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Article

1H-Indoles from Deoxybenzoin Schiff Bases by Deprotonation—SNAr Cyclization

by
Nash E. Nevels
and
Richard A. Bunce
*
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(19), 3894; https://doi.org/10.3390/molecules30193894
Submission received: 31 August 2025 / Revised: 15 September 2025 / Accepted: 23 September 2025 / Published: 26 September 2025
(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)
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Abstract

A transition metal-free synthesis of 1,2,5-trisubstituted 1H-indoles by a deprotonation–SNAr cyclization sequence from 1-aryl-2-(2-fluoro-5-nitrophenyl)ethan-1-one (deoxy-benzoin) Schiff bases is reported. The starting deoxybenzoins were prepared by Friedel-Crafts acylation of activated aromatic compounds by 2-(2-fluoro-5-nitrophenyl)acetyl chloride with AlCl3 or the corresponding acid with (CH3SO2)2O. The Schiff bases were generated by slow distillation of toluene (18–24 h) from a heated solution of each deoxybenzoin (1 equiv) with a benzyl- or phenethylamine, a high-boiling aliphatic amine, or an aniline derivative (5 equiv). Subsequent addition of N,N-dimethylformamide, 2 equiv of anhydrous K2CO3, and heating at 90–95 °C for 18–24 h completed the synthesis. Benzyl-, phenethyl-, and high-boiling amines gave excellent yields while the heating requirements for the initial condensation made volatile aliphatic amines difficult to use and gave low yields. Aniline reactivities correlated with substituent-derived base strength, although modified conditions allowed some yields to be improved. Several anticipated competing processes had minimal impact on the outcome of the cyclizations.

Graphical Abstract

1. Introduction

The search for new methods to prepare heterocyclic ring systems is a continuing challenge. New approaches require more efficient and environmentally friendly routes to previously inaccessible structures with straightforward procedures, inexpensive reagents and high functional group tolerance. It is with this goal that we have pursued new metal-free strategies terminated by an SNAr cyclization to access various heterocyclic scaffolds [1,2,3].
The current project sought to generate 1,2,5-trisubstituted 1H-indoles by deprotonation-cyclization of a Schiff bases derived from a 1,2-diarylethan-1-ones (deoxybenzoins) having an SNAr-activated aryl group at C2. We recently published an analogous approach to benzo[d]oxazoles [4] from various N-(2-fluoroaryl)anilides, activated by electron-withdrawing groups at C5, and hoped to extend this method to deoxybenzoin substrates to produce 1H-indoles (Scheme 1). The requisite anilides in this earlier project were easily synthesized from readily available commercial compounds. The ease of ring closure in N,N-dimethylformamide (DMF) with 2 equiv of K2CO3 correlated well with the potency of the activating groups at C5 of the acceptor ring with NO2 promoting cyclization at 90 °C, CN at 115 °C, CO2Me at 120 °C and CF3 at 130 °C. The analogous reaction to prepare 1H-indoles from deoxybenzoins, however, proved more difficult than anticipated and required considerable effort to optimize the conversion. Additionally, potential starting materials were limited as structures with C5 electron-withdrawing groups such as CN and CO2R were not readily available commercially or through synthesis. Furthermore, accessible substrates with weakly activating substituents, such as CF3, failed to give clean conversion to the desired products at the elevated temperatures required. Thus, the current study was restricted to precursors activated only by NO2.
Previous syntheses of 1,2-disubstituted 1H-indoles have utilized metal-catalyzed cyclizations of 2-alkynylanilines using a modified Larock reaction [5] (Figure 1). Ackermann and Kaspar [6] assembled these heterocycles from ortho-dihaloarenes, phenylacetylene, and various anilines using a two-catalyst system involving an N-heterocyclic carbene palladium complex and copper(I) iodide ((1) in Figure 1). Sakai and co-workers [7] employed indium(III) bromide in toluene to promote ring closure of N-alkyl- or N-acyl-2-alkynylanilines to the target compounds ((2) in Figure 1). The Lv group [8] described a one-pot Cu(II)-catalyzed coupling-cyclization of alkynylaniline substrates with aryl or alkyl boronic acids under aerobic conditions to prepare 1,2-disubstituted 1H-indoles decorated at C5 by alkyl, halo or cyano groups ((3) in Figure 1). Finally, Michalska and Grela [9] accessed these 1H-indole derivatives using a gold-catalyzed hydroamination procedure starting from N-alkyl-2-alkynylanilines ((4) in Figure 1). Overall, the number of approaches to 1H-indoles with this substitution pattern appears limited and further work is warranted.
1H-Indoles are core ring structures in many drug compounds that express a wide range of biological activities [10,11,12,13], although the 1,2,5-trisubstitution pattern is underrepresented. Several examples of compounds potentially available using the current reaction are pictured in Figure 2. 1H-Indole 1 has demonstrated significant anti-inflammatory properties through COX-2 inhibition (IC50 = 0.15 μM) [14]. Structure 2 is a potent LXRβ agonist (EC50 = 12 nM) which raises HDL levels and shows anti-diabetic activity in mice, but its outstanding activity is somewhat offset by undesirable upregulation of SREBP1-c gene expression that leads to lipogenesis in HepG2 cells [15]. Bazedoxifene (3), as its acetate salt, has proven effective in the treatment of peri- and postmenopausal osteoporosis [16] and has recently shown promise in the treatment of triple negative breast cancer [16,17].

2. Results and Discussion

The syntheses of the deoxybenzoin substrates are illustrated in Table 1. Two variants, based on the Friedel-Crafts acylation reaction were used. In Method A, 2-(2-fluoro-5-nitrophenyl)acetic acid (4) was converted to its acid chloride using thionyl chloride in benzene and reacted with an activated aromatic compound in the presence of AlCl3 to form 1-aryl-2-(2-fluoro-5-nitrophenyl)ethan-1-ones 5–11 [18]. Products generated in this manner were isolated in yields of 70–80%. For Method B, acid 4 was used directly to acylate aromatic precursors in the presence of methanesulfonic anhydride [19]. This approach, which allowed milder conditions, generally afforded slightly lower yields (50–70%), except in the case of 1,4-benzodioxane, which afforded the deoxybenzoin in 85% yield. As for all Friedel-Crafts acylations, success was observed primarily with electron-rich aromatic structures, although halogenated rings were also successfully reacted. Other deoxybenzoins bearing C5 SNAr activating groups, such as CN and CO2R, have not been reported previously and are not commercially available. One other precursor, activated by CF3, was prepared from commercial 2-(2-fluoro-5-(trifluoromethyl)phenyl)acetic acid, but the temperature required for the final cyclization (>130 °C) resulted in significant decomposition of the substrate.
The sequence began with the formation of the Schiff base by condensation of the deoxybenzoin with a primary amine. Only primary amines were used since two bonds to the nitrogen must be formed in the reaction. Complete conversion to the Schiff base was found to be problematic, presumably due to steric and electronic factors. Reaction progress was monitored by thin layer chromatography (TLC). Several reaction solvents–EtOH, DMF, benzene, and toluene–were evaluated, with the latter providing the best results. Trials with toluene using catalytic HCl and triethylamine as well as molecular sieves to remove the water afforded 1H-indoles in less than 25% isolated yields. The optimized procedure involved the use of 1 equiv of the deoxybenzoin with 5 equiv of the amine (2 or 3 equiv proved insufficient) and slow distillation of toluene from the reaction mixture at 120–125 °C during 18–24 h. Following removal of the toluene, the solvent was replaced with DMF, 2 equiv of anhydrous K2CO3 was added, and the mixture was heated at 90–95 °C for 18–24 h. As in most of our work to prepare heterocycles by SNAr cyclizations, 2 equiv of K2CO3 was sufficient for complete conversion; 1 equiv of base gave lower yields while 2.5 or 3 equiv offered no improvement.
The results of our study are summarized in Table 2 and spectra for all 1H-indoles can be found in the Supplementary Information. Benzylamines (entries 1, 2, 3, 11, 12, 14, 15, 16, 17, 20, 21, 24, 27, 28, 30 and 31; yields 55–86%) and phenethylamines (entries 4, 13, 18, 22, 26, 29 and 32; yields 62–86%) gave the best results as they were nonvolatile and not subject to electronic effects exerted by substituents on the aromatic ring. For high-boiling aliphatic amines (entry 5), a mixture of the deoxybenzoin and the amine (1:5 equiv) was treated in a similar manner to give the 1H-indole in excellent yield (77%). A larger excess (10 equiv) was necessary for volatile aliphatic amines (entries 6, 19 and 23), but the yields were lower (32–58%) due to inefficient condensation with the deoxybenzoin at low temperature and co-distillation of the amine with toluene. For aniline derivatives (entries 7, 8, 9 and 10), the results correlated with substituent-derived electronic effects that enhanced or diminished the basicity/nucleophilicity of the nitrogen. For the current study, we used a series of four anilines, listed from strongest to weakest base: 4-methoxyaniline (pKb = 8.7), aniline (pKb = 9.4), 4-fluoroaniline (pKb = 9.5) and 4-(trifluoromethyl)aniline (pKb = 11.4) [20]. Under standard conditions with 5 equiv of the amine, it was found that 4-methoxyaniline afforded a very high yield of the 1H-indole product (84%), aniline and 4-fluoroaniline gave poor yields (23% and 9%, respectively), and 4-(trifluoromethyl)aniline produced no isolable product. Yields for aniline and 4-fluoroaniline were increased to 42% and 82% by using 10 equiv of the aniline and performing the final ring closure at 120–125 °C. Although the requirement for a large excess of the amine is unclear, the dramatic increase in the yield of 1H-indole from 4-fluoroaniline likely results from resonance electron donation to the para position of the fluorinated aromatic system [21,22]. This phenomenon is known to activate these systems toward electrophilic aromatic substitution and should also increase the basicity of the C4 nitrogen in this compound. These observations suggest that formation of the Schiff base is the critical step of the sequence since stronger bases should be more reactive toward the deoxybenzoin carbonyl. It also demonstrates that other factors, beyond the basicity assessed from pKb values, can have a major impact on the reaction outcome.
Interestingly, two potential competing SNAr reactions were not observed in our study. In deoxybenzoins where C1 was substituted by a 4-fluoro- or 4-chloroarene (viz. 8–10), no addition was observed at the halogenated site despite modest activation by the C1 carbonyl. Additionally, an alternative cyclization involving initial addition of the amine to the 2-fluoro-5-nitrophenyl ring, followed by condensation of the newly added nitrogen at the C1 carbonyl was not observed. This process was expected to compete, although the attenuated nucleophilicity of the resulting aniline should prevent closure to the 1H-indole, and none of this adduct was observed. A third side reaction anticipated was deprotonation to give the deoxybenzoin enolate and ring closure from oxygen to give to the benzofuran product. While this process presumably occurs to a small extent in all the reactions, it was only significant and easily separable from the reaction of 4-fluoroaniline (5 equiv scale) when slow heating of the initial condensation from 80 to 125 °C yielded 5-nitro-2-phenylbenzofuran in 25% yield. At lower temperatures, the weakly basic aniline nitrogen was unable to effectively attack the carbonyl but instead removed an acidic methylene proton from the deoxybenzoin leading to cyclization through the conjugated carbonyl oxygen. The pKa of unsubstituted deoxybenzoin in DMSO is 17.7 [23] and undoubtedly lower for the nitroarene-bearing derivative. Thus, it is surprising that this reaction was less favorable than carbonyl addition at 125 °C using more basic/nucleophilic amines. The weakest base in the current study, 4-(trifluoromethyl)aniline, underwent significant decomposition and afforded no product from either pathway.
Information on the structures of the products was derived primarily from the 1H NMR spectra. The products showed a typical 1,3,4-substitution pattern for the NO2 substituted ring of the 1H-indole: a downfield doublet (J = 2.2 Hz) at ca δ 8.6 for the C4 proton ortho to NO2, a doublet of doublets (J = 9.0, 2.2 Hz) at ca δ 8.1 for the C6 proton ortho to the NO2, and a doublet (J = 9.0 Hz) between δ 7.4–7.1 for the C7 proton. Para-disubstituted aromatic substituents at C2 displayed a distinctive AA’BB’ pattern in the aromatic region of the spectrum and the C3 proton presented as a singlet or small doublet (J = 0.8 Hz) between δ 6.5–6.9. For the benzylamine-derived 1H-indoles, the methylene group appeared as a singlet at ca δ 5.4, while the phenethylamine-derived 1H-indoles displayed two triplets at ca δ 4.4 and δ 2.9 for the coupled methylene protons. Products derived from aliphatic amines exhibited predictable multiplicities and chemical shifts for hydrogens on the N1-substituted carbons as well as first order patterns for the remaining protons. 13C and 19F NMR were somewhat less useful for structure elucidation but did provide useful information on the numbers and types of carbons and fluorines, respectively.
A plausible mechanism to convert deoxybenzoins to 1H-indoles is depicted in Scheme 2 for the reaction of 5 with benzylamine to give 12. The initial step involves condensation of the amine with the carbonyl group of 5 to give the Schiff base. Although the imine tautomer A of this species is generally more stable than the enamine tautomer B [24], the reaction must proceed through an enamine-like intermediate CB, and thus, it is highly probable that B is involved to some extent as the reaction progresses [25]. Treatment of the Schiff base A with anhydrous K2CO3 in DMF would deprotonate the carbon α to the imine to give CA. The highly conjugated delocalized anion C would then close from CB on the fluorine-bearing carbon to give the Meisenheimer complex D and rearomatize by loss of KF to give the 1H-indole 12. Deprotonation of the enamine nitrogen in B (if present) would be directly close to the final product via CB. Although our reactions were performed under an atmosphere of dry nitrogen, it was found that these operations were not sensitive to oxygen and high yields were achieved even when the flask was briefly opened to air during the replacement of toluene with DMF.

