A New Methodology for Functionalization at the 3-Position of Indoles by a Combination of Boron Lewis Acid with Nitriles

Abstract

We discovered that a reagent comprising a combination of PhBCl₂ and nitriles was useful for syntheses of both 3-acylindoles and 1-(1H-indol-3-yl)alkylamine from indoles. The reaction proceeded selectively at the 3-position of indoles providing 3-acylindoles in moderate to high yields on treatment with the above reagent. Furthermore, the reaction provided the corresponding amine products in moderate to high yields after the intermediate imine was reduced by NaBH₃CN. These reactions proceeded under mild conditions and are applicable to the formation of indoles functionalized at the 3-position.

Sugasawa et al. reported that aniline underwent Friedel–Crafts type acylation with nitrile in the presence of BCl₃.¹⁾ On the basis of this observation, we reported that the substituted olefins reacting with nitrile as electrophilic reagents were effectively activated by boron Lewis acids (B-LAs). For example, the Prins-type reaction of monosubstituted or disubstituted alkenes,²⁾ the ene reaction of trisubstituted alkenes,³⁾ and the Hosomi–Sakurai reaction of allyltrimethylsilane⁴⁾ are noted.

Many indole compounds exist as natural products and are used as skeletons for synthesizing pharmaceuticals such as indomethacin and pindolol.^5,6) Therefore, the synthesis and reactivity studies of indole skeletons have been actively performed. Alkylation and acylation of indoles at their 3-position are the most important reactions of indole chemistry, and numerous methods have been reported.^7–14) Especially, the acylation of indoles at the 3-position has been the subject of considerable interest for a long time because their derivatives are key compounds in natural products syntheses and they have important biological activities.^15–18) However, among these, acylation using nitriles as reagents has been rarely reported.^19–22) In particular, a combination of B-LA and nitrile has not been reported. Thus, we intended to study the reactivity of the reagent consisting of a B-LA and nitrile towards indoles leading to a new method for introducing useful substituents at indole’s 3-position. This paper describes the successful results.

Here, we illustrate the expected reaction course in Chart 1. When indole (1) reacts with nitrile in the presence of B-LA, the iminium intermediate (2) would be produced. The hydrolysis of 2 should provide 3-acylindole (3) (route A), whereas the reduction of 2 should produce 1-(1H-indol-3-yl)alkylamine (4), whose nitrogen atom is derived from the nitrile (route B). In view of the above-mentioned speculation, we initiated the first experiment targeting the synthesis of 3-acylindole (3) by route A.

Chart 1. Attempted Syntheses of 3-Acylindole (3) and 1-(1H-Indol-3-yl)alkylamine (4)

Results and Discussion

Initially, we examined the reactivity of a variety of B-LAs. As the substrate, 1-methylindole (1a) was used because 1a is expected to be more stable and reactive than indole itself due to the 1-methyl group. For the nitrile, trichloroacetonitrile (5a) was utilized because of its high electrophilicity. The employed solvent, CH₂Cl₂, was used in previous studies providing good results.^2–4) As shown in Table 1, 3-acylindole (3aa) was obtained for all B-LAs. As shown in Entry 5, PhBCl₂ gave the best result from the view point of the reaction time and yield. 1a has been reported to bound to BCl₃ in the form of a salt at the 3-position in CH₂Cl₂.²³⁾ Presumably, this indole salt acts as an electrophile and thus it easily generated the dimer. We proposed that PhBCl₂ is more easily coordinated to nitriles than to the 3-position of 1a; thus, it was effectively reacted to give 3aa. Moreover, to avoid side reactions, the catalyst and nitrile were mixed first. The indole was added to the mixture after a while. We assume that above method is better. On the other hand, as we reported,^2–4) for the Lewis acid catalyst, only B-LAs were effective in the reaction of substituted olefins and nitriles. However, in the present experiment, AlCl₃ yielded (84%, result not shown) better than the B-LAs. Despite this result, we used the B-LA catalyst in this study because we assumed that AlCl₃ was not suitable for route B (Chart 1). Furthermore, solvents other than CH₂Cl₂ (e.g., Et₂O, toluene) produced 3aa in extremely poor yields.

Table 1. Acylation of 1-Methylindole (1a) with Trichloroacetonitrile (5a), Promoted by B-LA^a)

Entry	B-LA	Time (h)	Yield (%)b)
1	BCl3	21	50
2	BBr3	4	69
3	9-BBN-OTf	4	53
4	BF3·OEt2	17	14
5	PhBCl2	3	82

a) 1.0 eq of nitrile and 1.2 eq of B-LA were used. b) Isolated yield.

Second, we examined the reaction of several nitriles with 1-methylindole (1a) in the presence of PhBCl₂, which resulted in the highest yield of 3aa as a catalyst among all the B-LAs. The result is shown in Table 2. In the cases of aliphatic nitriles (Entries 1–9), moderate to good yields were obtained by nitriles bearing electron-withdrawing groups at the α-position of the cyano group (Entries 1–7). Considering this assumption, finding low yields in the cases of Entries 8 and 9 is reasonable. Also, in the cases of aromatic nitriles (Entries 10–13), a nitrile bearing electron-withdrawing group in the p-position of the cyano group (Entries 11 and 12) provided higher yields than benzonitrile (Entry 10), while the nitrile bearing electron-donating group decreased the yield (Entry 13). From the above results, in the cases of either aliphatic or aromatic nitriles, electron-withdrawing groups at the α- or p-position of the cyano group, the reaction was found to be liable to proceed.

Table 2. Acylation of 1-Methylindole (1a) with Various Nitriles (5a–m)^a)

Entry	Nitrile	R4=	Time (h)	Product	Yield (%)b)
1	5a	–CCl3	3	3aa	82
2	5b	–CHCl2	1	3ab	87
3	5c	–CH2Cl	1	3ac	53
4	5d	–CH2F	2	3ad	89
5	5e	–CH2Br	2	3ae	81
6	5f	–CH2I	2	3af	59c)
7	5g	–CH2Ph	26	3ag	52
8	5h	–CH2CH2Ph	18	3ah	4
9	5i	–CH3	19	3ai	41d)
10	5j	–Ph	24	3aj	25d)
11	5k	–C6H4-p-Cl	18	3ak	74d)
12	5l	–C6H4-p-NO2	19	3al	58
13	5m	–C6H4-p-CH3	23	3am	5d)

a) 1.2 eq of nitrile and 1.5 eq of PhBCl₂ were used unless otherwise indicated. b) Isolated yield. c) Furthermore, 6% of the deiodination product was obtained. d) 4.0 eq of nitrile and 4.2 eq of PhBCl₂ were used.

