An efficient and regioselective synthetic approach towards fluorinated quinolinylphosphonates

Abstract

A synthesis of quinolines substituted by both CF₂ and phosphonate groups at the 2- and 3-positions respectively, has been successfully described. In particular, the regioselective heterocyclisation of appropriate (2-cyclohexyliminomethyl)anilines with CF₂X-containing alkynylphosphonates promoted by K₂CO₃ was carried out in dry toluene under reflux. Substituents influenced this reaction either electronically or sterically.

---

Introduction

The quinoline core has been an important target for organic synthesis since it appears in various molecules with enhanced biological activity.¹ Such compounds frequently show anti-malaria, anti-cancer, anti-inflammatory, anti-fungal and also anti-HIV properties.² Thus, quinine A is a common anti-malarial agent isolated from cinchona tree bark in 1820 by Pelletier.³ Camptothecin B being often used as an anti-cancer agent has also exhibited a significant anti-retroviral activity at dose levels that are well tolerated by cells.⁴

In 1993 Chen et al. isolated benzo[h]quinoline (Toddaquinoline) C which is a constituent of many Asian folk medicines.⁵ Mefloquine D substituted by fluorinated groups, on the other hand, developed in the 1970s, is an orally administered medication for the treatment and prevention of malaria.⁶

The role of incorporating phosphonate and fluorinated groups into organic compounds (aromatic and/or heteroaromatic) to alter their pharmacological properties has been well documented in the literature.⁷ Particularly, the phosphonate group as phosphate mimics has proved to be valuable in numerous applications.^7c,8 On the other side, fluorine uniquely affects the properties of organic compounds, for instance an introduction of this atom/group into pharmaceuticals can provide better bioavailability, lipophilicity and metabolic stability, thus increasing the strength of a compound's interaction with protein.^7d Therefore, incorporating fluorine-containing groups into organophosphonates is indeed very desirable.

The syntheses of the quinoline ring have been usually performed via Friedlander,⁹ Combes,¹⁰ Skraup,¹¹ Doebner-von Miller,¹² Conrad-Limpach,¹³ and Pfitzinger¹⁴ methods. However, due to the fact that β-dicarbonyl substrates are applied, the possibility of synthesizing polyfunctionalised quinolines is, indeed, limited. Among them, ynones and other related systems were also used as starting materials, even though transition metal-promoted catalysis or the additional presence of an electrophile is required.¹⁵ It must be mentioned here that only a few examples regarding the heterocyclisation reaction of either symmetrical or terminal alkynes to achieve quinolines have been reported, although with poor regioselectivity.¹⁶ Nevertheless, to the best of our knowledge, there have been no reports hitherto published concerning unsymmetrical acetylenes towards the regioselective synthesis of 2,3-disubstituted quinolines, bearing –CF₂X and –P(O)(OEt)₂ groups, respectively. Hence, we wish to report for the first time a one-pot, efficient, straightforward, and regioselective methodology to produce fluorinated quinolinylphosphonates.

Results and discussion

Recently, we have reported the synthesis of fluorine- and phosphorus-containing azaxanthones via heterocyclisation of non-aromatic 1,2-aminoaldehydes with suitable CF₂X-containing acetylenephosphonates.^17a Therefore, we investigated the preparation of the desired quinolinylphosphonates by employing an ortho-aminobenzaldehyde to react with the respective alkyne 3a–e bearing –CF₂X and the phosphonate groups. Due to the fact that 2-aminobenzaldehyde 1 is susceptible to self-condensation,¹⁸ we then performed a Borsche's modification to utilize more stable o-aminobenzaldehyde imines 2 (Scheme 1).¹⁹ The desired imines were successfully synthesized by the condensation of an amine with an o-nitrobenzaldehyde followed by sodium sulfide reduction.²⁰

Scheme 1 Synthetic approach towards 2,3-difuntionalized quinolines 3a–t.

The heterocyclisation reaction of substrates 2 and 3 proceeded in the presence of a base in dry toluene under reflux to afford CF₂X-containing quinolinylphosphonates 4a–t (where X = F, Cl, Br, H and CF₃) in good to excellent yields (Table 2). The progress of the reaction was monitored by ¹⁹F and ³¹P NMR spectroscopy of the reaction mixture.

We observed that reacting 2a–d with 3a–e in the absence of a basic mediator did not occur, even at extended reaction times (entry 1, Table 1). To find optimum reaction conditions, a various mediators, such as K₂CO₃, NEt₃, i-Pr₂NEt and DABCO were employed (Table 1). These experiments were conducted by the action of a stoichiometric ratio of 2a and 3a in toluene under reflux. As a result, K₂CO₃ showed the best mediating ability furnishing product 4a in a 97% isolated yield (entry 2, Table 1). It should be pointed out that weaker bases, such as NEt₃ and i-Pr₂NEt provided 4a only in the range of 5–18% of isolated yields (entries 3–4, Table 1). Notwithstanding the very good conversion of 4 detected in the case of DABCO, the desired compound 4a was isolated in rather low yield (entry 6, Table 1), probably due to the decomposition of intermediates to an intractable material.

Table 1 Screening of the reaction conditions

Entry	Base	Solvent	R	Temp. [°C]	Convn.^a [%]	Yield^b [%]
a Conversion was established by ^19F and ^31P NMR after 12h. b Isolated yields.
1	None	Toluene	Cy	112	—	—
2	K2CO3	Toluene	Cy	112	100	97
3	K2CO3	Toluene	Cy	50	60	39
4	NEt3	Toluene	Cy	112	15	5
5	iPr2NEt	Toluene	Cy	112	50	18
6	DABCO	Toluene	Cy	112	100	31
7	K2CO3	Benzene	Cy	80	80	64
8	K2CO3	Acetone	Cy	56	50	30
9	K2CO3	DMSO	Cy	25	69	42
10	K2CO3	Toluene	Tol	112	100	96
11	K2CO3	Toluene	i-Bu	112	40	24

---

Furthermore, the role of the reaction medium, for instance toluene, benzene, acetone and DMSO upon the formation of the target products, was studied (Table 1). Regarding the conditions used, the reaction in toluene proceeded almost quantitatively (97%). Benzene, on the other hand, provided the target product 4a in only 64% isolated yield (entry 7, Table 1), whereas more polar solvents (acetone and DMSO) gave 4a in even lower yields (entries 8–9, Table 1).

In addition, we also screened a steric effect of alkyl/aryl groups adjacent to an azomethine moiety in 2 onto the synthetic efficiency, namely iso-butyl, cyclohexyl and p-methylphenyl. Interestingly, the cyclohexyl and p-toluidine differed only slightly in such heterocyclisations giving 4a in comparable reaction yields (entries 2 and 10, Table 1). However, iso-butyl as being a less bulky group provided 4a in a remarkably lower yield (entry 11, Table 1).