3. Materials and Methods

3.1. General Methods

Unless otherwise indicated, all reactions were performed under N2 in dry glassware. All commercial reagents and solvents were used as received. Reactions were followed by TLC on silica gel GF plates (Analtech No 21521, Newark, DE, USA). Preparative separations were performed on Davisil® grade 62, 70–200 mesh silica gel (Fisher Scientific, Pittsburgh, PA, USA) containing 0.5% of UV-05 phosphor (Sorbent Technologies, Norcross, GA, USA) slurry packed into quartz columns. Band elution for all chromatographic separations was detected using a hand-held 254-nm UV light source (Fisher Scientific, Pittsburgh, PA, USA). Melting points (uncorrected) were obtained using a MEL–TEMP apparatus (Cambridge, MA, USA). FT–IR spectra were run using an Agilent Cary 630 spectrometer (Santa Clara, CA, USA) fitted with an ATR sampling module. 1H and 13C NMR spectra were measured using a Bruker Avance 400 system (Billerica, MA, USA) at 400 MHz and 101 MHz, respectively, in CDCl3 (Cambridge Isotope, Andover, MA, USA) containing 0.05% v/v tetramethylsilane as the internal standard. Chemical shifts are given in δ (ppm) units relative to the standard and coupling constants (J) are given in Hz. 19F NMR spectra were collected at 376 MHz on the same instrument and are referenced to internal C6H5F at δ -113.15. Low-resolution mass spectra were obtained using a GC–MS instrument (Hewlett-Packard Model 1800A GCD, Palo Alto, CA, USA). Elemental analyses (±0.4%) on all new compounds were determined by Atlantic Microlabs, Inc. (Norcross, GA, USA).

3.2. Preparation of the 1-Aryl-2-(2-fluoro-5-nitrophenyl)lethan-1-one (Deoxybenzoin) Substrates

Method A: Friedel-Crafts reaction using AlCl3 [1]. The acid chloride of 2-(2-fluoro-5-nitrophenyl)acetic acid (4) was generated by dissolving the acid (2.00 g, 10.5 mmol, 1 equiv) in benzene, adding thionyl chloride (1.50 g, 0.92 mL, 12.6 mmol, 1.2 equiv) and refluxing for 2 h. The benzene was removed under vacuum and replaced with the aromatic compound to be substituted (5–10 mL). AlCl3 (1.1 equiv) was cautiously added, and the reaction was heated under reflux until TLC (25% EtOAc in hexane) indicated complete consumption of the acid chloride (2–3 h). The crude reaction mixture was added to concentrated HCl (20 mL) in ice (100 g). The mixture was extracted with EtOAc (2 × 15 mL) and the combined organic extracts were washed with saturated aqueous NaCl (1 × 25 mL), saturated aqueous NaHCO3 (1 × 25 mL) and additional NaCl solution (2 × 25 mL). After drying (MgSO4), removal of the EtOAc under vacuum and recrystallization from absolute ethanol, the deoxybenzoin derivative was isolated as a tan solid. The compounds prepared using this method are indicated below.
Method B: Friedel-Crafts reaction using methanesulfonic anhydride [2]. A solution of acid 4 (2.00 g, 10.5 mmol, 1 equiv), methanesulfonic anhydride (1.3–1.5 equiv) and the aromatic substrate (1.3–1.5 equiv) in benzene (or a less reactive aromatic solvent) was heated at 75–100 °C until TLC (50% EtOAc in hexane) indicated complete consumption of the acid (2–10 h). The reaction was boiled with 90% EtOH for 5 min, then cooled, added to saturated aqueous NaCl (50 mL), and extracted with EtOAc (2 × 25 mL). The remainder of the workup and purification scheme was as reported for Method A. The compounds prepared using this method are indicated below.

3.2.1. 2-(2-Fluoro-5-nitrophenyl)-1-phenylethan-1-one (5)

Method A; reaction of 4 with benzene gave 2.13 g of 5 (82%) as a tan solid, mp 80–82 °C; IR: 1680, 1531, 1343 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.24–8.19 (complex, 2H), 8.05 (m, 2H), 7.64 (tt, J = 7.4, 1.8 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 7.24 (t, J = 8.6 Hz, 1H), 4.44 (d, J = 1.5 Hz, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 194.5, 164.8 (d, J = 257.4 Hz), 144.2, 135.9, 133.9, 128.9, 128.5, 127.9 (d, J = 6.5 Hz), 125.0 (d, J = 10.2 Hz), 123.8 (d, J = 18.5 Hz), 116.3 (d, J = 24.9 Hz), 38.6 (d, J = 1.5 Hz); these NMR data matched those reported in the literature [26]; 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -105.9; MS, m/z for C14H10FNO3: 259; Anal. Calcd for C14H10FNO3: C, 64.87; H, 3.89; N, 5.40. Found: C, 64.68; H, 3.94; N, 5.35.

3.2.2. 2-(2-Fluoro-5-nitrophenyl)-1-(4-methylphenyl)ethan-1-one (6)

Methods A and B; reaction of 4 with toluene gave 2.19 g of 6 (80% from A) and 1.70 g (62% from B) as a tan solid, mp 97–98 °C; IR: 1676, 1523, 1344 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.22–8.18 (complex, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.23 (t, J = 8.6 Hz, 1H), 4.40 (d, J = 1.3 Hz, 2H), 2.44 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 194.2, 164.8 (d, J = 257.3 Hz), 144.8, 144.2, 138.5, 129.6, 128.4, 127.9 (d, J = 6.4 Hz), 125.0 (d, J = 10.3 Hz), 124.0 (d, J = 18.5 Hz), 116.3 (d, J = 24.9 Hz), 38.5 (d, J = 1.5 Hz), 21.7; 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -105.9; MS, m/z for C15H12FNO3: 273; Anal. Calcd for C15H12FNO3: C, 65.93; H, 4.43; N, 5.13. Found: C, 65.96; H, 4.42; N, 5.07.

3.2.3. 2-(2-Fluoro-5-nitrophenyl)-1-(4-methoxyphenyl)ethan-1-one (7)

Method A; reaction of 4 with anisole gave 2.26 g of 7 (78%) as a tan solid, mp 100–101 °C; IR: 2844, 1663, 1524, 1348 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.22–8.19 (complex, 2H), 8.02 (d, J = 8.9 Hz, 2H), 7.23 (t, J = 8.8 Hz, 1H), 6.99 (d, J = 8.9 Hz, 2H), 4.38 (d, J = 1.5 Hz, 2H), 3.90 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 193.0, 164.7 (d, J = 257.1 Hz), 164.1, 144.2, 130.7, 129.0, 127.9 (d, J = 6.5 Hz), 124.9 (d, J = 10.2 Hz), 124.2 (d, J = 18.5 Hz), 116.2 (d, J = 25.0 Hz), 114.1, 55.6, 38.2 (d, J = 1.5 Hz); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -106.0; MS, m/z for C15H12FNO4: 289; Anal. Calcd for C15H12FNO4: C, 62.28; H, 4.18; N, 4.84. Found: C, 62.32; H, 4.15; N, 4.76.