In the third study, we investigated the reactivity of the indole as substrates. The results are presented in Table 3. First, acylation of the unsubstituted indole (1b) proceeded only with low yields because of the formation of several byproducts (Entry 1). Indole is well known to undergo autoxidation and oligomerization by acid catalysts.^24–27) Next, 3-acylation of indoles bearing electron-withdrawing groups at the 1- or 2-positions did not proceed (Entries 2 and 3). In contrast, acylation of indoles bearing electron-donating groups such as alkyl or aryl groups at the 1- or 2-position proceeded in moderate to good yields (Entries 4–6). On the basis of these results, we considered that an increase in the electron density of the indole rings improved the electrophilic reaction for nitriles. For the comparatively lower yield in the case of Entry 6, we assumed the steric repulsion of the phenyl group at the 2-position to be a probable reason. Finally, we compared the reactivity of indoles bearing electron-withdrawing groups (Entries 7–9) or electron-donating group (Entry 10) at the 5-position. The indoles bearing electron-withdrawing groups resulted in better yields than the indole bearing an electron-donating group. Furthermore, we may emphasize the following. Starting material could be recovered from indoles bearing electron-withdrawing groups at the 5-position (Entries 7–9), whereas after the reaction was completed, none could be recovered for the indole bearing an electron-donating group at the 5-position (Entry 10). Consequently, this electron-withdrawing group should help the stability of the initiating indole without reducing the reactivity of the 3-position. This can also be deduced from the fact that the unsubstituted indole (Entry 1) decomposed immediately and produced many byproducts under acid catalysis.

Table 3. Acylation of Substituted Indoles (1b–j) with Trichloroacetonitrile (5a)^a,b)

Entry	Indole	R1=	R2=	R3=	Time (h)	Product	Yield (%)c)
1	1b	–H	–H	–H	17	3ba	20
2	1c	–SO2Ph	–H	–H	44	3ca	n.r.f)
3	1dd)	–H	–CO2Et	–H	17	3da	n.r.g)
4	1ae)	–CH3	–H	–H	3	3aa	82
5	1e	–H	–CH3	–H	17	3ea	89
6	1f	–CH3	–Ph	–H	24	3fa	57
7	1gd)	–H	–H	–Cl	19	3ga	40
8	1hd)	–H	–H	–CO2CH3	19	3ha	54
9	1i	–H	–H	–NO2	24	3ia	70
10	1j	–H	–H	–OCH3	22	3ja	6

a) CH₂Cl₂ solution of indole was used unless otherwise indicated. b) 1.2 eq of nitrile and 1.5 eq of PhBCl₂ were used. c) Isolated yield. d) CH₃NO₂ solution of indole was used. e) Liquid of 1a was added dropwise. f) 90% of 1c was recovered. g) 50% of 1d was recovered.

The aforementioned studies were performed using the very reactive trichloroacetonitrile (5a), to check the reactivity of indoles. Then, we considered the types of results that other nitriles provided. Thus, we performed the reactions using 2-methylindole (1e), which provided the best reactivity as a substrate. As for this result in Table 4, electron-withdrawing groups at the α-position of the cyano group also have a great influence on the yield, as in the case of Table 2. In the case of p-nitrobenzonitrile (Entry 5), the yield was much lower than expected from the results of Entry 12 in Table 2. We inferred that it was influenced by steric repulsion between the reagent (nitrile) and the methyl group at the 2-position of indole in this reaction. Kunori reported that acylation of 2-methylindole (1e) with o-tolunitrile did not proceed because it was influenced by steric repulsion between the 2-methyl group of 1e and o-tolunitrile as the reagent.²²⁾ Our result is consistent with Kunori’s result.

Table 4. Acylation of 2-Methylindole (1e) with Various Nitriles (5a–l)^a,b)

Entry	Nitrile	R4=	Time (h)	Product	Yield (%)c)
1	5a	–CCl3	17	3ea	89
2	5b	–CHCl2	19	3eb	71
3	5c	–CH2Cl	21	3ec	46
4	5e	–CH2Br	20	3ee	41
5	5l	–C6H4-p-NO2	16	3el	6

a) CH₂Cl₂ solution of 1e was used. b) 1.2 eq of nitrile and 1.5 eq of PhBCl₂ were used. c) Isolated yield.

The above results from Tables 3 and 4 provided a new procedure, wherein acylation of indole with a combination of B-LA and nitrile proceeded in the free (N–H) indoles as well as 1-methylindole (1a), i.e., this reaction will become standard for effective acylation because it does not require protection–deprotection steps of the indole nitrogen, similar to some Friedel–Crafts acylations.

The aforementioned results demonstrate that acylation by route A (Chart 1) progressed well. Accordingly, as expected in route B (Chart 1), we decided to verify that the 1-(1H-indol-3-yl)alkylamine (4) is obtained successfully by reducing the iminium intermediates (2). Recently, similar compounds of 4 has been reported to be obtained by the multicomponent reaction of indole, nitrile, and acid chloride in the presence of hydrozirconocene.^28–30) Moreover, Friedel–Crafts alkylation of indole with N-tosylaldimine to form a compound similar to 4 in the presence of a Brønsted acid has been reported.^31–35) However, these synthetic methods are limited, we are convinced that our reaction using a nitrile is worth studying. This work, as well as the acylation described in Tables 2–4, began synthesizing an electrophilic substitution reaction by a combination of a variety of indoles and various nitriles to result in the iminium intermediate (2). NaBH₃CN was added to this solution so that 2 was reduced. Amine (4) should have been formed during the reduction reaction. In addition, to obtain a more stable product the 1-(1H-indol-3-yl)alkylamine (4) was transformed to N-trifluoroacetyl compounds (4ba–ia) by adding trifluoroacetic anhydride (TFAA) to the reaction mixture containing this amine (4). The results are summarized in Table 5. For the results, the yields correspond to those of 3-acylindole (3).

Table 5. Syntheses of 1-(1H-Indol-3-yl)alkylamines from Substituted Indoles (1b–i) and Various Nitriles (5a–l)^a)

Entry	Indole	R1=	R2=	R3=	Nitrile	R4=	Time (h)	Product	Yield (%)b)
1	1bc)	–H	–H	–H	5a	–CCl3	21	4ba	24
2	1a	–CH3	–H	–H	5a	–CCl3	1	4aa	90
3	1a	–CH3	–H	–H	5b	–CHCl2	3	4ab	74
4	1a	–CH3	–H	–H	5c	–CH2Cl	6	4ac	52
5	1a	–CH3	–H	–H	5d	–CH2F	2	4ad	63
6	1a	–CH3	–H	–H	5l	–C6H4-p-NO2	17	4al	51
7	1ec)	–H	–CH3	–H	5a	–CCl3	17	4ea	77e)
8	1ec)	–H	–CH3	–H	5b	–CHCl2	21	4eb	37
9	1fc)	–CH3	–Ph	–H	5a	–CCl3	24	4fa	46
10	1hd)	–H	–H	–CO2CH3	5a	–CCl3	21	4ha	55
11	1id)	–H	–H	–NO2	5a	–CCl3	17	4ia	80

a) 1.2 eq of nitrile, 1.5 eq of PhBCl₂, and 1.5 eq of NaBH₃CN were used unless otherwise indicated. b) Isolated yield. c) CH₂Cl₂ solution of indole was used. d) CH₃NO₂ solution of indole was used. e) 4.5 eq of NaBH₃CN was used.

