C2-Selective Branched Alkylation of Benzimidazoles by Rhodium(I)-catalyzed C–H Activation

Abstract

Herein, we report a Rh(I)/bisphosphine/K₃PO₄ catalytic system allowing for the first time the selective branched C–H alkylation of benzimidazoles with Michael acceptors. Branched alkylation with N,N-dimethyl acrylamide was successfully applied to the alkylation of a broad range of benzimidazoles incorporating a variety of N-substituents and with both electron-rich and electron-poor functionality displayed at different sites of the arene. Moreover, the introduction of a quaternary carbon was achieved by alkylation with ethyl methacrylate. The method was also shown to be applicable to the C2-selective branched alkylation of azabenzimidazoles.

Graphical Abstract

The benzimidazole framework is among the most extensively used scaffolds in the pharmaceutical industry,¹ and the synthesis and functionalization of benzimidazoles have been the subject of a considerable number of studies.² Among them, the regioselective transition-metal catalyzed C–H functionalization of benzimidazoles has elicited significant interest because it allows rapid access to elaborated substrates from simple precursors.³ In particular, the direct C–H alkylation of C2-unsubstituted benzimidazoles with alkenes proceeds with complete atom economy.⁴ Both Rh and Ni catalyst systems have been reported to promote intermolecular benzimidazole C–H alkylations with very high linear selectivity, and depending on the reaction conditions and catalyst used, a vinyl group can be substituted with alkyl,⁵ aryl⁶ or electron withdrawing⁷ groups (Scheme 1, eq 1). In contrast, branched-selective intermolecular alkylation of benzimidazoles is limited to a single report, which employs styrenes with a Ni catalyst system (Scheme 1, eq 2).^8,9 We have recently demonstrated that a Rh(I)-precatalyst combined with the electron-poor ligand dAr^Fpe and K₃PO₄ enables the completely branched selective alkylation of pyridines in high yields.¹⁰ Herein, we report that this catalyst system can be extended to the branched selective alkylation of a wide range of benzimidazole and azabenzimidazole derivatives with N,N-dimethylacrylamide (eq 3) and to the first examples of branched-selective C–H alkylation to introduce a quaternary carbon with ethyl methacrylate (eq 4).

Scheme 1.

C2-Selective Alkylations of Benzimidazoles

After reevaluation of a broad range of reaction parameters, it was found that the optimal conditions previously reported for the branched alkylation of pyridines were also the most effective for the branched alkylation of N-methylbenzimidazole 1a with N,N-dimethylacrylamide 2. Under these conditions, product 3a was obtained in 71% yield, with exclusive regioselectivity in favor of the C2-position and with complete branched selectivity (Table 1, entry 1). K₃PO₄ was the base of choice as other inorganic bases either led to complete shut-down of the reaction or drastically reduced yields (Table 1, entries 2–4). The electron-deficient bisphosphine dAr^Fpe ((3,5-CF₃Ph)pe) was also a critical element of the catalytic system, and the use of its more electron-rich analog, dppe, only led to a 13% yield (Table 1, entry 5). Reducing the temperature to 100 °C seemed to promote competitive polymerization of the alkene partner (Table 1, entry 6), as did the replacement of acrylamide 2 by tert-butyl acrylate and ethyl acrylate (Table 1, entry 7–8). Mesitylene was evaluated in place of toluene as solvent because its boiling point of 165 °C is well above the reaction temperature of 120 °C, and gave a comparable reaction yield (Table 1, entry 9). However, toluene was employed for evaluating reaction scope because it can be readily purchased in anhydrous form. Other common solvents such as THF could be used in the reaction, but the yield was significantly lower (Table 1, entry 10).

Table 1.

Key Reaction Parameters

Entry	Change from Optimal Conditions	Yielda
1	None	71% (68%)
2	K2HPO4 instead of K3PO4	0%
3	K2CO3 instead of K3PO4	15%
4	KOPiv instead of K3PO4	0%
5	dppe instead of dArFpe	13%
6	100 °C instead of 120 °C	14%
7	EWG = CO2tBu instead of CONMe2	12%
8	EWG = CO2Et instead of CONMe2	14%b
9	Mesitylene instead of PhMe	74%
10	THF instead of PhMe	41%

^aDetermined from the crude reaction mixture by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields in parenthesis.

^b1H NMR also showed the presence of 17% yield of the linear product.

