English

• 1.   Introduction

  The indole scaffold is a privileged structure and ubiquitously present in nature. Indole-fused heterocycles, such as pyrimido[1, 6-a]-indol-1(2H)-one and 3, 4-dihydropyrimido- [1, 6-a]-indol-1(2H)-one analogues, are central skeleton of many biologically active natural products and drugs. In particular, pyrimido[1, 6-a]-indol-1(2H)-one and 3, 4-dihy- dropyrimido[1, 6-a]-indol-1(2H)-one are fluorescent material, 5-HT₃ receptor antagonist, natural product analogues, etc. (Figure 1).^[1] The synthesis of these indole-fused heterocycles either requires multistep synthesis or suffers from poor functional group tolerance. Therefore, the development of straightforward methods that allow rapid construction of these scaffolds remains challenge.^[2]

  Figure 1

  

  Figure 1.  Structures of functional and bioactive pyrimido- [1, 6-a]-indol-1(2H)-ones

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  Organofluorine chemistry is a rapidly evolving research field. The omnipresence of fluorinated compounds has been extensively studied in the fields of pharmaceutical industry and agrochemistry.^[3] Incorporation of fluorine and other fluorine-containing moieties into a molecule can alter its physicochemical and biological properties.^[4] Introducing fluorine-containing moieties into lead compounds has become an effective strategy for structural optimization. Traditionally, fluorine-containing molecules are synthesized with toxic reagents, such as diethylaminosulfur trifluoride or sulfur tetrafluoride.^[5] Meanwhile, these methodologies require harsh conditions, and suffer from narrow substrate scope. Due to the wide availability, fluoroalkyl bromides have become important building blocks in the fluoroalkylation reactions with high efficiency and practicability.^[6] In 2014, Zhang and co-workers developed highly selective gem-difluoroallylation (α/γ up to > 37:1) of aryl boronic acids using 3-bromo-3, 3- difluoropropene (BDFP) via Pd(0) catalyst.^[7] This methodology provides an efficient approach for the synthesis of fluorinated building blocks and bioactive molecules. However, the direct 3, 3-difluoroallylation of C—H bonds with BDFP is rare. To date, only few methods have been developed in the area of 3, 3-difluoroallylation of C—H bonds. For instance, our group has developed 8-amino- quinoline-aided Pd-catalyzed C—H 3, 3-difluoroallylation of benzamides (Scheme 1a).^[8] Recently, Zhang et al.^[9] reported a Mn(Ⅰ)-catalyzed 3, 3-difluoroallylation of 2- pyridones and indoles with BDFP (Scheme 1b). There is still a pressing need for the development of novel directing groups in order to achieve the 3, 3-difluoroallylated arenes. We chose N-ethoxycarbamoyl as the directing group for 3, 3-difluoroallylation for two reasons: (i) The N-ethoxy- carbamoyl directing group has been proved to be crucial for Ru- and Rh-catalyzed redox-neutral annulations and alkenylations in our previous reports.^[10] (ii) The NH of N-ethoxycarbamoyl directing group provides the possibility for subsequent cyclization reactions. Considering the construction of 3, 4-dihydropyrimido[1, 6-a]-indol-1(2H)- one analogues needs several steps: Henry reaction of 1H-indole-2-carbaldehyde derivatives with nitroalkanes followed by reduction and cyclization (Scheme 1c), ^[1d] the development of facile strategies for their synthesis, especially for fluorinated 3, 4-dihydropyrimido[1, 6-a]-indol- 1(2H)-one derivatives, would be valuable. Herein, we have developed a Rh(Ⅲ)-catalyzed direct functionalization of C—H bonds of N-ethoxycarbamoyl indoles with 3-bromo- 3, 3-difluoroprop-1-ene for the access of 3, 3-difluoroal- lylated indole derivatives (Scheme 1d). Meanwhile, sequential cyclization of these 3, 3-difluoroallylated indole derivatives with N-iodosuccinimide (NIS) could deliver novel fluorinated 3, 4-dihydropyrimido[1, 6-a]-indol-1(2H)- one scaffold, which will help in the search of new biologically active compounds and drug discovery.

  Scheme 1

  

  Scheme 1.  3, 3-Difluoroallylation of indoles via C—H activation

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  2.   Results and discussion

  Initially, the reaction of N-ethoxy-1H-indole-1-carbox- amide (1a) and 3-bromo-3, 3-difluoropropene (2a) in the presence of catalyst and base under 60 ℃ was examined (Table 1). To our delight, the desired product 3a was obtained in 31% yield with [RuCl₂(p-cymene)]₂ as the catalyst (Entry 1). Then Ir(Ⅲ) and Rh(Ⅲ) catalysts were investigated, and the desired product 3a was formed in 78% NMR yield with [RhCp*Cl₂]₂ as catalyst (Entries 2~3). For basic additives including organic and inorganic bases, NaOAc turned out to be optimal (Entries 3~9). Subsequently, screening other solvents, such as dioxane, tetrahydrofuran (THF) and alcohols, indicated EtOH to be the optimal solvent for this reaction giving 3a at 75% isolated yield (Entries 10~14). Increasing the reaction temperature to 80 ℃ led to a significantly lower yield of 3a (Entries 14~15). Decreasing the amounts of 2a, NaOAc or the catalyst loading led to the formation of 3a in lower yields (Entries 16~18). Furthermore, control experiments indicated that the difluoroallylation hardly proceeded in the absence of either catalyst or base (Entries 19~20). It should be mentioned that this reaction could be successfully conducted under air to afford 3a in 79% yield (Entry 21).

  Table 1

  

  Table 1.  Optimization of reaction conditions^a

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  Entry	Cat.	Base	Solvent	Yieldb/%
  1	[RuCl2(p-cymene)]2	NaOAc	MeOH	31
  2	[IrCp*Cl2]2	NaOAc	MeOH	NRc
  3	[RhCp*Cl2]2	NaOAc	MeOH	78
  4	[RhCp*Cl2]2	KOAc	MeOH	75
  5	[RhCp*Cl2]2	EtONa	MeOH	50
  6	[RhCp*Cl2]2	CsF	MeOH	24
  7	[RhCp*Cl2]2	Et3N	MeOH	60
  8	[RhCp*Cl2]2	DIPEA	MeOH	74
  9	[RhCp*Cl2]2	NaOTf	MeOH	NR
  10	[RhCp*Cl2]2	NaOAc	THF	70
  11	[RhCp*Cl2]2	NaOAc	Dioxane	58
  12	[RhCp*Cl2]2	NaOAc	DME	60
  13	[RhCp*Cl2]2	NaOAc	TFE	60
  14	[RhCp*Cl2]2	NaOAc	EtOH	82 (75)
  15d	[RhCp*Cl2]2	NaOAc	EtOH	56
  16e	[RhCp*Cl2]2	NaOAc	EtOH	79
  17f	[RhCp*Cl2]2	NaOAc	EtOH	69
  18g	[RhCp*Cl2]2	NaOAc	EtOH	68
  19	[RhCp*Cl2]2	—	EtOH	NR
  20	—	NaOAc	EtOH	NR
  21h	[RhCp*Cl2]2	NaOAc	EtOH	79
  a Reaction conditions: 1a (0.3 mmol, 1.0 equiv.), 2a (0.9 mmol, 3.0 equiv.), catalyst (10 mol%), base (2.0 equiv.), solvents (2.0 mL), a sealed tube at 60 ℃ (oil bath) for 24 h under argon. b Determined by 19F NMR using fluorobenzene as an internal standard, and the number in parentheses is isolated yield. c No reaction. d 80 ℃ (oil bath). e 2.5 equiv. 2a was used. f 5 mol% catalyst was used. g 1.5 equiv. NaOAc was used. h Under Air.

  After establishing the optimal reaction conditions, it is crucial to examine the scope of indoles (Table 2). N-ethoxycarbamoyl (EtONHCO) protected 3-methylin- dole (1b) and ethyl 3-indoleacetate (1c) gave the corresponding products in good yields. Various electron- donating and electron-withdrawing substituents including methyl (3d, 3g and 3m), ethyl (3r), methoxy (3e and 3n), ethoxy (3o), trifluoromethyl (3l) and ester (3k) at the 4-, 5-, 6-, and 7-position on benzene ring of indoles were tolerated in this reaction, affording the desired products in moderate to excellent yields (55%~94%). Meanwhile, halogen groups (3f, 3h~3j and 3p~3q) at benzene ring of indoles were well-tolerant to afford desired products in moderate yields (61%~80%). In addition, several disubstituted indoles (1s~1w) proved to be competent substrates, furnishing the desired corresponding products in yields ranging from 69% to 93%. Indoles with aliphatic ring (1y) and pyrrole-1-carboxamide (1aa) were also applicable in this reaction, affording 3y and 3aa in 30% and 40% yields, respectively. Unfortunately, no corresponding product was obtained and starting materials were recovered when using N-ethoxy-1H-pyrrolo[2, 3-b]pyridine-1-carbox- amide (1z) as the substrate. The influence of directing groups was investigated, and indole bearing N-methoxy- carbamoyl, N-tert-butoxycarbamoyl and N-benzyloxy- carbamoyl groups gave the product 3 in 60%, 23% and 78% yields, respectively. The low yield of the N-tert-but- oxycarbamoyl group case is probably due to the steric reasons. Disappointingly, substituted BDFPs 2b and 2c failed to give the desired product under the optimal conditions. Most starting materials 2b and 2c were recovered and no desired product was detected.

  Table 2

  

  Table 2.  Scope of indoles^a

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  a Reaction conditions: 1 (0.3 mmol, 1.0 equiv.), 2 (0.9 mmol, 3.0 equiv.), [RhCp*Cl2]2 (10 mol %) and NaOAc (2.0 equiv.) in EtOH (2.0 mL) at 60 ℃ (oil bath) for 24 h under argon. All listed yields are isolated ones.

