PRIMARY SYNTHESES

Metathetical reactions of pyrimidines have been studied widely over the last hundred years. Indeed, probably 90% of all known pyrimidines have been made from a relatively few pyrimidine substrates available by primary synthesis. 

Despite considerable localization of tt-electrons at the nitrogen atoms of pyrimidine, the ring system is still sufficiently aromatic to possess substantial stability. This is a great advantage in the primary synthesis of pyrimidines, in the synthesis of pyrimidines from the breakdown or modification of other heterocyclic systems and in the myriad of metatheses required to synthesize specifically substituted pyrimidines. 

The first primary synthesis of a pyrimidine from aliphatic fragments was carried out by Frankland and Kolbe in 1848. Since then, a great many quite distinct primary synthetic methods have been devised, although it is true to say that one of these (the Principal Synthesis ) has provided upward of 80% of all known pyrimidines, either directly or indirectly. 

The least troublesome routes to 3,4-dihydro- and 1,2,3,4-tetrahydro-quinazoline are probably the reduction of quinazoline by sodium borohydride, in water for the former or in methanol for the latter. Both must be isolated as salts. The dihydroquinazoline may be formed also by reduction with LAH in ether (65JHC157). In contrast, 5,6,7,8-tetrahy-droquinazoline is best made by primary synthesis from 2-formylcyclohexanone and for-mamide (57CB942) or from cyclohexanone and trisformamidomethane (60CB1402). 

Primary synthesis has limited application in making pyrimidine-carboxylic acids or even their esters. However, some pyrimidine-4(and 5)-carboxylic acids can be effectively so made. For example, bromomucic acid (785) reacts as an aidehydo ketone with S-methyl-thiourea to give 5-bromo-2-methylthiopyrimidine-4-carboxylic acid (786) directly (53JCS3129) while the Whitehead synthesis (Section 2.13.3.1.2<7) can give, for instance, 3-methylcytosine-5-carboxylic acid (787) (55MI21300). 

In fact, most pyrimidinecarboxylic acids are made by hydrolysis of the corresponding esters, nitriles or sometimes amides, many of which can be made more easily by primary synthesis than can the acids themselves. Thus, pyrimidine-5-carboxylic acid may be made by alkaline hydrolysis of its ethyl ester (62JOC2264) and pyrimidin-5-ylacetic acid (789 ... 

R = H) is made similarly from its ester (789 R = Et), itself prepared by several obvious steps (see (i) below) from the pyrimidine (788) which can be made by primary synthesis (66AP362). 4-Aminopyrimidine-5-carbonitrile (790 R = CN), which may be made by primary synthesis, undergoes hydrolysis in alkali to the amino acid (790 R = C02H) it may be made similarly from the amide (790 R = CONH2) (53JCS331). 

A second practical route to AT-unsubstituted amides is by the controlled hydrolysis of nitriles, which can often be made (in the 5-position) by primary synthesis or (elsewhere) by displacement of an ammonio grouping. Thus 4,6-dimethylpyrimidine-2-carbonitrile (798 R = CN) in warm aqueous ammonia gives the amide (798 R = CONH2) in good yield... 

Primary synthesis of nitrosopyrimidines is seldom worthwhile but it is at least possible. Thus, isonitrosomalononitrile and iV,iV-dimethylguanidine give the nitrosotriamine (829) by a Principal Synthesis (62JA3744). 

Primary synthesis of arylazopyrimidines is used (52JCS3448). It is exemplified in the condensation of phenylazomalondiamidine with diethyl oxalate to give the azopyrimidine (833) (66JCS(C)226). Finally, 5-phenylazopyrimidine may be made by the condensation of pyrimidin-5-amine with nitrosobenzene (5UCS1565) but the reaction seems to have been overlooked for many years. 

The primary synthesis of alkoxypyrimidines is exemplified in the condensation of dimethyl malonate with O-methylurea in methanolic sodium methoxide at room temperature to give the 2-methoxypyrimidine (854) (64M207) in the condensation of diethyl phenoxymalonate with formamidine in ethanolic sodium methoxide to give the 5-phenoxypyrimidine (855) (64ZOB1321) and in the condensation of butyl 2,4-dimethoxyacetoacetate with thiourea to give 5-methoxy-6-methoxymethyl-2-thiouracil (856) (58JA1664). 

The preparation of quinazoline-2(and 4)-thiones follows those of the corresponding pyrimidines (67HC(24-1)270) but there is at least one special primary synthesis for quinazoline-4(3H)-thiones, illustrated by the reaction of o-aminobenzonitrile with thioacetic acid at 110 °C to give 2-methylquinazoline-4(3H)-thione in 90% yield (53JA675). 