3.2.4. 2-(2-Fluoro-5-nitrophenyl)-1-(4-fluorophenyl)ethan-1-one (8)

Method A; reaction of 4 with fluorobenzene gave 2.17 g of 8 (78%) as a tan solid, mp 101–103 °C; IR: 1672, 1524, 1338 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.24–8.18 (complex, 2H), 8.10–8.05 (complex, 2H), 7.27–7.17 (complex, 3H), 4.40 (d, J = 0.8 Hz, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 192.9, 166.2 (d, J = 256.2 Hz), 164.7 (d, J = 257.2 Hz), 144.2. 132.4 (d, J = 3.0 Hz), 131.0 (d, J = 9.4 Hz), 127.9 (d, J = 6.3 Hz), 125.0 (d, J = 10.2 Hz), 123.5 (d, J = 18.4 Hz), 116.3 (d, J = 24.8 Hz), 116.1 (d, J = 22.0 Hz), 38.5 (d, J = 1.5 Hz); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -103.7, -106.0; MS, m/z for C14H9F2NO3: 277; Anal. Calcd for C14H9F2NO3: C, 60.66; H, 3.27; N, 5.05. Found: C, 60.52 H, 3.24; N, 5.01.

3.2.5. 1-(4-Fluoro-3-methylphenyl)-2-(2-fluoro-5-nitrophenyl)ethan-1-one (9)

Method B; reaction of 4 with 2-fluorotoluene gave 1.90 g of 9 (65%) as a tan solid, mp 105–107 °C; IR: 1675, 1524, 1331 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.24–8.18 (complex, 2H), 7.93–7.86 (complex, 2H), 7.24 (t, J = 8.8 Hz, 1H), 7.13 (t, J = 8.8 Hz, 1H), 4.39 (s, 2H), 2.36 (d, J = 2.0 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 193.2, 164.8 (d, J = 254.8 Hz), 164.7 (d, J = 257.2 Hz), 144.2 (d, J = 2.6 Hz), 132.2 (d, J = 6.7 Hz), 132.1 (d, J = 3.3 Hz), 128.3 (d, J = 9.5 Hz), 127.9 (d, J = 6.4 Hz), 125.9 (d, J = 19.0 Hz), 125.1 (d, J = 10.2 Hz), 123.7 (d, J = 18.5 Hz), 116.3 (d, J = 24.9 Hz), 115.6 (d, J = 23.2 Hz), 38.5 (d, J = 1.3 Hz), 14.6 (d, J = 3.5 Hz); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -106.0, -107.9; MS, m/z for C15H11F2NO3: 291; Anal. Calcd for C15H11F2NO3: C, 61.86; H, 3.81; N, 4.81. Found: C, 61.79; H, 3.78; N, 4.74.

3.2.6. 1-(4-Chlorophenyl)-2-(2-fluoro-5-nitrophenyl)ethan-1-one (10)

Method A; reaction of 4 with chlorobenzene gave 1.88 g of 10 (64%) as a tan solid, mp 87–89 °C; IR: 1680, 1523, 1334 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.24–8.18 (complex, 2H), 7.98 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.24 (t, J = 8.7 Hz, 1H), 4.40 (d, J = 1.3 Hz, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 193.4, 164.7 (d, J = 257.2 Hz), 144.2, 140.4, 134.2, 129.7, 129.3, 127.9 (d, J = 6.3 Hz), 125.2 (d, J = 10.2 Hz), 123.4 (d, J = 18.4 Hz), 116.3 (d, J = 24.8 Hz), 38.6 (d, J = 1.5 Hz); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -105.9; MS, m/z for C14H9ClFNO3: 293, 295 (ca. 3:1); Anal. Calcd for C14H9ClFNO3: C, 57.26; H, 3.09; N, 4.77. Found: C, 57.29; H, 3.05; N, 4.71.

3.2.7. 1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2-(2-fluoro-5-nitrophenyl)ethan-1-one (11)

Method B; reaction of 4 with 1,4-benzodioxane gave 2.71 g of 11 (85%) as a tan solid, mp 137–138 °C; IR: 1670, 1524, 1343 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.22–8.17 (complex, 2H), 7.59–7.56 (complex, 2H), 7.22 (t, J = 8.7 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 4.36–4.33 (complex, 4H), 4.30 (m, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 192.9, 164.7 (d, J = 257.3 Hz), 148.7, 144.8, 143.6, 129.7, 127.9 (d, J = 6.5 Hz), 124.9 (d, J = 10.2 Hz), 124.1 (d, J = 18.6 Hz), 122.5, 117.9, 117.5, 116.2 (d, J = 24.9 Hz), 64.8, 64.1, 38.2 (d, J = 1.5 Hz); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -105.9; MS, m/z for C16H12FNO5: 317; Anal. Calcd for C16H12FNO5: C, 60.57; H, 3.81; N, 4.41. Found: C, 60.43; H, 3.79; N, 4.33.

3.3. Representative Procedure to Prepare 1H-Indoles

Method C: A solution of the deoxybenzoin (0.1 g, 1.0 equiv) and the benzyl- or phenethylamine, the high-boiling aliphatic amine or the aniline derivative (5 equiv) in toluene (8 mL) was heated in a silicone oil bath at 120–125 °C for 18–24 h with slow distillation of the toluene. [Note: In addition to TLC indicating reaction was complete, droplets of water were observed in the condenser after all the toluene was removed.] The last traces of toluene and excess amine were carefully removed under high vacuum. The resulting residue, in each case, was dissolved in DMF (4 mL), anhydrous K2CO3 (2 equiv) was added, and the mixture was stirred at 90–95 °C for 18–24 h. The crude reaction mixture was added to saturated aqueous NaCl (25 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with saturated aqueous NaCl (3 × 20 mL) and then dried (MgSO4) and concentrated onto silica gel (2–3 g) under vacuum. The silica was added to the top of a 40 cm × 2 cm silica gel column and eluted with 2–5% EtOAc in hexane to remove unreacted amine and any benzofuran product. This was followed by elution with 10–25% EtOAc in hexane to give the 1H-indole product. Concentration of the eluent under vacuum gave a light yellow solid or oil which crystallized upon addition of 5% ether in hexane. Filtration of the solid gave the following 1H-indoles.
Method D: For volatile amines and two of the anilines, a mixture of the deoxybenzoin and the amine (1:10 equiv, respectively) were heated at the indicated temperature. Workup and purification were as described for Method C.

3.3.1. 1-Benzyl-5-nitro-2-phenyl-1H-indole (12)

Method C: Deoxybenzoin 5 (1 equiv) with benzylamine (5 equiv) gave indole 12 (101 mg, 80%) as a yellow solid, mp 123–124 °C; IR: 1523, 1344 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.2 Hz, 1H), 8.05 (dd, J = 9.0, 2.2 Hz, 1H), 7.43 (s, 5H), 7.32–7.24 (complex, 3H), 7.20 (d, J = 9.0 Hz, 1H), 6.97 (m, 2H), 6.80 (d, J = 0.8 Hz, 1H), 5.41 (s, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 145.0, 142.1, 140.6, 136.9, 131.4, 129.3, 129.0, 128.9, 128.8, 127.7, 127.5, 125.8, 117.7, 117.5, 109.4, 104.4, 48.1; these NMR data matched those reported in the literature [27]; MS (m/z): 328; Anal. Calcd for C21H16N2O2: C, 76.81; H, 4.91; N, 8.53; Found: C, 76.57; H, 4.89; N, 8.48.

3.3.2. 1-(3-Methoxybenzyl)-5-nitro-2-phenyl-1H-indole (13)

Method C: Deoxybenzoin 5 (1 equiv) with 3-methoxybenzylamine (5 equiv) gave indole 13 (114 mg, 83%) as a yellow solid, mp 126–127 °C; IR: 2838, 1520, 1336 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 9.0, 2.2 Hz, 1H), 7.46–7.42 (complex, 5H), 7.21 (m, 2H), 6.80 (coincident m, 1H and d, J = 0.8 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 6.51 (s, 1H) 5.37 (s, 2H), 3.71 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 160.1, 145.0, 142.2, 140.7, 138.6, 132.4, 130.1, 129.3, 129.0, 128.8, 127.5, 118.1, 117.7, 117.6, 112.7, 111.9, 110.4, 104.4, 55.2, 48.0; MS (m/z): 358; Anal. Calcd for C22H18N2O3: C, 73.73; H, 5.06; N, 7.82; Found: C, 73.61; H, 5.02; N, 7.76.

3.3.3. 5-Nitro-2-phenyl-1-(3-(trifluoromethyl)phenyl)-1H-indole (14)

Method C: Deoxybenzoin 5 (1 equiv) with 3-(trifluoromethyl)benzylamine (5 equiv) gave indole 14 (103 mg, 67%) as a yellow solid, mp 128–129 °C; IR: 1516, 1328, 1111, 1064 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 9.0, 2.2 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.47–7.38 (complex, 6H), 7.25 (s, 1H), 7.20 (d, J = 9.0 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 0.8 Hz, 1H), 5.45 (s, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 144.9, 142.4, 140.4, 137.9, 131.6, 131.23, 131.15, 129.6, 129.23, 129.15, 128.9, 127.7, 125.1, 123.8 (q, J = 272.5 Hz), 124.7 (q, J = 3.8 Hz), 122.9 (q, J = 3.8 Hz), 117.84, 117.80, 110.1, 47.6; 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -62.8; MS (m/z): 396; Anal. Calcd for C22H15F3N2O2: C, 66.67; H, 3.81; N, 7.07; Found: C, 66.55; H, 3.88; N, 7.08.