We then extended our study to investigate the scope of the process by taking differently substituted substrates 2a–d. Table 2 illustrates that the best results were observed when an electron-accepting group is connected to the aromatic ring, namely –CF₃2d (entries 4, 8, 12, 16 and 20, Table 2). As assumed, π-electron-donating groups, such as –OMe 2c significantly reduced the reaction yields; whereas –Cl 2b provided the target products 4 only in slightly lesser yields when compared to non-substituted 2a. Such findings can be easily explained by the increased nucleophilicity of the –NH₂ group due to the presence of π-EDG (–OMe, –Cl), thus affecting the efficiency of this heterocyclisation by lowering the reaction yields.

Table 2 Preparation of CF₂X-containing quinolinylphosphonates 4a–t

Entry	R^1	R^2	X	Product	Time [h]	Yield^a [%]
a Isolated yields
1	H	H	F	4a	10	97
2	Cl	H	F	4b	11	91
3	OMe	OMe	F	4c	13	80
4	H	CF3	F	4d	10	99
5	H	H	Cl	4e	11	90
6	Cl	H	Cl	4f	11	81
7	OMe	OMe	Cl	4g	13	71
8	H	CF3	Cl	4h	12	94
9	H	H	Br	4i	12	88
10	Cl	H	Br	4j	12	80
11	OMe	OMe	Br	4k	14	71
12	H	CF3	Br	4l	11	93
13	H	H	H	4m	13	60
14	Cl	H	H	4n	14	54
15	OMe	OMe	H	4o	16	42
16	H	CF3	H	4p	13	69
17	H	H	CF3	4q	14	65
18	Cl	H	CF3	4r	14	53
19	OMe	OMe	CF3	4s	15	40
20	H	CF3	CF3	4t	12	67

---

Finally, we found out that fluorine-containing groups attached to alkyne 3 influenced this cyclisation reaction either electronically or sterically. In general, the more electrophilic the carbon atom adjacent to the –CF₂X groups is, the better yields are observed. The –CF₃ group of 3a with the greatest electron-withdrawing property in this series, indeed, furnished the corresponding 4a–d in very good to excellent yields (entries 1–4, Table 2). Whereas 3b (X = Cl) and 3c (X = Br) provided products 4e–h and 4i–l in lower reaction yields, when compared to 4a, respectively (entries 5–12, Table 2). The significant lowering of the reaction yields of CF₂H–substituted quinolinylphosphonates 4m–p can be explained by the smaller EWG-effect (entries 13–16, Table 2). It must be pointed out that the –C₂F₅ group 3e due to the steric requirements resulted in compounds 4q–t in moderate yields, when compared to the –CF₃ group (entries 17–20, Table 2).¹⁷

Monitoring the reaction between 2a and 3a by ¹⁹F NMR under optimized conditions (entry 2, Table 1) after 12 h showed the presence of substrate 3a (δ_F −51.4), the desired product 4a (δ_F −63.8) along with a signal around δ_F ≈ −66 which could belong to the non-aromatic 1,4-dihydroquinoline derivative 6. Moreover, the presence of the Michael adduct between 2a and 3a was not detected during the experiments. Encouraged by the experimental data given, we wish to propose a plausible synthetic pathway, where the base-activated –NH₂ group (hydrogen-bonded complex) of an imine 5 regioselectively attacks the more electrophilic carbon of the acetylenephosphonate's triple bond via a Michael-type addition followed by a concerted cyclisation to form the thermodynamically unstable 1,4-dihydroquinoline derivative 6 which after aromatisation and elimination of the amine gives CF₂X-containing quinolinylphosphonates 4a–t (Scheme 2).

Scheme 2 Possible synthetic pathway to CF₂X-substituted quinolinylphosphonates 4a–t.

The structures of the new compounds were successfully established by ¹H, ¹³C, ¹⁹F and ³¹P NMR spectroscopy analysis along with high-resolution mass spectrometry. Additionally, the structure of diethyl (6,7-dimethoxy-2-(trifluoromethyl)quinolin-3-yl)phosphonate 4c²¹ was confirmed by single-crystal X-ray diffraction analysis (Fig. 1) and compound 4g by 2D NMR spectroscopy (¹³C–¹H HETCOR).

Fig. 1 An ORTEP image of compound 4c. (Light Grey = H; Grey = C; Blue = N; Orange = P; Green = F; Red = O).

In the ¹H NMR, a characteristic doublet with the coupling constant ³J_H–P = 16 Hz at δ_H ≈ 9.1 was assigned to a proton at the 4-position. The C(4) carbon atom, in the ¹³C NMR, emerged as a doublet at δ_C ≈ 147 (²J_C–P = 7 Hz). The C(2) carbon atom exhibits an appropriate multiplicity, such as quartet of doublets (²J_C–F = 35 Hz, ²J_C–P = 8 Hz) for 4a–d and triplet of doublets (²J_C–F = 29 Hz, ²J_C–P = 8 Hz) for 4e–t at δ_C ≈ 148. The phosphorus nucleus of the phosphonate group split the carbon atom to whom is this particular group linked, to a doublet at δ_C ≈ 120 with ¹J_C–P = 186 Hz.

Conclusions

In summary, we have demonstrated a novel, straightforward, efficient and regioselective synthetic methodology involving a base-promoted heterocyclisation reaction of unsymmetrical electron-deficient fluorinated acetylenephosphonates with o-aminobenzaldehyde imines to give CF₂X-containing quinolinylphosphonates in good to excellent yields. The role of reaction media and mediators as well as the effect of substituents on the aryl ring and –CF₂X groups, were additionally discussed.

Experimental details

General Remarks

All reagents from commercial suppliers were used without further purification. All solvents were freshly distilled before use from appropriate drying agents. All other reagents were recrystallized. Reactions were performed under an atmosphere of dry argon. Analytical TLCs were performed with silica gel 60 F254 plates. Column chromatography was carried out using silica gel 60 (230–400 mesh ASTM). Melting points were determined without correction. NMR spectra were obtained on a spectrometer operating at 400 MHz for ¹H (TMS), 376 MHz for ¹⁹F (CFCl₃), 161 MHz for ³¹P (H₃PO₄) and 100 MHz for ¹³C (TMS). All measurements were accomplished in solution in CDCl₃. Mass spectrometry was established on a MicroTOF-Q fitted with an ESI source.

Procedure for the Preparation of Imine Derivatives 2a–d

To the mixture of a nitrobenzaldehyde and MgSO₄ in dry DCM a cyclohexylamine was added slowly. Then the suspension was refluxed for 4 h, then cooled down to ambient temperature and filtered off the remained MgSO₄. The filtrate was next concentrated under reduced pressure to give pure imine derivative. Subsequently an imine was dissolved in ethanol and warmed up to 80 °C. To the hot solution solid Na₂S (hydrate) was slowly added. The solution was maintained for an additional 20 min, cooled down to 0 °C and kept for 4 h. Thus formed precipitate was filtered off and the solution concentrated under reduced pressure. To the crude product, H₂O was added and a new drop of precipitate was formed, filtered off, washed with H₂O (3 × 100 mL) and dried to produce pure 2-(cyclohexylimino)-methyl)aniline derivatives.

