4- Substituted 1,4-dihydropyridines, oxidation

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

The oxidation of 167 with Mn02/bentonite was performed without a solvent to give a mixture of 155 and 156, depending on the alkyl substituent in 9 100% yields after irradiation for 2 10 min (Scheme 34). The ease of oxidation of the 4-substituted dihydropyridines was found to be in the order R = H> alkyl > aryl (91SC2137). 

A solid-phase oxidative method for the conversion of 1,4-dihydropyridines to pyridines in good yields (76 90%) was carried out by employing phenyliodine(III) Z)w(trifluoroacetate) (FIFA) at room temperature. The dealkylation at the 4-position in the case of ethyl-, isopropyl-, and benzyl-substituted dihydropyridine derivatives with FIFA was circumvented by using elemental sulfur in solvent-free conditions under MWI for 5-7 min, compared to 3 5 min for the traditional heating to yield products 155 and 156 in 68% and 85% yields, respectively (Scheme 34) (99JCS(F1)1755). 

Nitropyridine and 4-nitropyridine A-oxide have been shown to react with iso-prene, 1-methoxy-l,3-butadiene, and Danishefsky s diene to produce isoquinoline cycloadducts. One asymmetric and asynchronous transition state (TS) was detected between the reactants and the cycloadduct with isoprene and two TS were observed when 1-methoxy-l,3-butadiene and Danishefsky s diene were used. The Diels-Alder reaction of highly substituted dihydropyridines with e-deficient alkenes produced highly substituted isoquinuclidines with high stereo- and regio-selectivity. The Diels-Alder cycloaddition of cyclopentadiene to lithium ion encapsulated [60]fullerene proceeds at a higher rate than with that of empty [60]fullerene. ... 

Pyridines can be made by condensation reactions of acyclic starting materials such as carbonyl compounds with ammonia. The most general of these methods is the Hantzsch pyridine synthesis. In this reaction, two molecules of a j8-dicarbonyl compound, an aldehyde, and ammonia combine in several steps (Worked Example 25-28) to give a substituted dihydropyridine, which is readily oxidized by nitric acid to the aromatic system. When the j8-dicarbonyl compound is a 3-ketoester, the resulting product is a 3,5-... 

An efficient Rh-catalyzed C-H alkenylation and electrocyclization sequence that provides easy access to highly substituted dihydropyridines 91 from a,p unsaturated imines and alkynes was reported by Ellman (Eq. (5.88)) [47]. The alkyne scope was good nonsymmetric alkynes gave the dihydropyridine products as single regioisomers in most cases. The 1,2-dihydropyridines can be oxidized efficiently to pyridines. 

Varma and Kumar (1999) reported the use of phenyliodine (III) bis(trifluoroacetate) (FIFA) or elemental sulfur for oxidation of 1,4-dihydropyri-dines to pyridines under microwave irradiations. Dealkylation at the 4-position in the cases of ethyl, isopropyl and benzyl substituted dihydropyridine derivatives with FIFA is circumvented by an alternative general procedure using elemental sulfur, which provides pyridines in good yield (68-90%). 

The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

Lavilla et al. have reported several stereocontrolled oxidative electrophilic additions to A-alkyl-l,4-dihydropyridines 34 leading to the synthesis of 3-halo-2-substituted-l,2,3,4-tetrahydropyridines 67 (98JOC2728). Adding a stoichiometric amount of iodine or NIS (A-iodosuccinimide) to a methanolic solution of 1 -methy 1-... 

The synthesis of 4-substituted pyridines via 1,4-addition of Grignard reagents to pyridinecarboxamides has been studied. After addition of Grignard reagents to pyridinecarboxamides 32, oxidation of the dihydropyridine intermediates with NCS or oxygen provides the substituted pyridines 33 in good yields <95T(51)9531>. 

If the lithiated dihydropyridine contains a removable substituent on the nitrogen and if subsequent removal of the substituent is accompanied by oxidation then substituted pyridines can be obtained [88AHC(44)-199]. Thus, pyridine can be converted to a l-(t< r/-butoxycarbonyl)-... 

Similar results are obtained from reaction of pyridine A-oxide derivatives with 146 and several transformations, including ring opening, have been described. Reaction of pyridinium salts and 146 gives the corresponding 4-substituted-1,4-dihydropyridine derivatives 212 (Scheme 7.65). 

