Synthesis of Functionalized A-trifluoroethyl Amine Scaffolds via Grignard Addition to N-aryl Hemiaminal Ethers †

The synthesis of a variety of a-branched trifluoroethyl amines was achieved by reaction of N-aryl hemiaminal ethers with organo-magnesium reagents. The design of compounds suitable for drug development is a multi-dimensional process that requires the ne tuning of molecular properties beyond potency. For instance, physical– chemical properties that directly affect hydrolytic stability and bioavailability of the compound must be addressed to avoid side effects in vivo. Due to the excellent pharmacological prole of uorinated drugs, the strategic incorporation of uorine atoms has nowadays become routine in medicinal chemistry development programs. 1 For instance, incorporation of a tri-uoromethyl substituent adjacent to an amine is a means to improve the metabolic stability and to attenuate the basicity of the compound by shiing its pK a value more towards those of amides. 2 Furthermore the C–CF 3 bond is substantially isopolar with the C]O bond and the triuoroethyl amine moiety has a structural similarity to the tetrahedral proteolytic transition state. 3 As a consequence, triuoroethyl amines can be used as versatile hydrolysis-resistant bioisosteres of amides 4 which retain the geometry of the amide bond and, in contrast to other mimetics 5 , also preserve the donating properties of the N–H bond. An illustrative example for the successful replacement of the amide functionality by a triuoroethyl amine is given by Odanacatib, a highly potent drug candidate for the inhibition of Cathepsin K. 6 Various methods for the synthesis of a-triuoromethylated amines have been described so far, 7 including hydrogenation 8 and aromatic substitution 9 of activated imines, as well as base-catalyzed asymmetric isomerization reactions of ketoimines. 10 Furthermore, nucleophilic addition reactions of various organo-metallics to triuoromethylated imines 11 and hydrazones 12 have been reported. In this context, Lauzon and Charette have shown that triuoromethyl amine derivatives can be prepared by copper-catalyzed nucleophilic addition of diorganozinc reagents to N-phosphinoylimines, using an excess of organozinc reagent. 13 Similarly, triuoromethylated a,a-dibranched carbinamines can be obtained from N-tert-butylsulnyl hemiaminals with organo-magnesium or organolithium reagents. 14 However, most of these approaches are either hampered by the high tendency of a,a,a-triuorethylimines to form hydrates or by the need of additional deprotection steps for further functionalization of the nitrogen atom. In a seminal paper, Mikami and coworkers showed that an excess of Grignard reagents can be used to prepare a-triuoromethylated amines from stable N,O-acetals of tri-uoroacetaldehyd. 15,16 This work was recently extended to the use of arylboroxines for palladium(II)-catalyzed synthesis of …