2-((Cyclohexylimino)methyl)aniline 2a.²². Yellowish solid (90%), Mp = 45–48 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.35–1.82 (m, 10H), 3.10 (m, 1H), 6.40 (br s, 2H), 6.62 (d, J = 8.3 Hz, 1H), 6.66 (td, J = 7.5 Hz, J = 1.3 Hz, 1H), 7.11 (td, J = 7.2 Hz, J = 1.9 Hz, 1H), 7.18 (dd, J = 7.7 Hz, J = 1.9 Hz, 1H), 8.35 (s, 1H); ¹³C NMR (100 MHz) δ 24.7, 25.9, 35.0, 69.0, 115.4, 115.6, 118.0, 130.5, 133.3, 148.5, 161.5; HRMS (ESI): calcd for C₁₃H₁₉N₂ [M+H]⁺ 203.1543, found 203.1543.

4-Chloro-2-((cyclohexylimino)methyl)aniline 2b. Yellowish solid (85%), Mp = 91–93 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.72–1.81 (m, 10H), 3.11 (m, 1H), 6.40 (br s, 2H), 6.57 (d, J = 9.5 Hz, 1H), 7.05 (dd, J = 9.5 Hz, J = 1.9 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 8.26 (s, 1H); ¹³C NMR (100 MHz) δ 24.6, 25.8, 34.9, 69.8, 116.8, 118.9, 120.3, 130.3, 132.3, 147.0, 160.2; HRMS (ESI): calcd for C₁₃H₁₈ClN₂ [M + H]⁺ 237.1153, found 237.1146.

2-((Cyclohexylimino)methyl)-4,5-dimethoxyaniline 2c. Yellowish solid (85%); Mp = 134–137 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.25–1.81 (m, 10H), 3.06 (m, 1H), 2.80 (s, 2H), 3.84 (s, 3H), 6.19 (s, 1H), 6.24 (br s, 2H), 6.69 (s, 1H), 8.25 (s, 1H); ¹³C NMR (100 MHz) δ 24.7, 25.8, 35.1, 55.8, 56.8, 69.7, 99.4, 110.1, 116.2, 140.4, 144.3, 151.7, 160.4; HRMS (ESI) calcd for C₁₅H₂₃N₂O₂ [M+H]⁺ 263.1754, found 263.1751.

2-((Cyclohexylimino)methyl)-5-(trifluoromethyl)aniline 2d. Yellowish crystals (80%); Mp = 60–63 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.53–1.84 (m, 10H), 3.14 (m, 1H), 6.64 (br s, 2H), 6.84 (m, 2H), 7.27 (s, 1H), 8.38 (s, 1H); ¹³C NMR (100 MHz) δ 24.6, 25.7, 34.8, 69.9, 112.3, 120.1, 123.5 (q, ¹J_C–F = 275.1 Hz), 131.5 (q, ²J_C–F = 30.5 Hz), 133.6, 148.4, 160.5; ¹⁹F NMR (376 MHz) δ −63.1; HRMS (ESI): calcd for C₁₄H₁₈F₃N₂ [M+H]⁺ 271.1417, found 271.1412.

General Procedure for the Preparation of CF₂-Containing Quinolinylphosphonates 4a–t

The mixture of 2-((cyclohexylimino)methyl)aniline derivative 2 (5 mmol) and K₂CO₃ (5 mmol) was dissolved in dry toluene (25 mL) at ambient temperature. To the reaction mixture an alkyne 3 (5 mmol) was charged slowly. The solution was warmed up to reflux and stirred for 10–12 h. The K₂CO₃ was filtered off and the remained solution concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using DCM : EtOAc (5 : 1 ratio) as eluent.

Diethyl (2-(trifluoromethyl)quinolin-3-yl)phosphonate 4a

Yellowish oil (97%); ¹H NMR (400 MHz, CDCl₃) δ 1.30 (t, J = 7.1 Hz, 6H), 4.15 (m, 4H), 7.67 (td, J = 8.2 Hz, J = 1.1 Hz, 1H), 7.85 (td, J = 8.2 Hz, J = 1.3 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 8.15 (dd, J = 8.7 Hz, J = 0.7 Hz, 1H), 9.09 (d, ³J_H–P = 16.5 Hz, 1H); ¹³C NMR (100 MHz) δ 16.1 (d, J = 6.5 Hz), 63.1 (d, J = 5.9 Hz), 119.8 (d, ¹J_C–P = 186.5 Hz), 121.4 (q, ¹J_C–F = 275.7 Hz), 127.1 (d, ³J_C–P = 12.1 Hz), 128.5, 129.6, 129.8, 132.9, 147.5 (qd, ²J_C–F = 35.9 Hz, ²J_C–P = 8.4 Hz), 147.6 (d, ²J_C–P = 6.8 Hz); ¹⁹F NMR (376 MHz) δ −63.8; ³¹P NMR (161 MHz) δ 13.6; HRMS (ESI): calcd for C₁₄H₁₆F₃NO₃P [M+H]⁺ 334.0814, found 334.0812.

Diethyl (6-chloro-2-(trifluoromethyl)quinolin-3-yl)phosphonate 4b. Colourless oil (91%); ¹H NMR (400 MHz, CDCl₃) δ 1.34 (t, J = 6.7 Hz, 6H), 4.16 (m, 2H), 4.24 (m, 2H), 7.84 (dd, J = 8.6 Hz, J = 2.4 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 9.05 (d, ³J_H–P = 16.1 Hz, 1H); ¹³C NMR (100 MHz) δ 16.2 (d, J = 6.5 Hz), 63.3 (d, J = 6.2 Hz), 121.5 (q, ¹J_C–F = 278.6 Hz), 121.8 (d, ¹J_C–P = 183.7 Hz), 127.1, 127.8 (d, ³J_C–P = 11.5 Hz), 131.5, 133.9, 135.7 (d, ⁴J_C–P = 1.8 Hz), 145.6, 146.6 (d, ²J_C–P = 6.6 Hz), 147.2 (qd, ²J_C–F = 36.2 Hz, ²J_C–P = 7.8 Hz); ¹⁹F NMR (376 MHz) δ −63.8; ³¹P NMR (161 MHz) δ 12.9; HRMS (ESI): calcd for C₁₄H₁₄ClF₃NNaO₃P [M+Na]⁺ 390.0244, found 390.0245.

