Effects of fluorine bonding and nonbonding interactions on ¹⁹F chemical shifts

Abstract

¹⁹F-NMR signals are sensitive to local electrostatic fields and are useful in probing protein structures and dynamics. Here, we used chemically identical ortho-F nuclei in N-phenyl γ-lactams to investigate the relationship between ¹⁹F NMR chemical shifts and local environments. By varying the structures at the C5- and C7-substituents, we demonstrated that ¹⁹F shifts and Hammett coefficients in Hammett plots follow typical relationships in bonding interactions, while manifesting reverse correlations in nonbonding contacts. Quantum mechanics calculations revealed that one of the ortho-F nuclei engages in n → π* orbital delocalization between F lone pair electrons (n) and a C=O/Ar=N antibonding orbital (π*), and the other ortho-F nucleus exhibits n ↔ σ orbital polarization between the n electrons and the C–H σ bonding orbital. As ¹⁹F NMR spectroscopy find increasing use in molecular sensors and biological sciences, our findings are valuable for designing sensitive probes, elucidating molecular structures, and quantifying analytes.

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1. Introduction

Fluorine is a particularly important element in the broader space of chemical biology. Many FDA approved drugs and commercial compounds such as pesticides and refrigerants are fluorinated.¹ There is a high degree of interaction between fluorine and biomolecules, which plays an important role in the functioning of fluorinated molecules.² Owing to the lack of naturally-occurring fluorinated organic molecules, fluorine is also a unique probe to investigate the structures and functions of biological molecules,³ and a feasible sensor to detect analytes of biological, medicinal, and environmental importance.⁴ Central to these studies is ¹⁹F NMR spectroscopy, which allows users to readily visualize ¹⁹F chemical shifts and splitting patterns depending on the fluorine local chemical environments.

The ¹⁹F isotope is 100% naturally abundant and shows a large NMR chemical shift range (∼300 ppm). The high resolution, coupled with high detection sensitivity and absence of background signals, affords well-resolved ¹⁹F resonances. To date, ¹⁹F NMR spectroscopy has been extensively applied in diverse biological, pharmaceutical, and material researches as evidenced by new reporter molecules and detection strategies.^3,4 Zhao and Swager,⁵ as well as our own work,⁶ showed that ¹⁹F signals are sensitive to chiral environments even though the stereogenic centers are several carbons away from the fluorine. Recently, Prof. Huang and Zhao confirmed that substituents adjacent and distal to F are both important to the resolving ability of ¹⁹F-labeled sensors.⁷ In fact, the rich information obtained from ¹⁹F NMR spectroscopy also allows us to monitor molecular interaction and dynamics. Related studies based on fluorinated ligands and/or fluorinated proteins have found their broad utilities in molecular recognition, protein/nucleic acid characterization,³ and fragment-based drug discovery.⁸ However, interpreting ¹⁹F NMR data from biomolecular mixtures can be challenging and is often complicated by the lack of knowledge in ¹⁹F chemical shift assignments, among others.

In order to better use of fluorinated molecules in biochemical applications, a comprehensive understanding of correlations between ¹⁹F chemical shift and the environment/structure is essential. It is well-recognized that ¹⁹F shielding is not only determined by magnetic anisotropies associated with the covalent bond system and with the circulation of π-electrons in aromatic rings, but also greatly influenced by van der Waals interactions, hydrogen bonding, and electric fields.⁹ Noncovalent interactions such as multipolar contacts in C–F⋯C=O and C–F⋯C=N pairs,¹⁰ hydrogen-bonding in C–F⋯H–N, C–F⋯H–O, and C–F⋯H–C pairs,¹¹ and interactions found in C–F⋯S^12a and C–F⋯π pairs,^12b have been reported. Sporadic data disclosed in literature suggest that C–F⋯H–X interactions shield ¹⁹F signals.¹³ Prof. Lectka confirmed that ¹⁹F signals in “jousting” C–F⋯H–C interactions display remarkable downfield shifts, likely due to dominating repulsive forces between C–F⋯H–C.¹⁴ Yet, the effects of C=O/C=N groups on ¹⁹F chemical shifts are not reported in the public domain, and a full understanding of relations between ¹⁹F chemical shifts and chemical environments remains elusive.

We have employed a slow rotating (on ¹⁹F NMR time scale), di-ortho-F substituted N-phenyl γ-lactam scaffold to study through-space contacts of F with remote functional groups such as stereogenic C9-amides and C9-esters, as shown in Fig. 1.¹⁵ Compounds are generally used as enantiomeric mixtures, as the individual enantiomer behaves the same spectroscopically. Assuming γ-lactam ring as a flat ring, we define the ortho-F nucleus siting on the same side of C9-substituents as syn-F, and the other ortho-F as anti-F (atom number assigned according to crystal structures, vide infra). By varying the p-substituent on C9-phenylamide, we showed that downfield ¹⁹F shifts δ_down display “reverse” a linear relationship with Hammett constants σ_para of the p-substituents. There are only small changes at the upfield ¹⁹F shifts δ_up in various C9-amide derivatives. We therefore assigned the downfield ¹⁹F signal to syn-F, and the upfield ¹⁹F peak to anti-F.¹⁶ In this report, we examined correlations of ¹⁹F chemical shifts with different C7- and C5-groups in γ-lactam-derived structures. We also carried out quantum calculations to investigate fluorine through-space contacts with the adjacent functional groups. Effects of through-bond and through-space interactions on ¹⁹F chemical shifts, as well as the through-space orbital delocalization are discussed.

Fig. 1 Assignments of syn-F and anti-F nuclei on N-phenyl group. The atom numbers are assigned according to crystal structures.

2. Results and discussion

In di-ortho-F substituted N-phenyl γ-lactam derivatives, structural modifications of γ-lactam ring initiate unequal perturbations on ortho-F nuclei regarding to their through-space interactions, but afford the same through-bond effects on syn-F and anti-F. Thus, converting C7-amide to C7-thioamide or C7-amidine moiety on the γ-lactam ring alters chemical environments around syn-F and anti-F differently, as exemplified in thioamides 2a–f and amidines 4a–q. Installing a substituent at C5 on N-phenyl group, as in compounds 6a–w, produces the same bonding and nonbonding effects on both ortho-F nuclei. Fig. 2 shows the chemical structures of compounds 1–6, where structures of 1a–f, 3a–e and 5a–i are used as references to the corresponding C9-esters/amides.

Fig. 2 Structures of compounds 1–6.

2.1. Synthetic schemes

Illustrative synthetic schemes for compounds 2–6 are provided in Fig. 3–5. Compounds 2a and 2b were converted from 1a and 1b, respectively, with Lawesson's reagent under mild conditions.¹⁷ For C7-phenylamidine derivatives 3 and 4, two synthetic routes were employed. The initial procedure requires the presence of POCl₃ in CH₂Cl₂ solution under refluxing conditions.¹⁸ This one-pot reaction was used to generate compounds 3a–e and 4a–e. A more versatile and productive approach was later developed using thioamide 2b as the starting material.¹⁹ As shown in Fig. 3, thioamide 2b was treated with mCPBA at 0 °C, followed by the addition of para-substituted phenylamines to give the desired amidines 4f–q. This process is compatible with basic para-substituents such as dimethylamine (NMe₂) and generally provides better yields than the POCl₃ route.

Fig. 3 Syntheses of compounds 2–4.

C5-substituted N-phenyl γ-lactams 6a–e, 6i–o and 6u were obtained through the synthetic routes as described previously, starting from appropriate 5-substituted anilines.¹⁵ The syntheses of 5f and 6f were attained by reducing the NO₂ group in 5e or 6e. Reductive aminations of 5f and 6f with NaBH₄ resulted in a mixture of anilines, which was separated by a column chromatography to give 5g/5h and 6g/6h. Acylation of 6f with different acylating agents (formal or acetic acid) afforded 6v and 6w in excellent yields, as illustrated in Fig. 4.

Fig. 4 Syntheses of compounds 5–6.

Fig. 5 shows the syntheses of 6p–t from 4-iodo 6l through Pd-catalyzed coupling reactions. Stille coupling was used to obtain 6p and 6q,²⁰ while Suzuki–Miyaura coupling afforded 6r. Formylation of aryl halides from 6l using t-butyl isocyanide as a C1 source and formate salts as a hydride donor provided 6s.²¹ Similarly, vinylation of 6l with a vinyl ether followed by hydrolysis furnished ketone 6t.²²

Fig. 5 Syntheses of compounds 6p–q from 6f and 6l. ^a dppe: 1,2-bis(diphenylphosphino)ethane; dppp: 1,3-bis(di-phenylphosphino)propane; dppf: 1,1′-bis(diphnylphosphino)-ferrocene.

2.2. C7-substituent effects on ortho-¹⁹F chemical shifts

We surveyed ¹⁹F shift changes when the γ-lactam C=O group was converted into C=S and C=NPh groups. All ¹⁹F NMR spectra were recorded in CDCl₃ solution at 25 °C. Compound concentrations were ∼10 mg mL⁻¹ and CFCl₃ was used as an internal standard. As shown in Tables 1 and 2, ¹⁹F NMR signals become deshielded from −117.82 to −117.49 and −117.05 ppm, respectively, from compounds 1a to 2a and 3a, likely due to their different electron-withdrawing abilities and polarizabilities. In chiral C9-ester series, thioamide 2b and amidine 4a display larger shift differences Δδ (1.16 and 1.09 ppm) between syn-F and anti-F signals than γ-lactam 1b (Δδ = 0.79 ppm). Therefore, the chemical environment differences between syn-F or anti-F nuclei increase from γ-lactam to thioamide and amidine counterparts.

Table 1 ¹⁹F NMR chemical shifts and calculated parameters for thioamide and amidine derivatives

R^1		δdown	δup	Δδ		δdown	δup	Δδ
H	1a	−117.82	−117.82	0	2a	−117.49	−117.49	0
CO2Me	1b	−117.14	−117.93	0.79	2b	−116.53	−117.69	1.16
CONH2	1c	−116.81	−118.15	1.34	2c	−116.21	−117.94	1.73
CONHMe	1d	−116.66	−118.21	1.55	2d	−116.10	−118.07	1.98
CONMe2	1e	−116.25	−118.23	1.98	2e	−115.59	−118.16	2.56

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Table 2 ¹⁹F NMR chemical shifts δ_down and δ_up, shift differences Δδ for amidines 3a–e and 4a–r (in ppm)^a

Cpd	R	δ^amidinedown	δ^amidineup	Δδ^amidine	σpara
a Δδ^amidine = δ^amidinedown − δ^amidineup; σpara is Hammett constants for para-substituents.
3a	H	−117.05	—	0	0
3b	Me	−117.06	—	0	−0.17
3c	OMe	−117.07	—	0	−0.27
3d	CF3	−117.18	—	0	0.54
3e	NO2	−117.30	—	0	0.78
4a	H	−116.31	−117.41	1.09	0
4b	Me	−116.26	−117.41	1.15	−0.17
4c	OMe	−116.31	−117.42	1.11	−0.27
4d	CF3	−116.49	−117.47	0.98	0.54
4e	NO2	−116.65	−117.48	0.83	0.78
4f	NMe2	−116.17	−117.37	1.20	−0.83
4g	OEt	−116.33	−117.42	1.09	−0.24
4h	F	−116.46	−117.47	1.01	0.06
4i	Cl	−116.46	−117.46	1.00	0.23
4j	Br	−116.46	−117.46	1.00	0.23
4k	I	−116.44	−117.44	1.00	0.18
4l	CN	−116.61	−117.48	0.87	0.66
4m	CHO	−116.53	−117.45	0.92	0.42
4n	COMe	−116.47	−117.42	0.94	0.5
4o	CO2Me	−116.49	−117.46	0.97	0.45
4p	CONMe2	−116.40	−117.42	1.01	—
4q	NHCOMe	−116.34	−117.40	1.06	0
4r	CH2=CH2	−116.33	−117.41	1.08	−0.02

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In both γ-lactam and thioamide derivatives (i.e., 1b–e and 2b–e), ¹⁹F shift differences Δδ increase when the C9-substituent changes from CO₂Me to CONH₂, CONHMe and CONMe₂ groups. Obviously, C9-substituents modulate ortho-F shielding in addition to C7-functional groups. The combination of the most polarizable groups at both C7- and C9-sites, i.e., C7–C=S and C9–CONMe₂, results in compound 2e displaying the largest chemical shift difference Δδ at 2.56 ppm. This result may be applicable to the design of molecular sensors, in which the purposely formed polarizable groups will expand ¹⁹F shift changes.