  Notably, a NIS-mediated intramolecular cyclization of these 3, 3-difluoroallylated indole derivatives 3 was performed to afford novel fluorinated 3, 4-dihydropyrimido- [1, 6-a]-indol-1(2H)-one scaffold 4 (Scheme 2).^[11] For instance, the 3, 3-difluoroallylated indoles derived from 3-methylindole and 3-methylindoles with halogens could proceed efficiently to generate novel fluorinated 3, 4-dihy- dropyrimido[1, 6-a]-indol-1(2H)-ones (4b and 4t~4w) in moderate to good yields. 3, 3-difluoroallylated indole with methoxy (3x) was applicable in this reaction as well, but affording 4x in lower yield (23%). Since the wide application of fluorine-containing compounds in pharmaceutical, these fluorinated 3, 4-dihydropyrimido[1, 6-a]-indol-1(2H)- ones would have significant potential for drug discovery. Meanwhile, these iodo-fluoroalkanes 4 could also serve as difluoroalkyl radical precursors for the preparation of complex fluorine-containing molecules in the presence of radical initiators.

  Scheme 2

  

  Scheme 2.  NIS-mediated intramolecular cyclization of 3

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  Additionally, in order to prove the potential for practical application, the gram-scale reaction was conducted (Scheme 3). To our delight, the efficiency was maintained (65% yield, for gram-scale reaction). To evaluate the efficiency and potential for the synthetic utility of the method, derivatization of the representative product 3a has been performed. The hydrogenative reduction of 3a furnished 5a in 85% yield, which provides a strategy for the synthesis of novel terminally difluoroalkane derivatives without using toxic reagents such as diethylaminosulfur trifluoride. Interestingly, fluorinated 3, 4-dihydropyrimido[1, 6-a]-in- dol-1(2H)-ones (4u) could undergo deiodination in present of AIBN and Bu₃SnH, furnishing 6u in good yield (78%).

  Scheme 3

  

  Scheme 3.  Gram-scale reaction and derivatization

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  To clarify the possible mechanism of this reaction, a series of control experiments were performed. Two independent reactions using 1a and 1a-D gave a KIE value of 1.24 indicating that the step of the C—H bond cleavage was unlikely involved in the rate-limiting step (Scheme 4a). Further, to investigate the electronic effects of this reaction, two competitive experiments between 4-F/4-OMe and 5-CF₃/5-Me substituted indoles were conducted, respectively. ¹H NMR analysis of the product mixture indicated a slight preference of C−H activation for the more electron poor substrate (Scheme 4b). Despite the failure in isolation of a cyclometalated rhodium complex, the formation of the rhodacyle 7 was confirmed by HRMS analysis (Scheme 4c).

  Scheme 4

  

  Scheme 4.  Mechanistic investigations

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  Based on the preliminary mechanistic experiments and previous studies^[10c~10e], a plausible catalytic cycle was proposed (Scheme 5). The first step is the formation of an active catalyst through anion exchange with sodium acetate. Next, the coordination of 1a and subsequent C—H bond cleavage of 1a occurs to produce a five-membered rhodacycle A. Then, rhodacycle A is coordinated and inserted with 2a to form a seven-membered rhodacycle intermediate C. Finally, C produces the desired product 3a via β-bromo elimination and regenerates the active rhodium species.

  Scheme 5

  

  Scheme 5.  Proposed mechanism

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  3.   Conclusions

  An efficient synthetic strategy for the rapid establishment of 3, 3-difluoroallylated indole derivatives via Rh(Ⅲ)-catalyzed C—H bond activation has been developed. This strategy featured broad synthetic generality, unique versatility and high efficiency. In addition, NIS- mediated intramolecular cyclization of these 3, 3-difluoro- allylated indole derivatives 3 was performed to afford novel fluorinated 3, 4-dihydropyrimido[1, 6-a]-indol-1(2H)- one scaffold 4, which provided a potential tool for the construction of fluorine-containing heterocycles for drug discovery.

  4.   Experimental section

  4.1   General information

  Analytical thin layer chromatography (TLC) was HSGF 254 (0.15~0.2 mm thickness). Preparative thin layer chromatography (PTLC) was HSGF 254 (0.4~0.5 mm thickness). All products were characterized by their NMR and MS spectra. ¹H NMR and ¹³C NMR spectra were recorded on a 400 MHz, 500 MHz or 600 MHz instrument. Chemical shifts were reported downfield from tetramethylsilane. High-resolution mass spectra (HRMS) were measured on a Micromass Ultra Q-TOF spectrometer. Other reagents (chemicals) were purchased from Alfa Aesar, Acros organics, TCI, J & K Chemicals, Energy Chemical and Adamas and used without further purification. Substrates 1a~1e^[10c], 1g~1o^[10c~10e], 1q~1s^[10c~10e] and 1aa~1da^{[10c, 10d, 12a]} were known compounds and all of them were prepared according to literature^{[10c~10e, 12a]}. Substrates 1f, 1p and 1t~1z were new compounds and prepared according to literature^[12b]. Substrates 2b^[7] and 2c^[13] were known compounds and all of them were prepared according to literature.

  4.2   General procedure for N-ethoxycarbamoyl indoles 1f, 1p and 1t~1z

  To a 100 mL round bottle charged with a stirring bar was added EtONH₂•HCl (80.0 mmol) and 20 mL tetrahydrofuran (THF). To the system was then added sodium hydroxide (powder, 1.0 equiv.). The system was then stirred at room temperature for about 3 h until the system became clear. To a 100 mL round bottle charged with stirring bar, were added indole (5.0 mmol, 1.0 equiv.), 1, 1'-carbonyldiimidazole (CDI, 7.5 mmol, 1.5 equiv.) and 4-dimethylaminepyridine (DMAP, 5 mol%). Then 20 mL of anhydrous acetonitrile was added to bottle under Ar. The system was refluxed at 85 ℃ (oil bath) overnight under Ar. After cooled to room temperature, the freshly prepared EtONH₂ solution (4 mol/L in THF, 2.0 equiv.) was added and then stirred at 80 ℃ (oil bath) for another 6~12 h. After cooled to room temperature, the solvents were removed under reduced pressure. The residue was subject to column chromatography on silica gel (hexanes/EtOAc, V/V=20/1~4/1) to afford the corresponding N-carbamoyl indoles.

  N-Ethoxy-4-fluoro-1H-indole-1-carboxamide (1f): Whi- te solid, 700 mg, 43% yield. m.p. 83~84 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.44 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.40 (d, J=3.7 Hz, 1H), 7.29~7.19 (m, 1H), 6.92 (dd, J=9.7, 8.0 Hz, 1H), 6.72 (dd, J=3.8, 0.7 Hz, 1H), 4.09 (d, J=7.1 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 156.1 (d, J=248.4 Hz), 153.2, 137.5 (d, J=9.5 Hz), 125.5 (d, J=7.4 Hz), 123.6, 119.1 (d, J=22.3 Hz), 110.8 (d, J=3.8 Hz), 108.2 (d, J=18.6 Hz), 103.9, 72.9, 13.6; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -121.52 (dd, J=9.4, 5.4 Hz). HRMS (ESI) calcd for C₁₁H₁₀FN₂O₂ [M-H]^- 221.0732, found 221.0727.

  6-Chloro-N-ethoxy-1H-indole-1-carboxamide (1p): White solid, 850 mg, 54% yield. m.p. 103~105℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.38 (s, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.38 (d, J=3.7 Hz, 1H), 7.20 (dd, J=8.3, 1.9 Hz, 1H), 6.58 (d, J=3.7 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 153.1, 135.8, 130.7, 128.5, 124.0, 123.7, 121.9, 115.1, 108.2, 72.9, 13.6. HRMS (ESI) calcd for C₁₁H₁₀ClN₂O₂ [M-H]^- 237.0436, found 237.0429.

  4-Bromo-N-ethoxy-3-methyl-1H-indole-1-carboxamide (1t): White solid, 1.1 g, 39% yield. m.p. 137~138 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.39 (s, 1H), 8.11 (dd, J=8.4, 0.9 Hz, 1H), 7.35 (dd, J=7.8, 0.9 Hz, 1H), 7.13 (q, J=1.3 Hz, 1H), 7.09 (t, J=8.1 Hz, 1H), 4.06 (q, J=7.0 Hz, 2H), 2.46 (d, J=1.4 Hz, 3H), 1.32 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 153.0, 137.2, 128.7, 127.2, 125.6, 122.1, 118.5, 114.9, 114.2, 72.8, 13.6, 13.0. HRMS (ESI) calcd for C₁₂H₁₂BrN₂O₂ [M-H]^- 295.0088, found 295.0082.

  N-Ethoxy-5-fluoro-3-methyl-1H-indole-1-carboxamide (1u): White solid, 880 mg, 56% yield. m.p. 122~124 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.18 (s, 1H), 8.09 (dd, J=9.0, 4.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 7.13 (dd, J=8.7, 2.6 Hz, 1H), 7.04 (td, J=9.0, 2.6 Hz, 1H), 4.06 (q, J=7.0 Hz, 2H), 2.21 (d, J=1.3 Hz, 3H), 1.32 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 159.4 (d, J=239.5 Hz), 153.3, 132.2, 131.9 (d, J=9.5 Hz), 121.8, 117.6 (d, J=4.1 Hz), 116.0 (d, J=9.1 Hz), 112.6 (d, J=25.1 Hz), 104.8 (d, J=23.5 Hz), 72.8, 13.6, 9.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -120.52 (td, J=9.4, 4.9 Hz). HRMS (ESI) calcd for C₁₂H₁₂FN₂O₂ [M-H]^- 235.0888, found 235.0884.

