Palladium-catalyzed radical cascade difluoroalkylation/cyclization of acrylamide with ethyl difluorobromoacetate

Abstract

An efficient Pd(0)-catalyzed radical cascade difluoroalkylation/cyclization of acrylamide with ethyl difluorobromoacetate was described. In addition, the reaction can be extended to perfluoroalkyl iodides and bromodifluoromethyl phosphonate. Mechanistic studies demonstrated that a radical addition/cyclization process was involved in the sequences.

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Introduction

The introduction of fluoroalkyl groups into organic molecules has become increasingly widespread in pharmaceuticals, agrochemicals and materials science, owing to the unique properties of the fluoroalkyl groups such as CF₂ that can dramatically improve the lipophilicity, metabolic stability, and bioavailability of bioactive molecules.¹ Therefore, the development of new and efficient methods for the synthesis of fluoroalkylated organic compounds has become a strategic topic of organic synthetic chemistry. Over the past few years, great progress has been achieved in this area, and typical stories have discussed several strategies for incorporating the difluoromethylene group (CF₂) into organic molecules by transition-metal-catalyzed as well as visible-light photoredox catalysis difluoromethylation reactions.² However, efficient synthetic methods for the fluoroalkylated heterocyclic compounds remain limited in pharmaceutically active molecules.³ The isoquinolinedione skeletons are important building blocks, which have been found in plant alkaloids, natural products and pharmaceuticals.⁴ Conceptually, the introduction of the fluoroalkyl groups into such a structural motif may offer a good opportunity to discover some intriguing new bioactive molecules.

Recently, a series of transition metals, such as nickel, iron, copper, ruthenium, and iridium, have been discovered to easily induce radical processes,⁵ while palladium-mediated radical reactions have not been well exploited. Nevertheless, Pd-catalyzed single electron transfer (SET) processes involving Pd(I) intermediates, leading to so-called Pd radical involved reactions, have caught great attention, which significantly expanding the scope of Pd-catalyzed reactions.⁶ For instance, as early as 1990, Chang reported a pioneering work using the palladium as a promoter of a free radical chain involving atom transfer.⁶ⁱ In 2014, the Wang group described a Pd-catalyzed intramolecular radical aryldifluoromethylation of activated alkenes to construct substituted difluoromethylated oxindoles.⁷ In 2015, Zhang and co-workers demonstrated the first example of a Pd-catalyzed Heck-type fluoroalkylation of alkenes with fluoroalkyl bromides involving free fluoroalkyl radicals generated from the Pd(0)/xantphos complex (Scheme 1a).⁸ Very recently, Liang et al. realized Pd-catalyzed radical cascade iododifluoromethylation/cyclization of 1,6-enynes with ethyl difluoroiodoacetate for the synthesis of iodine/difluoromethylene-containing pyrrolidines (Scheme 1b).⁹ With our ongoing studies on radical addition reactions of alkenes,¹⁰ we postulated that Pd-catalyzed single electron transfer processes can be introduced into radical addition/cyclization of N-alkyl-N-methacryloyl benzamides, leading to fluoroalkylated isoquinoline-1,3-diones (Scheme 1c). To the best of our knowledge, palladium has not been developed as the catalyst in this type of substrate.¹¹

Scheme 1 Pd(0)-catalyzed radical reactions.

Results and discussion

Initially, our investigation began with the reaction of N-methacryloyl-N-methylbenzamide with ethyl difluorobromoacetate in the presence of PdCl₂(PPh₃)₂ (10% mol), dppp (20% mol), and Ag₂CO₃ (2.0 equiv.) in dioxane (2.0 mL) at 100 °C under an argon atmosphere. To our delight, the expected product 3a was isolated in 29% yield after 12 h (Table 1, entry 1). Consequently, a series of solvents were evaluated, wherein dioxane gave a better result (entry 4). Then, different ligands such as dppf, dppe, DPE-phos and xantphos were also screened, and DPE-phos displayed high catalytic activity (entry 7). Subsequently, a survey on several representative bases indicated that K₂CO₃ was the best additive, giving the product 3a in 75% yield at 80 °C (entry 12). Other different palladium catalysts were also investigated for this transformation, and PdCl₂(PPh₃)₂ produced the best result (entries 12–15). It should be noted that no product was detected without palladium catalyst (entry 16). With other metal catalysts, such as NiCl₂(PPh₃)₂, CuI, Fe(acac)₃ and Co(acac)₃, no better results were observed (entries 17–20).

