Annelated pyridines

The applied Gould-Jacobs reaction is very often used to prepare angularly annelated pyridine-ring-substituted imidazoquinolines in inert media under conditions of thermal cyclocondensation, for example at temperatures above 250°C. 

The Diels-Alder methodology can also be applied in the synthesis of tricyclic heterocycles, as was demonstrated by reactions of 2-(2-trimethylsilylethynylphenyl-X)pyrimidines (X = 0, S, NCOMe, CHj, CO). They are converted in good yield on heating at 160°C into tricyclic annelated pyridines (89T6511) (Scheme 37). A similar reaction was found with the 2-(2-allylphenoxy)pyrimidines affording azaxanthenes (79H665) (Scheme 37). 

As an extension of this reaction the intramolecular cycloaddition of 5-propynyloxycycloalkanepyrimidines was studied. It was found that bi-and tricyclic annelated pyridine derivatives are formed by expulsion of either X-CH2-CN and/or HCN, respectively. A marked selectivity in the product formation was observed, depending on the size of the cycloalkane ring. With cyclohexapyrimidines a mixture of A and B is formed, while with the cycloheptapyrimidine derivative exclusive formation of the tricyclic compound B takes place (92T1643, 92T1657) (Scheme 39a). 

Double intramolecular /zcfcro-Diels-Alder reaction of 1,3-diynil-bis-a,)S-unsaturated hydrazones 139 and 140 is a good example of a thermal multiple Diels-Alder reaction and is a particularly attractive route to annelated pyridines [123]. The initial cycloadduct readily aromatizes by the loss of dimethylamine (Scheme 2.52) under thermal reaction conditions. 

Likewise, an efficient one-pot multicomponent synthesis of annelated 2-amino pyridines (e.g., 17) utilizing [4+2] cycloadditions has been described <06JOC3494>. The process involves the in situ generation of 1-aza-1,3-butadiene from a palladium-catalyzed coupling-isomerization reaction of aryl halides (e.g., 18) with propargyl V-tosylamines (e.g., 19). The resulting butadiene then undergoes cycloadditions with V.S -ketene acetals (e.g., 20) to form annelated pyridines (e.g., 17). 

The annelated pyridines QJ) and (M) are also obtained with cpCo(CO)2 as catalyst [77AG758, 77AG(E)708]. Using this variant of the cobalt-catalyzed cycloaddition, Schleich et al. opened up a new route to pyridox-ine (Vitamin 65) as its hydrochloride [Eq.(25)] (84HCA1274). 

Proton acid-base reactions are not particularly sensitive to stoic compression, and hence provide a good measure of inductive effects. For acid-base character, three sets of reference reactions can be used. The easiest of these to perform experimentally requires an analogy be drawn between the relative pK values of a series of protonated annelated pyridines and the pK values of the analogous isoelectronic benzene. The second is a direct measure of the kinetic acidity of the a- and P-sites on a soies of annelated benzenes. The third is a related direct assessment of kinetic acidity by protodetritiation. 

Figure 4. The p/Q values of annelated pyridines as determined by titrametric analysis.

Altiiough there are several naming systems for annelated pyridines, we have adopted the nomenclature system where the bond between positions 1,2 is the [a] bond 2,3 is the [b] bond 3,4 is the [c] bond and 4,5 is the [d] bond. 

Fig. 3. Reactivity effects in diazines and annelated pyridines 1, isoquinoline 2, quinoline 3, 1,10-phenanthroline 4, phthalazine 5, cinnoline 6, pyridazine 7. pyrimidine 8, pyrazine.

Finally, it should be noted that basicity of the nitrogen at the a-position decreases in the series of annelated pyridines as the angular strain of the fused ring increases [118]. This is in harmony with the interpretation of the MN effect presented in Section 5.1. More work on this topic is highly desirable. 

Further examples of the formation of annelated pyridines by nitrene insertion into methyl groups were obtained by pyrolysis of arylvinyl azides in toluene solution (Scheme 5).40 Evidence that these reactions also take place via initially formed azirines was secured by the isolation of 26 from the pyrolysis of 25.40... 

Intramolecular Diels-Alder reactions with the inverse electron demand of cyclic azadienes can be set up in pyrimidines which have a dienophilic side-chain such as a terminal alkyne group (360) (Scheme 60). Upon heating, an intramolecular Diels-Alder reaction (361) and a subsequent retro Diels-Alder reaction with loss of HCN take place to yield annelated pyridines (362). This reaction is exemplified by the preparation of furo[3,4-i]pyridin-7(5//)-one (363). The reactivity of intramolecular Diels-Alder reactions is strongly related to the conformational properties of the side-... 

Optically active estrone. Danishefsky and Cain have reported a synthesis of optically active estrone that utihzes the tris-annelating pyridine reagent (1). 

Recently, the group of Boruah achieved the synthesis of annelated pyridines from yfi-formyl enamides via a Henry reaction in a one-pot process [186]. Under the action of microwave irradiation, in the presence of a base, for example pyrrolidine, morpholine or piperidine, yields from 80 to 90% were obtained after 8 to 10 min (Scheme 10.96). 

The addition of various pyrrolidinocycloalkenes to 4-methyl-l,2,3-triazine 86c leads to cycloalkane- -annelated pyridines <1985H(23)2789, 1986H(24)29> and the extension of this work to the parent compound 1, 5-methyl-and higher methylated 1,2,3-triazines <1989H(29)1809>. 

Reaction of preformed enamines (or cyclic ketones and pyrrolidine) with 4,6-dimethyl-l,2,3-triazine 17m in a focused microwave reactor (atmospheric pressure, 270 W, 20 min, max. temp. 150 °C) allowed the preparation of various annelated pyridines with considerably improved yields <2001SL236> compared to the conventional thermal method (200-220°C in 1,2-dichlorobenzene) <1989H(29)1809>. 

Ch. 1 Synthetic and Natural Sources of the Pyridine Ring Ch. 2 Carbocyclic Annelated Pyridines Ch. 3 Macrocyclic Pyridines... 

A new one-stage synthesis of annelated pyridines, involving the cobalt-catalysed co-oligomerization of dialkynes HC=C(CH2)nC=CH (n = 3, 4, or 5) with nitriles RCN (R = alkyl or aryl), has been announced. Under high dilution and in the presence of cyclopentadienylcobalt dicarbonyl, co-oligomerization to pyridines of type (12) takes place in a remarkably selective manner, yields of 43—81% being realised. The process is particularly useful for the preparation of the otherwise not easily accessible 5,6,7,8-tetrahydroquinolines. An interesting extension of the reaction uses ethyl cyanoacetate in place of the nitrile RCN,... 

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