  5-Bromo-N-ethoxy-3-methyl-1H-indole-1-carboxamide (1v): White solid, 1.3 g, 46% yield. m.p. 155~156 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.13 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.40 (dd, J=8.7, 2.0 Hz, 1H), 7.13 (d, J=1.5 Hz, 1H), 4.07 (q, J=7.1 Hz, 2H), 2.22 (d, J=1.3 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 153.2, 134.5, 132.6, 127.7, 122.1, 121.4, 117.1, 116.4, 116.1, 72.8, 13.6, 9.7. HRMS (ESI) calcd for C₁₂H₁₂BrN₂O₂ [M-H]^- 295.0088, found 295.0085.

  6-Bromo-N-ethoxy-3-methyl-1H-indole-1-carboxamide (1w): White solid, 1.1 g, 43% yield. m.p. 97~98 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.33 (s, 1H), 8.19 (s, 1H), 7.35 (dd, J=8.4, 1.6 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 2.23 (d, J=1.3 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 153.1, 136.4, 129.7, 126.0, 120.8, 120.3, 118.6, 118.1, 117.7, 72.9, 13.6, 9.7. HRMS (ESI) calcd for C₁₂H₁₂BrN₂O₂ [M-H]^- 295.0088, found 295.0081.

  N-Ethoxy-5-methoxy-3-methyl-1H-indole-1-carboxamide (1x): White solid, 800 mg, 47% yield. m.p. 147~148 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.29 (s, 1H), 8.03~7.97 (m, 1H), 7.13 (d, J=1.5 Hz, 1H), 6.95~6.85 (m, 2H), 4.05 (q, J=7.0 Hz, 2H), 3.85 (s, 3H), 2.20 (d, J=1.4 Hz, 3H), 1.31 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 156.0, 153.6, 131.8, 130.4, 121.1, 117.4, 115.7, 113.3, 102.0, 72.6, 55.9, 13.6, 9.8. HRMS (ESI) calcd for C₁₃H₁₇N₂O₃ [M+H]⁺ 249.1234, found 249.1236.

  N-Ethoxy-5-(pyrrolidin-1-yl)-1H-indole-1-carboxamide (1y): White solid, 570 mg, 39% yield. m.p. 122~124 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.27 (s, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.35 (d, J=3.6 Hz, 1H), 6.68 (s, 1H), 6.66 (dd, J=8.9, 2.4 Hz, 1H), 6.47 (d, J=3.7 Hz, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.30 (t, J=6.4 Hz, 4H), 2.04~2.00 (m, 4H), 1.32 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 153.7, 144.9, 131.5, 127.4, 124.0, 115.1, 111.1, 108.1, 102.4, 72.6, 48.5, 25.5, 13.7. HRMS (ESI) calcd for C₁₅H₂₀N₃O₂ [M+H]⁺ 274.155, found 274.1528.

  N-Ethoxy-1H-pyrrolo[2, 3-b]pyridine-1-carboxamide (1z): Oil, 930 mg, 54% yield. ¹H NMR (400 MHz, Chloroform-d) δ: 12.12 (s, 1H), 8.27 (dd, J=4.9, 1.5 Hz, 1H), 7.94~7.88 (m, 2H), 7.17 (dd, J=7.8, 4.9 Hz, 1H), 6.54 (d, J=4.0 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ: 151.6, 146.1, 142.6, 130.3, 125.8, 123.4, 118.3, 104.0, 72.9, 13.6. HRMS (ESI) calcd for C₁₀H₁₂N₃O₂ [M+H]⁺ 206.0924, found 206.0923.

  4.3   General procedure for 3a~3y and 3aa~3da

  To a reaction tube were added N-ethoxy-1H-indole-1- carboxamide (1) (0.3 mmol), 3-bromo-3, 3-difluoroprop- 1-ene (2) (139 mg, 0.9 mmol), [RhCp*Cl₂]₂ (18 mg, 10 mol%), NaOAc (48 mg, 0.6 mmol), and then the reaction tube was evacuated and purged with Ar three times. Ethanol absolute (2.0 mL) was added to the tube through syringe. The solution was kept at 60 ℃ (oil bath) for 24 h under Ar. After cooled to room temperature, the reaction mixture was diluted with H₂O, extracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (hexanes/EtOAc, V/V=20/1~10/1) to give a corresponding product 3.

  2-(3, 3-Difluoroallyl)-N-ethoxy-1H-indole-1-carboxamide (3a): White solid, 62 mg, 75% yield. m.p. 98~100 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.21 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.24 (dd, J=8.3, 1.3 Hz, 1H), 7.19 (td, J=7.5, 1.1 Hz, 1H), 6.43 (s, 1H), 4.54 (dtd, J=24.7, 7.8, 2.0 Hz, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.67 (dq, J=7.8, 1.5 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.1 (dd, J=289.3, 286.4 Hz), 152.9, 139.8~138.1 (m), 135.4, 129.3, 123.5, 122.6, 121.0, 112.3, 106.5, 75.8 (dd, J=25.0, 19.2 Hz), 73.0, 22.3 (d, J=5.6 Hz), 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.39 (d, J=42.1 Hz), -89.59 (dd, J=42.1, 24.7 Hz). HRMS (ESI) calcd for C₁₄H₁₃F₂N₂O₂ [M-H]^- 279.0951, found 279.0946.

  2-(3, 3-Difluoroallyl)-N-ethoxy-3-methyl-1H-indole-1- carboxamide (3b): Yellow solid, 61 mg, 69% yield. m.p. 101~103 ℃; ¹H NMR (600 MHz, Chloroform-d) δ: 8.17 (s, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.24 (dd, J=8.1, 1.3 Hz, 1H), 7.21 (t, J=7.2 Hz, 1H), 4.54 (dtd, J=25.5, 7.7, 2.2 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.62 (dt, J=7.6, 1.8 Hz, 2H), 2.23 (s, 3H), 1.39 (t, J=7.1 Hz, 3H); ¹³C NMR (151 MHz, Chloroform-d) δ: 156.6 (dd, J=288.3, 286.7 Hz), 153.0, 134.4, 133.9, 130.6, 123.7, 122.3, 119.2, 114.2, 112.2, 76.8 (dd, J=23.5, 18.9 Hz), 73.0, 19.5 (d, J=5.3 Hz), 13.7, 8.5; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -88.72 (d, J=44.5 Hz), -89.65 (dd, J=44.6, 25.3 Hz). HRMS (ESI) calcd for C₁₅H₁₅F₂N₂O₂ [M-H]^- 293.1107, found 293.1103.

  Ethyl 2-(2-(3, 3-difluoroallyl)-1-(ethoxycarbamoyl)-1H- indol-3-yl)acetate (3c): White solid, 92 mg, 84% yield. m.p. 123~124 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.32 (s, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.29~7.22 (m, 1H), 7.24~7.17 (m, 1H), 4.55 (dtd, J=25.3, 7.6, 2.1 Hz, 1H), 4.20~4.12 (m, 2H), 4.16~4.08 (m, 2H), 3.68 (s, 2H), 3.66 (dt, J=7.7, 1.8 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 171.1, 156.6 (dd, J=288.5, 286.8 Hz), 152.5, 135.7~135.6 (m), 134.6, 129.4, 124.0, 122.6, 119.4, 112.2, 111.4, 77.1~75.6 (m), 73.0, 61.2, 30.1, 19.5 (d, J=5.5 Hz), 14.3, 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -88.26 (d, J=43.4 Hz), -89.21 (dd, J=43.7, 25.3 Hz). HRMS (ESI) calcd for C₁₈H₁₉F₂N₂O₄ [M-H]^- 365.1318, found 365.1316.

  2-(3, 3-Difluoroallyl)-N-ethoxy-4-methyl-1H-indole-1-carboxamide (3d): Yellow solid, 62 mg, 71% yield. m.p. 103~104 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.25 (s, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.16~7.09 (m, 1H), 6.95~7.00 (m, 1H), 6.45~6.40 (m, 1H), 4.55 (dtd, J=24.7, 7.8, 2.0 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.65 (dq, J=7.9, 1.5 Hz, 2H), 2.48 (s, 3H), 1.38 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.1 (dd, J=288.8, 286.4 Hz), 152.9, 138.5 (t, J=2.7 Hz), 135.1, 130.5, 128.9, 123.6, 123.0, 109.8, 104.9, 75.9 (dd, J=24.9, 19.2 Hz), 73.0, 22.3 (d, J=5.5 Hz), 18.6, 13.7; ¹⁹F NMR (376 MHz, Chloroform-d) δ: -87.37 (d, J=42.3 Hz), -89.67 (dd, J=42.2, 24.9 Hz). HRMS (ESI) calcd for C₁₅H₁₅F₂- N₂O₂ [M-H]^- 293.1107, found 293.1101.

  2-(3, 3-Difluoroallyl)-N-ethoxy-4-methoxy-1H-indole-1-carboxamide (3e): Yellow solid, 78 mg, 84% yield. m.p. 97~99 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.26 (s, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 6.62 (d, J=7.9 Hz, 1H), 6.53 (s, 1H), 4.53 (dtd, J=24.7, 7.9, 2.0 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.92 (s, 3H), 3.64 (dq, J=7.9, 1.5 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.1 (dd, J=289.3, 286.1 Hz), 153.1, 152.8, 137.7~137.4 (m), 136.6, 124.5, 119.5, 105.4, 103.4, 102.8, 75.8 (dd, J=25.0, 19.3 Hz), 73.0, 55.6, 22.3 (d, J=5.5 Hz), 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.51 (d, J=42.5 Hz), -89.78 (dd, J=42.5, 24.6 Hz). HRMS (ESI) calcd for C₁₅H₁₅F₂N₂O₃ [M-H]^- 309.1056, found 309.1050.

