Internal Lewis Acid Assisted Benzoic Acid Catalysis

Abstract

Internal Lewis acid assisted benzoic acid derivatives are introduced as new low-molecular-weight single-hydrogen-bond donor catalysts for the activation of nitroalkenes. Selected 2-borylbenzoic acid derivatives gave good yields of products in the addition of indoles to nitroalkenes. Control experiments suggest that both the internal Lewis acid coordination and the carboxylic acid functionalities are critical to the optimal performance of these catalysts.

Hydrogen-bond-donor (HBD) catalysis has emerged as a remarkable synthetic tool over the past decade.[ ¹ ] Many of the original and ongoing discoveries in this area are centered on the catalytic potential of small organic molecules that are able to operate through dual HBD interactions, such as ureas, thioureas, or guanidinium compounds 1 (Figure [1]).[ ² ] More recent developments have demonstrated the promise of single HBDs, such as phosphoric acids 2, as valuable catalysts for new reactions.[ ³ ] Although the power of both single and dual HBD catalysts in organic synthesis is undeniable, ongoing research efforts are dedicated toward overcoming challenges, such as limited reactivity patterns and high catalyst loadings, associated with these noncovalent organic catalysts. One strategy for addressing challenges in the area of HBD catalysis is that of identifying new families of HBDs that show enhanced activity and the ability to effect novel transformations. We describe our success with selected 2-borylbenzoic acids 3 as new internal Lewis acid assisted single HBD catalysts for the activation of nitroalkenes to nucleophilic attack.

Recent discoveries in our laboratory have demonstrated that the strategic incorporation of appropriate Lewis acids in urea catalyst scaffolds results in enhanced HBD catalytic activity, possibly because of increased acidity of the urea N–H protons.[4] [5] The studies focused on the ability of difluoroboryl ureas to operate as dual HBD catalysts with enhanced activities compared with those of conventional ureas in the activation of both nitroalkenes and nitrocyclopropanes for nucleophilic attack. Encouraged by the success of our boronate urea program, we hypothesized that it might be possible to activate benzoic acid derivatives by suitable placement of an appropriate Lewis acid to produce novel families of low-molecular-weight single HBD catalysts.[ ⁶ ] Specifically, we set out to test the hypothesis that 2-silyl- or 2-borylbenzoic acid derivatives might operate as internal Lewis acid assisted single HBD catalysts in the addition of indoles to nitroalkenes.

We began our study by screening 2-silylbenzoic acids 7a–d as potential catalysts for the addition of 1H-indole 5a to [(E)-2-nitrovinyl]benzene (4a) (Table [1]). Catalysts 7a–d were readily prepared in two steps from the corresponding aldehydes. First, the aldehyde was subjected to sequential ortho-lithiation and silylation by using the protocol developed by Comins and Brown.[ ⁷ ] The resulting silyl aldehyde was readily oxidized with potassium permanganate to give the required carboxylic acid.[ ⁸ ] Our initial attempt to catalyze the addition of 1H-indole (5a) to [(E)-2-nitrovinyl]benzene (4a) with catalyst 7a in dichloromethane was moderately successful, giving a 51% yield of product 6a after 24 hours at 23 °C (Table [1], entry 1). We hypothesized that the presence of an electron-withdrawing group in addition to the trimethylsilyl substituent might lead to an enhancement of the catalytic activity. However, the presence of a 4-fluoro substituent in the silylbenzoic acid 7b had little effect on the catalyst activity, affording 47% of indole 6a (entry 2) under identical reaction conditions. Further probing of the catalyst structure led us to conclude that the reactivity of the 2-silylbenzoic acid catalysts could, however, be significantly altered by the presence of substituents on the aromatic ring. The 4-trifluoromethyl-substituted catalyst 7c gave a good yield of indole 6a (61%, entry 3) and, as expected, catalyst 7d, derived from 4-methoxybenzaldehyde, showed a diminished catalyst reactivity, yielding only 42% of indole 6a (entry 4). The importance of the substituent effects was demonstrated by direct comparison of 2-silylbenzoic acids 7a–d with benzoic acid. All the substituted 2-silylbenzoic acid catalysts 7 gave higher yields of desired product than did the corresponding reaction with benzoic acid as the catalyst (25%, entry 9). The proposed hydrogen-bonding mode of action for the 2-silylbenzoic acid catalysts 7a–d is supported by the lack of reactivity observed by using the ester 10a as a control catalyst (entry 10).

Table 1 Screening of Potential Internal Lewis Acid Assisted Benzoic Acid Catalysts for Addition of 1H-Indole to [(E)-2-Nitrovinyl]benzene

Entrya	Catalystb		Yieldc (%)
1  2  3  4		7a: R = H  7b: R = F  7c: R = CF3  7d: R = OMe	51 47 61 42
5  6  7  8		8a: R = H  8b: R = F  8c: R = CF3  8d: R = OMe	70 53 51 40
9		9	25
10		10a: LA = TMS 10b: LA = Bpind	2  3
11		11	31

^a Reactions were performed by using 1.5 equiv of 1H-indole at a concentration of 2 M. See the supporting information for detailed experimental procedures.

^b In the absence of a catalyst, a 3% yield of product was isolated.

^c Isolated yield.

^d 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl.

Although we were pleased with the results obtained with catalyst 7c, we postulated that other Lewis acid groups might provide better catalyst activity through internal coordination of benzoic acids without reliance on the presence of additional electron-withdrawing substituents. It had been discovered previously in our laboratory that boronate ureas show superior catalytic performance to silicate ureas or conventional urea catalysts.[ ⁴ ] On the basis of these observations, we reasoned that the boron-activated benzoic acids 8a–d might show superior activity to the silicon-substituted benzoic acid catalysts 7a–d. The desired 2-borylbenzoic acid derivatives 8a–d were easily prepared by either a directed borylation approach or by a palladium-catalyzed borylation of methyl 2-bromobenzoate and subsequent saponification.[9] [10] Having prepared the necessary 2-borylbenzoic acids, we began testing them as catalysts for the addition of 1H-indole (5a) to [(E)-2-nitrovinyl]benzene (4a). We found that addition of 5a to 4a in the presence of 20 mol% of 8a in dichloromethane gave a 70% yield of 6a after 24 hours (Table [1], entry 5), a marked improvement over the best silicon-activated catalyst tested (7c). Next, we studied the effect of electron-donating or withdrawing substituents on the boron-activated benzoic acid scaffold. Interestingly, all the substituted catalysts 8b–d (entries 6–8, respectively) gave lower yields than did the unsubstituted catalyst 8a. Control experiments with the corresponding ester 10b as the catalyst provided some evidence regarding the mode of operation of the catalysts; no evidence was found of catalysis when 4a and 5a were treated with 20 mol% of methyl ester 10b under otherwise identical reaction conditions (entry 10). This suggests the carboxylic acid functionality is critical to the reactivity of the catalyst and we propose that it operates through hydrogen-bonding interactions. Catalysis of the reaction by boron can be ruled out, as the control catalysts 10b and 11 gave low yields of 6a (entries 10 and 11).

