The invention relates to a process for preparing 2,3,4-trisubstituted quinolines from ketimines and haloalkylamino reagents.

Quinolines are important precursors for pharmaceuticals and agrochemicals [(a) J. Sloop, J. Phys. Org. Chem., 2009, 22, 1 10-117; (b) A. R. Surrey and H. F. Hammer, J. Am. Chem. Soc., 1946, 68, 1 13-116; (c) W. Jonhson and B. G. Buetl, J. Am. Chem. Soc., 1952, 74, 4513-4516; (d) J. Mulero, G. Martinez, J. Oliva, S. Cermeno, J. M. Cayuela, P. Zafrilla, A. Martinez-Cacha and A. Barba, Food Chem, 2015, 180, 25-31].

The Combes reaction starting from e-diketones and anilines is an important method for the synthesis of quinolines {Chem. Ber., 1896, 29, 2456). However, the Combes reaction has only limited importance for the preparation of quinolines containing perhaloalkyl groups in position 2 and 4. J.Sloop et al. (J. Fluorine Chem., 2002, 118, 135-147) described an application of the Combes synthesis using anilines and fluorinated β-diketones in polyphosphoric acid. The fluorinated yfi-diketones usually prepared via Claisen condensation are hardly accesible. Especially in the case of fluorinated ^-diketones the yields of this reaction are rather low and the isolation of the highly volatile products is quite difficult. Moreover, a cyclization of unsymmetrical p-diketones under Combes conditions leads to the formation of regioisomers (see J.Sloop et al, J. Fluorine Chem., 2002, 118, 135-147). In addition, the isolation of quinolines from the reaction mixture containing polyphosphoric acid produces large amount of phosphorous-containing waste. Fallia at el. recently described a method for the preparation of 2,4- disubstituted quinolines, without a substituent in position 3 (see: F. Aribi et al., Org. Chemistry. Front, 2016, 3, 1392-1415).

In the light of the prior art described above, it is an object of the present invention to provide an efficient, regioselective process for preparing 2,3,4-trisubstituted quinolines using readily accessible starting materials yielding quinolines derivatives bearing a haloalkyl substituent in position 2 and/or 4. The object described above was achieved by a process for preparing a quinoline derivative of the formula (la)

(la), in which

R ¹ is Ci-Ce-haloalkyl or Ci-Ce-alkyl, R ² is -(C=0)OR ⁵ ,

R ³ is Ci-C6-haloalkyl or -Ci-C6-haloalkyl-Ci-C6-haloalkoxy, R ⁴ is H or halogen, and R ⁵ is Ci-Ce-alkyl, comprising the step of (a) reacting an enamine of the formula (II)

(II), in which the radicals are as defined above, with a haloalkylamino reagent, preferably fluoroalkylamino reagent, of the formula (III)

X R ⁶

R ³ -— N

X R ⁷

(HI), in which

X is F or CI,

R ⁶ and R ⁷ are each independently selected from Ci-C6-alkyl and Cs-Cs-cycloalkyl, in the presence of a Lewis acid.

Preferred are compounds of the formula (la), (II) and (III), in which

R ¹ is CH ₂ F, CF ₂ H, CF ₃ , C ₂ F ₅ or CH ₃ , R ³ is CF ₂ H, CF ₃ , CFHC1, CFHCF ₃ or CFHOCF3, R ⁴ is selected from H and halogen, X is F, R ⁶ , R ⁷ are each independently selected from CH ₃ and C2H5.

Most preferred are compounds of the formula (la), (II) and (III), in which

R ¹ is CF ₂ H, CF ₃ or CH ₃ ,

R ³ is CF ₂ H, CFHC1 or CFHOCF ₃ , R ⁴ is H or Cl,

X is F,

R ⁶ , R ⁷ are CH ₃ .

General definitions

In the definitions of the symbols given in the above formulae, collective terms were used which are generally representative of the following substituents:

Halogen: fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine and more preferably fluorine or chlorine. Ci-Ce-alkyl: saturated, straight-chain or branched hydrocarbyl radicals having 1 to 6 carbon atoms, for example (but not limited to) methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2- methylpropyl, 1 , 1 -dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2- trimethylpropyl, 1 ,2,2-trimethylpropyl, 1- ethyl- 1 -methylpropyl and l-ethyl-2-methylpropyl. This definition also applies to alkyl as part of a composite substituent, for example -NH-C(=0)0-Ci-C6-alkyl, unless defined elsewhere like, for example, haloalkyl.

Ci-Ce-alkoxy: saturated, straight-chain or branched alkoxy radicals having 1 to 6 carbon atoms, for example (but not limited to) methoxy, ethoxy, propoxy, 1 -methylethoxy, butoxy, 1 -methylpropoxy, 2- methylpropoxy, 1 , 1 -dimethylethoxy, pentoxy, 1 -methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2- dimethylpropoxy, 1 -ethylpropoxy, 1 , 1 -dimethylpropoxy and 1 ,2-dimethylpropoxy. This definition also applies to -Ci-C6-alkoxy as part of a composite substituent, for example -Ci-C6-haloalkyl-Ci-C6- haloalkoxy, unless defined elsewhere.

C3-C8-cycloalkyl: monocyclic saturated hydrocarbyl groups having 3 to 8 carbon ring members, for example (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl.

Ci-Ce-haloalkyl: straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as specified above, for example (but not limited to) -Ci-C3-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichloro fluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro- 2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1 , 1 , 1 -trifluoroprop-2-yl. This definition also applies to haloalkyl as part of a composite substituent, for example -Ci-C6-haloalkyl-Ci-C6-haloalkoxy, unless defined elsewhere. Ci-Ce-haloalkoxy: straight-chain or branched alkoxy groups having 1 to 6 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as specified above, for example (but not limited to) -Ci-C3-haloalkoxy, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloro fluoromethoxy, dichloro fluoromethoxy, chlorodifluoromethoxy, 1 - chloroethoxy, 1 -bromoethoxy, 1 -fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and l , l , l -trifluoroprop-2-oxy. This definition also applies to haloalkoxy as part of a composite substituent, for example -Ci-C6-haloalkyl-Ci-C6-haloalkoxy, unless defined elsewhere. Process description

The process is illustrated in Scheme 1 : Scheme 1 :

(le) step (e) (Id) (Ic) R ² = -CN R ² = -NH ₂ R ² = -NH-C(=0)0-C ₁ -C ₆ -alkyl

Optional:

De protection

reaction

step (d)

Quinoline derivatives of the formula (la) (compound of formula (I) with R ² = -(C=0)0-R ⁵ ) are prepared in that enamines of the formula (II) are reacted with fluoroalkylamino reagents of the formula (III) in the presence of a Lewis acid (step a). The compounds of the formula (I) with R ² = -COOH (lb), -NH- C(=0)0-Ci-C6-alkyl (Ic), -NH ₂ (Id) or -CN (Ie) may be obtained by modifying substituent R ² as follows:

The compound of the formula (la) may be further converted to the compound of the formula (lb) by means of a conventional saponification method, for example using an aqueous hydroxide solution, such as NaOH or KOH (step b).

The carboxylic acid of the formula (lb) may be further converted to the compound of the formula (Ic) by means of a conventional carbamate synthesis, for example by using a Curtius reaction (step c).

The carboxylic acid of the formula (lb) may alternatively be converted directly to the compound of the formula (Id) by means of a Curtius reaction and addition of water (step c').

The compound of the formula (Ic) may be further converted to the compound of the formula (Id) by cleavage of the N-alkoxycarbonyl group according to methods known in the art (step d, see for example WO 2006/081289). The compound of the formula (Id) may be further converted to the compound of the formula (Ie) by means of a Sandmeyer reaction using a nitrite, such as a -Ci-C i-alkyl nitrite, and CuCN (step e). The reaction is preferably conducted using acetonitrile as solvent.

Enamines (II) can be prepared by the condensation of anilines (IV) and acetoacetates (V) according to the literature procedure disclosed in (a) L. Troisi et ah , Tetrahedron, 2013, 69, 3878-3884; (b) I. V. Kutovaya et ah , Eur. J. Org. Chem. , 2015, 30, 6749-6761 ; (c) S. Prakash et ah , J. Fluorine Chem. , 2007, 128, 587-594.

