Synthesis of 3,4-dihydroisoquinoline N -oxides via palladium-catalyzed intramolecular cyclization of 2-alkylbenzaldoximes

A novel process for the synthesis of 3,4-dihydroisoquinoline N -oxides via Pd(PPh 3 ) 4 /PhCOOH-catalyzed intramolecular cyclization of 2-alkylbenzaldoximes was reported. The reaction of 2-alkylbenzaldoximes proceeded smoothly in the presence of 10 mol% Pd(PPh 3 ) 4 and 40 mol% PhCOOH in 1,4-dioxane at 100 o C to give the corresponding 3,4-dihydroisoquinoline N -oxides in good to high yields. A possible pathway for the production of 3,4-dihydroisoquinoline N -oxides via a π -allylpalladium complex was proposed. The present study provides a useful and new method for the formation of C-N bond in organic synthesis.


Introduction
3,4-Dihydroisoquinoline N-oxides are an important class of organic compounds because of their wide utility.They are often seen as building blocks in natural products 1 and are used as free radical trap in chemical and biochemical system. 2 Moreover, 3,4-dihydroisoquinoline N-oxides have been shown to have potential ability to cure many diseases of aging, such as stroke, Parkinson disease, Alzheimer disease and cancer development. 3They can also be used as antimicrobial agents, 4 pesticides (I), 5 and anti-HIV agents (II) (Figure 1). 61] Due to the importance of 3,4-dihydroisoquinolines N-oxides, much attention has been attracted to their organic synthesis.3][14][15] Several extra oxidants used in these reactions included H2O2, mCPBA, O2, cumene hydroperoxide and oxone, etc.However, the use of extra oxidants, complicated or noble metal catalysts, toxic additives, greater toxicity organic solvents and/or prolonged reaction times were usually needed in these processes.8][19] Similarly, these two methods had obvious drawbacks.Strong corrosive acid, such as CH3HSO3 or H2SO4, was needed in the former method, and hypertoxic cyanide or thermal unstable NH2OH was needed in the later method.These shortcomings limited their industrialized application.Therefore, the development of an efficient and environmentally benign protocol for the synthesis of 3,4-dihydroisoquinoilne N-oxides is still highly desired.
1][22][23][24] Previously, Yamamoto et al. reported the synthesis of piperidines and pyrrolidines, lactams, furans and lactones by hydroamination, 25 hydroamidation, 26 hydroalkoxylation 23 and hydrocarboxylation 27 of alkynes using a Pd(PPh3)4/PhCOOH combined catalyst system (Eq.1).Recently, several methods for the synthesis of isoquinoline N-oxides had been reported through cyclization reactions of 2-ethynylbenzaldehyde oximes (Eq.9][30][31] Based on the results of above researches, it occurred to us that the synthesis of 3,4-dihydroisoquinoline N-oxides from 2-alkylbenzaldoximes was possible with Pd(PPh3)4/PhCOOH combined catalyst system.With this in mind, intramolecular cyclization of 2alkylbenzaldoximes with Pd(PPh3)4/PhCOOH was investigated, and the result indicated that the reaction proceeded well to give the corresponding 3,4-dihydroisoquinoline N-oxides in good to high yields at mild reaction conditions (Eq. 3).The detailed results of the study are reported herein.

Results and Discussion
Initially, our research focused on the optimization of reaction conditions such as catalysts, solvents, temperature and acid, etc. and hoped to achieve a higher yield.The results were summarized in Table 1.2-(4-Phenylbut-3-ynyl)benzaldehyde oxime (1a) was employed as a model substrate.The reactions of 1a did not proceed in the absence of catalyst or acid (entries 1 and 2).When 1a was treated with 10 mol% Pd(PPh3)4, 40 mol% benzoic acid in 1,4-dioxane at 100 o C under argon, the corresponding 3,4-dihydroisoquinoline N-oxides (2a) as sole product was obtained in 99% isolated yield (entry 3).The results clearly indicated that combined use of Pd(PPh3)4 and PhCOOH was essential for the transformation.Catalyst screening revealed that Pd(PPh3)4 gave a higher yield, while PdCl2 and Pd2(dba)3•CHCl3 were not effective and afforded only trace amount and 40% yield (entries 4 and 5).Other acid sources such as CH3COOH, H2O and MeOH instead of PhCOOH were examined.Acetic acid was effective and gave 72% yield (entry 6).The use of H2O and MeOH did not afford the desired products (entries 7 and 8).Among the solvents such as AcOEt, benzene, CH3CN, THF and CH2Cl2 tested, the desired products were also obtained in good to high yields, however the yields were low in comparison to the 99% yield in 1,4-dioxane (entries 9-13).We further investigated the effect of the amount of Pd(PPh3)4, the amount of benzoic acid and temperature on the yields of 2a.The yields of 2a were decreased as the amount of Pd(PPh 3 ) 4 or PhCOOH decreased (entries 14 and 15).Decreasing temperature to 80 o C led to a moderate yield (entry 16).As shown in Figure 2a, the time profile of the reaction of 1a monitoring by NMR indicated that the substrate 1a was completely converted whereas the corresponding product 2a was obtained in the highest yield of 99% within 2 h. Figure 2b showed the peak changes of 1a and 2a by 1 H NMR at different reaction time.It can be seen that the methylene (-CH2-) peaks of 1a at 3.0 ppm became smaller and smaller as the time increased from 0 to 40 min, until its peaks of 1a disappeared at 2 h, whereas chemical shift was found to change at 40 min and the methylene (-CH2-) peaks of 2a at 3.1 ppm and 3.6 ppm occurred.Since then, the peaks changed from smaller to bigger, indicating clearly that the sole product 2a was produced and gave the best result at 2 h.With optimized conditions in hand, intramolecular cyclization of various substituted 2-alkylbenzaldoximes to corresponding 3,4-dihydroisoquinoline N-oxides was then investigated, and the results were summarized in Table 2.The reactions of 1b and 1c, having 4-methoxy phenyl and 2,6-dimethyl phenyl groups at the alkyne terminus produced smoothly to give products 2b and 2c in 81% and 76% yields, respectively (entries 2 and 3).Treatment of 1d, having an electron-withdrawing group, -COOMe, at the para-aromatic ring afforded good yield (entry 4).The yield of desired products were 81% (2b, entry 2), 76% (2c, entry 4), 80% (2d, entry 4) respectively.It was worth noting that, when substrates attached a bulk group (1g, entry 7), no desired products can be detected.We think that this may due to steric hindrance.In addition, methoxy and methylenedioxy were introduced to benzene ring (1e-1f, entries 5-6).The substrates 1e and 1f, in which the aromatic ring was substituted with RO groups, afforded products 2e and 2f in good to high yields (entries 5 and 6).But when R 1 group was methoxy group and R 2 group was trimethylsilyl group, the 3,4dihydroisoquinoline N-oxide 2g was not obtained at the present conditions.We tried various methods such as prolonging the reaction time or increasing the amount of palladium catalyst and benzoic acid, all of them failed to give the product 2g, and a mixture was (entry 7).
According to present results and previous works, [32][33][34] a plausible mechanism for the synthesis of 3,4dihydroisoquinoline N-oxide is illustrated in Scheme 1.Initially, Pd(0) catalyst reacted with benzoic acid to form hydridopalladium species A, hydropalladation of 2-alkylbenzaldoximes 1a with formed A gave the substituted phenylallene B. 35