Table 1 Optimization of reaction conditions^a

Entry	[Pd] (mol%)	Ligand (mol%)	Base (equiv.)	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), ethyl difluorobromoacetate (3.0 equiv.) in dioxane (2.0 mL) at 100 °C under an argon atmosphere for 12 h. b Isolated yields. c At 80 °C. d N.R. = no reaction.
1	PdCl2(PPh3)2 (10%)	Dppp (20%)	Ag2CO3 (2.0)	Toluene	29%
2	PdCl2(PPh3)2 (10%)	Dppf (20%)	Ag2CO3 (2.0)	Toluene	31%
3	PdCl2(PPh3)2 (10%)	Dppe (20%)	Ag2CO3 (2.0)	Toluene	5%
4	PdCl2(PPh3)2 (10%)	Dppp (20%)	Ag2CO3 (2.0)	Dioxane	37%
5	PdCl2(PPh3)2 (10%)	Dppp (20%)	Ag2CO3 (2.0)	DMA	<5%
6	PdCl2(PPh3)2 (10%)	Dppp (20%)	Ag2CO3 (2.0)	PhCF3	32%
7	PdCl2(PPh3)2 (10%)	DPE-phos (20%)	Ag2CO3 (2.0)	Dioxane	45%
8	PdCl2(PPh3)2 (10%)	DPE-phos (20%)	Cs2CO3 (2.0)	Dioxane	59%
9	PdCl2(PPh3)2 (10%)	Xantphos (20%)	Cs2CO3 (2.0)	Dioxane	40%
10	PdCl2(PPh3)2 (10%)	DPE-phos (20%)	Cs2CO3 (2.0)	Dioxane	49%
11^c	PdCl2(PPh3)2 (10%)	DPE-phos (20%)	Cs2CO3 (2.0)	Dioxane	64%
12 ^c	PdCl 2 (PPh 3 ) 2 (10%)	DPE-phos (20%)	K 2 CO 3 (2.0)	Dioxane	75%
13^c	PdCl2(PPh3)2 (10%)	DPE-phos (20%)	K3PO4 (2.0)	Dioxane	69%
14^c	Pd(PPh3)4 (5%)	DPE-phos (10%)	K2CO3 (2.0)	Dioxane	60%
15^c	Pd(OAc)2 (10%)	DPE-phos (20%)	K2CO3 (2.0)	Dioxane	55%
16^c	PdCl2(PPh3)2 (0%)	DPE-phos (0%)	K2CO3 (2.0)	Dioxane	N.R.^d
17	NiCl2(PPh3)2 (10%)	DPE-phos (20%)	K2CO3 (2.0)	Dioxane	N.R.^d
18	CuI (10%)	Phen (12%)	K2CO3 (2.0)	DMF	10%
19	Fe(acac)3 (5%)	—	Ag2CO3 (2.0)	Dioxane	20%
20	Co(acac)3 (5%)	—	Ag2CO3 (2.0)	Dioxane	N.R.^d

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Having identified suitable reaction conditions (Table 1, entry 12), the substrate scope of this radical addition/cyclization reactions was assessed (Scheme 2). Firstly, we set out to discuss the effect of substituent on the benzamide moiety in the reaction. Several useful functional groups were tolerated, including chloro, fluoro, trifluoromethyl, methyl, tertiary butyl and methoxyl substituents. Where, an electron-donating substituent favored product formation (Scheme 2, 3b, 3g), whereas an electron-withdrawing group slightly hindered the reaction (3c, 3d, 3f). In addition, the cyclization of methacryloyl m-methylbenzamide regioselectively yielded a single product 3h in moderate yield. When a sterically demanding ortho substituent was used, a lower yield was obtained (3i). Subsequently, the N-substituents of methacryloyl benzamides were investigated, and the ethyl, n-propyl, n-butyl, isopropyl, benzyl and phenyl groups on the N atom were compatible with this methodology. In contrast to previous report,¹¹ the substrate with phenyl group on the N atom gave a better yield (86%, 3o). Next, we investigated the performance of other fluoroalkyl compounds in the reaction. To our delight, a series of fluoroalkyl compounds such as BrCHFCOOEt, BrCF₂PO(OEt)₂, C₄F₉I, C₆F₁₃I and C₈F₁₇I were also tolerated in this reaction, leading to the desired fluorinated isoquinoline-1,3-diones in moderate to low yields because of low conversion of starting materials, where the substrate 1a can be recovered.¹² Interestingly, when C₄F₉I, C₆F₁₃I and C₈F₁₇I were used, the iodine/perfluoromethylene-containing isoquinoline-1,3-diones were obtained, which was contrast with previous report (3r, 3s, 3t).¹¹ Cinnamamide was also suitable in this reaction to deliver a difluoroacetylated quinolone-2-one (3u). In addition, an amusing bimolecular cascade addition/cyclization was observed using mono-substituted olefin as the substrate (3v). Unfortunately, sequential investigations demonstrated that the β-substituted olefin failed in this condition (3w). The heteroaryl substrate such as thienyl failed in this reaction because of the strong coordination of palladium catalyst with sulfur atom.

Scheme 2 Substrate scope of the difluoroalkylation/cyclization reaction. ^a The yield was obtained using 5.0 mmol 1a.

In addition, it is encouraging to find that orthofluorobenzamide produced two products in total 41% yield with nearly 1 : 1 ratio, which may be involved homolytic aromatic substitution (Scheme 3).¹³

Scheme 3 C–F bond cracking under Pd(0)-catalyzed conditions.

To give insight into the mechanism of this transformation, a series of control experiments were carried out. Firstly, when 2.0 equiv. of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or 2.0 equiv. of BHT (2,6-di-tert-butyl-4-methylphenol) as the typical radical scavengers were added into the standard conditions, the desired transformation was found to be completely suppressed (Scheme 4(1)). In addition, the reaction of N,N-diallyl-4-methylbenzenesulfonamide with ethyl difluorobromoacetate under the standard conditions resulted in the cyclized product 4a containing the bromine atom in a high yield of 87% (dr = 3 : 1) (Scheme 4(2)). Control experiments demonstrated that the difluoromethyl radical was involved in this process. Kinetic isotope experiment was also undertaken to better understand this reaction. When an intermolecular competition experiment between acrylamide 1a and its pentadeuterated analogue 1a-d₅ was performed, and no kinetic isotope effect was found (k_H/k_D = 1.0, Scheme 4(3)).¹⁴

Scheme 4 Radical trapping and KIE experiments.

