Synthesis of 2‐(Trifluoromethyl)Azetidines by Strain‐Release Reactions of 2‐(Trifluoromethyl)‐1‐Azabicyclo[1.1.0]Butanes

Abstract

Substituted azetidines are privileged heterocyclic scaffolds in medicinal chemistry and have become synthetic targets of high interest in recent years. With the goal of developing a new access to azetidines incorporating the pharmaceutically relevant trifluoromethyl group, the reactivity of 2‐(trifluoromethyl)‐1‐azabicyclo[1.1.0]butanes was investigated in polar strain‐release reactions. By using benzyl chloroformate or trifluoroacetic anhydride as reacting partners, diversely substituted 3‐chloroazetidines, 3‐substituted azetidines and azetidin‐3‐ols bearing a trifluoromethyl group at C2 could be readily synthesized. In addition, palladium‐catalyzed hydrogenolysis reactions provided an entry to cis‐3‐aryl‐2‐trifluoromethyl azetidines.

2‐(Trifluoromethyl)‐1‐azabicyclo[1.1.0]butanes, available by diastereoselective cyclopropanation of 2‐(trifluoromethyl)‐2H‐azirines, can be successfully involved in strain‐release ring‐opening processes, as illustrated by their reaction with benzyl chloroformate, trifluoroacetic anhydride or palladium‐catalyzed hydrogenolysis. These latter transformations allow access to diversely substituted 2‐(trifluoromethyl)azetidines which constitute scaffolds of potential interest in medicinal chemistry.

1. Introduction

Nitrogen heterocycles are prominent motifs in marketed drugs.^{[ 1 ]} Since increasing saturation was found to correlate with a higher success rate of drug candidates in the preclinical development phases,^{[ 2 ]} scaffolds rich in sp³‐hybridized carbons have attracted considerable interest.^{[ 1} , ^{3 ]} Compared to piperidines and pyrrolidines, four‐membered nitrogen heterocycles are much less encountered, except as components of β‐lactam antibiotics.^{[ 1 ]} However, azetidines are emerging as privileged heterocycles in medicinal chemistry, with potentially improved pharmacokinetic properties compared to their higher homologs.^{[ 4 ]} Examples of drugs incorporating an azetidine include baricitinib, used in the treatment of rheumatoid arthritis,^{[ 5 ]} and the anticancer agent cobimetinib.^{[ 6 ]} Replacement of a biaryl motif in the identified lead compound by an (aryloxy)azetidine led to the discovery of the oxytocin receptor antagonist PF‐3274167 and fluorescent probes were further devised based on the structure of this latter compound.^{[ 7 ]} The introduction of fluorinated groups is classically used to optimize the physicochemical and pharmacokinetic properties of lead compounds.^{[ 8 ]} In particular, fluorinated groups in the vicinity of an amine can lower the basicity of the nitrogen atom,^{[ 9 ]} which is often responsible for off‐target effects.^{[ 10 ]} Hence, trifluoromethyl‐substituted nitrogen heterocycles constitute an interesting class of compounds^{[ 11 ]} and 2‐(trifluoromethyl)‐azetidines have been considered as motifs for structure–activity relationships studies, as illustrated with the α4β7 integrin inhibitor I ^{[ 12 ]} and the ketohexokinase inhibitor II ^{[ 13 ]} (Figure 1). 

Figure 1.

Examples of bioactive azetidines.

Despite their potential interest, 2‐(trifluoromethyl)azetidines A constitute an underexplored class of nitrogen heterocycles and most of the strategies for their synthesis^{[ 14} , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ^{20 ]} rely on the formation of the C4─N bond (Scheme 1). One straightforward route is based on the intramolecular nucleophilic substitution of γ‐chloro‐(trifluoromethyl)amines (prepared from ethyl trifluoroacetoacetate) (Scheme 1, route a).^{[ 14 ]} Intramolecular nucleophilic substitution of a tosylate by the potassium salt of sulfonamides, arising from regioselective ring‐opening of the corresponding CF₃‐aziridines with potassium phenoxides, was also reported (Scheme 1, route b).^{[ 15 ]} Other examples include the intramolecular ring‐opening of an α‐(trifluoromethyl)‐α‐amino epoxide (Scheme 1, route c)^{[ 16 ]} or the cyclization of an α‐trifluoromethyl homoallylic amine induced by electrophilic activation of the double bond (Scheme 1, route d),^{[ 17 ]} both substrates arising from diastereoselective addition of organometallic reagents to chiral imines derived from phenylglycinol and fluoral.^{[ 16} , ^{17 ]} One example of C2─N bond formation by intramolecular nucleophilic substitution of a (trifluoromethyl)carbinyl mesylate was also disclosed (Scheme 1, route e).^{[ 18 ]} Recently, a highly functionalized 2‐(trifluoromethyl)azetidine was prepared by hydrogenation of the corresponding 2‐(trifluoromethyl)azetine, produced from diethyl acetylenedicarboxylate and trifluoroacetyl N‐Boc carbamate by a phosphine‐promoted aza‐Michael addition and subsequent intramolecular Wittig olefination (stepwise formation of C4─N and C3─C2 bonds) (Scheme 1, route f).^{[ 19 ]}