The C7-thioamide and the phenyl group in C7-amidines bring different electronic and steric influences on the pyrrolidine ring as compared to C7–C=O group. The subtle conformational differences among these compounds are manifested in the crystal structures of 2a, 3a and 5a, which we determined by X-ray crystallography. As revealed in Fig. S1,† the pyrrolidine ring in 2a and 3a displays similar puckered conformations with C9 extruding out of the plane, in contrast to near flat γ-lactam ring in 5a.¹⁵ The torsion angles for 2a, 3a and 5a are 81.56°, 65.31° and 62.63°, respectively, correlating to the increasing bulkiness of thioamide, amidine and amide groups. Meanwhile, the two phenyl groups in 3a adopts trans-configuration. Hence, the effects of various para-substituted phenylamidines on ¹⁹F chemical shifts are mostly instigated by electrostatic rather than steric effects. To evaluate the influences of C7-amidines on ¹⁹F shielding, we prepared compounds 3b–e and 4b–q. Table 2 compiles their ¹⁹F chemical shifts and shift differences Δδ between the syn-F and anti-F, along with Hammett constants σ_para.

As expected, achiral compounds 3a–e furnish convergent ¹⁹F signals for ortho-F nuclei. Electron-rich amidines 3b–c show deshielded ¹⁹F nuclei as compared to electron-deficient 3d–e. Close examination on divergent ¹⁹F chemical shifts in chiral compounds 4a–q shows that this “reverse” relationship between ¹⁹F shielding and electron-withdrawing abilities maintains.¹⁶ In fact, linear correlations of ortho-¹⁹F chemical shifts with Hammett constants σ_para is seen in Hammett plots, as illustrated in Fig. 6. The negative slope coefficient κ indicates that amidine groups affect ¹⁹F shielding predominately through noncovalent interaction, not chemical bonds for both syn-F and anti-F nuclei. Notably, the slope coefficient (κ = −0.29) for δ_down–σ_para curve is bigger (in absolute value) than that for δ_up–σ_para plot (κ = −0.06). Larger syn-¹⁹F chemical shift (δ_down) changes are likely originated from cooperative effects of nonbonding interactions of syn-F nucleus with C9-ester and C7-amidine.

Fig. 6 Hammett plots of ¹⁹F chemical shifts and shift differences versus σ_para: (a) δ^amidine_down–σ_para curve; (b) δ^amidine_up–σ_para curve (κ represents the slope coefficient).

2.3. C5-substituent effects on ¹⁹F chemical shifts

In C7- and C9-substituted molecules, the electronic properties of F nuclei are little affected. Alternatively, substituent changes on the N-phenyl ring allow us to modulate fluorine electronic properties. Any different responses of syn-F and anti-F to C5-substituent variations reflect the electronic effects of fluorine on nonbonding interactions. To that end, we prepared a series of C5-substituted N-phenyl derivatives 5a–h and 6a–w (meta-substituent relative to ortho-F nuclei, see Fig. 1) and examined their ¹⁹F NMR spectra. Tables 3 and 4 provide detailed ¹⁹F chemical shifts for 5a–h and 6a–w.

Table 3 ¹⁹F Chemical shifts and shift differences in para-substituted N-phenyl γ-lactam compounds (in ppm)

Cpd	R	σmeta	δ^metaref	Cpd	δdown	δup	Δδ^meta
1a	H	0	−117.82	1b	−117.14	−117.93	0.79
5a	Me	−0.07	−119.21	6a	−118.56	−119.35	0.79
5b	OMe	0.115	−117.42	6b	−116.75	−117.61	0.86
5c	CF3	0.43	−113.36	6c	−112.73	−113.43	0.70
5d	NO2	0.71	−110.99	6d	−110.57	−110.90	0.33
5e	CO2Me	0.37	−115.34	6e	−114.78	−115.42	0.64
5f	NH2	−0.16	−119.53	6f	−118.89	−119.70	0.81
5g	NHMe	−0.21	−119.85	6g	−119.31	−120.10	0.79
5h	NMe2	−0.15	−119.45	6h	−118.84	−119.67	0.83
5i	F	0.337	−114.61	6i	−113.93	−114.72	0.79

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Table 4 ¹⁹F Chemical shifts and shift differences in para-substituted N-phenyl γ-lactam compounds 6j–6w (in ppm)

Cpd	R	σmeta	δdown; δup	Δδ^meta
6j	Cl	0.373	−114.90, −115.58	0.68
6k	Br	0.39	−114.94, −115.73	0.788
6l	I	0.35	−115.44, −116.20	0.768
6m	Et	−0.07	−118.28, −119.07	0.798
6n	n-Pr	−0.07	−118.39, −119.16	0.77
6o	OEt	0.10	−117.02, −117.89	0.86
6p	CH2=CH2	0.05	−117.42, −118.16	0.74
6q	CH2=CHMe	0.05	−117.98, −118.75	0.77
6r	Ph	0.06	−116.85, −117.62	0.77
6s	CHO	0.35	−113.13, −113.72	0.59
6t	COMe	0.38	−114.25, −114.86	0.61
6u	CN	0.56	−111.95, −112.30	0.35
6v	NHCHO	0.19	−117.46, −117.98	0.52
6w	NHCOMe	0.21	−118.54, −119.11	0.57

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We expect that through-bond forces such as induction and resonance effects would be leading factors for C5-substituents to affect ¹⁹F chemical shifts. Indeed, plots of ¹⁹F chemical shifts δ from 5a–h, δ_down and δ_up from 6a–u versus Hammett constants σ_meta exhibit linear relationships, as demonstrated in 8 and S2.† The positive slope coefficients κ in the curves are in consistent with the conventional Hammett plots. Thus, ¹⁹F shielding variations in C5-substituted γ-lactams are predominately governed by either through-bond effects. It is worth to note that the chemical shifts of C5-amides 6v (R = NHCHO) and 6w (R = NHCOMe) are distinctly deviated from the linear curves, which we attribute to strong amide polarizable effects and their data are omitted from the plots in Fig. 7.

Fig. 7 Hammett plots of δ_down–σ_meta and δ_up–σ_meta for compounds 6a–w.

We envision that the magnitude of slope coefficient κ in a Hammett plot indicates the susceptibility of ¹⁹F shifts to substituent electronic characteristics. The slope coefficients for δ_down–σ_meta plots of C5-substituted γ-lactams (κ = 9.45 in Fig. 7) are much bigger than those for δ_down–σ_para plots of C7-amidines (κ = −0.29 in Fig. 6), proving that through-bond forces have greater impacts on ¹⁹F shielding than through-space interactions. In addition, the syn-F and anti-F nucleus behave differently in responding to their discrete surroundings, as the slope for δ_down–σ_meta plot (κ = 9.45) is smaller than that of δ_up–σ_meta curve (κ = 9.86). The asymmetric environments around anti-F and syn-F nuclei are shaped by not only C9-ester but also neighboring C7-amidine. Anti-F shielding is more sensitive to the changes of fluorine electronic property than syn-F, suggesting anti-F is closer to C7-amidine that syn-F. Thus, for the first time, we demonstrate that the slope coefficients in Hammett plots are useful in detecting the type and strength of fluorine involved bonding and nonbonding interactions.

2.4. X-ray crystal structures of C5-substituted N-phenyl γ-lactams

In N-phenyl γ-lactam derivatives, the asymmetric chemical environments around ortho-F nuclei are mainly regulated by C9-ester and neighboring C=O/CH₂ groups. The conjugation effects of C5-substituents hinder rotations around central N–Ph bond, enlarging chemical differences between syn-F and anti-F. To inspect the structural details of C5-substituted N-phenyl γ-lactams, we determined single crystal structures of 6da (C9-acid derivative of 6d) and 6h by X-ray crystallography. Fig. 8 shows computer generated drawings with atomic numbering for S-6da and R-6h. Table 4 lists parameters that define important atom distances and functional group orientations. CCDC 1904410 and 1915197 contain the supplementary crystallographic data for 6da and 6h, respectively.†

Fig. 8 Computer-generated drawings of crystal structures 6da and 6h. 6da is a C9-acid analogue of 6d.

As shown in Table 5, S-6da displays a small torsion angles ϕ at 57.59° due to C5–NO₂ resonance effects, affording strong van der Waals forces between F2⋯C=O (d_F2–O1 = 2.83 Å) and F1⋯CH₂ (d_F1–H8 = 2.45 Å). F2 is anti-F relative to equatorial C9-acid in S-6da. On the contrary, C5NMe₂ R-6h has larger torsion angle ϕ of 76.54° and longer distances from ortho-F nuclei to the nearby groups. None of the syn-F and anti-F nuclei approach to the C=O/CH₂ groups within the sum of van der Waals radius in R-6h. Despite marked differences in N-Ph torsion angles, C9-substituents in both S-6da and R-6h occupy similar pseudo-equatorial orientations, suggesting that there is no direct correlation between torsion angle ϕ and C9-substituent orientation. Significantly, strong nonbonding interactions as exemplified in structure S-6da correlates to small shift differences Δδ (Tables 3 and 4).

Table 5 Selected atom distances, dihedral angles, and torsion angles in the crystal structures of 6da and 6h^a

Parameter		S-6da	R-6h
a Sum of van der Waals radii: Rw(F–C) = 3.17 Å; Rw(F–O) = 2.99 Å; Rw(F–H) = 2.67 Å.
Dihedral angle β (carbonyl orientation)	β1[C7–C10–C9–C11]	−150.45	−145.27
	β2[N1–C8–C9–C11]	150.85	148.21
Torsion angle ϕ (between N–Ph and γ-lactam)	ϕ1[C1–C2–N1–C7]	−124.13	99.77
	ϕ2[C3–C2–N1–C7]	57.59	−76.54
Contact angle α (F to C=O groups)	α1[C3–F2–C(amide)]	82.34	74.07
	α2[F2–C=O]	71.08	91.45
	α1[C1–F1–C(amide)]	66.91	70.44
	α2[F1–C=O]	112.91	94.14
Distances d (F to C=O and CH2 groups)	dF1–C8(CH)	2.903	3.609
	dF1–H8(CH)	2.446	3.324
	dF1–O1(amide)	4.470	3.877
	dF1–C7(amide)	3.851	3.592
	dF2–C8(CH)	3.946	3.386
	dF2–H7(CH)	3.994	2.996
	dF2−O1(amide)	2.826	3.478
	dF2–C7(amide)	2.975	3.226
C–F bond lengths	dC1–F1	1.343	1.359
	dC3–F2	1.340	1.356
Distances of F to C9-carbonyl	dF2–O2 (F to axial carbonyl)	6.663	5.536
	dF2–C11 (F to axial carbonyl)	5.991	5.165
	dF1–O3 (F to axial carbonyl)	4.783	6.178
	dF1–C11 (F to axial carbonyl)	5.028	5.895

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2.5. Quantum mechanics calculation on nonbonding interactions between ortho-F nuclei and neighboring C=O/C=N/CH₂ groups

Having a wealth of valuable geometric and ¹⁹F NMR spectroscopic information in hand, we set to explore the nature of the interactions between ortho-F nuclei and neighboring C=O/C=N/CH₂ groups. We first carried out geometry optimizations using the Gaussian16 program with density functional theory (DFT) at the B3LYP/6-311G* level of theory.²³ We analyzed LUMO, HOMO and HOMO−1 orbitals in amide 1b, thioamide 2b and amidine 4a, and their molecular orbitals are depicted inFig. 9 and S3.†

Fig. 9 Molecular orbitals at HOMO energy levels in amide 1b, thioamide 2b, and HOMO−1 in amidine 4a (on 0.012 e au⁻³ electron density surface).