Scheme 2:

Fluoroalkylamino reagents of the formula (III) are commercially available or can prepared in situ, e.g. from amines of the formula -NHR ⁶ R ⁷ and haloalkenes.

In a preferred embodiment of the process according to the invention, the fluoroalkylamino reagents (III) are first reacted with the Lewis acid [LA] (see Scheme 3), preferably BF3, AICI3, SbCls, SbFs or ZnCL, more preferably BF3 or AICI3, and then the compound of the formula (II) is added, in substance or dissolved in a suitable solvent (cf. WO 2008/022777).

Scheme 3 :

(ill) (ill ¹ )

Especially preferred is BF3 as Lewis Acid. BF3 can be used as a gas or as a solution/complex in ether or acetonitrile.

For the process according to the invention 1 to 2 mol, preferred 1 to 1 ,5 mol, most preferred 1 to 1 ,2 mol compound of formula (III) is reacted with 1 mol compound of formula (II). The cyclization and formation of (I) is affected at temperatures of 0 °C to +80 °C, preferably at temperatures of +20 °C to +70 °C, more preferably at +30 °C to +70 °C and under standard pressure in presence of acid, preferably H2SO4, if necessary.

The reaction time is not critical and may, according to the batch size, be selected within a relatively wide range.

Suitable solvents are, for example, aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, and halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1 ,2-dimethoxyethane, 1,2- diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; amides such as NN-dimethylformamide, NN-dimethylacetamide, N-methylformanilide, N- methylpyrrolidone or hexamethylphosphoramide; sulphoxides such as dimethyl sulphoxide or sulphones such as sulpholane. Particular preference is given, for example, to THF, acetonitriles, ethers, toluene, cyclohexane or methylcyclohexane, and very particular preference, for example, to acetonitrile, THF, acetonitrile, ether or dichloromethane.

After the reaction has ended, for example, the solvents are removed and the product is isolated by purification on flash chromatography.

General Procedure

Synthesis of the compound of formula (II)

Ethyl-4,4-difluoro-3-(phenylamino)but-2-enoate (Il.a)

(Il.a) Under argon atmosphere, a solution of ethyl-4,4-difluoroacetoacetate (1 equiv., 8.43 mL, 64.4 mmol) was added to aniline (1 equiv., 5.87 mL, 64.4 mmol) in anhydrous dichloromethane (DCM) (110 mL) in presence of desiccant (e.g. 4 A MS). Then the reaction mixture was stirred for 4 h at room temperature. The desiccant was then filtered off on celite and washed with ether. The filtrate was concentrated under reduced pressure and purified by flash chromatography using a mixture of ethyl acetate (AcOEt) in pentane (2-98%) to provide the final compound (Il.a) as colourless oil in 36% yield (5.63 g). Compound can be used directly without any further purification to avoid its degradation on silica gel column. ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 9.93 (s, 1H, NH), 7.36 (t, ³ J _H . _H = 7.8 Hz, 2H, C _{3; 5} H), 7.22 (t, ³ J _H . _H = 7.4 Hz, 1H, C ₄ H), 7.15 (d, ³ J _H -H = 7.6 Hz, 2H, C¾ eH), 6.21 (t, ² J _H -F = 53.3 Hz, 1H, CHF ₂ ), 5.26 (s, 1H, C=CH), 4.20 (q, ³ J _H -H = 7.1 Hz, 2H, OCH2CH3), 1.31 (t, ³ J _H -H = 7.1 Hz, 3H, OCH ₂ C%) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -1 17.33 (dd, ² J _F -H = 53.3, ⁴ J _F . _H =1.8 Hz, CHF ₂ ) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 170.31 (s, CO), 151.37 (t, ² J _C -F = 23.2 Hz, CCHF ₂ ), 138.00 (s, Ci), 129.61 (s, C _{3; 5} ), 126.19 (s, C ₄ ), 124.83 (s, C _{¾ 6} ), 109.51 (t, 'J _C -F = 241.5 Hz, CHF ₂ ), 86.73 (t, ³ J _C -F = 7.0 Hz, C=CCHF ₂ ), 59.88 (s, CH2CH3), 14.49 (s, CH ₂ C%). HRMS (ESI positive) for Ci ₂ Hi ₄ F ₂ N0 ₂ [M ⁺ ] : calcd 242.0987, found 242.0972

Ethyl-4,4,4-trifluoro-3-(phenylamino)but-2-enoate (Il.b)

(li b)

A mixture of ethyl-4,4,4-trifluoroacetoacetate (1 equiv., 1.58 mL, 10.7 mmol) and aniline (1 equiv., 0.98 mL, 10.7 mmol) were put under reflux in acetic acid (1 equiv., 0.615 mL, 10.7 mmol) for 3 h. The reaction mixture was quenched by addition of saturated solution of sodium bicarbonate (NaHC0 ₃ ), extracted with ether, dried over sodium sulphate (Na2SO i), and concentrated in vacuo. The crude was purified by column chromatography, using a mixture of AcOEt in pentane (2-98%) to provide the final compound (Il.b) as colourless oil in 19% yield (530 mg). Both form imine-enamine were observed by NMR analysis, however the imine form was not stable and rapidly degraded into the enamine form. ENAMINE form ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 9.84 (s, 1H, NH), 7.37 - 7.30 (m, 2H, C _{3; 5} H), 7.28 - 7.22 (m, 1H, C ₄ H), 7.21 - 7.17 (m, 2H, C¾ ₆ H), 5.35 (s, 1H, C=CH), 4.22 (q, ³ J _H . _H = 7.1 Hz, 2H, OCH2CH3), 1.32 (t, ³ JH-H = 7.1 Hz, 3H, OCH ₂ C%) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -63.33 (s, CF ₃ ) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 169.81 (s, CO), 147.29 (q, ² J _C -F = 31.4 Hz, CCF ₃ ), 138.50 (s, Ci), 129.08 (s, C _{3; 5} ), 126.76 (s, C ₄ ), 126.13 (q, ⁵ J _C -F = 1.5 Hz, C¾ ₆ ), 120.37 (q, ^] J _C -F = 277.4 Hz, CF ₃ ), 88.67 (q, ³ J _C -F = 5.4 Hz, C=CCF ₃ ), 60.26 (s, C¾CH ₃ ), 14.44 (s, CH ₂ C%) ppm. IMINE form ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 7.40 - 7.32 (m, 2H, C ₃ , ₅ H), 7.20 - 7.14 (m, 1H, C ₄ H), 6.88 - 6.82 (m, 2H, C _{¾ 6} H), 4.15 (q, ³ J _H -H = 7.0 Hz, 2H, OC¾CH ₃ ), 3.41 (s, 2H, N=CC%), 1.24 (t, ³ J _H . _H = 7.1 Hz, 3H, OCH2CH3) ppm. ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ _Ρ = -72.64 (s, CF ₃ ) ppm.

Ethyl-3-(phenylamino)but-2-enoate (II.c)

(II.c)

Under argon atmosphere, a solution of ethyl-3-oxobutanoate (1 equiv, 8.14 mL, 64.4 mmol) was added to aniline (1 equiv, 5.87 mL, 64.4 mmol) in anhydrous DCM (110 mL) in presence of desiccant (e.g. 4 A MS). Then the reaction mixture was stirred for 24 h at room temperature. The desiccant was then filtered off on celite and washed with ether. The desire compound (II.c) was obtained as a brown oil in 95% yield (12.6 g). Compound was used directly without any further purification to avoid its degradation on silica gel column. ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 10.38 (s, 1H, NH), 7.36 - 7.28 (m, 2H, C _{3; 5} H), 7.19 - 7.12 (m, 1H, C ₄ H), 7.11 - 7.06 (m, 2H, C _{¾ 6} H), 4.69 (m, 1H, C=CH), 4.15 (q, ³ J _H -H = 7.1 Hz, 2H, OCH2CH3), 2.00 (m, 3H, CH ₃ ), 1.29 (t, ³ J _H . _H = 7.1 Hz, 3H, OCH ₂ C%) ppm. ¹³ C NMR (101 MHz, CDC1 ₃ ) δα = 170.35 (s, CO), 158.85 and 158.83 (d, iso ¹ - iso ² , CCH ₃ ), 139.34 (s, Ci), 129.03 (s, C _{3; 5} ), 124.86 (s, C ₄ ), 124.34 and 124.32 (d, iso ¹ - iso ² , C¾ e), 86.10 (s, C=CCH ₃ ), 58.69 (s, CHCH ₃ ), 20.25 and 20.24 (d, iso ¹ - iso ² , CH ₃ ), 14.57 (s, CH ₂ C%) ppm. Ethyl-3-[(4-chlorophenyl)amino]-4,4-difluorobut-2-enoate (II. d)