A one-pot reaction for synthesizing such side-chains at the 3-position in the indole nucleus (4ba–ia) did not exist previously. Obtaining this amine compound (4) using an acylating agent other than the nitrile is difficult. Hence, this is an advantage of using a nitrile as the acylating agent because this method efficiently synthesized an amine compound. Furthermore, it can be accomplished without wasting the nitrogen atom in the reagent; thus, it is consistent with green chemistry.

Therefore, we believe that this reaction will be an important novel synthesis. A basic compound having this side-chain in 4 is indolylglycine (6).^36–39) Indolylglycine (6) is a partial structure of leuconicine A (7), akuammicine (8), and strychnine (9).^40–42) Consequently, we expect this reaction to be used in their syntheses (Chart 2).

Chart 2. The Structures of Indolylglycine (6) and Structurally Related Natural Products

Conclusion

In conclusion, we have successfully developed a novel method for functionalization at the 3-position of indoles with a combination of a boron Lewis acid such as PhBCl₂ and nitriles. An important feature of the reaction is that it provides both the 3-acylindole and the 1-(1H-indol-3-yl)alkylamine via a common intermediate. This method provides a valuable addition to indole chemistry because of the simple procedure and mild reaction conditions.

Experimental

General Remarks

Column chromatography was performed using silica gel 60 (0.040–0.063 mm, 230–400 mesh ASTM, Merck). The ¹H spectra were recorded in CDCl₃/DMSO-d₆ solvents on a 400 MHz spectrometer using tetramethylsilane (TMS) (0.00 ppm) or dimethyl sulfoxide (DMSO) (2.49 ppm) as an internal standard. The ¹³C spectra were recorded in CDCl₃/DMSO-d₆ solvents on a 100 MHz spectrometer using a center peak of CDCl₃ (77.0 ppm) or DMSO-d₆ (39.7 ppm) as an internal standard.

General Procedure for Synthesizing 3-Acylindole Compounds (Exemplified by 3aa)

A 1.5 mL (1.5 mmol) of PhBCl₂ (1.0 mol/L in CH₂Cl₂) was added to CH₂Cl₂ solution (4 mL) of the nitrile (5a) (173 mg, 1.2 mmol) at room temperature under argon. The mixture was stirred for 15 min. The indole (1a) (131 mg, 1.0 mmol) was added dropwise to this solution at room temperature. The resulting solution was stirred for 3 h, and then 0.5 mol/L Na₂CO₃ was added to quench the reaction. The resulting mixture was extracted with CH₂Cl₂. The organic layer was washed with saturated brine, dried (MgSO₄), and evaporated. The crude product was purified using silica gel chromatography to provide 3aa (226 mg, 82% yield).

2,2,2-Trichloro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (3aa)

Brown prisms from ethyl acetate/hexane; mp 120–121°C; IR ν_max (KBr) cm⁻¹: 1654 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.42–8.40 (m, 1H, C₄-H), 8.19 (s, 1H, C₂-H), 7.38–7.35 (m, 3H, arom-H), 3.89 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 176.7, 138.0, 136.9, 128.3, 124.1, 123.6, 122.7, 110.0, 105.3, 96.8, 33.9; high resolution (HR)-MS (electrospray ionization (ESI)) m/z: Calcd for C₁₁H₈Cl₃NNaO (M+Na⁺) 297.9569. Found 297.9562.

2,2-Dichloro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (3ab)

Pale brown needles from ethyl acetate/hexane; mp 216–219°C; IR ν_max (KBr) cm⁻¹: 1641 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.35–8.33 (m, 1H, C₄-H), 8.11 (s, 1H, C₂-H), 7.41–7.35 (m, 3H, arom-H), 6.56 (s, 1H, CHCl₂), 3.91 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 181.7, 137.3, 137.1, 126.8, 124.0, 123.3, 122.2, 109.9, 109.3, 68.6, 33.6; HR-MS (ESI) m/z: Calcd for C₁₁H₉Cl₂NNaO (M+Na⁺) 263.9959. Found 263.9956.

2-Chloro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (3ac)

Brown prisms from ethyl acetate/hexane; mp 152–154°C; IR ν_max (KBr) cm⁻¹: 1652 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.33–8.31 (m, 1H, C₄-H), 7.73 (s, 1H, C₂-H), 7.33–7.30 (m, 3H, arom-H), 4.45 (s, 2H, CH₂Cl), 3.82 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 185.9, 137.3, 135.8, 126.3, 123.8, 123.0, 122.4, 113.4, 109.8, 46.0, 33.7; HR-MS (ESI) m/z: Calcd for C₁₁H₁₀ClNNaO (M+Na⁺) 230.0349. Found 230.0375.

2-Fluoro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (3ad)

Pale orange prisms from ethyl acetate/hexane; mp 118–120°C; IR ν_max (KBr) cm⁻¹: 1650 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.41–8.38 (m, 1H, C₄-H), 7.97 (d, 1H, J=2.0 Hz, C₂-H), 7.35–7.32 (m, 3H, arom-H), 5.20 (d, 2H, J=47.6 Hz, CH₂F), 3.84 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 189.6 (d, ²J_C–F=17.6 Hz), 137.0, 136.8 (d, ³J_C–F=6.4 Hz), 126.7, 123.8, 123.1, 122.5, 112.9 (d, ⁴J_C–F=3.7 Hz), 109.7, 85.2 (d, ¹J_C–F=183.6 Hz), 33.6; HR-MS (ESI) m/z: Calcd for C₁₁H₁₀FNNaO (M+Na⁺) 214.0644. Found 214.0617.