The design of compounds suitable for drug development is a multi-dimensional process that requires the ne tuning of molecular properties beyond potency.For instance, physicalchemical properties that directly affect hydrolytic stability and bioavailability of the compound must be addressed to avoid side effects in vivo.Due to the excellent pharmacological prole of uorinated drugs, the strategic incorporation of uorine atoms has nowadays become routine in medicinal chemistry development programs. 1For instance, incorporation of a tri-uoromethyl substituent adjacent to an amine is a means to improve the metabolic stability and to attenuate the basicity of the compound by shiing its pK a value more towards those of amides. 2 Furthermore the C-CF 3 bond is substantially isopolar with the C]O bond and the triuoroethyl amine moiety has a structural similarity to the tetrahedral proteolytic transition state. 3As a consequence, triuoroethyl amines can be used as versatile hydrolysis-resistant bioisosteres of amides 4 which retain the geometry of the amide bond and, in contrast to other mimetics 5 , also preserve the donating properties of the N-H bond.An illustrative example for the successful replacement of the amide functionality by a triuoroethyl amine is given by Odanacatib, a highly potent drug candidate for the inhibition of Cathepsin K. 6 Various methods for the synthesis of a-triuoromethylated amines have been described so far, 7 including hydrogenation 8 and aromatic substitution 9 of activated imines, as well as base-catalyzed asymmetric isomerization reactions of ketoimines. 10urthermore, nucleophilic addition reactions of various organometallics to triuoromethylated imines 11 and hydrazones 12 have been reported.In this context, Lauzon and Charette have shown that triuoromethyl amine derivatives can be prepared by copper-catalyzed nucleophilic addition of diorganozinc reagents to N-phosphinoylimines, using an excess of organozinc reagent. 13imilarly, triuoromethylated a,a-dibranched carbinamines can be obtained from N-tert-butylsulnyl hemiaminals with organomagnesium or organolithium reagents. 14However, most of these approaches are either hampered by the high tendency of a,a,a-triuorethylimines to form hydrates or by the need of additional deprotection steps for further functionalization of the nitrogen atom.In a seminal paper, Mikami and coworkers showed that an excess of Grignard reagents can be used to prepare a-triuoromethylated amines from stable N,O-acetals of tri-uoroacetaldehyd. 15,16 This work was recently extended to the use of arylboroxines for palladium(II)-catalyzed synthesis of a-(tri-uoromethyl)arylmethyl amines. 17erein, we report a systematic study on the synthesis of functionalized a-substituted triuoromethyl amines using Grignard reagents and readily available triuoromethylated hemiaminal ethers. 18The latter are shelf-stable compounds derived from 1-ethoxy-2,2,2-triuoroethanol and aromatic amines and can be converted into triuoromethylated aldimines in situ.Thus, upon treatment with Grignard reagent deprotonation should provide the corresponding imine which would then undergo nucleophilic attack by excess Grignard reagent to furnish the desired triuoromethyl amine (Scheme 1).Formation of the transient imine species was conrmed by observing the corresponding imine hydrate via HPLC-MS aer addition of MeMgBr to the reaction mixture.To determine the optimal conditions, 3-chloro-N-(1-ethoxy-2,2,2-triuoroethyl)aniline 1a was treated with MeMgBr in dry THF under argon at different reaction temperatures (Table 1).Thus, the addition proceeded smoothly at À78 C furnishing the desired triuoroethyl amine 2a in 74% yield aer one hour.Whereas higher temperatures above 0 C led to signicant formation of side and decomposition products, best yields were obtained at a temperature of À15 C (Table 1, entries 1-5).For complete conversion of the triuoromethyl N,O-acetals at least 2 eq.MeMgBr are required.However, larger excess of the nucleophile did not improve the yield signicantly.Similar results were obtained with N-(1-ethoxy-2,2,2-triuoroethyl)aniline 1b bearing a neutral aryl ring (Table 1, entries 7-9).
With the optimized reaction conditions in hands, the substrate scope of the nucleophilic addition was tested using various functionalized aryl N,O-acetals 1 and MeMgBr (Table 2).We were pleased to nd that besides halides also ester, triazole, triuoromethyl groups and morpholino substituents are well tolerated to provide the desired triuoroethyl amines 2 in fair to excellent yields (Table 2, entries 1, 5, 6 and 8).However, electron-rich aniline derivatives proceeded more sluggishly and led to formation of the desired product with only diminished yields (Table 2, entry 4).In contrast, both electron-decient and moderately electron-rich heteroaromatic N,O-acetals 1c and 1g-j were readily converted to the corresponding amines 2c, 2g-j (Table 2, entries 3, 7-10), thus giving access to compounds with potential applications in drug design.
Next, we turned our attention to other Grignard reagents for nucleophilic addition to triuoromethylated N,O-acetals.Thus,  a All reactions were performed according to the optimized procedure.
b Aer ash chromatography.c Use of 3 eq.MeMgBr.d Without further purication.upon treatment of 3-chlorophenyl hemiaminal 1a with several alkyl Grignard reagents, various a-branched triuoromethyl Narylamines 3a-e were obtained in moderate to good yields (Table 3, entries 1-6).Notably, even highly sterically hindered nucleophiles like t-BuMgCl or cyclohexylmagnesium bromide can be successfully employed in this reaction (Table 3, entries 4 and 5).Interestingly, by using i-PrMgCl, i-PrMgCl$LiCl and cyclohexylmethylmagnesium chloride as nucleophiles, also generation of the formal reduction product 3-chloro-N-(2,2,2-triuoroethyl)aniline 4 was observed.It is worth mentioning that the yield of this side-product was substantially higher with i-PrMgCl$LiCl (up to 30%) than with i-PrMgCl and cyclohexylmethylmagnesium chloride (Table 3, entries 1, 2 and 6).This is presumably due to the higher degree of complexation in the presence of LiCl, which facilitates hydride transfer to the substrate.Furthermore, nucleophilic addition of alkenyl Grignard reagents proceeded smoothly and provided the desired unsaturated triuoromethyl N-arylamines 3f, 3g and 3h in moderate to good yields (Table 3, entries 7-9).Finally, PhMgCl can be used for conversion of tri-uoromethyl N,O-acetals into triuoromethylated benzylamine derivatives.For instance, treatment of the pyrazine derivative 1i and the isoxazolyl hemiaminal ether 1j with 2 eq.PhMgCl afforded amines 5 and 6 in good yields (Scheme 2).
In summary, an efficient procedure for the synthesis of abranched triuoromethylated amines has been developed starting from stable N-aryl triuoromethyl hemiaminal ethers.Whereas alkyl amines were incompatible with N,O-acetal formation, a broad range of aromatic and heteroaromatic substrates can be applied successfully to allow for rapid generation of functionalized amine scaffolds for medicinal chemistry purposes aer addition of alkyl, alkenyl and aryl Grignard reagents.Moreover and in contrast to other known protocols, protecting group manipulations are not required if the resulting triuoromethylated amines are to be used as amide bio-isosteres for use in lead optimization.Further investigations in this direction and on the use of functionalized organometallic reagents are ongoing and will be reported in due course.

Scheme 1 a
Scheme 1

Table 1
Optimization studies a Yield of isolated product aer ash chromatography.b Reaction time of 2 h.

Table 2
Addition of MeMgBr to (hetero)aromatic N,O-acetals a

Table 3
Addition of Grignard reagents to 3-chlorophenyl N,O-acetal a Entry RMgX Yield of 3 (%) b Yield of 4 (%) b a All reactions were performed according to the optimized procedure.b Aer ash chromatography.c nd ¼ not detected.