Finally, the product 3a can be easily transformed into the alcohol derivative (Scheme 5). Reductive of 3a mediated by NaBH₄ was found to proceed smoothly at ambient temperature, affording the difluoromethylated isoquinoline-1,3-dione 3aa in 85% yield.

Scheme 5 Reductive reaction.

Conclusions

In conclusion, we have developed an efficient Pd(0)-catalyzed radical cascade difluoroalkylation/cyclization of acrylamide with ethyl difluorobromoacetate under mild reaction conditions. This reaction delivered a new method for the synthesis of difluoromethylated isoquinoline-1,3-dione. Mechanistic studies indicated that a radical addition/cyclization process was involved in the sequences.

Experimental

General remarks

Column chromatography was carried out on silica gel. Unless noted ¹H NMR spectra were recorded on 400 MHz in CDCl_3,¹³C NMR spectra were recorded on 100 MHz in CDCl₃, ¹⁹F NMR spectra were recorded on 376 MHz in CDCl_3, and ³¹P NMR spectra were recorded on 162 MHz in CDCl₃. IR spectra were recorded on an FT-IR spectrometer and only major peaks are reported in cm⁻¹. Melting points were determined on a microscopic apparatus and were uncorrected. All new products were further characterized by HRMS (high resolution mass spectra), high resolution mass spectrometry (HRMS) spectra was obtained on a micrOTOF-Q instrument equipped with an ESI source; copies of their ¹H NMR and ¹³C NMR spectra are provided.

The procedure for the synthesis of product 3

An oven-dried Schlenk tube (10 mL) was equipped with a magnetic stir bar, N-methacryloyl-N-methylbenzamide (1, 0.3 mmol), ethyl 2-bromo-2,2-difluoroacetate (2, 0.9 mmol), 10% PdCl₂(PPh₃)₂ (0.03 mmol, 21 mg), 20% DPE-phos (0.06 mmol, 32.3 mg), and K₂CO₃ (2 equiv., 82.8 mg). The flask was evacuated and backfilled with argon for 3 times. Then dioxane (2.0 mL) was added with syringe under argon. The reaction mixture was then stirred for 12 h at 80 °C. After the reaction, 3 mL water was added to quench the reaction, and the resulting mixture was extracted twice with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated. Purification of the crude product by flash column chromatography afforded the product 3 (petroleum ether/ethyl acetate as eluent (6 : 1)).

Ethyl 3-(2,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2,2-difluoropropanoate. Mp = 58–59 °C, 3a, 73 mg. ¹H NMR (400 MHz): 8.26–8.28 (m, 1H), 7.60–7.63 (m, 1H), 7.41–7.50 (m, 2H), 3.89–4.02 (m, 2H), 3.40 (s, 3H), 3.18–3.30 (m, 1H), 2.83–2.95 (m, 1H), 1.65 (s, 3H), 1.20 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz): 174.9, 163.8, 163.2, 140.6, 133.4, 129.1, 127.9, 125.9, 124.5, 116.9, 114.4, 114.3, 63.0, 45.0, 44.8, 44.6, 43.6, 43.5, 31.5, 27.3, 13.6; ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.99 (d, J = 263.2 Hz, 1 F), −104.4 (d, J = 267.0, 1F); IR: 2920, 1765, 1714, 1665, 1469, 1424, 1368, 1315, 1096, 1072, 1056, 767, 702; HRMS (ESI) m/z: calcd for C₁₆H₁₇NF₂NaO₄⁺: [M + Na⁺] = 348.1023; found: 348.1023.

Ethyl 2,2-difluoro-3-(2,4,6-trimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)propanoate. Mp = 87–89 °C, 3b, 71.2 mg, ¹H NMR (400 MHz): 8.15 (d, J = 8.0 Hz, 1H), 7.26–7.28 (m, 1H), 7.20 (s, 1H), 3.89–4.02 (m, 2H), 3.33 (s, 3H), 3.18–3.29 (m, 1H), 2.83–2.92 (m, 1H), 2.45 (s, 3H), 1.64 (s, 3H), 1.20 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.7 (d, J = 263.2 Hz, 1F), −104.6 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz): 175.0, 163.7, 163.6, 163.3, 162.9, 144.3, 140.6, 129.1, 128.9, 126.3, 122.0, 116.9, 114.4, 111.9, 62.9, 44.7, 44.5, 43.5, 43.4, 31.4, 29.6, 27.2, 21.8, 13.6; IR (cm⁻¹): 2986, 2941, 1770, 1714, 1668, 1614, 1463, 1455, 1360, 1309, 1222, 1175, 1099, 1056, 847, 777, 703; HRMS (ESI) m/z: calcd for C₁₇H₁₉F₂NNaO₄⁺: [M + Na⁺] = 362.1180; found: 362.1180.