  2-(3, 3-Difluoroallyl)-N-ethoxy-4-fluoro-1H-indole-1-carboxamide (3f): Yellow solid, 64 mg, 71% yield. m.p. 126~127 ℃; ¹H NMR (600 MHz, Chloroform-d) δ: 8.35 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.14 (td, J=8.2, 5.3 Hz, 1H), 6.85 (dd, J=9.5, 8.0 Hz, 1H), 6.50 (s, 1H), 4.51 (dtd, J=24.6, 7.8, 1.9 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.62 (dq, J=7.8, 1.5 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H); ¹³C NMR (151 MHz, Chloroform-d) δ: 157.2 (dd, J=289.6, 286.7 Hz), 155.9 (d, J=248.3 Hz), 152.4, 139.0, 137.7 (d, J=10.1 Hz), 124.2 (d, J=7.6 Hz), 118.1 (d, J=22.6 Hz), 108.3 (d, J=3.7 Hz), 107.8 (d, J=18.8 Hz), 101.9, 75.5 (dd, J=25.4, 19.2 Hz), 73.1, 22.2 (d, J=5.4 Hz), 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -86.95 (d, J=40.1 Hz), -89.20 (dd, J=41.0, 24.8 Hz), -121.46~-121.55 (m). HRMS (ESI) calcd for C₁₄H₁₂F₃N₂O₂ [M-H]^- 297.0856, found 297.0854.

  2-(3, 3-Difluoroallyl)-N-ethoxy-5-methyl-1H-indole-1-carboxamide (3g):Yellow solid, 61 mg, 70% yield. m.p. 85~86 ℃; ¹H NMR (600 MHz, Chloroform-d) δ: 8.25 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.27 (s, 1H), 7.03 (dd, J=8.5, 1.7 Hz, 1H), 6.34 (s, 1H), 4.53 (dtd, J=24.8, 7.8, 2.0 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.64 (dq, J=7.8, 1.5 Hz, 2H), 2.40 (s, 3H), 1.38 (t, J=7.0 Hz, 3H); ¹³C NMR (151 MHz, Chloroform-d) δ: 157.0 (dd, J=289.2, 286.2 Hz), 153.1, 139.2 (t, J=2.9 Hz) 133.5, 132.2, 129.6, 124.8, 120.8, 112.1, 106.3, 75.9 (dd, J=24.9, 19.2 Hz), 72.9, 22.4 (d, J=5.4 Hz), 21.3, 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.54 (d, J=42.9 Hz), -89.75 (dd, J=42.3, 24.4 Hz). HRMS (ESI) calcd for C₁₅H₁₅F₂N₂O₂ [M-H]^- 293.1107, found 293.1099.

  2-(3, 3-Difluoroallyl)-N-ethoxy-5-fluoro-1H-indole-1-carboxamide (3h): White solid, 64 mg, 71% yield. m.p. 109~111 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.20 (s, 1H), 7.58 (dd, J=9.0, 4.3 Hz, 1H), 7.14 (dd, J=8.7, 2.6 Hz, 1H), 6.95 (td, J=9.0, 2.6 Hz, 1H), 6.38 (s, 1H), 4.51 (dtd, J=24.6, 7.8, 2.0 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.63 (dq, J=8.0, 1.5 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, Chloroform-d) δ: 159.2 (d, J=239.1 Hz), 157.2 (dd, J=289.5, 286.6 Hz), 152.7, 140.7, 131.9, 130.1 (d, J=10.0 Hz), 113.3 (d, J=9.3 Hz), 111.3 (d, J=25.6 Hz), 106.5 (d, J=3.9 Hz), 106.3 (d, J=23.8 Hz), 75.6 (dd, J=25.3, 19.3 Hz), 73.1, 22.3 (d, J=5.4 Hz), 13.7. ¹⁹F NMR (376 MHz, Chloroform-d) δ: -86.97 (d, J=41.8 Hz), -89.24 (dd, J=42.2, 24.9 Hz), -121.05 (td, J=9.4, 4.5 Hz). HRMS (ESI) calcd for C₁₄H₁₂F₃N₂O₂ [M-H]^- 297.0856, found 297.0854.

  5-Chloro-2-(3, 3-difluoroallyl)-N-ethoxy-1H-indole-1-carboxamide (3i): Yellow solid, 63 mg, 67% yield. m.p. 116~118 ℃; ¹H NMR (600 MHz, Chloroform-d) δ: 8.22 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.17 (dd, J=8.8, 2.1 Hz, 1H), 6.36 (s, 1H), 4.51 (dtd, J=24.6, 7.8, 1.9 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H), 3.62 (dq, J=7.8, 1.6 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H); ¹³C NMR (151 MHz, Chloroform-d) δ: 157.1 (dd, J=289.6, 286.8 Hz), 152.5, 140.4 (t, J=2.8 Hz), 133.8, 130.4, 128.3, 123.6, 120.4, 113.3, 106.0, 75.5 (dd, J=25.4, 19.2 Hz), 73.1, 22.2 (d, J=5.4 Hz), 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -86.91 (d, J=41.4 Hz), -89.17 (dd, J=41.3, 24.4 Hz). HRMS (ESI) calcd for C₁₄H₁₂ClF₂N₂O₂ [M-H]^- 313.0561, found 313.0566.

  5-Bromo-2-(3, 3-difluoroallyl)-N-ethoxy-1H-indole-1-carboxamide (3j): White solid, 66 mg, 61% yield. m.p. 118~119 ℃; ¹H NMR (600 MHz, Chloroform-d) δ: 8.20 (s, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.31 (dd, J=8.8, 2.0 Hz, 1H), 6.36 (s, 1H), 4.51 (dtd, J=24.6, 7.8, 1.9 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.63 (d, J=7.7 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H); ¹³C NMR (151 MHz, Chloroform-d) δ: 157.2 (dd, J=289.6, 286.9 Hz), 152.4, 140.3~139.8 (m), 134.2, 130.9, 126.3, 123.5, 115.8, 113.7, 105.8, 75.5 (dd, J=25.5, 19.2 Hz), 73.1, 22.2 (d, J=5.5 Hz), 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -86.88 (d, J=40.4 Hz), -89.13 (dd, J=41.1, 24.3 Hz). HRMS (ESI) calcd for C₁₄H₁₂BrF₂N₂O₂ [M-H]^- 357.0056, found 357.0050.

  Methyl 2-(3, 3-difluoroallyl)-1-(ethoxycarbamoyl)-1H- indole-5-carboxylate (3k): White solid, 70 mg, 69% yield. m.p. 138~140 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.53 (s, 1H), 8.14 (d, J=1.7 Hz, 1H), 7.84 (dd, J=8.7, 1.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 6.46 (s, 1H), 4.51 (dtd, J=24.5, 7.8, 1.9 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.89 (s, 3H), 3.63 (dq, J=7.9, 1.5 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 167.6, 157.2 (dd, J=289.7, 286.9 Hz), 152.1, 140.8~139.5 (m), 138.1, 128.7, 124.8, 124.4, 123.1, 111.9, 106.8, 75.4 (dd, J=25.4, 19.3 Hz), 73.1, 52.2, 22.1 (d, J=5.6 Hz), 13.7; ¹⁹F NMR (376 MHz, Chloroform-d) δ: -86.82 (d, J=40.6 Hz), -89.06 (dd, J=41.1, 24.5 Hz). HRMS (ESI) calcd for C₁₆H₁₅F₂N₂O₄ [M-H]^- 337.1005, found 337.1010.

  2-(3, 3-Difluoroallyl)-N-ethoxy-5-(trifluoromethyl)-1H- indole-1-carboxamide (3l): Yellow solid, 57 mg, 55% yield. m.p. 105~106 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.29 (s, 1H), 7.78 (s, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.47 (dd, J=8.7, 1.8 Hz, 1H), 6.49 (s, 1H), 4.51 (dtd, J=24.5, 7.8, 1.9 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.65 (dq, J=7.8, 1.6 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.2 (dd, J=289.8, 287.0 Hz), 152.1, 140.7 (t, J=2.9 Hz), 137.0, 128.8, 125.1 (q, J=32.3 Hz), 124.8 (q, J=271.8 Hz), 120.3 (q, J=3.6 Hz), 118.3 (q, J=4.1 Hz), 112.5, 106.6, 75.4 (dd, J=25.5, 19.2 Hz), 73.2, 22.1 (d, J=5.6 Hz), 13.7; ¹⁹F NMR (376 MHz, Chloroform-d) δ: -61.01, -86.63 (d, J=40.7 Hz), -88.88 (dd, J=40.8, 24.5 Hz). HRMS (ESI) calcd for C₁₅H₁₂F₅N₂O₂ [M-H]^- 347.0824, found 347.0822.

  2-(3, 3-Difluoroallyl)-N-ethoxy-6-methyl-1H-indole-1-carboxamide (3m): White solid, 68 mg, 77% yield. m.p. 85~87 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.21 (s, 1H), 7.44 (s, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.36 (s, 1H), 4.52 (dtd, J=24.7, 7.8, 2.0 Hz, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.63 (dq, J=7.8, 1.5 Hz, 2H), 2.46 (s, 3H), 1.39 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.1 (dd, J=289.2, 286.2 Hz), 152.9, 138.6~138.0 (m), 135.8, 133.5, 127.0, 124.1, 120.5, 112.5, 106.4, 75.9 (dd, J=25.0, 19.1 Hz), 73.0, 22.3 (d, J=5.4 Hz), 22.1, 13.7; ¹⁹F NMR (376 MHz, Chloroform-d) δ: -87.50 (d, J=42.5 Hz), -89.68 (dd, J=42.3, 24.9 Hz). HRMS (ESI) calcd for C₁₅H₁₅F₂N₂O₂ [M-H]^- 293.1107, found 293.1108.