Scheme 1.

Synthetic approaches toward 2‐(trifluoromethyl)azetidines. Boc  =  t‐BuOC(= O), Ms = MeSO₂, Ts = para‐MeC₆H₄SO₂.

Alternatively, 2‐(trifluoromethyl)azetidines A can be obtained by reduction and/or functionalization of (trifluoromethyl)azetidinones B,^{[ 21 ]} the synthesis of which can be accomplished by cyclization of β‐amino‐β‐trifluoromethyl esters (C4─N bond formation), accessible by different methods (Scheme 1, route g).^{[ 22 ]} Some ring‐expansion reactions involving (trifluoromethyl)aziridine carboxylic acid derivatives have also been reported (Scheme 1, route h).^{[ 23 ]} Formation of both the C4─N and C2─C3 bonds can be achieved in a one‐pot manner by treatment of α‐chloro‐α‐trifluoromethyl sulfonamides with enolizable acid chlorides in the presence of a tertiary amine (Scheme 1, route i),^{[ 24 ]} by classical Staudinger cycloaddition between ketenes and trifluoromethyl imines (Scheme 1, route j)^{[ 25 ]} or copper‐promoted Kinugasa reaction between alkynes and trifluoromethyl nitrones (Scheme 1, route k).^{[ 26 ]}

In recent years, strain‐release ring‐opening reactions of 1‐azabicyclo[1.1.0]butanes (ABBs) have emerged as an appealing strategy for the synthesis of azetidines (Scheme 2).^{[ 27 ]} Besides the classical ring‐opening mode triggered by electrophilic activation of the nitrogen atom with concomitant nucleophilic attack of the resulting 1‐azoniabicyclo[1.1.0]butane intermediate (Scheme 2A), nucleophilic additions to azabicyclobutane 1, followed by functionalization of the nitrogen atom with an electrophilic agent, have been disclosed (Scheme 2B).^{[ 28 ]} The possibility to generate and functionalize 1‐azabicyclobut‐3‐yl‐lithium^{[ 29 ]} has resulted in the development of new strain‐release processes capitalizing either on 1,2‐ metallate rearrangement, spirocyclization, semipinacol rearrangement or Brook rearrangement followed by β‐elimination (Scheme 2C).^{[ 29} , ³⁰ , ^{31 ]} Recently, the first radical strain‐release reaction was reported, featuring addition of a sulfonyl radical to the nitrogen atom and subsequent coupling of the resulting radical at C3 with an iminyl radical. Both reactive radical species were generated from sulfonylimines through a catalytic photosensitized process (Scheme 2D).^{[ 32 ]} Polar strain‐release reactions have been classically achieved with ABBs devoid of substituents at C2, besides a few examples of hydration and hydrohalogenation involving 2,3‐disubstituted ABBs.^{[ 27} , ^{33 ]} Recently, Baran et al. disclosed the enantiocontrolled synthesis of an azetidine library by strain‐release functionalization of ABBs substituted at C2.^{[ 34 ]} Gram‐scale syntheses of diastereomeric ABBs 2 and 2′ (and their enantiomers), followed by stereospecific strain‐release reactions with a variety of nucleophiles (promoted by protonation of the nitrogen atom), delivered the corresponding azetidines 3 and 3′, respectively (Scheme 2E).^{[ 34 ]} The possibility to achieve the double functionalization of 2 (or stereoisomers thereof) by deprotonation–electrophilic trapping at C3, followed by ring‐opening, was also demonstrated.^{[ 34 ]}

Scheme 2.