3.3.4. 1-(2-Fluorophenethyl)-5-nitro-2-phenyl-1H-indole (15)

Method C: Deoxybenzoin 5 (1 equiv) with 2-fluorophenethylamine (5 equiv) gave indole 15 (95 mg, 69%) as a yellow solid, mp 121–123 °C; IR: 1518, 1344 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 9.0, 2.2 Hz, 1H), 7.49–7.44 (complex, 3H), 7.38 (d, J = 9.0 Hz, 1H), 7.38–7.34 (complex, 2H), 7.15 (m, 1H), 6.90 (m, 2H), 6.72 (td, J = 7.5, 1.7 Hz, 1H), 6.65 (d, J = 0.8 Hz, 1H), 4.44 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 7.3 Hz, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 159.7 (d, J = 246.2 Hz), 144.7, 144.5, 143.7, 142.2, 140.4, 129.4 (d, J = 8.1 Hz), 127.5, 127.4 (d, J = 3.8 Hz), 124.6 (d, J = 3.6 Hz), 124.4, 124.1, 124.0, 122.4, 118.2, 117.8, 117.5 (d, J = 5.4 Hz), 115.5 (d, J = 20.9 Hz), 110.1, 104.2, 64.2 (d, J = 11.6 Hz), 42.0 (d, J = 5.6 Hz); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -118.9; MS (m/z): 360; Anal. Calcd for C22H17FN2O2: C, 73.32; H, 4.75; N, 7.77; Found: C, 73.14; H, 4.76; N, 7.75.

3.3.5. 1-(3-Isopropoxypropyl)-5-nitro-2-phenyl-1H-indole (16)

Method C: Deoxybenzoin 5 (1 equiv) with 3-isopropoxypropylamine (5 equiv) gave indole 16 (101 mg, 77%) as a yellow solid, mp 44–45 °C; IR: 1512, 1328 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 2.3 Hz, 1H), 8.13 (dd, J = 9.1, 2.3 Hz, 1H), 7.52–7.46 (complex, 6H), 6.69 (d, J = 0.8 Hz, 1H), 4.35 (t, J = 7.1 Hz, 2H), 3.75 (septet, J = 6.1 Hz, 1H), 3.20 (t, J = 5.7 Hz, 2H), 1.87 (pentet, J = 6.0 Hz, 2H), 1.06 (d, J = 6.1 Hz, 6H); 13C {1H} NMR (101 MHz, CDCl3): δ 144.4, 141.8, 140.5, 131.9, 129.3, 128.79, 128.77, 127.2, 117.6, 117.1, 110.1, 104.5, 71.6, 64.2, 41.4, 30.7, 22.0; MS (m/z): 338; Anal. Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28; Found: C, 71.13; H, 6.51; N, 8.12.

3.3.6. 1-Cyclohexyl-5-nitro-2-phenyl-1H-indole (17)

Method D: Deoxybenzoin 5 (1 equiv) with cyclohexylamine (10 equiv) at a ring closing temperature of 90–95 °C gave indole 17 (72 mg, 58%) as a yellow solid, mp 120–121 °C; IR: 1516, 1328 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 2.3 Hz, 1H), 8.07 (dd, J = 9.2, 2.3 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.53–7.46 (complex, 3H), 7.45–7.41 (complex, 2H), 6.62 (s, 1H), 4.23 (tt, J = 12.5, 3.9 Hz, 1H), 2.37–2.23 (complex, 2H), 1.98–1.87 (complex, 4H), 1.74 (m, 1H), 1.35–1.24 (complex, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 144.8, 141.3, 138.7, 132.4, 129.5, 128.8, 128.7, 128.1, 117.7, 116.4, 112.2, 104.5, 56.9, 31.5, 26.1, 25.1; MS (m/z): 320; Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74; Found: C, 74.75; H, 6.24; N, 8.71.

3.3.7. 1-(4-Methoxyphenyl)-5-nitro-2-phenyl-1H-indole (18)

Method C: Deoxybenzoin 5 (1 equiv) with 4-methoxyaniline (5 equiv) gave indole 18 (111 mg, 84%) as a yellow solid, mp 169–171 °C; IR: 2837, 1516, 1333 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.63 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 9.1, 2.2 Hz, 1H), 7.28 (m, 5H), 7.22 (d, J = 9.1 Hz, 1H), 7.17 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 0.8 Hz, 1H), 3.86 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 159.3, 144.2, 142.3, 142.0, 131.3, 130.0, 129.01, 128.97, 128.4, 128.2, 127.3, 117.7, 117.6, 114.8, 110.6, 104.6, 55.5; MS (m/z): 344; Anal. Calcd for C21H16N2O3: C, 73.24; H, 4.68; N: 8.13; Found: C, 73.32; H, 4.74; N, 8.09.

3.3.8. 5-Nitro-1,2-diphenyl-1H-indole (19)

Method D: Deoxybenzoin 5 (1 equiv) with aniline (10 equiv) at a ring closure temperature of 120–125 °C gave indole 19 (51 mg, 42%) as a yellow solid, mp 187–188 °C (lit [28] mp 182–185 °C); using aniline (5 equiv) and a ring closure temperature of 90–95 °C produced 28 mg (23%) of 19; IR: 1516, 1328 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 2.2 Hz, 1H), 8.08 (dd, J = 9.1, 2.2 Hz, 1H), 7.49–7.40 (complex, 4H), 7.29–7.24 (complex 7H), 6.94 (d, J = 0.8 Hz, 1H); 13C {1H} NMR (101 MHz, CDCl3): δ 144.1, 142.5, 141.6, 137.3, 131.2, 129.7, 129.0, 128.4, 128.3, 128.2, 127.9, 127.5, 117.8, 117.6, 110.6, 105.0; MS (m/z): 314; Anal. Calcd for C20H14N2O2: C, 76.42; H, 4.49; N: 8.91; Found: C, 76.13; H, 4.44; N, 8.87.

3.3.9. 1-(4-Fluorophenyl)-5-nitro-2-phenyl-1H-indole (20)

Method D: Deoxybenzoin 5 (1 equiv) with 4-fluoroaniline (10 equiv) at a ring closure temperature of 120–125 °C gave indole 20 (105 mg, 82%) as a yellow solid, mp 149–150 °C; using 4-fluoroaniline (5 equiv) and a ring closure temperature of 90–95 °C produced 12 mg (9%) of 20; IR: 1516, 1325 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 9.1, 2.2 Hz, 1H), 7.32–7.28 (complex, 3H), 7.28–7.22 (complex, 5H), 7.16 (t, J = 8.3 Hz, 2H), 6.94 (d, J = 0.9 Hz, 1H); 13C {1H} NMR (101 MHz, CDCl3): δ 162.0 (d, J = 249.2 Hz), 144.1, 142.6, 141.7, 133.3 (d, J = 3.1 Hz), 131.0, 129.6 (d, J = 8.7 Hz), 129.0, 128.5, 128.4, 127.5, 118.0, 117.6, 116.7 (d, J = 22.8 Hz), 110.4, 105.1; 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -112.3; MS (m/z): 332; Anal. Calcd for C20H13FN2O2: C, 72.28; H, 3.94; N, 8.43; Found: C, 71.99; H, 3.91; N, 8.38.
In one case, a mixture of deoxybenzoin 5 (1 equiv) and 4-fluoroaniline (5 equiv) was slowly heated from 80 to 125 °C to give 5-nitro-2-phenylbenzofuran (20a, 32 mg, 25%) as the major product; light yellow solid, mp 156–158 °C (lit [29] mp 158–159 °C); IR: 1524, 1351 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 2.4 Hz, 1H), 8.22 (dd, J = 9.0, 2.4 Hz, 1H), 7.88 (m, 2H), 7.59 (d, J = 9.0 Hz, 1H), 7.49 (m, 2H), 7.43 (m, 1H), 7.13 (d, J = 0.9 Hz, 1H); 13C {1H} NMR (101 MHz, CDCl3): δ 159.3, 157.6, 144.4, 129.7, 129.6, 129.2, 129.0, 125.3, 120.1, 117.3, 111.4, 101.6; MS (m/z): 239.

3.3.10. 5-Nitro-2-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-indole (21)

Methods C or D: No 1H-indole product was isolated from reaction of 4-(trifluoromethyl)aniline with deoxybenzoin 5.

3.3.11. 1-Benzyl-2-(4-methylphenyl)-5-nitro-1H-indole (22)

Method C: Deoxybenzoin 6 (1 equiv) with benzylamine (5 equiv) gave indole 22 (98 mg, 78%) as a yellow solid, mp 127–128 °C; IR: 1523, 1321 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 2.2 Hz, 1H), 8.03 (dd, J = 9.0, 2.2 Hz, 1H), 7.34–7.27 (complex, 5H), 7.23 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 7.8 Hz, 2H), 6.76 (s, 1H), 5.39 (s, 2H), 2.40 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 145.2, 142.1, 140.6, 139.0, 137.0, 129.5, 129.1, 129.0, 128.4, 127.64, 127.55, 125.8, 117.5, 117.4, 110.4, 104.1, 48.0, 21.3; MS (m/z): 342; Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18; Found: C, 77.02; H, 5.29; N, 8.14.

3.3.12. 1-(3-Methoxybenzyl)-2-(4-methylphenyl)-5-nitro-1H-indole (23)

Method C: Deoxybenzoin 6 (1 equiv) with 3-methoxybenzylamine (5 equiv) gave indole 23 (105 mg, 77%) as a yellow solid, mp 93–94 °C; IR: 2844, 1602, 1523, 1321 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 9.1, 2.2 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.24–7.18 (complex, 4H), 6.80 (dd, J = 8.1, 2.5 Hz, 1H), 6.76 (d, J = 0.7 Hz, 1H), 6.57 (ddd, J = 7.8, 1.8, 0.9 Hz, 1H), 6.51 (t, J = 1.8 Hz, 1H), 5.36 (s, 2H), 3.71 (s, 3H), 2.40 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 160.1, 145.2, 142.1, 140.6, 139.0, 138.7, 130.1, 129.5, 129.2, 128.4, 127.6, 118.1, 117.5, 117.4, 112.6, 111.9, 110.4, 104.0, 55.2, 47.9, 22.3; MS (m/z): 372; Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52; Found: C, 74.38; H, 5.45; N, 7.50.

