Amination appropriate ring system

On saponification l-(2-methoxycarbonylphenyl)pyrrole yields l-(2-carboxyphenyl)pyrrole, m.p. 106-107°, which on reaction with polyphosphoric acid at 70° is cyclized to 9-keto-9H-pyrrolo-(l,2-a)indole in 28-32% yield. Through the choice of the appropriate amine and acetal components, the substituted l-(2-meth-oxycarbonylphenyl)pyrroles become readily available intermediates in the preparation of a variety of derivatives of the pyrrolo( 1,2-a) indole ring system. 

Bisagni and co-workers (113,116) also explored several synthetic routes to the tricyclic y-carbolines (5//-pyrido[4,3-i>]indole ring system). Unfortunately, the attractive one-step Nenitzescu reaction (114) proceeded in only 6% yield to afford 286 (113). The Fischer indolization sequence was far more efficient (Scheme 46) (113). Thus, condensation of phenylhydrazine with 279 in boiling diphenyl ether gave in one step the desired y-carboline 287 in excellent yield. Chlorination of the pyridone functionality gave chloropyridine 288, which was converted to the target amine-substituted y-carbolines 289—291 by heating with the appropriate amines. 

The pyrrolinyl- (6-11) and pyrrolyl-substituted (12-13) eudistomin skeletons were first prepared by Rinehart from 1-cyano-P-carboline (145), which can be obtained from the corresponding acid (28). Grignard reaction with appropriately protected 3-bromopropanal (Scheme 4) provided the necessary carbons with appropriate oxidation level for cyclization to either of these ring systems. The pyrrolyl-substituted eudistomins then result upon hydrolysis of the imine and acetal functions with concomitant cyclization in the presence of ammonia. The pyrrolinyl-eudistomins require reduction of the imine to the amine followed by acetal hydrolysis and simultaneous ring closure to isomer 147. Reduction of the imine 147 followed by allylic oxidation with sodium hypochlorite isomerizes 147 to the pyrrolinyl-eudistomin skeleton (149). 

Euchrestifoline (159) was isolated from the leaves of the Chinese medicinal plant M. euchrestifolia by Wu and co-workers [179]. The structurally related compound girinimbine (168) was obtained and characterized first by Chakraborty and co-workers from the stem bark of M. koenigii [180]. Retrosynthetic analysis of the tetracyclic ring system leads to bromobenzene (160) and 2,2,8-trimethyl-2/7-chromen-5-amine (161) as appropriate starting materials for application of our methodology (Scheme 35). The keto function was thought to be introduced via a regioselective Wacker oxidation of the chromene moiety. Compound 161... 

By far the most common approach to the 1,3-diazocine ring system has been and remains dependent on formation of the aminal functionality through condensation of appropriate one-carbon sources with diamines. Alkylation of a,(u-disulfonamides with methylene bromide affords modest yields (ca. 45%) of perhydrodiazocine derivatives (5 Ar=p-tolyl, phenyl) (Equation (7))... 

Direct amination by amide ion is possible with aromatic molecules which are susceptible to nucleophilic attack. This group includes many heterocyclic compounds, particularly derivatives of pyridine, quinoline and related ring systems, and also a number of benzenoid compounds containing appropriate electron-attracting substituents. These reactions may be conducted at elevated temperatures in di-methylaniline or a hydrocarbon for example, or at lower temperatmes in liquid ammonia. In the pyridine series, it is the electron-deficient a-position which is preferentially aminated, though substitution may occur if no a-site is available (reaction 6). The second stage... 

Nicotine has two nitrogen atoms, one as a cyclic tertiary amine and one in a pyridine ring. The basicities are easily distinguished, in that a pyridine system is much less basic than a simple amine. This is essentially a hybridization effect, the nitrogen lone pair in pyridine being held in an sp orbital. This means the lone pair electrons are held closer to the nitrogen, and are consequently less available for protonation than in an sp -hybridized aliphatic amine. Hence, as mentioned above, pyridine has p Ta approximately 5. It follows that pA"a 8.1 is more appropriate for the pyrrolidine nitrogen. 

The preparation of a number of l,4-diketopyrrolo[l,2-a]pyrazine derivatives with central nervous system (CNS) depressant properties is illustrated by the preparation of compound 362. 2,5-Dicarbethoxypyrrolidine (359) is treated with the appropriate amine to give 360, which reacts with 2-bromoacetylbromide to produce 361. Ring closure of 361 to 362 was promoted by heating 361 with sodamide (73FES463 75BRP1409185 84FES718). The synthesis of related CNS stimulants and depressants of type 363 have also been described (71USP3563992). 

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