-, and -6,6-bisallyl-piperazine-2,5-diones (91UP1). The starting material is an W-nitroacetyl amino acid ester that can be either mono-or bis-allylated at the methylene adjacent to the nitro group. Reduction of the N02 to NHOH using zinc/ ammonium chloride, followed by cyclization, leads to the desired products (Scheme 76). Compound (215) is unique in that it possesses a chiral center at C-3 and a quaternary carbon at C-6 on a l-hydroxypiperazine-2,5-dione system. 

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