2-Bromo-1-(1-methyl-1H-indole-3-yl)ethan-1-one (3ae)

Brown needles from ethyl acetate/hexane; mp 135–137°C; IR ν_max (KBr) cm⁻¹: 1635 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.36–8.34 (m, 1H, C₄-H), 7.82 (s, 1H, C₂-H), 7.36–7.33 (m, 3H, arom-H), 4.29 (s, 2H, CH₂Br), 3.87 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 186.1, 137.4, 136.2, 126.4, 123.8, 123.1, 122.6, 113.4, 109.8, 33.7, 31.7; HR-MS (ESI) m/z: Calcd for C₁₁H₁₀BrNNaO (M+Na⁺) 273.9843. Found 273.9872.

2-Iodo-1-(1-methyl-1H-indol-3-yl)ethan-1-one (3af)

Greenish brown needles from ethyl acetate/hexane; mp 156–159°C; IR ν_max (KBr) cm⁻¹: 1629 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.35–8.31 (m, 1H, C₄-H), 7.81 (s, 1H, C₂-H), 7.37–7.31 (m, 3H, arom-H), 4.24 (s, 2H, CH₂I), 3.87 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 187.6, 137.6, 136.1, 126.4, 123.7, 123.0, 122.7, 112.8, 109.7, 33.7, 3.4; HR-MS (ESI) m/z: Calcd for C₁₁H₁₀INNaO (M+Na⁺) 321.9705. Found 321.9714.

1-(1-Methyl-1H-indol-3yl)-2-phenylethan-1-one (3ag)¹⁹⁾

Yellowish colorless prisms from ethyl acetate/hexane; mp 114–117°C; IR ν_max (KBr) cm⁻¹: 1631 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.42–8.40 (m, 1H, C₄-H), 7.74 (s, 1H, C₂-H), 7.35–7.28 (m, 7H, arom-H), 7.25–7.23 (m, 1H, arom-H), 4.14 (s, 2H, CH₂Ph), 3.83 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 192.6, 137.4, 135.9, 135.7, 129.3, 128.5, 126.6, 123.5, 122.8, 122.7, 116.2, 109.5, 46.9, 33.5; HR-MS (ESI) m/z: Calcd for C₁₇H₁₅NNaO (M+Na⁺) 272.1051. Found 272.1066.

1-(1-Methyl-1H-indol-3yl)-3-phenylpropan-1-one (3ah)

Colorless prisms from chloroform/hexane; mp 66–69°C; IR ν_max (KBr) cm⁻¹: 1644 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.40–8.38 (m, 1H, C₄-H), 7.31–7.17 (m, 9H, arom-H), 3.79 (s, 3H, NCH₃), 3.18–3.08 (m, 4H, CH₂CH₂Ph); ¹³C-NMR (100 MHz, CDCl₃) δ: 194.4, 141.8, 137.4, 135.2, 128.49, 128.47, 126.3, 126.0, 123.3, 122.6, 122.5, 116.4, 109.6, 41.6, 33.4, 30.8; HR-MS (ESI) m/z: Calcd for C₁₈H₁₇NNaO (M+Na⁺) 286.1208. Found 286.1224.

1-(1-Methyl-1H-indol-3-yl)ethan-1-one (3ai)^11,19)

Pale brown needles from ethyl acetate/hexane; mp 104–106°C; IR ν_max (KBr) cm⁻¹: 1639 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.38–8.36 (m, 1H, C₄-H), 7.70 (s, 1H, C₂-H), 7.33–7.29 (m, 3H, arom-H), 3.84 (s, 3H, NCH₃), 2.52 (s, 3H, COCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 192.9, 137.4, 135.7, 126.2, 123.3, 122.5, 116.9, 109.6, 33.5, 27.6; HR-MS (ESI) m/z: Calcd for C₁₁H₁₁NNaO (M+Na⁺) 196.0738. Found 196.0756.

(1-Methyl-1H-indol-3-yl)(phenyl)methanone (3aj)^11,19)

Brown needles from chloroform/hexane; mp 116–118°C; IR ν_max (KBr) cm⁻¹: 1619 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.44–8.41 (m, 1H, C₄-H), 7.80 (dd, 2H, J=8.0, 1.6 Hz, arom-H), 7.54–7.52 (m, 2H, arom-H), 7.49–7.45 (m, 2H, arom-H), 7.36–7.34 (m, 3H, arom-H), 3.83 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 190.6, 140.7, 137.7, 137.3, 130.8, 128.4, 128.0, 127.0, 123.4, 122.56, 122.53, 115.4, 109.4, 33.3; HR-MS (ESI) m/z: Calcd for C₁₆H₁₃NNaO (M+Na⁺) 258.0895. Found 258.0887.

(4-Chlorophenyl)(1-methyl-1H-indol-3-yl)methanone (3ak)^11,19)

Pale brown prisms from ethyl acetate/hexane; mp 149–150°C; IR ν_max (KBr) cm⁻¹: 1625 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.39–8.37 (m, 1H, C₄-H), 7.73 (dd, 2H, J=8.4, 2.0 Hz, C_3′, C_5′-H), 7.48 (s, 1H, C₂-H), 7.43 (dd, 2H, J=8.4, 2.0 Hz, C_2′, C_6′-H), 7.36–7.32 (m, 3H, arom-H), 3.82 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 189.3, 139.2, 137.6, 137.5, 137.2, 130.0, 128.5, 127.0, 123.8, 122.8, 122.6, 115.3, 109.7, 33.6; HR-MS (ESI) m/z: Calcd for C₁₆H₁₂ClNNaO (M+Na⁺) 292.0505. Found 292.0500.

(1-Methyl-1H-indol-3-yl)(4-nitrophenyl)methanone (3al)^11,19)

Yellowish black prisms from chloroform/hexane; mp 191–193°C; IR ν_max (KBr) cm⁻¹: 1616 (CO), 1517, 1344 (NO₂); ¹H-NMR (400 MHz, CDCl₃) δ: 8.41–8.38 (m, 1H, C₄-H), 8.32 (dd, 2H, J=8.8, 2.0 Hz, C_3′, C_5′-H), 7.92 (dd, 2H, J=8.8, 2.0 Hz, C_2′, C_6′-H), 7.49 (s, 1H, C₂-H), 7.40–7.37 (m, 3H, arom-H), 3.87 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 188.3, 149.0, 146.2, 138.0, 137.6, 129.3, 126.8, 124.1, 123.5, 123.2, 122.6, 115.2, 109.8, 33.7; HR-MS (ESI) m/z: Calcd for C₁₆H₁₂N₂NaO₃ (M+Na⁺) 303.0746. Found 303.0739.