Hantzsch synthesis The reaction of 1,3-dicarbonyl compounds with aldehydes and NH3 provides a 1,4-dihydropyridine, which can be aromatized by oxidation with nitric acid or nitric oxide. Instead of NH3, primary amine can be used to give 1-substituted 1,4-dihydropyridines. 

The substituted 1,4-dihydropyridines 156 in dry acetonitrile, containing Bu4NC104, are oxidized in a one-electron step leading presumably to a radical-cation (157).235 The final product obtained in dry acetonitrile is a substituted pyridine (158) or pyridinium derivative (159), a two-electron product. This indicates a disproportionation of the initially formed radical-cation. By adding water to act as a base, the wave doubled in height indicating a deprotonation of the radical cation 157 to a radical that is oxidizable... 

A voltammetric study on various substituted 1,4-dihydropyridines in nonaqueous electrolyte showed that the oxidation is facilitated by electron-donating groups in the 2- or 6-positions and by electron-withdrawing groups in the 3- or 5-positions.220 The position of the discharge wave of various p-benzyl substituted 1,4-dihydropyridines (158) in DMF was related to the Hammett op constants only in the case of p-fluorobenzyl (158, X = F) did the linear correlation break down somewhat.221... 

Alkylpyridines.3 Highly selective alkylation of pyridine at C4 is possible by quatemization with this triflate followed by reaction with a Grignard reagent. Substitution occurs with almost complete regiospecificity ( > 99%) to give 4-alkyl-l, 4-dihydropyridines, which are oxidized by oxygen to 4-substituted pyridines (equation 1). 

There are several publications devoted to oxidative additions to dihydropyridines [337, 338, 339, 340, 341]. For instance, the addition of stochiometric amounts of iodine in a methanol solution of dihydropyridine 309 gives iodi-nated tetrahydropyrimidine 310 in a stereoselective manner [337]. The same result is obtained when the reaction is performed with AModosuccinimide (NIS) (Scheme 3.107). Interestingly, when the process is carried out in tetra-hydrofuran the incorporation of the succinimide moiety at position 2 yields 3-iodo-2-succinimidotetrahydropyridine 311. Using Af-bromosuccenimide, TV-chlorosuccenimide and 7V-fluoropyridinium trifluoromethanesulfonate produces 3-bromo-, 3-chloro- and 3 flouro-substituted pyridines [337]. 

Certain pyridines react with Grignard reagents in the 1,4-manner when substituted by electron-withdrawing groups such as a carboxamide <2000J(P1)4245, 2005JOC2000>. The intermediate dihydropyridine can conveniently be oxidized to the pyridine structure. An example of this is seen in the reaction of 6-chloronicotinic acid derivative 125 with an excess of o-tolylmagnesium chloride, followed by oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone... 

A photochemical investigation of 4-substituted-l,4-dihydropyridines has shown that exposure to UV light induced photooxidation with 1,4-elimination of H2 or R-H. It was determined that the light sensitivity of solid samples of 1,4-dihydropyridines was far less than that for samples in solution <2005BML3423>. Most solid samples showed only trace oxidation after 50 h continuous exposure while, on average, in solution 100% oxidation took 10-15 h. 

Dihydropyridines are inherently unstable and rapidly isomerize to other dihydropyridine isomers many also rapidly eliminate H2 to form pyridines. The exceptions are 3,4-dihydropyridines substituted at the 2- and 5-positions with electron-donating groups. However, even stable 3,4-dihydropyridines can be oxidized to the corresponding pyridine by the use of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) <1995T7161>. An example of the stability of these substituted 3,4-dihydropyridines is in the unexpected formation of 2-methoxy-3,4-dihydropyridine 45 rather than the expected pyridine 46 from the [3+3] cyclization of 4-amino-l-azabutadiene 44 with Fischer alkynylcarbene complex 43 (Equation 1) <2001NJC8>. The 2-methoxy group was proposed to stabilize an intermediate and result in elimination of the metal without aromatization. 

Selective bromine-mediated addition of BOC-protected-guanidine 81 to dihydropyridine 56 occurs across the electron-rich 5,6-alkene to give, after acid deprotection, r-2-amino-l,3a,5,7a-dihydroimidazo[4,5-b]pyridine 82 (Scheme 23). Aminal bond cleavage under basic conditions affords substituted 2-aminoimidazole 83 <2004OL3933>. Replacement of guanidine 81 with urea or thiourea leads, similarly, to 2-aminooxazoles or 2-ami-nothiazoles, respectively however, the yields are considerably lower than that of 82 due to the sensitivity of the ureas to bromine oxidation <2005JOC8208>. 

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