2,3,4,6-tetrasubstituted pyridines

An efficient procedure for the synthesis of 2,4,6-trisubstituted and 2,3.4,6-tetrasubstituted pyridines 5 and 6 involves the one-pot reaction of in situ generated a,p-unsaturated imines with carbanions <95TL(36)9297>. 

Scheme 2.44. lnCI3-mediated synthesis of various tetrasubstituted pyridines. 

Various methylenetetrahydrofurans were accessible by a combination of a Zn-promoted Michael addition and a cyclization using alkylidenemalonates and pro-pargyl alcohol as substrates, as reported by Nakamura and coworkers [108]. Tetrasubstituted pyridines of type 2-189 have been obtained through a solvent-free InCl3-promoted domino process of 2-187 and 2-188 (Scheme 2.44) [109]. 

In marked contrast to the above results, double nitrile insertion into both the titanium-alkyl and titanium—vinyl bonds occurs to form the diazatitanacycles 74. Treatment of these titanacycles with dry hydrogen chloride affords the tetrasubstituted pyridine derivatives 75 (Scheme 14.32) [74], On the other hand, 2,3-diphenyltitanacyclobutene reacts with various nitriles to afford the products of mono-insertion, which afford the corresponding unsaturated ketones upon hydrolysis [73,74]. 

Scheme 14.32. Preparation of tetrasubstituted pyridines by the reaction of titanacyclobutenes with nitriles.

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

A bromo cyclization of dienone 1 gives rise to excellent yields of tetrasubstituted pyridines (Equation 1) <2004SL811>. 

An N-l-diene-l-aza-1,3-butadiene was employed in a Diels-Alder reaction to synthesize the key intermediate, a tetrasubstituted pyridine, in the total synthesis of the pyridine-base natural product, piericidin (Scheme 53) <2005JA15704>. The concerted cyclization conditions were surprisingly mild, considering the steric demand of the dienophile and that the aromatization was not successful under a variety of basic conditions, but the Lewis acid cleanly affected the transformation. 

Conjugated heterocumulenes can act as heterodimers in [4+2] cycloadditions, reacting with aminoalkynes to give tetrasubstituted pyridines (Equation 111) <1997T4521>. The corresponding isoquinoline is formed if the reaction is heated to 140 °C. 

The Bohlmann-Rahtz reaction is a classic pyridine synthesis that has been studied and modified in many ways. Bagley et al. has elaborated on his previous work and reported an iodine-mediated catalytic Bohlmann-Rahtz reaction of aminodienone intermediates <05SL649>. This modified process is reported to be rapid at ambient temperatures resulting in good yields. Moreover, Bagley and co-workers presented a one-pot, three-component Bohhnann-Rahtz reaction to synthesize 2,3,6-trisubstituted and 2,3,4,6-tetrasubstituted pyridines 8 and 9 from P-ketoesters 10 and alkynes 11 as shown in Seheme 3 <05JOC1389>. 

The synthesis of the drug PNU-142721 19 required a series of electrophilic substitutions on 3-hydroxy pyridine5 33. Iodination of the chloride 35 went in the previously inaccessible 6-position to give 36. Now iodine-lithium exchange and reaction with acetaldehyde gave the secondary alcohol 37 and finally iodination gave the tetrasubstituted pyridine 38. Each new substituent is added as an electrophile in a specific position. Only the acetaldehyde had no choice. 

This chemistry, preceded by an electrophilic substitution on the N-oxide, finds a most important application in the synthesis of omeprazole, Astra(Zeneca) s anti-ulcer drug and one of the best selling medicines of recent years. Omeprazole 80 is a sulfoxide and has a 2,3,4,5-tetrasubstituted pyridine linked through the sulfur atom to a benzimidazole.8... 

The full scope of the acid-catalyzed one-step conversion of N-tert-bu-tylmethanimine, generated in situ from 1,3,5-tri-tm-butylhexahydro-1,3,5-triazine, to symmetrical 3,5-disubstituted pyridines employing enamines has been detailed.290 The generation of 2,3,5,6-tetrasubstituted pyridines from the thermal reaction of enolizable ketones with hex-amethylphosphoric triamide has been proposed to proceed by in situ generation and subsequent [4 + 2] cycloaddition of /V-methyl-1 -aza-1,3-butadienes with intermediate dimethylamino enamines.30... 

More recently, Bagley and coworkers prepared tri or tetrasubstituted pyridines by microwave irradiation of ethyl j5-aminocrotonate and a variety of alkynones in a single synthetic step and with total control of regiochemistry (Scheme 10.25) [60]. 