Fluorine nonbonding interactions are multifaceted. In our model molecules 1–6, interactions such as van der Waals contacts, coulombic (electrostatic and polarization), and orbital delocalization play important roles in governing overall conformation, and affecting ¹⁹F NMR chemical shifts.^24–26 It is known that lone pair electrons (n) on F can delocalize to the antibonding orbital (π*) of the adjacent C=O group from the C end.^25a However, ortho-F nucleus can only approach to C=O group sideways in γ-lactam derivatives due to conformational confinement. In fact, HOMO and LUMO orbitals in 1b suggest that there is repulsive interaction between p-type lone pair electrons on F and O atoms (coulombic n ↔ n repulsive interactions). On the other hand, the same ortho-F nucleus also engages n → π* orbital overlaps through donation of n electrons on F into antibonding π* orbitals in N=Ph* tautomeric form (Ph* denotes the ortho-F substituted phenyl group). This attractive contact offsets F⋯O repulsion and favors small torsion angle.

The interaction of lone pair electrons between ortho-F and S, however, is not apparent in thioamide 2b, as the van der Waals repulsive force between the ortho-F and large S atom dominates, furnishing a large torsion angle (vide supra).

Notably, a π* orbital located between N and the attaching phenyl group (i.e., N=Ar, a tautomer of phenylamidine, see Fig. 9) exists. Unlike repelling C–F⋯O=C interaction in γ-lactam 1b, the obvious n → π* orbital delocalization from lone pair electrons (n) on F to the antibonding orbital π* in N=Ar is deemed to stabilize C–F⋯N=Ar contact, although the attraction energy may be small.^2,25,28 Accordingly, para-NO₂ amidine 4e furnishes better n → π* orbital overlap than that of p-NMe₂ amidine 4f, as 4e majorly adopts Ar=N form 4e(b), (see Fig. 10 and S3†).

Fig. 10 Tautomers of amidine 4e.

C–F⋯H–C contacts in amidines 4 are little affected by the p-substituents, but are more likely influenced by C5-substituents in γ-lactams 6. Indeed, molecular orbital analysis of 4a indicates that lone pair electrons (n) on F clash sideway into the proximate C–H σ bonding orbital (n ↔ σ interaction, Fig. 11 and S4†).²⁷ Since both orbitals are occupied, such a F⋯H interaction is repulsive, and the short F⋯H distance is a consequence of steric crowding (buttressing), rather than any meaningful hydrogen bonding interaction.¹⁴ Strong F⋯H van der Waals repulsion is anticipated in C5–NO₂-γ-lactam 6d, where C5-conjugation effect shortens the F⋯H distance (Fig. 11and S4†). However, orbital polarization between n and σ orbitals in 6d seems insignificant, partly because fluorine is electron-deficient and less polarizable.

Fig. 11 HOMO−1 orbital in amidine 4a and HOMO orbital in C5–NO₂ γ-lactam 6d (on 0.012 e au⁻³ electron density surface, C–F⋯H–C portion).

2.6. Fluorine nonbonding interactions and ¹⁹F NMR chemical shift changes

Through-space interactions between ortho-F nuclei and their surrounding groups may be measured by shift differences Δδ_down (for syn-F) and Δδ_up (for anti-F) versus a corresponding reference chemical shift (δ_ref). Here we use C9-unsubstituted γ-lactams 5a–i as references for 6a-I, and achiral amidines 3a–e as references for 4a–e. Values of Δδ_down (=δ_down − δ_ref) and Δδ_up (= δ_up − δ_ref) reflects substituent effects on ¹⁹F NMR chemical shifts for F⋯O=C/N=C and F⋯H–C interactions, respectively. Table 6 lists Δδ_down and Δδ_up data for selected amidines and γ-lactams.

Table 6 ¹⁹F Chemical shift differences Δδ_down and Δδ_up for amidines 4a–d, N-phenyl γ-lactams 6a–d and 6h (in ppm)

Cpd	R	Δδdown	Δδup	dF–H^a (Å)
a F⋯H distances are obtained from optimized structures from QM calculations.b Data are from X-ray crystal structures.
4a	H	0.74	−0.36	2.550
4b	Me	0.80	−0.35	2.550
4c	OMe	0.76	−0.35	2.550
4d	CF3	0.69	−0.29	2.538
4e	NO2	0.65	−0.18	2.548
1b	H	0.68	−0.11	2.518
6a	Me	0.65	−0.14	2.585
6b	OMe	0.67	−0.19	2.639
6c	CF3	0.63	−0.07	2.508
6d	NO2	0.42	0.09	2.446^b
6h	NMe2	0.61	−0.22	3.324^b

---

Previously we established that ¹⁹F shielding variations correlate with dipole moments/polarizability in C–F⋯O=C interactions.^15,16 Our molecular orbital analysis confirms that ¹⁹F NMR signals are mostly affected by functional group polarity, where ¹⁹F chemical shifts are more deshielded when either F nucleus or C=O/Ar=N groups become more polarizable. As detailed in Table 6, ortho-F nuclei are more polarizable in C5–NMe₂ γ-lactam 6h than in C5–NO₂ 6d, leading to larger Δδ_down for 6h (0.61 ppm) than for 6d (0.42 ppm).

In C–F⋯H–C interactions, short F⋯H distances are associated with deshielded ¹⁹F signals (Table 6). Thus, upfield ¹⁹F signal δ_up in 6d displays the most downfield shift value (Δδ_up = 0.09 ppm), which is associated with the shortest d_F–H = 2.45 Å in γ-lactams. Similar correlation between Δδ_up and d_F–H is observed in amidine series, and documented in literature.¹⁴

3. Conclusions

In this work, we investigated the relationship between ¹⁹F NMR shielding changes and chemical environments in rotameric N-phenyl γ-lactam analogues. ¹⁹F shift changes in C7-amide/thioamide/amidine derivatives 1–3 confirmed that the neighboring C=O/C=S/C=N and CH₂ groups, together with stereogenic C9-substituent on γ-lactam ring, synergistically enhance chemical environment differences between syn-F and anti-F. Substituent surveys among C7-phenylamidines 4a–r and C5-substituted γ-lactams 6a–u revealed that through-bond effects track conventional relationships between ¹⁹F chemical shift (δ) and Hammett coefficient (σ), while through-space interactions display “reverse” correlations in δ–σ Hammett plots. In fact, the signs (positive or negative) of the slope coefficients κ in the Hammett plots specify the types of fluorine-participated molecular recognitions.

The absolute values of slope coefficients κ in δ–σ Hammett plots verified that nonbonding contacts (κ = −0.29 for F⋯N=Ar contacts) are much weaker than bonding interactions in amending ¹⁹F shielding (Fig. 6 and 7). Such results corroborated with our earlier observations from C9-amides series,¹⁶ where the nonbonding effects of C9-amides on ¹⁹F shielding afforded κ = −0.35 in the δ_down–σ_para Hammett plot. To the best of our knowledge, this is the first report to show that Hammett plots can be used to categorize fluorine nonbonding interactions, and to explicitly gauge the magnitude of these interactions using the slope coefficients κ from Hammett plots.

QM calculations established that repulsive interactions between F⋯O=C and F⋯H–C are the main schemes in N-phenyl γ-lactams, while a favorable, n → π* orbital delocalization from lone pair electrons (n) on F into Ar=N antibonding orbital π* exists in amidine analogous. All the orbital overlaps are supposed to be weak interactions. It is evident that more polarizable functional groups link to more deshielded ¹⁹F signals. On the other hand, C–F⋯H–C interaction comprises orbital polarizations between lone pair electrons on F and C–H σ bonding orbital (n ↔ σ). As both n and σ orbitals are occupied, this contact is considered steric repulsive, and is associated with ¹⁹F signal deshielding.

4. Experimental section

4.1. General information

Unless otherwise stated, all the reactions were carried out under atmosphere conditions. All chemical reagents were purchased from commercial sources and used without further purification. Flash column chromatography was performed with Agilent Technologies Claricep FlashSilica. All ¹H and ¹³C NMR experiments were carried out using a Bruker AVANCE 400 spectrometer or a Bruker AVANCE III 600 spectrometer. ¹⁹F NMR data was recorded using a Bruker AVANCE 400 spectrometer. Chemical shifts in ¹H, ¹⁹F and ¹³C NMR spectra were reported in parts per million (ppm). The residual solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl₃: δ (H) = 7.26 ppm, δ (C) = 77.16 ppm) for ¹H and ¹³C NMR spectra. For ¹⁹F NMR experiments, CFCl₃ was added as an internal reference (0.5% CFCl₃). All coupling constants (J values) were reported in Hertz (Hz). Multiplicities were reported as follows: singlet (s), doublet (d), doublet of doublets (dd), doublet of doublet of doublets (ddd), doublet of triplets (dt), triplet (t), triplet of doublets (td), quartet (q), and multiplet (m). High resolution mass spectra (HRMS) were obtained from an Agilent 6200 series TOF/6500 series spectrometer, using electrospray ionization (ESI) as an ion source. The MS spectra were assessed with an Agilent 1260-6120 spectrometer with an electrospray ionization (ESI) source, equipped with an Agilent SB-C18 (2.1 × 30 mm, 3.5 μm) column.

4.2. Compound characterization

4.2.1. General procedure for the synthesis of compounds 2a and 2b. To a solution of compound 1a (197 mg, 1.00 mmol) in THF (2 mL) was added Lawesson's reagent (202 mg, 0.50 mmol). The mixture was stirred at room temperature for 5 h. The reaction was quenched with saturated NaHCO₃ solution (10 mL), then extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/1) to give compound 2a (123 mg, 51%) as pale yellow oil. MS (ESI, pos. ion) m/z: 214.4 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.41–7.32 (m, 1H), 7.03 (t, J = 8.2 Hz, 2H), 4.00 (t, J = 7.2 Hz, 2H), 3.20 (t, J = 7.9 Hz, 2H), 2.39–2.28 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.49 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 206.1, 158.3 (dd, ¹J_CF = 253.8, 5.0 Hz), 130.2 (t, ³J_CF = 9.8 Hz), 117.6 (t, ³J_CF = 16.3 Hz), 112.6–112.2 (m), 57.0, 44.5, 21.6; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₀H₁₀F₂NS 214.0502; found: 214.0494.

Compound 2b: 133 mg, 58%, pale yellow oil. MS (ESI, pos. ion) m/z: 272.4 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.43–7.33 (m, 1H), 7.03 (t, J = 8.4 Hz, 2H), 4.23 (ABX, J = 10.7, 6.4, 8.4 Hz, 2H), 3.79 (s, 3H), 3.60–3.50 (m, 1H), 3.48–3.46 (m, 2H);¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.53 (s), −117.69 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 203.1, 172.1, 158.3 (dt, ³J_CF = 9.3, 5.0 Hz), 130.6 (t, ³J_CF = 9.8 Hz), 116.8 (t, ³J_CF = 16.1 Hz), 112.8–112.1 (m), 58.1, 52.8, 46.9, 39.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₂F₂NO₂S 272.0557; found: 272.0550.

4.2.2. General procedure for the synthesis of compounds 2c, 2d and 2e. To a solution of compound 2b (100 mg, 0.37 mmol) in 1,4-dioxane (2 mL) was added a LiOH (2 mL, 2 mol L⁻¹ in water). The mixture was stirred at 50 °C for 8 h. The reaction was cooled to room temperature, adjusted to pH = 2 with conc. HCl aqueous solution, then extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/50 to 2/1) to give compound 2f (88 mg, 93%) as pale yellow oil. MS (ESI, pos. ion) m/z: 258.2 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.82 (brs, 1H), 7.45–7.33 (m, 1H), 7.04 (t, J = 8.5 Hz, 2H), 4.32 (dd, J = 10.7, 6.0 Hz, 1H), 4.20 (t, J = 9.6 Hz, 1H), 3.67–3.56 (m, 1H), 3.51 (d, J = 7.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −115.56 (s), −117.59 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 202.8, 177.3, 158.3 (ddd, ³J_CF = 11.1, 6.8, 5.1 Hz), 130.7 (t, ³J_CF = 9.7 Hz), 116.7 (t, ³J_CF = 16.1 Hz), 112.6 (td, ³J_CF = 20.0, 3.3 Hz), 57.8, 46.7, 39.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₁H₁₀F₂NO₂S 258.0400; found: 258.0391.

