Synthesis of 10-methyl-8,10-diazabicyclo[4.3.1]decane as a new building block for nicotinic modulators

A convenient method for the synthesis of 10-methyl-8,10-diazabicyclo[4.3.1]decane, possessing a novel diazabicyclic ring system, as an important synthetic organic chemistry building block was developed using octanedioic acid as a starting material. The key transformation in the 5-step synthesis sequence involved a reaction of dimethyl 2,7-dibromooctanoate with methylamine, which resulted in the formation of cis -dimethyl 1-methylazepan-2,7-dicarboxylate. The latter was further transformed into bicyclic 8-benzyl-10-methyl-8,10-diazabicyclo[4.3.1]decane-7,9-dione under heating with benzylamine. Reduction of the formed bicyclic dione with lithium aluminium hydride resulted in 8-benzyl-10-methyl-8,10-diazabicyclo[4.3.1]decane,


Results and Discussion
To synthesize the desired 10-methyl-8,10-diazabicyclo[4.3.1]decane,we have selected a strategy in which the main step included the synthesis of intermediate cis-azepane dicarboxylate starting from commercially available suberic (octanedioic) acid, which was followed by the transformation of this intermediate into bicyclic 8,10-diazabicyclo[4.3.1]decane(Scheme 1).A similar strategy has been successfully applied for the preparation of 8-alkyl-3,8diazabicyclo[3.2.1]octanes from adipic acid, 15 as mentioned above.We initiated synthesis by preparing dimethyl 2,7-dibromooctanedioate (2) from suberic acid (1).It is known that bromination of suberic acid under Hell-Volhard reaction conditions results in racemic and meso-2,7-dibromosuberic acids as a mixture of diastereomers. 18In 1981, Tokuda et al. described a protocol to afford dimethyl 2,7-dibromooctanedioate as a mixture of rac and meso isomers via bromination of octanedioyl dichloride with a mixture of phosphorus tribromide and dry bromine followed by treatment of the crude intermediate product with absolute methanol. 19However, it was shown by Blackman and Baltzly 16 that the formation of the corresponding cyclic amines, which are in the required cis-configuration and can only serve as precursors of bicyclic derivatives, took part, when the starting dibrominated alkanedioate contains the mesoconfiguration, whereas the dibrominated rac-alkanedioate preferentially results in the transconfiguration product.
We started the preparation of dimethyl 2,7-dibromooctanedioate (2) by transformation of suberic acid (1) to octanedioyl dichloride (Scheme 1) via reaction with thionyl chloride as it was described in the aforementioned work. 19However, bromination of the obtained intermediate octanedioyl dichloride was carried out by us applying radical reaction pathway, when after addition of bromine the reaction flask was continuously irradiated with a 200 W mercury lamp.Treatment of the reaction mixture with methanol and distillation of the obtained product under high vacuum, resulted in the target dimethyl 2,7-dibromooctanedioate (2) in 84% isolated yield.The 1 H-and 13 C-NMR spectra of 2 revealed one set of signals, which indicated the formation of one of the two possible diastereomers only, that is, the radical bromination proceeded diastereoselectively.
The second and crucial step of the synthesis was the formation of the azepane cycle by the reaction of dibromodiester (2) with methylamine.It is known that diethyl meso-2,5dibomoadipate underwent cyclisation to the corresponding 5-membered pyrrolidine derivative by reacting with methylamine at room temperature. 15When the reaction of dibromodiester (2) with methylamine was performed under similar reaction conditions, the desired cyclic product, dimethyl cis-1-methylazepan-2,7-dicarboxylate (4), was separated by column chromatography with a 6% yield only.However, when the reaction temperature was elevated to 120 °C, a complex mixture of products was produced, from which the desired azepane 4 was obtained by yield of 28%.Notably, analysis of the crude product (before vacuum distillation) using 1 H and 13 C NMR spectroscopy and liquid chromatography/mass-spectrometry revealed the presence in the mixture of the second diastereomer, dimethyl trans-1-methylazepan-2,7-dicarboxylate (the ratio of cis/trans products in a crude mixture was approximately 10/1 in the 1 H NMR spectrum).The stereochemical outcome of the reaction can be rationalised by the SN2-type nucleophilic displacement of one of the bromine atoms of meso-dimethyl 2,7-dibromooctanedioate 2 by the nitrogen atom of methyl amine, which resulted in a Walden inversion to form the intermediate 3.
