Hetero-Diels-Alder reactions of N -phosphoryltrihaloacetimidoyl chlorides with 1,3-butadienes

Hetero-Diels-Alder reactions of N-phosphoryltrihaloacetimidoyl chlorides with 1,3-butadienes led to new 2-chloro-2-trihalomethyl substituted tetrahydropyridine adducts. Cycloadducts with CF 3 group undergo thermal or acid catalyzed dehydrochlorination affording respective dihydropyridines and subsequent aromatization to form 2-trifluoromethylpyridines. Trichloromethyl analogs under similar conditions undergo aromatization accompanied by unusual reduction of CCl 3 group to form respective 2-dichloromethyl substituted pyridines.


Introduction
Imidoyl chlorides combine the properties of acid chlorides and azomethynes.They are reactive and versatile chemical agents and have found wide application in organic synthesis and in the study of chemical reactivity. 1 Trihaloacetimidoyl chlorides are regarded as new promising building blocks for regioselective introduction of (poly)haloalkyl groups into acyclic or heterocyclic compounds. 2Cycloaddition across C=N bond of trihaloacetimidoyl chlorides would offer additional opportunities connected with the possibility to introduce regioselectively trihalomethyl group into a molecule and further transformations of primary products via chlorine atom participation.Replacement of hydrocarbon groups in molecules with their fluorinated analogs imparts a variety of useful properties to certain medicines, including enhanced binding interactions and metabolic stability. 3As a result, fluorine containing compounds are becoming increasingly important in both agrochemistry and medicine. 4On the other hand polychloroalkyl derivatives reveals as a rule greater herbicidal and fungicidal activity then their fluorinated counterparts. 5In the pyridine and dihydropyridine series a number of compounds bearing polyfluoro-and/or polyclorohaloalkyl substituents was found to possess useful pharmacological properties. 6At the same time the use of imidoyl chlorides for construction of heterocyclic ring by means of hetero-Diels-Alder reactions with 1,3-dienes remains almost unexplored. 7ow we report on a novel approach for hydrogenated -polyhalomethyl containing pyridines and respective pyridines based on cycloaddition reactions of Nphosphoryltrihaloacetimidoyl chlorides with 1,3-butadienes.