To a solution of compound 2f (200 mg, 0.78 mmol), aniline (1.00 equiv.) and HATU (443 mg, 1.17 mmol) in dichloromethane (30 mL) was added Et₃N (118 mg, 1.17 mmol). The mixture was stirred at room temperature for 8 h. The reaction was quenched with water (30 mL), then extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/1) to give compounds 2c, 2d and 2e.

Compound 2c (100 mg, 50%) as pale yellow oil. MS (ESI, pos. ion) m/z: 257.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.41–7.32 (m, 1H), 6.99 (t, J = 8.5 Hz, 2H), 5.79 (d, J = 57.9 Hz, 2H), 4.01 (dd, J = 9.4, 7.5 Hz, 1H), 3.88 (t, J = 9.0 Hz, 1H), 3.45–3.31 (m, 1H), 2.85 (ABX, J = 10.7, 6.4, 8.4 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.81 (s), −118.15 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 173.6, 172.4, 159.1 (dd, ¹J_CF = 253.0, ³J_CF = 4.9 Hz), 129.5 (t, ³J_CF = 9.9 Hz), 115.0 (t, ³J_CF = 16.4 Hz), 112.3 (d, ²J_CF = 21.8 Hz), 51.4, 38.6, 34.2; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₁H₁₁F₂N₂OS 257.0560; found: 257.0547.

Compound 2d (120 mg, 57%) as pale yellow oil. MS (ESI, pos. ion) m/z: 271.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.37 (dq, J = 8.5, 6.2 Hz, 1H), 7.01 (tt, J = 12.8, 6.4 Hz, 2H), 6.15 (brs, 1H), 4.35–4.26 (m, 1H), 4.11–4.02 (m, 1H), 3.46–3.33 (m, 3H), 2.83 (d, J = 4.8 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.10 (s), −118.07 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 203.5, 171.5, 158.2 (ddd, ²J_CF = 22.6, ³J_CF = 18.5, 4.9 Hz), 130.6 (t, ³J_CF = 9.7 Hz), 116.8 (t, ³J_CF = 16.1 Hz), 112.5 (ddd, ²J_CF = 33.3, ³J_CF = 19.5, 3.3 Hz), 59.0, 48.0, 41.2, 26.7; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₃F₂N₂OS 271.0717; found: 271.0704.

Compound 2e (140 mg, 63%) as pale yellow oil. MS (ESI, pos. ion) m/z: 285.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.34 (tt, J = 8.5, 6.2 Hz, 1H), 7.00 (ddd, J = 9.3, 3.6, 1.3 Hz, 2H), 4.45 (dd, J = 10.3, 7.7 Hz, 1H), 4.01 (dd, J = 10.2, 8.8 Hz, 1H), 3.82–3.70 (m, 1H), 3.47–3.29 (m, 2H), 3.05 (s, 3H), 2.97 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −115.59 (s), −118.16 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 202.9, 170.3, 158.2 (ddd, ³J_CF = 17.3, 13.7, 4.8 Hz), 130.4 (t, ³J_CF = 9.8 Hz), 116.9 (t, ³J_CF = 16.2 Hz), 112.4 (ddd, ²J_CF = 30.5, ³J_CF = 19.6, 3.5 Hz), 58.64, 47.6, 38.6, 37.5, 37.2, 36.0; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₅F₂N₂OS 285.0873; found: 285.0864.

4.2.3. General procedure for the synthesis of compounds 3a–3e and 4a–4e. Phosphorus oxychloride (1.03 g, 6.72 mmol) was added dropwise to a solution of compound 1a (1.54 g, 7.81 mmol) in dry dichloromethane (5.0 mL) and the reaction mixture was stirred for 3 h at room temperature. A solution of aniline (500 mg, 5.34 mmol) in dry dichloromethane (15 mL) was then added via cannula and the mixture was refluxed overnight. Then, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting solid was dissolved in aqueous hydrochloric acid (0.30 M, 100 mL) and extracted with dichloromethane (100 mL × 3). The aqueous phase was basified with sodium hydroxide aqueous solution (2.0 M, pH adjusted to 8) and extracted with ethyl acetate (100 mL × 3). The first organic extracts were concentrated in vacuo and the resulting solid was carried through the above procedure three more times. All ethyl acetate extracts were combined, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/4) to give compound 3a (615 mg, 30%) as colorless oil. MS (ESI, pos. ion) m/z: 273.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.25–7.16 (m, 3H), 7.02–6.91 (m, 3H), 6.83–6.81 (m, 2H), 3.70 (t, J = 6.8 Hz, 2H), 2.51 (t, J = 7.8 Hz, 2H), 2.19–2.12 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.05 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 161.5, 159.7 (dd, ¹J_CF = 252.0, ³J_CF = 5.6 Hz), 152.2, 128.7, 128.1 (t, ³J_CF = 10.0 Hz), 122.3, 122.2, 112.3 (dd, ³J_CF = 19.7, 4.1 Hz), 50.8, 26.9, 21.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₅F₂N₂ 273.1203; found: 273.1198.

Compound 3b: 630 mg, 41%, yellow oil. MS (ESI, pos. ion) m/z: 287.2 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.25–7.15 (m, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.96 (t, J = 8.2 Hz, 2H), 6.72 (d, J = 8.1 Hz, 2H), 3.69 (t, J = 6.8 Hz, 2H), 2.51 (t, J = 7.8 Hz, 2H), 2.27 (s, 3H), 2.20–2.10 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.06 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 161.6, 159.7 (dd, ¹J_CF = 252.1, ³J_CF = 5.8 Hz), 149.5, 131.5, 129.3, 128.0 (t, ³J_CF = 10.0 Hz), 121.9, 118.1, 112.3 (dd, ³J_CF = 18.4, 5.2 Hz), 50.8, 26.8, 21.4, 20.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₇F₂N₂ 287.1360; found: 287.1355.

Compound 3c: 270 mg, 45%, colorless oil. MS (ESI, pos. ion) m/z: 303.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.25–7.15 (m, 1H), 6.96 (t, J = 8.4 Hz, 2H), 6.76 (q, J = 8.9 Hz, 4H), 3.76 (s, 3H), 3.68 (t, J = 6.8 Hz, 2H), 2.50 (t, J = 7.7 Hz, 2H), 2.19–2.09 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.07 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 161.9, 159.7 (dd, ¹J_CF = 252.0, ³J_CF = 5.6 Hz), 155.2, 145.5, 128.0 (t, ³J_CF = 10.0 Hz), 122.8, 114.1, 112.3 (dd, ³J_CF = 19.8, 4.0 Hz), 55.6, 50.7, 26.9, 21.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₇F₂N₂O 303.1309; found: 303.1337.

Compound 3d: 201 mg, 13%, yellow oil. MS (ESI, pos. ion) m/z: 341.2([M + H]⁺); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.46 (d, J = 8.2 Hz, 2H), 7.28–7.19 (m, 1H), 6.98 (t, J = 8.2 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H), 3.73 (t, J = 6.8 Hz, 2H), 2.51 (t, J = 7.8 Hz, 2H), 2.23–2.13 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −62.09 (s), −117.18 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 161.6, 159.6 (dd, ³J_CF = 252.1, ³J_CF = 5.6 Hz), 155.6, 128.4 (t, ³J_CF = 10.0 Hz), 125.9 (d, ³J_CF = 3.6 Hz), 124.9–123.2 (m), 122.2, 117.6 (t, ³J_CF = 16.1 Hz), 112.3 (dd, ³J_CF = 18.4, 4.8 Hz), 50.8, 26.9, 21.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₄F₅N₂ 341.1077; found: 341.1086.

Compound 3e: 80 mg, 3%, yellow oil. MS (ESI, pos. ion) m/z: 318.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.09 (d, J = 8.4 Hz, 2H), 7.32–7.17 (m, 1H), 6.98 (t, J = 8.0 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 3.75 (t, J = 6.9 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H), 2.26–2.19 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.30 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 160.1 (d, ¹J_CF = 394.9 Hz), 159.4 (dd, ¹J_CF = 252.8, ³J_CF = 4.9 Hz), 142.9, 128.8 (t, ³J_CF = 10.0 Hz), 124.9, 122.5, 112.3 (dd, ³J_CF = 19.7, 3.8 Hz), 51.0, 27.3, 21.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₄F₂N₃O₂ 318.1054; found: 318.1045.

Compound 4a: 133 mg, 30%, colorless oil. MS (ESI, pos. ion) m/z: 331.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.29–7.17 (m, 3H), 6.97 (t, J = 8.3 Hz, 3H), 6.83–6.81 (m, 2H), 3.98–3.86 (m, 2H), 3.74 (s, 3H), 3.43–3.35 (m, 1H), 2.81 (ABX, J = 16.7, 8.2, 9.0 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.31 (s), −117.41 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.8, 159.6 (dd, ³J_CF = 251.7, ¹J_CF = 5.4 Hz), 158.8, 151.5, 128.9, 128.5 (t, ³J_CF = 10.0 Hz), 122.6, 121.9, 117.1 (t, ³J_CF = 16.0 Hz), 112.5 (td, ³J_CF = 12.2, 2.1 Hz), 52.5, 52.3, 39.3, 29.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₇F₂N₂O₂ 331.1258; found: 331.1269.

Compound 4b: 153 mg, 43%, yellow oil. MS (ESI, pos. ion) m/z: 345.2 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.21 (ddd, J = 14.6, 8.3, 6.3 Hz, 1H), 7.03 (d, J = 7.9 Hz, 2H), 6.95 (t, J = 8.8 Hz, 2H), 6.72 (d, J = 8.0 Hz, 2H), 3.95–3.86 (m, 2H), 3.73 (s, 3H), 3.37 (p, J = 8.1 Hz, 1H), 2.81 (ABX, J = 16.7, 8.2, 9.0 Hz, 2H), 2.27 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.26, −117.41 (s).¹³C NMR (101 MHz, CDCl₃): δ (ppm) 172.9, 159.7 (dd, ¹J_CF = 251.4, ³J_CF = 5.4 Hz), 159.1, 148.8, 131.9, 129.5, 128.5 (t, ³J_CF = 10.0 Hz), 121.8, 117.2 (t, ³J_CF = 16.0 Hz), 112.3 (dd, ³J_CF = 18.5, 11.3 Hz), 52.5, 52.3, 39.3, 29.9, 20.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₉F₂N₂O₂ 345.1415; found: 345.1424.

Compound 4c: 167 mg, 40%, pale yellow oil. MS (ESI, pos. ion) m/z: 361.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.26–7.19 (m, 1H), 6.97 (t, J = 8.6 Hz, 2H), 6.80–6.73 (m, 4H), 3.96–3.84 (m, 2H), 3.76 (s, 3H), 3.74 (s, 3H), 3.42–3.36 (m, 1H), 2.80 (ABX, J = 16.7, 8.3, 9.0 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.31 (s), −117.42 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.9, 159.6 (d, ¹J_CF = 251.7 Hz), 159.3, 155.4, 144.8, 128.4 (t, ³J_CF = 10.0 Hz), 122.7, 117.2 (t, ³J_CF = 15.9 Hz), 114.2, 112.3 (td, ³J_CF = 19.9, 3.2 Hz), 55.57, 52.53, 52.26, 39.35, 29.92; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₉F₂N₂O₃ 361.1364; found: 361.1361.

Compound 4d: 166 mg, 21%, colorless oil. MS (ESI, pos. ion) m/z: 399.2 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.48 (d, J = 8.2 Hz, 2H), 7.26 (dt, J = 8.3, 6.3 Hz, 1H), 6.99 (t, J = 8.6 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 3.94 (d, J = 7.7 Hz, 2H), 3.46–3.35 (m, 1H), 2.80 (ABX, J = 16.8, 7.9, 9.0 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −62.20 (s), −116.49 (s), −117.47 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 172.7, 159.6 (dd, ¹J_CF = 252.6, ³J_CF = 5.3 Hz), 159.1, 154.9, 128.9 (t, ³J_CF = 9.9 Hz), 126.2 (d, ³J_CF = 3.6 Hz), 122.1, 116.7, 112.4 (dd, ²J_CF = 21.8, ³J_CF 10.2 Hz), 52.7, 52.5, 39.3, 30.0; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₆F₅N₂O₂ 399.1132; found: 399.1125.

