Hydropyrazines

The central ring of 1-deazaflavins remains a pyrazine in X, a di-hydropyrazine in the two-electron-reduced form, XI, and continues to dominate the chemistry with oxygen. Like the parent riboflavins, and unlike the 5-deazaflavins, the dihydro- 1-deaza system, XI, is reoxidized by 02 in a fraction of a second in air-saturated solutions (Table II) the semiquinone is accessible and 1-deazaFAD enzymes show full catalytic competence with flavoprotein dehydrogenases and oxidases (24). Turnover numbers vary from about 1% to 100% that of cognate FAD-enzymes but this variation reflects the -280 mV vs. —200 mV E° values, respectively, for 1-deazariboflavin vs. riboflavin. The redox steps may or may not limit Vmax with a given enzyme (15, 24). 

Primary synthetic routes to pyrazines or hydropyrazines from aliphatic or carbocyclic synthons are so numerous and diverse that any system of classification cannot be satisfactory in all respects. The approach adopted here is based on the ways in which the six ring atoms of pyrazine can be supplied by synthons, as indicated in the Contents headings. 

The cyclization of an N—C—C—N—C—C synthon has been used widely to make pyrazines and hydropyrazines. Because the terminal nitrogen atom is usually an amino or related group, examples are classified according to the substituent (or unsaturation) at the terminal carbon atom of the synthon The nature of the synthon naturally determines the degree of aromaticity in the product. 

This synthesis usually gives hydropyrazines but appropriate substituents in the substrate can ensure autooxidation to pyrazines, as illustrated in the first of the following examples ... 

Not unnaturally, the synthesis of a pyrazine or hydropyrazine from a single C—N—C—C—N—C synthon is rare. However, the cyclization of A,A -dibenzyli-dene or NJV -diacyl derivatives of ethylenediamines has proven possible, as indicated in the following examples ... 

Ethylenediamine (98) and l-methylprop-2-ynol (99) gave 2,3-dimethyl-5,6-di-hydropyrazine (100) [Hg(OAc)2, CHC13, reflux, 7 h 51%) homologues likewise.210... 

Note Reduction of such an oxime gives the corresponding aminoketone that spontaneously self-condenses under appropriate conditions to afford a hydropyrazine, and... 

This chapter covers the preparations, physical properties, and reactions of pyrazine and its C-alkyl, C-aryl,. V-alkyl, or A/ -aryI derivatives as well as their respective di-, tetra-, and hexahydro derivatives (the last usually known as piperazines). In addition, it includes methods for introducing alkyl or aryl groups (substituted or otherwise) into pyrazines and hydropyrazines already bearing substituents and the reactions specific to the alkyl or aryl groups in such products. For simplicity, the term alkylpyrazine in this chapter is intended to include alkyl-, alkenyl-, alkynyl-, cycloalkyl-, and aralkylpyrazines likewise, the term arylpyrazine includes both aryl- and heteroarylpyrazines. 

Note Pyrazine may be C-alkylated directly, e.g., by alkyl radicals also by addition to give an alkylated hydropyrazine, sometimes amenable to subsequent... 

The following classified examples illustrate the methods that have been used recently for C-alkylation of pyrazines and hydropyrazines (see also Section 3.1.3 for the alkylation of unsubstituted pyrazine). 

Note This type of alkylation is applicable only to hydropyrazines and the products are frequently considered as alkylidene derivatives, despite the fact that they can usually be formulated as the tautomeric alkylpyrazines (with the extra double bond within the pyrazine ring). 

Dimethylpyrazine (169) gave 2,5-dimethyl-l,4-bis(triisopropylsilyl)-l,4-di-hydropyrazine (170) (ClSiPb3, K, 20°C, 2 days 43% confirmed in structure by X-ray analysis) 552 analogues likewise or by transtrialkylsilylation.552... 

Preparation of ethyl (3/ S)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-l,2,3,4-tetra-hydropyrazine-l-yl acetate... 

Pyrazine and hydropyrazines, H, °C, and 15N NMR of 88M162. Pyrazine derivatives, synthesis based on HCN derivatives 87AHC-(41)1. 

A number of alkoxypyrazines have been prepared from hydropyrazines. 5-(4 -Amino-3, 5 -dibromobenzenesulfonylimino)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetra-hydropyrazine (32) refluxed with 2N sodium hydroxide gave 2-(4 -amino-3, 5-dibromobenzenesulfonamido)-3-hydroxy-6-methoxypyrazine (881). Rperazine-2,5-dione (33) with an excess of triethyloxonium fluoroborate in dichloromethane gave... 

Hydrolysis of 2-amino-3-hydroxy-l-methylpyrazinium toluenesulfonate (87) with aqueous sodium hydroxide at 95° afforded 3-hydroxy-l-methyl-2-oxo-l, 2-dihydropyrazine which was also prepared in poor yield from the action of nitrous acid on 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (832) and hydrolysis of 6-chloro-l-methyl-2-oxo-3,5-diphenyl-1,2-dihydropyrazine with boiling methanolic sodium methoxide (followed by acidification) gave 6-hydroxy-l-methyl-2-oxo-3,5-diphenyl-1,2-dihydropyrazine (873). 1,3,6-Trimethyl-2-oxo-1,2-dihydropyrazine methiodide has been converted through l,4,6-trimethyl-3-methylene-2-oxo-l,2,3,4-tetrahy dropy razine and 3-benzoylmethylene-1,4,6-trimethyl-2-oxo-1,2,3,4-tetra-hydropyrazine (in water) to 1,4,6-trimethyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazine (1129). 

The chemistry of hydropyrazines (including piperazines) has not been treated in the comprehensive manner used for the pyrazines in this volume because it is, strictly speaking, beyond the scope of this work. To provide an entry to the literature, references to reviews of the older literature are summarized in Table XI.1 (35-39, 1524-1534), and a selection of preparations and reactions, drawn from more recent publications are discussed. 

Cyclization of iV-(2, 2-dimethoxyethyl)benzenesulfonamide [PhSOjNHCHjCH-(OMe)2l has been shown to give l,4-dibenzenesulfonyl-2-hydroxy-l,2,3,4-tetra-hydropyrazine (68) or l,4-dibenzenesulfonyl-2,5-dihydroxypiperazine according to the conditions (1602, cf. 1603) and the latter was readily dehydrated to (68) (1602). A similar preparation of the tosyl analogue was also reported (1602). 

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