(ll.d)

Under argon atmosphere, an excess of ethyl-4,4-difluoroacetoacetate (2 equiv., 10.4 g, 8.16 mL, 62.3 mmol) was added to / chloroaniline (1 equiv., 3.98 g, 31.2 mmol) in anhydrous DCM (56 mL) in presence of desiccant (e.g. 4 A MS). Then the reaction mixture was stirred for 21 h at room temperature. The desiccant was then filtered off on celite and washed with ether. The filtrate was concentrated under reduced pressure and used without any further purification. The purity was estimated around 75%. The desire compound (II. d) was obtained as a brown oily mixture in 90% (7.73 g). ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 9.85 (s, 1H, NH), 7.31 (d, ³ J _H -H = 8.7 Hz, 2H, C _{3; 5} H), 7.09 (d, ³ J _H -H = 8.6 Hz, 2H, C _{¾ 6} H), 6.15 (t, ² JH-F = 53.3 Hz, 1H, CHF ₂ ), 5.25 (s, 1H, C=CH), 4.20 (q, ³ J _H -H = 7.1 Hz, 2H, OCH2CH3), 1.31 (t, ³ JH-H = 7.1 Hz, 3H, OCH2CH3) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -116.93 (dd, ² J _F -H = 53.3, ⁴ J _F . _H = 1.2 Hz) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 170.22 (s, CO), 150.88 (t, ² J _C -F = 22.9 Hz, CCHF ₂ ), 136.71 (s, C ₄ ), 131.80 (s, Ci), 129.70 (s, C ₃ , 5), 126.15 (s, C¾ e), 109.81 (t, ^] J _C -F = 242.0 Hz, CHF ₂ ), 87.87 (t, ³ JC-F = 7.2 Hz, C=CCHF ₂ ), 60.06 (s, CH2CH3), 14.47 (s, CH ₂ C%) ppm. HRMS (ESI positive) for C12H13CIF2NO2 [M ⁺ ]: calcd 276.0597, found 276.0605.

Synthesis of the compound of the formula (III')

^-(l-Chloro-l^-difluoroethylideneJ-A^methylmethanaminium tetrafluoroborate (III'. a)

(IN'.a) l-Chloro-l,2,2-trifluoroethene (1 equiv., 0.195 mL, 2.58 mmol) was liquefied in a Schlenk apparatus under argon at -78 °C. Dimethylamine 2 M in THF (1 equiv., 2 M, 1.29 mL, 2.58 mmol) was added slowly via syringe at -78 °C. After 5 min, cold bath was replaced by water bath and the mixture was stirred for 15 min. Boron trifluoride diethyl etherate (BF3*Et20) (1 equiv., 0.328 mL, 2.59 mmol) was added via syringe and the reaction mixture was stirred for 30 min. Anhydrous DCM was then added to precipitate the salts. (In case of polymerization, addition of anhydrous acetonitrile (MeCN) solubilizes the mixture). Yield of (III'. a) was estimated at 99% (589 mg) according to ¾ NMR analysis. ¾ NMR (400 MHz, DMSO) δ _Η = 7.16 (d, ² J _H -F = 48.8 Hz, 1H, CHFC1), 2.97 and 2.87 (2 * s, 6H, N(CH ₃ ) ₂ ⁺ ) ppm ¹⁹ F NMR (376 MHz, DMSO) δ _Ρ = -144.34 (d, ² J _F -H = 48.8 Hz, CHFC1), -148.03 (s, CF), -148.08 (s, BF ₄ ^" ) ppm.

C NMR analysis of the corresponding amide after hydrolysis:

¹³ C NMR (126 MHz, DMSO) 8 _C = 163.20 (d, ² J _C -F = 23.9 Hz, CO), 91.52 (d, 'J _C -F = 244.8 Hz, CHFC1), 36.26 and 35.70 (2 * s, CH ₃ ) ppm.

^-(l^-Difluoro-l-^rifluoromethoxyJethylideneJ-^-methylmet hanaminium tetrafluoroborate (Ill'.b)

(Ill'.b) first step of the synthesis of the compounds (Ia-3) and (Ia-6) below.

Step a: Synthesis of the compound of the formula (la)

Ethyl-2,4-bis(difluoromethyl)quinoline-3-carboxylate (Ia-1)

(la-1) Under an argon atmosphere, a solution of 1,1,2,2-tetrafluoro-NN-dimethylethan-l -amine (TFEDMA) was activated by adding BF3*Et20 (1.2 equiv., 3.53 mL, 27.9 mmol) in a solution of TFEDMA (1.2 equiv., 3.26 mL, 27.9 mmol) in dry MeCN (50 mL) and stirred for 15 min. Then a solution of ethyl-4,4- difluoro-3-(phenylamino)but-2-enoate (II.a) (1 equiv., 5.6 g, 23.2 mmol) in dry MeCN (50 mL) was slowly added to this mixture via syringe. After 15 min at room temperature, the mixture was heated at 50 °C for 19 h. MeCN was removed under reduced pressure and the reaction mixture was purified by flash chromatography using a gradient of AcOEt in cyclohexane (0-5%) to provide the final compound (Ia-1) as colourless solid in 89% yield (6.24 g). ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 8.40 (dd, ³ J _H . _H = 8.6,

⁵ JH-F =1.4 Hz, 1H, CsH), 8.23 (d, ³ J _H . _H = 8.4 Hz, 1H, C ₈ H), 7.88 (ddd, ³ J _H -HI = 8.4, ³ J _H . _H4 =7.0, ⁴ J _H -m =1.2 Hz, 1H, C ₆ H), 7.76 (ddd, ³ J _H -m = 8.3, ³ J _H -m =7.0, ⁴ J _H -m =1.0 Hz, 1H, C ₇ H), 7.19 (t, ² J _H -F = 52.9 Hz, 1H, C4CHF2), 6.93 (t, ² JH-F = 54.6 Hz, 1H, C2CHF2), 4.53 (q, ³ J _H -H = 7.2 Hz, 2H, OCH2CH3), 1.44 (t, ³ JH-H = 7.2 Hz, 3H, OCH ₂ C%) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -109.64 (dd, ² J _F -H = 53.0, ⁵ J _F -H =2.0 Hz, C4CHF2), -115.25 (d, ² J _F -H = 54.6 Hz, C2CHF2) ppm. ¹³ C NMR (101 MHz, CDCI3) δα = 165.32 (s, CO), 148.26 (t, ² JC-F = 25.3 Hz, C ₂ ), 147.56 (s, C4CC5), 137.17 (t, ² J _C -F = 23.3 Hz, C ₄ ), 131.84 (s, C ₆ ), 130.80 (s, C ₈ ), 129.99 (s, C ₇ ), 125.43 (t, ⁴ J _C . _F = 3.7 Hz, C ₅ ), 124.21 (t, ³ J _C . _F = 6.6 Hz, C ₃ ), 123.57 (s, Cg N), 114.08 (t, ^] JC-F = 242.4 Hz, C2CHF2), 112.93 (t, ^] J _C -F = 241.4 Hz, C4CHF2), 63.30 (s, CH2CH3), 14.03 (s, CH2CH3) ppm. IR v (cm ¹ ): 2988-2901 (C _sp3 H), 1721 C14H11F4NO2 (301): calcd (%) N 4.65, C 55.82, H 3.68, found N 4.63, C 55.86, H 3.78. MP: 65.5 - 66.7 °C.