3.3.13. 2-(4-Methylphenyl)-5-nitro-1-phenethyl-1H-indole (24)

Method C: Deoxybenzoin 6 (1 equiv) with phenethylamine (5 equiv) gave indole 24 (81 mg, 62%) as a yellow solid, mp 120–122 °C; IR: 1523, 1321 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 9.1, 2.2 Hz, 1H), 7.32 (d, J = 9.1 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.19–7.15 (complex, 3H), 6.87–6.85 (complex, 2H), 6.62 (d, J = 0.8 Hz, 1H), 4.40 (t, J = 7.5 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.44 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 144.7, 141.8, 140.0, 138.8, 137.5, 129.4, 129.3, 128.7, 128.63, 128.58, 127.4, 126.8, 117.6, 117.1, 109.7, 104.2, 45.9, 36.2, 21.4; MS (m/z): 356; Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86; Found: C, 77.40; H, 5.67; N, 7.89.

3.3.14. 1-Benzyl-2-(4-methoxyphenyl)-5-nitro-1H-indole (25)

Method C: Deoxybenzoin 7 (1 equiv) with benzylamine (5 equiv) gave indole 25 (106 mg, 86%) as a yellow solid, mp 143–144 °C; IR: 2837, 1516, 1328 cm−1; 1H NMR (400 MHz, CDCl3: δ 8.60 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 9.1, 2.2 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.31–7.24 (complex, 3H), 7.18 (d, J = 9.0 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.74 (s, 1H), 5.39 (s, 2H), 3.84 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 160.2, 145.0, 142.1, 140.5, 137.0, 130.6, 129.0, 127.7, 127.6, 125.8, 123.7, 117.4, 117.3, 114.3, 110.3, 103.8, 55.4, 48.0; MS (m/z): 358; Anal. Calcd for C22H18N2O3: C, 73.73; H, 5.06; N, 7.82; Found: C, 73.66; H, 5.05; N, 7.79.

3.3.15. 1-(3-Methoxybenzyl)-2-(4-methoxyphenyl)-5-nitro-1H-indole (26)

Method C: Deoxybenzoin 7 (1 equiv) with 3-methoxybenzylamine (5 equiv) gave indole 26 (107 mg, 80%) was isolated as a yellow solid, mp 118–119 °C; IR: 2842, 1516, 1325 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 2.2 Hz, 1H), 8.03 (dd, J = 9.0, 2.2 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.79 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 6.72 (d, J = 0.9 Hz, 1H), 6.56 (ddd, J = 7.6, 1.7, 0.9 Hz, 1H), 6.51 (t, J = 2.2 Hz, 1H), 5.35 (s, 2H), 3.84 (s, 3H), 3.71 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 160.2, 160.1, 144.9, 142.1, 140.6, 138.7, 130.6, 130.1, 127.5, 123.6, 118.0, 117.4, 117.3, 114.3, 112.6, 111.8, 110.3, 103.7, 55.4, 55.2, 47.9; MS (m/z): 388; Anal. Calcd for C23H20N2O4: C, 71.12; H, 5.19; N, 7.21; Found: C, 70.98; H, 5.16; N, 7.15.

3.3.16. 1-(2-Chlorobenzyl)-2-(4-methoxyphenyl)-5-nitro-1H-indole (27)

Method C: Deoxybenzoin 7 (1 equiv) with 2-chlorobenzylamine (5 equiv) gave indole 27 (104 mg, 77%) was isolated as a yellow solid, mp 147–149 °C; IR: 2841, 1516, 1328 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.2 Hz, 1H), 8.05 (dd, J = 9.0, 2.2 Hz, 1H), 7.44 (dd, J = 8.0, 1.3 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.23 (td, J = 7.9, 1.6 Hz, 1H), 7.14–7.08 (complex, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 0.9 Hz, 1H), 6.52 (dd, J = 7.5, 1.6 Hz, 1H), 5.43 (s, 2H), 3.83 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 160.2, 145.0, 142.3, 140.4, 134.4, 131.9, 130.3, 129.8, 128.9, 127.6, 127.4, 126.8, 123.3, 117.50, 117.48, 114.4, 110.1, 103.9, 55.4, 46.0; MS (m/z): 392, 394 (ca 3:1); Anal. Calcd for C22H17ClN2O3: C, 67.26; H, 4.36; N, 7.13; Found: C, 67.25; H, 4.39; N, 7.18.

3.3.17. 2-(4-Methoxyphenyl)-5-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole (28)

Method C: Deoxybenzoin 7 (1 equiv) with 3-(trifluoromethyl)benzylamine (5 equiv) gave indole 28 (119 mg, 81%) as a yellow solid, mp 115–117 °C; IR: 2844, 1516, 1328, 1105, 1071 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.2 Hz, 1H), 8.08 (dd, J = 9.0, 2.2 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.26 (obscured, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 0.8 Hz, 1H), 5.43 (s, 2H), 3.85 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 160.3, 144.8, 142.3, 140.3, 138.1, 131.5, 131.4 (q, J = 32.5 Hz), 130.6, 129.6, 129.2, 127.7, 124.7 (q, J = 3.7 Hz), 123.8 (q, J = 272.5 Hz), 122.9 (q, J = 3.8 Hz), 117.62, 117.58, 114.4, 109.9, 104.3, 55.4, 47.6; 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -62.8; MS (m/z): 426; Anal. Calcd for C23H17F3N2O3: C, 64.79; H, 4.02; N, 6.57; Found: C, 64.89; H, 3.91; N, 6.59.

3.3.18. 2-(4-Methoxyphenyl)-5-nitro-1-phenethyl-1H-indole (29)

Method C: Deoxybenzoin 7 (1 equiv) with phenethylamine (5 equiv) gave indole 29 (97 mg, 75%) as a yellow solid, mp 141–143 °C; IR: 2838, 1516, 1334 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 9.1, 2.2 Hz, 1H), 7.32 (d, J = 9.1 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.19–7.15 (complex, 3H), 6.98 (d, J = 8.8 Hz, 2H), 6.87–6.82 (complex, 2H), 6.59 (d, J = 0.7 Hz, 1H), 4.38 (t, J = 7.5 Hz, 2H), 3.89 (s, 3H), 2.92 (t, J = 7.5 Hz, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 160.0, 144.5, 141.7, 139.9, 137.5, 130.7, 128.63, 128.59, 127.4, 126.8, 123.9, 117.5, 117.0, 114.1, 109.6, 104.0, 55.4, 45.8, 36.2; MS (m/z): 372; Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52; Found: C, 74.07; H, 5.38; N, 7.51.

3.3.19. 1-Hexyl-2-(4-methoxyphenyl)-5-nitro-1H-indole (30)

Method D: Deoxybenzoin 7 (1 equiv) with hexylamine (10 equiv) at a ring closing temperature of 90–95 °C gave indole 30 (44 mg, 36%) was isolated as a yellow solid, mp 69–70 °C; IR: 2835, 1516, 1330 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 2.2 Hz, 1H), 8.11 (dd, J = 9.0, 2.2 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.61 (d, J = 0.8 Hz, 1H), 4.15 (t, J = 7.6 Hz, 2H), 3.89 (s, 3H), 1.67 (pentet, J = 7.1 Hz, 2H), 1.25–1.12 (complex, 6H), 0.81 (t, J = 6.6 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 160.0, 144.5, 141.6, 140.0, 130.7, 127.4, 124.2, 117.5, 116.9, 114.2, 109.7, 103.8, 55.4, 44.3, 31.2, 29.9, 26.3, 22.4, 13.9; MS (m/z): 352; Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95; Found: C, 71.64; H, 6.91; N, 7.93.

3.3.20. 1-Benzyl-2-(4-fluorophenyl)-5-nitro-1H-indole (31)

Method C: Deoxybenzoin 8 (1 equiv) with benzylamine (5 equiv) gave indole 31 (102 mg, 85%) as a yellow solid, mp 129–130 °C; IR: 1510, 1335 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 9.0, 2.2 Hz, 1H), 7.38 (dd, J = 8.8, 5.2 Hz, 2H), 7.35–7.25 (complex, 3H), 7.22 (d, J = 9.0 Hz, 1H), 7.11 (t, J = 8.7 Hz, 2H), 6.95 (m, 2H), 6.78 (d, J = 0.7 Hz, 1H), 5.37 (s, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 163.1 (d, J = 249.5 Hz,), 143.9, 142.2, 140.6, 136.7, 131.1 (d, J = 8.2 Hz), 129.1, 127.8, 127.5 (d, J = 3.5 Hz), 127.4, 125.7, 117.7, 116.9 (d, J = 21.8 Hz), 110.4, 104.5, 48.0 (1 aromatic carbon unresolved); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -111.9; MS (m/z): 346; Anal. Calcd for C21H15FN2O2: C, 72.82; H, 4.37; N, 8.09; Found: C, 72.73; H, 4.33; N, 8.06.

3.3.21. 2-(4-Fluorophenyl)-5-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole (32)

Method C: Deoxybenzoin 8 (1 equiv) with 3-(trifluoromethyl)benzylamine (5 equiv) gave indole 32 (81 mg, 55%) as a yellow solid, mp 129–130 °C; IR: 1516, 1327 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 9.0, 2.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 8.8, 5.2 Hz, 2H), 7.24 (br s, 1H), 7.21 (d, J = 9.0 Hz, 1H), 7.13 (t, J = 8.7 Hz, 2H), 7.05 (br d, J = 7.8 Hz, 1H), 6.80 (d, J = 0.8 Hz, 1H), 5.42 (s, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 163.2 (d, J = 250.1 Hz), 143.7, 142.4, 140.4, 137.8, 131.5 (q, J = 32.6 Hz), 131.1 (d, J = 8.2 Hz), 129.7, 129.1, 127.5, 127.2 (d, J = 3.6 Hz), 124.8 (q, J = 3.8 Hz), 123.7 (q, J = 272.5 Hz), 122.8 (q, J = 3.8 Hz), 117.94, 117.86, 116.1 (d, J = 21.7 Hz), 110.1, 105.0, 47.6; 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -62.9, -111.5; MS (m/z): 414: Anal. Calcd for C22H14F4N2O2: C, 63.77; H, 3.41; N, 6.76; Found: C, 63.49; H, 3.40; N, 6.70.

