2 pyridines, cyclisation

A useful method for the preparation of functionalised thiazoles has been described. Palladium catalysed cross coupling reactions between 4-thiazolyl-5-acetyl triflates 36 and alkynes afforded 4-alkynyl-5-acetylthiazoles 37 in good yields (56-82%). If 37 is then treated with ammonia in methanol, thiazolo[5,4-c]pyridines 39 are formed, probably via the intermediate imine 38 which then undergos a regioselective 6-endo dig cyclisation <99EJOC3117>. 

Oxazolidinones have also been used as intermediates in simple transformations utilising their peculiar reactivity. The absolute configuration of WBoc-P-aminoalcohol 213 can be easily inverted via Sn2 cyclisation to oxazolidinone 214 <00TL10071>. Treatment with Olah s reagent (HF-Pyridine) of 4-alkyl-5,5-diphenyl-oxazolidinones 216 afforded the corresponding a-(fluorodiphenylmethyl)alkylamines 217 <00TA2033>. 

Vilsmeier reaction of the 3a-azaazulenones (80) yielded the aldehydes (83). Wittig reaction converted 83 into the esters (84), which could be cyclisized to cycl[4,3,2]azines (85) by a pyridine-piperidine mixture.105-107... 

Japanese workers recently designed a synthesis of 5-amino-2,3-dihydrothiepino[2,3- >]pyridine-4-carbonitrile 2 based on Thorpe-Ziegler cyclisation of 2-(3-cyanopropylthio)pyridine-3-carbonitrile 1. Treatment of 1 with potassium t-butoxide however, did not, give 2, but produced the thieno[2,3-/i][l,6]naphthyridine 3 in 82% yield. 

The radical reductive cyclisation of diesters to acyloins (see also Section 5.9.1, p. 628) is an important method of synthesis for ring sizes from four-membered upwards. The example selected here is 2-hydroxy-3-methylcyclopent-2-enone ( corylone ) (29) (Expt 7.10), which is an important perfumery and flavouring material.53 In the first step (i), methyl acrylate is converted into its dimer with tris(cyclohexyl)phosphine in pyridine solution.5b Step (ii) is the protection of the double bond by conversion into the dimethylamino adduct. The acyloin reaction is step (iii), and the product is trapped as its bis(trimethylsilyl)ether. Finally, in step (iv), the protecting dimethylamino and trimethylsilyl groups are removed by passage down a column of silica gel. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

Disconnection of both C-N bonds of a pyridine 50 gives an ene-dione 51 but the alkene has to be cis for cyclisation to be possible and conjugated m-enones are rather unstable. It is usually easier to remove the double bond to reveal the saturated 1,5-diketone 52 that can be made by the methods of chapter 21. This usually means conjugate addition of an enolate to an enone. 

Thermal electrocyclic reactions of 1-azahexatriene systems can be used to obtain imidazo[4,5-c]pyridines (25) [95H(41)161] and the thermal cyclisation of 2-alkynylbenzene-diazonium salts (the Richter reaction) has been extended to the synthesis of pyrazolopyridazines (26) (Scheme 17) [95LA775],... 

The cyclisation of o-alkenylphenols features in two approaches to the chroman ring system. The Hg-mediated cyclisation of (7) affords the chroman-4-ols (8) and (9) which can be separated after debenzylation, providing the chroman unit of the calophyllum coumarins (95S630). 2-Cyclohexenylphenols undergo a 6-endo cyclisation to fused chromans on treatment with pyridine hydrobromide perbromide (95CJC1727). 

Thermolysis of 3-(2,2-dicyanovinyl)-4-(l-piperidyl)pyridine (15, X = CH2) in DMSO produces the naphthyridine (16, X = CH2) by means of the "tert-amino effect" proposed by Meth-Cohn and Suschitzky <95SL622>. Where, however, X is a N, O or S an alternative cyclisation takes place, when the pyridoazepines (17) are formed. This new variant of the "rert-amino effect" is postulated to arise by the intermediate formation of (18). 

Reaction of the l-aryl-2-phenacylcyclopropanes with chlorosulphonyl isocyanate and subsequent removal of the chlorosulphonyl group with benzenethiol in pyridine affords the 4,5-dihydro-1,3-oxazepines (91) <95SCI939> and in a reaction sequence in which an aziridine is the source of nitrogen, methyl l-benzyloxycarbonylaziridine-2-carboxylate reacts with 2-(N-benzyl-A -/t /7-butoxycarbonyl)aminoethanol to give the derivative (92) which, after removal of the Boc group, is subject to a reductive cyclisation to yield the hexahydro-l,4-oxazepine (93) <95CPBI 137>. 