Diethyl (6,7-dimethoxy-2-(trifluoromethyl)quinolin-3-yl)phosphonate 4c. Yellowish crystals (80%); Mp = 186–190 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.33 (t, J = 7.2 Hz, 6H), 4.02 (s, 3H), 4.05 (s, 3H), 4.13 (m, 2H), 4.23 (m, 2H), 7.16 (s, 1H), 7.51 (s, 1H), 8.93 (d, ³J_H–P = 16.2 Hz, 1H); ¹³C NMR (100 MHz) δ 16.2 (d, J = 6.4 Hz), 56.4, 56.6, 62.9 (d, J = 6.1 Hz), 105.3, 108.2, 117.4 (d, ¹J_C–P = 186.7 Hz), 117.4 (q, ¹J_C–F = 275.8 Hz), 123.5 (d, ³J_C–P = 11.1 Hz), 144.8 (d, ²J_C–P = 7.4 Hz), 145.1 (qd, ²J_C–F = 35.4 Hz, ²J_C–P = 8.7 Hz), 152.2, 155.4; ¹⁹F NMR (376 MHz) δ −63.3; ³¹P NMR (161 MHz) δ 14.7 Hz; HRMS (ESI): calcd for C₁₆H₁₉F₃NNaO₅P [M+Na]⁺ 416.0845, found 416.0858.

Diethyl (2,7-bis(trifluoromethyl)quinolin-3-yl)phosphonate 4d. Yellowish oil (99%); ¹H NMR (400 MHz, CDCl₃) δ 1.36 (t, J = 6.9 Hz, 6H), 4.18 (m, 2H), 4.28 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.56 (s, 1H), 9.24 (d, ³J_H–P = 16.5 Hz, 1H); ¹³C NMR (100 MHz) δ 16.2 (d, J = 6.4 Hz), 63.4 (d, J = 6.1 Hz), 120.8 (q, ¹J_C–F = 276.5 Hz), 122.2 (d, ¹J_C–P = 185.5 Hz), 123.2 (q, ¹J_C–F = 270.8 Hz), 125.8 (qd, ⁴J_C–F = 3.2 Hz, ⁴J_C–P = 1.2 Hz), 127.8 (qd, ⁴J_C–F = 4.2 Hz, ⁴J_C–P = 1.3 Hz), 128.5 (dq, ³J_C–P = 11.9 Hz, ⁵J_C–F = 1.1 Hz), 129.8, 134.5 (q, ²J_C–F = 33.6 Hz), 146.2, 147.7 (d, ²J_C–P = 6.8 Hz), 148.6 (qd, ²J_C–F = 35.8 Hz, ²J_C–P = 8.9 Hz); ¹⁹F NMR (376 MHz) δ −63.0 (s, –CF₃), −64.0 (s, –CF₃); ³¹P NMR (161 MHz) δ 12.5; HRMS (ESI): calcd for C₁₅H₁₄F₆NNaO₃P [M+Na]⁺ 424.0508, found 424.0508.

Diethyl (2-(chlorodifluoromethyl)quinolin-3-yl)phosphonate 4e. Yellowish oil (90%); ¹H NMR (400 MHz, CDCl₃) δ 1.34 (t, J = 7.0 Hz, 6H), 4.15 (m, 2H), 4.22 (m, 2H), 7.69 (td, J = 8.1 Hz, J = 1.1 Hz, 1H), 7.87 (tt, J = 6.9 Hz, J = 1.4 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 9.13 (d, ³J_H–P = 16.4 Hz, 1H); ¹³C NMR (161 MHz) δ 16.3 (d, J = 6.7 Hz), 63.1 (d, J = 6.2 Hz), 118.5 (d, ¹J_C–P = 186.7 Hz), 124.1 (t, ¹J_C–F = 294.2 Hz), 126.8 (d, ³J_C–P = 11.7 Hz), 128.5, 129.5 (d, ⁵J_C–P = 1.2 Hz), 129.8 (d, ⁴J_C–P = 1.5 Hz), 133.0, 147.2 (dt, ⁴J_C–P = 1.4 Hz, ⁴J_C–F = 0.9 Hz), 147.8 (d, ²J_C–P = 7.2 Hz), 151.3 (td, ²J_C–F = 29.7 Hz, ²J_C–P = 8.7 Hz); ¹⁹F NMR (376 MHz) δ −51.9; ³¹P NMR (161 MHz) δ 13.9; HRMS (ESI): calcd for C₁₄H₁₅ClF₂NNaO₃P [M+Na]⁺ 372.0338, found 372.0323.

Diethyl (6-chloro-2-(chlorodifluoromethyl)quinolin-3-yl)phosphonate 4f. Colourless crystals (81%); Mp = 74–77 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, J = 6.9 Hz, 6H), 4.16 (m, 2H), 4.22 (m, 2H), 7.82 (dd, J = 9.1 Hz, J = 2.2 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 9.05 (d, ³J_H–P = 16.3 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.5 Hz), 63.3 (d, J = 6.3 Hz), 119.8 (d, ¹J_C–P = 186.7 Hz), 123.9 (td, ¹J_C–F = 293.0 Hz, ³J_C–P = 2.1 Hz), 127.1, 127.5 (d, ³J_C–P = 12.5 Hz), 131.5 (d, ⁴J_C–P = 1.9 Hz), 133.9, 135.6 (d, ⁵J_C–P = 1.5 Hz), 145.5 (dt, ⁴J_C–P = 1.3 Hz, ⁴J_C–F = 0.9 Hz), 146.7 (d, ²J_C–P = 7.1 Hz), 151.7 (td, ²J_C–F = 30.1 Hz, ²J_C–P = 8.6 Hz); ¹⁹F NMR (376 MHz) δ −52.1; ³¹P NMR (161 MHz) δ 13.3; HRMS (ESI): calcd for C₁₄H₁₄Cl₂F₂NNaO₃P [M+Na]⁺ 405.9949, found 405.9955.

Diethyl (2-(chlorodifluoromethyl)-6,7-dimethoxyquinolin-3-yl)phosphonate 4g. Colourless crystals (71%); Mp = 160–165 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.32 (t, J = 7.0 Hz, 6H), 4.00 (s, 3H), 4.02 (s, 3H), 4.12 (m, 2H), 4.21 (m, 2H), 7.13 (s, 1H), 7.47 (s, 1H), 8.89 (d, ³J_H–P = 15.2 Hz, 1H); ¹³C NMR (100 MHz) δ 16.2 (d, J = 6.8 Hz), 56.3, 56.6, 62.9 (d, J = 6.1 Hz), 105.3, 108.0, 116.5 (d, ¹J_C–P = 187.4 Hz), 123.2 (d, ³J_C–P = 11.8 Hz), 124.3 (td, ¹J_C–F = 293.5 Hz, ³J_C–P = 3.6 Hz), 144.9 (d, ²J_C–P = 7.2 Hz), 149.6 (td, ²J_C–F = 29.5 Hz, ²J_C–P = 7.3 Hz), 152.1, 155.3; ¹⁹F NMR (376 MHz) δ −51.3; ³¹P NMR (161 MHz) δ 14.9; HRMS (ESI): calcd for C₁₆H₁₉ClF₂NNaO₅P [M+Na]⁺ 432.0550, found 432.0558.