The optimized conditions proved to be very general, and broad scope was observed for the benzimidazole coupling partner (Scheme 2). Substitution at the N1-position with a methyl, phenyl or benzyloxymethyl (BOM) protecting group led to excellent yields of the corresponding benzimidazoles 3a–c, and scale-up of the alkylation of benzimidazole 1a from 0.4 to 7.6 mmol did not lead to a significant change in yield. Benzimidazoles substituted at the C5, C6, or C7 positions with a wide range of electron-withdrawing groups such as esters (3d–e), sulfonyl (3f), chloro (3g), nitrile (3h) or trifluoromethyl (3i–l) provided alkylation products in good to excellent yields. Only benzimidazole 3l, bearing a trifluoromethyl substituent at the C4-position, was obtained in a low yield of 12%. Electron-donating group such as methoxy or methyl were also very well tolerated when used in conjunction with a BOM-protecting group (3m–o). Because we previously reported that azines could be efficiently alkylated using the present method, it was a surprise for us to see that azine-fused imidazoles 1p and 1q could be selectively alkylated at the C2-position without any undesired alkylation on the azine ring. Electron-withdrawing and electron-donating substituents were well tolerated in these cases as well (3r–s). In very preliminary studies, an N-methyl and an N-BOM substituted imidazole were evaluated under the standard reaction conditions but starting material was primarily recovered (3t and 3u). It is possible that alkylation might occur under different reaction conditions or with imidazoles having alternative substitution patterns.

Scheme 2.

Scope of the Reaction Using N,N-Dimethylacrylamide

Although broad in scope with respect to the benzimidazole substituents, this method is primarily restricted to N,N-disubstituted acrylamides as the Michael acceptor. We therefore demonstrated that the amide products can be easily transformed to the corresponding aldehydes by treatment with Schwartz reagent (Scheme 3).¹¹ Owing to the instability of the aldehyde products to long-term storage, they were isolated and characterized as their O-methyl oximes derivatives 4 after treatment with NH₂-OMe•HCl. Given that aldehydes are among the most versatile functional handles in organic chemistry, this method can potentially be used to access a very broad range of branched benzimidazole derivatives.

Scheme 3.

Transformations of Product Amide

The introduction of a quaternary carbon center by Rh(I)-catalyzed C–H bond additions to methacrylate derivatives was also investigated (Scheme 4). While N,N-dimethyl methacrylamide did not provided any desired product, ethyl methacrylate (5) proved to be a suitable alkene partner thus allowing the direct incorporation of a quaternary center (Scheme 4). However, in contrast to what was observed in the scope exploration using N,N-dimethylacrylamide, we found that the branched to linear alkylation selectivity of this reaction is dependent upon the substitution pattern of the nitrogen heterocycle 1. Indeed, while the use of N-BOM-benzimidazole (1c) led to both branched and linear products in 32% (6c) and 34% (6c’) yields, respectively, electron-poor heterocycles provided the branched products such as 6j and 6q with high selectively and in excellent yields. We also found that the reaction was very sensitive to any adventitious water, which resulted in low yields of product. The greater sensitivity of the alkylation reaction to water when ethyl methacrylate (5) is used instead of N,N-dimethylacrylamide (2) potentially arises from the higher propensity of ethyl methacrylate to oligomerize under basic conditions.

Scheme 4.

Direct Incorporation of Quaternary Centers with Ethyl Methacrylate

In summary, we have developed a Rh(I)-catalyzed C2-selective alkylation of benzimidazole derivatives with N,N-dimethylacrylamide with complete branched selectivity. This transformation complements the previously reported branched alkylation of benzimidazoles by styrenes and the linear alkylation of benzimidazoles by Michael acceptors. Alkylated benzimidazoles featuring a broad range of different electronic properties can be accessed in good to excellent yields, and the amide products can be easily converted to aldehydes as versatile synthetic intermediates, thereby making the reported method useful for drug discovery applications. Moreover, the branched alkylation of benzimidazole derivatives with ethyl methacrylate was achieved for the preparation of products incorporating a quaternary carbon.

