The Synthesis and Acid-base Properties of α-(Fluoromethyl)- and α-(Difluoromethyl)-substituted Cyclobutane Building Blocks

Aim. To synthesize cyclobutane-derived amines and carboxylic acids bearing CH 2 F or CHF 2 groups in the α position; to deter - mine the regularities of the effect of fluoroalkyl substituents on the acid-base properties of the title compounds. Results and discussion. Synthetic approaches to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluorome - thyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids have been developed. It has been found that the p K a (p K a (H)) values measured for the title compounds, as well as for their non-substituted and CF 3 -substituted analogues, are consistent with the electron-withdrawing effect of the corresponding fluoroalkyl substituents. Experimental part. The synthesis of the title compounds commenced from the known ethyl 1-(hydroxymethyl)cyclobutane - carboxylate or the product of its Swern oxidation (the corresponding aldehyde) and included fluorination, alkaline ester hydrolysis (for carboxylic acids), and modified Curtius rearrangement (for amines). The p K a value was determined from the pre-equivalence point part of the titration curve using the standard acid-base titration. Conclusions. A newly developed synthetic approach to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluo - romethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids allows to obtain the title compounds in multigram quantities (up to 97 g). With a single exception, the acid-base properties of these products, as well as their parent non-substituted and CF 3 -substituted analogues, change in a monotonous manner in accordance with inductive electronic effect of the fluorine atom(s).


■ Introduction
Introducing fluorinated substituents into the molecules of interest is a well-recognized design approach in modern drug discovery, and it is supported by numerous recent success stories [1 -5]. Fluorine atoms or fluoroalkyl groups can improve the compound potency, physicochemical properties relevant to medicinal chemistry, or the metabolic stability. On the other hand, cyclobutane derivatives have become increasingly popular in drug discovery [6,7] as small sp 3 -rich threedimensional structural motifs fully compliant with recent trends in this area [8]. Therefore, it is not surprising that functionalized cyclobutanes containing fluoroalkyl substituents have become very promising building blocks that have already confirmed their value for medicinal chemistry. For example, they were used in the discovery of cannabinoid receptor type 2 (CB 2 ) antagonists [9], FMS-like tyrosine kinase 3 (FLT3) inhibitors [10], or interleukin-1 receptor-associated kinase 4 (IRAK-4) inhibitors [11] (Figure 1).
Meanwhile, the simplest fluoroalkyl-substituted cyclobutane-derived amines and carboxylic acids have been insufficiently represented in the literature until recently. The corresponding a-, β-, and γ-CF 3 -substituted building blocks have been studied most thoroughly ( Figure 2) [12 -17]. Among the CH 2 F-and CHF 2 -substituted analogues,    β-substituted derivatives were described by our group recently [16]. On the contrary, cyclobutanederived amines and carboxylic acids bearing CH 2 F or CHF 2 groups in the a position (compounds 1 -4) are unknown in the literature to date. In this work, we were focused on the development of an efficient approach to the synthesis of compounds 1 -4 allowing for their preparation on a multigram scale. In addition to that, acidbase properties of the products synthesized, as well as their CF 3 -substituted analogues 5 and 6 were evaluated and compared to the parent nonsubstituted compounds to determine the effects of CH 2 F, CHF 2 , and CF 3 groups in the series studied.