Encouraged by the promise shown by our newly designed single HBD catalysts, particularly 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (8a), we set out to explore some physical properties of the substituted benzoic acids in an effort to collect evidence for the importance of internal Lewis acid coordination in relation to the catalytic activity. Internal coordination of carbonyl functionalities and boron in five-membered rings similar to 8a has been observed before;[ ¹¹ ] however, to the best of our knowledge, this concept has not been applied in the enhancement of single HBD catalyst activity. First, we used infrared spectroscopy to probe the strength of the carbonyl bond. In the presence of internal Lewis acid coordination, the carbonyl bond should be weaker, leading to a shift in the peak to a lower frequency in the IR spectrum. A direct comparison of analogous catalysts 7a, 8a, and 9 showed carbonyl frequencies of 1690, 1679, and 1689 cm^–1, respectively (Figure [2]). These results show that 8a has a frequency that is about 10 cm^–1 lower than that of either of the catalysts 7a and 9, confirming that internal Lewis acid coordination may be important in the reactivity of 2-borylbenzoic acid catalysts but not in that of 2-silylbenzoic acid catalysts. Additional evidence for internal Lewis acid coordination in 2-borylbenzoic acid 8a was found in the ¹¹B NMR spectrum. The boron peak for this compound occurred at 10.1 ppm in perdeuteriodimethyl sulfoxide relative to the boron trifluoride etherate standard, a shift that would be expected for a tetracoordinate boron atom.[ ^11b ] The peak for a tricoordinate boron bonded to two oxygen atoms and one carbon would be expected to be closer to 30 ppm. Interestingly, only 8a showed the tetracoordinate upfield shift suggesting the presence of internal coordination to boron; compounds 8b–d showed shifts between 29 and 32 ppm, suggesting the presence of a tricoordinate boron. The reduced reactivity of control catalyst 11, a 3-borylbenzoic acid, provided further support for the operation of 8a as an internal Lewis acid assisted single HBD catalyst.

Having identified the optimal single HBD catalyst 8a, we examined the limits of its reaction with respect to the catalyst loading (Scheme [1]). The optimal reaction conditions were found to be 20 mol% of the HBD catalyst in dichloromethane for 48 hours. Reducing the catalyst loading to 10 mol% gave a yield of 74% of 6a under otherwise identical reaction conditions. As expected, further reductions in the catalyst loading gave smaller amounts of the desired adduct 6a.

Next, we directed our efforts toward surveying the scope of the reaction in terms of both the nitroalkene and the indole (Table [2]). The presence of electron-donating or electron-withdrawing substituents on the nitrostyrene was tolerated in the reaction, which gave rise to high yields of the corresponding product in each case. 1-Methoxy-4-[(E)-2-nitrovinyl]benzene gave a 79% yield of 6b after 48 hours in dichloromethane at room temperature (Table [2], entry 2). 4-Bromo-[(E)-2-nitrovinyl]benzene underwent nucleophilic attack by 1H-indole (5a) in the presence of catalyst 8a to give a high yield (72%) of product 6c (entry 3). 2-[(E)-2-Nitrovinyl]furan gave the corresponding product 6d in 85% yield (entry 4). We were pleased to observe that alkyl aldehyde derived nitroalkenes were also activated by the 2-borylbenzoic acid 8a. 1H-Indole (5a) underwent addition to [(E)-2-nitrovinyl]cyclohexane to give the product 6e in a good yield (64%; entry 5). The less sterically encumbered (1E)-1-nitrohex-1-ene was better tolerated in the process, yielding an 81% yield of product 6f (entry 6). Substituted indoles also operated well as the nucleophilic component in the conjugate addition reaction. 5-Methoxy-1H-indole gave an excellent yield (79%) of product 6g after 48 hours in the presence of 8a (entry 7). The less electron-rich 5-bromo-1H-indole showed a somewhat more sluggish reaction, giving a 69% yield of 6h after 48 hours (entry 8). Even methyl 1H-indole-4-carboxylate added to 4-[(E)-2-nitrovinyl]benzene under these conditions, albeit in modest yield (41%; entry 9).[ ¹² ] It was interesting to find that 1-methyl-1H-indole was a rather poor substrate for the reaction, yielding only a 14% yield of product 6j (entry 10).

Table 2 Examination of the Substrate Scope

Entrya	R1	5	R2	R3	Product	Yieldb (%)
1	Ph	5a	H	H	6a	83
2	4-MeOC6H4	5b	H	H	6b	79
3	4-BrC6H4	5c	H	H	6c	72
4	2-furyl	5d	H	H	6d	85
5	Cy	5e	H	H	6e	64
6	Bu	5f	H	H	6f	81
7	Ph	5g	5-MeO	H	6g	79
8	Ph	5h	5-Br	H	6h	69
9	Ph	5i	4-CO2Me	H	6i	41
10	Ph	5j	H	Me	6j	14

^a Reactions were performed by using 1.5 equiv of indole at a concentration of 2 M. See Supporting Information for detailed experimental procedures.

^b Isolated yield.

The proposed catalytic cycle begins with hydrogen bonding of the benzoic acid 8a to the nitro group of the nitroalkene 4 to form the activated nitroalkene I (Scheme [2]).[ ¹³ ] Next, hydrogen bonding of the indole to the benzoic acid catalyst generates II, an intermediate that is activated for nucleophilic attack. The bifunctional role of 8a in the catalytic cycle, as suggested in II, is supported by the lower activity of 1-methyl-1H-indole in the reaction (entry 9, Table [2]). The indole subsequently undergoes 1,4-addition to the nitroalkene followed by proton transfer to afford III. The catalyst 8a is then released back into the cycle with simultaneous formation of product 6.

In summary, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (8a) is introduced as a new low-molecular-weight single-hydrogen-bond-donor catalyst for the activation of nitroalkenes. The strategic placement of the boronate ester group in the position ortho to the carboxylic acid functionality enhances the catalytic activity of 8a, probably through internal Lewis acid coordination. Borylbenzoic acid 8a operates as a general catalyst in the addition of a variety of indoles to both aromatic and aliphatic nitroalkenes. Further exploration of internal Lewis acid assisted single HBD catalysts, including the design of asymmetric variants, is ongoing in our laboratory.

CH₂Cl₂, toluene, and DMF were purified by passage through a bed of activated alumina.[ ¹⁴ ] Reaction products were purified by flash chromatography using Aldrich 60 Å (40–63 µm). Analytical TLC was performed on EMD Chemicals 0.25-μm silica gel 60-F₂₅₄ plates with visualization by UV radiation or by KMnO₄ or ceric ammonium molybdate stains followed by heating. Melting points were measured on a Thermo Scientific Mel-Temp apparatus and are uncorrected. IR spectra were recorded for KBr pellets on a Perkin­Elmer Spectrum 100R spectrophotometer. ¹H NMR spectra were recorded in deuterated solvents on a Bruker Avance DPX 400 (400 MHz) spectrometer; chemical shifts are reported in ppm relative to the solvent as internal standard (CHCl₃: δ = 7.26; DMSO δ = 2.50). Splitting patterns that could not be interpreted or easily visualized were designated as multiplet (m) or broad (br). Proton-decoupled ¹³C NMR spectra were recorded on a Bruker Avance DPX 400 (100 MHz) spectrometer and are reported in ppm relative to the solvent as internal standard (CHCl₃: δ = 77.0; DMSO: δ = 39.5). Proton-decoupled ¹⁹F NMR spectra were recorded on a Bruker Avance DPX 400 spectrometer and are reported in ppm using C₆H₅CF₃ as an external standard (δ = –63.72). ¹¹B NMR spectra were recorded on a Bruker Avance DPX 500 spectrometer and are reported in ppm relative to BF₃·OEt₂ as an external standard (δ = 0.00). ESI MS were recorded on a Bruker MicrOTOF mass spectrometer. GC analysis data were obtained on Agilent 6850 Series GC System with a 7673 Series Injector and an HP-1 30-m capillary column (19091Z-413E). 2-(Dihydroxyboryl)benzoic acid and methyl 2-(dihydroxyboryl)benzoate were purchased from Boron Molecular and used without further purification. 2-Amino-4-(trifluoromethyl)benzoic acid was purchased from TCI America and used without further purification. Unless otherwise noted, all other commercially available reagents and solvents were purchased from Sigma-Aldrich and used without further purification.