Diethyl (2-(chlorodifluoromethyl)-7-(trifluoromethyl)quinolin-3-yl)phosphonate 4h. Colourless oil (94%); ¹H NMR (400 MHz, CDCl₃) δ 1.37 (t, J = 7.1 Hz, 6H), 4.18 (m, 2H), 4.28 (m, 2H), 7.90 (dd, J = 8.5 Hz, J = 1.6 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.55 (q, ⁴J_H–F = 0.9 Hz, 1H), 9.24 (d, ³J_H–P = 16.3 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.5 Hz), 63.4 (d, J = 6.2 Hz), 121.2 (d, ¹J_C–P = 184.4 Hz), 123.4 (q, ¹J_C–F = 274.3 Hz), 123.8 (td, ¹J_C–F = 293.2 Hz, ³J_C–P = 1.1 Hz), 125.2 (qd, ⁴J_C–F = 3.2 Hz, ⁴J_C–P = 1.2 Hz), 127.7 (qd, ⁴J_C–F = 4.3 Hz, ⁴J_C–P = 1.4 Hz), 128.3 (d, ³J_C–P = 11.6 Hz), 129.8, 134.5 (q, ²J_C–F = 33.4 Hz), 146.3, 147.8 (d, ²J_C–P = 6.9 Hz), 152.8 (td, ²J_C–F = 30.6 Hz, ²J_C–P = 8.2 Hz); ¹⁹F NMR (376 MHz) δ −52.4 (s, –CF₂Cl), −63.0 (s, –CF₃); ³¹P NMR (161 MHz) δ 12.9; HRMS (ESI): calcd for C₁₅H₁₄ClF₅NNaO₃P [M+Na]⁺ 440.0212, found 440.0217.

Diethyl (2-(bromodifluoromethyl)quinolin-3-yl)phosphonate 4i. Brownish oil (88%); ¹H NMR (400 MHz, CDCl₃) δ 1.34 (t, J = 7.2 Hz, 6H), 4.15 (m, 2H), 4.23 (m, 2H), 7.67 (td, J = 7.9 Hz, J = 0.9 Hz, 1H), 7.85 (td, J = 6.9 Hz, J = 1.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 9.09 (d, ³J_H-P = 16.4 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.2 Hz), 63.1 (d, J = 6.2 Hz), 116.5 (td, ¹J_C–F = 306.9 Hz, ³J_C–P = 1.4 Hz), 118.5 (d, ¹J_C–P = 186.2 Hz), 126.8 (d, ³J_C–P = 11.5 Hz), 128.5, 129.5 (d, ⁵J_C–P = 1.0 Hz), 129.8 (d, ⁴J_C–P = 1.5 Hz), 133.0, 147.2 (dt, ⁴J_C–P = 1.4 Hz, ⁴J_C–F = 0.9 Hz), 147.8 (d, ²J_C–P = 6.7 Hz), 152.5 (td, ²J_C–F = 26.8 Hz, ²J_C–P = 8.3 Hz); ¹⁹F NMR (376 MHz) δ −47.5; ³¹P NMR (161 MHz) δ 14.0 (t, ⁴J_P–F = 0.9 Hz); HRMS (ESI): calcd for C₁₄H₁₆BrF₂NO₃P [M+H]⁺ 394.0014, found 394.0017.

Diethyl (2-(bromodifluoromethyl)-6-chloroquinolin-3-yl)phosphonate 4j. Orange crystals (80%); Mp = 118–121 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.37 (t, J = 7.0 Hz, 6H), 4.17 (m, 2H), 4.26 (m, 2H), 7.82 (dd, J = 8.9 Hz, J = 2.2 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 9.04 (d, ³J_H-P = 16.3 Hz, 1H); ¹³C NMR (100 MHz) δ 16.4 (d, J = 6.6 Hz), 63.3 (d, J = 6.2 Hz), 116.3 (td, ¹J_C–F = 308.9 Hz, ³J_C–P = 0.9 Hz), 119.8 (d, ¹J_C–P = 185.6 Hz), 127.1, 127.5 (d, ³J_C–P = 11.9 Hz), 131.4 (d, ⁴J_C–P = 1.9 Hz), 134.0, 135.6 (d, ⁵J_C–P = 1.7 Hz), 145.5, 146.8 (d, ²J_C–P = 7.3 Hz), 152.9 (td, ²J_C–F = 27.4 Hz, ²J_C–P = 8.7 Hz); ¹⁹F NMR (376 MHz) δ −47.8; ³¹P NMR (161 MHz) δ 13.3; HRMS (ESI): calcd for C₁₄H₁₄BrClF₂NNaO₃P [M+Na]⁺ 449.9443, found 449.9442.

Diethyl (2-(bromodifluoromethyl)-6,7-dimethoxyquinolin-3-yl)phosphonate 4k. Yellow crystals (71%); Mp = 155–160 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.32 (t, J = 7.1 Hz, 6H), 3.99 (s, 3H), 4.01 (s, 3H), 4.12 (m, 2H), 4.22 (m, 2H), 7.12 (s, 1H), 7.45 (s, 1H), 8.87 (d, ³J_H–P = 16.0 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.6 Hz), 56.4, 56.6, 62.9 (d, J = 6.0 Hz), 105.3, 107.9, 115.9 (d, ¹J_C–P = 187.7 Hz), 116.9 (t, ¹J_C–F = 306.3 Hz), 123.1 (d, ³J_C–P = 10.7 Hz), 144.8 (d, ²J_C–P = 7.8 Hz), 150.9 (td, ²J_C–F = 26.5 Hz, ²J_C–P = 8.6 Hz), 152.1, 155.4; ¹⁹F NMR (376 MHz) δ −46.8; ³¹P NMR (161 MHz) δ 15.0; HRMS (ESI): calcd for C₁₆H₂₀BrF₂NO₅P [M+H]⁺ 454.0225, found 454.0221.

Diethyl (2-(bromodifluoromethyl)-7-(trifluoromethyl)quinolin-3-yl)phosphonate 4l. Brownish oil (93%); ¹H NMR (400 MHz, CDCl₃) δ 1.39 (t, J = 7.0 Hz, 6H), 4.20 (m, 2H), 4.30 (m, 2H), 7.90 (dd, J = 8.3 Hz, J = 1.9 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.55 (q, ⁴J_H–F = 0.7 Hz, 1H), 9.23 (d, ³J_H–P = 16.3 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.2 Hz), 63.4 (d, J = 5.9 Hz), 116.1 (t, ¹J_C–F = 305.9 Hz), 120.8 (d, ¹J_C–P = 183.6 Hz), 123.6 (q, ¹J_C–F = 275.7 Hz), 125.1 (qd, ⁴J_C–F = 2.8 Hz, ⁴J_C–P = 1.3 Hz), 127.7 (qd, ⁴J_C–F = 4.3 Hz, ⁴J_C–P = 1.3 Hz), 128.2 (d, ³J_C–P = 10.7 Hz), 129.8, 134.6 (q, ²J_C–F = 32.9 Hz), 146.3, 147.8 (d, ²J_C–P = 6.5 Hz), 154.0 (td, ²J_C–F = 27.6 Hz, ²J_C–P = 8.7 Hz); ¹⁹F NMR (376 MHz) δ −48.3 (s, –CF₂Br), −63.0 (s, –CF₃); ³¹P NMR (161 MHz) δ 12.9; HRMS (ESI): calcd for C₁₅H₁₄BrF₅NNaO₃P [M+Na]⁺ 483.9713, found 483.9712.