Ethyl-4-(chlorofluoromethyl)-2-(difluoromethyl)quinoline- 3-carboxylate (Ia-2)

(la-2)

Under an argon atmosphere, a solution of ethyl-4,4-difluoro-3-(phenylamino)but-2-enoate (II.a) (1 equiv., 1.56 g, 3.87 mmol) in dry MeCN (8.40 mL) was slowly added to a solution of N-(2-chloro-l,2- difluoroethylidene)-N-methylmethanaminium tetrafluoroborate (Ill.a) (1.30 equiv., 1.19 g, 5.2 mmol) in dry MeCN (8.40 mL) via syringe. After 15 min at room temperature, the mixture was heated at 50 °C for 19 h. MeCN was removed under reduced pressure and the reaction mixture was purified by flash chromatography using a gradient of AcOEt in cyclohexane (0-5%) to provide the final compound (Ia-2) as a yellow oil in 85% yield (1.04 g). ¾ NMR (400 MHz, CDCI3) δ _Η = 8.48 (d, ³ J _H . _H = 8.6 Hz, 1H, CsH), 8.23 (d, ³ J _H -H = 7.9 Hz, 1H, C ₈ H), 7.88 (ddd, ³ J _H -m = 8.4, ³ J _H . _H4 =6.9, ⁴ J _H -m = 1.3 Hz, 1H, C ₆ H), 7.77 (ddd, ³ J _H -H2 = 8.4, ³ J _H . _H3 =6.9, ⁴ J _H -m =1.3 Hz, 1H, C ₇ H), 7.62 (d, ² J _H -F = 48.6 Hz, 1H, C4CHFCI), 6.93 (t, ² JH-F = 54.6 Hz, 1H, C2CHF2), 4.61 - 4.44 (m, 2H, OCH2CH3), 1.45 (t, ³ J _H . _H = 7.2 Hz, 3H, OCH2CH3) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -115.30 (d, ² J _F -H = 54.6 Hz, C2CHF2), -133.91 (d, ² JF-H = 48.6 Hz, CACHFCI) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 165.40 (s, CO), 148.30 (t, ² J _C -F = 25.2 Hz, C ₂ ), 147.71 (s, C4CC5), 140.20 (d, ² J _C -F = 21.2 Hz, C ₄ ), 131.77 (s, C ₆ ), 131.02 (s, C ₈ ), 129.71 (s, Cv), 125.43 (d, ⁴ JC-F = 5.7 Hz, C ₅ ), 123.07 (s, CgCN), 122.10 (d, ³ J _C . _F = 5.3 Hz, C ₃ ), 114.03 (t, ^] J _C -F = 244.1 Hz, C2CHF2), 96.76 (d, ^] J _C -F = 244.6 Hz, CACHFCI), 63.26 (s, CH2CH3), 14.04 (s, CH2CH3) ppm. IR v (cm ¹ ): 2987-2907 (C _sp3 H), 1727 C14H11F3CINO2 (317): calcd (%) N 4.41, C 52.93, H 3.49, found N 4.32, C 52.63, H 3.59.

Ethyl-2-(difluoromethyl)-4-(fluoro(trifluoromethoxy)methy l)quinoline-3-carboxylate (Ia-3)

(Ia-3) l,l,2-Trifluoro-2-(trifluoromethoxy)ethene (1 equiv., 0.8 mL, 7.23 mmol) was liquefied in a Schlenk apparatus under argon at -78 °C. Dimethylamine 2 M in THF (1 equiv., 2 M, 3.62 mL, 7.24 mmol) was added slowly via syringe at -78 °C. After 5 min, cold bath was replaced by water bath and the mixture was stirred for 15 min. BF3*Et20 (1 equiv., 0.92 mL, 7.26 mmol) was added via syringe and the reaction mixture was stirred for 30 min. The yield of the desire compound N-(l,2-difluoro-2- (trifluoromethoxy)ethylidene)-N-methylmethanaminium tetrafluoroborate (Ill.b) was estimated at 85% and directly submitted into the next step. Under an argon atmosphere, a solution of ethyl-4,4-difluoro-3- (phenylamino)but-2-enoate (Ia-3) (1 equiv., 1.56 g, 3.87 mmol) in dry MeCN (8.40 mL) was slowly added to a solution of N-(l,2-difluoro-2-(trifluoromethoxy)ethylidene)-N-methylmeth anaminium tetrafluoroborate (Ill.b) (1.57 equiv., 1.7 g, 6.1 mmol) in dry MeCN (8.40 mL) via syringe. After 15 min at room temperature, the mixture was heated at 50 °C for 19 h. MeCN was removed under reduced pressure and the reaction mixture was purified by flash chromatography using a gradient of AcOEt in cyclohexane (0-20%>) to provide the final compound (I.c) as colourless solid in 97%> yield (1.38 g). ¾ NMR (400 MHz, CDCI3) δ _Η = 8.41 (d, ³ J _H -H = S.6 HZ, lH, C ₅ H), 8.23 (d, ³ J _H -H = SA HZ, lH, C ₈ H), 7.93 - 7.82 (m, 1H, C ₇ H), 7.82 - 7.67 (m, 1H, C ₆ H), 7.28 (d, ² J _H -F = 54.8 Hz, 1H, C4CHFOCF3), 6.95 (t, ² J _H -F = 54.6 Hz, 1H, C2CHF2), 4.61 - 4.45 (m, 2H, OCH2CH3), 1.44 (t, ³ J _H -H = 7.2 Hz, 3H, OCH ₂ C%) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -59.39 (d, ⁴ J _F . _F = 4.9 Hz, C4CHFOC 3), -114.33 - -116.46 (m, A ₂ B ₂ , Δν = 485.13 Hz, C2CHF2), -120.55 (dqd, ² J _F -H = 54.9, ⁴ J _F . _F = 4.8, ⁵ J _F -H =2.1 Hz, C4CH OCF3) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 165.28 (s, CO), 148.35 (t, ² J _C -F = 25.3 Hz, C ₂ ), 147.68 (s, CgCN), 136.42 (d, ² JC-F = 24.1 Hz, C ₄ ), 131.91 (s, C ₇ ), 130.87 (s, C ₈ ), 130.02 (s, C ₆ ), 125.63 (d, ⁴ J _C . _F = 4.9 Hz, C ₅ ), 123.97 (d, ³ Jc- _F = 6.2 Hz, C ₃ ), 123.46 (s, C4CC5), 121.08 (qd, ^] J _C -F = 262.6, ³ J _C . _F = 1.7 Hz, C4CHFOC 3), 114.05 (t, 'Jc-F = 244.1 Hz, C2CHF2), 103.11 (dq, 'J _C -F = 232.2, ³ J _C . _F = 3.9 Hz, C4CH OCF3), 63.42 (s, CH2CH3), 13.90 (s, CH2CH3) ppm. IR v (cm ¹ ): 2991-2943 (C _sp3 H), 1727 (C=Oester). CisHuFgNOs (367): calcd (%) N 3.81, C 49.06, H 3.02, found N 3.74, C 49.23, H 3.18. MP: 43.3 - 44.8 °C.

6-Chloro-2,4-bis(difluoromethyl)quinoline-3-carboxylate (Ia-4)

(la^)

