Synthesis of new 7-azabicyclo[2.2.1]heptane derivatives

The synthesis of new 7-azabicyclo[2.2.1]heptane derivatives has been achieved in a four-step synthetic sequence, starting from readily available cyclohex-3-enecarboxylic acid, Curtius reaction, stereoselective bromination leading to major benzyl( cis -3, trans -4-dibromocyclohex-1- yl)carbamates (amides or sulfonamides), followed by NaH-mediated intramolecular cyclization. The synthesis and free radical cyclization of precursors 4 - 7 , as well as the synthesis of a conformationally constrained epibatidine analogue 3 exploiting the reactivity of the 7-azabicyclo[2.2.1]hept-2-yl radical in intramolecular reactions, are described. The N -sulfonyl functional motif is the only one to afford a cyclized product when incorporated in the radical precursor.


Introduction
Epibatidine 1, 1 an alkaloid isolated from the skin of the Ecuadorian poison frog Epipedobates tricolor, 2 is a powerful analgesic agent 200 times more potent than morphine, with high affinity for the nicotinic acetylcholine receptor (nAChR). 3 Epibatidine strongly binds at 42 subtype nAChRs, showing values several times higher than nicotine (2) 2 (Figure 1).However, the toxic effects associated with this drug have hampered its clinical application.In the last years a number of methodologies have been reported for the total synthesis of epibatidine and 7-azabicyclo[2.2.1]heptane derivatives.5a In the search for epibatidine-type compounds devoid of secondary effects, a number of structure-activity relationship studies have been reported.Thus, great attention has been paid to the synthesis and biological evaluation of epibatidine analogues, 5b either heterocyclic 6 or conformationally constrained. 7e have recently described the synthesis of 7-substituted exo-2-bromo-7azabicyclo[2.2.1]heptane derivatives 8,9 following a potent method based on a four-step synthetic sequence, starting from readily available cyclohex-3-enecarboxylic acid, Curtius reaction, stereoselective bromination leading to major tert-butyl (or benzyl) (cis-3,trans-4dibromocyclohex-1-yl)carbamates (or 2,2,2-trifluoroacetamides), 10 followed by NaH-mediated intramolecular cyclization (Scheme 1).Our current interest in the synthesis and biological evaluation of new epibatidine analogues using intermolecular free radical reactions exploiting the reactivity of the 7azabicyclo[2.2.1]hept-2-yl radical, 12 prompted us to apply this strategy to prepare conformationally constrained epibatidine analogues of type I (Figure 2).In Scheme 2 we show our general approach for the synthesis of this type of compounds, based on the intramolecular free radical cyclization of species II, readily available from precursors III bearing convenient radical acceptors at C7 and good leaving groups at C2 (Scheme 2).Although the synthesis and reactivity of 7-norbornenyl, 13 norborn-5-en-2-yl, 14 norborn-2yl 15,16 radicals is well known, the chemistry of 7-azabicyclo[2.2.1]hept-2-yl radicals has been scarcely investigated.Fraser and Swingle reported the chlorination of 7-trichloroacetyl-7azabicyclo[2.2.1]heptane with sulfuryl chloride in the presence of benzoyl peroxide. 17More recently, and when this work was in progress, Armstrong and co-workers reported what appears to be the first intramolecular cyclization of a precursor in this series, namely exo-2-bromo-7-(toluene-4-sulfonyl)-7-azabicyclo[2.2.1]heptane. 18ere we report the synthesis of the conformationally constrained epibatidine analogues 3, the preparation of radical precursors 4-7 and their intramolecular free radical reactions (Figure 2).

Results and Discussion
Under slow addition of HSnBu3, radical precursor 4 8,9 gave the reduced uncyclized product 8 in 36% yield, while small amounts of alcohols 9 and 10 (Scheme 3) were also isolated.The structure and relative configuration of the alcohols at C2 was easily established by NMR spectroscopic analysis on the corresponding acetates 11 and 12. Fast addition of HSnBu3 afforded a higher yield of 8 (84%), along with 8% of dechlorinated product 13 (Scheme 3).To sum up, from precursor 4, no cyclized products were detected, regardless of the reaction conditions employed.Scheme 4. Synthesis and free radical cyclization of compound 5.
In order to prepare precursor 5, our first choice was to apply our synthetic sequence 9 starting with cyclohex-3-enecarboxylic acid, and a Curtius type reaction with 2-chloronicotinic acid.Unfortunately, we were unable to obtain a convenient yield of the desired amide.Consequently, we were forced to use carbamate 14, 9 promote the deprotection reaction, and transform the free, not isolated amine 15 19 into amide 17 by simple amidation reaction with 2-chloronicotinic acid chloride 16 20 (Scheme 4).As previously reported for analogous amides, bromination 11 of cyclohex-3-enamide 17 provided a mixture of minor 1,4-cis-and major 1,4-trans-3,4-dibromo derivatives, 18 and 19, that were easily separated, and transformed (only for pure 1,4-trans-3,4dibromo 19) into precursor 5 by reaction with NaH in DMF 8 (Scheme 4).Free radical cyclization of compound 5 under slow addition gave the partially reduced, uncyclized derivative 20, and the fully dehalogenated compound 21 (Scheme 4), as the only reaction products.
Next, precursor 6 was synthesized in good overall yield as shown in Scheme 5, from 3cyclohex-3-enecarboxylic acid 22, via intermediates 24 21 and compound 26.Unfortunately, the free radical cyclization of bromide 6 gave a complex reaction mixture, and no pure defined compound could be isolated and characterized.In retrospect, the success of the Curtius reaction of cyclohex-3-enecarboxylic acid 22 with acrylic acid (Scheme 5), and the failure to accomplish the same reaction with nicotinic acid (see above) was surprising, but we have no rationale for this behaviour.In fact, in this project we were able to carry out the same Curtius reaction with acetic acid to provide acetamide 27, 22  Scheme 6. Synthetic pathway for the preparation of compound 30.
The synthesis of precursor 7 was readily achieved from carbamate 31 8,9 via intermediate 32, 23 obtained after reaction with trifluoroacetic acid, and treatment with p-tosyl chloride (Scheme 7).At this point we considered the copper(II)-catalyzed oxidative cyclization of unsaturated sulfonylamides, 24 but our efforts to achieve a satisfactory result were fruitless, and we turned to our initial plan.Consequently, bromination of compound 32, as usual 11 gave compounds 33 (70%) and 34 (20%).Then, major N-(cis-3-trans-4-dibromocyclohexyl)-4methylbenzenesulfonamide 33, submitted to NaH-mediated cyclization, gave precursor 7.This compound was identical in its spectroscopic data to the compound reported by Armstrong, 18 but was prepared in four steps in 41% overall yield from cyclohex-3-ene carboxylic acid, a stable product, while the previously reported synthesis takes place in four steps also, but in 11% overall yield from 2-methoxy-3,4-dihydropyran, a flammable product that must be used with caution. 25inally, and as expected and reported, free radical cyclization of precursor 7 provided the ring closure derivative 3 in 30% yield, a product which showed analytical and spectroscopic data in good agreement with its structure, and similar to those described. 18