  2-(3, 3-Difluoroallyl)-N-ethoxy-6-methoxy-1H-indole-1-carboxamide (3n): Yellow solid, 87 mg, 94% yield. m.p. 78~79 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.21 (s, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 6.81 (dd, J=8.6, 2.3 Hz, 1H), 6.32 (s, 1H), 4.50 (dtd, J=24.7, 7.8, 2.0 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H), 3.82 (s, 3H), 3.59 (dq, J=7.8, 1.5 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.2, 157.0 (dd, J=289.2, 286.4 Hz), 153.0, 137.7~137.2 (m), 136.4, 123.2, 121.3, 110.9, 106.3, 97.9, 75.9 (dd, J=24.9, 19.1 Hz), 73.0, 55.9, 22.3 (d, J=5.4 Hz), 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.50 (d, J=42.9 Hz), -89.69 (dd, J=42.6, 25.2 Hz). HRMS (ESI) calcd for C₁₅H₁₅F₂N₂O₃ [M-H]^- 309.1056, found 309.1051.

  2-(3, 3-Difluoroallyl)-N, 6-diethoxy-1H-indole-1-carbo-xamide (3o): White solid, 65 mg, 67% yield. m.p. 81~83 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.21 (s, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 6.81 (dd, J=8.5, 2.2 Hz, 1H), 6.32 (s, 1H), 4.51 (dtd, J=24.8, 7.8, 2.1 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 4.03 (q, J=7.0 Hz, 2H), 3.60 (dq, J=7.8, 1.6 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H), 1.38 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.0 (dd, J=289.3, 286.2 Hz), 156.5, 153.0, 138.9~137.3 (m), 136.3, 123.1, 121.3, 111.5, 106.3, 98.6, 75.9 (dd, J=24.8, 19.2 Hz), 73.0, 64.3, 22.3 (d, J=5.3 Hz), 15.0, 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.54 (d, J=42.6 Hz), -89.73 (dd, J=42.3, 24.7 Hz). HRMS (ESI) calcd for C₁₆H₁₇F₂N₂O₃ [M-H]^- 323.1213, found 323.1207.

  6-Chloro-2-(3, 3-difluoroallyl)-N-ethoxy-1H-indole-1-carboxamide (3p): Yellow solid, 75 mg, 79% yield. m.p. 98~99 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.20 (s, 1H), 7.65~7.63 (m, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.15 (dd, J=8.3, 1.8 Hz, 1H), 6.39 (s, 1H), 4.51 (dtd, J=24.6, 7.8, 2.0 Hz, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.62 (dq, J=7.8, 1.5 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.2 (dd, J=289.5, 286.8 Hz), 152.4, 139.8~139.4 (m), 135.8, 129.4, 127.7, 123.2, 121.6, 112.6, 106.3, 75.5 (dd, J=25.3, 19.1 Hz), 73.2, 22.2 (d, J=5.6 Hz), 13.7; ¹⁹F NMR (376 MHz, Chloroform-d) δ: -86.91 (d, J=41.6 Hz), -89.18 (dd, J=41.7, 24.7 Hz). HRMS (ESI) calcd for C₁₄H₁₂ClF₂N₂O₂ [M-H]^- 313.0561, found 313.0557.

  2-(3, 3-Difluoroallyl)-N-ethoxy-7-fluoro-1H-indole-1-carboxamide (3q): Yellow solid, 72 mg, 80% yield. m.p. 86~88 ℃; ¹H NMR (600 MHz, Chloroform-d) δ: 8.56 (s, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.09 (td, J=7.9, 4.5 Hz, 1H), 6.95 (ddd, J=12.7, 8.0, 1.0 Hz, 1H), 6.46~6.38 (m, 1H), 4.51 (dtd, J=24.5, 7.8, 2.0 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.57 (dq, J=7.8, 1.5 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H); ¹³C NMR (151 MHz, Chloroform-d) δ: 157.1 (dd, J=289.7, 286.5 Hz), 151.3, 148.7 (d, J=244.0 Hz), 140.2, 132.6 (d, J=3.8 Hz), 122.8 (d, J=6.9 Hz), 116.7 (d, J=3.5 Hz), 109.6 (d, J=19.4 Hz), 105.8, 75.4 (dd, J=25.5, 19.2 Hz), 72.9, 21.5 (d, J=5.5 Hz), 13.6; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.04 (d, J=41.1 Hz), -89.25 (dd, J=41.1, 24.7 Hz), -126.12. HRMS (ESI) calcd for C₁₄H₁₄F₃N₂O₂ [M+H]⁺ 299.1002, found 299.1000.

  2-(3, 3-Difluoroallyl)-N-ethoxy-7-ethyl-1H-indole-1-car-boxamide (3r): Yellow solid, 64 mg, 69% yield. m.p. 86~88 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.21 (s, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.36 (s, 1H), 4.50 (dtd, J=24.5, 7.7, 1.9 Hz, 1H), 4.21~4.04 (m, 2H), 3.48 (dq, J=7.7, 1.5 Hz, 2H), 2.89 (q, J=7.5 Hz, 2H), 1.38~1.28 (m, 6H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.0 (dd, J=289.3, 286.6 Hz), 138.0, 135.1, 129.7, 128.0, 123.3, 122.5, 118.4, 104.7, 75.4 (dd, J=25.4, 19.3 Hz), 72.8, 24.6, 21.0 (d, J=5.4 Hz), 14.4, 13.6; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.07 (d, J=41.3 Hz), -89.36 (dd, J=40.9, 24.6 Hz). HRMS (ESI) calcd for C₁₆H₁₇F₂N₂O₂ [M-H]^- 307.1264, found 307.1260.

  6-Chloro-2-(3, 3-difluoroallyl)-N-ethoxy-5-fluoro-1H-indole-1-carboxamide (3s): White solid, 73 mg, 72% yield. m.p. 107~108 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.10 (s, 1H), 7.72 (d, J=6.0 Hz, 1H), 7.23 (d, J=8.9 Hz, 1H), 6.38 (s, 1H), 4.51 (dt, J=24.6, 7.8 Hz, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.64 (d, J=7.8 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.2 (dd, J=289.7, 286.9 Hz), 154.4 (d, J=242.1 Hz), 152.3, 140.9 (t, J=2.8 Hz), 131.8, 128.3 (d, J=8.9 Hz), 116.8 (d, J=20.6 Hz), 114.1, 107.0 (d, J=23.6 Hz), 106.3 (d, J=3.8 Hz), 75.3 (dd, J=25.5, 19.3 Hz), 73.2, 22.2 (d, J=5.4 Hz), 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -86.66 (d, J=40.6 Hz), -88.93 (dd, J=40.6, 24.5 Hz), -122.73 (t, J=7.6 Hz). HRMS (ESI) calcd for C₁₄H₁₁ClF₃N₂O₂ [M-H]^- 331.0467, found 331.0460.

  4-Bromo-2-(3, 3-difluoroallyl)-N-ethoxy-3-methyl-1H-indole-1-carboxamide (3t): White solid, 73 mg, 72% yield. m.p. 138~139 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.25 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.02 (t, J=8.0 Hz, 1H), 4.44 (dtd, J=25.2, 7.6, 2.1 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H), 3.56 (d, J=7.5 Hz, 2H), 2.48 (s, 3H), 1.36 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 156.6 (dd, J=288.8, 287.4 Hz), 152.0, 136.1, 134.8, 128.0, 126.9, 124.2, 114.9, 114.6, 111.0, 76.4 (dd, J=23.8, 18.9 Hz), 73.1, 19.0 (d, J=5.3 Hz), 13.6, 11.2; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -88.15 (d, J=44.3 Hz), -89.03 (dd, J=44.8, 25.8 Hz). HRMS (ESI) calcd for C₁₅H₁₄BrF₂N₂O₂ [M-H]^- 371.0212, found 371.0203.

  2-(3, 3-Difluoroallyl)-N-ethoxy-5-fluoro-3-methyl-1H-indole-1-carboxamide (3u): White solid, 87 mg, 93% yield. m.p. 139~140 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.14 (s, 1H), 7.57 (dd, J=9.0, 4.3 Hz, 1H), 7.11 (dd, J=8.8, 2.6 Hz, 1H), 6.95 (td, J=9.0, 2.6 Hz, 1H), 4.51 (dtd, J=25.4, 7.6, 2.1 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H), 3.59 (dt, J=7.6, 1.8 Hz, 2H), 2.18 (s, 3H), 1.37 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 159.1 (d, J=239.3 Hz), 159.1~154.2 (m), 152.9, 135.5, 131.6 (d, J=9.4 Hz), 130.9, 114.2 (d, J=4.0 Hz), 113.2 (d, J=9.2 Hz), 111.4 (d, J=25.5 Hz), 104.7 (d, J=23.4 Hz), 76.5 (dd, J=23.8, 18.8 Hz), 73.0, 19.6 (d, J=5.3 Hz), 13.7, 8.5; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -88.34 (d, J=44.4 Hz), -89.32 (dd, J=44.9, 25.7 Hz), -121.14 (dq, J=10.2, 5.3 Hz). HRMS (ESI) calcd for C₁₅H₁₄F₃N₂O₂ [M-H]^- 311.1013, found 311.1006.

  5-Bromo-2-(3, 3-difluoroallyl)-N-ethoxy-3-methyl-1H-indole-1-carboxamide (3v): White solid, 86 mg, 76% yield. m.p. 145~146 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.13 (s, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.32 (dd, J=8.7, 2.0 Hz, 1H), 4.50 (dtd, J=25.3, 7.7, 2.1 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.59 (dt, J=7.7, 1.8 Hz, 2H), 2.19 (s, 3H), 1.37 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 156.7 (dd, J=288.6, 287.4 Hz), 152.6, 135.0, 133.3, 132.3, 126.4, 122.0, 115.6, 113.7, 76.5 (dd, J=23.8, 18.8 Hz), 73.1, 19.5 (d, J=5.3 Hz), 13.7, 8.4; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -88.16 (d, J=44.1 Hz), -89.17 (dd, J=44.7, 25.7 Hz). HRMS (ESI) calcd for C₁₅H₁₄BrF₂N₂O₂ [M-H]^- 371.0212, found 371.0208.

