An improved, gram-scale synthesis of protected 3-haloazetidines: rapid diversified synthesis of azetidine-3-carboxylic acids

Azetidines are increasingly important heterocycles found in a variety of natural products and pharmaceutical compounds. Protected 3-haloazetidines, widely used and versatile building blocks in medicinal chemistry, have been prepared in a one-pot, gram-scale strain-release reaction of 1-azabicyclo[1.1.0]butane from commercially available starting materials. These intermediates were subsequently used to prepare a series of high value azetidine-3-carboxylic acid derivatives including the first reported synthesis of 1-( tert -butoxy- carbonyl)-3-((trifluoromethyl)thio)azetidine-3-carboxylic acid


Introduction
2][3] 3-Substituted azetidines, in particular, are increasingly prevalent in medicinal chemistry as either linking fragments or rigidifying moieties. 4,5][8][9][10] The S1P receptors regulate a wide variety of biological functions including cell proliferation, migration, and survival; as such, they present attractive targets for developing treatments of inflammatory diseases, autoimmunity, and cancer. 11,12Despite the myriad uses for azetidines, methods for their synthesis and functionalization still lag behind their larger counterparts: pyrrolidine and piperidine.2][3] This building block approach requires the ready availability of a diverse collection of azetidinyl fragments.One such moiety, tert-butyl 3-iodoazetidine-1-carboxylate (6), was first reported by Billotte in 1998. 13When converted into the corresponding organozinc compound, it was shown to undergo facile palladium-catalyzed crosscoupling with (hetero)aryl halides.Since its initial report, the iodide 6 has proven to serve as a valuable intermediate in azetidine synthesis and functionalization through numerous published methodologies, including an iron-and cobalt-catalyzed arylation with Grignard reagents, 14 Suzuki couplings with arenes [15][16][17] or alkenes, 18 Minisci reactions with heteroarenes, 19,20 etherification with aryl boronic acids, 21 reductive couplings with 3-bromo-2,1-borazaronanaphthalenes 22 or chloroformates, 23 and a nickel-catalyzed enantioselective conjunctive coupling with vinyl boronates. 24Furthermore, the iodide 6 has been used as a precursor to other small azetidine fragments including the corresponding hydrazine, 25 sulfone 26 or sulfinate salts, 27 and potassium tetrafluoroborate. 28nfortunately, the currently available route to the iodide 6 is lengthy and time consuming (Scheme 1). 13,29ver six days, epichlorohydrin (7) is allowed to condense with benzhydrylamine (8) to furnish alcohol 9, which is then mesylated to afford 10.A protecting group swap is accomplished over three steps to give Bocprotected azetidine 11 in good yield.Displacement of the mesylate with KI in DMSO produces the target compound 6.More recently, Gandelman reported an iododecarboxylation reaction where iodide 6 was prepared in 75% yield by treating Boc-protected azetidine-3-carboxylic acid (15, the synthesis of which is detailed below) with 1,3-diiodo-5,5-dimethylhydantoin under irradiation conditions. 30s discussed above, azetidine-3-carboxylic acid (15) is another valuable azetidinyl fragment that has found repeated utility in medicinal chemistry. 31,32For many years, the sole route to this compound required elaborating mesylate 10 (as prepared above in Scheme 1 from 7) through a further sequence of cyanation, hydrolysis, and deprotection to yield 15. 29 Researchers at Merck improved upon this as shown in Scheme 2. 33 Triflation of the commercially available diethyl bis(hydroxymethyl)malonate (12) followed by cyclization with benzylamine gave the diester 13.A two-step hydrolysis afforded diacid 14 in high yield.Under carefully pHcontrolled conditions, diacid 14 was monodecarboxylated to the benzyl-protected 15; a final hydrogenolysis furnished the deprotected azetidine-3-carboxylic acid (15).This sequence, especially on large scale, represents a significant improvement on the route beginning with epichlorohydrin (7).