■ Results and discussion
The synthetic part of our work commenced from hydroxy ester 7 that was prepared on a 100-g scale starting from ethyl cyclobutanecarboxylate using the method reported [18]. To obtain the CH 2 F-substituted series, compound 7 was mesylated and then subjected to the reaction with tetramethylammonium fluoride (TMAF) in refluxing toluene to give an fluoroorganic intermediate 8 (Scheme 1). Compound 8 was not isolated in a pure form, but subjected to the next step, namely the alkaline hydrolysis, to provide target carboxylic acid 1 (38 % yield from 7). The reaction of compound 1 with diphenyl phosphoroyl azide (DPPA) in the presence of triethylamine and then with tert-butanol (the modified Curtius reaction protocol) gave carbamate 9 that was immediately subjected to acid-promoted deprotection resulting in amine 2 in the form of hydrochloride (55 % yield from 1).
The synthesis of CHF 2 -substituted analogues included a similar reaction sequence commencing from aldehyde 10 -a product of the Swern oxidation of compound 7 according to the reported procedure [18]. In particular, deoxoflurionation of compound 10 with morph-DAST in CH 2 Cl 2 gave intermediate ester 11 that was subjected to alkaline hydrolysis providing carboxylic acid 3 (58 % yield from 10) (Scheme 2). Surprisingly, the modified Curtius rearrangement protocol described above did not work well with compound 3 when tert-butanol was used as the reagent for the intermediate isocyanate quenching, possibly due to the steric effects. Meanwhile, Teoc-protected derivative 12 (Teoc -2-(trimethylsilyl)ethoxycarbonyl) was formed efficiently when tert-butanol was replaced with 2-(trimethylsilyl)ethanol. After acid-promoted deprotection, amine 4 was obtained as hydrochloride in 64 % yield (from 3).
The pK a values of carboxylic acids 1, 3, and 5, as well as the pK a (H) values of amines 2, 4, and 6 were determined by the acid-base titration according to the previously reported protocol [19]. It was found that, generally, the pK a values followed rules-of-thumb reported previously for the analogous acyclic series (DpK a ≈ 1.7 and 0.7 per each fluorine atom in the positions β and γ to the (de)protonation site, respectively) [20] (Table 1). These results confirm that the inductive effect of the fluorine atoms is the main factor governing acidic/basic properties within the series studied. The only exception was compound 5 that was somewhat less acidic than might be expected ( Figure 3); perhaps, some intramolecular interactions (e.g., H•••F or F•••C=O) might be responsible for this behavior.

■ Conclusions
A newly developed synthetic approach to 1-(fluoromethyl)-and 1-(difluoromethyl)cyclobutanamines, 1-(fluoromethyl)-and 1-(difluoromethyl)cyclobutanecarboxylic acids allows to obtain the title compounds in multigram quantities (up to 97 g). The acid-base properties of these products, as well as their parent non-substituted and CF 3 -substituted analogues, change in a monotonous manner in accordance with inductive electronic effect of the fluorine atom(s). In particular, the DpK a values were ca. 0.7 and 1.7 units per single fluorine atom for carboxylic acids and amines, respectively. The only exception was 1-(trifluoromethyl)cyclobutanecarboxylic acid that was somewhat less acidic than might be expected; perhaps, some intramolecular interactions might be responsible for this behavior.

■ Experimental part
The solvents were purified according to the standard procedures [21]. All starting materials were available from Enamine Ltd. or purchased from other commercial sources. Melting points were measured on a MPA100 OptiMelt automated melting point system. 1  Coupling constants (J) were given in Hz. Spectra were reported as follows: chemical shift (δ, ppm), integration, multiplicity, and coupling constants (Hz).  High-resolution mass spectra were obtained on an Agilent 1260 Infinity UHPLC instrument coupled with an Agilent 6224 Accurate Mass TOF mass spectrometer. For compounds 1 -4 synthesized, the yields, melting points, data of high-resolution mass spectra (HRMS) ( Table 2), 1 H NMR spectra (Table 3), 13 C NMR spectra (Table 4), and 19 F NMR spectra (Table 5) were given in a tabular format.

1-(Fluoromethyl)cyclobutanecarboxylic acid (1)
To a pre-cooled (-15 °C) solution of compound 7 [18] (120 g, 0.76 mol) and Et 3 N (125 mL, 0.90 mol) in CH 2 Cl 2 (1000 mL), MsCl (65.8 mL, 0.85 mol) was added in a dropwise manner while keeping the internal temperature below -10 °C. After additional stirring for 30 min, the thick suspension obtained was washed with ice-cold water (3×150 mL), the organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure to give a crude mesylate (ca. 185 g), which was immediately used in the next step without purification.
The amount of the mesylate obtained and freshly dried TMAF (119 g, 1.28 mol) were mixed in toluene (900 mL), and the resulting mixture was stirred at reflux overnight. The progress of the reaction was monitored by 1 H NMR; in case of incomplete conversion an additional portion of TMAF was added. After the reaction completion, the resulting mixture was cooled to room temperature, diluted with hexanes (700 mL), washed with ice-cold water (3×200 mL), dried over Na 2 SO 4 and evaporated under reduced pressure to give a crude compound 8 (ca. 110 g).
The amount of compound 8 obtained was dissolved in MeOH (800 mL), and the solution was cooled to 0 °C on an ice-water bath. An aqueous solution of KOH (47.6 mL, 0.50 M, 0.85 mol) was added while keeping the internal temperature below 5 °C. The resulting turbid solution was stirred for 2 h, and most of the organic solvent was evaporated under reduced pressure. The residue was washed with CH 2 Cl 2 (2×100 mL), tBuOMe (2×100 mL), diluted with a fresh portion of CH 2 Cl 2 (300 mL), and acidified with 10 % aq NaHSO 4 (1100 mL). The aqueous layer was additionally     washed with CH 2 Cl 2 (2×300 mL) and discarded. The combined organic layers were washed with brine (2×100 mL), dried over Na 2 SO 4 , and evaporated under reduced pressure to give compound 1 as a beige solid (38.2 g, 0.29 mol, 38 % yield over three steps).