Conclusions
We developed a novel and efficient method for the synthesis of 3,4-dihydroisoquinoline N-oxides via palladium-catalyzed intramolecular cyclization of 2-alkylbenzaldoximes.The combined use of Pd(PPh3)4/benzoic acid as catalyst showed the high catalytic acitivity and gave desired products in good to high yields.Our present study provides a new and useful method for the generation of C-N bond and has also meaningful results for the synthesis of nitrogen heterocycles.

Experimental Section
General. 1 H and 13 C NMR spectra were operated at 400 and 100 MHz respectively.The reactions were monitored by thin-layer chromatography (TLC).Column chromatography was performed on neutral silica gel (60N, 45-75 μm) and hexane/AcOEt was used as an eluent.The catalyst Pd(PPh3)4 was prepared according to the literature procedure. 36All starting materials used in our study were prepared in the laboratory.TLC was performed on aluminum-precoated plates of silica gel 60 with an HSGF254 indicator and visualized under UV light or developed by immersion in the solution of 0.6 % KMnO4 and 6 % K2CO3 in water.
Synthesis of substrates 1a, 1e, 1f.Taking 1a as example, to 1-phenyl-1-propyne (12 mmol, 1.5 mL), nbutyllithium (12 mmol, 1.15 mL) and HgCl2 (0.15 mmol, 40 mg) was added in 20 mL THF under argon in a 50 mL three-necked flask.After stirring for 1 h at -78 o C, 2-bromobenzyl bromide (10 mmol, 2.5 g) was added in to the reaction mixture and then reacted for 5-10 h at room temperature (monitored by TLC).The reaction mixture was washed with saturated NH4Cl solutions, dried with anhydrous MgSO4 and extracted with Et2O. 37he concentrated yellow oil was added with n-butyllithium (20 mmol, 1.88 mL) at -78 o C.After 1 h, DMF (12 mmol, 0.93 mL) was added dropwise into this mixture.Then, the reaction was brought to room temperature for 5-10 h (monitored by TLC), and quenched by saturated NH4Cl, and the resulting residue was purified through a short silica gel column using hexane/EtOAc as eluent. 38After removing the solvent, hydroxylammonium chloride (4.5 mmol, 312 mg) was added and sodium acetate (4.5 mmol, 123 mg) into a mixed solution of ethanol and water (6 mL) with the volume ration of 1:1.After a certain period of time, this reaction was quenched with saturated NaHCO3 and purified by silica gel column (hexane/EtOAc) to afford desired substrates 1a, 1e, 1f. 39ynthesis of substrates 1b, 1c, 1d, 1g.The procedures for preparing substrates 1b, 1c, 1d, 1g were similar.During the reaction, trimethylsilyl was removed by potassium fluoride using methanol and tetrahydrofuran as solvent to afford terminal alkynes. 40

Figure 2 .
Figure 2. (a) Time profile of the cyclization of 1a.(b) The peak changes of 1a and 2a by 1 H NMR at different time.

Table 1 .
Optimization of reaction conditions a a Reaction conditions: The reaction of 1a (0.05 mmol) in the presence of 10 mol% Pd catalysts and 40 mol% acid was carried out at 100 O C in 1,4-dioxane (1 mL) under Ar.b Yield were determined by 1 H NMR spectroscopy with p-xylene as internal standard.c Isolated yields.d 5 mol% Pd(PPh3)4 was used.e 20 mol% PhCOOH was used.f At 80 O C.