Ethyl 3-(6-chloro-2,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)-2,2-difluoropropanoate. Mp = 101–103 °C, 3c, 59.3 mg, ¹H NMR (400 MHz): 8.21–8.23 (m, 1H), 7.43–7.46 (m, 1H), 7.40 (s, 1H), 4.04–4.10 (m, 2H), 3.39 (s, 3H), 3.25–3.32 (m, 1H), 2.79–2.90 (m, 1H), 1.66 (s, 3H), 1.26 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −100.5 (d, J = 267.0, 1 F), −103.9 (d, J = 267.0, 1F); ¹³C NMR (100 MHz): 174.3, 163.3, 163.0, 162.9, 162.7, 142.4, 140.1, 130.7, 128.5, 126.1, 123.0, 116.7, 114.2, 111.7, 63.2, 44.9, 44.7, 44.5, 43.6, 43.6, 31.3, 29.6, 27.4, 22.6, 13.7; IR (cm⁻¹): 2992, 2929, 1768, 1716, 1669, 1599, 1429, 1357, 1311, 1224, 1082, 737, 698; HRMS (ESI) m/z: calcd for C₁₆H₁₆F₂NClNaO₄⁺: [M + Na⁺] = 382.0634; found: 382.0653.

Ethyl 2,2-difluoro-3-(6-fluoro-2,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)propanoate. Mp = 76–78 °C, 3d, 51.5 mg, ¹H NMR (400 MHz, CDCl₃): 8.29–8.32 (m, 1H), 7.15–7.19 (m, 1H), 7.09–7.12 (m, 1H), 4.06–4.13 (m, 2H), 3.34 (s, 3H), 3.25–3.32 (m, 1H), 2.76–2.88 (m, 1H), 1.65 (s, 3H), 1.26 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −101.09 (d, J = 267.0 Hz, 1F), −103.46 (d, J = 267.0 Hz, 1F), −103.64 (s, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.4, 167.2, 164.6, 163.1, 162.8, 162.7, 143.8, 143.7, 132.2, 132.1, 120.9, 115.9, 115.7, 114.2, 112.9, 111.7, 63.2, 44.9, 44.7, 44.5, 43.8, 43.7, 31.4, 27.3, 13.7; IR (cm⁻¹): 2992, 1764, 1717, 1671, 1360, 1311, 1079, 776, 698; HRMS (ESI) m/z: calcd for C₁₆H₁₆F₃NNaO₄⁺: [M + Na⁺] = 366.0929; found: 366.0930.

Ethyl 2,2-difluoro-3-(6-methoxy-2,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)propanoate. Mp = 89–90 °C, 3e, 56.5 mg, ¹H NMR (400 MHz, CDCl₃): 8.21–8.23 (m, 1H), 6.97–6.99 (m, 1H), 6.84–6.85 (m, 1H), 3.93–4.02 (m, 2H), 3.90 (s, 3H), 3.37 (s, 3H), 3.18–3.31 (m, 1H), 2.82–2.90 (m, 1H), 1.64 (s, 3H), 1.21 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.42 (d, J = 267.0 Hz, 1F), −104.74 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.9, 163.7, 163.4, 163.3, 142.7, 131.4, 117.5, 116.9, 114.4, 114.3, 113.7, 111.8, 111.2, 62.9, 55.5, 44.7, 44.5, 43.8, 43.7, 31.5, 27.1, 13.6; IR (cm⁻¹): 2985, 2944, 1768, 1762, 1712, 1668, 1610, 1360, 1307, 1082, 850, 778, 702; HRMS (ESI) m/z: calcd for C₁₇H₁₉F₂NNaO₅⁺: [M + Na⁺] = 378.1129; found: 378.1141.

Ethyl 3-(2,4-dimethyl-1,3-dioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)-2,2-difluoropropanoate. Mp = 81–83 °C, 3f, 74.3 mg, ¹H NMR (400 MHz, CDCl₃): 8.41–8.43 (m, 1H), 7.69–7.73 (m, 2H), 4.03–4.13 (m, 2H), 3.32 (s, 3H), 3.29–3.36 (m, 1H), 2.85–2.97 (m, 1H), 1.69 (s, 3H), 1.22–1.26 (m, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −63.45 to −63.15 (m, 3F), −100.96 (d, J = 267.0 Hz, 1F), −103.12 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.2, 163.3, 162.9, 162.7, 141.6, 134.9, 130.0, 124.6, 121.9, 116.7, 114.2, 114.1, 111.7, 63.2, 44.9, 44.6, 44.4, 43.7, 31.3, 27.5, 13.6; IR (cm⁻¹): 2985, 2939, 1766, 1712, 1669, 1316, 1290, 1069, 855, 786, 705; HRMS (ESI) m/z: calcd for C₁₇H₁₆F₅NNaO₄⁺: [M + Na⁺] = 416.0897; found: 416.0898.

Ethyl 3-(6-(tert-butyl)-2,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)-2,2-difluoropropanoate. Oil, 3g, 91.5 mg, ¹H NMR (400 MHz, CDCl₃): 8.18–8.20 (d, J = 8.0 Hz, 1H), 7.48–7.50 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 3.98–4.02 (m, 1H), 3.81–3.85 (m, 1H), 3.39 (s, 3H), 3.24–3.34 (m, 1H), 2.89–3.01 (m, 1H), 1.66 (s, 3H), 1.37 (s, 9H), 1.15–1.19 (m, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.26 (d, J = 267.0 Hz, 1F), −104.31 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 175.2, 163.7, 157.2, 140.1, 128.7, 121.9, 116.9, 114.4, 112.7, 111.9, 62.8, 44.6, 44.3, 43.8, 43.7, 35.2, 31.6, 30.9, 28.9, 27.1, 13.6; IR (cm⁻¹): 2966, 1761, 1715, 1669, 1611, 1428, 1357, 1309, 1229, 1182, 849, 782, 707; HRMS (ESI) m/z: calcd for C₂₀H₂₅F₂NNaO₄⁺: [M + Na⁺] = 404.1649; found: 404.1661.