(1-Methyl-1H-indol-3-yl)(p-tolyl)methanone (3am)¹⁹⁾

Pale yellow needles from chloroform/hexane; mp 143–144°C; IR ν_max (KBr) cm⁻¹: 1617 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.43–8.39 (m, 1H, C₄-H), 7.74 (dd, 2H, J=6.4, 2.0 Hz, arom-H), 7.54 (s, 1H, C₂-H), 7.39–7.31 (m, 3H, arom-H), 7.28 (d, 2H, J=8.0 Hz, arom-H), 3.85 (s, 3H, NCH₃), 2.44 (s, 3H, C₆H₄CH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 190.6, 141.5, 140.3, 138.2, 137.5, 128.9, 128.8, 127.2, 123.5, 122.7, 122.5, 115.7, 109.5, 33.5, 21.5; HR-MS (ESI) m/z: Calcd for C₁₇H₁₅NNaO (M+Na⁺) 272.1051. Found 272.1027.

2,2,2-Trichloro-1-(1H-indol-3-yl)ethan-1-one (3ba)

Pale green prisms from ethyl acetate/hexane; mp 234–237°C; IR ν_max (KBr) cm⁻¹: 3251 (NH), 1639 (CO); ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.52 (br s, 1H, NH), 8.58 (d, 1H, J=3.2 Hz, C₂-H), 8.19–8.15 (m, 1H, arom-H), 7.59–7.55 (m, 1H, arom-H), 7.32–7.28 (m, 2H, arom-H); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 176.8, 136.7, 136.2, 127.2, 123.9, 123.2, 121.3, 113.0, 104.8, 96.6; HR-MS (ESI) m/z: Calcd for C₁₀H₆Cl₃NNaO (M+Na⁺) 283.9413. Found 283.9429.

2,2,2-Trichloro-1-(2-methyl-1H-indol-3-yl)ethan-1-one (3ea)

Brown needles from chloroform/hexane; mp 166–168°C; IR ν_max (KBr) cm⁻¹: 3307 (NH), 1633 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.77 (br s, 1H, NH), 8.25 (dd, 1H, J=7.2, 1.2 Hz, C₄-H), 7.36–7.34 (m, 1H, arom-H), 7.30–7.24 (m, 2H, arom-H), 2.80 (s, 3H, arom-CH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 178.4, 150.5, 134.4, 124.8, 123.9, 123.0, 122.2, 110.9, 106.7, 97.7, 17.1; HR-MS (ESI) m/z: Calcd for C₁₁H₈Cl₃NNaO (M+Na⁺) 297.9569. Found 297.9545.

2,2,2-Trichloro-1-(1-methyl-2-phenyl-1H-indol-3-yl)ethan-1-one (3fa)

Yellowish brown prisms from chloroform/hexane; mp 132–133°C; IR ν_max (KBr) cm⁻¹: 1675 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.29–8.27 (m, 1H, C₄-H), 7.52–7.48 (m, 3H, arom-H), 7.43–7.40 (m, 1H, arom-H), 7.38–7.35 (m, 4H, arom-H), 3.56 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 179.0, 150.8, 137.0, 131.6, 129.8, 129.3, 128.6, 124.7, 123.7, 123.3, 122.4, 110.2, 107.5, 97.4, 31.2; HR-MS (ESI) m/z: Calcd for C₁₇H₁₂Cl₃NNaO (M+Na⁺) 373.9882. Found 373.9854.

2,2,2-Trichloro-1-(5-chloro-1H-indol-3-yl)ethan-1-one (3ga)

Brown prisms from ethyl acetate/hexane; mp 238–243°C; IR ν_max (KBr) cm⁻¹: 3259 (NH), 1654 (CO); ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.69 (br s, 1H, NH), 8.65 (d, 1H, J=3.6 Hz, C₂-H), 8.14 (d, 1H, J=2.0 Hz, C₄-H), 7.59 (dd, 1H, J=8.8, 0.4 Hz, C₇-H), 7.33 (dd, 1H, J=8.8, 2.4 Hz, C₆-H); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 176.9, 138.0, 134.8, 128.4, 128.0, 124.0, 120.5, 114.7, 104.6, 96.2; HR-MS (ESI) m/z: Calcd for C₁₀H₅Cl₄NNaO (M+Na⁺) 317.9023. Found 317.9014.

Methyl-3-(2,2,2-trichloroacetyl)-1H-indole-5-carboxylate (3ha)

Orangish yellow needles from ethyl acetate/hexane; mp 228–230°C; IR ν_max (KBr) cm⁻¹: 3243 (NH), 1687 (COO), 1666 (CO); ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.82 (br s, 1H, NH), 8.86 (s, 1H, C₄-H), 8.79 (s, 1H, C₂-H), 7.91 (dd, 1H, J=8.8, 1.6 Hz, arom-H), 7.66 (d, 1H, J=8.4 Hz, arom-H), 3.88 (s, 3H, COOCH₃); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 177.1, 166.9, 139.0, 138.7, 126.9, 124.8, 124.5, 123.5, 113.3, 105.7, 96.2, 52.2; HR-MS (ESI) m/z: Calcd for C₁₂H₈Cl₃NNaO₃ (M+Na⁺) 341.9467. Found 341.9485.

2,2,2-Trichloro-1-(5-nitro-1H-indol-3-yl)ethan-1-one (3ia)

Yellowish colorless needles from ethyl acetate/hexane; mp 253–254°C; IR ν_max (KBr) cm⁻¹: 3224 (NH), 1654 (CO), 1533, 1336 (NO₂); ¹H-NMR (400 MHz, DMSO-d₆) δ: 13.07 (br s, 1H, NH), 9.02 (d, 1H, J=2.0 Hz, C₄-H), 8.86 (d, 1H, J=2.0 Hz, C₂-H), 8.19 (dd, 1H, J=9.2, 2.0 Hz, C₆-H), 7.77 (d, 1H, J=8.8 Hz, C₇-H); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 177.1, 143.7, 140.2, 139.6, 126.7, 119.3, 117.6, 114.0, 106.4, 95.9; HR-MS (ESI) m/z: Calcd for C₁₀H₅Cl₃N₂NaO₃ (M+Na⁺) 328.9263. Found 328.9274.

2,2,2-Trichloro-1-(5-methoxy-1H-indol-3-yl)ethan-1-one (3ja)

Green needles from chloroform/hexane; mp 198–201°C; IR ν_max (KBr) cm⁻¹: 3255 (NH), 1641 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (br s, 1H, NH), 8.31 (d, 1H, J=2.8 Hz, C₂-H), 7.92 (s, 1H, C₄-H), 7.35 (d, 1H, J=8.8 Hz, C₇-H), 6.97 (d, 1H, J=8.8 Hz, C₆-H), 3.90 (s, 3H, arom-OCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 177.5, 157.1, 134.1, 130.1, 128.3, 115.0, 112.4, 106.9, 103.7, 96.6, 55.7; HR-MS (ESI) m/z: Calcd for C₁₁H₈Cl₃NNaO₂ (M+Na⁺) 313.9518. Found 313.9490.