2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic Acid (8a)

A 100-mL flame-dried flask equipped with a Dean–Stark trap and a reflux condenser was charged with 2-(dihydroxyboryl)benzoic acid (2.00 g, 12.0 mmol) and pinacol (1.43 g, 12.1 mmol). Toluene (25 mL) was added and the heterogeneous mixture was refluxed with vigorous stirring for 24 h. The mixture was then allowed to cool to r.t. and the solvent was removed in vacuo. Excess pinacol was removed by trituration of the resulting white solid in Et₂O to give a white powder; yield: 2.89 g (97%); mp 331.2–333.6 °C

IR (KBr): 2975, 1679, 1451, 1152, 1088 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.38 (d, J = 7.2 Hz, 1 H), 7.33–7.24 (m, 2 H), 7.13 (m, 1 H), 1.09 (s, 12 H).

¹³C NMR (100 MHz, DMSO-d ₆: δ = 173.1, 138.1, 130.1, 128.7, 125.7, 122.2, 77.6, 25.5; the carbon bonded to the boron atom was not seen as a result of broadening.[ ¹⁵ ]

¹¹B NMR (160 MHz, DMSO-d ₆): δ = 10.4 (br s).

HRMS (ESI): m/z [M – H]^– calcd for C₁₃H₁₆BO₄: 247.1147; found: 247.1147.

Methyl 2-Bromo-4-fluorobenzoate

As previously reported,[ ¹⁶ ] 2-bromo-4-fluorobenzoic acid (1.00 g, 4.6 mmol) was dissolved in MeOH (6 mL), concd aq HCl (50 µL) was added, and the mixture was heated to 65 °C for 24 h then cooled to r.t. The resulting mixture was extracted with CH₂Cl₂ (3 × 50 mL) and the extracts were washed successively with aq NaHCO₃ and brine, dried (Na₂SO₄), and concentrated to give a clear oil; yield: 850 mg (80%).

¹H NMR (400 MHz, CDCl₃): δ = 7.88 (dd, J = 8.8, 6.0 Hz, 1 H), 7.40 (dd, J = 8.0, 2.4 Hz, 1 H), 7.07 (ddd, J = 10.4, 7.6, 2.4 Hz, 1 H), 3.92 (s, 3 H).

Methyl 4-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The borylation procedure was adapted from one used for a similar compound.[ ¹⁷ ] An oven-dried 50-mL Schlenk flask in a glove box was charged with methyl 2-bromo-4-fluorobenzoate (500 mg, 2.15 mmol), bis(pinacolato)diboron (589 mg, 2.36 mmol, 1.1 equiv), PdCl₂(dppf)·CH₂Cl₂ (89 mg, 0.108 mmol, 5 mol%), and KOAc (645 mg 6.45 mmol, 3.0 equiv). The flask was sealed with a septum, removed from the glove box, and purged with N₂ (3×). 1,4-Dioxane (11.2 mL) was added and the mixture was heated to 80 °C for 24 h under N₂. The cooled mixture was filtered through Celite, which was subsequently washed with EtOAc (100 mL). The organic phase was then washed successively with H₂O (2 × 100 mL) and brine, dried (MgSO₄), and concentrated. The crude product was purified by column chromatography (silica gel, 10% EtOAc–hexanes) to give a clear oil; yield: 546 mg (91%).

¹H NMR (400 MHz, CDCl₃): δ = 7.96 (dd, J = 8.4, 5.2 Hz, 1 H), 7.14 (dd, J = 8.8, 2.8 Hz, 1 H), 7.07 (dt, J = 8.4, 2.4 Hz, 1 H), 3.90 (s, 3 H), 1.42 (s, 12 H).

4-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic Acid (8b)

Methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (100 mg, 0.376 mmol) was dissolved in THF (2.0 mL) in an 8-mL vial under argon. A 2 M aq soln of LiOH (0.50 mL, 1 mmol) was added at 23 °C and the mixture was stirred at 23 °C for ~1 h. When the reaction reached completion (TLC), the mixture was diluted with H₂O, acidified, and extracted with EtOAc (3 × 50 mL). The organic layer was then washed with brine, dried (MgSO₄), and concentrated to give a white solid; yield: 74 mg (77%); mp 136.2–137.9 °C.

IR (KBr): 2980, 1675 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.13–8.00 (m, 1 H), 7.17 (d, J = 7.2 Hz, 1 H), 7.15–7.05 (m, 1 H), 1.39 (s, 12 H).

¹³C NMR (100 MHz, CDCl₃: δ = 168.9, 164.5 (d, J = 250 Hz), 131.2, 129.8, 117.2 (d, J = 20 Hz), 115.3 (d, J = 22 Hz), 82.43, 24.6; the carbon bonded to the boron atom was not seen as a result of broadening.[ ¹⁵ ]

¹⁹F NMR (376 MHz, CDCl₃): δ = –105.7.

¹¹B NMR (160 MHz, CDCl₃): δ = 30.1 (br s).

HRMS (ESI): m/z [M – H]^– calcd for C₁₃H₁₅BFO₄: 265.1047; found: 265.1045.

2-Bromo-4-(trifluoromethyl)benzoic Acid

A modified version of a previously published procedure was used.[ ¹⁸ ] 2-Amino-4-(trifluoromethyl)benzoic acid (2.05 g, 10.0 mmol, 1 equiv) was dissolved in a mixture of AcOH (6 mL), 48% aq HBr (4 mL), and H₂O (4 mL), and the mixture was cooled to –10 °C. A soln of NaNO₂ (690 mg, 10.0 mmol, 1 equiv) in H₂O (2 mL) was added dropwise over 5 min. The temperature was then raised to 0 °C and the mixture was stirred at 0 °C for 3 h. The resulting slurry was added dropwise over 20 min from a syringe to a soln of CuBr (1.435 g, 10.0 mmol, 1 equiv) in 48% aq HBr (5 mL) at 60 °C. The resulting mixture was then heated for 1 h at 60 °C, allowed to cool to 23 °C, and poured into ice-cold H₂O (200 mL). The precipitate was collected in vacuo and washed with H₂O (100 mL). The solid was stirred in boiling CH₂Cl₂ for 5 min and then removed by vacuum filtration. The filtrate was concentrated to give as a tan solid; yield: 1.884 g (70%).

¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.0 Hz, 1 H), 7.98 (s, 1 H), 7.68 (d, J = 8.0 Hz, 1 H).

Methyl 2-Bromo-4-(trifluoromethyl)benzoate

Methylation was accomplished by a previously reported procedure.[ ¹⁹ ] 2-Bromo-4-(trifluoromethyl)benzoic acid (422 mg, 1.57 mmol) was dissolved in DMF (4.2 mL) under argon. K₂CO₃ (240 mg, 1.73 mmol, 1.1 equiv) and MeI (120 µL, 1.88 mmol, 1.2 equiv) were added, and the mixture was stirred at 23 °C for 24 h. The resulting mixture was poured into H₂O (100 mL) and the H₂O was extracted with EtOAc (3 × 40 mL). The organic layers were combined, washed successively with aq NaHCO₃, H₂O, and brine then dried (Na₂SO₄) and concentrated to give an orange oil; yield: 427 mg (96%).

¹H NMR (400 MHz, CDCl₃): δ = 7.92 (s, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 3.97 (s, 3 H).