Under an argon atmosphere, a solution of TFEDMA was activated by adding BF3*Et20 (1.2 equiv., 0.628 mL, 4.96 mmol) in a solution of TFEDMA (1.2 equiv., 0.58 mL, 4.96 mmol) in dry MeCN (9 mL) and stirred for 15 min. Then a solution of ethyl-3-[(4-chlorophenyl)amino]-4,4-difluorobut-2-enoate (II. d) (1 equiv., 1.52 g, 4.13 mmol) in dry MeCN (9 mL) was slowly added to this mixture via syringe. After 15 min at room temperature, the mixture was heated at 50 °C for 19 h. Then concentrated sulphuric acid (H2SO4) (10 equiv., 18 M, 2.29 mL, 41.3 mmol) was added and the reaction mixture was heated at 50 °C for 4 h. Ice was added and the organic layer was extracted with AcOEt, washed with water and dried over Na2S04. The reaction mixture was purified by column chromatography, using a gradient of AcOEt in cyclohexane (0-5%) to provide the final compound (Ia-4) as a beige solid in 26% yield (358 mg). ¾ NMR (400 MHz, CDCI3) δ _Η = 8.39 (dd, ⁴ J _H -H = 3.7, ⁵ J _H -F = 1.8 Hz, 1H, C ₅ H), 8.17 (d, ³ JH-H = 9.0 Hz, 1H, C ₈ H), 7.83 (dd, ³ J _H -H = 9.0, ⁴ J _H -H = 2.2 Hz, 1H, C ₇ H), 7.12 (t, ² J _H -F = 52.0 Hz, 1H, C4CHF2), 6.91 (t, ² JH-F = 54.5 Hz, 1H, C2CHF2), 4.53 (q, ³ J _H -H = 7.2 Hz, 2H, OCH2CH3), 1.45 (t, ³ J _H -H = 7.2 Hz, 3H, OCH ₂ C%) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -109.66 (dd, ² J _F -H = 52.8, ⁵ J _F -H = 1.7 Hz, C4CHF2), -115.46 (d, ² JF-H = 54.5 Hz, C2CHF2) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 164.91 (s, CO), 148.53 (t, ² JC-F = 25.5 Hz, C ₂ ), 145.99 (s, C ₆ ), 137.61 - 135.84 (m, C4-C4CC5), 132.99 (s, C ₇ ), 132.22 (s, C ₈ ), 125.09 (t, ³ Jc-F = 6.7 Hz, C ₃ ), 124.63 (t, ⁴ J _C . _F = 4.2 Hz, C ₅ ), 124.18 (s, Cg N), 113.86 (t, ^] J _C -F = 245.4 Hz, C2CHF2), 112.69 (t, ^ = 241.5 Hz, C4CHF2), 63.53 (s, C¾CH ₃ ), 14.04 (s, CH ₂ C%) ppm. IR v (cm ¹ ): 2990-2941 (C _sp3 H), 1721 C14H10F4NCIO2 (335): calcd (%) N 4.17, C 50.09, H 3.00, found N 3.98, C 49.59, H 3.19. MP: 71.9 - 74.3 °C. Ethyl-4-(difluoromethyl)-2-(trifluoromethyl)quinoline-3-carb oxylate (Ia-5)

(la-5)

Under an argon atmosphere, a solution of TFEDMA was activated by adding BF3*Et20 (1.2 equiv., 0.191 mL, 1.51 mmol) in a solution of TFEDMA (1.2 equiv., 0.176 mL, 1.51 mmol) in dry MeCN (2.70 mL) and stirred for 15 min. Then a solution of ethyl-4,4,4-trifluoro-3-(phenylamino)but-2-enoate (Il.b) (1 equiv., 406 mg, 1.26 mmol) in dry MeCN (2.70 mL) was slowly added to this mixture via syringe. After 15 min at room temperature, the mixture was heated at 50 °C for 19 h. MeCN was removed under reduced pressure and the reaction mixture was purified by flash chromatography using a gradient of AcOEt in cyclohexane (0-5%) to provide the final compound (Ia-5) as colourless solid in 80%> yield (316 mg). ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 8.44 (dd, ³ J _H . _H = 8.6, ⁵ J _H -F =2.0 Hz, 1H, C ₅ H), 8.31 (dd, ³ J _H . H = 8.5, ⁶ JH-F = 0.6 Hz, 1H, C ₈ H), 7.95 (ddd, ³ J _H -m = 8.4, ³ J _H . _H4 = 6.9, ⁴ J _H -m = 1.3 Hz, 1H, C ₆ H), 7.83 (ddd, ³ J _H -H2 = 8.4, ³ J _H . _H3 = 6.9, ⁴ J _H -m = 1.3 Hz, 1H, C ₇ H), 7.13 (t, ² J _H -F = 52.8 Hz, 1H, C4CHF2), 4.52 (q, ³ JH-H = 7.2 Hz, 2H, OCH2CH3), 1.44 (t, ³ J _H . _H = 7.2 Hz, 3H, OCH2CH3) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -64.17 (s, C2CF3), -109.48 (dd, ² J _F -H = 52.7, ⁵ J _F -H = 2.0 Hz, C4CHF2) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 164.90 (s, CO), 147.30 (s, C4CC5), 143.72 (q, ² J _C -F = 35.0 Hz, C ₂ ), 137.33 (t, ² J _C -F = 23.5 Hz, C ₄ ), 132.19 (s, C ₆ ), 131.17 (s, C ₈ ), 130.75 (s, C ₇ ), 125.37 (t, ⁴ J _C . _F = 3.7 Hz, C ₅ ), 124.04 (s, Cg N), 123.97 (s, C ₃ ), 121.03 (q, ¹ J _C -F = 276.7 Hz, C2CF3), 112.86 (t, ^] J _C -F = 241.8 Hz, C4CHF2), 63.56 (s, CH2CH3), 13.99 (s, CH2CH3). IR v (cm ¹ ): 2987-2901 (C _sp3 H), 1731 (C ). C14H10F5NO2 (319): calcd (%) N 4.39, C 52.67, H 3.16, found N 4.39, C 52.80, H 3.27. MP: 79.8 - 80.8 °C.

Ethyl-4-[fluoro(trifluoromethoxy)methyl]-2-(trifluorometh yl)quinoline-3-carboxylate (Ia-6)

l,l,2-Trifluoro-2-(trifluoromethoxy)ethene (1 equiv., 0.4 mL, 3.62 mmol) was liquefied in a Schlenk apparatus under argon at -78 °C. Dimethylamine 2 M in THF (1 equiv., 2 M, 1.81 mL, 3.62 mmol) was added slowly via syringe at -78 °C. After 5 min, cold bath was replaced by water bath and the mixture was stirred for 15 min. BF3*Et20 (1 equiv., 0.46 mL, 3.62 mmol) was added via syringe and the reaction mixture was stirred for 30 min. The yield of the desire compound N-(l,2-difluoro-2- (trifluoromethoxy)ethylidene)-N-methylmethanaminium tetrafluoroborate (Ill.b) was estimated at 85% and directly submitted into the next step. Under an argon atmosphere, a solution of ethyl-4,4,4-trifluoro- 3-(phenylamino)but-2-enoate (Il.b) (1 equiv., 503 mg, 1.94 mmol) in dry MeCN (4.20 mL) was slowly added to a solution of N-(l,2-difluoro-2-(trifluoromethoxy)ethylidene)-N-methylmeth anaminium tetrafluoroborate (Ill.b) (1.57 equiv., 852 mg, 3.06 mmol) in dry MeCN (4.20 mL) via syringe. After 15 min at room temperature, the mixture was heated at 50 °C for 19 h. MeCN was removed under reduced pressure and the reaction mixture was purified by flash chromatography using a gradient of AcOEt in cyclohexane (0-20%>) to provide the final compound (Ia-6) as colourless solid in 74%> yield (551 mg). ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 8.45 (d, ³ J _H . _H = 8.6 Hz, 1H, C ₅ H), 8.31 (dd, ³ J _H . _H = 8.5, ⁶ J _H -F = 0.6 Hz, 1H, C ₈ H), 7.95 (ddd, ³ J _H .m = 8.4, ³ J„. _H4 = 6.9, ⁴ J _H -m = 1.3 Hz, 1H, C ₆ H), 7.84 (ddd, ³ J _H -m = 8.4, ³ J„. _H3 = 6.9, ⁴ JH-HI = 1.3 Hz, 1H, C ₇ H), 7.21 (d, ² J _H -F = 54.6 Hz, 1H, C4CH OCF3), 4.62 - 4.43 (m, 2Η, OCH2CH3), 1.43 (t, ³ JH-H = 7.2 Hz, 3H, OCH ₂ C%) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -59.40 (d, ⁴ JF-F = 4.8 Hz, C4CHFOC 3), -64.17 (s, C2CF3), -120.38 (dqd, ² J _F -H = 54.5, ⁴ J _F . _F = 4.9, ⁵ J _F -H = 2.1 Hz, C4CH OCF3) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 164.87 (s, CO), 147.43 (s, C4CC5), 143.76 (q, ² J _C - F = 35.2 Hz, C ₂ ), 136.59 (d, ² J _C -F = 24.4 Hz, C ₄ ), 132.27 (s, C ₆ ), 131.22 (s, C ₈ ), 130.79 (s, C ₇ ), 125.59 (d, ⁴ JC-F = 4.9 Hz, C ₅ ), 123.86 (s, Cg N), 123.80 (s, C ₃ ), 121.04 (qd, ^] J _C -F = 262.9, ³ J _C . _F = 1.6 Hz, C4CHFOC 3), 121.01 (q, ^] J _C -F = 276.7 Hz, C2CF3), 103.06 (dq, ^] J _C -F = 232.7, ³ J _C . _F = 3.9 Hz, C4CH OCF3), 63.69 (s, CH2CH3), 13.88 (s, CH2CH3) ppm. IR v (cm ¹ ): 2987-2901 (C _sp3 H), 1728 (C=Oester). C15H10F7NO3 (385): calcd (%) N 3.64, C 46.77, H 2.62, found N 3.58, C 47.10, H 2.71. MP: 57.8 - 59.5 °C.