Strain‐release reactions of 1‐azabicyclo[1.1.0]butanes leading to azetidines. pin = Pinacolato.

In conjunction with our interest in ring‐expansion reactions leading to nitrogen heterocycles incorporating the pharmaceutically relevant trifluoromethyl group at C2,^{[ 35 ]} we would like to report herein the first examples of strain‐release reactions involving a new class of ABBs C, possessing a trifluoromethyl group at C2, promoted either by electrophilic reagents (benzyl chloroformate, trifluoroacetic anhydride) or under palladium‐catalyzed hydrogenolysis conditions, as a route to diversely substituted 2‐(trifluoromethyl)azetidines D–F, respectively (Scheme 2F).

2. Results and Discussion

With the goal of harnessing strain‐release reactions for the synthesis of 2‐(trifluoromethyl)azetidines, several issues had to be addressed. The first one was related to the accessibility of the requisite substrates, i.e., 2‐(trifluoromethyl)‐1‐azabicyclo[1.1.0]‐butanes C, the preparation of which had never been reported. By analogy with known routes toward ABBs,^{[ 27} , ^{36 ]} cyclopropanation of 2‐(trifluoromethyl)‐2H‐azirines^{[ 37} , ^{38 ]} with sulfur ylides emerged as a viable option. Azirine 4a was prepared from phenylacetylene according to a known copper‐catalyzed azido‐trifluoromethylation, accompanied by loss of nitrogen gas, using 1‐trifluoromethyl‐1,2‐benziodoxol‐3‐(1H)‐one (Togni's reagent II) and Me₃SiN₃, in the presence of NaOAc and Cu(OAc)₂ (5 mol%) (MeCN, 80°C, 6 h, 72% yield).^{[ 37a ]} Azirine 4a was then involved in a cyclopropanation by treatment with (dimethylsulfonium)methylide (generated by deprotonation of Me₃SI with n‐BuLi, THF, −20°C, 1 h) which afforded the desired 2‐trifluoromethyl ABB 5a (76%) as a single detectable diastereomer (dr > 96:4, by ¹H NMR spectroscopy). As previously reported for other substituted azirines,^{[ 27c ]} addition of the sulfur ylide preferentially occurred on the less hindered face of the C═N bond of 4a (opposite to the CF₃ group). The second issue was related to the reactivity of ABB 5a in strain‐release reactions. Indeed, the CF₃ substituent is sterically hindered (size ranging in between ethyl and isopropyl groups)^{[ 39 ]} and its electron‐withdrawing effect could decrease the ability of the nitrogen atom to react with electrophilic species. However, treatment of 5a with benzyl chloroformate (2 equiv) triggered the expected strain‐release reaction under mild conditions (acetone, RT, 16 h) and afforded the desired 3‐chloro‐2‐(trifluoromethyl)azetidine 6a in good yield (91%), as a single detectable diastereomer (dr > 96:4). The relative stereochemistry of 6a was assigned at this stage by analogy with literature results concerning the stereochemical outcome of polar strain‐release reactions involving ABBs^{[ 27} , ³³ , ^{34 ]} and was later confirmed in our studies (vide infra). Thus, electrophilic activation of the nitrogen atom of 5a by the chloroformate should produce a 1‐azoniabicyclo[1.1.0]butane intermediate and nucleophilic addition of the released chloride ion should proceed through a reactant‐like transition state TS1 in which a 2p‐orbital at C3 lies along the C3─N axis, with concerted C3─Cl bond formation and concurrent C3─N bond cleavage (Scheme 3).^{[ 27d ]}

Scheme 3.

Synthesis and reactivity of the 2‐(trifluoromethyl)ABB 5a.