A-Silyl-l-azaallyl anions 6 add to diphenylpropionone to form 2,3,4,6-tetrasubstituted pyridines 7 <97H271>. 

Tri-substituted pyridine derivatives 201 were prepared by Katritzky et al. using a-benzotriazolyl ketones 199 and a,P-unsaturated ketones 200 in the presence of ammonitun acetate in refluxing acetic acid in good yields.Fused 2,3,4,6-tetrasubstituted pyridines 203 were also formed from the appropriate fused bicyclic ketone substrates 202. ... 

In 1999, Katritzky reported a novel [3+2+1] synthesis of 2,4,6-trisubstituted pyridine derivatives that used the Michael addition of a-benzotriazolyl ketones to a,P-unsaturated carbonyl compounds. This reaction resembles the Krohnke pyridine synthesis and is an extension of Katritzky s earlier studies with benzotriazolyl derivatives that provided access to pyridones, 2-thiopyridones, 5-alkyl-2,4-diphenylpyridines and 2-aminopyridines. This approach is attractive as both components are readily synthesized or commercially available. The availability of these starting materials allows for an efficient access to structurally diverse 2,4,6-triaryl pyridines when combined with ammonium acetate in acetic acid at reflux. In addition, it is possible to access fused 2,3,4,6-tetrasubstituted pyridines from the requisite fused bicyclic ketone starting material. The preparation of the pyridine ring via benzotriazole methodology has resulted in improved yields for many compounds and the opportunity to synthesize molecules with a substitution pattern that would be difficult to prepare by other methods. 

Fused 2,3,4,6-tetrasubstituted pyridines 7, 9 and 10 can be prepared by two complimentary procedures from fused bicyclic ketones. In the first synthetic approach it is the a,P-unsaturated ketone 6 that is part of the fused ring system. 

Scheme 11 A metal-free"click"approach to tetrasubstituted pyridines.

A procedure by using enamino ester and alkynone as the substrates was developed as well [2]. 2,3,4,6-Tetrasubstituted pyridines were prepared in a single step. Various acids, such as acetic acid, Amberlyst 15 ion exchange resin, zinc(II) bromide or ytterbium(III) triflate, can be applied as promoter for the cycUzation step of the Michael addition adduct. 4-(3-Oxoalkyl)isoxazoles found could be applied as starting material for pyridine synthesis as well [3],... 

The using of y0-ketoester, ammonia, and alkynone as substrates, with Brousted acid (AcOH) or Lewis acid (ZnBr2) or Amberlyst 15 ion exchange resin as the promotor, to synthesis 2,3,6-trisubstituted or 2,3,4,6-tetrasubstituted pyridines was also reported [67]. Good yields and total regiocontrol can be obtained. 

Recently, alkynyl oximes have attracted attention as an intriguing substrate in catalytic skeletal rearrangements. Nakamura et al. reported that 0-propargylic oximes 88 derived from a,(3-unsaturated aldehydes in the presence of eopper catalysts afforded 2,3,4,5-tetrasubstituted pyridine oxides 89 (Scheme 27.32) [41]. The reaction proceeds via tandem copper-catalyzed 2,3-rearrangement and b-ir-electrocyclization of the resulting N-allenylnitrone intermediate 90. 

The enantioselective intramolecular formal 2+4-cycloaddition of acrylates and a, -unsaturated imines (99) catalysed by chiral phosphines (100), derived from amino acids, produced A-heterocycles (101) (Scheme 31). Chiral dirhodium(II) carboxamidates (102) catalysed the hetero-Diels-Alder reactions between 2-aza-3-silyloxy-l,3-butadienes and aldehydes to yield all cw-substituted l,3-oxazinan-4-ones in high yields and high enantioselectivity (98% ee)P The nickel-catalysed 4 + 2-cycloaddition of a, -unsaturated oximes with alkynes yielded 2,3,4,6-tetrasubstituted pyridine derivatives. The reaction of isoquinoline, an activated alkyne, and 4-oxo-4//-l-benzopyran-3-carboxaldehyde (103), in ionic solvents, produced 9a//,15//-benzo[a][l]benzopyrano[2,3-/t]quinolizine derivatives (105) via the zwitterion (104) selectively and in good yields (Scheme 32).The Diels-Alder cycloaddition of ethyl 3-(tetrazol-5-yl)-l,2-diaza-l,3-butadiene-l-carboxylates with -rich heterocycles, nucleophilic olefins, and cumulenes formed 3-tetrazolyl-l,4,5,6-tetrahydropyridazines regioselectively. The silver-catalysed formal inverse-electron-demand Diels-Alder... 

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