1-(Fluoromethyl)cyclobutanamine hydrochloride (2×HCl)
To a solution of compound 1 (38.2 g, 0.29 mol) in toluene (500 mL), Et 3 N (61.4 mL, 0.44 mol) was added in one portion. The resulting solution was cooled to 0 °C on an ice-water bath, and DPPA (87.8 g, 0.32 mol) was added portionwise while keeping the internal temperature below 5 °C. After the addition, the reaction mixture was slowly heated to 70 °C and then stirred at the same temperature for 3 h. After the gas evolution ceased, the mixture was heated to intensive reflux, and tert-butanol (83 mL, 0.87 mol) was added in a dropwise manner, following by additional stirring at reflux overnight. The resulting solution was cooled to room temperature, diluted with t-BuOMe (300 mL), washed successively with 10 % aq KHSO 4 (2×100 mL), saturated aq NaHCO 3 (2×100 mL), and brine (50 mL). The organic phase was dried over Na 2 SO 4 and evaporated under reduced pressure to give a crude compound 9 (ca. 43.3 g).
To a solution of the amount of 9 obtained in tBuOMe (250 mL), 10 M HCl in 1,4-dioxane (35 mL) was added in one portion at 0 °C, and the resulting mixture was stirred overnight. The resulting suspension was filtered, the precipitate was washed with tBuOMe (3×75 mL) and dried in vacuo (0.1 mbar) to give target product 2×HCl as a colorless solid (22.7 g, 0.16 mol, 55 % yield over two steps).

1-(Difluoromethyl)cyclobutanecarboxylic acid (3)
To an ice-cold solution of aldehyde 10 [18] (174 g, 1.11 mol) in CH 2 Cl 2 (2 L), a solution of morph-DAST (291 g, 1.67 mol) in CH 2 Cl 2 (300 mL) was added dropwise while maintaining the temperature below 5 °C. When the addition was complete, the resulting mixture was left to stir at room temperature overnight. The reaction mixture was slowly poured into saturated aq NaHCO 3 , the aqueous phase was separated and extracted with CH 2 Cl 2 (500 mL). The combined organic extracts were washed with brine (200 mL), dried over Na 2 SO 4 , and evaporated in vacuo.
The residue was purified by distillation (b. p. 51 °C / 5 mbar) to give crude ester 11 (ca. 125 g) as a colorless liquid.
To a solution of the amount of compound 11 obtained in MeOH (1 L), NaOH (84.3 g, 2.11 mol) was added portionwise (an exotherm was observed during the addition). After 2 h of stirring, the reaction mixture was evaporated in vacuo and partitioned between water (1 L) and CH 2 Cl 2 (1 L). The organic phase was discarded, and the aqueous phase was acidified with 6 M aq HCl to to pH ca. 3, extracted with CH 2 Cl 2 (2×1 L). The combined organic phases were washed with brine (300 mL), dried over Na 2 SO 4 , and evaporated to give carboxylic acid 3 (97.0 g, 58 % from 10) as a colorless oil.

1-(Difluoromethyl)cyclobutanamine hydrochloride (4×HCl)
To a solution of carboxylic acid 3 (97.0 g, 0.646 mol) in toluene (1 L), Et 3 N (99.0 g, 0.711 mol) was added, and the resulting mixture was heated to 100 °C. DPPA (179 g, 0.65 mol) was added dropwise at such a rate to maintain a gentle reflux. When the gas evolution ceased, 2-(trimethylsilyl)ethanol (84.1 g, 0.711 mol) was added in one portion, and the heating was continued for 18 h. The reaction mixture was allowed to cool to room temperature, washed with saturated aq K 2 CO 3 (300 mL), brine (300 mL), dried over Na 2 SO 4 , and evaporated in vacuo to give carbamate 12 (ca. 141 g) as a brown solid used in the next step without further purification.
The amount of compound 12 obtained was suspended in 6 M aq HCl and refluxed until all solids dissolved. The resulting mixture was evaporated to dryness and triturated with tBuOMe (1 L). The precipitate was filtered, washed with tBuOMe (2×400 mL), and dried in vacuo to give 4×HCl (84.1 g, 64 % yield) as a colorless solid.