The scope of the ring‐opening with benzyl chloroformate was examined with different substituted 2‐(trifluoromethyl)ABBs 5b‐5s (Scheme 4). Alkyl substituents (Me, t‐Bu) or a phenyl group could be present at the para position of the aromatic ring at C3, as illustrated with the isolation of the 3‐chloroazetidines 6b (86%), 6c (84%) and 6d (70%), respectively. The azabicyclic substrates 5e‐5 h, possessing an electron‐withdrawing substituent at the para position of the phenyl group all reacted smoothly with benzyl chloroformate and delivered the corresponding 3‐chloro‐azetidines 6e‐6 h (61%–85%). It is noteworthy that ABB 5 h, incorporating a p‐nitrophenyl group, reacted equally well thereby suggesting that there is no significant positive charge build‐up at C3 in the transition state. Because of the strong electron‐donating character of the p‐methoxyphenyl group, azabicyclobutane 5i underwent significant decomposition under the reaction conditions and although azetidine 6i was effectively detected in the reaction mixture, this compound could not be isolated in pure form. Electron‐donating substituents were however well tolerated at the meta position of the aromatic ring, as shown with the formation of azetidines 6j‐6l (67%–82%). The presence of a fluorine atom at the meta position is also possible and azetidine 6 m was isolated in 67% yield. Substrate 5n, possessing an ortho‐chlorophenyl group at C3, did not react under the previous conditions, presumably for steric reasons. Fortunately, the use of an excess of ClCO₂Bn (5 equiv) and refluxing the reaction mixture enabled complete conversion of 5n into 3‐chloroazetidine 6n (67%). Azabicyclobutanes 5o, substituted by a naphthyl group, and 5p, by a 2‐chloropyridine, afforded azetidines 6o (71%) and 6p (75%), respectively. The reactivity of ABBs 5q‐5s incorporating an aliphatic chain at C3 was also examined. An excess of ClCO₂Bn (5 equiv) was required to observe complete conversion of 5q into azetidine 6q (44%, two steps from azirine 4q). In the case of 5r and 5s bearing a longer and conformationally more mobile alkyl chain at C3, compared to substrate 5q, refluxing conditions were required to obtain azetidines 6r (72%) and 6s (94%) (Scheme 4).

Scheme 4.

Scope of the ring‐opening of 2‐(trifluoromethyl)‐1‐azabicyclo[1.1.0]‐butanes 5a‐5s with benzyl chloroformate. Bn = Benzyl, Bz = Benzoyl.

Transformation of the C─Cl bond in the 3‐chloro‐2‐(trifluoro‐methyl)azetidines resulting from the latter strain‐release reaction was investigated. The radical reduction of 6b with n‐Bu₃SnH in the presence of AIBN (20 mol%) (toluene, 80°C, 1 h) afforded a mixture of the diastereomeric azetidines 7/7′ in a 55:45 ratio (separated by preparative TLC and isolated in 29% and 34% yields, respectively). Abstraction of an hydrogen atom from n‐Bu₃SnH by the configurationally labile benzylic radical intermediate 8 can occur trans or cis to the CF₃ group and produce the cis‐ and trans‐2‐(trifluoromethyl)azetidines 7 and 7′, respectively. The corresponding transition states TS2 and TS2’ both suffer from steric interactions, between the CF₃ substituent and the p‐tolyl group or n‐Bu₃SnH, respectively, thereby explaining the low diastereomeric ratio (Scheme 5).^{[ 40 ]}

Scheme 5.

Radical reduction of the C─Cl bond in azetidine 6b. AIBN  =  azobis(isobutyronitrile). p‐Tol = para‐Tolyl.

Because spirocycles, especially those incorporating four‐membered rings, are scaffolds of interest in medicinal chemistry,^{[ 41 ]} the construction of a 2‐azaspiro[3.4]octane ring system was explored from 3‐chloroazetidine 6s, possessing an appropriately located remote alkyne. The reductive radical cyclization was achieved by treatment of 6s with (Me₃Si)₃SiH in the presence of AIBN (10 mol%) (toluene, 80°C, 2.5 h, followed by treatment with n‐Bu₄NF to facilitate separation of the silylated byproducts). Azaspirocyclic compound 9 was formed as a single detectable diastereomer and was isolated in 64% yield. The relative stereochemistry of 9, assigned by NMR (NOESY),^{[ 42 ]} is consistent with a 5‐exo‐dig cyclization of the azetidinyl radical 10 proceeding trans to the CF₃ substituent. In addition, the Z configuration of the exocyclic alkene was explained by preferential hydrogen atom transfer from the silane on the less‐hindered face of the configurationally labile vinylic and benzylic radical intermediate 11. Cleavage of the benzylidene moiety in 9 was then achieved by ozonolysis, followed by reduction with PPh₃, to afford azaspirocyclic ketone 12 (94%) (Scheme 6).

Scheme 6.

Synthesis of azaspirocyclic compounds 9 and 12.