EXPERIMENTAL SECTION

General Experimental

Unless otherwise indicated, all reactions were performed under a nitrogen gas atmosphere in oven-dried glassware cooled down under nitrogen gas. Toluene, diethyl ether, dichloromethane and THF were degassed by argon sparging and purified by elution through a column of activated alumina under an argon atmosphere prior to use. Mesitylene was dried and distilled under nitrogen from CaH₂ and then was degassed by sparging with N₂. 1,2-Bis(bis(3,5-bis(trifluoromethyl)phenyl)phosphino) ethane (dAr^Fpe) was synthesized according to a modified literature procedure. All other catalyst and ligands were purchased from Strem Chemical and used without further purification. Potassium phosphate was dried at 160 °C under high vacuum prior to use. N-Methylbenzimidazole 1a was recrystallized from Et₂O/pentane prior to use. All liquid azoles and N,N-dimethylacrylamide 2 were dried by elution through a small column of activated basic alumina and degassed by nitrogen sparging prior to use. Ethyl methacrylate 4 was dried over CaCl₂, distilled under reduced pressure under nitrogen and then degassed by nitrogen sparging prior to use. All other reagents were purchased from commercial sources and used without further purification. All microwave-heated reactions were performed in a Biotage Initiator+ microwave reactor, which employs an external IR sensor. Flash column chromatography was performed over Grade 60 silica gel (230–400mesh). Preparative TLC was performed over silica gel-coated glass plates (20x20 cm, 1000 or 2000 μm). Reverse-phase column chromatography was performed on pre-packed cartridges of C18 silica gel using an automated purification system. NMR chemical shifts (δ) are reported in ppm relative to CHCl₃ (δ = 7.26 ppm), acetone (δ = 2.05 ppm), H₂O (δ = 4.79 ppm), or (CH₃)₂SO (δ = 2.50 ppm) for ¹H-NMR, CDCl₃ (δ = 77.16 ppm) or (CD₃)₂CO (δ = 29.8 ppm), for ¹³C-NMR, 85% aqueous H₃PO₄ for ³¹P-NMR (external reference, δ = 0 ppm) and trifluoroacetic acid for ¹⁹F-NMR (external reference, δ = -76.55 ppm). All ¹³C NMR are proton decoupled. All ¹⁹F and ³¹P NMR are carbon decoupled. The multiplicity and shape of NMR signals are designated by the following abbreviations: s singlet, d doublet, t triplet, q quartet, m multiplet, app apparent. Coupling constants (J values) are reported in Hertz (Hz). High-resolution mass spectra (HRMS) were recorded on a quadrupole time-of-flight mass spectrometer after electrospray ionization. Melting points (Mp) are reported uncorrected.

1,2-Bis(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)ethane (dAr^Fpe)

A freshly titrated solution of iPrMgBr (1.10 M in THF, 26.3 mL, 28.9 mmol, 6.7 equiv)¹² was charged in an oven-dried round-bottom flask previously flushed with nitrogen. Additional dry diethyl ether (30 mL) was added, and the resulting solution was cooled down to −10 °C. Neat 1-bromo-3,5-bis(trifluoromethyl)benzene (5.20 mL, 30.2 mmol, 7.0 equiv) was added dropwise over 20 min, the reaction mixture was stirred at −10 °C for 1 h, then allowed to warm-up to room temperature and stirred for 3 h. The resulting clear brown solution was cooled down to 0 °C, and neat 1,2-bis(dichlorophosphino)ethane (0.65 mL, 4.3 mmol, 1.0 equiv) was added dropwise over 5 min. The resulting suspension was allowed to warm-up to room temperature and stirred for 16 h. The resulting suspension was cooled to 0 °C and quenched with an aqueous saturated NH₄Cl solution. The organic solvents were removed in vacuo, and water and ethyl acetate were added to the resulting slurry until two clear phases were obtained. The phases were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated in vacuo to give an orange solid. This solid was then washed with small amounts of peroxide-free and BHT-free diethyl ether until a white powder was obtained, which was then dried under high-vacuum to give the desired product (3.96 g, 4.20 mmol, 97% yield). ¹H and ¹⁹F NMR matched the reported data.^{13 1}H NMR (600 MHz, Acetone-d⁶) δ 8.11 (s, 8H), 8.05 (s, 4H), 2.73 (t, J = 5.3 Hz, 4H); ¹⁹F NMR (150 MHz, Acetone-d⁶) δ -63.5; ³¹P NMR (200 MHz, Acetone-d⁶) δ -9.4.

1-Phenyl-1H-benzo[d]imidazole (1b)

1H-Benzimidazole (236 mg, 2.00 mmol, 1.0 equiv) and Cs₂CO₃ (3.26 g, 10.0 mmol, 5.0 equiv) were weighted in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by dry DMA (20 mL) and fluorobenzene (0.88 mL, 9.3 mmol, 4.7 equiv). The vial was sealed with a teflon-lined cap and heated at 190 °C in a Biotage Initiator+ microwave reactor for 16 h. The reaction mixture was poured on water and Et₂O, the phases were separated and the aqueous phase was extracted three times with Et₂O. The combined organic phases were dried over Na₂SO₄ and concentrated in vacuo to give the crude product. Purification by flash chromatography over silica gel (60% EtOAc/petroleum ether) gave the desired product 1b as a colorless oil (370 mg, 1.90 mmol, 95% yield). ¹H NMR spectra matched the reported data.^{14 1}H NMR (600 MHz, CDCl₃) δ 8.13 (s, 1H), 7.93 – 7.84 (m, 1H), 7.62 – 7.50 (m, 5H), 7.50 – 7.43 (m, 1H), 7.39 – 7.29 (m, 2H).