3.3.22. 2-(4-Fluorophenyl)-5-nitro-1-phenethyl-1H-indole (33)

Method C: Deoxybenzoin 8 (1 equiv) with phenethylamine (5 equiv) gave indole 33 (103 mg, 79%) as a yellow solid, mp 129–130 °C; IR: 1516, 1338 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 9.0, 2.2 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.23–7.09 (complex, 7H), 6.79 (m, 2H), 6.60 (s, 1H), 4.39 (t, J = 7.2 Hz, 2H), 2.92 (t, J = 7.2 Hz, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 163.0 (d, J = 249.3 Hz), 143.5, 141.9, 139.8, 137.4, 131.2 (d, J = 8.4 Hz), 128.7, 128.6, 127.7 (d, J = 3.4 Hz), 127.3, 126.9, 117.8, 117.4, 115.7 (d, J = 21.7 Hz), 109.8, 104.5, 45.8, 36.1; 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -112.3; MS (m/z): 360; Anal. Calcd for C22H17FN2O2: C, 73.32; H, 4.75; N, 7.77; Found: C, 73.19; H, 4.77; N, 7.73.

3.3.23. 1-Isobutyl-2-(4-fluorophenyl)-5-nitro-1H-indole (34)

Method D: Deoxybenzoin 8 (1 equiv) with isobutylamine (10 equiv) at a ring closing temperature of 90–95 °C gave indole 34 (36 mg, 32%) as a yellow solid, mp 93–94 °C; IR: 1516, 1320 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 9.1, 2,2 Hz, 1H), 7.45 (dd, J = 8.7, 5.3 Hz, 2H), 7.38 (d, J = 9.1 Hz, 1H), 7.19 (t, J = 8.7 Hz, 2H), 6.65 (d, J = 0.8 Hz, 1H), 4.02 (d, J = 7.6 Hz, 2H), 1.96 (nonet, J = 6.9 Hz, 1H), 0.68 (d, J = 6.7 Hz, 6H); 13C {1H} NMR (101 MHz, CDCl3): δ 161.9 (d, J = 249.1 Hz), 142.7, 140.7, 139.4, 130.5 (d, J = 8.3 Hz), 127.2 (d, J = 3.4 Hz), 126.1, 116.7, 116.2, 114.8 (d, J = 21.7 Hz), 109.2, 103.7, 50.6, 28.1, 19.0; 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -112.3; MS (m/z): 312; Anal. Calcd for C18H17FN2O2: C, 69.22; H, 5.49; N, 8.97; Found: C, 69.10; H, 5.49; N, 8.94.

3.3.24. 1-Benzyl-2-(4-fluoro-3-methylphenyl)-5-nitro-1H-indole (35)

Method C: Deoxybenzoin 9 (1 equiv) with benzylamine (5 equiv) gave indole 35 (103 mg, 83%) as a yellow solid, mp 124–125 °C; IR: 1516, 1325 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 9.0, 2.2 Hz, 1H), 7.32–7.25 (complex, 3H), 7.24–7.17 (complex, 3H), 7.04 (d, J = 9.0 Hz, 1H), 6.95 (m, 2H), 6.75 (d, J = 0.8 Hz, 1H), 5.37 (s, 2H), 2.26 (d, J = 1.9 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 161.7 (d, J = 248.1 Hz), 144.2, 142.2, 140.5, 136.9, 132.7 (d, J = 5.5 Hz), 129.0, 128.3 (d, J = 8.4 Hz), 127.8, 127.4, 127.1 (d, J = 3.9 Hz), 125.8, 125.5 (d, J = 17.7 Hz), 117.62, 117.57, 115.4 (d, J = 22.7 Hz), 110.3, 104.3, 48.0, 14.7 (d, J = 3.5 Hz); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -116.3; MS (m/z): 360; Anal. Calcd for C22H17FN2O2: C, 73.32; H, 4.75; N, 7.77; Found: C, 73.16; H, 4.76; N, 7.79.

3.3.25. 2-(4-Fluoro-3-methylphenyl)-5-nitro-1-phenethyl-1H-indole (36)

Method C: Deoxybenzoin 9 (1 equiv) with phenethylamine (5 equiv) gave indole 36 (102 mg, 80%) as a yellow solid, mp 126–128 °C; IR: 1516, 1329 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 9.0, 2.2 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.21–7.13 (complex, 3H), 7.08–7.01 (complex, 2H), 6.98 (d, J = 7.1 Hz, 1H), 6.78 (m, 2H), 6.57 (s, 1H), 4.39 (t, J = 7.2 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 2.31 (d, J = 2.0 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 161.6 (d, J = 247.9 Hz), 143.9, 141.9, 139.8, 137.5, 132.7 (d, J = 5.4 Hz), 128.6, 128.4 (d, J = 8.2 Hz), 127.4, 127.3, 126.8, 125.3 (d, J = 17.6 Hz), 117.7, 117.3, 115.2 (d, J = 22.7 Hz), 109.8, 104.3, 45.1, 36.1, 14.6 (d, J = 3.5 Hz), (1 aromatic carbon unresolved); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -116.7; MS (m/z): 374; Anal. Calcd for C23H19FN2O2: C, 73.78; H, 5.12; N, 7.48; Found: C, 73.58; H, 5.07; N, 7.46.

3.3.26. 2-(4–Fluoro-3-methylphenyl)-1-(2-fluorophenethyl)-5-nitro-1H-indole (37)

Method C: Deoxybenzoin 9 (1 equiv) with 2-fluorophenethylamine (5 equiv) gave indole 37 (101 mg, 75%) as a yellow solid, mp 129–130 °C; IR: 1516, 1328 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 9.0, 2.2 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.20–7.05 (complex, 4H), 6.91 (m, 2H), 6.71 (td, J = 7.8, 1.9 Hz, 1H), 6.58 (d, J = 0.8 Hz, 1H), 4.41 (t, J = 7.2 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.33 (d, J = 2.0 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3): δ 161.6 (d, J = 247.7 Hz), 161.2 (d, J = 245.5 Hz), 143.7, 141.9, 139.9, 132.6 (d, J = 5.5 Hz), 130.9 (d, J = 4.7 Hz), 128.8 (d, J = 8.2 Hz), 128.3 (d, J = 8.3 Hz), 127.3, 127.2 (d, J = 3.8 Hz), 125.4 (d, J = 17.7 Hz), 124.3 (d, J = 13.1 Hz), 124.2, 117.7, 117.3, 115.33 (d, J = 21.7 Hz), 115.28 (d, J = 22.8 Hz), 109.7, 104.3, 44.2, 30.0 (d, J = 1.9 Hz), 14.6 (d, J = 3.5 Hz); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -116.6, -118.9; MS (m/z): 392; Anal. Calcd for C23H18F2N2O2: C, 70.40; H, 4.62; N, 7.14; Found: C, 70.29; H, 4.54; N, 7.16.

3.3.27. 1-Benzyl-2-(4-chlorophenyl)-5-nitro-1H-indole (38)

Method C: Deoxybenzoin 10 (1 equiv) with benzylamine (5 equiv) gave indole 38 (95 mg, 77%) as a yellow solid, mp 129–130 °C; IR: 1516, 1331 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 9.1, 2.2 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.33–7.27 (complex, 3H), 7.22 (d, J = 9.1 Hz, 1H), 6.95 (m, 2H), 6.80 (d, J = 0.8 Hz, 1H), 5.38 (s, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 143.7, 142.3, 140.7, 136.7, 135.2, 130.5, 129.8, 129.1, 127.8, 127.4, 125.7, 117.80, 117.76, 110.5, 104.7, 48.1 (1 aromatic carbon unresolved); MS (m/z) 362, 364 (ca 3:1); Anal. Calcd for C21H15ClN2O2: C, 69.52; H, 4.17; N, 7.72; Found: C, 69.23; H, 4.10; N, 7.71.

3.3.28. 2-(4-Chlorophenyl)-5-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole (39)

Method C: Deoxybenzoin 10 (1 equiv) with 3-(trifluoromethyl)benzylamine (5 equiv) gave indole 39 (91 mg, 62%) as a yellow solid, mp 150–151 °C; IR: 1516, 1333, 1111, 1071 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.63 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 9.1, 2.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.40 (obscured, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.30 (br s, 1H), 7.21 (d, J = 9.1 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 0.8 Hz, 1H), 5.43 (s, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 143.5, 142.5, 140.5, 137.7, 135.5, 131.5 (q, J = 32.5 Hz), 130.4, 129.7, 129.6, 129.2, 129.0, 127.5, 124.8 (q, J = 3.6 Hz), 123.7 (q, J = 272.5 Hz), 122.7 (q, J = 3.7 Hz), 118.1, 117.9, 110.1, 105.2, 47.6; 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -62.9; MS (m/z): 430, 432 (ca 3:1); Anal. Calcd for C22H14ClF3N2O2: C, 61.34; H, 3.28; N, 6.50; Found: C, 61.07; H, 3.33; N, 6.45.

3.3.29. 2-(4-Chlorophenyl)-5-nitro-1-phenethyl-1H-indole (40)

Method C: Deoxybenzoin 10 (1 equiv) with phenethylamine (5 equiv) gave indole 40 (93 mg, 73%) as a yellow solid, mp 153–154 °C; IR: 1516, 1333 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 9.1, 2.2 Hz, 1H), 7.40 d, J = 8.5 Hz, 2H), 7.36 (d, J = 9.1 Hz, 1H), 7.21–7.12 (obscured, 3H), 7.16 (d, J = 8.6 Hz, 2H), 6.78 (m, 2H), 6.61 (s, 1H), 4.40 (t, J = 7.2 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 143.3, 142.0, 140.0, 137.3, 134.9, 130.6, 130.1, 128.9, 128.7, 128.6, 127.3, 126.9, 117.8, 117.5, 109.9, 104.7, 45.8, 36.1; MS (m/z): 376, 378 (ca 3:1); Anal. Calcd for C22H17ClN2O2: C, 70.12; H, 4.55; N, 7.43; Found: C, 69.98; H, 4.49; N, 7.49.