Methyl 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoate

The borylation procedure was adapted from one used for a similar compound.[ ¹⁷ ] An oven-dried 25-mL Schlenk flask in a glove box was charged with methyl 2-bromo-4-(trifluoromethyl)benzoate (300 mg, 1.06 mmol), bis(pinacolato)diboron (290 mg, 1.16 mmol, 1.1 equiv), PdCl₂(dppf)·CH₂Cl₂ (44 mg, 0.053 mmol, 5 mol%), and KOAc (318 mg, 3.18 mmol, 3.0 equiv). The flask was sealed with a septum, removed from the glove box, and purged with N₂ (3×). 1,4-Dioxane (5.6 mL) was added and the mixture was heated to 80 °C for 24 h under N₂ then cooled to r.t. The mixture was then filtered through Celite, which was subsequently washed with EtOAc (100 mL). The filtrate was washed successively with H₂O (2 × 100 mL) and brine then dried (MgSO₄) and concentrated. The crude product was purified by column chromatography (silica gel, 10% EtOAc–hexanes) to give a light-yellow oil; yield: 317 mg (91%).

¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 8.4 Hz, 1 H), 7.74 (s, 1 H), 7.70–7.65 (m, 1 H), 3.95 (s, 3 H), 1.43 (s, 12 H).

2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoic Acid (8c)

Methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)4-(trifluoromethyl)benzoate (100 mg, 0.303 mmol) was dissolved in THF (2 mL) under argon in an 8-mL vial. A 2 M aq soln of LiOH ( 0.50 mL, 1 mmol) was added at 23 °C and the mixture was stirred at 23 °C for ~1 h. When the reaction was complete (TLC), the mixture was diluted with H₂O, acidified, and extracted with EtOAc (3 × 50 mL). The organic extracts were combined, washed with brine, dried (MgSO₄), and concentrated to give a white solid; yield: 85 mg (85%), mp 133.3–136.4 °C.

IR (KBr): 2990, 1696, 1500, 1360, 1309, 1137, 1076 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 11.45 (br s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.77 (s, 1 H), 7.19 (d, J = 8.0 Hz, 1 H), 1.42 (s, 12 H).

¹³C NMR (100 MHz, CDCl₃: δ = 172.3, 135.8, 134.4 (q, J = 33 Hz), 130.1, 129.4 (m), 126.3 (q, J = 3 Hz), 123.8 (q, J = 271 Hz), 84.8, 24.9; the carbon bonded to the boron atom was not seen as a result of broadening.[ ¹⁵ ]

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.20.

¹¹B NMR (160 MHz, CDCl₃): δ = 30.8 (br s).

HRMS (ESI): m/z [M – H]^– calcd for C₁₄H₁₅BF₃O₄: 315.1015; found: 315.1013.

(2-Formyl-4-methoxyphenyl)boronic Acid

The o-borylation procedure was adapted from one used for a similar compound.[ ⁹ ] MeNH(CH₂)NMe₂ (0.82 mL, 6.4 mmol) was dissolved in dry THF (16 mL) under argon and the mixture was cooled to –20 °C. A 1.3 M soln of BuLi in hexanes (4.8 mL, 6.2 mmol) was added dropwise at –20 °C and the mixture was stirred at –20 °C for 15 min. Freshly distilled 4-methoxybenzaldehyde (0.73 mL, 6.0 mmol) was then added at –20 °C and the mixture was stirred at –20 °C for an additional 15 min. An additional portion of the 1.3 M BuLi soln (3.9 mL, 18 mmol) was added at –20 °C and the mixture was stirred at –20 °C for 24 h. The soln was then cooled to –78 °C and a soln of (i-PrO)₃B (8.3 mL, 36 mmol, 6.0 equiv) in toluene (10 mL) was added. The mixture was stirred at –78 °C for 1 h, allowed to warm to 23 °C, and stirred for an additional 2 h. The resulting slurry was then poured into 1 M aq HCl (50 mL) and stirred at 23 °C for 30 min. The layers were separated and the aqueous layer was extracted with Et₂O (3 × 75 mL). The organic layers were combined, washed with brine, dried (MgSO₄), and concentrated to give a yellow oil that was purified by chromatography (silica gel, 5% MeOH–CH₂Cl₂) followed by crystallization by precipitation from hot EtOAc with cold hexanes to give a white solid; yield: 549 mg (47%).

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.97 (s, 1 H), 8.23 (br s, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.10–7.04 (m, 2 H), 3.85 (s, 3 H).

2-(Dihydroxyboryl)-5-methoxybenzoic Acid

The oxidation procedure was adapted from one reported in the literature.[ ²⁰ ] (2-Formyl-4-methoxyphenyl)boronic acid (400 mg, 2.22 mmol) was dissolved in 2.5 M aq NaOH (3.6 mL) and treated with a soln of KMnO₄ (350 mg, 2.22 mmol) in H₂O (13 mL) at 23 °C for 4 h. The mixture was then filtered through Celite. The filtrate was acidified, extracted with EtOAc (3 × 80 mL), dried (Na₂SO₄), and concentrated to give a light-yellow foam; yield: 195 mg (45%).

¹H NMR (400 MHz, CD₃OD): δ = 7.90 (d, J = 8.8 Hz, 1 H), 6.99–6.90 (m, 2 H), 3.86 (s, 3 H).

5-Methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic Acid (8d)

A flame-dried round-bottomed flask equipped with Dean–Stark trap and a reflux condenser was charged with 2-(dihydroxyboryl)-5-­methoxybenzoic acid (110 mg, 0.561 mmol) and pinacol (70 mg, 0.589 mmol). Toluene (6 mL) was added and the mixture was stirred at the reflux for 20 h. The mixture was then allowed to cool to 23 °C and the toluene was removed in vacuo to give a yellow solid that was stirred for 30 min with Et₂O (5 mL) and then filtered. The filtrate was concentrated to give a white solid; yield: 141 mg (90%); mp 170.2–172.5 °C.

IR (KBr): 2981, 1675, 1604, 1560, 1411, 1228, 1145 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.79 (d, 8.6 Hz, 1 H), 6.98 (dd, J = 8.6, 2.4 Hz, 1 H), 8.66 (d, J = 2.4 Hz, 1 H), 3.82 (s, 3 H), 1.29 (s, 12 H).

¹³C NMR (100 MHz, DMSO-d ₆: δ = 168.7, 161.9, 130.2, 126.2, 116.4, 113.8, 83.0, 55.3, 24.6; the carbon bonded to the boron atom was not seen as a result of broadening.[ ¹⁵ ]

¹¹B NMR (160 MHz, DMSO-d ₆): δ = 29.6 (br s).

HRMS (ESI): m/z [M – H]^– calcd for C₁₄H₁₈BO₅: 277.1247; found: 277.1246.

Methyl 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (10b)

A flame-dried, 25-mL, round-bottomed flask equipped with a Dean–Stark trap and a reflux condenser was charged with [2-(methoxycarbonyl)phenyl]boronic acid (500 mg, 2.78 mmol), pinacol (328 mg, 2.78 mmol), and toluene (5 mL). The mixture was refluxed for 24 h under N₂, cooled to 23 °C, and concentrated. The crude product was purified by column chromatography (silica gel, 15% EtOAc–hexanes) give a colorless oil; yield: 648 mg (89%).

¹H NMR (400 MHz, CDCl₃): δ = 7.97–7.91 (m, 1 H), 7.53–7.46 (m, 2 H), 7.45–7.37 (m, 1 H), 3.91 (s, 3 H), 1.419 (s, 12 H).

