Unusual synthesis of 1-(4-fluorobenzyl)- N -(1-(1-(4-fluorobenzyl)-6- isopropoxy-1 H -benzo[ d ]imidazol-2-yl)piperidin-4-yl)-6-isopropoxy- 1 H -benzo[ d ]imidazol-2-amine

The title compound was formed while attempting the synthesis of 1-(4-fluorobenzyl)-6- isopropoxy-N -(1-methylpiperidin-4-yl)-1 H -benzo[ d ]imidazol-2-amine,


Introduction
Hismanal ® (1, astemizole) is a histamine H 1 -receptor antagonist which was used clinically to alleviate allergy symptoms until 1999 when it was pulled out of market owing to cardiovascular side effects. 1 Norastemizole (2) is a metabolite of astemizole and is found to be a more potent histamine H 1 -receptor antagonist with lesser side effects. 2 We had designed several analogs of norastemizole and during the synthesis of one such analog (3), an unusual reaction was encountered which is being reported here.While following literature procedures for similar reactions 3,4 S N Ar amination of 1-(4-fluorobenzyl)-2-chloro-6isopropoxy-1H-benzo [d]imidazole (12) with 1-methylpiperidin-4-amine (6)

Results and Discussion
Compound 4, which apparently is easily synthesizable from 2 equivalents of compound 12 and 1 equivalent of 4-piperidinamine, was obtained in a rather unusual fashion while following scheme 1 to prepare compound 3. Briefly, 1-methylpiperidin-4-amine (6) was prepared from commercially available carbamate 5 by LiAlH 4 reduction. 53-Fluoro-4-nitrophenol (7) was isopropylated under anhydrous basic conditions 6 and aminated 7 by 4-fluorobenzylamine in presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to produce compound 9. Compound 9 was then reduced by hydrogenation over Raney Ni 8 and isolated as dihydrochloride 10 (free base was found to be air and/or light sensitive).Raney Ni was specifically chosen to avoid Ndebenzylation.Treatment of compound 10 with 1/3 equivalents of triphosgene under basic conditions 9 resulted in formation of benzimidazolone 11, which was in turn converted to compound 12 by the action of POCl 3 . 10Finally when compound 12 was reacted with two equivalents of compound 6 to obtain compound 3 according to literature reports on similar reactions, 3,4 compound 4 was the only product isolated while substantial amount of compound 12 was recovered.Although synthesis of compound 3 requires one equivalent each of compound 6 and compound 12, excess of compound 6 was used to trap the released HCl. Isolation of compound 4 from the final reaction mixture was a surprise since such a reaction is rather atypical if not completely unprecedented. 11The most plausible mechanism is outlined in Scheme 2. The desired product 3 is probably an intermediate which forms a quaternary salt with another equivalent for 2-chlorobenzimidazole 12 which decomposes to compound 4 after loss of CH 3 Cl.Since majority of 2-chlorobenzimidazole 12 was recovered after 72 hr reaction time (c.f.Experimental), formation of compound 3 appears to be rate limiting and reaction of compound 3 with compound 6 is much faster than the reaction of compound 12 with compound 6 (Scheme 2).A similar mechanism is widely used for N-demethylation using alkyl chloroformates (Scheme 3). 11Use of simple alkyl chloroformates necessitates an additional carbamate deprotection step but this may be avoided by use of α-chloroethyl chloroformate. 11

Scheme 3. Mechanism of N-demethylation using alkyl chloroformates
Upon close examination, the apparent feasibility of quaternization of compound 12 may be explained.The cation formed after the ionization of 1-alkyl-2-chloro-6-alkoxy-benzimidazole is resonance stabilized by the lone pair on the O atom (Scheme 4).This also explains why the behavior witnessed during this investigation is not seen earlier in similar situations which were devoid of facilitating alkoxy (or similar group) at the appropriate position.
In conclusion, a novel mode of amination of 1-(4-fluorobenzyl)-2-chloro-6-isopropyloxy-1H-benzo[d]imidazole by tertiary amine is reported.The alkoxy group at position 6 appears to play crucial role in this amination process facilitating N-demethylation of the tertiary amine.Although this procedure appears to be applicable to a specific class of compounds, the observation is unprecedented and novel.