2,2-Dichloro-1-(2-methyl-1H-indol-3-yl)ethan-1-one (3eb)

Brown needles from ethyl acetate/hexane; mp 191–194°C; IR ν_max (KBr) cm⁻¹: 3280 (NH), 1623 (CO); ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.31 (br s, 1H, NH), 8.00–7.96 (m, 1H, C₄-H), 7.43–7.39 (m, 1H, arom-H), 7.32 (s, 1H, CHCl₂), 7.22–7.17 (m, 2H, arom-H), 2.74 (s, 3H, arom-CH₃); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 180.8, 147.7, 135.2, 126.2, 122.7, 122.3, 121.0, 111.8, 108.0, 71.0, 15.2; HR-MS (ESI) m/z: Calcd for C₁₁H₉Cl₂NNaO (M+Na⁺) 263.9959. Found 263.9961.

2-Chloro-1-(2-methyl-1H-indol-3-yl)ethan-1-one (3ec)

Pale brown needles from ethyl acetate/hexane; mp 217–220°C; IR ν_max (KBr) cm⁻¹: 3259 (NH), 1627 (CO); ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.01 (br s, 1H, NH), 7.99–7.97 (m, 1H, C₄-H), 7.39–7.36 (m, 1H, arom-H), 7.16–7.14 (m, 2H, arom-H), 4.91 (s, 2H, CH₂Cl), 2.69 (s, 3H, arom-CH₃); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 186.2, 145.4, 134.9, 126.7, 122.3, 121.8, 120.8, 111.5, 111.0, 49.7, 15.2; HR-MS (ESI) m/z: Calcd for C₁₁H₁₀ClNNaO (M+Na⁺) 230.0349. Found 230.0356.

2-Bromo-1-(2-methyl-1H-indol-3-yl)ethan-1-one (3ee)

Pale brown needles from ethyl acetate/hexane; mp 183–186°C; IR ν_max (KBr) cm⁻¹: 3303 (NH), 1633 (CO); ¹H-NMR (400 MHz, CDCl₃) δ: 10.07 (br s, 1H, NH) 7.91 (d, 1H, J=8.0 Hz, C₄-H), 7.36 (d, 1H, J=7.6 Hz, arom-H), 7.30–7.20 (m, 2H, arom-H), 4.47 (s, 2H, CH₂Br), 2.76 (s, 3H, arom-CH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 187.3, 146.5, 134.9, 126.2, 122.6, 122.4, 120.7, 111.3, 100.0, 35.5, 15.5; HR-MS (ESI) m/z: Calcd for C₁₁H₁₀BrNNaO (M+Na⁺) 273.9843. Found 273.9857.

(2-Methyl-1H-indol-3-yl)(4-nitrophenyl)methanone (3el)

Yellow needles from ethyl acetate/hexane; mp 233–234°C; IR ν_max (KBr) cm⁻¹: 3191 (NH), 1735 (CO), 1525, 1346 (NO₂); ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.12 (br s, 1H, NH), 8.34 (dd, 2H, J=7.2, 1.6 Hz, C_3′, C_5′-H), 7.81 (dd, 2H, J=6.8, 2.0 Hz, C_2′, C_6′-H), 7.40 (d, 1H, J=8.0 Hz, C₄-H), 7.33 (d, 1H, J=8.0 Hz, C₇-H), 7.14 (ddd, 1H, J=8.0, 8.0, 1.2 Hz, arom-H), 7.03 (ddd, 1H, J=8.0, 8.0, 0.8 Hz, arom-H), 2.36 (s, 3H, arom-CH₃); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 189.9, 148.7, 147.5, 145.9, 135.2, 129.2, 127.1, 123.9, 122.4, 121.6, 120.1, 112.1, 111.6, 14.6; HR-MS (ESI) m/z: Calcd for C₁₆H₁₂N₂NaO₃ (M+Na⁺) 303.0746. Found 303.0743.

General Procedure for Synthesizing 1-(1H-Indol-3-yl)alkylamine Compounds (Exemplified by 4aa)

A 1.5 mL (1.5 mmol) of PhBCl₂ (1.0 mol/L in CH₂Cl₂) was added to CH₂Cl₂ solution (4 mL) of nitrile (5a) (173 mg, 1.2 mmol) at room temperature under argon. The mixture was stirred for 15 min. The indole (1a) (131 mg, 1.0 mmol) was added dropwise to this solution at room temperature. After the resulting solution was stirred for 1 h, NaBH₃CN (105 mg, 1.5 mmol) and 3 mL of CH₃NO₂ were added, and the mixture was stirred for 2 h at 0°C. Next 0.5 mol/L Na₂CO₃ was added to quench the reaction. The resulting mixture was extracted with CH₂Cl₂. The organic layer was washed with saturated brine, dried (MgSO₄), and evaporated to yield the crude product. To this crude product was added CH₂Cl₂ (6 mL) and dropwise TFAA (455 mg, 2.17 mmol), and the mixture was stirred for 2 h at room temperature. The mixture was evaporated and purified using silica gel chromatography to provide 4aa (336 mg, 90% yield).

2,2,2-Trifluoro-N-(2,2,2-trichloro-1-(1-methyl-1H-indol-3-yl)ethyl)acetamide (4aa)

Colorless prisms from ethyl acetate/hexane; mp 175–176°C; IR ν_max (KBr) cm⁻¹: 3318, 1716 (NHCO); ¹H-NMR (400 MHz, CDCl₃) δ: 7.69 (dd, 1H, J=8.0, 0.8 Hz, C₄-H), 7.36–7.34 (m, 2H, arom-H), 7.29 (ddd, 1H, J=8.0, 8.0, 1.2 Hz, arom-H), 7.21 (ddd, 1H, J=8.0, 8.0, 1.2 Hz, arom-H), 7.05 (br d, 1H, J=9.6 Hz, NHCO), 6.30 (d, 1H, J=10.0 Hz, CHCCl₃), 3.82 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 156.3 (q, ²J_C–F=37.8 Hz), 136.2, 128.2, 127.0, 122.7, 120.6, 118.9, 115.7 (q, ¹J_C–F=286.4 Hz), 109.8, 107.4, 101.2, 61.4, 33.1; HR-MS (ESI) m/z: Calcd for C₁₃H₁₀Cl₃F₃N₂NaO (M+Na⁺) 394.9709. Found 394.9700.

