Synthesis of 3-fluoropyrrolidines and 3-fluoroazetidines

A synthetic route towards 1-t -butoxycarbonyl-3-fluoro-3-methylpyrrolidine and 1-t - butoxycarbonyl-3-fluoro-3-methylazetidine, which are interesting building blocks for pharmaceutical compounds, is described. The key steps include a bromofluorination of appropriate alkenyl azides, followed by reduction to the corresponding amines and subsequent cyclization, yielding the 3-fluorinated azaheterocycles.


Introduction
Site-selective fluorination has become an important strategy for developing new bioactive compounds, which is reflected by the numerous papers in the area of organofluorine chemistry in the last decade. 1The intensified research dealing with the synthesis of new fluorinated organic compounds has resulted in numerous new commercial applications in pharmaceutical chemistry and agrochemistry. 2 More specifically, 3-fluoropyrrolidines and 3-fluoroazetidines are recognised as valuable building blocks in physiologically active compounds.3-Fluoropyrrolidines exhibit interesting biological activities, such as purine nucleoside phosphorylase (PNP) inhibitors 3 and kinesin spindle protein (KSP) inhibitors, 4 while 3fluoroazetidines are promising in the treatment of diabetes type 2 5 and colon cancer. 6he main synthetic pathways so far toward these 3-monofluorinated pyrrolidines and azetidines dealt with the deoxofluorination of the corresponding 3-hydroxylated heterocycles using DAST (diethylaminosulfur trifluoride) or related deoxofluorinating agents, such as Deoxo-Fluor ® or morphDAST ® . 7Another strategy to obtain 3-fluoropyrrolidines made use of the electrophilic fluorinating reagent NFSI (N-fluorodibenzenesulfonimide) to convert γ-lactams into the corresponding α-fluorinated derivatives.Subsequent reduction of the carbonyl function then led to the desired 3-fluoropyrrolidines. 8 Earlier research at our department demonstrated the use of N-(alkylidene or 1arylmethylidene)-2-propenylamines 9 and N-(diphenylmethylidene)-2-propenylamines 10 as suitable precursors for the synthesis of new 3-alkyl-and 3-aryl-3-fluoroazetidines. A regioselective bromofluorination of the carbon-carbon double bond of N-alkenylimines afforded the corresponding bromofluorinated N-alkylimines, which were subsequently treated with reducing agents to obtain the corresponding amines, yielding the desired 3-fluoroazetidines after cyclization via intramolecular substitution of the bromine atom.In continuation of our interest in fluorinated azaheterocycles, 11 we herein describe an alternative and optimized procedure for the synthesis of 1-t-butoxycarbonyl-3-fluoro-3-methylazetidine, and the application towards 1-tbutoxycarbonyl-3-fluoro-3-methylpyrrolidine, which are both of considerable pharmaceutical interest.
Unfortunately, this bromofluorination reaction proved unsuccessful and yielded mainly benzophenone due to iminium ion formation and hydrolysis during work-up.Attempts to isolate the bromofluorinated imine 6 directly from the reaction mixture without aqueous work-up, and subsequent use in following reactions failed.

Scheme 1
Since the bromofluorination of N-butenylimine 5 did not result in suitable precursors for the synthesis of fluoropyrrolidines, the bromofluorination reaction was evaluated using 4-azido-2methyl-1-butene 3 as substrate.The halogenation of alkenes in the presence of an azide functionality is known in literature. 14Indeed, 4-azido-2-methyl-1-butene 3 was very smoothly converted into the bromofluorinated analogue 7 by reaction with Et3N .3HF and NBS in dichloromethane at 0 °C (Scheme 2).Although no problems have been observed in our hands, precautions should be taken into account to preclude the presence of residual sodium azide because treatment with Et3N .3HF could give rise to formation of explosive HN3 (CAUTION).Therefore, the intermediate azide 3 should be washed thoroughly with water and purified prior to its use in following reactions.All reactions and isolation operations should be performed in a closed fume hood with a safety screen.The resulting 4-azido-1-bromo-2-fluoro-2-methylbutane 7, which was pure enough to use without purification, was subsequently treated with hydrogen gas (5 bar) over Pd/C in the presence of Boc2O, thereby trapping the resulting amine in situ affording the N-Boc amine 8 in good yield after chromatographic purification (87%).In a final step toward the desired 3-fluoro-3-methylpyrrolidine 9, tert-butyl 4-bromo-3-fluoro-3methylbutylcarbamate 8 was treated with sodium hydride in DMF at room temperature for 1h, affording pure 3-fluoropyrrolidine 9 in 73% yield.