Pyrimidine N-oxides may be made directly or via their N-alkoxy analogues by means of the Principal Synthesis or other primary synthesis. The alternative route is peroxide oxidation of the parent pyrimidine but this can lead to a mixture of 1- and 3-oxides if the substrate is unsymmetrical about the 2,5-axis of the molecule. 

The O-alkyl derivatives of those A-oxides, which exist partly or entirely as (V-hydroxy tautomers, may be made by primary synthesis (as above) or by alkylation. Thus, 5,5-diethyl-1-hydroxybarbituric acid (936 R = H) with methyl iodide/sodium ethoxide gives the 1-methoxy derivative (936 R = Me) or with benzenesulfonyl chloride/ethoxide it gives the alkylated derivative (936 R = PhS02) (78AJC2517). 

The simplest pyrimidine antibiotic is bacimethrin, 5-hydroxymethyl-2-methoxypyrimidin-4-amine (985), which was isolated in 1961 from Bacillus megatherium and is active against several yeasts and bacteria in vitro as well as against staphylococcal infections in vivo it has some anticarcinoma activity in mice (69MI21301). It may be synthesized by LAH reduction of ethyl 4-amino-2-methoxypyrimidine-5-carboxylate (984) which may be made by primary synthesis in poor yield, or better, from the sulfone (983) (B-68MI21304). 

Pyrimidine, 5-acetyI-2,4-dimethyI-synthesis, 3, 125 Pyrimidine, acylamino-deaeylation, 3, 85 Pyrimidine, alkoxy-hydrolysis, 3, 91 Primary Synthesis, 3, 134 synthesis, 3, 132, 134 Pyrimidine, 2-alkoxy-aminolysis, 3, 92 rearrangement, 3, 92, 135 synthesis, 3, 134 transalkoxylation, 3, 92 Pyrimidine, 4-alkoxy-aminolysis, 3, 92 rearrangement, 3, 92, 135 synthesis, 3, 134 transalkoxylation, 3, 92 Pyrimidine, 6-alkoxy-aminolysis, 3, 92 rearrangement, 3, 92, 135 synthesis, 3, 134 transalkoxylation, 3, 92 Pyrimidine, alkyl-halogenation, 3, 76 nitration, 3, 77 oxidation, 3, 76 synthesis, 3, 124... 

Pyrimidine-2,4( 1 ff,3H)-dione, 5,6-dihydro-1-methyl-Primary Synthesis, 3, 134 Pyrimidine-2,4( 1 H,3H)-dione, 5,6-dimethyl-oxidation, 3, 76... 

This is by far the most used type of primary synthesis for quinoxalines. It usually involves the cyclocondensation of an o-phenylenediamine (or closely related substrate) with a synthon containing an oxalyl [—C(=0)—C(=0)—] or equivalent [e.g., HC(=0)—C=N] grouping. For convenience, discussion of this synthesis is subdivided according to the type of synthon used to produce formally aromatic quinoxalines the formation of similar ring-reduced quinoxalines (mostly from related synthons at a lower oxidation state) is included in each such category. 

This category of primary synthesis is extremely rare in the quinoxaline series, although a few examples have been reported in recent literature. Thus a mixture of neat 1,2-benzenediamine (331) and an excess of p-bromobenzaldehyde heated at 350°C for 5 min afforded (with aerial oxidation ) 2,3-bis(p-bromophenyl) quinoxaline (332) in 50% yield " " and analogs were made similarly but usually in poor to mediocre yield after separation from byproducts." " In addition, an... 

Heteromonocyclic compounds other than pyrazines may be used as substrates or synthons for the primary synthesis of quinoxalines. All such syntheses are covered... 

At least two derivatives of pyran have been used for the primary synthesis of quinoxalines. Thus o-phenylenediamine (390) and 6-(p-methoxyphenyl)-6-methyl-5,6-dihydro-2//-pyran-2,5-dione (391) in methylene chloride at 20°C open to the air for 48 h gave 3-[2-hydroxy-2-(p-methoxyphenyl)propionyl]methyl-3,4-dihydro-... 

Heterobicyclic compounds are important substrates (or synthons) for the primary synthesis of quinoxalines. Such procedures are arranged alphabetically here according to the system name of each substrate/synthon so used. 

There is an extensive literature on the use of 2,1,3-benzoxadiazole 1-oxide [often called benzofuroxanie) (BFO) (462)] as a substrate for the primary synthesis of quinoxaline 1,4-dioxides and occasionally quinoxaline mono-A -oxides or even simple quinoxalines. Very few substituted derivatives of the parent substrate (462) have been employed in recent years. The general mechanism clearly involves a fission (usually amine-catalyzed) of the oxadiazole ring followed by reaction with an ancillary synthon. The following examples are divided according to the type of synthon employed. 

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