2.7- Naphthyridines primary syntheses

The primary synthesis of 1,5-naphthyridines may be accomplished by double cyclization of appropriate aliphatic substrates by cyclization of appropriately substituted pyridines by cyclocondensation of pyridine substrates with one or more aliphatic synthons or from other heterocyclic substrates by degradation, rearrangement, or the like. Partially or fully reduced 1,5-naphthyridines are often made by somewhat similar procedures such cases are usually illustrated toward the end of each subsection. Some reviews of naphthyridine chemistry contain material on the primary synthesis of 1,5-naphthyridines49 52 61 231 265 670 1260 1273 1430 1432... 

Most such naphthyridinones have been made by primary synthesis (see Chapter 1) and some by hydrolysis of halogeno-1,5-naphthyridines (see Section 3.2.3). Other preparative routes are illustrated by the following examples. 

Acetyl-l-benzyl-3,4,4a,5,6,7-hexahydro-l,5-naphthyridine-2,7(l//)-dione (15) (a byproduct from a primary synthesis) appears to have undergone partial dehydrogenation and N— (9-transacylation to afford 7-acetoxy-l-benzyl-3,4-dihydro-1,5-naphthyridin-2( 1 //)-one (16) (Pd/C, xylene, 130°C, 30 h ... 

Note One such sulfone has been prepared by primary synthesis (see Section 1.3.3) another by oxidation of an alkylthio-1,5-naphthyridine (see a preceding subsection). 

The primary synthesis of 1,6-naphthyridines has been accomplished by condensation of two or more aliphatic substrates by cycbzation of a single pyridine substrate by condensation of a pyridine substrate with an aliphatic synthon that provides one, two, three, or even four ring atoms by condensation of a pyridine substrate with two or more synthons or from other heterocyclic substrates by degradation, rearrangement, or other elaborative processes. 

Some existing reviews of naphthyridine chemistry contain at least some information on the primary synthesis of 1,6-naphthyridine derivatives.49-52,55,... 

Less profound reduction of 1,6-naphthyridine afforded 1,2,3,4-tetrahydro-1,6-naphthyridine (7) (Pd/C, EtOH, H2, 20°C, 1 atm, 6 h 75%) 47 a somewhat similar procedure gave the same product (7) and a minor isomeric product, possibly 5,6,7,8-tetrahydro-l,6-naphthyridine.1243 Ostensibly, the hydro derivative (7) has also been made by a primary synthesis involving reductive cyclization of 4-(2-carboxyethyl)-3-nitropyriidne 1-oxide,134 but the melting points differ markedly. 

Note All reported alkoxy-l,6-naphthyridines appear to have been made by primary synthesis (see Chapter 8), alcoholysis of halogeno-l,6-naphthyri-dines (see Section 10.2.1), or O-alkylation of 1,6-naphthyridinones (see Section 11.1.2). 

Note These oxides have been made either by primary synthesis (see Chapter 8) or, more frequently, by oxidation of the corresponding 1,6-naphthyridines (see Section 9.1 for some simple oxides as well as the examples given here). 

Preparation. Most such nitriles have been made by primary synthesis (see Chapter 8). However, 1,6-naphthyridine A-oxides undergo oxidative cyana-tion, as illustrated here. 1,6-Naphthyridine 1-oxide (24) gave 1,6-naphthyr-idine-2-carbonitrile 1-oxide (25) [substrate, K3Fe(CN)6, KCN, H20, 0°C, 3 h 58%] l,6-naphthyridme-5-carbonitrile 6-oxide (29%) and a separable mixture of l,6-naphthyridine-2-carbonitrile 1,6-dioxide (30%), 1,6-naphthyridine 5-carbonitrile 1,6-dioxide (14%), and l,6-naphthyridine-2,5-dicarbomtrile... 

Naphthyridine has been made197 by a primary synthesis (see Section 15.3), but the best preparative route is probably the first of the following indirect examples. 

In almost all cases, the alkyl/aryl group in such naphthyridines has been put there by primary synthesis (see Chapter 15). However, such groups have occasionally been inserted subsequently, as illustrated by the following examples. 

Note A few such oxides have been made by primary synthesis (see Chapter 15), and the oxidation of unsubstituted 1,7-naphthyridine to its mono- and di-A-oxides has been covered in Section 16.1.3. 

Like the primary syntheses of other naphthyridines, the primary synthesis of 1,8-naphthyridines may be done by cyclization of appropriate aliphatic substrates, with or without auxiliary synthons, by cyclization of appropriately substituted pyridines with or without synthons, or from other heterocyclic substrates by several processes. 

Many alkyl or aryl-1,8-naphthyridines have been made by primary synthesis (see Chapter 22). Other procedures involve the introduction of substituted or unsubstituted alkyl or aryl groups into existing 1,8-naphthyridines or the interconversion of such groups already in place. The following examples illustrate the methods used. 

Two important routes to 1,8-naphthyridinones have been covered already by primary synthesis (Chapter 22) and the hydrolysis of halogeno- 1,8-naphthyridines... 

Note Reported preparative routes have been covered already primary synthesis (Chapter 22), by thiolysis of halogeno-1,8-naphthyridines (at the end of Section 24.2), or by thiation of 1,8-naphthyridinones (Section 25.1.2). 

One or both of these carbonyl entities has (have) been made by primary synthesis (see Chapter 22), by oxidation of alkyl-1,8-naphthyridines (see Section 23.2.2), or by the procedures illustrated in the following examples. 

Several heterocyclic systems other than pyridine have been used as substrates for the primary synthesis of 2,6-naphthyridines. The procedures are illustrated in the following examples. 

Several such oxides have been made by primary synthesis for example, 3-phenylethynyl-4-pyridinecarbaldehyde oxime (47) gave 3-phenyl-2,6-naphthyridine 2-oxide (48) (K2C03, EtOH, reflux 80%).641... 

Most such amines have been made by primary synthesis (see Section 29.1) or by aminolysis of halogeno-2,6-naphthyridines (see Section 29.3.2). In addition, some have been made by direct C-amination,54 as illustrated in the following examples. 

A number of these esters have been prepared by primary synthesis (see Section 30.1). In addition, several such esters have been isolated from diverse plant species neozeylanicine, methyl 1-methyl-2,7-naphthyridine-4-carboxylate (85), from Strychnos cocculoides502 and Neoneuclea zeylanica 597 methyl 5-methy 1-2,7-naphthyridine 4-carboxylate (86), from S. cocculoides 502 4-meth-oxycarbonyl-7-methyl-2,4a,5,6,7,7a-hexahydro-l //-cyclopentapyridin-6-yl 1-methyl-l,2-dihydro-2,7-naphthyridine-4-carboxylate (87), from Scaevola racemigera 931 and three others skin to the last and from the same source.931... 

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