Compound 4e: 15 mg, 4%, pale yellow oil. MS (ESI, pos. ion) m/z: 376.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.13 (d, J = 8.2 Hz, 2H), 7.30–7.23 (m, 1H), 6.98 (t, J = 8.0 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 3.97 (d, J = 7.5 Hz, 2H), 3.76 (s, 3H), 3.48–3.40 (m, 1H), 2.56 (ABX, J = 16.7, 7.6, 8.9 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.65 (s), −117.47 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.5, 159.3 (dd, ¹J_CF = 252.9, ³J_CF = 3.6 Hz), 158.9, 158.1, 143.1, 129.1 (t, ³J_CF = 9.9 Hz), 124.9, 122.3, 116.3, 112.5–112.1 (m), 52.7, 52.6, 39.1, 30.1; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₆F₂N₃O₄ 376.1109; found: 376.1108.

4.2.4. General procedure for the synthesis of compounds 4f–4r. A solution of 3–chlorobenzenecarboperoxoic acid (1.30 g, 7.53 mmol) in dichloromethane (20 mL) was added dropwise to a solution of compound 2b (500 mg, 1.84 mmol) and N,N-dimethylbenzene-1,4-diamine (505 mg, 3.71 mmol) in dichloromethane (7 mL) below 5 °C. The reaction mixture was stirred at 0 °C for 30 minutes then concentrated in vacuo and the resulting solid was dissolved in ethyl acetate (50 mL). The solution was washed with saturated sodium carbonate aqueous solution (50 mL × 2) and brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/4) to give compound 4f (330 mg, 48%) as a pale brown oil. MS (ESI, pos. ion) m/z: 374.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.25–7.17 (m, 1H), 6.96 (t, J = 8.6 Hz, 2H), 6.70 (dd, J = 23.2, 8.9 Hz, 4H), 3.93–3.84 (m, 2H), 3.73 (s, 3H), 3.41–3.33 (m, 1H), 2.87 (s, 6H), 2.92 (ABX, J = 16.7, 8.4, 9.0 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.17 (s), −117.37 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.9, 159.7 (dd, ¹J_CF = 250.8, 5.3 Hz), 159.0, 147.0, 142.0, 128.3 (t, ³J_CF = 10.0 Hz), 122.5, 117.4 (t, ³J_CF = 16.0 Hz), 114.0, 112.5–112.1 (m), 52.4, 52.2, 41.5, 39.4, 30.0; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₂F₂N₃O₂ 374.1680; found: 374.1687.

Compound 4g: 168 mg, 65%, pale brown oil. MS (ESI, pos. ion) m/z: 349.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.28–7.19 (m, 1H, Ph–F), 6.97 (t, J = 8.5 Hz, 2H, Ph–F), 6.92 (d, J = 8.7 Hz, 2H, Ph–N=C), 6.79–6.73 (m, 2H, Ph–N=C), 3.92 (d, J = 7.8 Hz, 2H, CH₂N), 3.74 (s, 3H, Me), 3.44–3.32 (m, 1H, CH), 2.79 (ABX, J = 16.7, 8.1, 9.0 Hz, 2H, CNCH₂); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.46 (s), −117.47 (s), −122.76 (s); ¹³C NMR (150 MHz, CDCl₃): δ (ppm) 172.8, 160.4 (d, ³J_CF = 3.6 Hz), 159.9, 159.5, 158.8, 158.3, 147.6 (d, ³J_CF = 2.6 Hz), 128.6 (t, ³J_CF = 10.0 Hz), 123.0 (d, ³J_CF = 7.9 Hz), 117.0 (t, ³J_CF = 16.0 Hz), 115.5, 115.4, 112.5–112.2 (m), 52.6, 52.4, 39.3, 29.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₆F₃N₂O₂ 349.1164; found: 349.1155.

Compound 4h: 554 mg, 82%, pale brown oil. MS (ESI, pos. ion) m/z: 365.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.28–7.19 (m, 1H, Ph–F), 7.18 (d, J = 8.6 Hz, 2H, Ph–Cl), 6.97 (t, J = 8.5 Hz, 2H, Ph–F), 6.75 (d, J = 8.6 Hz, 2H, Ph–Cl), 3.92 (d, J = 7.7 Hz, 2H, CH₂N), 3.74 (s, 3H, Me), 3.45–3.33 (m, 1H, CH), 2.79 (ABX, J = 16.7, 8.0, 9.0 Hz, 2H, CNCH₂); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.46 (s), −117.46 (s); ¹³C NMR (150 MHz, CDCl₃): δ (ppm) 172.7, 160.4 (d, ³J_CF = 5.5 Hz), 159.3, 158.7, 150.2, 128.9, 128.7 (t, ³J_CF = 10.0 Hz), 127.8, 123.3, 116.9 (t, ³J_CF = 16.0 Hz), 112.6–112.2 (m), 52.6, 52.4, 39.3, 29.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₆ClF₂N₂O₂ 365.0868; found: 365.0851.

Compound 4i: 700 mg, 91%, pale brown oil. MS (ESI, pos. ion) m/z: 409.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.33 (d, J = 8.5 Hz, 2H, Ph–Br), 7.29–7.19 (m, 1H, Ph–F), 6.97 (t, J = 8.5 Hz, 2H, Ph–F), 6.70 (d, J = 8.5 Hz, 2H, Ph–Br), 3.92 (d, J = 7.7 Hz, 2H, CH₂N), 3.74 (s, 3H, Me), 3.45–3.33 (m, 1H, CH), 2.79 (ABX, J = 16.7, 8.0, 9.0 Hz, 2H, CNCH₂); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.46 (s), −117.46 (s); ¹³C NMR (150 MHz, CDCl₃): δ (ppm) 172.7, 160.4 (d, ³J_CF = 5.2 Hz), 159.2, 158.7, 150.7, 131.8, 128.7 (t, ³J_CF = 10.0 Hz), 123.8, 116.8 (t, ³J_CF = 16.0 Hz), 115.5, 112.6–112.2 (m), 52.6, 52.4, 39.3, 29.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₆BrF₂N₂O₂ 409.0363; found: 409.0345.

Compound 4j: 433 mg, 52%, pale brown oil. MS (ESI, pos. ion) m/z: 457.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.51 (d, J = 8.5 Hz, 2H, Ph–I), 7.31–7.18 (m, 1H, Ph–F), 6.97 (t, J = 8.6 Hz, 2H, Ph–F), 6.59 (d, J = 8.5 Hz, 2H, Ph–I), 3.92 (d, J = 7.7 Hz, 2H, CH₂N), 3.74 (s, 3H, Me), 3.45–3.32 (m, 1H, CH), 2.79 (ABX, J = 16.7, 8.0, 9.0 Hz, 2H, CNCH₂); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.44 (s), −117.44 (s); ¹³C NMR (150 MHz, CDCl₃): δ (ppm) 172.7, 160.4 (d, ³J_CF = 5.4 Hz), 159.1, 158.7 (d, ³J_CF = 4.5 Hz), 151.4, 137.8, 128.7 (t, ³J_CF = 10.0 Hz), 124.3, 117.4, 116.8 (t, ³J_CF = 16.0 Hz), 112.5–112.2 (m), 85.9, 52.6, 52.4, 39.2, 29.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₆F₂IN₂O₂ 457.0225; found: 457.0212.

Compound 4k: 96 mg, 28%, yellow oil. MS (ESI, pos. ion) m/z: 356.2 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.52 (d, J = 7.7 Hz, 2H, Ph–CN), 7.32–7.21 (m, 1H, Ph–F), 6.99 (t, J = 8.4 Hz, 2H, Ph–F), 6.88 (d, J = 8.0 Hz, 2H, Ph–CN), 3.95 (d, J = 7.6 Hz, 2H, CH₂N), 3.76 (s, 3H, Me), 3.48–3.36 (m, 1H, CH), 2.81 (ABX, J = 16.8, 7.6, 8.8 Hz, 2H, CNCH₂); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.61 (s), −117.48 (s); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 172.5, 160.7, 159.0, 158.2, 156.0, 133.2, 129.0 (t, ³J_CF = 10.0 Hz), 122.8, 119.7, 112.4 (dd, ³J_CF = 17.0, 10.9 Hz), 105.7, 52.7, 52.5, 39.2, 30.0; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₆F₂N₃O₂ 356.1211; found: 356.1204.

Compound 4l: 123 mg, 62%, yellow oil. MS (ESI, pos. ion) m/z: 389.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.93 (d, J = 8.3 Hz, 2H, Ph–CO₂Me), 7.29–7.21 (m, 1H, Ph–F), 6.98 (t, J = 8.7 Hz, 2H, Ph–F), 6.87 (d, J = 8.3 Hz, 2H, Ph–CO₂Me), 3.95 (d, J = 7.7 Hz, 2H, CH₂N), 3.88 (s, 3H, Ph–CO₂Me), 3.75 (s, 3H, Me), 3.47–3.36 (m, 1H, CH), 2.82 (ABX, J = 16.8, 7.9, 9.0 Hz, 2H, CNCH₂); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.49 (s), −117.46 (s); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 172.7, 167.3, 160.9, 158.8, 158.3, 156.2, 130.8, 128.9 (t, ³J_CF = 10.0 Hz), 124.5, 121.9, 116.7, 112.6–112.1 (m), 52.6, 52.5, 51.9, 39.3, 30.0; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₁₉F₂N₂O₄ 389.1313; found: 389.1307.

Compound 4m: 150 mg, 70%, yellow oil. MS (ESI, pos. ion) m/z: 388.5 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.33 (d, J = 8.6 Hz, 2H, Ph–NH), 7.25–7.18 (m, 1H, Ph–F), 7.17 (br. s, 1H, NH), 6.96 (t, J = 8.7 Hz, 2H, Ph–F), 6.77 (d, J = 8.5 Hz, 2H, Ph–NH), 3.96–3.85 (m, 2H, CH₂N), 3.74 (s, 3H, Me), 2.80 (ABX, J = 16.8, 8.0, 9.0 Hz, 2H, CNCH₂), 2.13 (s, 3H, COMe); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.34 (s), −117.40 (s); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 172.8, 168.4, 160.8 (d, ³J_CF = 5.3 Hz), 159.6, 158.3, 147.6, 133.3, 128.7 (t, ³J_CF = 9.9 Hz), 122.2, 120.9, 117.0 (t, ³J_CF = 16.0 Hz), 112.3 (dd, ³J_CF = 18.5, 9.8 Hz), 52.6, 52.4, 39.3, 30.1, 24.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₀F₂N₃O₃ 388.1473; found: 388.1469.

Compound 4n: 150 mg, 22%, pale yellow oil. MS (ESI, pos. ion) m/z: 373.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.88 (d, J = 8.1 Hz, 2H, Ph–COMe), 7.29–7.22 (m, 1H, Ph–F), 6.97 (t, J = 8.6 Hz, 2H, Ph–F), 6.89 (d, J = 8.1 Hz, 2H, Ph–COMe), 3.96 (d, J = 7.7 Hz, 2H, CH₂N), 3.75 (s, 3H, Me), 3.46–3.38 (m, 1H, CH), 2.77 (ABX, J = 16.8, 7.9, 9.0 Hz, 2H, CNCH₂), 2.55 (s, 3H, COMe); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.47 (s), −117.42 (s); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 197.3, 172.5, 160.7, 158.7, 158.1, 156.3, 131.9, 129.6, 128.8 (t, ³J_CF = 9.9 Hz), 121.9, 116.6 (t, ³J_CF = 15.8 Hz), 112.2 (dd, ³J_CF = 19.7, 7.8 Hz), 52.5, 52.4, 39.1, 29.9, 26.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₁₉F₂N₂O₃ 373.1364; found: 373.1356.