Ethyl-4-(difluoromethyl)-2-methylquinoline-3-carboxylate (Ia-7)

(la-7)

Under an argon atmosphere, a solution of TFEDMA was activated by adding BF3*Et20 (1.2 equiv., 0.224 mL, 1.77 mmol) in a solution of TFEDMA (1.2 equiv., 0.207 mL, 1.77 mmol) in dry MeCN (3.20 mL) and stirred for 15 min. Then a solution of ethyl-3-(phenylamino)but-2-enoate (II. c) (1 equiv., 0.466 g, 1.47 mmol) in dry MeCN (3.20 mL) was slowly added to this mixture via syringe. After 15 min at room temperature, the mixture was heated at 50 °C for 19 h. Then concentrated H2SO4 (20 equiv., 18 M, 1.64 mL, 29.5 mmol) was added and the reaction mixture was heated at 50 °C overnight. Ice was added and the organic layer was extracted with AcOEt, washed with water and dried over Na2SO i. The reaction mixture was purified by column chromatography, using a gradient of AcOEt in cyclohexane (0- 100%). Traces of desire compound (Ia-7) were obtained as a clear yellow oil. ¾ NMR (500 MHz, CDCI3) δ _Η = 8.25 (dd, ³ JH-H = S.5, ⁵ J _H -F =\ .6 HZ, lH, C ₅ H), 8.09 (d, ³ J _H -H = SA HZ, lH, C ₈ H), 7.79 (ddd, ³ JH-H2 = 8.4, ³ JH-H4 = 6.9, JH-HI = 1.3 Hz, 1H, C ₇ H), 7.63 (ddd, ³ J _H -m = 8.3, ³ J _H -m = 6.9, ⁴ J _H -m = 1.2 Hz, 1H, C ₆ H), 7.10 (t, ² JH-F = 53.3 Hz, 1H, C4CHF2), 4.51 (q, ³ J _H -H = 7.2 Hz, 2H, OCH2CH3), 2.77 (s, 3H, CH ₃ ), 1.45 (t, ³ JH-H = 7.2 Hz, 3H, OCH ₂ C%) ppm. ¹⁹ F NMR (376 MHz, CDCI3) 8F = -110.31 (dd, ² J _F -H = 53.2, ^S J _F .H = 1.9 Hz, C4CHF2) ppm. ¹³ C NMR (126 MHz, CDCI3) be = 167.51 (s, CO), 154.78 (s, C ₂ ), 148.29 (s, C4CC5), 134.78 (t, ² J _C -F = 22.6 Hz, C ₄ ), 130.97 (s, C ₇ ), 129.72 (s, C ₈ ), 127.73 (s, C ₆ ), 126.54 (t, ³ JC-F = 6.0 Hz, C ₃ ), 124.79 (t, ⁴ J _C . _F = 2.9 Hz, C ₅ ), 121.72 (s, Cg N), 113.38 (t, ^] J _C -F = 241.2 Hz, C4CHF2), 62.67 (s, CH2CH3), 23.83 (s, C2CH3), 14.26 (s, CH2CH3) ppm. IR v (cm ¹ ): 2986-2929 (Csp ₃ H), 1726 (C=Oester). C14H13F2NO2 (265): calcd (%) N 5.28, C 63.39, H 4.94, found N 4.89, C 63.62, H 5.21.

Ethyl-4-[fluoro(trifluoromethoxy)methyl]-2-methylquinolin e-3-carboxylate (Ia-8)

(la-8) l,l,2-Trifluoro-2-(trifluoromethoxy)ethene (1 equiv., 0.8 mL, 7.23 mmol) was liquefied in a Schlenk apparatus under argon at -78 °C. Dimethylamine 2 M in THF (1 equiv., 2 M, 3.62 mL, 7.24 mmol) was added slowly via syringe at -78 °C. After 5 min, cold bath was replaced by water bath and the mixture was stirred for 15 min. BF3*Et20 (1 equiv., 0.92 mL, 7.26 mmol) was added via syringe and the reaction mixture was stirred for 30 min. The yield of the desire compound N-(l,2-difluoro-2- (trifluoromethoxy)ethylidene)-N-methylmethanaminium tetrafluoroborate (Ill.b) was estimated at 85%> and directly submitted into the next step. Under an argon atmosphere, a solution of ethyl-3- (phenylamino)but-2-enoate (II. c) (1 equiv., 1.21 g, 3.82 mmol) in dry MeCN (8.30 mL) was slowly added to a solution of N-(l,2-difluoro-2-(trifluoromethoxy)ethylidene)-N-methylmeth anaminium tetrafluoroborate (Ill.b) (1.59 equiv., 1.7 g, 6.1 mmol) in dry MeCN (8.30 mL) via syringe. After 15 min at room temperature, the mixture was heated at 50 °C for 19 h. Then concentrated H2SO4 (10 equiv., 18 M, 2.12 mL, 38.2 mmol) was added and the reaction mixture was heated at 50 °C for 4 h. Ice was added and the organic layer was extracted with AcOEt, washed with water and dried over Na2SO i. The reaction mixture was purified by column chromatography, using a gradient of AcOEt in cyclohexane (0- 20%) to provide the final compound (Ia-8) as a light yellow oil in 27% yield (346 mg). ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 8.25 (d, ³ J _H . _H = 8.6 Hz, ⁵ J _H -F = 1.5, 1H, C ₅ H), 8.09 (dd, ³ J _H . _H = 8.5, ⁶ J _H -F = 0.6 Hz, 1H, C ₈ H), 7.79 (ddd, ³ J _H -m = 8.4, ³ J„. _H4 = 6.9, ⁴ J _H -m = 1.3 Hz, 1H, C ₇ H), 7.63 (ddd, ³ J _H .m = 8.4, ³ J„. _H3 = 6.9, ⁴ J _H -H2 = 1.3 Hz, 1H, C ₆ H), 7.16 (d, ² J _H -F = 55.1 Hz, 1H, C4CH OCF3), 4.58 - 4.44 (m, 2Η, OCH2CH3), 2.77 (s, 3H, C2CH3), 1.44 (t, ³ J _H . _H = 7.2 Hz, 3H, OCH ₂ C%) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -59.28 (d, ⁴ JF-F = 5.2 Hz, C4CHFOC 3), -121.02 (dqd, ² J _F -H = 55.1, ⁴ J _F . _F = 5.0, ⁵ J _F -H = 1.9 Hz, C4CH OCF3) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 167.32 (s, CO), 154.81 (s, C ₂ ), 148.41 (s, C4CC5), 134.01 (d, ² JC-F = 23.4 Hz, C ₄ ), 131.04 (s, C ₇ ), 129.79 (s, C ₈ ), 127.77 (s, C ₆ ), 126.45 (d, ³ J _C . _F = 5.7 Hz, C ₃ ), 124.90 (d, ⁴ J _C . _F = 3.9 Hz, C ₅ ), 121.52 (s, Cg N), 121.11 (qd, ^] J _C -F = 262.2, ³ J _C . _F = 1.7 Hz, C4CHFOC 3), 103.55 (dq, ^] J _C -F =232.2, ³ J _C . _F = 3.9 Hz, C4CH OCF3), 62.76 (s, CH2CH3), 23.96 (s, C2CH3), 14.12 (s, CH2CH3) ppm. IR v (cm ¹ ): 2987 (C _sp3 H), 1727 HRMS (ESI positive) for C15H14F4NO3 [M ⁺ ]: calcd 332.0904, found 332.0898.