As a key structural feature of the anticancer drug cobimetinib,^{[ 5 ]} the azetidin‐3‐ol moiety is also employed in structure–activity relationships aimed at tuning the pharmacological properties of lead compounds.^{[ 43 ]} With the goal of developing an access to 2‐(trifluoromethyl)azetidin‐3‐ols, the polar ring‐opening of 2‐(trifluoromethyl)ABBs was investigated with trifluoroacetic anhydride in order to facilitate subsequent cleavage of the acyl residues on the nitrogen atom and the oxygen atom at C3 in the adduct. In addition, this latter reagent has already been employed to trigger strain‐release ring‐opening reactions of ABBs.^{[ 30a ]} Compound 5b was reacted with trifluoroacetic anhydride (CH₂Cl₂, RT, 6 h) to trigger the formation of the azonium intermediate 13, the ring‐opening of which was achieved either by the trifluoroacetate anion or adventitious traces of water to provide 14 and/or 14′. After treatment with a 10% aqueous solution of NaOH (MeOH, RT, 18 h), the desired 2‐(trifluoromethyl)azetidin‐3‐ol 15b was obtained with high diastereomeric purity (dr = 96:4) in 74% overall yield (Scheme 7).

Scheme 7.

Strain‐release reaction of 5b with trifluoroacetic anhydride.

The scope of this formal hydration process was extended to some of the other 2‐(trifluoromethyl)ABBs synthesized previously. Azetidin‐3‐ols 15c, 15d, 15f‐15 h were obtained in good yields (70%–84%) regardless of the electronic properties of the substituent at the para position of the phenyl group at C3. Azetidinol 15k, possessing a benzyloxy group at the meta position of the aromatic group, was isolated in moderate yield (49%) but the reaction proceeded well in the presence of a 2‐chloropyridine ring, as shown with the isolation of 15p (71%) (Scheme 8).

Scheme 8.

Synthesis of substituted 2‐(trifluoromethyl)azetidin‐3‐ols.

An alkyl chain can also be present at C3, as illustrated with the synthesis of 15q (69%). The relative stereochemistry of the crystalline azetidinol 15f was determined by x‐ray diffraction analysis,^{[ 44 ]} showing a trans relationship between the hydroxyl and the trifluoromethyl groups, thereby supporting the stereochemical assignments made previously for the polar ring‐opening reactions of 2‐(trifluoromethyl)ABBs (Scheme 8).

The disappointing stereochemical outcome of the radical hydrodechlorination of 3‐chloroazetidine 6b, which provided a diastereomeric mixture of 7/7′ (Scheme 5), led us to investigate an alternative strain‐release reductive process. For 2‐(trifluoromethyl)ABBs bearing a phenyl group at C3, we reasoned that reductive cleavage of the benzylic C3─N bond could be accomplished by palladium‐catalyzed hydrogenolysis. Indeed, treatment of azabicyclobutane 5a with Pd/C (10 mol%) under an atmosphere of hydrogen gas, in the presence of Boc₂O to avoid catalyst poisoning (EtOAc, RT),^{[ 45 ]} afforded the N‐Boc 2‐trifluoromethyl‐3‐phenyl azetidine 16a (81%), as a single cis diastereomer, the configuration of which was assigned by NMR spectroscopy.^{[ 42 ]} Similarly, hydrogenolysis of ABBs 5c and 5 g provided the cis‐2,3‐disubstituted azetidines 16c (96%) and 16 g (54%).^{[ 46 ]} The observed stereochemical outcome is consistent with hydrogenolysis of the C3─N bond occurring with inversion of configuration at C3, as usually observed in the case of benzylic amines (Scheme 9).^{[ 47} , ^{48 ]}

Scheme 9.

Palladium‐catalyzed hydrogenolysis of 3‐aryl‐2‐(trifluoromethyl)‐1‐azabicyclo[1.1.0]butanes.

Furthermore, we demonstrated that the trifluoromethyl group has a remarkable influence on the stereochemical outcome of the latter transformation. Indeed, hydrogenolysis of azabicyclobutane 17, possessing a silyloxymethyl group at C2, proceeded in a nearly stereorandom manner and afforded a 52:48 mixture of the corresponding diastereomeric cis‐ and trans‐N‐Boc azetidines 18 and 18′ (84% combined yield) (Scheme 10).

Scheme 10.

Palladium‐catalyzed hydrogenolysis of azabicyclobutane 17. TBS  = Sit‐BuMe₂.