Scheme 2
N-Boc-3-fluoro-3-methylpyrrolidine 9 was thus obtained via a 5-step reaction sequence with a good overall yield of 43%, starting from cheap 3-methyl-3-buten-1-ol 1.This synthetic pathway is quite attractive since almost no side reactions occur, which avoids the need for chromatographic purification of the intermediates.
Having in hand an efficient method for the synthesis of 3-fluoropyrrolidine 9, the above described methodology was extended toward the synthesis of 3-fluoroazetidine 14.Starting from 2-methyl-2-propenyl chloride 10, the envisaged 3-fluoro-3-methylazetidine 14 was obtained via a 4-step reaction sequence, applying analogous synthetic transformations as described above for the synthesis of fluoropyrrolidine 9 (Scheme 3).The reaction of 2-methyl-2-propenyl chloride 10 with sodium azide in DMSO at room temperature for 2.5h gave the corresponding azide 11 15 in quantitative yield and the latter was used as substrate for the bromofluorination reaction using NBS and Et3N .3HF (CAUTION: see above).Subsequent hydrogenation of the azide by treatment with hydrogen over Pd/C in ethyl acetate in the presence of Boc2O resulted in the N-Boc amine 13 in 29% yield after purification by flash chromatography.Deprotonation of the obtained N-Boc protected 3-bromo-2-fluoro-2-methylpropylamine 13 by sodium hydride in DMF gave rise to the envisaged 3-fluoroazetidine 14 in 76% yield.In the latter case, it is clear that the ring closing reaction after deprotonation takes considerably longer reaction times as compared to the formation of the pyrrolidine 9 from amine 8 (i.e.23 hours reaction in case of azetidine 14, and 1 hour for the pyrrolidine 9).This is completely in line with the higher ring strain energy of azetidines compared to pyrrolidines.

Scheme 3 Conclusion
In conclusion, a short and efficient route towards 1-t-butoxycarbonyl-3-fluoro-3-methylpyrrolidine was developed.The synthetic pathway included the bromofluorination of of 3-azido-2-methylprop-1-ene, followed by reduction of the azide function and in situ trapping of the formed amine by Boc2O, and finally ring closure via deprotonation of the carbamate N-H using sodium hydride in DMF.This strategy was extended toward the synthesis of 1-Boc-3-fluoro-3methylazetidine.Both fluorinated heterocycles are useful building blocks in medicinal chemistry.

Experimental Section
General. 1 H NMR spectra were recorded on a Jeol Eclipse+ 300 NMR spectrometer (300 MHz) with tetramethylsilane as internal standard. 13C NMR spectra (75 MHz) and 19 F NMR spectra (282 MHz) were also recorded with this spectrometer.IR spectra were measured with a Perkin Elmer Spectrum BX FT-IR spectrometer.Melting points were determined in open capillary tubes with a Büchi B-450 melting point apparatus.Electrospray (ES) mass spectra were recorded using a Agilent 1100 Series MS (4000V) mass spectrometer.Electron impact (EI) mass spectra were recorded using a HP 6890 GC coupled with a HP 5973 MSD (mass selective detector).Dichloromethane was dried over calcium hydride, other solvents were used as received from the supplier.