Ethyl 2,2-difluoro-3-(2,4,7-trimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)propanoate. Mp = 37–38 °C, 3h, 51 mg, ¹H NMR (400 MHz): 8.08 (s, 1H), 7.43–7.45 (m, 1H), 7.28–7.32 (m, 1H), 3.90–4.02 (m, 2H), 3.32 (s, 3H), 3.19–3.28 (m, 1H), 2.82–2.90 (m, 1H), 2.43 (s, 3H), 1.63 (s, 3H), 1.20 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.9 (d, J = 267.0 Hz, 1F), −104.5 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz): 175.1, 163.9, 163.6, 163.2, 162.9, 137.8, 137.7, 134.4, 129.1, 124.3, 116.9, 114.4, 111.9, 62.9, 45.0, 44.8, 44.6, 43.3, 43.2, 31.4, 27.3, 20.9, 13.5; IR (cm⁻¹): 2986, 2942, 1767, 1715, 1669, 1308, 1226, 1181, 1104, 1081, 838, 782, 709; HRMS (ESI) m/z: calcd for C₁₇H₁₉F₂NNaO₄⁺: [M + Na⁺] = 362.1180; found: 362.1174.

Ethyl 2,2-difluoro-3-(2,4,8-trimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)propanoate. Mp = 96–98 °C, 3i, 49 mg, ¹H NMR (400 MHz, CDCl₃): 7.45–7.49 (m, 1H), 7.25–7.31 (m, 2H), 3.91–4.03 (m, 2H), 3.37 (s, 3H), 3.23–3.30 (m, 1H), 2.82–2.94 (m, 1H), 2.80 (s, 3H), 1.65 (s, 3H), 1.19–1.22 (m, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.72 (d, J = 267.0 Hz, 1F), −104.49 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.6, 164.3, 163.3, 142.8, 141.9, 132.2, 131.8, 124.2, 122.8, 116.9, 114.4, 111.9, 62.9, 45.3, 45.1, 44.9, 43.6, 43.5, 31.9, 27.3, 24.0, 13.6; IR (cm⁻¹): 2992, 1765, 1720, 1673, 1330, 1306, 1173, 1133, 1076, 855; HRMS (ESI) m/z: calcd for C₁₇H₁₉F₂NNaO₄⁺: [M + Na⁺] = 362.1180; found: 362.1176.

Ethyl 3-(2-ethyl-4-methyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)-2,2-difluoropropanoate. Mp = 72–73 °C, 3j, 51 mg, ¹H NMR (400 MHz, CDCl₃): 8.27–8.29 (m, 1H), 7.60–7.63 (m, 1H), 7.41–7.48 (m, 2H), 4.01–4.10 (m, 2H), 3.89–4.00 (m, 2H), 3.24–3.31 (m, 1H), 2.84–2.96 (m, 1H), 1.65 (s, 3H), 1.18–1.25 (m, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.41 (d, J = 267.0 Hz, 1F), −104.33 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.3, 163.5, 163.2, 162.9, 140.6, 133.3, 127.8, 124.7, 116.9, 114.5, 114.4, 111.9, 62.9, 44.7, 44.4, 43.5, 43.4, 35.7, 31.5, 13.6, 12.6; IR (cm⁻¹): 2988, 2941, 1768, 1714, 1669, 1371, 1361, 1259, 1098, 1084, 766, 705; HRMS (ESI) m/z: calcd for C₁₇H₁₉F₂NNaO₄⁺: [M + Na⁺] = 362.1180; found: 362.1152.

Ethyl 2,2-difluoro-3-(4-methyl-1,3-dioxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)propanoate. Oil, 3k, 53 mg, ¹H NMR (400 MHz, CDCl₃): 8.26–8.28 (m, 1H), 7.60–7.62 (m, 1H), 7.41–7.48 (m, 2H), 3.88–4.02 (m, 4H), 3.25–3.31 (m, 1H), 2.85–2.93 (m, 1H), 1.66–1.70 (m, 2H), 1.64 (s, 3H), 1.18 (t, J = 8.0 Hz, 3H), 0.96 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.42 (d, J = 267.0 Hz, 1F), −104.26 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.5, 163.5, 163.5, 163.2, 162.9, 140.6, 133.3, 127.8, 124.6, 116.9, 114.4, 111.9, 62.9, 44.5, 44.3, 43.5, 42.4, 31.7, 20.8, 13.6, 11.3; IR (cm⁻¹): 2972, 2878, 1767, 1714, 1668, 1359, 1241, 1114, 1103, 766, 704; HRMS (ESI) m/z: calcd for C₁₈H₂₁F₂NNaO₄⁺: [M + Na⁺] = 376.1336; found: 376.1357.

Ethyl 3-(2-butyl-4-methyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)-2,2-difluoropropanoate. Oil, 3l, 84 mg, ¹H NMR (400 MHz, CDCl₃): 8.26–8.28 (m, 1H), 7.60–7.64 (m, 1H), 7.41–7.48 (m, 2H), 3.88–4.03 (m, 4H), 3.25–3.32 (m, 1H), 2.85–2.97 (m, 1H), 1.64 (s, 3H), 1.58–1.62 (m, 2H), 1.42 (m, 2H), 1.18 (t, J = 8.0 Hz, 3H), 0.96 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.36 (d, J = 267.0 Hz, 1F), −104.34 (d, J = 263.2 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.5, 163.5, 163.4, 163.2, 162.9, 140.6, 133.3, 127.8, 124.6, 116.9, 114.4, 111.9, 62.9, 44.5, 44.3, 43.5, 40.5, 31.7, 29.5, 20.2, 13.7, 13.6; IR (cm⁻¹): 2962, 2874, 1768, 1714, 1669, 1467, 1359, 1299, 1230, 1103, 766, 704; HRMS (ESI) m/z: calcd for C₁₉H₂₃F₂NNaO₄⁺: [M + Na⁺] = 390.1493; found: 390.1500.