N-(2,2-Dichloro-1-(1-methyl-1H-indol-3-yl)ethyl)-2,2,2-trifluoroacetamide (4ab)

Brown needles from chloroform/hexane; mp 126–128°C; IR ν_max (KBr) cm⁻¹: 3280, 1700 (NHCO); ¹H-NMR (400 MHz, CDCl₃) δ: 7.59 (d, 1H, J=8.0 Hz, C₄-H), 7.36 (d, 1H, J=8.0 Hz, arom-H), 7.32–7.28 (m, 2H, arom-H), 7.19 (ddd, 1H, J=7.6, 7.6, 0.8 Hz, arom-H), 6.90 (br d, 1H, J=8.0 Hz, NHCO), 6.27 (d, 1H, J=3.2 Hz, CHCHCl₂), 5.96 (dd, 1H, J=8.8, 3.2 Hz, CHCHCl₂), 3.82 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 156.8 (q, ²J_C–F=37.7 Hz), 136.6, 127.5, 126.3, 122.7, 120.4, 118.4, 115.7 (q, ¹J_C–F=286.1 Hz), 109.8, 107.6, 73.2, 54.2, 33.1; HR-MS (ESI) m/z: Calcd for C₁₃H₁₁Cl₂F₃N₂NaO (M+Na⁺) 361.0098. Found 361.0083.

N-(2-chloro-1-(1-methyl-1H-indol-3-yl)ethyl)-2,2,2-trifluoroacetamide (4ac)

Pale orange needles from chloroform/hexane; mp 135–137°C; IR ν_max (KBr) cm⁻¹: 3251, 1689 (NHCO); ¹H-NMR (400 MHz, CDCl₃) δ: 7.55 (d, 1H, J=8.0 Hz, C₄-H), 7.35 (d, 1H, J=8.4 Hz, C₇-H), 7.29 (t, 1H, J=7.6 Hz, arom-H), 7.21 (s, 1H, C₂-H), 7.17 (t, 1H, J=7.6 Hz, arom-H), 6.71 (br s, 1H, NHCO), 5.70–5.65 (m, 1H, CHCH₂Cl), 4.11–4.03 (m, 2H, CHCH₂Cl), 3.79 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 156.6 (q, ²J_C–F=37.2 Hz), 136.9, 127.2, 125.9, 122.6, 120.1, 118.4, 115.7 (q, ¹J_C–F=286.2 Hz), 109.9, 109.8, 48.0, 45.9, 33.0; HR-MS (ESI) m/z: Calcd for C₁₃H₁₂ClF₃N₂NaO (M+Na⁺) 327.0488. Found 327.0459.

2,2,2-Trifluoro-N-(2-fluoro-1-(1-methyl-1H-indol-3-yl)ethyl)acetamide (4ad)

Colorless needles from ethyl acetate/hexane; mp 152–154°C; IR ν_max (KBr) cm⁻¹: 3272, 1693 (NHCO); ¹H-NMR (400 MHz, CDCl₃) δ: 7.58 (d, 1H, J=8.0 Hz, C₄-H), 7.35 (d, 1H, J=8.4 Hz, arom-H), 7.29 (dd, 1H, J=7.6, 6.8 Hz, arom-H), 7.21–7.16 (m, 2H, arom-H), 6.63 (br s, 1H, NHCO), 5.66–5.55 (m, 1H, CHCH₂F), 4.98–4.80 (m, 2H, CHCH₂F), 3.80 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 156.6 (q, ²J_C–F=37.1 Hz), 136.8, 127.6 (d, ³J_C–F=3.7 Hz), 126.2, 122.6, 120.1, 118.6, 115.7 (q, ¹J_C–F=286.2 Hz), 109.7, 109.1 (d, ⁴J_C–F=2.8 Hz), 84.1 (d, ¹J_C–F=173.8 Hz), 47.0 (d, ²J_C–F=19.4 Hz), 32.9; HR-MS (ESI) m/z: Calcd for C₁₃H₁₂F₄N₂NaO (M+Na⁺) 311.0783. Found 311.0776.

2,2,2-Trifluoro-N-((1-methyl-1H-indol-3-yl)(4-nitrophenyl)methyl)acetamide (4al)

Yellowish green needles from ethyl acetate/hexane; mp 218–221°C; IR ν_max (KBr) cm⁻¹: 3299, 1695 (NHCO), 1511, 1348 (NO₂); ¹H-NMR (400 MHz, CDCl₃) δ: 8.25 (dd, 2H, J=8.8, 2.0 Hz, C_3′, C_5′-H), 7.55 (dd, 2H, J=8.8, 2.0 Hz, C_2′, C_6′-H), 7.40 (dd, 1H, J=8.0, 0.8 Hz, C₄-H), 7.36 (d, 1H, J=8.4 Hz, arom-H), 7.31 (ddd, 1H, J=7.6, 7.6, 0.8 Hz, arom-H), 7.16 (ddd, 1H, J=8.0, 7.4, 1.2 Hz, arom-H), 6.88 (br d, 1H, J=6.8 Hz, NHCO), 6.64 (s, 1H, C₂-H), 6.55 (d, 1H, J=7.2 Hz, CHC₆H₄NO₂), 3.74 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 156.6 (q, ²J_C–F=37.4 Hz), 147.5, 146.6, 137.5, 128.5, 127.5, 125.6, 124.0, 122.9, 120.4, 118.5, 115.7 (q, ¹J_C–F=286.5 Hz), 112.1, 110.0, 50.9, 32.9; HR-MS (ESI) m/z: Calcd for C₁₈H₁₄F₃N₃NaO₃ (M+Na⁺) 400.0885. Found 400.0862.

2,2,2-Trifluoro-N-(2,2,2-trichloro-1-(1H-indol-3-yl)ethyl)acetamide (4ba)

Brown prisms from chloroform/hexane; mp 183–186°C; IR ν_max (KBr) cm⁻¹: 3388 (NH), 3332, 1708 (NHCO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.36 (br s, 1H, NH), 7.72 (d, 1H, J=8.0 Hz, C₄-H), 7.53 (d, 1H, J=2.4 Hz, C₂-H), 7.45–7.42 (m, 1H, arom-H), 7.30–7.21 (m, 2H, arom-H), 7.02 (br d, 1H, J=9.2 Hz, NHCO), 6.33 (d, 1H, J=9.6 Hz, CHCCl₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 156.4 (q, ²J_C–F=38.0 Hz), 135.3, 126.4, 123.7, 123.2, 121.0, 118.8, 115.7 (q, ¹J_C–F=285.6 Hz), 111.6, 109.2, 101.0, 61.3; HR-MS (ESI) m/z: Calcd for C₁₂H₈Cl₃F₃N₂NaO (M+Na⁺) 380.9552. Found 380.9525.