Methyl 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The borylation procedure was adapted from one used for a similar compound.[ ¹⁷ ] An oven-dried 10-mL Schlenk flask in a glove box was charged with methyl 3-bromobenzoate (100.0 mg, 0.465 mmol), bis(pinacolato)diboron (127 mg, 0.508 mmol, 1.1 equiv), PdCl₂(dppf)·CH₂Cl₂ (20 mg, 0.024 mmol, 5 mol%), and KOAc (140 mg, 1.40 mmol, 3.0 equiv). The flask was sealed with a septum, removed from the glove box, and purged with N₂ (3×). 1,4-Dioxane (2.4 mL) was added and the mixture was heated at 80 °C for 24 h under N₂ The mixture was then cooled to r.t. and filtered through Celite, which was washed with EtOAc (100 mL). The filtrate was washed successively with H₂O (2 × 100 mL) and brine, dried (MgSO₄), and concentrated. The crude product was purified by column chromatography (silica gel, 10% EtOAc–hexanes) to give a light-yellow oil; yield: 114 mg, (93%).

¹H NMR (400 MHz, CDCl₃): δ = 8.47 (s, 1 H), 8.12 (d, J = 12.4 Hz, 1 H), 7.98 (d, J = 12.0 Hz, 1 H), 7.45 (t, 12.0 Hz, 1 H), 3.92 (s, 3 H), 1.36 (s, 12 H).

3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic Acid (11)

Methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (114 mg, 0.435 mmol) was dissolved in THF (2 mL) under argon in an 8-mL vial. A 2 M aq soln of LiOH (0.50 mL, 1 mmol) was added at 23 °C and the mixture was stirred at 23 °C for 18 h. When the reaction reached completion (TLC), the mixture was diluted with H₂O, acidified, and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine, dried (MgSO₄), and concentrated to give a white solid; yield: 79 mg (73%).

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.94 (br s, 1 H), 8.26 (s, 1 H), 8.05 (d, J = 7.6 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 1.31 (s, 12 H).

¹¹B NMR (160 MHz, DMSO-d ₆): δ = 29.8 (br s).

2-Silylbenzoic Acids 7a–d: General Procedure

The ortho-lithiation procedure developed by Comins and Brown was adopted.[ ⁷ ] MeNH(CH₂)NMe₂ (0.82 mL, 6.4 mmol) was dissolved in dry THF (16 mL) under argon and the mixture was cooled to –20 °C. A 1.3 M soln of BuLi in hexanes (4.8 mL, 6.2 mmol) was added dropwise at –20 °C and the mixture was stirred at –20 °C for 15 min. Freshly distilled aldehyde (6.0 mmol) was then added at –20 °C and the mixture was stirred at –20 °C for an additional 15 min. An additional portion of the 1.3 M BuLi soln (3.9 mL, 18 mmol) was added at –20 °C and the mixture was stirred at –20 °C for 24 h. The mixture was then cooled to –40 °C and freshly distilled TMSCl (4.57 mL, 36 mmol) was added dropwise. The mixture was stirred at –40 °C for 30 min and then at 23 °C for 30 min, after which the reaction was quenched by pouring the mixture into 1 M aq HCl (50 mL). The mixture was extracted with Et₂O, washed with brine, and dried (MgSO₄). The yellow residue was purified by column chromatography (0–5% EtOAc in hexanes) to give the corresponding 2-(trimethylsilyl)benzaldehyde as a colorless oil, which was oxidized by means of the procedure developed by Schultz et al.[ ⁸ ]

The (2-trimethylsilyl)benzaldehyde (2.6 mmol) was added to a 50-mL flask and dissolved in mixture of acetone (7.2 mL) and H₂O (1.2 mL). The soln was cooled to 0 °C and KMnO₄ (0.50 g, 3.2 mmol) was added slowly with rapid stirring. After 5 min, the mixture was allowed to warm to 23 °C and stirred at 23 °C. When the reaction was complete (TLC, ~1.5 h), the acetone was removed in vacuo and the residue was dissolved in concd aq Na₂SO₃ and filtered through Celite, which was washed with CH₂Cl₂ (100 mL) and H₂O (50 mL). The filtrate was acidified to a pH of ~2.5 then extracted with CH₂Cl₂ (3 × 50 mL). The extracts were dried (Na₂SO₄) and concentrated to give the pure (2-trimethylsilyl)benzoic acid.

2-(Trimethylsilyl)benzoic Acid (7a)

White solid; yield: 74% (two steps); mp 93.0–94.5 °C

IR (KBr): 2948, 1690, 1588, 1471, 1409, 1110 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 12.53 (br s, 1 H), 8.19 (d, J = 7.6 Hz, 1 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.58 (dt, J = 7.6, 1.6 Hz, 1 H), 7.48 (dt, J = 7.6, 1.6 Hz, 1 H), 0.37 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.9, 144.0, 135.8, 134.3, 132.6, 131.1, 129.1, 0.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₄NaO₂Si: 217.0655; found: 217.0644.

4-Fluoro-2-(trimethylsilyl)benzoic Acid (7b)

White solid; yield: 49% (two steps); mp 109.8–111.7 °C.

IR (KBr): 2954, 1698, 1576, 1423, 1312, 1252, 1212, 1130 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 12.37 (br s, 1 H), 8.22 (dd, J = 8.4, 5.2 Hz, 1 H), 7.40 (dd, J = 9.2, 2.8 Hz, 1 H), 7.12 (m, 1 H), 0.36 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃: δ = 172.6, 165.6 (d, J = 255 Hz), 148.68 (d, J = 5 Hz), 134.0 (d, J = 9 Hz), 130.1 (d, J = 3 Hz), 122.8 (d, J = 20 Hz), 115.8 (d, J = 22 Hz), 0.3.

¹⁹F NMR (376 MHz, CDCl₃): δ = –105.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₃FNaO₂Si: 235.0561; found: 235.0553.

4-(Trifluoromethyl)-2-(trimethylsilyl)benzoic Acid (7c)

White solid; yield: 86% (two steps); mp 129.5–130.8 °C.

IR (KBr): 2955, 1705, 1482, 1411, 1321, 1264, 1136, 1077 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 11.28 (br s, 1 H), 8.27 (d, J = 8.2 Hz, 1 H), 7.96 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 0.40 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃: δ = 172.7, 145.5, 137.5, 133.9 (q, J = 32 Hz), 132.3, 131.29, 126.0, 124.0 (q, J = 270 Hz), 0.3.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₃F₃NaO₂Si: 285.0529; found: 285.0527.

4-Methoxy-2-(trimethylsilyl)benzoic Acid (7d)

White solid; yield: 86% (two steps); mp 136.8–138.0 °C.

IR (KBr): 2951, 1682, 1585, 1417, 1318, 1240, 1138 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 12.60 (br s, 1 H), 8.20 (d, J = 8.8 Hz, 1 H), 7.24 (d, J = 2.8 Hz, 1 H), 6.93 (dd, J = 8.8, 2.8 Hz, 1 H), 3.89 (s, 3 H), 0.36 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.2, 162.9, 146.8, 133.8, 126.4, 122.4, 112.9, 55.5, 0.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₆NaO₃Si: 247.0761; found: 247.0754.

Methyl 2-(Trimethylsilyl)benzoate 10a

The esterification was performed according to a previously described procedure.[ ⁸ ] A flame-dried, 10-mL, round-bottomed flask equipped with a reflux condenser was charged with (2-trimethylsilyl)benzoic acid (75 mg, 0.39 mmol), K₂CO₃ (133 mg, 0.958 mmol, 2.5 equiv), acetone (3.5 mL), and MeOSO₂OMe (90 µL, 0.96 mmol, 2.5 equiv), and the mixture was heated at 56 °C for 24 h. The mixture was then cooled to 23 °C and the reaction was quenched by addition of H₂O (1 mL). The resulting mixture was stirred at 23 °C for 1 h then extracted with EtOAc (3 × 20 mL). The extracts were washed successively with aq NaHCO₃ and brine, dried (Na₂SO₄), and concentrated in vacuo to give a colorless oil; yield; 72 mg (90%).