1-((Benzyloxy)methyl)-1H-benzo[d]imidazole (1c)

Under N₂, at 0 °C, to a solution of 1H-benzimidazole (1.00 g, 8.46 mmol, 1.0 equiv) in dry DMF (20 mL) was added NaH (60% w/w in oil, 340 mg, 8.87 mmol, 1.05 equiv) in one portion. The reaction mixture was stirred at 0 °C for 10 min, then neat BOM-Cl (90% purity, 1.38 mL, 8.90 mmol, 1.05 equiv) was added dropwise. The resulting solution was stirred at rt for 16 h. The reaction mixture was then poured onto a 10% w/w LiCl aqueous solution, EtOAc was added, the phases were separated, and the organic phase was washed three more times with a 10% w/w LiCl solution. The organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a yellow oil. Purification by flash chromatography over silica gel (60 to 100% EtOAc/petroleum ether) gave the desired product 1c as a white amorphous solid (1.27 g, 5.33 mmol, 63% yield). ¹H NMR spectra matched the reported data.^{15 1}H NMR (600 MHz, CDCl₃) δ 7.95 (s, 1H), 7.86 – 7.82 (m 1H), 7.56 – 7.53 (m, 1H), 7.38 – 7.31 (m, 5H), 7.30 – 7.26 (m, 2H), 5.60 (s, 2H), 4.47 (s, 2H).

Benzimidazole-5-carboxylic acid ethyl ester

Benzimidazole-5-carboxylic acid (1.00 g, 6.17 mmol, 1.0 equiv) was dissolved in EtOH (15.5 mL), treated with concentrated H₂SO₄ (0.36 mL, 6.9 mmol, 1.1 equiv), and heated to reflux for 24 h. After cooling to room temperature, the mixture was poured onto ice, and 5 N aqueous NaOH was added until pH~9 was reached. The mixture was extracted with EtOAc (3x30 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. Purification by flash chromatography over silica gel (100% EtOAc) gave the desired product benzimidazole-5-carboxylic acid ethyl ester as a cream-colored amorphous solid (751 mg, 3.95 mmol, 64% yield). ¹H NMR matched the reported data.^{16 1}H NMR (500 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.67 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).

Ethyl 1-((benzyloxy)methyl)-1H-benzo[d]imidazole-5-carboxylate (1d)

Benzimidazole-5-carboxylic acid ethyl ester (0.50 g, 2.6 mmol, 1 equiv) was dissolved in DMF (2.5 mL), and the reaction solution was cooled to 0 °C. Sodium hydride (60% w/w in oil, 91 mg, 3.9 mmol, 1.5 equiv) was added, and the reaction mixture was stirred for 15 min followed by the addition of BOM-Cl (90% purity, 0.41 mL, 2.6 mmol, 1.0 equiv). The reaction mixture was then stirred for 45 min at room temperature, and the reaction was quenched with 0.25 mL of a 30% w/w aqueous NH₃. The solvents were removed in vacuo and the residue was partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane (3x5 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by flash chromatography over silica gel (65% EtOAc/hexanes) gave the desired product 1d as a white amorphous solid (220 mg, 0.71 mmol, 27% yield). mp 82–85 °C; IR (neat) 3066, 2982, 2937, 1709, 1622, 1461, 1278, 1245, 1193, 1058, 748, 702 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.02 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.38 – 7.32 (m, 3H), 7.26 – 7.28 (m, 2H), 5.61 (s, 2H), 4.47 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 167.0, 144.7, 143.9, 136.8, 136.0, 128.9, 128.6, 128.2, 125.7, 125.3, 123.0, 110.2, 73.6, 70.5, 61.1, 14.6; HRMS (ESI+, m/z) [M+H]⁺ calcd for C₁₈H₁₉N₂O₃⁺: 311.1390, found: 311.1410.

1-Methyl-5-methylsulfonyl-benzimidazole (1f)

1-Fluoro-4-methylsulfonyl-2-nitrobenzene (1.00 g, 4.57 mmol, 1.0 equiv) was weighted in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by a 2 M solution of MeNH₂ in THF (11.4 mL, 22.8 mmol, 5 equiv). The vial was sealed with a teflon-lined cap and the mixture was stirred at room temperature for 30 min. The reaction mixture was then concentrated in vacuo, and the resulting residue was suspended in Et₂O and filtered to give crude N-methyl-4-(methylsulfonyl)-2-nitroaniline. This solid was then transferred to a 250 mL Morton flask, to which was added Pd/C (1.06 g, 10 mol %), and the solids were suspended in EtOH (100 mL), placed under an atmosphere of H₂, and stirred at room temperature for 2.5 h. The reaction mixture was then filtered through pad of celite, rinsed with MeOH and concentrated to give crude N-methyl-4-(methylsulfonyl)benzene-1,2-diamine. The crude reaction product was transferred into a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8cm), to which was added formic acid (90% w/w in water, 17.1 mL, 407 mmol, 90 equiv). The vial was sealed with a teflon-lined cap and heated at 150 C in a Biotage Initiator+ microwave reactor for 1 h. The solution was made basic with 2M NaOH followed by concentrated NaOH until a pH ~9 was reached. The mixture was extracted with CH₂Cl₂ (3x50 mL), and the organic layers were combined, dried over Na₂SO₄ and concentrated in vacuo. Purification by flash chromatography over silica gel (100% EtOAc) gave the desired product 1f as a pale orange amorphous solid (711 mg, 3.40 mmol, 68% yield). mp 162–164 °C; IR (neat) 3081, 2995, 2904, 1612, 1501, 1329, 1284, 1259, 1136, 1061, 769, 637 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.42 (s, 1H), 8.04 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 3.92 (s, 3H), 3.09 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 146.4, 143.5, 138.0, 134.7, 121.9, 121.0, 110.4, 45.3, 31.6; HRMS (ESI+, m/z) [M+H]⁺ calcd for C₉H₁₁N₂O₂S⁺: 211.0536, found: 211.0528.