  6-Bromo-2-(3, 3-difluoroallyl)-N-ethoxy-3-methyl-1H-indole-1-carboxamide (3w): White solid, 105 mg, 93% yield. m.p. 123~124 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.08 (s, 1H), 7.81 (s, 1H), 7.36~7.30 (m, 2H), 4.57~4.45 (m, 1H), 4.18 (q, J=6.9 Hz, 2H), 3.60 (d, J=7.4 Hz, 2H), 2.21 (s, 3H), 1.39 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 156.7 (dd, J=288.4, 287.4 Hz), 152.5, 135.3, 134.3, 129.3, 125.5, 120.3, 117.1, 115.4, 114.1, 76.4 (dd, J=23.7, 18.7 Hz), 73.1, 19.4 (d, J=5.3 Hz), 13.7, 8.4; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -88.21 (d, J=43.5 Hz), -89.23 (dd, J=43.5, 25.3 Hz). HRMS (ESI) calcd for C₁₅H₁₄BrF₂N₂O₂ [M-H]^- 371.0212, found 371.0206.

  2-(3, 3-Difluoroallyl)-N-ethoxy-5-methoxy-3-methyl-1H- indole-1-carboxamide (3x): White solid, 75 mg, 77% yield. m.p. 120~122 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.12 (s, 1H), 7.53 (d, J=8.9 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 6.85 (dd, J=9.0, 2.6 Hz, 1H), 4.55 (dtd, J=25.5, 7.7, 2.2 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H), 3.85 (s, 3H), 3.60 (dt, J=7.8, 1.7 Hz, 2H), 2.19 (s, 3H), 1.38 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 159.1~154.0 (m), 155.8, 153.2, 134.7, 131.6, 129.1, 114.1, 113.3, 112.4, 101.8, 76.8 (dd, J=23.4, 18.8 Hz), 72.9, 55.9, 19.6 (d, J=5.3 Hz), 13.7, 8.6; ¹⁹F NMR (376 MHz, Chloroform-d) δ: -88.75 (d, J=44.8 Hz), -89.69 (dd, J=45.0, 25.5 Hz). HRMS (ESI) calcd for C₁₆H₁₉F₂N₂O₃ [M+H]⁺ 325.1358, found 325.1355.

  2-(3, 3-Difluoroallyl)-N-ethoxy-5-(pyrrolidin-1-yl)-1H-indole-1-carboxamide (3y): White solid, 33 mg, 30 % yield. m.p. 143~145 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.19 (s, 1H), 7.48 (d, J=8.9 Hz, 1H), 6.60 (s, 1H), 6.54 (d, J=9.0 Hz, 1H), 6.28 (s, 1H), 4.55 (dtd, J=24.9, 7.8, 2.1 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.63 (dd, J=7.8, 1.5 Hz, 2H), 3.27 (s, 4H), 2.04~1.97 (m, 4H), 1.37 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 157.0 (dd, J=289.1, 285.8 Hz), 153.6, 144.8, 139.6, 130.8, 127.4, 113.2, 109.8, 106.7, 102.0, 76.0 (dd, J=24.6, 19.1 Hz), 72.8, 48.4, 25.5, 22.7 (d, J=5.3 Hz), 13.7; ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.85 (d, J=43.2 Hz), -90.05 (dd, J=43.1, 25.0 Hz). HRMS (ESI) calcd for C₁₈H₂₂F₂N₃O₂ [M+H]⁺ 350.1675, found 350.1671.

  2, 5-Bis(3, 3-difluoroallyl)-N-ethoxy-1H-pyrrole-1-car-boxamide (3aa): Yellow solid, 38 mg, 40% yield. m.p. 52~54 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.19 (s, 1H), 5.89 (s, 2H), 4.36 (dtd, J=24.6, 7.7, 2.0 Hz, 2H), 4.08 (q, J=7.0 Hz, 2H), 3.37 (dt, J=7.7, 1.8 Hz, 4H), 1.33 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 156.8 (dd, J=288.9, 286.8 Hz), 152.0, 131.1, 109.3, 76.2 (dd, J=24.2, 19.2 Hz), 72.9, 21.2 (d, J=5.3 Hz), 13.6; ¹⁹F NMR (376 MHz, Chloroform-d) δ: -87.63 (d, J=43.5 Hz), -89.86 (dd, J=43.7, 24.8 Hz). HRMS (ESI) calcd for C₁₃H₁₃F₄N₂O₂ [M-H]^- 305.0919, found 305.0917.

  2-(3, 3-Difluoroallyl)-N-methoxy-1H-indole-1-carboxa-mide (3ba): White solid, 48 mg, 60% yield. m.p. 70~71 ℃; ¹H NMR (400 MHz, Chloroform-d) δ: 8.46 (s, 1H), 7.64 (dq, J=8.3, 0.9 Hz, 1H), 7.49 (ddd, J=7.5, 1.5, 0.7 Hz, 1H), 7.22 (ddd, J=8.3, 7.3, 1.5 Hz, 1H), 7.17 (td, J=7.5, 1.2 Hz, 1H), 6.41 (q, J=1.1 Hz, 1H), 4.51 (dtd, J=24.7, 7.8, 2.0 Hz, 1H), 3.92 (s, 3H), 3.63 (dq, J=7.8, 1.5 Hz, 2H); ¹³C NMR (101 MHz, Chloroform-d) δ: 157.1 (dd, J=289.4, 286.4 Hz), 152.8, 139.0, 135.3, 129.2, 123.5, 122.7, 120.9, 112.4, 106.6, 75.7 (dd, J=25.0, 19.1 Hz), 65.0, 22.3 (d, J=5.5 Hz); ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.38 (d, J=41.9 Hz), -89.58 (dd, J=42.2, 24.8 Hz). HRMS (ESI) calcd for C₁₃H₁₁F₂N₂O₂ [M-H]^- 265.0794, found 265.0791.

  N-(tert-Butoxy)-2-(3, 3-difluoroallyl)-1H-indole-1-carboxamide (3ca): White solid, 27 mg, 23% yield. m.p. 95~97 ℃; ¹H NMR (400 MHz, Chloroform-d) δ: 7.80 (s, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.51 (dt, J=7.5, 1.1 Hz, 1H), 7.27~7.22 (m, 1H), 7.18 (td, J=7.7, 0.9 Hz, 1H), 6.43 (s, 1H), 4.57 (dtd, J=24.8, 7.8, 2.0 Hz, 1H), 3.66 (dq, J=7.9, 1.5 Hz, 2H), 1.42 (s, 9H); ¹³C NMR (101 MHz, Chloroform-d) δ: 157.1 (dd, J=289.0, 286.4 Hz), 154.1, 139.9~138.6 (m), 135.3, 129.3, 123.5, 122.6, 121.0, 112.1, 106.4, 82.8, 75.8 (dd, J=25.1, 19.0 Hz), 26.7, 22.3 (d, J=5.5 Hz); ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.43 (d, J=42.5 Hz), -89.71 (dd, J=42.2, 24.8 Hz). HRMS (ESI) calcd for C₁₆H₁₉F₂N₂O₂ [M+H]⁺ 309.1409, found 309.1407.

  N-(Benzyloxy)-2-(3, 3-difluoroallyl)-1H-indole-1-carbo-xamide (3da): White solid, 77 mg, 78% yield. m.p. 74~75 ℃; ¹H NMR (400 MHz, Chloroform-d) δ: 8.11 (s, 1H), 7.51~7.39 (m, 6H), 7.33 (dq, J=7.7, 0.9 Hz, 1H), 7.17~7.07 (m, 2H), 6.42~6.35 (m, 1H), 5.08 (s, 2H), 4.51 (dtd, J=24.7, 7.8, 2.0 Hz, 1H), 3.62 (dq, J=7.8, 1.5 Hz, 2H); ¹³C NMR (101 MHz, Chloroform-d) δ: 157.1 (dd, J=289.4, 286.2 Hz), 152.4, 139.0 (d, J=2.8 Hz), 135.3, 135.2, 129.5, 129.2, 129.2, 129.0, 123.4, 122.6, 120.8, 112.3, 106.5, 78.8, 75.8 (dd, J=25.2, 19.2 Hz), 22.2 (d, J=5.5 Hz); ¹⁹F NMR (471 MHz, Chloroform-d) δ: -87.32 (d, J=41.8 Hz), -89.55 (dd, J=41.9, 24.6 Hz). HRMS (ESI) calcd for C₁₉H₁₅F₂N₂O₂ [M-H]^- 341.1107, found 341.1102.

  4.4   General procedure for 4b and 4t~4x

  To a reaction tube were added 2-(3, 3-difluoroallyl)-N- ethoxy-3-methyl-1H-indole-1-carboxamide (3) (0.2 mmol), NIS (90 mg, 0.4 mmol, 2.0 equiv.), and acetonitrile (2.0 mL). The solution was kept at room temperature for 8 h. Then it was quenched with aqueous Na₂S₂O₃, extracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [V(hexane)/ V(EtOAc)=20/1~15/1] to give a corresponding product 4.

