Cycloalkenopyridines by ring transformations of diazines and triazines

This paper is a short review on the synthesis of 2,3-cycloalkenopyridines and 3,4-cycloalkenopyridines by inter-and intra-molecular cycloadditions.


Introduction
It is observed that many natural occurring biologically active compounds feature the presence of a cycloalkenopyridine ring as basic skeleton.This observation induced the development of a range of synthetic methods to prepare pharmaceuticals and agrochemicals, containing the cycloalkenopyridine ring as an important building block. 1 Almost all of these methods are based on condensation of appropriately substituted cycloalkanones with a reagent which is able to form the pyridine ring.Since the six-membered hetaroaromatics, especially diazines and triazines posses the suitable azadiene arrangements to undergo inter-and intramolecular [4+2] inverse electron demand Diels-Alder cycloadditions leading to pyridines, 2,3,4 this methodology offers a more recent approach to the synthesis of cycloalkenopyridines.This paper deals with a short review on the synthesis of 2,3-cycloalkenopyridines and 3,4-cycloalkenopyridines by inter-and intra-molecular cycloadditions.

Scheme 1
The highly strained intermediate 3 could not be isolated, indicating that the addition reaction is the rate-determining step and that the elimination of hydrogen cyanide and pyrrolidine is fast.The fact that under these mild condition reactions the elimination of pyrrolidine so easily takes place, seems to suggest that the trans orientation of the hydrogen and the pyrrolidino group on the bridgehead positions in intermediate 3 is converted into the cis-trans orientation yielding intermediate 5 (Scheme 2).This isomerisation is probably facilitated by the presence of the nitro grouping in the aci form 5.

Scheme 3
A further application of this cycloaddition reaction provided the 3-nitro derivatives of 5,6,7,8-tetrahydro-8-methylquinoline 10, of 5,6,7,8-tetrahydro-5,8-methanoquinoline 11 and of 10,11-dihydro-5H-benzo [4,5]cyclohepta [1,2-b]pyridine 12 5 (Scheme 4).A number of 2,3-cycloalkenopyridines has been reported to be formed by intramolecular cycloadditions reactions with inverse electron demand with pyrimidines and triazines containing a molecular chain of appropriate length between the heterocycle and the dienophile.Due to the entropic assistance of the molecular chain connecting the reactants the intramolecular cycloadditions are usually more reactive than the intermolecular cycloadditions.In general the effect of the tether on the reactivity of the Diels-Alder cycloadditions is the largest with a chain length of five or six atoms.The syntheses of 2,3-cycloalkenopyridines is most successful with pyrimidines and triazines substituted with an ω-pentynyl or a ω-hexynyl side chain.The electron ARKAT USA, Inc.
rich acetylenic moiety present in the tether acts as the dienophile adding across the azadiene part of the heterocyclic ring.It creates a cycloadduct which after the retro Diels-Alder reaction yields the cycloalkenopyridine.
On heating of 5-R-2-(pent-4-yn-1-yl) pyrimidine 13a-c at 210 o C in nitrobenzene under nitrogen in good yield the 5-R-cyclopenta[b]pyridine 15a-c was obtained. 8The reaction probably occurs via the intermediacy of cycloadduct 14 which by expulsion of hydrogen cyanide yields the required product (Scheme 5).The rate of the reaction was dependent on the electronic character of substituent R (NO2>H>Ph).The rate increase of the 5-nitro compound 13b, compared to the unsubstituted one 13a is certainly due to the enhancement of the electron deficiency of the pyrimidine ring.The rate retarding effect of the 5-phenyl group in 13c may very probably be ascribed to its steric hindrance in the formation of the cycloadduct 14.Considerable rate enhancements are observed upon quaternization of the pyrimidine ring or on protonation, for example, when the reaction is carried out in trifluoroacetic acid. 9heme 5