Because 3‐aryl ABBs underwent hydrogenolysis in the presence of the heterogeneous Pd/C catalyst, it was of interest to examine whether the 3‐aryl‐1‐azabicyclobutyl moiety could be compatible with classical palladium‐catalyzed cross‐coupling reactions. It was demonstrated that ABB 5f, bearing a p‐iodophenyl group, could be successfully involved in a Suzuki–Miyaura coupling with phenylboronic acid [Pd₂dba_3•CHCl₃ (5 mol%)_, SPhos (20 mol%), K₃PO₄·H₂O, 1,4‐dioxane, 50°C]^{[ 49 ]} or a Sonogashira coupling with propargyl alcohol [PdCl₂(PPh₃)₂ (3 mol%), CuI (4 mol%), Et₃N, RT]. The desired products 5d (85%) and 5t (91%), respectively, were isolated in good yields. Subsequent hydrogenolysis of ABBs 5d and 5t, catalyzed by Pd/C in the presence of Boc₂O, eventually led to the cis‐2,3‐disubstituted N‐Boc azetidines 16d (66%) and 16t (89%), with additional hydrogenation of the disubstituted alkyne in the latter case (Scheme 11).

Scheme 11.

Palladium catalyzed cross‐coupling and hydrogenolysis reactions from azabicyclobutane 5f. dba = Dibenzylideneacetone.

3. Conclusion

In summary, 2‐(trifluoromethyl)‐1‐azabicyclo[1.1.0]butanes, which are readily available by cyclopropanation of 2‐(trifluoromethyl)‐2H‐azirines, can be involved in polar strain‐release reactions, despite the presence of the electron‐withdrawing and sterically hindered trifluoromethyl substituent. Reaction of this new family of azabicyclobutanes with benzyl chloroformate and trifluoroacetic anhydride provides access to 3‐chloroazetidines or azetidin‐3‐ols, respectively, possessing an (hetero)aryl or an alkyl group at C3 and a trifluoromethyl substituent at C2. In addition, palladium‐catalyzed hydrogenolysis of 3‐aryl‐2‐trifluoromethyl‐1‐azabicyclobutanes enables a convenient access to the corresponding cis‐2,3‐disubstituted azetidines. The 2‐(trifluoromethyl)azetidines arising from these transformations constitute building blocks of potential interest in medicinal chemistry. These results not only highlight the interest of new families of azabicyclobutanes, as precursors of azetidines, but also complements the repertoire of transformations in which these strained substrates can be involved.

4. Experimental Section

4.1. General Ethods

Infrared (IR) spectra were recorded with attenuated total reflectance (ATR) sampling technique. ¹H NMR spectra were recorded at 400 MHz and data are reported as follows: chemical shift in ppm from tetramethylsilane referenced to the residual isotopomer solvent signal (CHCl₃: δ  = 7.26 ppm), multiplicity, integration. ¹³C{¹H} NMR spectra (broadband ¹H‐decoupled) were recorded at 100 MHz and data are reported as follows: chemical shift in ppm from tetramethylsilane referenced to the solvent signal (CDCl₃: δ  = 77.16 ppm), carbon environment (deduced from DEPT experiments). ¹⁹F{¹H} NMR spectra (broadband ¹H‐decoupled), were recorded at 376 MHz and data are reported as follows: chemical shift in ppm referenced to external CFCl₃ (δ = 0 ppm), integration. High resolution mass spectra were obtained by electrospray ionization (ESI) with an orbitrap mass analyzer. Purification by flash column chromatography was performed on silica gel (230‐400 mesh).

4.2. Representative Procedures

4.2.1. Synthesis of 2‐trifluoromethyl‐1‐azabicyclo[1.1.0]butanes

(2R*,3S*)‐3‐Phenyl‐2‐(trifluoromethyl)‐1‐azabicyclo[1.1.0]butane (5a)