Step b: Saponiflcation reaction

2,4-Bis(difluoromethyl)quinoline-3-carboxylic acid (Ib-1)

(lb-1)

To a stirred solution of potassium hydroxide (KOH) (8 equiv., 10.6 g, 189 mmol) in 60%> ethanol aqueous solution (187 ml) was added the ethyl-2,4-bis(difluoromethyl)quinoline-3-carboxylate (Ia-1) (1 equiv., 7.14 g, 23.7 mmol). The yellow reaction mixture was stirred under reflux for 2 h. The mixture was quenched with concentrated hydrochloric acid (HQ) until pH 1. EtOH was removed under vacuum and organics compounds were extracted with AcOEt, washed with water, dried over Na2S04, and concentrated under reduced pressure. The desired compound (Ib-1) was obtained as colourless solid in 99% yield (6.44 g). ¾ NMR (400 MHz, DMSO) δ _Η = 8.39 (d, ³ J _H . _H = 7.7 Hz, 1H, C ₅ H), 8.27 (d, ³ J _H -H = 7.8 Hz, 1H, C ₈ H), 8.07 - 7.99 (m, 1H, C ₆ H), 7.97 - 7.88 (m, 1H, C ₇ H), 7.70 (t, ² J _H -F = 52.1 Hz, 1H, C4CHF2), 7.27 (t, ² JH-F = 53.7 Hz, 1H, C2CHF2) ppm. ¹⁹ F NMR (376 MHz, DMSO) δ _Ρ = -106.25 (dd, ² JF-H = 52.0, ⁵ JF-H = 1.7 Hz, C4CHF2), -110.60 (d, ² J _F -H = 53.7 Hz, C2CHF2) ppm. ¹³ C NMR (101 MHz, DMSO) δα = 166.11 (s, CO), 147.73 (t, ² J _C -F = 24.2 Hz, C ₂ ), 146.40 (s, C4CC5), 135.53 (t, ² J _C -F = 22.7 Hz, C ₄ ), 132.02 (s, C ₆ ), 130.33 (s, C ₇ ), 130.20 (s, C ₈ ), 125.21 (t, ³ J _C . _F = 6.1 Hz, C ₃ ), 124.74 (s, C ₅ ), 123.07 (s, CgCN), 1 13.02 (t, 'J _C -F = 241.7 Hz, C ₂ CHF ₂ ), 1 12.87 (t, 'J _C -F = 240.4 Hz, C ₄ CHF ₂ ) ppm. IR v (cm ¹ ): 3418 (OH), 1696 C12H7F4NO2 (273): calcd (%) N 5.13, C 52.76, H 2.58, found N 5.03, C 52.80, H 2.75. MP: 183.1 - 184 °C.

2-(Difluoromethyl)-4-[fluoro(trifluoromethoxy)methyl]quin oline-3-carboxylic acid (Ib-3)

(Ib-3)

To a stirred solution of KOH (8 equiv., 305 mg, 5.45 mmol) in 60% ethanol aqueous solution (5.40 ml) was added the ethyl-2-(difluoromethyl)-4-[fluoro(trifluoromethoxy)methyl]q uinoline-3-carboxylate (Ia- 3) (1 equiv., 250 mg, 0.681 mmol). The yellow reaction mixture was stirred under reflux for 4 h. The mixture was quenched with concentrated HCl until pH 1. EtOH was removed under vacuum and organics compounds were extracted with AcOEt, washed with water, dried over Na2SO i, and concentrated under reduced pressure. The desired compound (Ib-3) was obtained as a light beige solid in

86% yield (197 mg). ¾ NMR (400 MHz, DMSO) δ _Η = 8.38 (d, J _H -H = 8.5 Hz, 1 H, C ₅ H), 8.28 (d, J _H -H = 8.4 Hz, 1H, CgH), 8.04 (t, ³ J _H . _H = 7.7 Hz, 1 H, C ₆ H), 7.96 (t, ³ J _H . _H = 7.5 Hz, 1 H, C ₇ H), 7.88 (d, ² J _H -F = 54.0 Hz, 1H, C4CH OCF3), 7.30 (t, ² J _H -F = 53.7 Hz, 1H, C2CHF2) ppm. ¹⁹ F NMR (376 MHz, DMSO) δ _Ρ = -57.85 (d, ⁴ JF-F = 4.8 Hz, C4CHFOC 3), -1 14.57 - -1 16.64 (m, A ₂ B ₂ , Δν = 459.45 Hz, C2CHF2), - 122.18 - -122.61 (m, C4CH OCF3) ppm. ¹³ C NMR (101 MHz, DMSO) 8 _C = 166.04 (s, CO), 147.96 (t, ² JC-F = 23.8 Hz, C ₂ ), 146.51 (s, CgCN), 134.67 (d, ² J _C -F = 23.3 Hz, C ₄ ), 132.12 (s, C ₇ ), 130.43 (s, C ₆ ), 130.34 (s, Cg), 125.59 - 125.22 (m, C ₃ ), 124.71 (d, ⁴ J _C . _F = 3.9 Hz, C ₅ ), 122.86 (s, C4CC5), 120.55 (qd, ^] JC-F = 261.6, ³ JC-F = 1.2 Hz, C4CHFOC 3), 1 12.80 (t, ^] J _C -F = 241.5 Hz, C2CHF2), 103.06 (dq, ^] J _C -F = 230.2, ³ JC-F = 3.8 Hz, C4CH OCF3) ppm. IR v (cm ¹ ): 2920 (C _sp3 H), 1714 CoHvFeNOs (339): calcd (%) N 4.13, C 46.03, H 2.08, found N 4.02, C 46.87, H 2.39. MP: 183.3 - 185.5 °C. 6-Chloro-2,4-bis(difluoromethyl)quinoline-3-carboxylic acid (Ib-4)

(lb-4)

To a stirred solution of KOH (8 equiv., 0.585 g, 10.4 mmol) in 60% ethanol aqueous solution (10.30 ml) was the added 6-chloro-2,4-bis(difluoromethyl)quinoline-3-carboxylate (Ia-4) (1 equiv., 0.583 g, 1.3 mmol). The yellow reaction mixture was stirred under reflux for 4 h. The mixture was quenched with concentrated HCl until pH 1. A precipitate was formed. It was filtrated off, washed with water and dried under reduced pressure to provide the desire compound (Ib-4) as a light beige solid in 41% yield (531 mg). ¾ NMR (400 MHz, Acetone ^d6 ) δ _Η = 8.45 (dd, ⁴ J _H -H = 3.7, ⁵ J _H -F = 1.8 Hz, 1H, C ₅ H), 8.30 (d, ³ J _H . _H = 9.0 Hz, 1H, C ₈ H), 8.04 (dd, ³ J _H . _H = 9.0, ⁴ J _H -H = 2.2 Hz, 1H, C ₇ H), 7.63 (t, ² J _H -F = 52.3 Hz, 1H, C4CHF2), 7.20 (t, ² JH-F = 54.1 Hz, 1H, C2CHF2) ppm. ¹⁹ F NMR (376 MHz, Acetone ^d6 ) δ _Ρ = -111.47 (d, ² JF-H = 52.2 Hz, C4CHF2), -116.87 (d, ² J _F -H = 54.1 Hz, C2CHF2) ppm. ¹³ C NMR (101 MHz, Acetone ^d6 ) 8c = 166.01 (s, CO), 149.66 (t, ² J _C -F = 24.7 Hz, C ₂ ), 146.77 (s, C ₆ ), 136.89 (t, ² J _C -F = 23.4 Hz, C ₄ ), 136.61 (s, C4CC5), 133.57 (s, C ₇ ), 133.43 (s, C ₈ ), 126.53 (t, ³ J _C . _F = 6A Hz, C ₃ ), 125.03 (s, C ₈ N), 124.94 (t, ⁴ JC-F = 3.7 Hz, C ₅ ), 1 14.20 (t, 'J _C -F = 242.1 Hz, C2CHF2), 1 14.05 (t, 'J _C -F = 240.4 Hz, C4CHF2) ppm. IR v (cm ¹ ): 2918 (C _sp3 H), 1725-1706 C12H6F4NCIO2 (307): calcd (%) N 4.55, C 46.85, H 1.97, found N 4.43, C 47.22, H 2.27. MP: 236.2 - 237.2 °C.