In this particular instance the correct oxidation level automatically results from the condensation reaction, giving pyrrole 2.16 directly. In other cases cyclisation does not afford the correct oxidation level and an unsaturated system has to be oxidised to achieve aromaticity. For instance, 1,5-diketones 1.27 react with ammonia to give dihydropyridines 1.28 which can be oxidised to pyridines 1.29. 

A typical pyrilium salt synthesis is illustrated by the preparation of salt 9.12. The precursor to 9.12 is pyran 9.11, available by dehydration of 1,5-diketone 9.10. Note the similarity of this sequence to the Hantzch pyridine synthesis, Chapter 5. Also, the dehydrative cyclisation of a diketone to oxygen heterocycle 9.11 is reminiscent of furan synthesis, Chapter 2. 

B-2) More common rings, which however can not be adequately treated once cyclised. For instance it is difficult to halogenate pyridine in certain ring positions. Therefore when a halogen is required in those positions, it is introduced into an aliphatic molecule which is then cyclised during the synthesis. 

On the other hand if a pyridine structure which is amenable to halogenation is required, then the pyridine is halogenated and connected ready made with the rest of the molecular structure no special cyclisation being required. 

Pyridine pesticides are usually synthesized by starting with pyridine or a picoline nucleus, which is then further treated by halogenation, ammoniation, oxidation, etc. Quite often however it is impossible to introduce the desired substituents into the adequate ring position, in which case the corresponding aliphatic compound is prepared and then cyclised. 

Co-condensation of 2,6-bis(bromomethyl)pyridine, 4, with a variety of dithiols, 5, yields not only the [1+1] cyclisation product, e.g. 6, but also—by working at higher concentration—the [2+2] cyclised ligand.9,10 An example of this is provided by the formation of the tetradentate ligand 7 and the mixed donor macrocycle 8. 

One of the main drawbacks of the intermolecular reaction is that to achieve good yields and selectivity it is frequently necessary to run reactions to low conversion rates or use the heteroaromatic base in vast excess. Such a limitation does not apply when conducting reactions intramolecularly and in recent times much attention has been focussed on such variants. A number of synthetically useful orr/jo-cyclisation and j so-substitution reactions have been uncovered providing new routes condensed heteroaromatic ring systems and substituted pyridines. Reactions can be effected at neutral pH and may occur to each of the carbon centres in the pyridine ring system. As these recent advances have not been summarised previously, much of this review will be devoted to the intramolecular reaction. 

The addition of an aryl radical intermediate to a pyridine featured as a key step in a total synthesis of the alkaloid toddaquinoline by Harrowven and Nunn <98TL5875, 00TL6681, 01T4447>. Thus, cyclisation of azastilbene 148 using tributyltin hydride and AIBN, led to both the desired product, toddaquinoline methyl ether 149, and an unwanted regioisomer 150 (Scheme 41). 

Notably, when the same cyclisation was carried out using sodium cobalt(I)salophen, the reaction became selective for toddaquinoline methyl ether <00TL6681>. This apparent diehotomy was attributed to the formation of a Lewis acid - Lewis base complex between cobalt(II)salophen and the pyridine moiety. Loss of bromide from the radical anion 151 generates aryl radieal 152 which adds to the proximal pyridine giving 153. Dehydrocobaltation to toddaquinoline methyl ether 149 completes the sequence (Scheme 42). Notably, as the pyridine ring is activated by complexation to the Lewis acidic Co(II), the eyelisation is more akin to a Minisci reaction. Consequently, cyclisation to C6 is promoted in this case <01T4447>. 

The same group went on to show that radical cyclisations to C3 of a pyridine were also favourable at neutral pH <01TL9061, 030BC4047>. Thus, on treatment with tributyltin hydride and AIBN, azastilbene 154 underwent cyclisation to benzo[/]quinoline 155 in 47% yield (Scheme 43), while the corresponding reaction with iodide 157 gave benzo[/i]isoquinoline 159 in near quantitative yield (Scheme 44). 

A study of the cyclisation of aryl radical intermediates to quinolines uncovered some striking differences in the reactivity profile of quinolines and pyridines towards radical intermediates <01TL2907, 02T3387>. Most notably, cyclisations involving quinolines were generally more efficient when the heterocycle and radical precursor were conjoined using a saturated tether. Moreover, in each case products derived from orf/io-cyclisation were observed irrespective of the nature of the tethering chain or its point of attachment to the quinoline (Schemes 53 - 55). 

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