¹H NMR (400 MHz, CDCl₃): δ = 8.00 (dd, J = 7.6, 1.6 Hz, 1 H), 7.69 (dd, J = 7.2, 1.6 Hz, 1 H), 7.50 (dt, J = 7.2, 1.6 Hz, 1 H), 7.42 (dt, J = 7.6, 1.6 Hz, 1 H), 3.91 (s, 3 H), 0.326 (s, 9 H).

Substituted Indoles 6a–j; General Procedure

A dry 4-mL vial equipped with a magnetic stirrer bar was charged with the appropriate catalyst (0.075 mmol, 20 mol%) and nitroalkene (0.376 mmol). CH₂Cl₂ (90 µL), the indole, (0.564 mmol, 1.5 equiv), and a second portion of CH₂Cl₂ (100 µL) were added sequentially. The vial was then sealed and the mixture was stirred under ambient conditions for the appropriate time. Finally, the mixture was immediately purified by flash column chromatography (silica gel).

3-(2-Nitro-1-phenylethyl)-1H-indole (6a)

Purified by column chromatography (5–20% EtOAc–hexanes) to give a light-yellow solid: 83.2 mg (83%).

¹H NMR (400 MHz, CDCl₃): δ = 8.07 (br s, 1 H), 7.45 (app d, J = 7.6 Hz, 1 H), 7.38–7.29 (m, 5 H), 7.29–7.24 (m, 1 H), 7.20 (app t, J = 8.0 Hz, 1 H), 7.09 (app t, J = 6.8 Hz, 1 H), 7.03 (app d, J = 2.0 Hz, 1 H), 5.20 (app t, J = 8.0 Hz, 1 H), 5.07 (dd, J = 12.4, 7.6 Hz, 1 H), 4.95 (dd, J = 12.4, 8.4 Hz, 1 H).

All spectral data matched those that were previously reported.[ ²¹ ]

3-[1-(4-Methoxyphenyl)-2-nitroethyl]-1H-indole (6b)

Purified by column chromatography (5–25% EtOAc–hexanes) to give a white crystalline solid; yield: 86.3 mg (79%).

¹H NMR (400 MHz, CDCl₃): δ = 8.07 (br s, 1 H), 7.43 (app d, J = 8.0 Hz, 1 H), 7.36 (app d, J = 8.0 Hz, 1 H), 7.28–7.23 (m, 2 H), 7.23–7.18 (app t, J = 8.0, 0.8 Hz, 1 H), 7.08 (app td, J = 8.0, 0.8 Hz, 1 H), 7.02 (app d, J = 2.0 Hz, 1 H), 6.88–6.83 (m, 2 H), 5.14 (app t, J = 8.8 Hz, 1 H), 5.05 (dd, J = 12.4, 8.4 Hz, 1 H), 4.90 (dd, J = 12.4, 8.4 Hz, 1 H), 3.78 (s, 3 H).

All spectral data matched those that were previously reported.[ ²¹ ]

3-[1-(4-Bromophenyl)-2-nitroethyl]-1H-indole (6c)

Purified by column chromatography (5–25% EtOAc–hexanes) to give a light-yellow solid; yield: 92.1 mg (72%).

¹H NMR (400 MHz, CDCl₃): δ = 8.11 (br s, 1 H), 7.45 (app d, J = 8.4, 2.4 Hz, 2 H), 7.42–7.35 (m, 2 H), 7.24–7.18 (m, 3 H), 7.09 (app td, J = 7.0, 1.2 Hz, 1 H), 7.04–7.01 (m, 1 H), 5.16 (app t, J = 7.6 Hz, 1 H), 5.05 (dd, J = 12.4, 7.4 Hz, 1 H), 4.91 (dd, J = 12.4, 8.8 Hz, 1 H).

All spectral data matched those that were previously reported.[ ²¹ ]

3-[1-(2-Furyl)-2-nitroethyl]-1H-indole (6d)

Purified by column chromatography (5–20% EtOAc–hexanes) to give a light-yellow solid; yield: 81.5 mg (85%).

¹H NMR (400 MHz, CDCl₃): δ = 8.12 (br s, 1 H), 7.56 (app d, J = 8.0 Hz, 1 H), 7.41–7.36 (m, 2 H), 7.23 (app dt, J = 7.2, 1.2 Hz, 1 H), 7.17–7.12 (m, 2 H), 6.31 (dd, J = 3.2, 1.6 Hz, 1 H), 6.17 (app d, J = 3.2 Hz, 1 H), 5.26 (app t, J = 8.0 Hz, 1 H), 5.06 (dd, J = 12.4, 8.0 Hz, 1 H), 4.92 (dd, J = 12.4, 7.2 Hz, 1 H).

All spectral data matched those that were previously reported.[ ²² ]

3-(1-Cyclohexyl-2-nitroethyl)-1H-indole (6e)

Purified by column chromatography (5–15% EtOAc–hexanes) to give a light-yellow solid; yield: 65.4 mg (64%).

¹H NMR (400 MHz, CDCl₃): δ = 8.05 (br s, 1 H), 7.60 (m, 1 H), 7.36 (m, 1 H), 7.21 (m, 1 H), 7.13 (m, 1 H), 7.00 (s, 1 H), 4.86–4.78 (m, 1 H), 4.78–4.68 (m, 1 H), 3.72–3.65 (m, 1 H), 1.89–1.65 (m, 6 H), 1.30–0.95 (m, 5 H).

All spectral data matched those that were previously reported.[ ²³ ]

3-[1-(Nitromethyl)pentyl]-1H-indole (6f)

Purified by column chromatography (5–15% EtOAc–hexanes) to give a light-yellow solid; yield: 75.6 mg (81%).

¹H NMR (400 MHz, CDCl₃): δ = 8.08 (br s, 1 H), 7.65 (m, 1 H), 7.40 (m, 1 H), 7.24 (m, 1 H), 7.17 (m, 1 H), 7.07 (m, 1 H), 4.75–4.61 (m, 2 H), 3.87–3.77 (m, 1 H), 1.96–1.75 (m, 2 H), 1.40–1.22 (m, 4 H), 0.86 (t, J = 7.0 Hz, 3 H).

All spectral data matched those that were previously reported.[ ²⁴ ]

5-Methoxy-3-(2-nitro-1-phenylethyl)-1H-indole (6g)

Purified by column chromatography (5–20% EtOAc–hexanes) to give a light-yellow solid; yield: 86.2 mg (79%).

¹H NMR (400 MHz, CDCl₃): δ = 7.98 (br s, 1 H), 7.37–7.24 (m, 6 H), 7.01 (app d, J = 2.4 Hz, 1 H), 6.88 (app d, J = 2.4 Hz, 1 H), 6.86 (br s, 1 H), 5.16 (app t, J = 8.0 Hz, 1 H), 5.06 (dd, J = 12.4, 7.6 Hz, 1 H), 4.95 (dd, J = 12.4, 8.4 Hz, 1 H), 3.79 (s, 3 H).

All spectral data matched those that were previously reported.[ ²¹ ]

5-Bromo-3-(2-nitro-1-phenylethyl)-1H-indole (6h)

Purified by column chromatography (5–30% EtOAc–hexanes) to give a light-yellow solid; yield: 89.5 mg (69%).

