Pyrazinones cyclization

Bicychc pyrazinones foimd in several natural products were synthesized via Michael addition of heterocyclic amines to nitro olefin followed by reduction/cyclization of the nitro group of the adduct [20] (Scheme 5). Further elaboration of the C-6 methoxycarbonyl group in pyrazinone to the n-propyl guanidine group could result in the synthesis of indoloperamine. 

This approach offers unique opportunities for the generation of multi-functionalized cyclic 2-azadiene systems. A wide variation of the substitution pattern at the positions N-1 and C-6 can be determined by an appropriate choice of the aldehyde and amine. Various substituents can easily be introduced at the C-3 position via addition/elimination reactions on the sensitive imidoyl chloride moiety [24]. Upon reaction with bi-functional reagent, an adequately AT-protected 2(lH)-pyrazinone was elaborated into C-nucleoside analogues (Scheme 8). The desired skeleton and functionalities were obtained by oxidation-cyclization reaction followed by photochemical removal of the protective o-nitrobenzyl group [25]. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

The same authors reported in a later study <2000H(3)69> that pyrazinone 340 is also a suitable starting material for a such transformation. The reaction proceeds in two steps the starting pyrazinone 340 when treated with benzonitrile oxide yields an addition product 341 which undergoes oxidative cyclization in the presence of iodine-potassium iodide to the ring-closed [l,2,4]oxadiazolo[4,5-tf]pyrazines 342. 

One more useful synthetic application of primary Michael adducts onto 2-chloro-2-cyclopropylideneacetates 1 is the recently reported new approach to oc-tahydrospirocyclopropanepyrazinopyrazines 182. In the first step, the adducts of primary amines onto 1-Me (or 1-fBu) were coupled with AT-Boc- or N-Vmoc-protected glycine derivatives and the resulting products 178, after deprotection, cyclized under mildly basic conditions to give the spirocyclopropanehexahydro-pyrazinones 179,180 and hexahydrodiazepinediones 181 (Scheme 53) [89]. 

C=N bond formation has also been achieved starting from two additional carbonyl functions properly installed in an Ugi component. Cyclization has been accomplished in this case through a Paal-Knorr reaction of the dicarbonyl compound generated by the Ugi condensation, leading to pyrazinones [107]. 

A similar reaction of vincinal aromatic or heterocyclic diamines 104 with 2-benzoylamino-3-chloropropenoic acid 102 resulted in sprro-2-oxazolines fused to a pyrazinone nucleus 108. It is believed that the enamide 102 first isomerizes to the A-acyl imine 103 followed by Michael addition of the diamine 104. The resulting Michael adduct 105 cyclizes to 106 or 107 either of which leads to the same oxazoline 108. Single-crystal X-ray confirmed the structure of 108. Unsymmetrical diamines gave two isomeric products with the predominant product... 

Thieno[3,4- ] and [3,4-f]pyridine derivatives can be generated from a cycloaddition reaction of oxazinones with l,4-dichloro-2-butyne to afford polyhalogenated pyridine products which cyclize to thienopyridines (Scheme 39) <2001T4203>. In a similar reaction, pyrazinones, 122, containing alkynyl substituents cyclize to form thieno[3,4-3] and [3,4-i ]pyridine derivatives <2002TL799, 2004T429>. 

Similarly, from 2-chloro(l//)-pyrazinone, the azides 498a-d were obtained and these underwent reversible cyclization to the fused tetrazoles 499a-d (Scheme 62) <2004OL4223, 2005JC0490>. 

Af-Benzyl-/V- (/V-o-methoxyphcnylcarbamoyl)mcthyl glycine (29) underwent de-hydrative cyclization to 4-benzyl-6-hydroxy-l-o-methoxyphenyl-3,4-dihydro-2(1 H)- pyrazinone (30) (l,r-carbonyldiimidazole, THF, 30 —> 65°C, 17 h 83% other reagents gave lower yields).487... 

Such substrates are seldom used but tert-butyl (I - I -W-methoxy-A-methylcar-bamoyl)-3-methylbutyl]carbamoyl -2-phenylethyl aminoformate (44) gave 3-ben-zyl-6-isobutyl-2(l//)-pyrazinone (45) (21%) by two deprotections (LiAlH4 and HC1—dioxane) and a final cyclization in acetonitrile during 13 h.1510... 

The important conversion of pyrazinones into halogenopyrazines has been covered in Section 4.1.1. An unusual aminolytic cyclization has been reported709 and other reactions are discussed in the subsections that follow. 

Highly-functionalized piperidines are available from readily-available pyrazinones by way of Diels-Alder cyclization and acid-catalyzed methanolysis. Products are reported as single stereoisomers <03T5047>. 

Bcnzyl-3-(3-hydroxypropyl)-5-inelhoxy-2(l//)-pyrazinone (163) gave 9-benzyl-8-methoxy-2-oxa-7,9-diazabicyclo[4.2.2]dec-7-en- 10-one (164) (dichlorodi-cyanobenzoquinone, PhH, reflux, N2, 90 min 47%) also related cyclizations. ... 

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