Scheme 5
A strong rate accelerating effect was observed when in the α position of the side chain dicyano groups are present.0 which suggests that the repulsion effect of the two neighbouring cyano groups reduces the internal C2-Cα-Cβ angle, leading to a closer proximity of the acetylenic reaction center to the C2 and C5 of the pyrimidine ring (compare structures A and B in Scheme 5).It results in added entropic assistence and consequently rate enhancement.An alternative explanation concerns the change of the conformational equilibria of the electron-rich side chain connected with the electron-poor pyrimidine.It has been suggested 8 that the reactive syn rotamers are higher populated due to the presence of cyano substituents connecting the reaction centers. 11,12om 1,2,3-triazines 1,2,3-Triazine 18, when reacting with the pyrrolidinocycloalkenes (2,n=1,2,4,6,8) in dry chloroform at 100-120 o C gives, usually in moderate-to-poor yields, the corresponding 2,3cycloalkenopyridines 19. 13,14The reaction can be described to occur by cycloaddition across the N-3 and C-6 of the 1,2,3-triazine ring, whereby the nucleophilic carbon of the dienophile is attached to C-6 (Scheme 6).Loss of nitrogen and pyrrolidine gave the required product.Similar reactions were also reported with the 3-methyl-, 4-methyl-and 4,6-dimethyl-1,2,3-triazine, although the rate of the reaction is lower due to the electron donating influence of the methyl Group, requiring more energetic reaction conditions.Trimethyl-1,2,3-triazine is unreactive.It has been reported that under microwave irradiation a dramatic shortening of reaction time can be achieved. 15he property of 18 to undergo inverse cycloadditions has been found a useful application in the synthesis of the quinoline derivative .
Heating of compound 34(n=1) in bromobenzene at reflux temperature gave the corresponding cyclopenta[b]pyridine 35(n=1) in reasonable yields.The reaction involves a cycloadduct which after expulsion of nitrogen gives the required product.Similarly from 34(n=2) the 8-methylsulfonyl-5,6,7,8-tetrahydroquinolines 35(n=2) are obtained. 19As expected the rate of formation of the tetrahydroquinolines was substantially lower than that of the cyclopenta[b]pyridines due to the longer carbon chain linking the diene and the acetylenic Group, retarding the formation of the cycloadduct.ring, yielding cycloadducts 37, which by nitrogen expulsion and pyrrolidine elimination convert to the cyclopenta[c]pyridine derivatives 38 (Scheme 9). 20Similarly, reaction of 36a-c,e with 1pyrrolidinocyclohexene 2(n=2) provides the corresponding 3-acyl-5,6,7,8tetrahydroisoquinolines 39a-c,e. 20The rate of the transformation is lower than the reaction with 1-pyrroldinocyclopentene, probably due to steric hindrance in the formation of the cyclohexenoadduct.It is of interest to mention that 3-acetyl-1-methylthio-5,6,7,8tetrahydroisoquinoline 39e is a useful key intermediate in the Fisher preparation of 2(3-(5,6,7,8tetrahydroisoquinolinyl))indole 40, the precursor in the synthesis of the zwitterionic indole alkaloid sempervirine 41 (Scheme 9). 21Using the same methodology also the seven-and eightmembered analogs of sempervirine, i.e. 42 and 43 are also prepared. 22t is of interest to mention that from the reaction mixture, obtained when reacting 5-cyano-3isopropylthio-1,2,4-triazine 44 with 1-pyrrolidinocyclohexene 2(n=2) not the expected 3-cyano1isopropylthioisoquinoline 47 was obtained, but an isomeric mixture of the addition products 3cyano-1-isopropylthio-4a,5,6,7,8,8a-hexahydro-8a-pyrrolidino-isoquinoline 46a and 46b. 18They are formed after nitrogen extrusion from the highly strained cycloadduct 45 (Scheme 10).The formation of 46 is one of the few examples of a reaction in which the precursor of the final product could be isolated.Treatment of 46 with acid gives 47.