Ethyl 2,2-difluoro-3-(2-isopropyl-4-methyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)propanoate. Oil, 3m, 61.4 mg, ¹H NMR (400 MHz, CDCl₃): 8.24–8.26 (m, 1H), 7.58–7.62 (m, 1H), 7.38–7.46 (m, 2H), 5.18–5.25 (m, 1H), 3.88–3.99 (m, 2H), 3.22–3.30 (m, 1H), 2.81–2.90 (m, 1H), 1.63 (s, 3H), 1.49 (t, J = 4.0 Hz, 6H), 1.20 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.26 (d, J = 267.0 Hz, 1F), −104.31 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.7, 163.8, 163.6, 162.9, 140.5, 133.1, 127.7, 125.2, 117.0, 114.5, 114.4, 111.9, 62.9, 45.6, 44.6, 44.4, 43.8, 31.5, 19.3, 13.6; IR (cm⁻¹): 2984, 2937, 1766, 1713, 1667, 1357, 1264, 1180, 1090, 766, 706; HRMS (ESI) m/z: calcd for C₁₈H₂₁F₂NNaO₄⁺: [M + Na⁺] = 376.1336; found: 376.1354.

Ethyl 3-(2-benzyl-4-methyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)-2,2-difluoropropanoate. Oil, 3n, 81 mg, ¹H NMR (400 MHz, CDCl₃): 8.26–8.28 (m, 1H), 7.59–7.63 (m, 1H), 7.41–7.46 (m, 4H), 7.20–7.31 (m, 3H), 5.16–5.26 (m, 2H), 3.86–3.97 (m, 2H), 3.27–3.33 (m, 1H), 2.85–2.97 (m, 1H), 1.62 (s, 3H), 1.18 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.50 (d, J = 267.0 Hz, 1F), −103.76 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.6, 163.5, 163.2, 162.9, 140.6, 136.8, 133.5, 128.3, 127.3, 124.5, 116.8, 114.3, 111.8, 62.9, 44.5, 44.3, 44.0, 43.9, 43.8, 31.8, 13.6; IR (cm⁻¹): 2984, 1765, 1715, 1672, 1352, 1233, 1083, 764, 704; HRMS (ESI) m/z: calcd for C₂₂H₂₁F₂NNaO₄⁺: [M + Na⁺] = 424.1336; found: 424.1336.

Ethyl 2,2-difluoro-3-(4-methyl-1,3-dioxo-2-phenyl-1,2,3,4-tetrahydroisoquinolin-4-yl)propanoate. Mp = 133–134 °C, 3o, 100 mg, ¹H NMR (400 MHz, CDCl₃): 8.28–8.30 (m, 1H), 7.65–7.69 (m, 1H), 7.43–7.50 (m, 5H), 7.22–7.25 (m, 2H), 3.88–4.02 (m, 2H), 3.25–3.32 (m, 1H), 2.91–3.03 (m, 1H), 1.75 (s, 3H), 1.19 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.21 (d, J = 267.0 Hz, 1F), −104.06 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.7, 163.7, 163.5, 163.1, 162.8, 140.7, 133.7, 128.2, 124.6, 117.1, 114.6, 114.5, 112.0, 63.0, 44.9, 44.7, 44.1, 44.0, 31.5, 13.5; IR (cm⁻¹): 2988, 1764, 1723, 1679, 1369, 1262, 1082, 762, 698; HRMS (ESI) m/z: calcd for C₂₁H₁₉F₂NNaO₄⁺: [M + Na⁺] = 410.1180; found: 410.1202.

Ethyl 3-(2,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-fluoropropanoate. Dr = 1 : 1, oil, 3p, 56.2 mg, ¹H NMR (400 MHz, CDCl₃): 8.25–8.32 (m, 1H), 7.62–7.72 (m, 1H), 7.43–7.52 (m, 2H), 4.66–4.81 (m, 0.5H), 4.26–4.41 (m, 0.5H), 4.13–4.18 (m, 1H), 3.94–4.00 (m, 1H), 3.38–3.40 (m, 3H), 2.96–3.08 (m, 1H), 2.41–2.68 (m, 1H), 1.66–1.69 (m, 3H), 1.17–1.27 (m, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −190.6 (s, 0.5F), −193.1 (s, 0.5F); ¹³C NMR (100 MHz, CDCl₃): 175.5, 168.5, 163.9, 163.7, 141.6, 141.0, 134.1, 133.6, 129.1, 127.9, 127.6, 125.6, 125.2, 125.1, 124.6, 87.3, 85.5, 61.8, 61.7, 44.7, 44.1, 43.9, 43.0, 42.8, 30.7, 30.1, 27.2, 13.9, 13.8; IR (cm⁻¹): 2983, 1752, 1716, 1422, 1363, 1307, 1212, 1100, 768; HRMS (ESI) m/z: calcd for C₁₆H₁₈FNNaO₄⁺: [M + Na⁺] = 330.1118; found: 330.1129.