Conclusions
We have reported the synthesis and reactivity of the 7-azabicyclo[2.2.1]hept-2-yl radicals in intramolecular reaction processes, and have shown the scope and limitations of this strategy for the synthesis of conformationally constrained epibatidine analogues.We have detailed the synthesis and free radical cyclization of radical precursors 4-7.In overall, a carbonyl functional group as in a carbamate (precursor 4), or in an amide (precursor 5 and 6), to link the radical trap to the nitrogen at the C7 position, provides precursors that gave reduced, uncyclized reaction products.Conversely, the N-sulfonyl motif is the only ones able to afford a cyclized product in acceptable chemical yields.As a result we have described here the synthesis of the constrained epibatidine analogue 3.

Experimental Section
General Procedures.Melting points were determined on a microscope type apparatus, and are uncorrected. 1 Where anhydrous solvents were needed, they were purified following the usual procedures.In particular, dry DMF was critical for the outcome of the cyclization reaction, and was either distilled at reduced pressure or bought from commercial sources.Column chromatography was performed on silica gel 60 (230 mesh).

Synthesis and intramolecular free radical reaction of precursor 4. A. Slow addition of HSnBu3
To a deoxygenated solution of carbamate 4 8,9 (58 mg, 0.17 mmol) in dry toluene (8 mL, 0.02 M) and AIBN (5 mg), HSnBu3 (0.07 mL, 0.25 mmol, 1.5 equiv) in dry, deoxygenated toluene (2 mL) containing AIBN (5 mg) was slowly added in 14 h at 95 ºC.After the addition the mixture was heated at the same temperature for 10 h more.The reaction was cooled at rt, the solvent was removed, the residue was dissolved in ethyl ether, and washed with an aqueous saturated KF solution.The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated.The crude was submitted to chromatography (20%  50% hexane: AcOEt), to give compound 8 (

Acetylation of alcohols 9 and 10. General Method
The alcohols were treated with a mixture of Ac2O/ py (1: 1, vol), at rt for 21h.Then, the solvents and reagents were evaporated, and the residue was submitted to chromatography (25% hexane: AcOEt) to give the expected compounds.Following the General Method for acetylation compound 9 (14.9 mg, 0.05 mmol) was treated with Ac2O/py (2 mL, 2 mL) to give compound 11 ( B. Fast addition of HSnBu3.HSnBu3 (0.07 mL, 0.25 mmmol, 1.7 equiv) in dry toluene (0.5 mL) was added to compound 4 (52 mg, 0.15 mmol) in toluene (0.02M) under reflux.After addition the mixture was heated at the same temperature for 3 h.The reaction was cooled at rt, the solvent was removed, and the residue was dissolved in ethyl ether and washed with an aqueous saturated KF solution.The organic phase was dried over Na2SO4, filtered and the solvent evaporated.The crude was submitted to chromatography (20%  50% hexane: AcOEt) to yield 6-chloropyridin-3-yl) methyl-
The mass was extracted with AcOEt (x3), and the organic phase was dried over Na2SO4, filtered, and evaporated.The crude was submitted to chromatography (75% hexane: AcOEt) affording N-(trans-

Scheme 2 .
Scheme 2. Intramolecular free radical reaction for the preparation odf compounds I.

22 Scheme 5 .
Scheme 5.Synthetic pathway for the preparation of target compound 6.
that submitted to the standard protocol afford, via intermediate 29, afforded bromide 30 (Scheme 6).
Mass spectra were recorded on a GC/MS spectrometer with an API-ES ionization source.Elemental analyses were performed at CQO (CSIC, Spain).TLC was performed on silica F254 and detection by UV light at 254 nm or by charring with either ninhydrin, anisaldehyde or phosphomolybdic-H2SO4 dyeing reagents.