  3-(Difluoroiodomethyl)-2-ethoxy-5-methyl-3, 4-dihydro-pyrimido[1, 6-a]indol-1(2H)-one (4b): White solid, 37 mg, 44% yield. m.p. 126~128 ℃; ¹H NMR (500 MHz, Acetone-d₆) δ: 8.26 (dt, J=8.2, 1.0 Hz, 1H), 7.49 (dt, J=7.5, 1.0 Hz, 1H), 7.29~7.26 (m, 1H), 7.23 (td, J=7.4, 1.2 Hz, 1H), 4.74~4.67 (m, 1H), 4.25~4.14 (m, 2H), 3.61 (dd, J=5.1, 2.2 Hz, 2H), 2.22 (t, J=1.1 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ: 149.6, 135.9, 131.8, 127.0, 124.8, 123.6, 119.3, 115.5, 113.0, 103.7 (dd, J=319.0, 317.3 Hz), 71.6, 67.4 (dd, J=23.0, 19.9 Hz), 24.1 (d, J=2.9 Hz), 13.8, 8.1; ¹⁹F NMR (471 MHz, Acetone-d₆) δ: -44.93 (d, J=189.4 Hz), -46.95 (dd, J=189.2, 15.1 Hz). HRMS (ESI) calcd for C₁₅H₁₆F₂I- N₂O₂ [M+H]⁺ 421.0219, found 421.0211.

  6-Bromo-3-(difluoroiodomethyl)-2-ethoxy-5-methyl-3, 4- dihydropyrimido[1, 6-a]indol-1(2H)-one (4t): Yellow solid, 53 mg, 54% yield. m.p. 175~177 ℃; ¹H NMR (500 MHz, Acetone-d₆) δ: 8.33 (d, J=8.2 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 4.78~4.68 (m, 1H), 4.27~4.12 (m, 2H), 3.68~3.54 (m, 2H), 2.45 (d, J=1.4 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ: 149.0, 137.3, 129.3, 129.2, 128.1, 125.9, 115.0, 114.3, 113.3, 105.9~100.3 (m), 71.7, 67.1 (dd, J=23.6, 19.9 Hz), 24.0 (t, J=2.8 Hz), 13.7, 11.1; ¹⁹F NMR (471 MHz, Acetone-d₆) δ: -45.55 (d, J=190.6 Hz), -47.14 (dd, J=190.9, 14.8 Hz). HRMS (ESI) calcd for C₁₅H₁₅BrF₂IN₂O₂ [M+H]⁺ 498.9324, found 498.9311.

  3-(Difluoroiodomethyl)-2-ethoxy-7-fluoro-5-methyl-3, 4-dihydropyrimido[1, 6-a]indol-1(2H)-one (4u): Yellow solid, 50 mg, 57% yield. m.p. 112~113 ℃; ¹H NMR (500 MHz, Acetone-d₆) δ: 8.23 (dd, J=8.9, 4.7 Hz, 1H), 7.23 (dd, J=9.2, 2.6 Hz, 1H), 7.05 (td, J=9.2, 2.6 Hz, 1H), 4.76~4.68 (m, 1H), 4.27~4.13 (m, 2H), 3.63 (d, J=4.4 Hz, 2H), 2.22 (s, 3H), 1.29 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ: 160.4 (d, J=237.4 Hz), 149.4, 133.0 (d, J=9.7 Hz), 132.3, 129.2, 116.6 (d, J=9.1 Hz), 113.0 (d, J=3.9 Hz), 112.2 (d, J=25.1 Hz), 105.1 (d, J=24.1 Hz), 103.5 (dd, J=318.9, 317.7 Hz), 71.7, 67.5 (dd, J=23.3, 19.9 Hz), 24.2 (t, J=2.9 Hz), 13.9, 8.2; ¹⁹F NMR (471 MHz, Acetone-d₆) δ: -45.22 (d, J=190.9 Hz), -46.99 (dd, J=190.2, 17.1 Hz), -117.55~-125.51 (m). HRMS (ESI) calcd for C₁₅H₁₅F₃IN₂O₂ [M+H]⁺439.0125, found 439.0124.

  7-Bromo-3-(difluoroiodomethyl)-2-ethoxy-5-methyl-3, 4- dihydropyrimido[1, 6-a]indol-1(2H)-one (4v): Yellow solid, 67 mg, 68% yield. m.p. 134~136 ℃; ¹H NMR (500 MHz, Acetone-d₆) δ: 8.18 (d, J=8.7 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.41 (dd, J=8.7, 2.0 Hz, 1H), 4.77~4.69 (m, 1H), 4.27~4.11 (m, 2H), 3.64 (d, J=4.2 Hz, 2H), 2.23 (s, 3H), 1.29 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ: 149.3, 134.7, 133.8, 128.9, 127.5, 122.2, 117.2, 116.6, 112.6, 106.2~100.6 (m), 71.8, 67.4 (dd, J=23.4, 20.2 Hz), 24.1 (d, J=3.3 Hz), 13.9, 8.1; ¹⁹F NMR (471 MHz, Acetone-d₆) δ: -45.36 (d, J=190.8 Hz), -46.90 (dd, J=190.3, 14.4 Hz). HRMS (ESI) calcd for C₁₅H₁₅Br- F₂IN₂O₂ [M+H]⁺ 498.9324, found 498.9324.

  8-Bromo-3-(difluoroiodomethyl)-2-ethoxy-5-methyl-3, 4-dihydropyrimido[1, 6-a]indol-1(2H)-one (4w): Yellow solid, 50 mg, 50% yield. m.p. 163~165 ℃; ¹H NMR (500 MHz, Acetone-d₆) δ: 8.48 (d, J=1.8 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.4, 1.8 Hz, 1H), 4.80~4.72 (m, 1H), 4.30~4.16 (m, 2H), 3.66 (d, J=4.3 Hz, 2H), 2.26 (s, 3H), 1.33 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ: 149.3, 136.5, 130.9, 128.2, 126.6, 121.0, 118.3, 117.9, 113.1, 106.5~100.1 (m), 71.8, 67.3 (dd, J=23.3, 20.3 Hz), 24.0 (t, J=2.9 Hz), 13.9, 8.1; ¹⁹F NMR (471 MHz, Acetone-d₆) δ: -45.35 (d, J=190.8 Hz), -46.69 (dd, J=190.5, 14.5 Hz). HRMS (ESI) calcd for C₁₅H₁₅BrF₂IN₂O₂ [M+H]⁺ 498.9324, found 498.9314.

  3-(Difluoroiodomethyl)-2-ethoxy-7-methoxy-5-methyl-3, 4-dihydropyrimido[1, 6-a]indol-1(2H)-one (4x): White solid, 25 mg, 23% yield. m.p. 104~106 ℃; ¹H NMR (400 MHz, Acetone-d₆) δ: 8.12 (d, J=8.9 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8.9, 2.5 Hz, 1H), 4.73~4.62 (m, 1H), 4.26~4.10 (m, 2H), 3.84 (s, 3H), 3.59 (d, J=4.3 Hz, 2H), 2.19 (t, J=1.0 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ: 157.2, 149.5, 132.7, 130.3, 127.6, 116.1, 113.1, 112.9, 106.4~100.8 (m), 102.3, 71.5, 67.5 (dd, J=22.8, 19.8 Hz), 55.9, 24.1 (d, J=3.0 Hz), 13.8, 8.1; ¹⁹F NMR (471 MHz, Acetone-d₆) δ: -44.80 (d, J=189.1 Hz), -46.66 (dd, J=189.2, 14.7 Hz). HRMS (ESI) calcd for C₁₆H₁₈F₂IN₂O₃ [M+H]⁺ 451.0325, found 451.0326.

  4.5   Gram scale reaction for synthesis of 3a

  To a round bottom flask were added N-ethoxy-1H-in- dole-1-carboxamide (1a) (1.00 g, 4.9 mmol, 1.0 equiv.), 3-bromo-3, 3-difluoroprop-1-ene 2a (2.31 g, 14.69 mmol, 3.0 equiv.), [RhCp*Cl₂]₂ (302.9 mg, 0.49 mmol, 10 mol%), NaOAc (804 mg, 9.8 mmol, 2.0 equiv.), and ethanol absolute (33.0 mL), and then the round bottom flask was evacuated and purged with Ar three times. The solution was kept at 60 ℃ (oil bath) for 24 h. Then it was diluted with H₂O, extracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [V(hexanes)/ V(EtOAc)=20/1~10/1] to give a corresponding product 3a (0.894 g, 65% yield).

  4.6   General procedure for synthesis of 5a

  To a round bottom flask were added 2-(3, 3-difluoroall- yl)-N-ethoxy-1H-indole-1-carboxamide (3a) (56 mg, 0.2 mmol), Pd(OH)₂/C (11.2 mg, palladium hydroxide 20% on carbon, ca. 50% water), and MeOH (2 mL), then the round bottom flask was evacuated and purged with H₂ three times. The reaction was kept at room temperature for 3 h. Then it was filtered through celite and the residue was washed with EtOAc three times. The filtrate was concentrated to dryness. The crude mixture was purified by silica gel column chromatography [V(hexanes)/V(EtOAc)=20/1~10/1] to give a corresponding product 5a (48 mg, 85% yield).

  2-(3, 3-Difluoropropyl)-N-ethoxyindoline-1-carboxamide (5a): Oil, 48 mg, 85% yield. ¹H NMR (400 MHz, Acetone-d₆) δ: 9.21 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.21~7.14 (m, 1H), 7.13 (t, J=7.7 Hz, 1H), 6.92 (td, J=7.5, 1.1 Hz, 1H), 6.00 (tt, J=57.0, 4.1 Hz, 1H), 4.62~4.49 (m, 1H), 3.93 (q, J=7.0 Hz, 2H), 3.34 (dd, J=16.2, 9.3 Hz, 1H), 2.86 (dd, J=16.2, 1.6 Hz, 1H), 1.99~1.68 (m, 4H), 1.20 (t, J=7.0 Hz, 3H); ¹³C NMR (126 MHz, Acetone-d₆) δ: 156.5, 143.8, 130.7, 128.0, 125.7, 123.1, 118.4 (t, J=237.2 Hz), 116.1, 71.9, 58.5, 34.3, 30.2 (t, J=21.2 Hz), 27.4 (t, J=5.3 Hz), 13.9; ¹⁹F NMR (471 MHz, Acetone-d₆) δ: -116.59~-116.90 (m). HRMS (ESI) calcd for C₁₄H₁₇F₂N₂O₂ [M-H]^- 283.1264, found 283.1266.