Compound 4o: 150 mg, 57%, yellow oil. MS (ESI, pos. ion) m/z: 356.9 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.29 (d, J = 8.1 Hz, 2H, Ph–CH=CH₂), 7.25–7.19 (m, 1H, Ph–F), 6.98 (t, J = 8.7 Hz, 2H, Ph–F), 6.78 (d, J = 8.2 Hz, 2H, Ph–CH=CH₂), 6.66 (dd, J = 17.6, 10.9 Hz, 1H, Ph–CH=CH₂), 5.63 (d, J = 17.6 Hz, 1H, Ph–CH=CH₂), 5.11 (d, J = 10.9 Hz, 1H, Ph–CH=CH₂), 3.97–3.87 (m, 2H, CH₂N), 3.75 (s, 3H, Me), 3.46–3.38 (m, 1H, CH), 2.82 (ABX, J = 16.7, 8.1, 9.0 Hz, 2H, CNCH₂); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.33 (s), −117.41 (s); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 172.8, 160.9 (d, ³J_CF = 5.5 Hz), 158.8, 158.4 (d, ³J_CF = 5.4 Hz), 151.4, 136.9, 132.2), 128.5 (t, ³J_CF = 10.0 Hz), 126.9, 122.1, 117.1 (t, ³J_CF = 16.0 Hz), 112.4 (dd, ³J_CF = 16.9, 12.8 Hz), 111.7, 52.5, 52.3, 39.4, 30.0; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₁₉F₂N₂O₂ 357.1415; found: 357.1438.

Compound 4p: 126 mg, 43%, yellow oil. MS (ESI, pos. ion) m/z: 375.3 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.21 (td, J = 8.4, 4.2 Hz,1H, Ph–F), 6.96 (t, J = 8.6 Hz, 2H, Ph–F), 6.75 (q, J = 8.9 Hz, 4H, Ph–OCH₂CH₃), 3.97 (q, J = 7.0 Hz, 2H, OCH₂), 3.93–3.86 (m, 2H, CH₂N), 3.73 (s, 3H, OMe), 3.43–3.31 (m, 1H, CH), 2.80 (ABX, J = 16.7, 8.2, 9.0 Hz, 2H, CNCH₂), 1.38 (t, J = 7.0 Hz, 3H, OCH₂CH₃); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.33 (s), −117.42 (s); ¹³C NMR (150 MHz, CDCl₃): δ (ppm) 172.9, 160.9 (d, ³J_CF = 5.5 Hz), 159.1, 158.4, 154.8, 144.8, 128.4 (t, ³J_CF = 10.0 Hz), 122.6, 117.3 (t, ³J_CF = 16.0 Hz), 114.9, 112.5–112.1 (m), 63.8, 52.5, 52.2, 39.4, 29.9, 15.1; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₁F₂N₂O₃ 375.1520; found:375.1540.

Compound 4q: 180 mg, 81%, pale yellow oil. MS (ESI, pos. ion) m/z: 402.5 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.32 (d, J = 8.2 Hz, 2H, Ph–CO), 7.29–7.18 (m, 1H, Ph–F), 6.98 (t, J = 8.6 Hz, 2H, Ph–F), 6.84 (d, J = 8.1 Hz, 2H, Ph–CO), 3.99–3.87 (m, 2H, CH₂N), 3.75 (s, 3H, Me), 3.47–3.34 (m, 1H, CH), 3.16–2.92 (m, 6H, NMe₂), 2.80 (ABX, J = 16.8, 7.9, 9.0 Hz, 2H, CNCH₂); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.40 (s), −117.42 (s); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 172.6, 172.0, 171.1 (d, ³J_CF = 7.4 Hz), 160.7 (d, ³J_CF = 5.4 Hz), 158.9, 158.2 (d, ³J_CF = 5.4 Hz), 152.9, 130.3, 128.6 (t, ³J_CF = 10.0 Hz), 128.2, 121.6, 116.8 (t, ³J_CF = 16.0 Hz), 112.2 (ddd, ²J_CF = 20.2, ³J_CF = 11.2, 3.1 Hz), 60.4, 52.5, 52.3, 39.2, 29.9, 21.0, 14.2; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₂F₂N₃O₃ 402.1629; found: 402.1620.

4.2.5. General procedure for the synthesis of compounds 5b and 5e. To a solution of 2,6-difluoro-4-methoxyaniline (200 mg, 1.26 mmol) and Et₃N (191 mg, 1.89 mmol) in CH₂Cl₂ (2 mL) was added 4-chlorobutanoyl chloride (355 mg, 2.51 mmol) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 3 h, quenched with water (10 mL) and extracted with CH₂Cl₂ (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 3/7) to give 4-chloro-N-(2,6-difluoro-4-methoxyphenyl)butanamide (5bc) (300 mg, 91%) as colorless oil; MS (ESI, pos. ion) m/z: 264.3 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.75 (brs, 1H), 6.44 (d, J = 9.4 Hz, 2H), 3.73 (s, 3H), 3.60 (t, J = 6.2 Hz, 2H), 2.53 (t, J = 7.1 Hz, 2H), 2.19–2.08 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.68 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 171.6 (d, ³J_CF = 12.1 Hz), 158.7 (dd, ¹J_CF = 248.5, ³J_CF = 7.8 Hz), 159.4 (t, ³J_CF = 13.3 Hz), 106.4 (t, ³J_CF = 17.2 Hz), 98.1 (dd, ²J_CF = 23.1, ³J_CF = 4.0 Hz), 55.9, 44.3, 32.7, 28.2; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₁H₁₃ClF₂NO₂ 264.0603; found: 264.0598.

To a solution of compound 5bc (300 mg, 1.14 mmol) in DMF (2 mL) was added DBU (260 mg, 1.71 mmol) at room temperature. The reaction mixture was heated at 100 °C and stirred overnight. The reaction was quenched with water (10 mL) and extracted with CH₂Cl₂ (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/5) to give compound 5b (220 mg, 85%) as pale yellow oil; MS (ESI, pos. ion) m/z: 228.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.51 (d, J = 9.5 Hz, 2H), 3.77 (s, 3H), 3.70 (t, J = 7.0 Hz, 2H), 2.54 (t, J = 8.1 Hz, 2H), 2.31–2.14 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.42 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 175.3, 159.6 (dd, ¹J_CF = 250.2, ³J_CF = 8.2 Hz), 160.2 (t, ³J_CF = 13.5 Hz), 108.3 (t, ³J_CF = 17.2 Hz), 98.7 (dd, ²J_CF = 23.0, ³J_CF = 4.3 Hz), 56.1, 49.6, 30.4, 19.2; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₁H₁₂F₂NO₂ 228.0836; found: 228.0831.

Compound 5ec: 322 mg, 88%, pale yellow oil. MS (ESI, pos. ion) m/z: 292.0 ([M + H]⁺).¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.60 (d, J = 8.0 Hz, 2H), 7.24 (brs, 1H), 3.92 (s, 3H), 3.66 (t, J = 6.1 Hz, 2H), 2.64 (t, J = 7.0 Hz, 2H), 2.25–2.15 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.47 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 170.4, 164.7, 157.1 (dd, ¹J_CF = 251.8, ³J_CF = 4.7 Hz), 129.7, 118.3 (t, ³J_CF = 16.5 Hz), 113.2 (dd, ²J_CF = 21.6, ³J_CF = 4.3 Hz), 52.9, 44.3, 27.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₃ClF₂NO₃ 292.0552, found: 292.0548.

Compound 5e: 133 mg, 82%, pale yellow oil. MS (ESI, pos. ion) m/z: 256.3 [M + H]⁺.¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.63 (d, J = 8.2 Hz, 2H), 3.92 (s, 3H), 3.79 (t, J = 7.0 Hz, 2H), 2.57 (t, J = 8.1 Hz, 2H), 2.28 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −115.34 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 174.6, 164.6 (t, ³J_CF = 3.2 Hz), 159.8 (d, ³J_CF = 5.3 Hz), 157.3 (d, ³J_CF = 5.4 Hz), 130.9 (t, ³J_CF = 9.1 Hz), 120.1 (t, ³J_CF = 16.5 Hz), 113.5 (m), 52.9, 49.3, 30.4, 19.6; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₂F₂NO₃ 256.0785, found: 256.0785.

4.2.6. General procedure for the synthesis of compounds 5c, 5d and 5i. To a solution of 2,6-difluoro-4-(trifluoromethyl)aniline (200 mg, 1.01 mmol) and NaH (50 mg, 60% dispersion in mineral oil) in DMF (2 mL) was added 4-chlorobutanoyl chloride (143 mg, 1.01 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water (10 mL) and extracted with CH₂Cl₂ (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/1) to give compound 5c (150 mg, 56%) as pale yellow oil; MS (ESI, pos. ion) m/z: 266.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.27 (d, J = 7.0 Hz, 2H), 3.79 (t, J = 7.0 Hz, 2H), 2.59 (t, J = 8.1 Hz, 2H), 2.35–2.24 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −63.66 (s), −113.36 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 174.6, 159.6 (d, ³J_CF = 5.6 Hz), 157.9 (d, ³J_CF = 5.6 Hz), 131.0–131.3 (m), 123.9 (t, ³J_CF = 2.9 Hz), 122.1 (t, ³J_CF = 2.9 Hz), 119.2 (t, ³J_CF = 16.0 Hz), 110.1–109.8 (m), 49.1, 30.2, 19.5; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₁H₉F₅NO 266.0604, found: 266.0591.

Compound 5d: 175 mg, 13%, yellow oil. MS (ESI, pos. ion) m/z: 243.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.94–7.86 (m, 2H, Ph), 3.83 (t, J = 7.0 Hz, 2H, CH₂N), 2.60 (t, J = 8.1 Hz, 2H, COCH₂), 2.38–2.27 (m, 2H, CH₂); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −110.99 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 174.5, 159.6 (d, ³J_CF = 5.9 Hz), 157.0 (d, ³J_CF = 5.9 Hz), 146.7 (t, ³J_CF = 10.4 Hz), 122.4 (t, ³J_CF = 16.3 Hz), 108.8–108.3 (m), 49.1 (t, ³J_CF = 2.1 Hz), 30.3, 19.7; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₀H₉F₂N₂O₃ 243.0581, found: 243.0572.

Compound 5i: 66 mg, 62%, yellow oil. MS (ESI, pos. ion) m/z: 216.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.80–6.72 (m, 2H), 3.72 (t, J = 7.0 Hz, 2H), 2.56 (t, J = 8.1 Hz, 2H), 2.33–2.17 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −108.04 (t, J = 5.6 Hz), −114.61 (d, J = 7.1 Hz); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 175.0, 162.5 (t, ³J_CF = 14.9 Hz), 160.8 (t, ³J_CF = 14.9 Hz), 159.3 (ddd, ¹J_CF = 253.3, ³J_CF = 15.3, 7.7 Hz), 112.4 (td, ³J_CF = 16.8, 5.0 Hz), 101.5–100.5 (m), 49.4, 30.3, 19.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₀H₉F₃NO 216.0636, found: 216.0631.

Compound 5f: To a solution of compound 5d (500 mg, 2.0 mmol) in MeOH (10 mL) was added Pd/C (50 mg, 10%) and charged with H₂. The reaction mixture was heated to 60 °C and stirred for 5 h, then cooled to room temperature. The mixture was filtered and the filter was concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/hexanes (v/v) = 1/10 to 2/3) to give compound 5f (360 mg, 80%) as pale yellow oil; MS (ESI, pos. ion) m/z: 213.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.27–6.08 (m, 2H), 4.22 (brs, 2H), 3.66 (t, J = 7.0 Hz, 2H), 2.52 (t, J = 8.1 Hz, 2H), 2.33–2.08 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −119.53 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 175.5, 159.8 (dd, ¹J_CF = 248.1, ³J_CF = 8.0 Hz), 148.3 (t, ³J_CF = 13.4 Hz), 105.0 (t, ³J_CF = 17.3 Hz), 98.4–98.0 (m), 49.9, 30.5, 19.1; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₀H₁₁F₂N₂O 213.0839, found: 213.0840.

Compound 5g and Compound 5h: To a solution of compound 5f (246 mg, 1.16 mmol), sulfuric acid (1.5 mL) and formaldehyde (261 mg, 3.48 mmol, 40% in water) in methanol (10 mL) was added NaBH₄ (226 mg, 5.79 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved with EtOAc (100 mL). The organic phase was washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/1) to give compound 5g (31 mg, 12%) as pale yellow oil and compound 5h (66 mg, 24%) as pale yellow oil.