3.3.30. 1-Benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl-)-5-nitro-1H-indole (41)

Method C: Deoxybenzoin 11 (1 equiv) with benzylamine (5 equiv) gave indole 41 (103 mg, 85%) as a yellow solid, mp 124–125 °C; IR: 1518, 1336 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.59 (d, J = 2.2 Hz, 1H), 8.03 (dd, J = 9.1, 2.2 Hz, 1H), 7.31–7.24 (complex, 3H), 7.16 (d, J = 9.1 Hz, 1H), 6.96 (m, 3H), 6.89 (m, 2H), 6.73 (d, J = 0.8 Hz, 1H), 5.41 (s, 2H), 4.29 (m, 4H); 13C {1H} NMR (101 MHz, CDCl3): δ 144.7, 144.4, 143.7, 142.1, 140.5, 136.9, 129.0, 127.7, 127.5, 125.8, 124.6, 122.5, 118.3, 117.7, 117.5, 117.4, 110.4, 103.9, 64.5, 64.3, 48.0; MS (m/z): 386; Anal. Calcd for C23H18N2O4: C, 71.49; H, 4.70; N, 7.25; Found: C, 71.43; H, 4.73; N, 7.29.

3.3.31. 2-(2,3-Dihydobenzo[b][1,4]dioxin-6-yl)-1-(2-fluorobenzyl)-5-nitro-1H-indole (42)

Method C: Deoxybenzoin 11 (1 equiv) with 2-fluorobenzylamine (5 equiv) gave indole 42 (109 mg, 86%) as a yellow solid, mp 153–155 °C; IR: 1520, 1334 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 2.2 Hz, 1H), 8.05 (dd, J = 9.0, 2.2 Hz, 1H), 7.25 (m, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.09 (ddd, J = 10.1, 8.3, 1.2 Hz, 1H), 6.98 (td, J = 7.6, 1.2 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.88 (dd, J = 8.3, 2.0 Hz, 1H), 6.74 (d, J = 0.8 Hz, 1H), 6.56 (td, J = 7.6, 1.7 Hz, 1H), 5.45 (s, 2H), 4.30 (m, 4H); 13C {1H} NMR (101 MHz, CDCl3): δ 159.7 (d, J = 246.2 Hz), 144.7, 144.5, 143.7, 142.2, 140.4, 129.4 (d, J = 8.1 Hz), 127.5, 127.4 (d, J = 3.9 Hz), 124.6 (d, J = 3.6 Hz), 124.4, 124.0 (d, J = 14.2 Hz), 122.4, 118.2, 117.7, 117.52, 117.47, 115.5 (d, J = 20.8 Hz), 110.1, 104.2, 64.5, 64.3, 42.0 (d, J = 5.5 Hz); 19F {1H} NMR (376 MHz, CDCl3 referenced to C6H5F): δ -118.9; MS (m/z): 404; Anal. Calcd for C23H17FN2O4: C, 68.31; H, 4.24; N, 6.93; Found: C, 68.19; H, 4.27; N, 6.89.

3.3.32. 2-(2,3-Dihydobenzo[b][1,4]dioxin-6-yl)-5-nitro-1-phenethyl-1H-indole (43)

Method C: Deoxybenzoin 11 (1 equiv) with phenethylamine (5 equiv) gave indole 43 (109 mg, 86%) as a yellow solid, mp 104–105 °C; IR: 1516, 1334 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 9.1, 2.2 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.16 (m, 3H), 6.94 (d, J = 8.3 Hz, 1H), 6.87 (m, 2H), 6.84 (dd, J = 2.1 Hz, 1H), 6.80 (dd, J = 8.3, 2.1 Hz, 1H), 6.53 (d, J = 0.8 Hz, 1H), 4.41 (t, J = 7.5 Hz, 2H), 4.33 (m, 4H), 2.92 (t, J = 7.5 Hz, 2H); 13C {1H} NMR (101 MHz, CDCl3): δ 144.22, 144.17, 143.6, 141.8, 139.9, 137.6, 128.6, 127.3, 126.9, 124.9, 122.5, 118.4, 117.6, 117.5, 117.1, 109.7, 104.1, 64.5, 64.4, 45.9, 36.2 (1 aromatic carbon unresolved); MS (m/z): 400; Anal. Calcd for C24H20N2O4: C, 71.99; H, 5.03; N, 7.00; Found: C, 71.95; H, 4.98; N, 6.97.

4. Conclusions

A new transition metal-free approach to the synthesis of 1,2,5-trisubstituted 1H-indoles has been developed via deprotonation-SNAr cyclization of Schiff bases derived from 1-aryl-2-(2-fluoro-5-nitrophenyl)ethan-1-one (deoxybenzoin) precursors. This study was inspired by an earlier synthesis of benzo[d]oxazoles from suitably substituted N-(2-fluoroaryl)anilides which readily cyclized using an analogous strategy. However, due to the limited availability of deoxybenzoins bearing C2 fluoroaromatics with C5 SNAr activating groups, only the substrate having NO2 activation was fully explored. One attempt with a CF3-substituted acceptor ring was unsuccessful as the elevated temperature required for the ring closure resulted in significant degradation of the substrate. Seven NO2-activated deoxybenzoins were prepared using two variants of the Friedel-Crafts acylation. Once in hand, these precursors were converted to their Schiff bases by condensation with 5 equiv of a primary amine in boiling toluene slowly distilled at 120–125 °C for 18–24 h. Solvent replacement with dry DMF, addition of 2 equiv of anhydrous K2CO3, and further heating at 90–95 °C for 18–24 h then afforded the 1H-indole products in 32–86% yields following aqueous workup and chromatography. The reaction proceeded best with benzyl- and phenethylamines. High-boiling aliphatic primary amines also gave high yields of the desired heterocycles. A 10-fold excess of volatile amines was required but gave lower conversions due to inefficient reaction at lower temperatures and co-distillation with toluene during the condensation step. Anilines afforded excellent yields when rings were substituted with electron-donating groups and low yields (or no yields) when electron-withdrawing substituents were present. A 10-fold excess of aniline and 4-fluoroaniline and a cyclization temperature of 120–125 °C was required for successful 1H-indole formation and, due to resonance electron donation, 4-fluoroaniline proved to be an excellent nucleophile in this reaction. The conversion likely starts from the imine form of the Schiff base, but the conjugated enamine undoubtedly also participates in this process. Several predicted side reactions, e.g., competing nucleophilic aromatic substitutions and cyclization from the oxygen of an intermediate enolate did not cause major deviations from the desired reaction path. We are continuing our efforts to utilize the SNAr reaction as a terminating reaction in the synthesis of heterocyclic targets.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30193894/s1, Copies of 1H NMR and 13C NMR spectra for all substrates and 1H-indole products are provided. 19F NMR spectra are provided for compounds that incorporate fluorine.

Author Contributions

Project conception, project administration, data curation, formal analysis, and writing the manuscript text, R.A.B.; investigation, methodology, formal analysis and writing the experimental section, R.A.B. and N.E.N.; reviewing and editing, R.A.B. and N.E.N. All authors have read and agreed to the published version of the manuscript.

Funding

The authors are indebted to the OSU College of Arts and Sciences for funds to purchase several departmental instruments including an FT-IR and a 400 MHz NMR unit for the Oklahoma State-wide NMR facility. The NMR facility was initially established with support from the NSF (BIR-9512269), the Oklahoma State Regents for Higher Education, the W. M. Keck Foundation, and Conoco, Inc.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

N.E.N.: an undergraduate researcher, wishes to thank R.A.B. for support since the Summer of 2024.

Conflicts of Interest

The authors declare that this study received funding from Conoco, Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