1-Methyl-6-chloro-1H-benzo[d]imidazole (1g)

4-Chloro-2-fluoro-1-nitro-benzene (1.00 g, 5.70 mmol, 1.0 equiv) was weighted in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by a 2 M solution of MeNH₂ in THF (14.2 mL, 28.5 mmol, 5 equiv). The vial was sealed with a teflon-lined cap and the reaction mixture was stirred at room temperature for 1 h. The resulting suspension was filtered over a sintered glass funnel and the filtrate was concentrated in vacuo to give crude 5-chloro-N-methyl-2-nitroaniline as an orange solid. A slurry of Raney nickel in water was then charged in a 100 mL round-bottom flask, the water was evaporated in vacuo to give ca. 1.8 g of dry Raney nickel (30.7 mmol, 4.8 equiv). Crude 5-chloro-N-methyl-2-nitroaniline was then added to the Raney nickel as a solution in MeOH (50 mL), and the resulting suspension was vigorously stirred under a hydrogen atmosphere for 2 h. The resulting colorless suspension was filtered over a bed of celite (Et₂O washings) and then concentrated in vacuo to give crude 5-chloro-N1-methylbenzene-1,2-diamine as a black oil. This oil was then transferred into a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8cm), to which was added formic acid (90% w/w in water, 20.4 mL, 486 mmol, 85 equiv). The vial was sealed with a teflon-lined cap and heated at 150 °C for 2.5 h in a Biotage Initiator+ microwave reactor. The reaction mixture was concentrated in vacuo to give a bright pink solid. Purification by reverse-phase flash chromatography over C18 silica gel (20 to 40% MeCN+0.1% TFA/H₂O+0.1% TFA) gave the desired product as its TFA salt, which was then treated with an aqueous saturated solution of NaHCO₃. Extraction with EtOAc, followed by drying with Na₂SO₄ and in vacuo concentration led to the desired product 1g as a white amorphous solid (720 mg, 4.32 mmol, 76% overall yield). ¹H NMR spectra matched the reported data.^{17 1}H NMR (600 MHz, CDCl₃) δ 7.84 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.7, 2.0 Hz, 1H), 3.81 (s, 3H).

1-Methyl-1H-benzo[d]imidazole-5-carbonitrile (1h)

4-Chloro-3-nitro-benzonitrile (1.00 g, 5.48 mmol, 1.0 equiv) was weighted in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by a 2 M solution of MeNH₂ in THF (13.7 mL, 2M in THF, 5 equiv). The vial was sealed with a teflon-lined cap, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then concentrated in vacuo. The resulting residue was suspended in Et₂O and filtered to give crude 4-methylamino-3-nitro-benzonitrile, which was then suspended in EtOH/H₂O (10:1, 19 mL) under N₂ at room temperature. Iron powder (1.00 g, 1.79 mmol, 3.3 equiv) and CaCl₂ (0.45 g, 4.1 mmol, 0.7 equiv) were added to the reaction mixture, and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was re-dissolved in CH₂Cl₂, washed with water and brine, and dried over Na₂SO₄. The solvent was removed in vacuo to give crude 3-amino-4-methylamino-benzonitrile. To trimethyl orthoformate (15.8 mL) was added the 3-amino-4-methylamino-benzonitrile and para-toluenesulfonic acid monohydrate (17 mg, 0.089 mmol, 0.016 equiv). The reaction mixture was stirred at 100 °C for 2.5 h, after which time the mixture was cooled and water (60 mL) was added. The solution was partitioned with EtOAc (2x90 mL) and the organic layers were combined, dried with MgSO₄ and concentrated. Purification by flash chromatography over silica gel (100% EtOAc) gave the desired product 1h as a light brown amorphous solid (339 mg, 2.15 mmol, 39% overall yield). mp 136–137 °C; IR (neat) 3090, 3030, 2955, 2223, 1614, 1503, 1470, 1332, 1260, 877, 825, 646 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.14 (s, 1H), 8.00 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 146.0, 143.5, 137.3, 126.5, 125.7, 119.9, 110.7, 105.8, 31.5; HRMS (ESI+, m/z) [M+H]⁺ calcd for C₉H₈N₃⁺: 158.0713, found: 158.0719.