Diethyl (2-(2,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)-1,1-difluoroethyl)phosphonate. Mp = 102–104 °C, 3q, 28 mg, ¹H NMR (400 MHz, CDCl₃): 8.26–8.28 (m, 1H), 7.61–7.63 (m, 1H), 7.45 (m, 2H), 4.12–4.24 (m, 4H), 3.40 (s, 3H), 3.28–3.37 (m, 1H), 2.77–2.89 (m, 1H), 1.65 (s, 3H), 1.35–1.38 (m, 3H), 1.28–1.31 (m, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −107.2 to −108.3 (dd, J = 105.3 Hz, 109.0, 1F), −111.1 to −112.2 (dd, J = 97.7 Hz, 105.3 Hz, 1F); ³¹P NMR (162 MHz, CDCl₃): δ 31.43, 5.91, 5.29, 5.25, 4.63, −0.99, −20.02; ¹³C NMR (100 MHz, CDCl₃): 175.0, 163.9, 141.6, 133.4, 128.8, 128.6, 128.3, 127.5, 126.8, 125.9, 123.9, 120.7, 118.6, 64.7, 63.5, 43.7, 43.3, 43.2, 31.4, 29.5, 27.2, 22.5, 16.2, 16.0, 13.9; IR (cm⁻¹): 2988, 2929, 1670, 1272, 1037, 736; HRMS (ESI) m/z: calcd for C₁₇H₂₃F₂NPO₅⁺: [M + H⁺] = 390.1282; found: 390.1276.

7-Iodo-2,4-dimethyl-4-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-isoquinoline-1,3(2H,4H)-dione. Mp = 229–230 °C, 3r, 33 mg, ¹H NMR (400 MHz, CDCl₃): 8.57 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 3.38–3.52 (m, 4H), 2.74–2.87 (m, 1H), 1.72 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −81.07 (t, J = 11.3 Hz, 3F), −107.79 (d, J = 274.5 Hz, 1F), −113.16 (d, J = 274.5 Hz, 1F), −125.27 (d, J = 406.1 Hz, 2F), −125.85 to −126.06 (m, 2F); ¹³C NMR (100 MHz, CDCl₃): 174.4, 163.5, 140.3, 139.0, 132.2, 127.6, 126.7, 124.8, 43.2, 40.6, 31.9, 29.7, 27.6; IR (cm⁻¹): 1715, 1670, 1226, 1130; HRMS (ESI) m/z: calcd for C₁₆H₁₁F₉NINaO₂⁺: [M + Na⁺] = 569.9588; found: 569.9590.

7-Iodo-2,4-dimethyl-4-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)isoquinoline-1,3(2H,4H)-dione. 3s, 58 mg, mp = 137–138 °C, ¹H NMR (400 MHz, CDCl₃): 8.59 (s, 1H), 7.98–8.00 (m, 1H), 7.57–7.59 (m, 1H), 3.40–3.54 (m, 1H), 3.46 (s, 3H), 2.76–2.83 (m, 1H), 1.74 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −80.89 (s, 3 F), −107.59 (d, J = 282.0 Hz, 1F), −112.87 (d, J = 285.8 Hz, 1F), −121.8 (br, 2F), −122.9 (br, 2F), −123.8 (br, 2F), −126.2 (br, 2F); ¹³C NMR (100 MHz, CDCl₃): 174.4, 163.5, 140.3, 139.0, 132.2, 127.6, 126.7, 124.8, 43.3, 40.7, 31.8, 27.6; IR (cm⁻¹): 2964, 1718, 1672, 1433, 1358, 1308, 1238, 1200, 1122, 1058, 832, 787, 737, 707; HRMS (ESI) m/z: calcd for C₁₈H₁₁F₁₃INNaO₂⁺ [M + Na⁺] = 669.9525; found: 669.9527.

4-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-Heptadecafluorononyl)-7-iodo-2,4-dimethylisoquinoline-1,3(2H,4H)-dione. 3t, 89 mg, mp = 232–234 °C, ¹H NMR (400 MHz, CDCl₃): 8.59 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 3.42–3.54 (m, 1H), 3.46 (s, 3H), 2.76–2.87 (m, 1H), 1.74 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): 174.4, 163.5, 140.3, 139.0, 132.2, 127.6, 126.7, 124.8, 43.3, 40.7, 31.8, 27.6; ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −80.9 (s, 3F), −107.6 (d, J = 274.5 Hz, 2F), −112.8 (d, J = 270.7 Hz, 2F), −121.6 (br, 2F), −122.0 (br, 2F), −122.8 (br, 2F), −123.8 (br, 2F), −126.2 (br, 2F); IR (cm⁻¹): 2958, 2927, 1718, 1673, 1358, 1309, 1241, 1208, 1149, 733, 722; HRMS (ESI) m/z: calcd for C₂₀H₁₁F₁₇INNaO₂⁺ [M + Na⁺] = 769.9461; found: 769.9465.