A solution of n‐BuLi (0.83 mL, 2.5 M in hexanes, 2.07 mmol, 1.5 equiv) was added dropwise to a suspension of trimethylsulfonium iodide (421 mg, 2.07 mmol, 1.5 equiv) in anhydrous THF (20 mL) at −20°C. After 0.5 h stirring at −20°C, a solution of azirine 4a ^{[ 37a ]} (255 mg, 1.38 mmol) was added. The reaction mixture was stirred for 0.5 h at −20°C and was then hydrolyzed with a saturated aqueous solution of NH₄Cl. The resulting mixture was diluted with CH₂Cl₂ and H₂O, the layers were separated and the aqueous phase was extracted with CH₂Cl₂. The combined organic layers were successively washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure (bath temperature < 20°C, volatile compound). The residue was purified by flash column chromatography on silica gel (Pentane/Et₂O, 95:5) to afford 208 mg (76%) of 5a as a yellow oil. IR (ATR): υ ^∼ = 1436, 1395, 1288, 1155, 1140, 903, 883, 756, 696 cm⁻¹ _; ¹H NMR (400 MHz, CDCl₃): δ  =  7.46–7.43 (m, 2H), 7.40–7.37 (m, 3H), 2.57 (dd, J = 2.3, 1.0 Hz, 1H), 2.15 (app. br q, J  = 5.6 Hz, 1H), 1.68 (d, J = 2.4 Hz, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃): δ  =  130.0 (C), 129.0 (CH), 128.7 (2 × CH), 128.4 (2 × CH), 121.2 (C, q, ¹ J _C‐F  = 275 Hz), 60.7 (CH, q, ² J _C‐F = 36.8 Hz), 53.0 (CH₂), 33.4 (C, q, ³ J _C‐F  = 2.3 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ  =  −67.1 (s, 3F) ppm; HRMS (ESI): m/z calcd for C₁₀H₉F₃N⁺: 200.0682 [M+H⁺]; found: 200.0684.

4.2.2. Ring‐opening of 2‐trifluoromethyl‐1‐azabicyclo[1.1.0]butanes with benzyl chloroformate

Benzyl (2S*,3R*)‐3‐chloro‐2‐phenyl‐2‐(trifluoromethyl)azetidine‐1‐carboxylate (6a)

Benzyl chloroformate (0.29 mL, 2.00 mmol, 2 equiv) was added to a solution of azabicyclobutane 5a (200 mg, 1.00 mmol) in anhydrous acetone (2 mL) at RT. After 16 h stirring at RT, the reaction mixture was hydrolyzed with a saturated aqueous solution of NaHCO₃. The resulting mixture was diluted with CH₂Cl₂ and H₂O, the layers were separated and the aqueous phase was extracted with CH₂Cl₂. The combined organic layers were successively washed with a saturated aqueous solution of NaHCO₃ and brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Petroleum ether/Et₂O, 90:10) to afford 338 mg (91%) of 6a as a pale yellow oil. IR (ATR): υ ^∼ =  1724, 1498, 1449, 1406, 1346, 1277, 1225, 1147, 1005, 989, 736, 696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ  = 7.46–7.31 (m, 10H), 5.25 (d, AB system, J = 12.5 Hz, 1H), 5.22 (d, AB system, J  = 12.5 Hz, 1H), 5.13 (q, J  = 6.7 Hz, 1H), 5.12 (d, AB system, J  = 10.3 Hz, 1H), 4.50 (d, AB system, J  = 10.2 Hz, 1H) ppm; ¹³C{¹H} NMR (100 MHz, CDCl₃): δ  =  156.4 (C), 135.6 (C), 135.4 (C), 129.5 (CH), 128.8 (2 × CH), 128.6 (2 × CH), 128.5 (CH), 128.1 (2 × CH), 127.3 (CH), 122.5 (C, q, ¹ J _C‐F = 282 Hz), 75.3 (CH, q, ² J _C‐F = 32.1 Hz), 68.0 (CH₂), 66.2 (C), 62.7 (CH₂) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ  =  −72.3 (s, 3F) ppm; HRMS (ESI): m/z calcd for C₁₈H₁₅ClF₃NO₂Na⁺: 392.0636 [M(³⁵Cl)+Na⁺]; found: 392.0638.

