2-Substituted 1,2-dihydropyridines

Lehn and coworkers have profitably employed tartaric acid-containing crown ethers as enzyme models. The rate of proton transfer to an ammonium-substituted pyridinium substrate from a tetra-l,4-dihydropyridine-substituted crown ether was considerably enhanced compared to that for a simple 1,4-dihydropyridine. The reaction showed first order kinetic data and was inhibited by potassium ions. Intramolecular proton transfer from receptor to substrate was thus inferred via the hydrogen bonded receptor-substrate complex shown in Figure 16a (78CC143). 

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. 

Dihydropyridines substituted at the 3- and/or 4-positions undergo selective acylation with trichloroacetic anhydride to give 5-trichloroacetyl-l,4-dihydropyridines 136, which are easily converted by the haloform reaction to esters 137 (Scheme 37) <1998TL9275, 2002T8099, 2003TL4711>. Hydrogenation, over platinum oxide, of... 

Strong heat and light stabilizing effect was attributed to unconventional HAS, 1,4-dihydropyridine substituted with a phosphonate moiety and to piperidine containing a nitrone moiety [278]. 

Figure 5 Fast SFC analysis of the S-enantiomer of clevidipine after hydrolysis into its corresponding acid. Column and conditions Chiralpak AD 50 x 4.6 mm ID at 30°C, mobile phase carbon dioxide with 28% of 2-propanol, flow rate 4.0 ml min backpressure 150 bar, UV detection at 240 nm. Sample preparation and work-up 2 mg of S-clevidipine substance was dissolved in 0.5ml of methanol followed by 50 pi of 1 mol r sodium hydroxide. After 10 min, 1 ml of water and 50 pi of sulfuric acid, 1 mol l was added and 0.5ml of dichloromethane as extraction medium. After brief vortexing and centrifugation 5 pi of the lower organic phase was loaded manually and injected. Upper trace sample, lower trace sample with 0.1% of S-acid added. (Reproduced with permission from Gyllenhaal O (2001) Fast enantioselective separation of clevidipine and a dihydropyridine substituted acid by SFC on Chiral pak AD. Fresenius Journal of Analytical Chemistry 369-. 54-56 Springer.)...

Specialtyydmines. Some substituted nitrogenous compounds can provide similar benefits. Esters of 2-aminocrotonate and bis-2-aminocrotonate, and appropriately substituted dihydropyridines, eg, 3,5-his-lauryloxycarhoxy-2,6-dimethyl-1,4-dihydropyridine [37044-66-7] and... 

Dyestuffs. The use of thiophene-based dyestuffs has been largely the result of the access of 2-amino-3-substituted thiophenes via new cycHzation chemistry techniques (61). Intermediates of type (8) are available from development of this work. Such intermediates act as the azo-component and, when coupled with pyrazolones, aminopyrazoles, phenols, 2,6-dihydropyridines, etc, have produced numerous monoazo disperse dyes. These dyes impart yeUow—green, red—green, or violet—green colorations to synthetic fibers, with exceUent fastness to light as weU as to wet- and dry-heat treatments (62-64). 

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. 

Utilizing the Zincke reaction of salts such as 112 (Scheme 8.4.38), Binay et al. prepared 4-substituted-3-oxazolyl dihydropyridines as NADH models for use in asymmetric reductions. They found that high purity of the Zincke salts was required for efficient reaction with R-(+)-l-phenylethyl amine, for example. As shown in that case (Scheme 8.4.38), chiral A-substituents could be introduced, and 1,4-reduction produced the NADH analogs (e.g. 114). 

An important extension of this work deals with the preparation of N-substituted l,4-dihydropyridine-3,5-diearboxylates. Tliirty examples have been deseribed (92SC3291). In most eases the reported yields (10-95%) are higher than those mentioned in the literature. Tire most signifieant results eoneern the synthesis of 1-aryl derivatives, whieh are hardly aeeessible by elassie methods. One should mention that the aminoeyelohexadiene 84 has been isolated as a by-produet when starting from ethyl A-benzylaminobut-3-enoate (Seheme 26). 

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 methodology based on the addition of nucleophiles at the a- and y -positions of A -alkylpyridinium salts to give substituted 1,2- and 1,4-dihydropyridines (often not isolated) as intermediates, respectively, which can be further elaborated into complex polycyclic alkaloids, was reviewed by Joan Bosch and M.-Lluiesa Bennasar in 1995 (95SL587). 

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

Many dihydropyridines that are of therapeutic interest are unsymmetrically substituted at C-3 and C-5. The synthesis of such compounds is possible from separately prepared Knoevenagel condensation products 6, as is outlined in the following scheme for nitrendipine 8, which is used in the medical treatment of high blood pressure." ... 

The corresponding 4-(iodomethyl)-l,4-dihydropyridine undergoes rapid transformation to the 4//-azepine 2 under milder conditions (e.g., on a silica gel column or on a TLC plate).120 4//-Azepines are also formed by the ring expansion of 4-(chloromethyl)-l,4-dihydropyridines with a variety of other nucleophiles, but, in general, are not isolated since they readily suffer addition of the nucleophile to yield 4-substituted 4,5-dihydro-l//-azepines.120 121-132... 

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>. 

Reaction of 9-benzyloxy-3,4-dihydro-277-pyrido[2,l- ][l,3]oxazinium mesylate with C5H9NH2 and BnNH2 occurred at position 9a, while with sterically hindered amines (e.g., Bu NH2, secondary amines), PhNH2 and NaN3 reacted at position 2 to give l-(3-hydroxypropyl)-2-(substituted imino)-3-benzyloxy-l,2-dihydropyridines and... 

The effect of structural variation on crystal structure was studied for 12 phenyl-substituted derivatives of 6-amino-2-phenylsulfonylimino-l,2-dihydropyridine [37], The title compound contains both hydrogen bond donor and acceptor sites, and the... 

A one-pot synthesis of N-substituted 4-aryl-l,4-dihydropyridines (Scheme 8.34) was recently [52] mentioned at the Fifth International Electronic Conference on Syn-... 

A series of 4-phenyl-1,4-dihydropyridines 146 substituted at the ortho- and K z-positions of the phenyl ring with NO-donating furoxan moieties and their non-NO-releasing furazan analogs were synthesized by a multistep protocol (Scheme 37) <1998JME5393>. 

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