Results and Discussion
We have found that N-dichlorophosphoryltrihaloacetimidoyl chlorides 1a,b readily react with 1,3-dienes 2a,b under mild conditions to afford functionalized tetrahydropyridines 3a-d (Scheme 1).Remarkably, the reaction with non-symmetrical diene 2b proceeds regioselectively with the formation of 4-methyl substituted isomers 3b,d.Cycloaddition is favored by electron-withdrawing substituents X in imine 1 (CF3 > CCl3) and electron releasing substituents R in diene 2 (Me > H).Thus, reaction of 1a with 2 easily proceeds at room temperature and with exothermic effect (in case of 2a), while trichloro analog 1b reacts with 2a only at heating (ether, 5 hrs).For the completion of reaction of 1b and 2b boiling in benzene is necessary.Under these conditions in addition to 3d, 50%, 5-chloro-6dichloromethyl-1-dichlorophosphoryl-4-methyl-1,2-dihydropyridine 4, 12%, and 2-chloro-4methyl-2-trichloromethyl-1,2,3,6-tetrahydropyridine 5, 3%, were isolated by column chromatography.Replacing the dichlorophosphoryl group at nitrogen atom in 1a with less electron-withdrawing (EtO)2P(O) substituent (σI 0.65 and 0.35, respectively), 8 essentially retards its reactivity toward 2. The reaction of respective imidoyl chloride, CF3C(Cl)=NP(O)(OEt)2, with diene 2a proceeds only at prolonged heating in benzene; cycloaddition under these conditions is accompanied by other processes leading to a complex mixture.As a result, cycloaddition product 6 was not isolated and detected only spectrally (F -63.7 ppm, P 8.3 ppm).Slow transformation 3a→7a occurs even at room temperature.Nitrogen bases (DBU, DABCO, Et3N) or carboxylic acid additives favor the reaction.Thus, in solutions of CF3COOD the elimination of HCl from 3a,b is completed within 24 hrs at room temperature.The same is true for CF3COOH or AcOH solutions but in these cases the formation of 7 is complicated by their partial transformation into respective pyridines 8. Dihydropyridines 7 are oily rather unstable compounds, easily soluble in organic solvents.Even at room temperatures they are gradually (~4 weeks) converted into resinous-like hardly soluble substances.Upon thermal distillation or heating in aq HCl-dioxane compounds 7 undergo aromatization to afford 2trifluoromethyl substituted pyridines 8 in 63-81% yields.
The behavior of 2-trichloromethyl tetrahydropyridines 3c,d is quite different from that of their trifluoromethyl analogs.Upon distillation in vacuum, heating in aq HCl-dioxane solution, or on treatment with CF3COOH, they give 2-dichloromethyl pyridines 9 (Scheme 3) rather than expected pyridines with trichloromethyl group.Reduction of trichloromethyl group during conversion of tetrahydropyridines 3c,d to respective pyridines 9a,b is quite unexpected.The following peculiarities are characteristic of this unusual transformation: 1) the reaction is promoted by acids; 2) the intermediate dihydropyridines analogous to 7 (Scheme 2) were not detected in the course reaction; 3) the performance of the reaction in CF3COOD does not lead to incorporation of the of deuterium into dichloromethyl group of 9. Hydrophosphoryl compounds were reported to convert activated trichloromethyl group into dichloromethyl one. 9In view of these data we first regarded the possibility of reduction of CCl3 group with the participation of Cl2POH, that could be in principle generated from 3c,d.However, our attempts to execute reduction of trichloromethyl group of model 4,5-dimethyl-2-(trichloromethyl)pyridine 10 by reacting it with diethylphosphonate, (EtO)2P(O)H, under different conditions, failed.
Taking into account the above observations the following pathway of reaction should be outlined (Scheme 4).
Generation of positive charge at phosphorus atom in intermediate A promotes the rupture of P-N bond and facilitates the elimination of POCl3.Release of sterical strains caused by voluminous 1,2-substituents in A also favours transformation A→B.The greater sterical volume of trichloromethyl group as compared with trifluoromethyl one is likely one of the reasons accounting for distinctions in behavior of tetrahydropyridines 3a,b and 3c,d.Electronwithdrawing CCl3 group and positive charge on nitrogen atom obviously promotes 1,3-proton shift (B→C) in C-N=C triad; 2c,11 moreover, in azaallylic triad proton tends to migrate to the carbon atom bearing more electron-withdrawing substituent. 11,12Finally, elimination of hydrogen chloride in C, favored by the presence of onium center, and subsequent aromatization of intermediate D by means of prototropic shift affords dichloromethylpyridines 9.It is worthwhile to note that according to proposed scheme hydrogen of CHCl2 groups comes from hydrogenated pyridine ring rather than from outer source, accounting for the absence of H-D exchange in the cause of CCl3→CHCl2 conversion.The spectral and analytical data of compounds obtained are in complete agreement with their structure.The hydrogenated trifluoromethylpyridines 3a,b, 7a,b, and pyridines 8a,b give clearly distinguishable 19 F NMR characteristics (F -75.8 ÷ -77.4 ppm, -63.2 ÷ -63.3 ppm, and -67.4 ÷ -68.8 ppm, respectively) that allow easy monitoring of the process and identification of the products in the reaction mixture.The regiochemistry of cycloaddition with non-symmetrical diene 2b was unambiguously confirmed by 1 H NMR spectra of pyridines 8b, 9b in which characteristic splitting of the 6-H signals was observed:  8.4-8.6 ppm, 3 J H 6 H 5 5 Hz.

Conclusions
In summary, based on hetero Diels-Alder reactions of N-phosphoryltrihaloacetimidoyl chlorides with 1,3-butadienes, we have developed a simple and efficient synthesis of functionalized 2trihalomethyl tetrahydropyridines, 2-trifluoromethyl dihydropyridines, and pyridines bearing CHCl2 or CF3 group in -position.

Experimental Section
General.IR spectra were obtained with an UR-20 instrument.A solution of the tetrahydropyridine 3a (3.3 g, 10 mmol) in 3 mL of trifluoroacetic acid-d1 was stirred for 25 hrs, the solvent was evaporated in vacuum at 30-35 o C to afford oily compound 7a, which was purified by column chromatography (silica gel, hexane/ethyl acetate 10:1).Yield: 1.85 g (64%). 1