  4.7   General procedure for synthesis of 6u

  To a round bottom flask were added 3-(difluoroiodome-thyl)-2-ethoxy-7-fluoro-5-methyl-3, 4-dihydropyrimido-[1, 6-a]indol-1(2H)-one (4u) (88 mg, 0.2 mmol), AIBN (13.2 mg, 0.08 mmol, 0.4 equiv.), Bu₃SnH (292.3 mg, 1 mmol, 5equiv.) and benzene (5 mL). The reaction was kept at 80 ℃ (oil bath) for 0.5 h, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [V(hexanes)/V(EtOAc)=50/1~10/1] to give a corresponding product 6u (49 mg, 78% yield).

  3-(Difluoromethyl)-2-ethoxy-7-fluoro-5-methyl-3, 4-di-hydropyrimido[1, 6-a]indol-1(2H)-one (6u): White solid, 49 mg, 78% yield. m.p. 136~137 ℃; ¹H NMR (500 MHz, Chloroform-d) δ: 8.25 (dd, J=9.4, 4.5 Hz, 1H), 7.12~7.04 (m, 1H), 7.01 (td, J=9.2, 2.3 Hz, 1H), 6.17 (td, J=55.5, 54.2, 2.6 Hz, 1H), 4.23 (p, J=7.5 Hz, 2H), 4.18~4.09 (m, 2H), 3.40~3.25 (m, 2H), 1.35 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ: 159.8 (d, J=239.6 Hz), 151.8, 132.1 (d, J=9.6 Hz), 131.3, 128.1, 116.3 (d, J=9.1 Hz), 113.0 (dd, J=249.1, 244.2 Hz), 112.2 (d, J=4.0 Hz), 112.0 (d, J=25.0 Hz), 104.3 (d, J=23.9 Hz), 72.1, 60.0 (dd, J=29.2, 22.8 Hz), 19.4, 13.6, 8.3;¹⁹F NMR (471 MHz, Chloroform-d) δ: -119.91 (q, J=9.4, 7.9 Hz), -128.92 (dd, J=291.8, 54.8 Hz), -131.71 (ddd, J=290.9, 56.5, 20.8 Hz). HRMS (ESI) calcd for C₁₅H₁₆F₃N₂O₂ [M+H]⁺ 313.1158, found 313.1156.

  4.8   KIE experiment.

  To a reaction tube were added N-ethoxy-1H-indole- 1-carboxamide (1a) (60 mg, 0.3 mmol), 3-bromo-3, 3- difluoroprop-1-ene (2a) (139 mg, 0.9 mmol), [RhCp*Cl₂]₂ (18 mg, 10 mol%), NaOAc (48 mg, 0.6 mmol), and then the reaction tube was evacuated and purged with Ar three times. Ethanol absolute (2.0 mL) was added to the tube through syringe. The solution was kept at 60 ℃ (oil bath) for 1min under Ar. Immediately the reaction mixture was diluted with H₂O, extracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [V(hexanes)/V(EtOAc)=20/1~10/1] to give a corresponding product 3a (52 mg, 63% yield).

  To a reaction tube were added N-ethoxy-1H-indole- 1-carboxamide ([D]-1a) (60 mg, 0.3 mmol), 3-bromo- 3, 3-difluoroprop-1-ene (2a) (139 mg, 0.9 mmol), [RhCp*Cl₂]₂ (18 mg, 10 mol%), NaOAc (48 mg, 0.6 mmol), and then the reaction tube was evacuated and purged with Ar three times. Ethanol absolute (2.0 mL) was added to the tube through syringe. The solution was kept at 60 ℃ for 1 min under Ar. Immediately the reaction mixture was diluted with H₂O, extracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [V(hexanes)/V(EtOAc)=20/1~10/1] to give corresponding product 3a (42 mg, 51% yield). An intramolecular kinetic isotopic effect of this reaction was thus determined to be k_H/k_D=1.24.

  4.9   Competition experiment

  To a reaction tube were added N-ethoxy-4-methoxy-1H- indole-1-carboxamide (1e) (35 mg, 0.15 mmol), N-ethoxy-4- fluoro-1H-indole-1-carboxamide (1f) (34 mg, 0.15 mmol), 3-bromo-3, 3-difluoroprop-1-ene (2a) (70 mg, 0.45 mmol), [RhCp*Cl₂]₂ (9 mg, 10 mol%), NaOAc (24 mg, 0.3 mmol), and then the reaction tube was evacuated and purged with Ar three times. Ethanol absolute (1.0 mL) was added to the tube through syringe. The solution was kept at 60 ℃ (oil bath) for 24 h under Ar. After cooled to room temperature, the reaction mixture was diluted with H₂O, extracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [V(hexanes)/V(EtOAc)=20/1~10/1] to give mixture products. The ratio of products 3f/3e was analyzed by ¹H NMR.

  To a reaction tube was added N-ethoxy-5-methyl- 1H-indole-1-carboxamide (1g) (33 mg, 0.15 mmol), N-ethoxy-5-(trifluoromethyl)-1H-indole-1-carboxamide (1l) (41 mg, 0.15 mmol), 3-bromo-3, 3-difluoroprop-1-ene (2a) (70 mg, 0.45 mmol), [RhCp*Cl₂]₂ (9 mg, 10 mol%), NaOAc (24 mg, 0.3 mmol), and then the reaction tube was evacuated and purged with Ar three times. Ethanol absolute (1.0 mL) was added to the tube through syringe. The solution was kept at 60 ℃ (oil bath) for 24 h under Ar. After cooled to room temperature, the reaction mixture was diluted with H₂O, extracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography [V(hexanes)/V(EtOAc)=20/1~10/1] to give mixture products. The ratio of products 3l/3g was analyzed by ¹H NMR.

  4.10   General procedure for synthesis of rhodacyle 7

  Pyridine (15.8 mg, 0.20 mmol) was added to a solution of [RhCp*Cl₂]₂ (61.8 mg, 0.10 mmol) in DCM (8 mL) at room temperature. After stirring for 4 h, N-ethoxy-1H- indole-1-carboxamide (1a) (40.8 mg, 0.20 mmol), NaOAc (41.0 mg, 0.50 mmol), and Na₂CO₃ (21.6 mg, 0.20 mmol) were added to the solution, and the reaction mixture was stirred for another 12 h. After completion, the solution was evaporated under reduced pressure and washed with diethyl ether. HRMS analysis of the organometallic products indicated the formation of rhodacyle 7. HRMS (ESI) calcd for C₂₁H₂₆N₂O₂Rh [M+H-C₅H₅N]⁺ 441.1044, found 441.1033.

  Supporting Information  ¹H NMR, ¹³C NMR and ¹⁹F NMR spectra scans of all new compounds. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
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• 

  Figure 1  Structures of functional and bioactive pyrimido- [1, 6-a]-indol-1(2H)-ones

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  Scheme 1  3, 3-Difluoroallylation of indoles via C—H activation

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  Scheme 2  NIS-mediated intramolecular cyclization of 3

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  Scheme 3  Gram-scale reaction and derivatization

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  Scheme 4  Mechanistic investigations

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  Scheme 5  Proposed mechanism

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  Table 1.  Optimization of reaction conditions^a

  Entry	Cat.	Base	Solvent	Yieldb/%
  1	[RuCl2(p-cymene)]2	NaOAc	MeOH	31
  2	[IrCp*Cl2]2	NaOAc	MeOH	NRc
  3	[RhCp*Cl2]2	NaOAc	MeOH	78
  4	[RhCp*Cl2]2	KOAc	MeOH	75
  5	[RhCp*Cl2]2	EtONa	MeOH	50
  6	[RhCp*Cl2]2	CsF	MeOH	24
  7	[RhCp*Cl2]2	Et3N	MeOH	60
  8	[RhCp*Cl2]2	DIPEA	MeOH	74
  9	[RhCp*Cl2]2	NaOTf	MeOH	NR
  10	[RhCp*Cl2]2	NaOAc	THF	70
  11	[RhCp*Cl2]2	NaOAc	Dioxane	58
  12	[RhCp*Cl2]2	NaOAc	DME	60
  13	[RhCp*Cl2]2	NaOAc	TFE	60
  14	[RhCp*Cl2]2	NaOAc	EtOH	82 (75)
  15d	[RhCp*Cl2]2	NaOAc	EtOH	56
  16e	[RhCp*Cl2]2	NaOAc	EtOH	79
  17f	[RhCp*Cl2]2	NaOAc	EtOH	69
  18g	[RhCp*Cl2]2	NaOAc	EtOH	68
  19	[RhCp*Cl2]2	—	EtOH	NR
  20	—	NaOAc	EtOH	NR
  21h	[RhCp*Cl2]2	NaOAc	EtOH	79
  a Reaction conditions: 1a (0.3 mmol, 1.0 equiv.), 2a (0.9 mmol, 3.0 equiv.), catalyst (10 mol%), base (2.0 equiv.), solvents (2.0 mL), a sealed tube at 60 ℃ (oil bath) for 24 h under argon. b Determined by 19F NMR using fluorobenzene as an internal standard, and the number in parentheses is isolated yield. c No reaction. d 80 ℃ (oil bath). e 2.5 equiv. 2a was used. f 5 mol% catalyst was used. g 1.5 equiv. NaOAc was used. h Under Air.

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  Table 2.  Scope of indoles^a

  a Reaction conditions: 1 (0.3 mmol, 1.0 equiv.), 2 (0.9 mmol, 3.0 equiv.), [RhCp*Cl2]2 (10 mol %) and NaOAc (2.0 equiv.) in EtOH (2.0 mL) at 60 ℃ (oil bath) for 24 h under argon. All listed yields are isolated ones.

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•