Compound 5g: MS (ESI, pos. ion) m/z: 227.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.16–6.02 (m, 2H), 4.39 (brs, 1H), 3.66 (t, J = 7.0 Hz, 2H), 2.75 (s, 3H), 2.53 (t, J = 8.1 Hz, 2H), 2.28–2.12 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −119.85 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 175.5, 159.9 (dd, ¹J_CF = 247.3, ³J_CF = 8.4 Hz), 150.4 (t, ³J_CF = 12.9 Hz), 103.7 (t, ³J_CF = 17.5 Hz), 95.4 (d, ²J_CF = 26.3 Hz), 50.0, 30.5 (d, ³J_CF = 3.6 Hz), 19.1; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₁H₁₃F₂N₂O 227.0996, found: 227.0995.

Compound 5h: MS (ESI, pos. ion) m/z: 241.2 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.29–6.11 (m, 2H), 3.67 (t, J = 7.0 Hz, 2H), 2.92 (s, 6H), 2.53 (t, J = 8.1 Hz, 2H), 2.28–2.10 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −119.45 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 175.4, 159.8 (dd, ¹J_CF = 246.5, ³J_CF = 8.8 Hz), 150.9 (t, ³J_CF = 13.1 Hz), 103.2 (t, ³J_CF = 17.3 Hz), 95.8–95.0 (m), 49.9, 40.3, 30.5, 19.1; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₅F₂N₂O 241.1152, found: 241.1168.

4.2.7. General procedure for the synthesis of compounds 6a–6w. A mixture of 4-substituted-2,6-difluoroaniline (10 mmol) and 2-methylenesuccinic acid (1.30 g, 10 mmol) was heated at 180 °C for 7 h in a sealed tube. The reaction vessel was then cooled to room temperature. The crude product (brown oil) was dissolved in MeOH (50 mL) and concentrated sulfuric acid (0.5 mL) was added. The reaction mixture was refluxed for 4 h and then concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/hexanes (v/v) = 1/10 to 1/2) to give compound 6.

Compound 6a: 368 mg, 43%, pale yellow oil. MS (ESI, pos. ion) m/z: 270.3 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.78 (d, J = 9.3 Hz, 2H), 3.93 (m, 2H), 3.77 (s, 3H), 3.47 (m, 1H), 2.85 (ABX, J = 17.2, 7.8, 9.6 Hz, 2H), 2.34 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −118.56 (s), −119.35 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 172.7, 172.3, 158.6 (dd, ¹J_CF = 251.9, ³J_CF = 5.8 Hz), 140.8 (t, ³J_CF = 9.5 Hz), 112.8 (dd, ³J_CF = 19.9, 2.7 Hz), 112.0 (t, ³J_CF = 16.7 Hz), 52.7, 50.9, 37.4, 33.4, 21.5; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₄F₂NO₃ 270.0942; found: 270.0936.

Compound 6b: 657 mg, 75%, pale yellow oil. MS (ESI, pos. ion) m/z: 286.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.52 (m, 2H), 3.93 (m, 2H), 3.77 (s, 3H), 3.47 (m, 1H), 2.85 (ABX, J = 17.2, 7.8, 9.6 Hz, 2H), 2.34 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.75 (s), −117.60 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 172.8, 172.4, 159.6 (dd, ¹J_CF = 250.7, ³J_CF = 8.0 Hz), 160.5 (t, ³J_CF = 13.5 Hz), 107.6 (t, ³J_CF = 17.1 Hz), 98.7 (dd, ²J_CF = 23.9, ³J_CF = 3.2 Hz), 56.1, 52.6, 51.1, 37, 33.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₄F₂NO₄ 286.0891; found: 286.0859.

Compound 6c: 365 mg, 54%, pale yellow oil. MS (ESI, pos. ion) m/z: 314.0 ([M + H]⁺); ¹H NMR (600 MHz, CDCl₃): δ (ppm) 7.28 (d, J = 8.2 Hz, 2H), 4.02 (dd, J = 9.6, 6.6 Hz, 1H), 3.97 (t, J = 9.1 Hz, 1H), 3.79 (s, 3H), 3.51 (dt, J = 16.1, 8.0 Hz, 1H), 2.88 (ABX, J = 17.5, 7.6, 9.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −63.69 (s), −112.71 (s), −113.42 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.5, 172.0, 158.8 (dd, ¹J_CF = 255.9, ³J_CF = 5.2 Hz), 131.9–131.8 (m), 131.7–131.4 (m), 123.4, 121.6, 118.6–118.1 (m), 110.2 (d, ²J_CF = 23.5 Hz), 52.9, 50.6, 37.5, 33.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₁F₅NO₃ 314.0840; found: 314.0795.

Compound 6e: 429 mg, 43%, pale yellow oil. MS (ESI, pos. ion) m/z: 314.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.66 (d, J = 8.6 Hz, 2H), 4.05 (m, 2H), 3.93 (s, 3H), 3.79 (s, 3H), 3.53 (m, 1H), 2.96 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −114.76 (s), −115.37 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 173.8, 172.4, 164.5 (t, ³J_CF = 3.0 Hz), 158.5 (dd, ¹J_CF = 254.3, ³J_CF = 5.1 Hz), 131.9 (t, ³J_CF = 9.2 Hz), 118.5 (t, ³J_CF = 16.4 Hz), 113.6 (dd, ²J_CF = 22.1, ³J_CF = 3.3 Hz), 53.0 (d, ³J_CF = 13.1 Hz), 51.2, 37.4, 33.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₄F₂NO₅ 314.0840; found: 314.0795.

Compound 6f: the method as compound 5f. 390 mg, 93%, yellow oil. MS (ESI, pos. ion) m/z: 271.3 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.18 (d, J = 10.2 Hz, 2H), 4.04 (brs, 2H), 3.92–3.80 (m, 2H), 3.77 (s, 3H), 3.50–3.34 (m, 1H), 2.82 (ABX, J = 17.2, 7.8, 9.7 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −118.89 (s), −119.70 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 172.9 (s), 172.7 (s), 159.8 (dd, ¹J_CF = 248.6, ³J_CF = 7.7 Hz), 148.5 (t, ³J_CF = 13.5 Hz), 104.3 (t, ³J_CF = 16.3 Hz), 98.2 (d, ²J_CF = 23.8 Hz), 52.6, 51.34, 37.2, 33.; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₃F₂N₂O3 271.0894, found: 271.0809.

Compound 6g: the method as compound 5g. 36 mg, 8%, yellow oil. MS (ESI, pos. ion) m/z: 285.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.08 (d, J = 10.9 Hz, 2H), 4.33 (d, J = 4.3 Hz, 1H), 3.86 (p, J = 9.6 Hz, 2H), 3.76 (s, 3H), 3.49–3.36 (m, 1H), 2.83 (ABX, J = 17.2, 7.9, 9.7 Hz, 2H), 2.74 (d, J = 5.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −119.31 (s), −120.0988 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.9, 172.9, 159.9 (dd, ¹J_CF = 247.6, ³J_CF = 8.2 Hz), 150.7 (t, ³J_CF = 13.5 Hz), 102.6 (t, ³J_CF = 17.5 Hz), 95.3 (dd, ²J_CF = 23.5, ³J_CF = 7.5 Hz), 52.6, 51.4, 37.1, 33.4, 30.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₅F₂N₂O₃ 285.1051, found: 285.1050.

Compound 6h: the method as compound 5h. 58 mg, 13%, yellow oil. MS (ESI, pos. ion) m/z: 299.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.21 (d, J = 12.0 Hz, 2H), 3.88 (m, 2H), 3.77 (s, 3H), 3.44 (m, 1H), 2.93 (s, 6H), 2.83 (ABX, J = 17.2, 8.0, 9.7 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −118.84 (s), −119.67 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 173.0, 172.7, 159.8 (dd, ¹J_CF = 246.9, ³J_CF = 8.4 Hz), 151.2 (t, ³J_CF = 13.1 Hz), 102.2 (t, ³J_CF = 17.6 Hz), 95.4 (dd, ²J_CF = 24.0, ³J_CF = 3.7 Hz), 52.6, 51.3, 40.3, 37.2, 33.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₇F₂N₂O₃ 299.1207, found: 299.1218.

Compound 6i: 85 mg, 61%, yellow oil. MS (ESI, pos. ion) m/z: 274.2 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.74 (p, J = 3.2 Hz, 2H), 3.97–3.84 (m, 2H), 3.76 (s, 3H), 3.46 (dt, J = 16.1, 8.0 Hz, 1H), 2.83 (ABX, J = 17.3, 7.7, 9.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −107.20 (t, J = 6.0 Hz), −113.92 (s), −114.72 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.6, 172.3, 162.7 (t, ³J_CF = 14.8 Hz), 161.0 (t, ³J_CF = 14.8 Hz), 159.2 (ddd, ¹J_CF = 254.0, ³J_CF = 15.3, 7.4 Hz), 111.5 (td, ³J_CF = 16.6, 5.1 Hz), 101.2 (t, ²J_CF = 25.1 Hz), 52.7, 50.7, 37.2, 33.2; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₁F₃NO₃ 274.0691, found: 274.0647.

Compound 6j: 132 mg, 59%, yellow oil. MS (ESI, pos. ion) m/z: 290.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.97 (d, J = 8.1 Hz, 2H), 3.88 (p, J = 9.5 Hz, 2H), 3.71 (s, 3H), 3.43 (dt, J = 16.0, 7.8 Hz, 1H), 2.79 (ABX, J = 17.4, 7.6, 9.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −114.90 (s), −115.58 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.4, 172.1, 158.6 (dd, ¹J_CF = 255.7, ³J_CF = 6.3 Hz), 134.4 (t, ³J_CF = 12.7 Hz), 113.8 (t, ³J_CF = 16.5 Hz), 113.3 (dd, ²J_CF = 23.1, ³J_CF = 1.5 Hz), 52.6, 50.5, 37.1, 33.0; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₁ClF₂NO₃ 290.0396, found: 290.0349.

Compound 6k: 112 mg, 42%, yellow oil. MS (ESI, pos. ion) m/z: 334.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.18 (d, J = 7.8 Hz, 2H), 4.00–3.87 (m, 2H), 3.78 (s, 3H), 3.53–3.40 (m, 1H), 2.85 (ABX, J = 17.4, 7.7, 9.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −114.94 (s), −115.72 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.6, 172.1, 158.8 (dd, ¹J_CF = 256.8, ³J_CF = 6.0 Hz), 121.5 (t, ³J_CF = 11.8 Hz), 116.4 (d, ²J_CF = 22.9 Hz), 114.4 (t, ³J_CF = 16.2 Hz), 52.8, 50.7, 37.4, 33.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₁BrF₂NO₃ 333.9890, found: 333.9885.

Compound 6l: 65 mg, 37%, yellow oil. MS (ESI, pos. ion) m/z: 382.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.36 (d, J = 7.6 Hz, 2H), 4.01–3.84 (m, 2H), 3.78 (s, 3H), 3.53–3.39 (m, 1H), 2.84 (ABX, J = 17.4, 7.7, 9.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −115.44 (s), −116.20 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.6, 172.1, 158.5 (dd, ¹J_CF = 258.2, ³J_CF = 5.4 Hz), 122.1 (d, ²J_CF = 22.2 Hz), 115.2 (t, ³J_CF = 16.3 Hz), 91.0 (t, ³J_CF = 10.0 Hz), 52.8, 50.6, 37.4, 33.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₁F₂INO₃ 381.9752, found: 381.9997.

Compound 6o: 154 mg, 73%, yellow oil. MS (ESI, pos. ion) m/z: 300.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.50 (d, J = 10.1 Hz, 2H), 3.98 (q, J = 7.0 Hz, 2H), 3.95–3.83 (m, 2H), 3.77 (s, 3H), 3.52–3.38 (m, 1H), 2.84 (ABX, J = 17.2, 7.8, 9.6 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.02 (s), −117.89 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.8, 172.5, 159.5 (dd, ¹J_CF = 250.2, ³J_CF = 8.0 Hz), 159.8 (t, ³J_CF = 13.3 Hz), 107.2 (t, ³J_CF = 17.1 Hz), 99.1 (dd, ²J_CF = 23.5, ³J_CF = 2.9 Hz), 64.6, 52.7, 51.1, 37.2, 33.4, 14.6; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₆F₂NO₄ 300.1047, found: 300.1048.