Experimental Section
General Procedures.All chemicals and reagents including ethyl 4-aminopiperidine-1carboxylate (5) and 3-fluoro-4-nitrophenol (7) were obtained from Aldrich Chemical Co.Column chromatography purifications were undertaken using silica gel (230-400 mesh) obtained from Aldrich Chemical Co. 1 H NMR spectra were recorded on a Bruker AMX 500 NMR spectrometer at 500 MHz and mass spectra were obtained on VG-Analytical (Manchester, UK) VG-70 SEQ spectrometer.ARKAT 1-Methylpiperidin-4-amine (6).A solution of compound 5 (5.16 g, 30 mmol) in dry ether (100 ml) was cooled by an ice-bath to 0-5ºC.Under anhydrous conditions, LiAlH 4 (2.84 g, 75 mmol) was added in portions with stirring.After 30 minutes the ice-bath was replaced with an oil-bath and the reaction mixture was slowly heated to reflux (44 o C bath temperature).The reaction mixture was refluxed for 17 h.Thin layer chromatography using precoated fluorescent silica gel and a developing solvent of 1:5 MeOH: CHCl 3 showed the formation of a slower moving product.After cooling the reaction mixture by an ice-bath, additional amount of ether (100 ml) was added.The unreacted LiAlH 4 was quenched by dropwise addition of 10% aq.NaOH solution until the effervescence subsided.The resulting slurry was filtered and the solid cake was washed with ether (100 ml).Combined filtrate was rotary evaporated under vacuum at rt to obtain compound 6 as clear liquid.Yield 76%.R f = 0.21 (MeOH/CHCl 3 , 1:5).The product was characterized as dihydrochloride salt which was formed as follows.Under anhydrous conditions, freshly generated dry hydrogen chloride gas (by action of conc.H 2 SO 4 on NaCl) was passed briskly for 3 minutes through the solution of compound 6 (100 mg) in ether (5 ml).The white precipitate thus obtained was retained by decanting the majority of the ether and the product was dried under vacuum.

N-(4-Fluorobenzyl)-5-isopropoxy-2-nitrobenzenamine (9)
. Compound 8 (5.5 g, 27.6 mmol), 4-fluorobenzylamine (4.15 g, 33.3 mmol) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 5.04 g, 33.2 mmol) was dissolved in CH 3 CN (150 ml).The resulting mixture was refluxed (bath temperature 90 o C) for 17 h.Thin layer chromatography using precoated fluorescent silica gel and a developing solvent of 1:9 EtOAc:hexanes showed the formation of a slower moving product.The reaction mixture was rotary evaporated to dryness and the residue was purified by silica gel column chromatography using CHCl 3 as eluent.Fractions containing pure product were pooled and rotary evaporated to get the desired product as yellow crystalline solid.Compound 9. Yield: 76%.R f = 0.62 (EtOAc/ hexanes, 1:9); 1  (5.9 g, 19.4 mmol), Raney Ni (7.0 g) and EtOH (300 ml) were charged in a hydrogenation bottle and the Parr hydrogenation apparatus was set-up with H 2 pressure at 60 psi.The reaction was carried out at rt for 6 h during which time the yellow color of the starting material disappeared.Thin layer chromatography using precoated fluorescent silica gel in CHCl 3 showed the formation of a slower moving product (air and/or light sensitive).The reaction mixture was filtered over suction in a flask containing conc.HCl (10 ml).The filtrate was rotary evaporated to dryness to yield the desired product as dihydrochloride salt in pure form.Compound 10.Yield: 95%).R f = 0.56 (CHCl 3 ). 1