Compound 3 undergoes ring-closure by the substitution of the second bromine atom to provide the final product 4, which is in the cis-configuration.The presence in the crude reaction product of the corresponding trans-isomer as a side-product can be explained by a partial transformation of the starting meso-2 to rac-2 under the reaction conditions. 16It is important to note, that the use of milder reaction conditions or the application of aromatic solvents such as toluene or xylene instead THF, did not increase the yield of the target product 4.
Using liquid chromatography/mass-spectrometry it was established also that during the reaction of 2 with methylamine at elevated temperature, the ester groups of intermediate substrates underwent partially the reactions of aminolysis to yield the corresponding amides as side products, including methylamide 5a, with lowering the yield of the target product.More ever, the amide 5a can take part in the intramolecular cyclisation to form bicyclic 8,10-dimethyl-8,10-diazabicyclo[4.3.1]decane-7,9-dione6a.Indeed, heating of the reaction residue obtained after separation of 4 at 205 o C, afforded imide 6a with the isolated yield 10%.It is worth to point out that azepane ring is present in various natural medicinally important bioactive compounds, such as bengamides [20][21][22] and balanols 23,24 and their synthetic analogues, while azepane quaternary amino acids found application in the preparation of conformationally constrained peptidomimetics. 25,26urthermore, we investigated the aminolysis of diester 4 with benzylamine.To determine the optimum reaction conditions for increasing the yield, this reaction was studied under various conditions.Heating of diester 4 with benzylamine in xylene at 120 °C for 20 h, afforded monoamide 5b as a main product in a 69% yield.The structure of 5b was confirmed by methods of NMR spectroscopy.The assignments presented in Fig. 1a, b were based on the combined application of standard NMR techniques such as NOESY, APT, HSQC and HMBC. 27hen the aminolysis of diester 4 with benzylamine was performed at 160 °C (oil bath temperature) for 48 h, it resulted in a mixture of monoamide 5b, and the corresponding diamide, whereas only traces of bicyclic imide 6b were detected.Much better yield of 6b was obtained, when after heating at 160 °C for a prolonged time, the reaction mixture was placed under high vacuum to remove unreacted reagents, and the residue was heated at elevated temperatures (205 °C) for 24 h.Vacuum distillation of the obtained mixture and subsequent crystallisation of the crude product resulted in bicyclic imide 6b in a 42% yield  8) is a waxy solid that absorbs moisture and carbon dioxide upon exposure to air.meso-Dimethyl 2,7-dibromooctanedioate (2).To a round-bottom flask (1000 mL) equipped with a magnetic stirrer, an inert gas inlet and connected to a scrubber, octanedioic acid (440 g, 2.53 mol) and thionyl chloride (633 g, 5.32 mol) were added.The mixture was heated at 40 °C for 4 h with stirring until gas evolution was seased.Consequently temperature was raised to 90 °C and bromine (832 g, 5.2 mol) was added dropwise to a mixture over a period of 4 h (while the flask was continuously irradiated with a 200 W mercury lamp).Finally, absolute methanol (250 mL) was added dropwise (vigorous gas evolution!) and a flask was cooled down to rt.The reaction mixture was washed with distilled water (50 mL), concentrated aqueous sodium acetate (100 mL) and aqueous sodium sulphite (100 mL).The separated organic phase was dried in a high vacuum at 90 °C to yield 864 g (95%) of the crude product, which was distilled at 140 °C under a vacuum (0.1-0.3 mbar) to yield 764 g (84%) of liquid and colourless diester 2. IR (NaCl window, νmax, cm decan-7,9-dione (6a).To a glass liner (250 mL) methylamine (9.4 g, 303 mmol, dissolved in 100 mL of dry THF) and compound 2 (36 g, 100 mmol, dissolved in 100 mL of dry THF) were added.The liner was placed in a high pressure stainless steel reactor and the reaction mixture was heated with stirring at 120 °C for 2 h.Then the reaction mixture was filtered and the solvent was evaporated at reduced pressure.The residue was distilled at 140 °C under vacuum (0.1-0.3 mbar) to yield 13.0 g of a crude product, which was purified by column chromatography on silica gel (eluent: hexane-ethyl acetate, 5:1) to yield 6.5 g (28%) of compound 4 as a colourless liquid.IR (NaCl window, νmax, cm The vacuum distillation residue, obtained after evaporation of azepane 4 as described above, was heated in original 100 ml distillation flask with stirring at 200 °C under argon atmosphere for 6 h.Then the reaction mixture was distilled at 160 °C under a vacuum (<0.2 mbar) to yield 6.0 g of a crude product.Product was redistilled in vacuum (<0.1 mbar) at 120 °C (yield 2.80 g) and once again for 5 h at 80 °C to afford compound 6a as a greenish-yellow liquid.Yield 2.0 g (10%).IR (NaCl window, νmax, cm

8-Benzyl-10-methyl-8,10-diazabicyclo[4.3.1]decan-7,9-dione (6b).