1-Methyl-7-(trifluoromethyl)-1H-benzo[d]imidazole (1i)

2-Chloro-1-nitro-3-(trifluoromethyl)benzene (1.20 g, 5.32 mmol, 1.0 equiv) was weighed in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by a 2 M solution of MeNH₂ in THF (12 mL, 24 mmol, 4.5 equiv). The vial was sealed with a teflon-lined cap and heated at 150 °C for 15 min in a Biotage Initiator+ microwave reactor. The resulting suspension was filtered over a sintered glass funnel, and the filtrate was concentrated in vacuo to give crude N-methyl-2-nitro-6-(trifluoromethyl)aniline as a yellow solid. This solid was then transferred to a 250 mL Morton flask, to which was added PtO₂ (134 mg, 0.591 mmol, 0.11 equiv) and absolute ethanol (50 mL). This suspension was vigorously stirred under a hydrogen atmosphere for 2 h. The resulting colorless suspension was filtered over a bed of celite (Et₂O washings) and then concentrated in vacuo to give crude N1-methyl-6-(trifluoromethyl)benzene-1,2-diamine as an orange oil. This oil was then transferred into a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), to which was added formic acid (90% w/w in water, 15.0 mL, 358 mmol, 67 equiv). The vial was sealed with a teflon-lined cap and heated at 150 °C for 10 min in a Biotage Initiator+ microwave reactor. The reaction mixture was concentrated in vacuo to give a red oil. Purification by flash chromatography over silica gel (80% EtOAc/petroleum ether) gave the desired product 1i as a pale yellow amorphous solid (702 mg, 3.51 mmol, 66% overall yield). ¹H NMR spectra matched the reported data.^{18 1}H NMR (600 MHz, CDCl₃) δ 8.01 (d, J = 8.2 Hz, 1H), 7.94 (s, broad, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.35 (t_app, J = 7.9 Hz, 1H), 4.00 (q, J = 1.8 Hz, 3H); ¹⁹F NMR (470 MHz, CDCl₃) δ -55.02.

1-Methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (1j)

2-Chloro-1-nitro-4-(trifluoromethyl) benzene (1.00 g, 4.43 mmol, 1.0 equiv) was weighted in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by a 2 M solution of MeNH₂ in THF (11.0 mL, 22.2 mmol, 5 equiv). The vial was sealed with a teflon-lined cap and heated at 150 °C for 30 min in a Biotage Initiator+ microwave reactor. The resulting suspension was filtered over a sintered glass funnel, and the filtrate was concentrated in vacuo to give crude N-methyl-2-nitro-5-(trifluoromethyl)aniline as a bright orange solid. This solid was then transferred to a 250 mL Morton flask, to which was added PtO₂ (113 mg, 0.500 mmol, 0.11 equiv) and absolute ethanol (50 mL). This suspension was vigorously stirred under a hydrogen atmosphere for 2 h. The resulting colorless suspension was filtered over a bed of celite (Et₂O washings) and then concentrated in vacuo to give crude N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine as an orange oil. This oil was then transferred into a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), to which was added formic acid (90% w/w in water, 15.0 mL, 358 mmol, 80 equiv). The vial was sealed with a teflon-lined cap and heated at 150 °C for 10 min in a Biotage Initiator+ microwave reactor. The reaction mixture was concentrated in vacuo to give a red oil. Purification by flash chromatography over silica gel (50% acetone/petroleum ether) gave the desired product 1j as a white amorphous solid (745 mg, 3.72 mmol, 84% overall yield). mp 96–98 °C; IR (neat) 3031, 1507, 1338, 1302, 1160, 1093, 1063, 901, 814, 663 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.98 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 (dd, J = 8.5, 1.2 Hz, 1H), 3.88 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 146.0, 145.9, 134.1, 125.4 (q, J = 32 Hz), 124.9 (q, J = 272 Hz), 120.9, 119.2 (q, J = 4 Hz), 107.4 (q, J = 5 Hz), 31.4; ¹⁹F NMR (470 MHz, CDCl₃) δ -60.67; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₉H₈F₃N₂⁺: 201.0634, found: 201.0633.