Diethyl (2-(difluoromethyl)quinolin-3-yl)phosphonate 4m. Colourless oil (60%); ¹H NMR (400 MHz, CDCl₃) δ 1.32 (t, J = 7.1 Hz, 6H), 4.12 (m, 2H), 4.22 (m, 2H), 7.31 (t, ²J_H–F = 53.7 Hz, 1H), 7.67 (td, J = 7.5 Hz, J = 0.7 Hz, 1H), 7.86 (td, J = 8.3 Hz, J = 1.2 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.90 (d, ³J_H–P = 15.4 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.4 Hz), 63.2 (d, J = 5.8 Hz), 110.9 (t, ¹J_C–F = 242.1 Hz), 120.1 (dt, ¹J_C–P = 184.1 Hz, ³J_C–F = 2.8 Hz), 127.0 (dt, ³J_C–P = 11.9 Hz, ⁵J_C–F = 1.4 Hz), 128.5, 129.0, 130.1 (d, ⁴J_C–P = 1.2 Hz), 132.7, 145.4 (d, ²J_C–P = 7.5 Hz), 148.5, 151.4 (td, ²J_C–F = 21.7 Hz, ²J_C–P = 11.3 Hz); ¹⁹F NMR (376 MHz) δ −115.7 (d, ²J_F–H = 53.9 Hz); ³¹P NMR (161 MHz) δ 15.0 (t, ⁴J_P–F = 1.2 Hz); HRMS (ESI): calcd for C₁₄H₁₇F₂NO₃P [M+H]⁺ 316.0909, found 316.0912.

Diethyl (6-chloro-2-(difluoromethyl)quinolin-3-yl)phosphonate 4n. Colourless oil (54%); ¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, J = 7.2 Hz, 6H), 4.14 (m, 2H), 4.25 (m, 2H), 7.31 (t, ²J_H–F = 53.8 Hz, 1H), 7.82 (dd, J = 8.9 Hz, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 9.3 Hz, 1H), 8.82 (d, ³J_H–P = 15.8 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.2 Hz), 63.3 (d, J = 5.6 Hz), 110.7 (t, ¹J_C–F = 242.5 Hz), 121.3 (dt, ¹J_C–P = 183.7 Hz, ³J_C–F = 3.3 Hz), 127.1, 127.6 (dt, ³J_C–P = 12.5 Hz, ⁵J_C–F = 1.5 Hz), 131.7 (d, ⁴J_C–P = 1.4 Hz), 133.7, 135.1 (d, ⁵J_C–P = 1.8 Hz), 144.3 (d, ²J_C–P = 7.1 Hz), 146.9, 151.8 (td, ²J_C–F = 21.8 Hz, ²J_C–P = 10.8 Hz); ¹⁹F NMR (376 MHz) δ −115.8 (d, ²J_F–H = 53.4 Hz); ³¹P NMR (161 MHz) δ 14.3; HRMS (ESI): calcd for C₁₄H₁₅ClF₂NNaO₃P [M+Na]⁺ 372.0338, found 372.0344.

Diethyl (2-(difluoromethyl)-6,7-dimethoxyquinolin-3-yl)phosphonate 4o. Yellowish crystals (42%); Mp = 169–173 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.33 (t, J = 7.1 Hz, 6H), 4.02 (s, 3H), 4.04 (s, 3H) 4.09 (m, 2H), 4.18 (m, 2H), 7.12 (s, 1H), 7.29 (t, ²J_H–F = 54.0 Hz, 1H), 7.56 (s, 1H), 8.69 (d, ³J_H–P = 14.9 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.4 Hz), 56.4, 56.6, 62.9 (d, J = 5.3 Hz), 105.4, 108.3, 110.8 (t, ¹J_C–F = 239.6 Hz), 117.9 (dt, ¹J_C–P = 184.9 Hz, ³J_C–F = 3.4 Hz), 123.3 (dt, ³J_C–P = 11.7 Hz, ⁵J_C–F = 0.8 Hz), 142.4 (d, ²J_C–P = 6.6 Hz), 146.9, 149.7 (td, ²J_C–F = 20.6 Hz, ²J_C–P = 11.2 Hz), 151.7, 155.2; ¹⁹F NMR (376 MHz) δ −115.2 (d, ²J_F–H = 50.5 Hz); ³¹P NMR (161 MHz) δ 14.3 (t, ⁴J_P–F = 1.3 Hz); HRMS (ESI): calcd for C₁₆H₂₀F₂NNaO₅P [M+Na]⁺ 398.0939, found 398.0949.

Diethyl (2-(difluoromethyl)-7-(trifluoromethyl)quinolin-3-yl)phosphonate 4p. Brownish oil (69%); ¹H NMR (400 MHz, CDCl₃) δ 1.37 (t, J = 7.0 Hz, 6H), 4.17 (m, 2H), 4.27 (m, 2H), 7.33 (t, ²J_H–F = 53.3 Hz, 1H), 7.89 (dd, J = 8.5 Hz, J = 1.7 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.62 (s, 1H), 9.00 (d, ³J_H–P = 15.7 Hz, 1H); ¹³C NMR (100 MHz) δ 16.4 (d, J = 6.3 Hz), 63.5 (d, J = 5.8 Hz), 110.6 (td, ¹J_C–F = 242.0 Hz, ³J_C–P = 2.0 Hz), 122.6 (dt, ¹J_C–P = 183.1 Hz, ³J_C–F = 3.1 Hz), 123.4 (q, ¹J_C–F = 271.9 Hz), 124.7 (qd, ⁴J_C–F = 2.1 Hz, ⁴J_C–P = 1.0 Hz), 127.9 (qd, ⁴J_C–F = 3.8 Hz, ⁴J_C–P = 0.9 Hz), 128.5 (d, ³J_C–P = 12.5 Hz), 129.9, 134.3 (q, ²J_C–F = 32.6 Hz), 147.8 (d, ²J_C–P = 7.9 Hz), 147.6, 153.1 (td, ²J_C–F = 23.2 Hz, ²J_C–P = 11.6 Hz); ¹⁹F NMR (376 MHz) δ −63.0 (s, –CF₃), −116.0 (d, ²J_F–H = 52.6 Hz, –CF₂H); ³¹P NMR (161 MHz) δ 13.8; HRMS (ESI): calcd for C₁₅H₁₆F₅NO₃P [M+H]⁺ 384.0782, found 384.0784.