2,2,2-Trifluoro-N-(2,2,2-trichloro-1-(2-methyl-1H-indol-3-yl)ethyl)acetamide (4ea)

Colorless needles from chloroform/hexane; mp 143–144°C; IR ν_max (KBr) cm⁻¹: 3438 (NH), 3399, 1722 (NHCO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.16 (br s, 1H, NH), 7.65 (dd, 1H, J=6.8, 1.6 Hz, C₄-H), 7.55 (br d, 1H, J=8.8 Hz, NHCO), 7.34 (dd, 1H, J=6.0, 2.0 Hz, arom-H), 7.20–7.14 (m, 2H, arom-H), 6.06 (d, 1H, J=9.6 Hz, CHCCl₃), 2.56 (s, 3H, arom-CH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 156.5 (q, ²J_C–F=37.7 Hz), 136.8, 135.2, 125.5, 121.9, 120.7, 119.1, 115.7 (q, ¹J_C–F=286.1 Hz), 111.2, 104.3, 102.6, 63.2, 13.1; HR-MS (ESI) m/z: Calcd for C₁₃H₁₀Cl₃F₃N₂NaO (M+Na⁺) 394.9709. Found 394.9734.

N-(2,2-Dichloro-1-(2-methyl-1H-indol-3-yl)ethyl)-2,2,2-trifluoroacetamide (4eb)

Brown needles from chloroform/hexane; mp 111–115°C; IR ν_max (KBr) cm⁻¹: 3403, 1716 (NHCO); ¹H-NMR (400 MHz, CDCl₃) δ: 8.16 (br s, 1H, NH), 7.56 (dd, 1H, J=7.2, 1.2 Hz, C₄-H), 7.33 (dd, 1H, J=6.8, 1.6 Hz, C₇-H), 7.28 (br d, 1H, J=7.6 Hz, NHCO), 7.20–7.13 (m, 2H, arom-H), 6.22 (d, 1H, J=5.2 Hz, CHCHCl₂), 5.72 (dd, 1H, J=8.0, 5.2 Hz, CHCHCl₂), 2.48 (s, 3H, arom-CH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 157.0 (q, ²J_C–F=37.7 Hz), 135.2, 135.0, 125.6, 122.0, 120.6, 117.9, 115.7 (q, ¹J_C–F=286.5 Hz), 111.3, 104.6, 73.8, 55.9, 12.5; HR-MS (ESI) m/z: Calcd for C₁₃H₁₁Cl₂F₃N₂NaO (M+Na⁺) 361.0098. Found 361.0079.

2,2,2-Trifluoro-N-(2,2,2-trichloro-1-(1-methyl-2-phenyl-1H-indol-3-yl)ethyl)acetamide (4fa)

Greenish black prisms from chloroform/hexane; mp 119–123°C; IR ν_max (KBr) cm⁻¹: 3401, 1724 (NHCO); ¹H-NMR (400 MHz, CDCl₃) δ: 7.81 (d, 1H, J=8.0 Hz, C₄-H), 7.58–7.53 (m, 4H, arom-H), 7.42–7.38 (m, 3H, arom-H, NHCO), 7.31 (ddd, 1H, J=7.6, 7.6, 0.8 Hz, arom-H), 7.24 (ddd, 1H, J=8.0, 8.0, 0.8 Hz, arom-H), 6.17 (d, 1H, J=9.6 Hz, CHCCl₃), 3.54 (s, 3H, NCH₃); ¹³C-NMR (100 MHz, CDCl₃) δ: 156.2 (q, ²J_C–F=37.8 Hz), 136.9, 131.2, 131.0, 130.6, 129.4, 129.3, 128.6, 122.3, 120.8, 120.1, 115.7 (q, ¹J_C–F=285.8 Hz), 110.3, 104.4, 101.9, 63.4, 30.9; HR-MS (ESI) m/z: Calcd for C₁₉H₁₄Cl₃F₃N₂NaO (M+Na⁺) 471.0022. Found 471.0021.

Methyl-3-(2,2,2-trichloro-1-(2,2,2-trifluoroacetamido)ethyl)-1H-indole-5-carboxylate (4ha)

Brown prisms from ethyl acetate/hexane; mp 192–194°C; IR ν_max (KBr) cm⁻¹: 3392, 1710 (COO), 1677 (NHCO); ¹H-NMR (400 MHz, DMSO-d₆) δ: 11.88 (br s, 1H, NH), 10.63 (br d, 1H, J=9.6 Hz, NHCO), 8.34 (s, 1H, C₄-H), 8.04 (d, 1H, J=2.4 Hz, C₂-H), 7.78 (dd, 1H, J=8.4, 1.2 Hz, C₆-H), 7.54 (d, 1H, J=8.4 Hz, C₇-H), 6.31 (d, 1H, J=9.2 Hz, CHCCl₃), 3.85 (s, 3H, COOCH₃); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 167.1, 156.8 (q, ²J_C–F=37.7 Hz), 137.8, 128.5, 126.8, 122.8, 121.6, 120.4, 116.0 (q, ¹J_C–F=286.0 Hz), 112.2, 108.8, 101.8, 60.3, 52.0; HR-MS (ESI) m/z: Calcd for C₁₄H₁₀Cl₃F₃N₂NaO₃ (M+Na⁺) 438.9607. Found 438.9587.

2,2,2-Trifluoro-N-(2,2,2-trichloro-1-(5-nitro-1H-indol-3-yl)ethyl)acetamide (4ia)

Yellowish brown prisms from ethyl acetate/hexane; mp 224–225°C; IR ν_max (KBr) cm⁻¹: 3318 (NH), 1716 (NHCO), 1517, 1332 (NO₂); ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.17 (br d, 1H, J=1.2 Hz, NH), 10.63 (br d, 1H, J=9.6 Hz, NHCO), 8.74 (d, 1H, J=2.4 Hz, C₄-H), 8.16 (d, 1H, J=2.4 Hz, C₂-H), 8.04 (dd, 1H, J=9.2, 2.4 Hz, C₆-H), 7.63 (d, 1H, J=8.8 Hz, C₇-H), 6.42 (d, 1H, J=9.6 Hz, CHCCl₃); ¹³C-NMR (100 MHz, DMSO-d₆) δ: 156.7 (q, ²J_C–F=37.8 Hz), 141.6, 138.4, 130.7, 126.3, 117.2, 115.9 (q, ¹J_C–F=285.9 Hz), 115.6, 112.7, 110.2, 101.6, 60.4; HR-MS (ESI) m/z: Calcd forC₁₂H₇Cl₃F₃N₃NaO₃ (M+Na⁺) 425.9403. Found 425.9433.

Conflict of Interest

The authors declare no conflict of interest.

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