1-Methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (1k)

1-Chloro-2-nitro-4-(trifluoromethyl) benzene (1.00 g, 4.43 mmol, 1.0 equiv) was weighted in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by a 2 M solution of MeNH₂ in THF (11.0 mL, 22.2 mmol, 5 equiv). The vial was sealed with a teflon-lined cap and heated at 150 °C for 15 min in a Biotage Initiator+ microwave reactor. The resulting suspension was filtered over a sintered glass funnel, and the filtrate was concentrated in vacuo to give crude N-methyl-2-nitro-4-(trifluoromethyl)aniline as a bright orange solid. This solid was then transferred to a 250 mL Morton flask, to which was added PtO₂ (113 mg, 0.500 mmol, 0.11 equiv) and absolute ethanol (50 mL). This suspension was vigorously stirred under a hydrogen atmosphere for 2 h. The resulting colorless suspension was filtered over a bed of celite (Et₂O washings) and then concentrated in vacuo to give crude N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine as an orange oil. This oil was then transferred into a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), to which was added formic acid (90% w/w in water, 15.0 mL, 358 mmol, 80 equiv). The vial was sealed with a teflon-lined cap and heated at 150 °C for 10 min in a Biotage Initiator+ microwave reactor. The reaction mixture was concentrated in vacuo to give a red oil. Purification by flash chromatography over silica gel (50% acetone/petroleum ether) gave the desired product 1k as a white amorphous solid (676 mg, 3.38 mmol, 76% overall yield). ¹H NMR spectra matched the reported data.^{19 1}H NMR (600 MHz, CDCl₃) δ 8.08 (s, 1H), 7.96 (s, 1H), 7.56 (dd, J = 8.5, 1.2 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H); ¹⁹F NMR (470 MHz, CDCl₃) δ -60.60.

1-Methyl-4-(trifluoromethyl)-1H-benzo[d]imidazole (1l)

1-Chloro-2-nitro-4-(trifluoromethyl) benzene (1.15 g, 5.10 mmol, 1.0 equiv) was weighted in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by powdered silicon carbide (1.15 g) and by a 2 M solution of MeNH₂ in THF (12.0 mL, 24.0 mmol, 4.7 equiv). The vial was sealed with a teflon-lined cap and heated at 190 °C for 30 min in a Biotage Initiator+ microwave reactor. The resulting suspension was filtered over a sintered glass funnel, and the filtrate was concentrated in vacuo to give a bright orange solid. This solid was then purified by flash chromatography over silica gel (10% diethyl ether/petroleum ether) to give pure 2-chloro-N-methyl-6-trifluoromethyl-aniline as a bright orange solid (450 mg, 2.15 mmol, 42% yield). This solid was then transferred to a 50 mL Morton flask, to which was added PtO₂ (46 mg, 0.20 mmol, 0.1 equiv) and absolute ethanol (16 mL). This suspension was vigorously stirred under a hydrogen atmosphere for 2 h. The resulting colorless suspension was filtered over a bed of celite (Et₂O washings) and then concentrated in vacuo to give crude N1-methyl-3-(trifluoromethyl)benzene-1,2-diamine as an orange oil. This oil was then transferred into a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), to which was added formic acid (90% w/w in water, 5.50 mL, 131 mmol, 60 equiv). The vial was sealed with a teflon-lined cap and heated at 150 °C for 10 min in a Biotage Initiator+ microwave reactor. The reaction mixture was concentrated in vacuo to give a red oil. Purification by flash chromatography over silica gel (80% EtOAc/petroleum ether) gave the desired product 1l as a pale yellow amorphous solid (208 mg, 1.04 mmol, 20% overall yield). ¹H NMR spectra matched the reported data.^{18 1}H NMR (600 MHz, CDCl₃) δ 7.99 (s, 1H), 7.58 (dd_app, J = 7.7, 2.3 Hz, 2H), 7.38 (t_app, J = 7.7 Hz, 1H), 3.90 (s, 3H); ¹⁹F NMR (470 MHz, CDCl₃) δ -60.96.

1-((Benzyloxy)methyl)-6-methoxy-1H-benzo[d]imidazole (1m) and 1-((Benzyloxy)methyl)-5-methoxy-1H-benzo[d]imidazole (1n)