Ethyl 2,2-difluoro-2-(1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)acetate. Dr = 2 : 1, mp = 163–165 °C, 3u, 43 mg, ¹H NMR (400 MHz, CDCl₃): 7.32–7.34 (m, 2H), 7.25–7.28 (m, 4H), 7.13–7.15 (m, 1H), 6.77–6.78 (m, 1H), 6.48–6.50 (m, 1H), 4.61–4.64 (m, 0.6H), 4.21–4.26 (m, 1.2H), 3.78 (s, 0.4H), 3.17–3.21 (m, 2.5H), 2.57–2.60 (m, 1H), 1.27 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −101.77 (s, 1F), −111.50 (s, 1F); ¹³C NMR (100 MHz, CDCl₃): 170.5, 149.0, 143.4, 141.9, 128.7, 127.4, 127.2, 126.6, 126.2, 112.8, 62.7, 55.2, 40.6, 37.2, 13.9; IR (cm⁻¹): 2933, 1760, 1648, 1615, 1270, 1096, 827, 765, 701; HRMS (ESI) m/z: calcd for C₂₀H₁₉F₂NNaO₃⁺: [M + Na⁺] = 382.1231; found: 382.1226.

Ethyl 2,2-difluoro-4-((2-methyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)-5-(N-methyl-benzamido)-5-oxopentanoate. Oil, 3v, 67.5 mg, ¹H NMR (400 MHz, CDCl₃): 8.24–8.26 (m, 1H), 7.61–7.65 (m, 1H), 7.52–7.54 (m, 1H), 7.45–7.49 (m, 1H), 7.36–7.43 (m, 5H), 3.87–4.00 (m, 2H), 3.33 (s, 3H), 3.17–3.24 (m, 1H), 3.08 (s, 3H), 2.82–2.94 (m, 1H), 2.53–2.61 (m, 1H), 2.32–2.40 (m, 1H), 2.11–2.19 (m, 1H), 1.90–1.98 (m, 1H), 1.19 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −99.43 (d, J = 263.2 Hz, 1F), −104.21 (d, J = 267.0 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.3, 173.8, 173.7, 163.4, 163.3, 163.0, 162.7, 135.0, 133.7, 132.4, 129.1, 128.7, 128.2, 128.0, 125.9, 125.8, 116.8, 114.2, 111.8, 72.7, 63.0, 46.8, 45.5, 45.2, 45.0, 39.2, 32.6, 27.2, 13.6; IR (cm⁻¹): 2953, 1765, 1672, 1307, 1223, 1085, 729, 701; HRMS (ESI) m/z: calcd for C₂₆H₂₆F₂N₂NaO₆⁺: [M + Na⁺] = 523.1657; found: 523.1657.

Ethyl 2,2-difluoro-3(8-fluoro-2,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)propanoate. Mp = 116–117 °C, 3x, 22 mg, ¹H NMR (400 MHz, CDCl₃): 7.57–7.62 (m, 1H), 7.24–7.27 (m, 1H), 7.13–7.19 (m, 1H), 4.02–4.12 (m, 2H), 3.37 (s, 3H), 3.25–3.32 (m, 1H), 2.80–2.92 (m, 1H), 1.67 (s, 3H), 1.25 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −101.11 (d, J = 267.0, 1F), −103.29 (d, J = 267.0, 1F), −108.76 (s, 1F); ¹³C NMR (100 MHz, CDCl₃): 174.1, 163.9, 163.2, 162.9, 161.2, 160.7, 160.6, 143.3, 134.5, 134.4, 121.9, 116.8, 116.4, 116.2, 114.3, 113.6, 111.8, 63.1, 45.2, 44.9, 44.7, 43.5, 31.8, 27.2, 13.7; IR (cm⁻¹): 2988, 1764, 1716, 1675, 1613, 1473, 1071, 812, 780, 698; HRMS (ESI) m/z: calcd for C₁₆H₁₆F₃NNaO₄⁺: [M + Na⁺] = 366.0929; found: 366.0945.

Ethyl 3-(4-(bromomethyl)-1-tosylpyrrolidin-3-yl)-2,2-difluoropropanoate. Dr = 3 : 1, 4a, 118.2 mg, oil, ¹H NMR (400 MHz, CDCl₃): 7.70–7.74 (m, 2H), 7.32–7.36 (m, 2H), 4.29–4.32 (m, 2H), 3.63–3.67 (m, 0.3H), 3.47–3.50 (m, 1H), 3.38–3.45 (m, 1H), 3.20–3.36 (m, 1H), 3.06–3.13 (m, 1H), 2.93–3.04 (m, 0.5H), 2.85–2.90 (m, 0.6H), 2.48–2.60 (m, 1H), 2.44 (s, 3H), 2.09–2.28 (m, 1.8H), 1.75–2.03 (m, 1.7H), 1.34 (t, J = 8.0 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −104.40 (d, J = 263.2 Hz, 1F), −106.36 (d, J = 259.44 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): 163.7, 163.4, 163.1, 143.8, 143.7, 143.4, 133.8, 133.4, 132.8, 129.8, 127.6, 127.3, 117.7, 115.2, 112.7, 63.2, 63.0, 54.4, 51.1, 45.7, 43.8, 35.1, 32.5, 32.0, 31.8, 22.6, 21.4, 13.8, 13.2; IR (cm⁻¹): 2968, 2931, 1765, 1600, 1342, 1163, 1097, 1055, 814, 665; HRMS (ESI) m/z: calcd for C₁₇H₂₂F₂BrNNaSO₄⁺: [M + Na⁺] = 476.0319; found: 476.0317.

Acknowledgements

We thank the National Science Foundation of China NSF 21402066, the Natural Science Foundation of Jiangsu Province (BK20140139), and the Fundamental Research Funds for the Central Universities (JUSRP11419) for financial support. Financial support from MOE & SAFEA for the 111 project (B13025) is also gratefully acknowledged.

Notes and references

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14. See the ESI for details.†.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra05744f

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