Diethyl (2-(perfluoroethyl)quinolin-3-yl)phosphonate 4q. Yellowish oil (65%); ¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, J = 7.0 Hz, 6H), 4.15 (m, 2H), 4.25 (m, 2H), 7.74 (t, J = 7.5 Hz, 1H), 7.91 (td, J = 7.2 Hz, J = 1.3 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 9.20 (d, ³J_H–P = 16.5 Hz, 1H); ¹³C NMR (100 MHz) δ 16.2 (d, J = 6.5 Hz), 63.1 (d, J = 6.2 Hz), 112.0 (tq, ¹J_C–F = 258.8 Hz, ²J_C–F = 34.1 Hz), 119.0 (qt, ¹J_C–F = 289.5 Hz, ²J_C–F = 35.6 Hz), 120.7 (d, ¹J_C–P = 186.1 Hz), 126.7 (d, ³J_C–P = 11.4 Hz), 128.6, 129.8, 130.0 (d, ⁴J_C–P = 1.1 Hz), 132.9, 146.8 (dt, ⁴J_C–P = 1.4 Hz, ⁴J_C–F = 0.9 Hz), 147.5 (td, ²J_C–F = 28.9 Hz, ²J_C–P = 7.9 Hz), 147.9 (d, ²J_C–P = 7.2 Hz); ¹⁹F NMR (376 MHz) δ −79.9 (s, –CF₂CF₃), −108.1 (s, –CF₂CF₃); ³¹P NMR (161 MHz) δ 14.1; HRMS (ESI): calcd for C₁₅H₁₆F₅NO₃P [M+H]⁺ 384.0782, found 384.0784.

Diethyl (6-chloro-2-(perfluoroethyl)quinolin-3-yl)phosphonate 4r. Yellowish oil (53%); ¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, J = 7.0 Hz, 6H), 4.15 (m, 2H), 4.26 (m, 2H), 7.83 (dd, J = 8.9 Hz, J = 2.3 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 9.11 (d, ³J_H–P = 16.5 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.2 Hz), 63.2 (d, J = 6.3 Hz), 114.5 (tq, ¹J_C–F = 260.1 Hz, ²J_C–F = 34.5 Hz), 122.3 (qt, ¹J_C–F = 287.0 Hz, ²J_C–F = 36.5 Hz), 122.5 (d, ¹J_C–P = 184.8 Hz), 127.1, 127.4 (d, ³J_C–P = 11.8 Hz), 131.6, 133.9, 135.9, 145.2 (dt, ⁴J_C–P = 1.7 Hz, ⁴J_C–F = 0.8 Hz), 146.6 (td, ²J_C–F = 28.0 Hz, ²J_C–P = 7.2 Hz), 146.8 (d, ²J_C–P = 7.8 Hz); ¹⁹F NMR (376 MHz) δ −79.9 (s, –CF₂CF₃), −108.1 (s, –CF₂CF₃); ³¹P NMR (161 MHz) δ 13.4; HRMS (ESI): calcd for C₁₅H₁₄ClF₅NNaO₃P [M+Na]⁺ 440.0212, found 440.0216.

Diethyl (6,7-dimethoxy-2-(perfluoroethyl)quinolin-3-yl)phosphonate 4s. Colourless crystals (40%); Mp = 151–154 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.34 (t, J = 7.0 Hz, 6H), 4.04 (s, 3H), 4.07 (s, 3H), 4.13 (m, 2H), 4.24 (m, 2H), 7.16 (s, 1H), 7.46 (s, 1H), 8.97 (d, ³J_H–P = 16.2 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.4 Hz), 56.4, 56.7, 62.9 (d, J = 5.9 Hz), 105.3, 108.1, 111.9 (tq, ¹J_C–F = 256.7 Hz, ²J_C–F = 36.7 Hz), 118.4 (d, ¹J_C–P = 187.6 Hz), 119.3 (qt, ¹J_C–F = 288.2 Hz, ²J_C–F = 37.9 Hz), 123.2 (d, ³J_C–P = 11.7 Hz), 144.6, 145.0 (d, ²J_C–P = 6.8 Hz), 145.3 (td, ²J_C–F = 27.9 Hz, ²J_C–P = 9.5 Hz), 152.2, 155.3; ¹⁹F NMR (376 MHz) δ −80.1 (s, –CF₂CF₃), −108.1 (s, –CF₂CF₃); ³¹P NMR (161 MHz) δ 15.1 (t, ⁴J_F–P = 1.5 Hz); HRMS (ESI): calcd for C₁₇H₁₉F₅NNaO₅P [M+Na]⁺ 466.0813, found 466.0814.

Diethyl (2-(perfluoroethyl)-7-(trifluoromethyl)quinolin-3-yl)phosphonate 4t. Yellowish oil (67%); ¹H NMR (400 MHz, CDCl₃) δ 1.36 (t, J = 6.8 Hz, 6H), 4.18 (m, 2H), 4.28 (m, 2H), 7.92 (d, J = 9.5 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.52 (s, 1H), 9.28 (d, ³J_H–P = 16.3 Hz, 1H); ¹³C NMR (100 MHz) δ 16.3 (d, J = 6.8 Hz), 63.4 (d, J = 6.4 Hz), 112.9 (tq, ¹J_C–F = 266.4 Hz, ²J_C–F = 35.2 Hz), 122.6 (d, ¹J_C–P = 187.1 Hz), 122.7 (qt, ¹J_C–F = 288.9 Hz, ²J_C–F = 35.6 Hz), 123.0 (q, ¹J_C–F = 276.0 Hz), 125.5 (qd, ⁴J_C–F = 2.0 Hz, ⁴J_C–P = 0.8 Hz), 127.8 (qd, ⁴J_C–F = 5.0 Hz, ⁴J_C–P = 1.3 Hz), 128.3 (d, ³J_C–P = 12.9 Hz), 134.7 (q, ²J_C–F = 33.8 Hz), 145.9, 147.8 (d, ²J_C–P = 8.6 Hz), 147.9 (td, ²J_C–F = 24.0 Hz, ²J_C–P = 10.0 Hz); ¹⁹F NMR (376 MHz) δ − 62.9 (s, –CF₃), −79.8 (s, –CF₂CF₃), −108.3 (s, –CF₂CF₃); ³¹P NMR (161 MHz) δ 12.9; HRMS (ESI): calcd for C₁₆H₁₄F₈NNaO₃P [M+Na]⁺ 474.0574, found 474.0569.

Acknowledgements

B. D. acknowledges Jacobs University Bremen for a doctoral scholarship. S. N. T and G.-V. R. are thankful to the Deutsche Forschungsgemeinschaft (436 RUS 113/961/0-1) for financial support. Dr Bassem S. Bassil is thanked for the XRD data analysis.