Step c: The Curtius reaction

Carbamate synthesis: i-butyl-A^^^-bisidifluoromethylJquinolin-S-yl] carbamate (Ic-1)

(lc-1)

To a solution of 2,4-bis(difluoromethyl)quinoline-3-carboxylic acid (Ib-1) (1 equiv., 802 mg, 2.56 mmol) in i-butyl alcohol (10 mL) was added NEt3 (1.6 equiv., 0.552 mL, 4.09 mmol) and diphenylphosphoryl azide (DPPA) (1.3 equiv., 0.718 mL, 3.32 mmol). The reactor was not totally sealed in order to let the gas moving and the mixture was stirred at 100 °C overnight. The reaction mixture was cooled down and diluted with water. Organic layer was extracted with AcOEt, washed with NaHC03 followed by brine, dried over Na2S04 and concentrated under vacuum. Compound was purified by flash chromatography using a gradient of AcOEt in cyclohexane (0-20%). The i-butyl-N-[2,4- bis(difluoromethyl)quinolin-3-yl] carbamate (Ic-1) was obtained as a beige solid in 64% yield (0.567 g). ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 8.47 (d, ³ J _H . _H = 7.9 Hz, 1H, C ₅ H), 8.16 (d, ³ J _H . _H = 8.5 Hz, 1H, C ₈ H), 7.82 (t, ³ JH-H = 7.4 Hz, 1H, C ₇ H), 7.73 (t, ³ J _H . _H = 7.5 Hz, 1H, C ₆ H), 7.21 (t, ² J _H -F = 53.7 Hz, 1H, C4CHF2), 6.85 (t, ² JH-F = 54.2 Hz, 1H, C2CHF2), 6.65 (s, 1H, NH), 1.69 - 1.20 (m, 9H, f-Bu) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -112.09 (s, C4CHF2), -113.57 (d, ² J _F -H = 52.5 Hz, C2CHF2) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 154.31 (s, CO), 149.51 - 146.66 (m, C ₂ ), 146.01 (s, C4CC5), 137.39 - 134.67 (m, C ₄ ), 130.46 (s, C _{7; 8} ), 129.61 (s, C ₆ ), 127.05 (s, CgCN), 125.59 (t, ⁴ J _C -F = .9 Hz, C ₅ ), 125.13 (s, C ₃ ), 116.89 (t, 'Jc-F = 240.1 Hz, C2CHF2), 112.55 (t, 'J _C -F = 238.5 Hz, C4CHF2), 82.57 (s, COOC(CH ₃ ) ₃ ), 28.14 (s, ί-Bu) ppm. IR v (cm ¹ ): 3675 (NH), 2978-2901 (C _sp3 H), 1704 C16H16F4N2O2 (344): calcd (%) N 8.14, C 55.81, H 4.68, found N 8.01, C 56.22, H 4.79. MP: 135.6 - 136.5 °C.

Step d : Deprotection reaction

2,4-Bis(difluoromethyl)quinolin-3-amine (Id-1)

(ld-1) i-Butyl-N-[2,4-bis(difluoromethyl)quinolin-3-yl] carbamate (Ic-1) (1 equiv., 566 mg, 1.32 mmol) was dissolved in dichloroethane (DCE) (4.53 mL) and treated with trifluoroacetic acid (TFA) (20.9 equiv., 2.04 mL, 27.5 mmol). After 4 hr at room temperature, the mixture was quenched with water and a solution of NaHC03 until neutral pH. Organic layer was extracted with DCM, washed with water, dried over Na2S04 and concentrated under reduced pressure. The 2,4-bis(difluoromethyl)quinolin-3-amine (Id-1) was obtained as a yellow solid in 98% yield (315 mg). ¾ NMR (400 MHz, CDCI3) δ _Η = 8.00 (dd, ³ JH-H = 8.3, ⁴ J _H -H = 1.1 HZ, lH, C ₅ H), 7.83 (d, ³ J _H -H = 8.6 Hz, 1H, C ₈ H), 7.62 - 7.57 (m, 1H, C ₆ H), 7.51 (ddd, ³ J _H -H2 = 8.2, ³ J _H . _H3 = 6.9, ⁴ J _H -m = 1.3 Hz, 1H, C ₇ H), 7.43 (t, ² J _H -F = 53.7 Hz, 1H, C4CHF2), 6.84 (t, ² JH-F = 54.2 Hz, 1H, C2CHF2), 5.08 (s, 2H, NH ₂ ) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -116.50 (d, ² J _F . H = 56.4 Hz, C4CHF2), -116.63 (d, ² J _F -H = 52.6 Hz, C2CHF2) ppm. ¹³ C NMR (101 MHz, CDCI3) δα = 141.95 (t, ² JC-F = 26.1 Hz, C ₂ ), 140.35 (s, CgCN), 137.10 (s, C ₃ ), 130.85 (s, C ₅ ), 129.93 (s, C ₆ ), 126.92 (t, ³ Jc-F = 4.9 Hz, C4CC5), 126.21 (s, C ₇ ), 119.97 (s, C ₈ ), 118.65 (t, ^] J _C -F = 239.4 Hz, C2CHF2), 114.58 (t, ² Jc-F = 20.4 Hz, C ₄ ), 113.90 (t, 'J _C -F = 234.9 Hz, C4CHF2) ppm. IR v (cm ¹ ): 3533-3238 (NH + C _sp2 H), 1635-1591 (C=C). CiiH ₈ F ₄ N2 (244): calcd (%) N 11.37, C 54.11, H 3.30, found N 11.34, C 54.19, H 3.39. MP: 68.3 - 70.3 °C.

Step e: The Sandmeyer reaction 2,4-Bis(difluoromethyl)quinoline-3-carbonitrile (Ie-1)

(le-1)

In a solution of 2,4-bis(difluoromethyl)quinolin-3-amine (Id-1) (1 equiv., 247 mg, 1.01 mmol) in dry MeCN (5 mL), was added under argon, copper(I) cyanide (Cu(I)CN) (1 equiv., 90.6 mg, 1.01 mmol). The yellow suspension was stirred for 10 min and i-butyl nitrite (i-BuONO) (4 equiv., 0.485 mL, 4.05 mmol) was added. The brown mixture was stirred for 20 min at room temperature. Then the flask was fitted with a reflux condenser and heated at 60 °C for 4 h. After cooling to room temperature, the mixture was diluted with saturated aqueous NaHC03 and extracted with AcOEt. Organic layer was washed with water and brine, dried over Na2S04 and concentrated under reduced pressure. The reaction mixture was purified on flash chromatography using a gradient of AcOEt in cyclohexane (0-5%) to provide the final compound (le-1) as colourless solid in 47% yield (121 mg). ¾ NMR (400 MHz, CDC1 ₃ ) δ _Η = 8.51 (dd, ³ JH-H = S.6, ⁵ J _H -F = 1.7 Hz, 1H, C ₅ H), 8.30 (d, ³ J _H -H = SA HZ, lH, C ₈ H), 8.04 (ddd, ³ JH-H2 = 8.4, ³ JH-H4 = 7.0, ⁴ JH-HI = 1.3 Hz, 1H, C ₇ H), 7.89 (ddd, ³ J _H -m = 8.4, ³ J„. _H3 = 7.0, ⁴ J _H -m = 1.2 Hz, 1H, C ₆ H), 7.47 (t, ² JH-F = 52.4 Hz, 1H, C4CHF2), 6.93 (t, ² J _H -F = 53.6 Hz, 1H, C2CHF2) ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ _Ρ = -109.07 (dd, ² J _F -H = 52.4, ⁵ J _F -H = 2.0 Hz, C4CHF2), -113.13 (d, ² J _F -H = 53.7 Hz, C2CHF2) ppm. ¹³ C NMR (101 MHz, CDCI3) be = 150.64 (t, ² J _C -F = 26.9 Hz, C ₂ ), 148.16 (s, Cg N), 144.60 (t, ² JC-F = 24.6 Hz, C ₄ ), 134.07 (s, C ₇ ), 131.14 and (2 * s, C ₆ , s), 125.70 (t, ⁴ J _C . _F = 3.8 Hz, C ₅ ), 123.07 (s, C4CC5), 114.09 (t, ^] J _C -F = 243 A Hz, C2CHF2), 113.23 (t, ^] J _C -F = 242 J Hz, C4CHF2), 112.20 (s, C ₃ CN), 102.62 (t, ³ JC-F = 6.6 Hz, C ₃ ) ppm. IR v (cm ¹ ): 2988-2901 (C _sp3 H), 2234 (CN). C12H6F4N2 (254): calcd (%) N 11.02, C 56.70, H 2.38, found N 10.96, C 56.28, H 2.43. MP: 130.6 - 132.3 °C.