References

  1. Annor-Gyamfi, J.K.; Ametsetor, E.; Meraz, K.; Bunce, R.A. Dihydroquinolines, dihydronaphthyridines and quinolones from by domino reactions of Morita-Baylis–Hillman acetates. Molecules 2021, 26, 890. [Google Scholar] [CrossRef]
  2. Ametsetor, E.; Farthing, S.; Bunce, R.A. Domino aza-Michael-SNAr-heteroaromatization route to C5-substituted N-alkyl-1H-indole-3-carboxylic esters. Molecules 2022, 27, 6998. [Google Scholar] [CrossRef]
  3. Magi, S.; Fobi, K.; Ametsetor, E.; Bunce, R.A. Domino synthesis of 1,2,5-trisubstituted 1H-indole-3-carboxylic esters using a [3+2] strategy. Molecules 2025, 30, 444. [Google Scholar] [CrossRef]
  4. Nevels, N.E.; Subera, L.; Bunce, R.A. Benzo[d]oxazoles from anilides by N-deprotonation–O-SNAr cyclization. Molecules 2024, 29, 4322. [Google Scholar] [CrossRef]
  5. Larock, R.C.; Yum, E.K. Synthesis of indoles via palladium-catalyzed heteroannulation of internal alkynes. J. Am. Chem. Soc. 1991, 113, 6689–6690. [Google Scholar] [CrossRef]
  6. Kaspar, L.T.; Ackermann, L. Three-component indole synthesis using ortho-dihaloarenes. Tetrahedron 2005, 61, 11311–11316. [Google Scholar] [CrossRef]
  7. Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T. InBr3-promoted divergent approach to polysubstituted indoles and quinolines from 2-ethynylanilines: Switch from an intramolecular cyclization to an intermolecular dimerization by a type of terminal substituent group. J. Org. Chem. 2008, 73, 4160–4165. [Google Scholar] [CrossRef] [PubMed]
  8. Gao, J.; Shao, Y.; Zhu, J.; Zhu, J.; Mao, H.; Wang, X.; Lv, X. One-pot approach to 1,2-disubstituted indoles via Cu(II)-catalyzed coupling/cyclization under aerobic conditions and its application for the synthesis of polycyclic indoles. J. Org. Chem. 2014, 79, 9000–9008. [Google Scholar] [CrossRef]
  9. Michalska, M.; Grela, K. Simple and mild synthesis of indoles via hydroamination reaction catalysed by NHC–gold complexes: Looking for optimized conditions. Synlett 2016, 27, 599–603. [Google Scholar] [CrossRef]
  10. Lal, S.; Snape, T.J. 2-Arylindoles: A privileged molecular scaffold with potent, broad-ranging pharmacological activity. Curr. Med. Chem. 2012, 19, 4828–4837. [Google Scholar] [CrossRef]
  11. Sravanthi, T.V.; Manju, S.I. Indoles—A promising scaffold for drug development. Eur. J. Pharm. Sci. 2016, 91, 1–10. [Google Scholar] [CrossRef] [PubMed]
  12. Chadha, N.; Silakari, O. Indoles as therapeutics of interest in medicinal chemistry: Bird’s eye view. Eur. J. Med. Chem. 2017, 134, 159–184. [Google Scholar] [CrossRef] [PubMed]
  13. Kumar, S.; Ritika. A brief review of the biological potential of indole derivatives. Fut. J. Pharm. Sci. 2020, 6, 121. [Google Scholar] [CrossRef]
  14. Shaker, A.M.M.; Abdelall, E.K.A.; Abdellatif, K.R.A.; Abdel-Rahman, H.M. Design, synthesis, and biological evaluation of 2-(4-(methylsulfonyl)phenyl)indole derivatives with promising COX-2 inhibitory activity. J. Appl. Pharm. Sci. 2018, 8, 001–008. [Google Scholar] [CrossRef]
  15. Kher, S.; Lake, K.; Sircar, I.; Pannala, M.; Bakir, F.; Zapf, J.; Xu, K.; Zhang, S.-H.; Liu, J.; Morera, L.; et al. 2-Aryl-N-acyl indole derivatives as liver X receptor (LXR) agonists. Bioorg. Med. Chem. Lett. 2007, 17, 4442–4446. [Google Scholar] [CrossRef]
  16. Fabian, C.J.; Nye, L.; Powers, K.R.; Nydegger, J.L.; Kreutzjans, A.L.; Phillips, T.A.; Metheny, T.; Winblad, O.; Zalles, C.M.; Hagan, C.R.; et al. Effect of Bazedoxifene and conjugated estrogen (Duavee) on breat cancer risk biomarkers in high-risk women: A pilot study. Cancer Prev. Res. 2019, 12, 711–720. [Google Scholar] [CrossRef]
  17. Tian, J.; Chen, X.; Fu, S.; Zhang, R.; Pan, L.; Cao, Y.; Wu, A.; Xiao, H.; Lin, H.-J.; Lo, H.-W.; et al. Bazedoxifene is a novel IL6/GP130 inhibitor for treating negative breast cancer. Breast Cancer Res. Treat. 2019, 175, 553–566. [Google Scholar] [CrossRef]
  18. Furniss, B.S.; Hannaford, A.J.; Smith, P.W.G.; Tatchell, A.R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; John Wiley and Sons: Hoboken, NJ, USA, 1989; pp. 1006–1017. [Google Scholar]
  19. Wilkinson, M.C. “Greener” Friedel-Crafts acylations: A metal- and halogen-free methodology. Org. Lett. 2011, 13, 2232–2235. [Google Scholar] [CrossRef]
  20. Brown, H.C.; McDaniel, D.H.; Häfliger, O. Determination of Organic Structures by Physical Methods; Braude, E.A., Nachod, F.C., Eds.; Academic Press: New York, NY, USA, 1955; Volume 1, pp. 567–662. [Google Scholar]
  21. Ault, A. The activating effect of fluorine in electrophilic aromatic substitution. J. Chem. Educ. 1966, 43, 329–330. [Google Scholar] [CrossRef]
  22. Rosenthal, J.; Schuster, D.I. The anomalous reactivity of fluorobenzene in electrophilic aromatic substitution and related phenomena. J. Chem. Educ. 2003, 80, 679–690. [Google Scholar] [CrossRef]
  23. Bordwell, F.G.; Harrelson Jr, J.A. Acidities and homolytic bond dissociation energies of the a-C–H bonds in ketones in DMSO. Can. J. Chem. 1990, 68, 1714–1718. [Google Scholar] [CrossRef]
  24. Lammertsma, K.; Prasad, B.V. Imine—Enamine tautomerism. J. Am. Chem. Soc. 1994, 116, 642–650. [Google Scholar] [CrossRef]
  25. Magoo, D.; Aggarwal, K.; Gupta, S.; Meena, K. Enamines and their variants as intermediates for the synthesis of aza-heterocycles with applications in MCRs. Tetrahedron 2022, 103, 132545. [Google Scholar] [CrossRef]
  26. Bunce, R.A.; Nago, T.; White, B. (±)-1,2-Dialkyl-5-nitro-2,3-dihydro-1H-indoles by a tandem reductive amination-SNAr reaction. J. Heterocycl. Chem. 2009, 46, 629–634. [Google Scholar] [CrossRef]
  27. Mclaughlin, M.; Palucki, M.; Davies, I.W. Efficient access to azaindoles and indoles. Org. Lett. 2006, 8, 3307–3310. [Google Scholar] [CrossRef]
  28. Ghobrial, M.; Mihovilovic, M.D.; Schnürch, M. Exploration of C–H and N–H bond functionalization towards 1-(1,2-diarylindol-3-yl)tetrahydroisoquinolines. Beilstein J. Org. Chem. 2014, 10, 2186–2199. [Google Scholar] [CrossRef]
  29. Delogu, G.L.; Kumar, A.; Gatto, G.; Bustelo, F.; Saavedra, L.M.; Rodríguez-Franco, M.I.; Laguna, R.; Viña, D. Synthesis and in vitro study of nitro- and methoxy-2-phenylbenzofurans as human monoamine oxidase inhibitors. Bioorg. Chem. 2021, 107, 104616. [Google Scholar] [CrossRef]
Molecules 30 03894 sch001
Scheme 1. Previous and current strategy for heterocycle closure by intramolecular SNAr reaction.
Scheme 1. Previous and current strategy for heterocycle closure by intramolecular SNAr reaction.
Molecules 30 03894 sch001
Molecules 30 03894 g001
Figure 1. Previous syntheses of 1,2,5-trisubstituted 1H-indoles.
Figure 1. Previous syntheses of 1,2,5-trisubstituted 1H-indoles.
Molecules 30 03894 g001
Molecules 30 03894 g002
Figure 2. Drug candidates incorporating 1H-indoles with 1,2- and 1,2,5-substitution patterns.
Figure 2. Drug candidates incorporating 1H-indoles with 1,2- and 1,2,5-substitution patterns.
Molecules 30 03894 g002
Molecules 30 03894 sch002
Scheme 2. Plausible mechanism for formation of 1H-indole 12 from deoxybenzoin 5 and benzylamine.
Scheme 2. Plausible mechanism for formation of 1H-indole 12 from deoxybenzoin 5 and benzylamine.
Molecules 30 03894 sch002
Table 1. Synthesis of deoxybenzoin 1H-indole precursors.
Table 1. Synthesis of deoxybenzoin 1H-indole precursors.
Molecules 30 03894 i001
ArMethodYield (%)
Phenyl (5)A82
4-Methylphenyl (6)A or B80 (A) 62 (B)
4-Methoxyphenyl (7)A78
4-Fluorophenyl (8)A78
1-(4-Fluoro-3-methylphenyl) (9)B65
1-(4-Chlorophenyl) (10)A64
1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl) (11)B85
Table 2. 1,2,5-Trisubstituted 1H-indoles prepared.
Table 2. 1,2,5-Trisubstituted 1H-indoles prepared.
Molecules 30 03894 i002
EntrySubstrateXYZProductYield (%)
15–H–H–CH2C6H51280
2 –CH2C6H4-3-OCH31383
3 –CH2C6H4-3-CF31467
4 –CH2CH2C6H4-2-F1569
5 –CH2CH2CH2O-i-Pr1677
6 –c-C6H111758
7 –C6H4-4-OCH31884
8 –C6H51942 a
9 –C6H4-4-F2082 b
10 –C6H4-4-CF3210
116–CH3–H–CH2C6H52278
12 –CH2C6H4-3-OCH32377
13 –CH2CH2C6H52462
147–OCH3–H–CH2C6H52586
15 –CH2C6H4-3-OCH32680
16 –CH2C6H4-2-Cl2777
17 –CH2C6H4-3-CF32881
18 –CH2CH2C6H52975
19 –CH2(CH2)4CH33036
208–F–H–CH2C6H53185
21 –CH2C6H4-3-CF33255
22 –CH2CH2C6H53379
23 –CH2CH(CH3)23432
249–F–CH3–CH2C6H53583
25 –CH2CH2C6H53680
26 –CH2CH2C6H4-2-F3775
2710–Cl–H–CH2C6H53877
28 –CH2C6H4-3-CF33962
29 –CH2CH2C6H54073
3011–OCH2CH2O––CH2C6H54185
31 –CH2C6H4-2-F4286
32 –CH2CH2C6H54386
a 10 equiv of aniline was used at a reaction temperature of 120–125 °C. When 5 equiv of aniline was used at a reaction temperature of 90–95 C, the yield was 23%. b 10 equiv of 4-fluoroaniline was used at a reaction temperature of 120–125 °C. When 5 equiv of 4-fluoroaniline was used at a reaction temperature of 90–95 °C, the yield was 9%.
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MDPI and ACS Style

Nevels, N.E.; Bunce, R.A. 1H-Indoles from Deoxybenzoin Schiff Bases by Deprotonation—SNAr Cyclization. Molecules 2025, 30, 3894. https://doi.org/10.3390/molecules30193894

AMA Style

Nevels NE, Bunce RA. 1H-Indoles from Deoxybenzoin Schiff Bases by Deprotonation—SNAr Cyclization. Molecules. 2025; 30(19):3894. https://doi.org/10.3390/molecules30193894

Chicago/Turabian Style

Nevels, Nash E., and Richard A. Bunce. 2025. "1H-Indoles from Deoxybenzoin Schiff Bases by Deprotonation—SNAr Cyclization" Molecules 30, no. 19: 3894. https://doi.org/10.3390/molecules30193894

APA Style

Nevels, N. E., & Bunce, R. A. (2025). 1H-Indoles from Deoxybenzoin Schiff Bases by Deprotonation—SNAr Cyclization. Molecules, 30(19), 3894. https://doi.org/10.3390/molecules30193894

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