References

1. (a) J. P. Michael, Nat. Prod. Rep., 2007, 24, 223; (b) J. P. Michael, Nat. Prod. Rep., 2005, 22, 627; (c) G. Roma, M. D. Braccio, G. Grossi, F. Mattioli and M. Ghia, Eur. J. Med. Chem., 2000, 35, 1021; (d) Y.-L. Chen, K.-C. Fang, J.-Y. Sheu, S.-L. Hsu and C.-C. Tzeng, J. Med. Chem., 2001, 44, 2374.
2. (a) S. Kumar, S. Bawa and H. Gupta, Mini-Rev. Med. Chem., 2009, 14, 1648; (b) R. Musiol, M. Serda, S. Hensel-Bielowska and J. Polanski, Curr. Med. Chem., 2010, 17, 1960; (c) K. Kaur, M. Jain, P. R. Reddy and R. Jain, Eur. J. Med. Chem., 2010, 45, 3245; (d) R. Alajarin and C. Burgosin Modern Heterocyclic Chemistry, ed. J. Alvarez-Builla, J. J. Vaquero, J. Barluenga, 2011, Vol. 3, pp 1527–1629.
3. J. Achan, A. O. Talisuna, A. Erhart, A. Yeka, J. K. Tibenderana, F. N. Baliraine, P. J. Rosenthal and U. D‘Alessandro, Malar. J., 2011, 10, 144 and references cited therein..
4. (a) H. C. Richard, Tetrahedron, 1981, 37, 1047; (b) A. Perzyna, C. Marty, M. Facompré, J.-F. Goossens, N. Pommery, P. Colson, C. Houssier, R. Houssin, J.-P. Hénichart and C. Bailly, J. Med. Chem., 2002, 45, 5809; (c) M. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail and G. A. Sim, J. Am. Chem. Soc., 1966, 88, 3888; (d) D. Wu, Tetrahedron, 2003, 59, 8649.
5. (a) I.-S. Chen, I.-L. Tsai, S.-J. Wu, W.-S. Sheen, T. Ishikawa and H. Ishii, Phytochemistry, 1993, 34, 1449; (b) D. C. Harrowven, M. I. T. Nunn, N. J. Blumire and D. R. Fenwick, Tetrahedron Lett., 2000, 41, 6681; (c) D. C. Harrowven, M. I. T. Nunn, N. J. Blumire and D. R. Fenwick, Tetrahedron, 2001, 57, 4447.
6. (a) J. D. Maguire, E. Krisin, H. Marwoto, T. L. Richie, D. J. Fryauff and J. K. Baird, Clin. Infect. Dis., 2006, 42, 1067; (b) J. Wiesner, R. Ortmann, H. Jomaa and M. Schlitzer, Angew. Chem., Int. Ed., 2003, 42, 5274.
7. (a) R. Engel in Handbook of Organophosphorus Chemistry, M. Dekker, Inc.New York, 1992; (b) Fluorine in Medicinal Chemistry and Chemical Biology, ed. I. Ojima, John Wiley & Sons, 2009; (c) V. D. Romanenko and V. P. Kukhar, Chem. Rev., 2006, 106, 3868; (d) K. Müller, C. Faeh and F. Diederich, Science, 2007, 317, 1881; (e) Fluorinated Heterocyclic Compounds: Synthesis, Chemistry and Applications, ed. V. A. Petrov, John Wiley & Sons, Inc., Hoboken, New Jersey, 2009; (f) D. O'Hagan, Chem. Soc. Rev., 2008, 37, 308; (g) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320–330.
8. R. Engel, Chem. Rev., 1977, 77, 349.
9. (a) C. C. Cheng and S. J. Yan, Org. React., John Wiley & Sons, New York, 1982, 28, 37; (b) J. Marco-Contelles, E. Pérez-Mayoral, A. Samadi, M. A. D. C. Carreiras and E. Soriano, Chem. Rev., 2009, 109, 2652; (c) M. Shiri, M. A. Zolfigol, H. G. Kruger and Z. Tanbakouchian, Adv. Heterocycl. Chem., 2011, 102, 139.
10. F. W. Bergstrom, Chem. Rev., 1944, 35, 156.
11. R. H. F. Manske and M. Kukla, Org. React., 1953, 7, 59.
12. F. W. Bergstrom, Chem. Rev., 1944, 35, 153.
13. R. H. Reitsema, Chem. Rev., 1948, 43, 47.
14. G. Jones in The Chemistry of Heterocyclic Compounds, ed. A. Weissberger and E. C. Taylor, John Wiley & Sons, Chichester, 1977, 32, Part I, pp 93–318.
15. (a) C. C. Cho, N. Y. Lee, T.-J. Kim and S. C. Shim, J. Heterocycl. Chem., 2004, 41, 409; (b) A. Arcadi, M. Aschi, F. Marinelli and M. Verdecchia, Tetrahedron, 2008, 64, 5354; (c) A. Arcadi, F. Marinelli and E. Rossi, Tetrahedron, 1999, 55, 13233; (d) S. Cacchi, G. Fabrizi and F. Marinelli, Synlett, 1999, 401, 404; (e) F. Nissen and H. Detert, Eur. J. Org. Chem., 2011, 2011, 2845; (f) R. Yanada, K. Hashimoto, R. Tokizane, Y. Miwa, H. Minami, K. Yanada, M. Ishikura and Y. Takemoto, J. Org. Chem., 2008, 73, 5135; (g) X. Zhang, M. A. Campo, T. Yao and R. C. Larock, Org. Lett., 2005, 7, 763; (h) X. Zhang, T. Yao, M. A. Campo and R. C. Larock, Tetrahedron, 2010, 66, 1177; (i) J. Zhao, C. Peng, L. Liu, Y. Wang and Q. Zhu, J. Org. Chem., 2010, 75, 7502.
16. (a) H. Li, C. Wang, H. Huang, X. Xu and Y. Li, Tetrahedron Lett., 2011, 52, 1108; (b) H. Li, X. Xu, J. Yang, X. Xie, H. Huang and Y. Li, Tetrahedron Lett., 2011, 52, 530; (c) N. T. Patil and V. S. Raut, J. Org. Chem., 2010, 75, 6961; (d) B. Madhav, S. N. Murthy, K. R. Rao and Y. V. D. Nageswar, Helv. Chim. Acta, 2010, 93, 257; (e) J. B. Hendrickson, R. Rees and J. F. Templeton, J. Am. Chem. Soc., 1964, 86, 107.
17. (a) B. Duda, S. N. Tverdomed and G.-V. Röschenthaler, Org. Biomol. Chem., 2011, 9, 8228; (b) B. Duda, S. N. Tverdomed and G.-V. Röschenthaler, J. Org. Chem., 2011, 76, 71.
18. (a) P. Friedlander and S. Henriques, Chem. Ber., 1882, 15, 2572; (b) S. G. McGeachin, Can. J. Chem., 1966, 44, 2323; (c) A. Abert and H. Yamamoto, J. Chem. Soc. B, 1966, 956.
19. W. Borsche and W. Ried, Liebigs Ann. Chem., 1943, 554, 269.
20. H. K. Porter, Org. React., 1973, 20, 455.
21. CCDC 884142 (for 4c) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.
22. J. Vicente, M. T. Chicote, A. J. Martinez-Martinez, D. Bautista and P. G. Jones, Org. Biomol. Chem., 2011, 9, 2279.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental details and the copy of ¹H, ¹³C, ¹⁹F, ³¹P NMR and HRMS spectra of new compounds. CCDC reference number 884142. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra21212a

---