¹H NMR (400 MHz, CDCl₃): δ = 8.14 (br s, 1 H), 7.55 (app d, J = 2.0 Hz, 1 H), 7.37–7.24 (m, 7 H), 7.08 (app d, J = 2.4 Hz, 1 H), 5.13 (app t, J = 8.0 Hz, 1 H), 5.03 (dd, J = 12.4, 8.0 Hz, 1 H), 4.92 (dd, J = 12.4, 8.0 Hz, 1 H).

All spectral data matched those that were previously reported.[ ²⁵ ]

Methyl 3-(2-nitro-1-phenylethyl)-1H-indole-4-carboxylate (6i)

Purified by column chromatography (5–35% EtOAc–hexanes) to give a white foam; yield: 51.2 mg (42%).

¹H NMR (400 MHz, CDCl₃): δ = 8.35 (br s, 1 H), 7.60 (app dd, J = 7.2, 0.8 Hz, 1 H), 7.52 (app dd, J = 8.0, 0.8 Hz, 1 H), 7.31–7.19 (m, 6 H), 7.08 (app dd, J = 2.8 Hz, 0.8 Hz, 1 H), 5.83 (app t, J = 8.0 Hz, 1 H), 5.06 (dd, J = 13.2, 7.4 Hz, 1 H), 4.86 (dd, J = 13.2, 8.4 Hz, 1 H), 3.85 (s, 3 H).

All spectral data matched those that were previously reported.[ ¹² ]

1-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole (6j)

Purified by column chromatography (5–15% EtOAc–hexanes) to give a light-yellow solid; yield: 15.2 mg (14%).

¹H NMR (400 MHz, CDCl₃): δ = 7.45 (app d, J = 8.0 Hz, 1 H), 7.37–7.20 (m, 7 H), 7.10–7.07 (m, 1 H), 6.86 (s, 1 H), 5.19 (app t, J = 8.0 Hz, 1 H), 5.06 (dd, J = 12.4, 7.6 Hz, 1 H), 4.94 (dd, J = 12.4, 8.4 Hz, 1 H), 3.75 (s, 3 H).

All spectral data matched those that were previously reported.[ ²⁵ ]

Acknowledgment

This work was generously supported by The Ohio State University. We thank the Ohio BioProducts Innovation Center (OBIC) for the grant that provided the Bruker Micro TOF instrument used to obtain mass spectral data.

• References

• 1 Berkessel A, Gröger H. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis. Wiley-VHC; Weinheim: 2005
  CrossrefSearch in Google Scholar
• 2a Takemoto Y. Chem. Pharm. Bull. 2010; 58: 593
  CrossrefPubMedSearch in Google Scholar
• 2b Connon SJ, Kavanagh SA, Piccinini A. Org. Biomol. Chem. 2008; 6: 1339
  CrossrefSearch in Google Scholar
• 2c Zhang ZG, Schreiner PR. Chem. Soc. Rev. 2009; 38: 1187
  CrossrefPubMedSearch in Google Scholar
• 2d Takemoto Y. Org. Biomol. Chem. 2005; 3: 4299
  CrossrefPubMedSearch in Google Scholar
• 3a Kampen D, Reisinger CM, List B. Top. Curr. Chem. 2010; 291: 385
  Search in Google Scholar
• 3b You S, Cai Q, Zeng M. Chem. Soc. Rev. 2009; 38: 2190
  CrossrefSearch in Google Scholar
• 3c Akiyama T. Chem. Rev. 2007; 107: 5744
  CrossrefPubMedSearch in Google Scholar
• 4a So SS, Burkett JA, Mattson AE. Org. Lett. 2011; 13: 716
  CrossrefSearch in Google Scholar
• 4b So SS, Auvil TJ, Garza VJ. Org. Lett. 2012; 14: 444
  CrossrefSearch in Google Scholar

For examples of internal Lewis acid assisted ureas in the context of molecular recognition, see:
• 5a Hughes MP, Shang MY, Smith BD. J. Org. Chem. 1996; 61: 4510
  CrossrefSearch in Google Scholar
• 5b Hughes MP, Smith BD. J. Org. Chem. 1997; 62: 4492
  CrossrefSearch in Google Scholar

For selected recent examples of carboxylic acids operating as hydrogen-bond-donor catalysts, see:
• 6a Hasimoto T, Kimura H, Nakatsu H, Maruoka K. J. Org. Chem. 2011; 76: 6030
  CrossrefSearch in Google Scholar
• 6b Hasimoto T, Kimura H, Maruoka K. Angew. Chem. Int. Ed. 2010; 49: 6844
  CrossrefSearch in Google Scholar
• 6c Hashimoto T, Maruoka K. J. Am. Chem. Soc. 2007; 129: 100054
  Search in Google Scholar
• 6d Momiyama N, Yamamoto H. J. Am. Chem. Soc. 2005; 127: 1080
  CrossrefSearch in Google Scholar
• 7 Comins DL, Brown JD. J. Org. Chem. 1984; 49: 1078
  CrossrefSearch in Google Scholar
• 8 Schultz AG, Antoulinakis EG. J. Org. Chem. 1996; 61: 4555
  CrossrefSearch in Google Scholar
• 9 Blight BA, Leigh DA, McNab H, Thomson PI. T, Hunter CA. Nat. Chem. 2011; 3: 244
  Search in Google Scholar
• 10 Smallheer JM, Corte JR. US 2005228000, 2005

For examples of internal activation of carbonyl functionalities with boron in structures similar to 8a, see:
• 11a Omae I. Appl. Organomet. Chem. 2010; 24: 347
  Search in Google Scholar
• 11b Besong G, Jarowicki K, Kocienski PJ, Sliwinski E, Boyle FT. Org. Biomol. Chem. 2006; 4: 2193
  CrossrefSearch in Google Scholar
• 11c Liu X.-C, Hubbard JL, Scouten WH. J. Organomet. Chem. 1995; 493: 91
  CrossrefSearch in Google Scholar
• 11d Murafuji T, Sugihara Y, Moriya T, Mikata Y, Yano S. New J. Chem. 1999; 23: 683
  CrossrefSearch in Google Scholar
• 11e Murafuji T, Sugimoto K, Yanagimoto S, Moriya T, Sugihara Y, Mikata Y, Kato M, Yano S. Heterocycles 2001; 54: 929
  CrossrefSearch in Google Scholar
• 11f Toyota S, Asakura M, Sakaue T. Bull. Chem. Soc. Jpn. 2002; 75: 2667
  CrossrefSearch in Google Scholar
• 12 The only previously reported addition of methyl indole-4-carboxylate to a nitrostyrene required elevated temperatures, see: Gmeiner P, Sommer J, Höfner G. Arch. Pharm. (Weinheim, Ger.) 1995; 328: 329
  CrossrefSearch in Google Scholar
• 13 This proposed mechanism is based on a mechanism for the phosphoric acid catalyzed activation of nitroalkenes for nucleophilic attack by indoles, see: Itoh J, Fuchibe K, Akiyama T. Angew. Chem. Int. Ed. 2008; 47: 4016
  CrossrefPubMedSearch in Google Scholar
• 14 Pangborn AB, Giardello MA, Grubbs RH, Rosen RK, Timmers FJ. Organometallics 1996; 15: 1518
  CrossrefSearch in Google Scholar
• 15 Wrackmeyer B In Modern Magnetic Resonance. Webb GA. Springer; Dordrecht: 2006
  Search in Google Scholar
• 16 Berggren K, Davidsson O, Fjellstroem O, Gustafsson D, Hanessian S, Inghardt T, Någård M, Nilsson I, Therrien E, Van Otterlo W. WO 2005058826, 2005
• 17 Smallheer JM, Corte JR. US 2005228000, 2005
• 18 LaTorse M.-P, Schmitz C. US 5514719, 1996
• 19 Kolczewski S, Pinard E. US 2011053904, 2011
• 20 Ruzié C, Krayer M, Balasubramanian T, Lindsey JS. J. Org. Chem. 2008; 73: 5806
  CrossrefSearch in Google Scholar
• 21 Ganesh M, Seidel D. J. Am. Chem. Soc. 2008; 130: 16464
  CrossrefSearch in Google Scholar
• 22 Xiang J, Tong H, Yu Y. Synth. Commun. 2011; 41: 372
  CrossrefSearch in Google Scholar
• 23 Lu SF, Du DM, Xu J. Org. Lett. 2006; 8: 2115
  CrossrefSearch in Google Scholar
• 24 Wu J, Li X, Wu F, Wan B. Org. Lett. 2011; 13: 4834
  CrossrefPubMedSearch in Google Scholar
• 25 An LT, Zou JP, Zhang LL, Zhang Y. Tetrahedron Lett. 2007; 48: 4297
  CrossrefPubMedSearch in Google Scholar