Scheme 2. Merck synthesis of azetidine-3-carboxylic acid (15).
Given the substantial utility of both 3-iodoazetidine 6 and azetidine-3-carboxylic acid (15), an opportunity existed to develop a more streamlined route to various protected 3-haloazetidines that would also serve as a diversity point to generate other azetidine fragments as well as a series of functionalized azetidine-3carboxylic acid derivatives.Scheme 3. Two-step, gram-scale synthesis of protected 3-iodoazetidines (6 and 19) from allylamine (16).
Over the last few years, the bromide 20 (an analog of iodide 6) has been used in several new reactions, including a reductive cross-coupling with (hetero)aryl bromides, 41 an aqueous Lipshutz-Negishi cross-coupling with aryl electrophiles, 42 and a metallaphotoredox-catalyzed cross-coupling with (hetero)aryl halides. 43Much like the other azetidines previously discussed, bromide 20 has traditionally been prepared from mesylate 11. 14 However, by using a strain-release concept instead, bromide 20 was readily prepared in 79% yield on gramscale by substituting LiBr for NaI (Scheme 4).Replacing Boc 2 O with Fmoc-Cl allowed for the synthesis of bromoazetidine 21, which could prove promising for peptide applications. 44Taken as a whole, the strainrelease methodology allows for a "mix-and-match" approach to the synthesis of protected 3-haloazetidines.Depending on the given downstream application, the protecting group (Boc, Ts, Fmoc) and halide (Br, I) can be interchanged as needed while still using the same one-pot sequence from hydrobromide salt 17.Scheme 4. Gram-scale synthesis of protected 3-bromoazetidines (20-21).
2][3] They are typically prepared from epichlorohydrin (7) as outlined in Scheme 1. 29 As an alternative one-pot approach, 3-hydroxyazetidine 24 was synthesized in good yield by sequentially treating 3-iodoazetidine 6 with KOAc and KOH (Scheme 6). 45A modification of Billotte's procedure was used to improve the reported yield of the acylation of iodide 6 (38%  77%). 13The reaction proceeds in one-pot via zinc insertion into the C-I bond, conversion to a zinc-copper species, and trapping with benzoyl chloride to afford azetidine 25.Scheme 6. Diversification of 3-iodoazetidine 6 to 3-hydroxyazetidine 24 and 3-acylazetidine 25.
Cyanoazetidine 22 also has significant potential as a diversifiable intermediate for the synthesis of 3substituted azetidine-3-carboxylic acids (Scheme 7).The treatment of cyanoazetidine 22 with LiHMDS in THF at -78 o C for 30 minutes proved the optimal conditions for deprotonation.Trapping of the resulting anion with methyl iodide, allyl bromide, or 3-(trimethylsilyl)propargyl bromide gave good yields of the corresponding 3,3disubstituted azetidines 26, 28, and 30.Hydrolysis as previously described furnished 3-substituted azetidine-3carboxylic acid derivatives 27, 29, and 31.If desired, the cyanoazetidine 30 could be obtained directly as the unprotected acetylene by treatment with TBAF in the same pot as the propargylation (see experimental section for details).Propargyl azetidine 31, in particular, may find utility as a click-based reagent in the synthesis of unnatural peptidomimetics or other bioactive lead compounds. 46Notwithstanding the popularity of fluorinated compounds in medicinal chemistry, 47 no known examples have been reported of fully saturated 3-(trifluoromethylthiolated)azetidines.After deprotonation, azetidine 22 was treated with N-methyl-N-(trifluoromethylthio)aniline (32) 48 to give the trifluoromethylthiolated azetidine 33 whose structure was confirmed by X-ray crystallography.Standard hydrolysis conditions completed the first synthesis of 1-(tert-butoxycarbonyl)-3-[(trifluoromethyl)thio]azetidine-3-carboxylic acid (34, Scheme 8).