4.2.3. Ring‐opening of 2‐trifluoromethyl‐1‐azabicyclo[1.1.0]butanes with trifluoroacetic anhydride

(2R*,3R*)‐3‐Phenyl‐2‐(trifluoromethyl)azetidin‐3‐ol (15b)

Trifluoroacetic anhydride (12 µL, 0.086 mmol, 1.2 equiv) was added to a solution of azabicyclobutane 5b (15 mg, 0.070 mmol) in CH₂Cl₂ (1 mL) at 0°C. After 6 h stirring at RT, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (0.5 mL) and a 10% aqueous solution of NaOH (0.5 mL) was added to the resulting solution. After stirring for 18 h at RT, the reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Et₂O) to afford 12 mg (74%) of 15b as a colorless oil. IR (ATR): υ ^∼  =  3317 (br), 1615, 1515, 1290, 1206, 1173, 1121, 902, 822, 730, 672 cm⁻¹;¹H NMR (400 MHz, CDCl₃): δ  =  7.47 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 4.44 (qd, J  = 7.6, 0.8 Hz, 1H), 4.17 (d, J = 8.4 Hz, 1H), 3.82 (d, J = 8.4 Hz, 1H), 2.92–1.92 (m, app. br s, weak intensity, 2H, NH+OH), 2.37 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ  =  138.5 (C), 135.8 (C), 129.2 (2 × CH), 126.2 (2 × CH), 123.9 (C, q, ¹ J _C‐F = 279 Hz), 69.4 (CH, q, ² J _C‐F = 30.5 Hz), 58.4 (CH₂), 21.3 (CH₃) ppm (one C signal overlaps with those of CDCl₃ ); ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ  =  −73.8 (s, 3F) ppm; HRMS (ESI⁺): m/z calcd for C₁₁H₁₃F₃NO⁺: 232.0944 [M+H⁺]; found: 232.0943.

4.2.4. Representative procedure for palladium‐catalyzed hydrogenolysis of 2‐trifluoromethyl‐1‐azabicyclo[1.1.0]butanes

tert‐Butyl (2R*,3S*)‐3‐phenyl‐2‐(trifluoromethyl)azetidine‐1‐carboxylate (16a)

Pd (10%)/C (96 mg, 0.090 mmol, 10 mol%) and Boc₂O (394 mg, 1.81 mmol, 2 equiv) were successively added to a solution of azabicyclobutane 5a (180 mg, 0.904 mmol) in EtOAc (7 mL) under an argon atmosphere. The reaction mixture was evacuated under reduced pressure (10 mmHg) and backfilled with argon. The reaction mixture was evacuated again under reduced pressure and backfilled with hydrogen gas (balloon) (this process was repeated three times). After stirring for 2 h at RT, the reaction mixture was evacuated under reduced pressure, backfilled with argon gas and then filtered through Celite (EtOAc). The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (Petroleum ether/EtOAc, 90:10) to afford 221 mg (81%) of 16a as a colorless oil. IR (ATR): υ ^∼ =  1707, 1380, 1368, 1350, 1282, 1238, 1131, 973, 911, 860, 767, 732, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ  = 7.38–7.28 (m, 5H), 4.82 (dq, J = 9.1, 7.3 Hz, 1H), 4.46–4.41 (m, 1H), 4.31–4.21 (m, 2H), 1.49 (s, 9H) ppm; ¹H NMR (400 MHz, C₆D₆) δ  = 7.12–6.93 (m, 5H), 4.41 (m, app. br s, 1H), 4.12 (dd, J  = 8.7, 7.2 Hz, 1H), 3.79 (app. t, J = 9.0 Hz, 1H), 3.34 (m, 1H), 1.44 (s, 9H) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃) δ  = 155.6 (C), 134.5 (C), 128.7 (2 × CH), 128.4 (2 × CH), 127.8 (CH), 123.9 (C, q, ¹ J _C‐F = 283 Hz), 81.0 (C), 64.6 (CH, q, ² J _C‐F = 31.5 Hz), 52.0 (CH₂), 36.4 (CH), 28.3 (3 × CH₃) ppm; ¹³C{¹H} NMR (101 MHz, C₆D₆) δ  = 155.5 (C), 134.9 (C), 128.8 (2 × CH), 128.5 (2 × CH), 127.8 (CH), 124.6 (C, q, ¹ J _C‐F = 283 Hz), 80.4 (C), 64.7 (CH, q, ² J _C‐F = 31.1 Hz), 52.0 (CH₂), 36.3 (CH), 28.2 (3 × CH₃) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ  = −70.9 (s, 3F) ppm. HRMS (ESI): m/z calcd for C₁₅H₁₈F₃NO₂Na⁺: 324.1182 [M+Na⁺]; found: 324.1181.

Conflict of Interest Statements

The authors declare no conflicts of interest.

Supporting information

Supporting Information

Data Availability Statement

The data that support the findings of this study are available in the supporting information of this article.