A round-bottom flask (500 mL) was equipped with a magnetic stirrer and a Vigreux column (with a mounted Claisen adapter, a side-on Liebig condenser and a top inert gas inlet).Compound 4 (158.6 g, 692 mmol), benzyl amine (78 g, 729 mmol) and xylene (150 mL) were added and the reaction mixture was heated at 160 °C (oil bath temperature) with stirring over a period of 72 h under argon.Formed methanol was removed by continual rectification.The solvent (xylene) was evaporated at reduced pressure and then unreacted starting materials were removed under vacuum (0.1-0.3 mbar) at 120 °C.The residue was heated at 205 °C for 24 h under argon.Finally, the mixture was distilled at 180 °C under a vacuum (0.1-0.3 mbar).The collected condensate was crystallized from ethyl acetate (20 mL) to yield dione 6b (55.0 g).After filtration of the product, the filtrate was kept at -18 °C for 24 h to give an additional amount of the dione 6b.The total yield 79.  .To a round-bottom flask (50 mL) equipped with a magnetic stirrer, an Allihn condenser and an argon adapter, compound 6a (2.8 g, 14.2 mmol), absolute dioxane (15 mL) and LiAlH4 (pellets, 1.0 g, 26.3 mmol) were placed and the mixture was stirred in an oil bath at 120 °C for 20 h under argon atmosphere.The reaction mixture was cooled down and a mixture of water (1 mL) and dioxane (2 mL) was added dropwise under vigorous stirring.After 1 h to the mixture an aqueous NaOH solution (30%, 4 mL) was added.The formed inorganic solids were filtered off, the organic phase was separated and evaporated under reduced pressure.The resulting liquid was purified by distillation under a vacuum (0.1-0.2 mbar) at 60 °C to afford the target product 7a, as a colourless liquid.Yield 1.2 g (50%).IR (ATR, νmax, cm  .To a round-bottom flask (500 mL) equipped with a magnetic stirrer, an Allihn condenser and an argon adapter, compound 6b (31.3 g, 115 mmol), absolute dioxane (250 mL) and LiAlH4 (pellets, 5.6 g, 147 mmol) were placed and the mixture was stirred at 120 °C for 20 h under argon atmosphere.The reaction mixture was cooled down and a mixture of water (6 mL) and dioxane (10 mL) was added dropwise under vigorous stirring.After 1 h an aqueous NaOH solution (30%, 30 mL) was added.The formed inorganic solids were filtered off, the organic phase was separated and evaporated under reduced pressure.The residue was purified by distillation under a vacuum (0.1-0.2 mbar) at 125 °C to afford the target product 7b, as a colourless liquid.Yield   (8).To a glass liner (300 mL) under an argon atmosphere absolute ethanol (80 mL), compound 7b (19.0 g, 77 mmol) and 10% palladium on charcoal (0.8 g) were added.The hydrogenation was carried out in a high pressure stainless steel reactor by stirring the mixture at 100 °C under hydrogen atmosphere (50 bar) for 40 h.After cooling down and decompression, the reaction mixture was filtered off, the solvent evaporated at reduced pressure and the resulting liquid was distilled at 70 °C under a vacuum (0.1-0.2 mbar) to afford the target compound 8 as a waxy solid.Yield 9.5 g (79%). 1 H NMR (300 MHz, CDCl3): H 1.45-1.75(m, 6H), 1.87-2.00(m, 2H), 2.16 (s, 1H), 2.49 (s, 3H), 2.51 (d, 2H, J 12.4 Hz), 2.65 (m, 2H), 2.95 (dd, 2H, J 12.1, 4.0 Hz). 13