Conclusions
In summary, a short, gram-scale synthesis of protected 3-haloazetidines 6, 19, 20, and 21 via 1-azabicyclo-[1.1.0]butane(18) has been reported.By using this method, the halide and protecting group can be "mixedand-matched" as desired in order to tailor the azetidine fragment to its intended downstream application.The concise synthesis, along with readily available starting materials, should enable the widespread use of this method.This route allows for the rapid preparation of numerous protected azetidines including 3hydroxyazetidine 24, 3-acylazetidine 25, azetidine-3-carboxylic acid 23 and a series of 3-substituted azetidine-3-carboxylic acid derivatives 27, 29, 31, and 34.Other applications exploring the utility of 1azabicyclo[1.1.0]butane(18) in the preparation and functionalization of azetidines and their implications in the synthesis of anticancer compounds are currently in progress and will be reported in due course.

Experimental Section
General.Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated.Anhydrous tetrahydrofuran (THF), acetonitrile (MeCN), and dimethylformamide (DMF) were obtained by passing the previously degassed solvent through an activated alumina column (PPT Glass Contour Solvent Purification System).Anhydrous dimethylsulfoxide (DMSO) was purchased from Acros (Extra Dry over Molecular Sieves) and used as received.Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous material, unless otherwise stated.Room temperature (rt) refers to ambient temperature in the laboratory (ca.22-24 o C).Reactions were monitored by LC-MS or thin layer chromatography (TLC) carried out on 250 m SiliCycle SiliaPlates (TLC Glass-Backed Extra Hard Layer, 60 Å), using shortwave UV light as the visualizing agent and iodine or KMnO 4 and heat as developing agents.Flash column chromatography was performed with a Biotage Isolera One (ZIP or SNAP Ultra cartridges) or with traditional glass flash columns using SiliCycle SiliaFlash® P60 (particle size 40 -63 μm).NMR spectra were recorded on a Bruker Ascend TM 500 MHz spectrometer and were calibrated using residual undeuterated solvent as an internal reference (CDCl 3 : 7.26 ppm 1 H NMR, 77.16 ppm 13 1-Amino-2,3-dibromopropane hydrobromide (17).Br 2 (10 mL, 0.196 mol, 2.1 equiv.) was added slowly to icecold ethanol (25 mL) in a 125 mL round bottom flask at 0 o C and stirred vigorously (the flask was covered with ice up to the neck to prevent fuming).Allylamine (7.0 mL, 0.0936 mol, 1 equiv.)was added very slowly to the Br 2 /EtOH solution.After allowing the reaction mixture to warm to rt, stirring was continued at the same temperature overnight.Small portions of ice-cold diethyl ether (5 x 10 mL) were added to the red-brown colored reaction mixture which was then filtered to obtain the crude compound 17.The crude material was recrystallized using methanol to give the pure hydrobromide salt 17 (20.9g, 75%    tert-Butyl 3-benzoylazetidine-1-carboxylate (25).To a flame-dried reaction tube was added Zn dust (35.3 mg, 0.540 mmol, 1.3 equiv.)and dry THF (0.3 mL) under argon.1,2-Dibromoethane (4.3 µL, 0.050 mmol, 0.12 equiv.) was added at rt and stirred at 65 o C for 5 min.The resulting mixture was cooled to rt, TMSCl (5.8 µL, 0.0457 mmol, 0.11 equiv.) was added, and the reaction mixture stirred at rt for 30 min.A solution of tert-butyl 3-iodoazetidine-1-carboxylate (6) (117.5 mg, 0.415 mmol, 1 equiv.) in THF (0.3 mL) was added and the resulting mixture stirred at 65 o C for ca.30 min.(zinc insertion was monitored by TLC).When the zinc insertion was complete, the reaction mixture was cooled to -15 o C and a freshly made solution of 1M CuCN2LiCl 50 (0.415 mL, 0.415 mmol, 1 equiv.)was added and stirring continued for another 1 h at the same temperature.Benzoyl chloride (58 µL, 0.498 mmol, 1.2 equiv.) was added via syringe and the mixture stirred overnight at rt.The reaction was filtered through a short pad of celite and extracted with ethyl acetate (3 x 15 mL).The combined organic extracts were washed with brine (15 mL), dried over Na 2 SO 4 , and concentrated.The crude material was purified by flash chromatography (silica gel, 5-40% EtOAc in hexanes) to give the desired product