• References

• 1 Berkessel A, Gröger H. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis. Wiley-VHC; Weinheim: 2005
  CrossrefSearch in Google Scholar
• 2a Takemoto Y. Chem. Pharm. Bull. 2010; 58: 593
  CrossrefPubMedSearch in Google Scholar
• 2b Connon SJ, Kavanagh SA, Piccinini A. Org. Biomol. Chem. 2008; 6: 1339
  CrossrefSearch in Google Scholar
• 2c Zhang ZG, Schreiner PR. Chem. Soc. Rev. 2009; 38: 1187
  CrossrefPubMedSearch in Google Scholar
• 2d Takemoto Y. Org. Biomol. Chem. 2005; 3: 4299
  CrossrefPubMedSearch in Google Scholar
• 3a Kampen D, Reisinger CM, List B. Top. Curr. Chem. 2010; 291: 385
  Search in Google Scholar
• 3b You S, Cai Q, Zeng M. Chem. Soc. Rev. 2009; 38: 2190
  CrossrefSearch in Google Scholar
• 3c Akiyama T. Chem. Rev. 2007; 107: 5744
  CrossrefPubMedSearch in Google Scholar
• 4a So SS, Burkett JA, Mattson AE. Org. Lett. 2011; 13: 716
  CrossrefSearch in Google Scholar
• 4b So SS, Auvil TJ, Garza VJ. Org. Lett. 2012; 14: 444
  CrossrefSearch in Google Scholar

For examples of internal Lewis acid assisted ureas in the context of molecular recognition, see:
• 5a Hughes MP, Shang MY, Smith BD. J. Org. Chem. 1996; 61: 4510
  CrossrefSearch in Google Scholar
• 5b Hughes MP, Smith BD. J. Org. Chem. 1997; 62: 4492
  CrossrefSearch in Google Scholar

For selected recent examples of carboxylic acids operating as hydrogen-bond-donor catalysts, see:
• 6a Hasimoto T, Kimura H, Nakatsu H, Maruoka K. J. Org. Chem. 2011; 76: 6030
  CrossrefSearch in Google Scholar
• 6b Hasimoto T, Kimura H, Maruoka K. Angew. Chem. Int. Ed. 2010; 49: 6844
  CrossrefSearch in Google Scholar
• 6c Hashimoto T, Maruoka K. J. Am. Chem. Soc. 2007; 129: 100054
  Search in Google Scholar
• 6d Momiyama N, Yamamoto H. J. Am. Chem. Soc. 2005; 127: 1080
  CrossrefSearch in Google Scholar
• 7 Comins DL, Brown JD. J. Org. Chem. 1984; 49: 1078
  CrossrefSearch in Google Scholar
• 8 Schultz AG, Antoulinakis EG. J. Org. Chem. 1996; 61: 4555
  CrossrefSearch in Google Scholar
• 9 Blight BA, Leigh DA, McNab H, Thomson PI. T, Hunter CA. Nat. Chem. 2011; 3: 244
  Search in Google Scholar
• 10 Smallheer JM, Corte JR. US 2005228000, 2005

For examples of internal activation of carbonyl functionalities with boron in structures similar to 8a, see:
• 11a Omae I. Appl. Organomet. Chem. 2010; 24: 347
  Search in Google Scholar
• 11b Besong G, Jarowicki K, Kocienski PJ, Sliwinski E, Boyle FT. Org. Biomol. Chem. 2006; 4: 2193
  CrossrefSearch in Google Scholar
• 11c Liu X.-C, Hubbard JL, Scouten WH. J. Organomet. Chem. 1995; 493: 91
  CrossrefSearch in Google Scholar
• 11d Murafuji T, Sugihara Y, Moriya T, Mikata Y, Yano S. New J. Chem. 1999; 23: 683
  CrossrefSearch in Google Scholar
• 11e Murafuji T, Sugimoto K, Yanagimoto S, Moriya T, Sugihara Y, Mikata Y, Kato M, Yano S. Heterocycles 2001; 54: 929
  CrossrefSearch in Google Scholar
• 11f Toyota S, Asakura M, Sakaue T. Bull. Chem. Soc. Jpn. 2002; 75: 2667
  CrossrefSearch in Google Scholar
• 12 The only previously reported addition of methyl indole-4-carboxylate to a nitrostyrene required elevated temperatures, see: Gmeiner P, Sommer J, Höfner G. Arch. Pharm. (Weinheim, Ger.) 1995; 328: 329
  CrossrefSearch in Google Scholar
• 13 This proposed mechanism is based on a mechanism for the phosphoric acid catalyzed activation of nitroalkenes for nucleophilic attack by indoles, see: Itoh J, Fuchibe K, Akiyama T. Angew. Chem. Int. Ed. 2008; 47: 4016
  CrossrefPubMedSearch in Google Scholar
• 14 Pangborn AB, Giardello MA, Grubbs RH, Rosen RK, Timmers FJ. Organometallics 1996; 15: 1518
  CrossrefSearch in Google Scholar
• 15 Wrackmeyer B In Modern Magnetic Resonance. Webb GA. Springer; Dordrecht: 2006
  Search in Google Scholar
• 16 Berggren K, Davidsson O, Fjellstroem O, Gustafsson D, Hanessian S, Inghardt T, Någård M, Nilsson I, Therrien E, Van Otterlo W. WO 2005058826, 2005
• 17 Smallheer JM, Corte JR. US 2005228000, 2005
• 18 LaTorse M.-P, Schmitz C. US 5514719, 1996
• 19 Kolczewski S, Pinard E. US 2011053904, 2011
• 20 Ruzié C, Krayer M, Balasubramanian T, Lindsey JS. J. Org. Chem. 2008; 73: 5806
  CrossrefSearch in Google Scholar
• 21 Ganesh M, Seidel D. J. Am. Chem. Soc. 2008; 130: 16464
  CrossrefSearch in Google Scholar
• 22 Xiang J, Tong H, Yu Y. Synth. Commun. 2011; 41: 372
  CrossrefSearch in Google Scholar
• 23 Lu SF, Du DM, Xu J. Org. Lett. 2006; 8: 2115
  CrossrefSearch in Google Scholar
• 24 Wu J, Li X, Wu F, Wan B. Org. Lett. 2011; 13: 4834
  CrossrefPubMedSearch in Google Scholar
• 25 An LT, Zou JP, Zhang LL, Zhang Y. Tetrahedron Lett. 2007; 48: 4297
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material