Desymmetrizing Hantzsch pyridines via promoter-free benzylic C-H functionalization

1,4-Dihydropyridines are an important class of calcium channel blockers. However, difficulties in the preparation of nonsymmetric Hantzsch esters impede further development in this area. Benzylic C-H functionalization of Hantzsch pyridines is an efficient approach to nonsymmetric Hantzsch pyridines. We herein report a promoter-free benzylic C-H functionalization of pyridines, which allows preparation of a variety of pyridines unsymmetrically substituted in the 2/6-positions. A plausible mechanism is proposed for this reaction. This work provides a new way to prepare unsymmetrical pyridines and enriches the scope of C-H functionalization of aza-arenes.

Recently, two research groups 13,14 have reported that the direct benzylic C-H bond functionalization of azaarenes leads to nonsymmetric pyridines bearing cyano groups (CN), which have the potential to act as a chemical handle.We are very interested in applying these methods by direct benzylic C-H bond functionalization of Hantzsch pyridines to construct a variety of asymmetric Hantszch pyridine derivatives, which, by themselves or after reduction to asymmetric 1,4-DHPs, might show antianginal, antiarrhythmic, or antihypertensive bioactivity.

Results and Discussion
Initially, 1a (2-benzylidenemalononitrile) and 2a (Hantzsch pyridine) were both dissolved in PEG-400 and heated to 100 o C for 24 hr. 14However, no product was detected (Table 1, entry 1).Then if the mixture was suspended in H 2 O and heated at 100 o C for 10 hr, 13 the desired product 3a could be obtained in 50 % yield (entry 2).To further optimize the reaction conditions, we carried out further trials.Under the condition of Pd/C (5 mol%) + TsOH (10 %) in MeOH under reflux for 20 hr, 59 % of the desired product was achieved (entry 3).When TsOH (10 %) was employed as acidic catalyst and toluene was used as solvent, 3a was obtained in 60 % yield (entry 4).Interestingly, promoter-free conditions gave a slightly higher yield (entry 5).Therefore it seems that the promoter does not contribute much to the reaction; the reaction temperature is the important factor.Under promoter-free conditions we tried three different solvents at reflux.It turned out that refluxing in xylene for 10 hr gave the best results (88 % in 10 hr).See Table 1.
With the optimal conditions in hand, we were eager to know whether this reaction could tolerate different functional groups.Reactions of alkenes with different functional groups and pyridines bearing electron-withdrawing groups were carried out, and the results are listed in Table 2. Refluxing in xylene, all of the alkenes reacted smoothly with Hantzsch pyridines 2, although the yields of the products were variable.For alkenes with a 3-aryl group, the electronic nature of the functional group at the para position affects the reaction yield.When it is an electron-donating group, the yield decreases markedly (see 3b).However, an electron withdrawing group does not affect the yield much (see 3c and 3d).Interestingly, when alkenes with nitro group on different position of the aryl group are tested, it is found that meta-nitro substitution gives higher yield than para-nitro substitution, while a nitro group in the ortho postion makes the yield drop (see 3d, 3e and 3f).In terms of electron-deficient alkenes with heteroaryl group, electron donating furyl and thienyl both gave poor yields (see 3h and 3i).We were curious to know whether an alkyl group on the alkene would retard this reaction because of its electron donating capability.6][17][18] The reaction did occur although the yield is, not surprisingly, unsatisfactory.(see 3j) When a Hantszch pyridine bearing a 4-phenyl group was used as the nucleophile, the addition product was isolated in reasonable yield (see 3l).Furthermore, microwave irradiation was tried on reactions with poor yields (see 3b, 3g-j), and yields were improved somewhat except for that of 3j.It is also interesting to find that a 2-methyl is preferred to a 4-methyl for the C-H functionalization of a Hantzsch pyridine (see 3k).With the weak electron-donating group, phenyl, on the 4-position of the Hantzsch pyridine, the outcome of the reaction is much better than that of the 4-methyl Hantzsch pyridine (see 3k and 3l).Solvent (2mL) was added into reaction vessel charged with compound 1 (1.0 mmol) and 2 (1.2 mmol), the vessel was purged with nitrogen and them heated under reflux for 10 hours.b Isolated yield, the yield in parenthesis is that obtained under microwave irradiation for 10 hours.
To understand the mechanism of this promoter-free C-H functionalization reaction, several easily accessible methylpyridines were subjected to these reaction conditions and the results are listed in Table 3.As observed above, a methyl in the 2-position reacts more readily than one at the 4-position, while a methyl in a 3-position does not participate in the reaction at all.From the above findings, the reaction mechanism could be postulated as shown in Scheme 1.There is an equilibrium between compound 2 and its enamine tautomer 2*, which is the Michael donor in the reaction but much less stable than ground state compound 2. Intermediate 2* adds to electron-deficient compound 1 to give product 3 via nucleophilic conjugate addition.

Conclusions
A promoter-free benzylic C-H functionalization on substituted pyridine with electron deficient alkene is found, which can tolerate a variety of pyridine substrates.Fourteen compounds have been prepared by this method, might be applied to a series of bioassay to find out interesting pharmaceutical activities.This promoter-free benzylic C-H functionalization could be an effective tool to prepare nonsymmetric pyridine derivatives.

Experimental Section
General.The solvents used were analytical reagent purchased from Sinopharm Chemical Reagent Co, Ltd.The starting materials used were prepared in-house from chemicals purchased from Sinopharm.The reactions described in this manuscript were performed in standard laboratory glassware.Melting points were recorded on a WRS-1B digital melting point recorder from Shanghai Precision Scientific Instrument Corporation.Infrared spectra were recorded on a Nicolet Avatar 370 DTGS machine. 1 H NMR and 13 C NMR spectra were obtained on a Bruker AV400 equipment.MS data were recorded on a Shimadzu LCMS-2010EV mass spectrometer or an Agilent 5973N GC/MS.The HRMS were run using an Agilent 6224 TOF LC/MS or a Thermo LXQ Linear Ion Trap Mass Spectrometer.

General procedure (Method A) for preparation of unsymmetrical Hantzsch pyridines
Xylene (2 mL) was added into reaction vessel charged with compound 1 (1.0 mmol) and 2 (1.2 mmol), the vessel was purged with nitrogen and then heated under reflux for 10 hr.The reaction mixture was then subjected to flash chromatography to give the required product.

Alternative procedure (Method B)
Xylene (2 mL) was added into reaction vessel charged with compound 1 (1.0 mmol) and 2 (1.2 mmol), the vessel was irradiated with microwave at 250W for 10 hr.The reaction mixture was then subjected to flash chromatography to give the product.

Table 1 .
Screening of benzylic C-H functionalization of Hantzsch pyridine 2a with electron deficient alkene 1a a b Isolated yield.

Table 3 .
Benzylic C-H functionalization of methyl pyridines 4 with 2-benzylidenemalononitrile 1a a b Isolated yield.c No desired product isolated.