Compound 6u: 65 mg, 33%, yellow oil. MS (ESI, pos. ion) m/z: 281.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.30 (d, J = 7.8 Hz, 2H), 4.06–3.89 (m, 2H), 3.77 (s, 3H), 3.55–3.41 (m, 1H), 2.85 (ABX, J = 17.5, 7.5, 9.5 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −111.95 (s), −112.30 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.3, 171.8, 158.7 (dd, ¹J_CF = 257.0, ³J_CF = 5.7 Hz), 120.3 (t, ³J_CF = 16.0 Hz), 116.6 (dd, ²J_CF = 23.9, ³J_CF = 3.8 Hz), 116.2 (t, ³J_CF = 3.2 Hz), 112.6 (t, ³J_CF = 11.6 Hz), 52.8, 50.5, 37.5, 33.2; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₁F₂N₂O₃ 281.0738, found: 281.0728.

Compound 6p: To a solution of compound 6l (260 mg, 0.68 mmol), tributyl(vinyl)stannane (221 mg, 0.70 mmol) and chlorolithium (95 mg, 2.25 mmol) in DMF (5 mL) was added PdCl₂(PPh₃)₂ (62 mg, 0.1 mmol) and charged with N₂. The reaction mixture was heated to 80 °C and stirred overnight, then concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/5) to give compound 6p (140 mg, 73%) as colorless oil; MS (ESI, pos. ion) m/z: 282.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.00 (d, J = 9.5 Hz, 2H), 6.60 (dd, J = 17.5, 10.8 Hz, 1H), 5.75 (d, J = 17.5 Hz, 1H), 5.38 (d, J = 10.8 Hz, 1H), 4.03–3.86 (m, 2H), 3.78 (s, 3H), 3.54–3.41 (m, 1H), 2.86 (ABX, J = 17.3, 7.8, 9.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.42 (s), −118.16 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.7, 172.2, 158.9 (dd, ¹J_CF = 252.2, ³J_CF = 6.0 Hz), 139.7 (t, ³J_CF = 9.4 Hz), 134.6, 117.4, 113.8 (t, ³J_CF = 16.9 Hz), 109.8 (d, ²J_CF = 20.7 Hz), 52.7, 50.9, 37.4, 33.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₄F₂NO₃ 282.0942, found: 282.0931.

Compound 6q: the method as compound 6p. 337 mg, 81%, colorless oil. MS (ESI, pos. ion) m/z: 296.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.91 (d, J = 9.8 Hz, 2H), 6.35–6.18 (m, 2H), 4.01–3.85 (m, 2H), 3.78 (s, 3H), 3.54–3.40 (m, 1H), 2.85 (ABX, J = 17.3, 7.8, 9.6 Hz, 2H), 1.87 (d, J = 5.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.98 (s), −118.75 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.7, 172.3, 158.9 (dd, ¹J_CF = 251.5, ³J_CF = 6.0 Hz), 140.2 (t, ³J_CF = 9.7 Hz), 129.7, 128.9, 112.7 (t, ³J_CF = 16.8 Hz), 109.3 (d, ²J_CF = 20.4 Hz), 52.7, 50.9, 37.4, 33.4, 18.5; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₆F₂NO₃ 296.1098, found: 296.1099.

Compound 6m: the method as compound 5f. 82 mg, 91%, colorless oil. MS (ESI, pos. ion) m/z: 284.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.81 (d, J = 9.3 Hz, 2H), 4.00–3.85 (m, 2H), 3.77 (s, 3H), 3.47 (dt, J = 16.4, 8.1 Hz, 1H), 2.85 (ABX, J = 17.2, 7.8, 9.6 Hz, 2H), 2.63 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −118.28 (s), −119.07 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) 172.7, 172.3, 158.7 (dd, ¹J_CF = 252.0, ³J_CF = 5.8 Hz), 147.0 (t, ³J_CF = 8.8 Hz), 112.0 (t, ³J_CF = 16.7 Hz), 111.6 (d, ³J_CF = 19.8 Hz), 52.6, 50.9, 37.3, 33.4, 28.8, 14.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₆F₂NO₃ 284.1098, found: 284.1092.

Compound 6n: the method as compound 5f. 77 mg, 84%, colorless oil. MS (ESI, pos. ion) m/z: 298.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 6.78 (d, J = 9.4 Hz, 2H), 4.01–3.84 (m, 2H), 3.76 (s, 3H), 3.52–3.39 (m, 1H), 2.84 (ABX, J = 17.2, 7.8, 9.6 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H), 1.68–1.54 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −118.39 (s), −119.16 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.7, 172.3, 158.6 (dd, ¹J_CF = 252.0, ³J_CF = 5.6 Hz), 145.5 (t, ³J_CF = 8.8 Hz), 112.0 (t, ³J_CF = 17.0 Hz), 52.7, 50.9, 37.8, 37.3, 33.4, 24.0, 13.7; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₈F₂NO₃ 298.1255, found: 298.1252.

Compound 6r: to a solution of compound 6l (383 mg, 1.00 mmol), phenylboronic acid (247 mg, 2.03 mmol) and sodium carbonate (233 mg, 2.2 mmol) in 1,4-dioxane (2 mL) and water (2 mL) was added Pd(dppf)Cl₂·CH₂Cl₂ (165 mg, 0.20 mmol) and charged with N₂. The reaction mixture was heated to 100 °C and stirred overnight, then concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/1) to give compound 6r (270 mg, 82%) as colorless oil; MS (ESI, pos. ion) m/z: 332.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.49 (d, J = 7.4 Hz, 2H), 7.40 (m, 3H), 7.18 (d, J = 9.7 Hz, 2H), 3.97 (p, J = 9.6 Hz, 2H), 3.76 (s, 3H), 3.55–3.42 (m, 1H), 2.86 (ABX, J = 17.4, 7.6, 9.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −116.85 (s), −117.62 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 172.8, 172.7, 158.9 (dd, ¹J_CF = 252.4, ³J_CF = 5.9 Hz), 143.4 (t, ³J_CF = 9.6 Hz), 138.3, 129.2, 128.8, 127.0, 113.3 (t, ³J_CF = 16.8 Hz), 110.8 (dd, ²J_CF = 20.9, ³J_CF = 2.7 Hz), 52.7, 51.0, 37.3, 33.4; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₆F₂NO₃ 332.1098, found: 332.1089.

Compound 6s: to a solution of compound 6l (439 mg, 1.15 mmol), 1,2-bis(diphenylphosphino)ethane (50 mg, 0.12 mmol), diacetylpalladium (14 mg, 0.07 mmol) and formyloxysodium (165 mg, 2.43 mmol) in DMSO (4 mL) was added 2,2-dimethylpropanenitrile (1.5 mL) and charged with N₂. The reaction mixture was heated to 120 °C and stirred overnight, then concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/1) to give compound 6s (160 mg, 49%) as colorless oil; MS (ESI, pos. ion) m/z: 284.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 9.92 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 4.12–3.91 (m, 2H), 3.79 (s, 3H), 3.57–3.44 (m, 1H), 2.89 (ABX, J = 17.4, 7.6, 9.6 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −113.13 (s), −113.72 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) 188.8, 172.4, 171.9, 159.2 (dd, ¹J_CF = 256.7, ³J_CF = 4.6 Hz), 136.7 (t, ³J_CF = 7.2 Hz), 130.0 (d, ³J_CF = 4.4 Hz), 120.6 (t, ³J_CF = 16.5 Hz), 113.0 (d, ²J_CF = 20.7 Hz), 52.8, 50.6, 37.5, 33.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₂F₂NO₄ 284.0734, found: 284.0750.

Compound 6t: to a solution of compound 6l (382 mg, 1.00 mmol), 1,3-bis(diphenylphosphino)propane (87 mg, 0.20 mmol), diacetylpalladium (27 mg, 0.14 mmol) and Na₂CO₃ (298 mg, 2.81 mmol) in n-butanol (3 mL) was added 1-vinyloxybutane (504 mg, 5.03 mmol) and charged with N₂. The reaction mixture was heated to 120 °C and stirred overnight, then concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/2) to give compound 6t (122 mg, 41%) as colorless oil; MS (ESI, pos. ion) m/z: 298.4 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 7.56 (d, J = 8.8 Hz, 2H), 4.08–3.91 (m, 2H), 3.79 (s, 3H), 3.50 (dt, J = 16.0, 8.0 Hz, 1H), 2.89 (ABX, J = 17.4, 7.7, 9.5 Hz, 2H), 2.58 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −114.25, 114.86 (s); ¹³C NMR (101 MHz, CDCl₃) δ 194.8, 172.5, 171.9, 158.8 (dd, ¹J_CF = 255.3, ³J_CF = 5.2 Hz), 137.8 (t, ³J_CF = 7.2 Hz), 130.1 (d, ³J_CF = 3.4 Hz), 119.6–119.0 (m), 112.2 (d, ³J_CF = 18.4 Hz), 52.8, 50.7, 37.5, 33.4, 26.6; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₄F₂NO₄ 298.0891, found: 298.0902.

Compound 6v: a solution of compound 6f (568 mg, 2.10 mmol) in formic acid (7 mL) was heated to reflux and stirred for 1 h. The reaction was quenched with saturated Na₂CO₃ solution (100 mL), then extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 3/1) to give compound 6v (322 mg, 51%) as yellow oil; MS (ESI, pos. ion) m/z: 299.0 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 9.04 (s, 1H), 8.20 (s, 1H), 7.08 (d, J = 12.6 Hz, 2H), 3.99–3.83 (m, 2H), 3.78 (s, 3H), 3.55–3.43 (m, 1H), 2.89 (ABX, J = 17.4, 7.4, 9.7 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −117.46 (s), −117.98 (s); ¹³C NMR (101 MHz, CDCl₃): δ (ppm) ¹³C NMR (101 MHz, CDCl₃) δ 173.8, 172.5, 159.6, 158.7 (dd, ¹J_CF = 250.3, ³J_CF = 6.6 Hz), 139.1 (t, ³J_CF = 13.4 Hz), 109.6 (t, ³J_CF = 17.0 Hz), 103.9 (dd, ²J_CF = 24.7, ³J_CF = 3.0 Hz), 52.8, 51.4, 37.2, 33.5; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₃F₂N₂O₄ 299.0843, found: 299.0841.

Compound 6w: to a solution of compound 6f (139 mg, 0.51 mmol), acetic acid (163 mg, 2.72 mmol), and Et₃N (298 mg, 2.81 mmol) in CH₂Cl₂ (10 mL) was added HATU (383 mg, 1.01 mmol). The reaction mixture was heated to reflux and stirred overnight, then concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/0) to give compound 6w (139 mg, 87%) as yellow oil; MS (ESI, pos. ion) m/z: 313.1 ([M + H]⁺); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 9.09 (s, 1H), 7.04 (d, J = 10.8 Hz, 2H), 3.96–3.84 (m, 2H), 3.78 (s, 3H), 3.55–3.43 (m, 1H), 2.91 (ABX, J = 17.4, 7.4, 9.7 Hz, 2H), 2.05 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃): δ (ppm) −118.54 (s), −119.11 (s); ¹³C NMR (151 MHz, CDCl₃): δ (ppm) ¹³C NMR (101 MHz, CDCl₃) δ 174.0, 172.6, 169.4, 158.7 (dd, ¹J_CF = 249.3, ³J_CF = 6.6 Hz), 140.4 (t, ³J_CF = 13.4 Hz), 108.6 (t, ³J_CF = 17.1 Hz), 103.3 (d, ²J_CF = 25.8 Hz), 52.9, 51.6, 37.1, 33.6, 24.2; HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₅F₂N₂O₄ 313.1000, found: 313.0999.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1904410 and 1915197. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2ra06660b

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