Under N₂, at 0 °C, to a solution of 5-methoxy-1H-benzo[d]imidazole (1.00 g, 6.76 mmol, 1.0 equiv) in dry DMF (15 mL) was added NaH (60% w/w in oil, 405 mg, 10.1 mmol, 1.50 equiv) in one portion. The reaction mixture was stirred at 0 °C for 1 h, then neat BOM-Cl (90% pure, 1.25 mL, 8.10 mmol, 1.2 equiv) was added dropwise. The resulting solution stirred at rt for 16 h. The reaction mixture was then poured onto a 10% w/w LiCl aqueous solution, EtOAc was added, the phases were separated, and the organic phase was washed three more times with a 10% w/w LiCl solution. The organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a yellow oil. Purification by flash chromatography over silica gel (60 to 100% EtOAc/CH₂Cl₂) gave, by order of elution, the desired products 1m (325 mg, 1.21 mmol, 18% yield) as a pale yellow amorphous solid and 1n (175 mg, 0.652 mmol, 10% yield) as a pale yellow oil. (1m): mp 67–70 °C; IR (neat) 3099, 2836, 1627, 1587, 1505, 1453, 1361, 1279, 1092, 1022, 955, 817, 733 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.83 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.38 –7.30 (m, 3H), 7.30 – 7.24 (m, 2H), 6.99 – 6.90 (m, 2H), 5.53 (s, 2H), 4.45 (s, 2H), 3.86 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 157.3, 142.3, 138.6, 136.3, 134.4, 128.8, 128.5, 128.2, 121.1, 112.5, 93.8, 73.4, 70.0, 56.0; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₆H₁₇N₂O₂⁺: 269.1285, found: 269.1285. (1n): IR (neat) 2939, 1623, 1593, 1487, 1442, 1349, 1218, 1142, 1071, 941, 829, 697 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.88 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.37–7.28 (m, 4 H), 7.27–7.24 (m, 2H), 6.98 (dd, J = 8.8, 1.7 Hz, 1H), 5.53 (s, 2H), 4.43 (s, 2H), 3.87 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 156.7, 145.1, 143.4, 136.2, 128.8, 128.4, 128.2, 128.1, 113.8, 110.9, 102.6, 73.6, 70.1, 55.9; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₆H₁₇N₂O₂⁺: 269.1285, found: 269.1281.

1-((Benzyloxy)methyl)-5,6-dimethyl-1H-benzo[d]imidazole (1o)

5,6-Dimethylbenzimidazole (0.500 g, 3.42 mmol, 1.0 equiv) was dissolved in DMF (2.5 mL), and the reaction solution was cooled to 0 °C. Sodium hydride (60% w/w oil oil, 118 mg, 5.13 mmol, 1.5 equiv) was added, and the reaction mixture was stirred for 15 min before the addition of BOM-Cl (90% purity, 0.53 mL, 3.42 mmol, 1.0 equiv). The reaction mixture was stirred for 45 min at room temperature, and the reaction was quenched with 0.25 mL of a 30% w/w aqueous NH₃. The solvents were removed in vacuo and the residue was partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane (3x5 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by flash chromatography over silica gel (90% EtOAc/hexanes) gave the desired product 1o as a pale yellow amorphous solid (778 mg, 2.92 mmol, 85% yield). mp 98–99 °C; IR (neat) 3089, 2970, 2883, 1704, 1495, 1356, 1215, 1093, 1001, 844, 742, 697 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.83 (s, 1H), 7.59 (s, 1H), 7.38 – 7.26 (m, 6H), 5.52 (s, 2H), 4.43 (s, 2H), 2.40 (s, 6H); ¹³C NMR (151 MHz, CDCl₃) δ 142.8, 142.5, 136.3, 132.9, 132.2, 131.8, 128.7, 128.4, 128.1, 120.5, 110.6, 73.3, 70.0, 20.7, 20.4; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₇H₁₉N₂O⁺: 267.1492, found: 267.1512.

1-Methyl-1H-imidazo[4,5-b]pyridine (1p)

3-Fluoro-2-nitro-pyridine (1.00 g, 7.04 mmol, 1.0 equiv) was weighted in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by a 2 M solution of MeNH₂ in THF (17.6 mL, 35.2 mmol, 5 equiv). The vial was sealed with a teflon-lined cap and stirred at rt for 30 min. The resulting suspension was filtered over a sintered glass funnel and the filtrate was concentrated in vacuo to give crude N-methyl-2-nitropyridin-3-amine as a bright yellow solid. This solid was then transferred to a 250 mL Morton flask, to which was added 5% w/w Pd/C (749 mg, 0.352 mmol, 0.05 equiv) and absolute ethanol (50 mL). This suspension was vigorously stirred under a hydrogen atmosphere for 2 h. The resulting colorless suspension was filtered over a bed of celite (Et₂O washings) and then concentrated in vacuo to give crude N3-methylpyridine-2,3-diamine as a beige solid. This oil was then transferred into a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8cm), to which was added formic acid (90% w/w in water, 23.6 mL, 564 mmol, 80 equiv). The vial was sealed with a teflon-lined cap and heated at 150°C for 20 min in a Biotage microwave Initiator+ reactor. The reaction mixture was concentrated in vacuo to give a red oil. Purification by flash chromatography over silica gel (100% acetone) gave the desired product 1p as beige crystals (560 mg, 4.21 mmol, 60% overall yield). ¹H NMR spectra matched the reported data.^{20 1}H NMR (600 MHz, D₂O) δ 8.24 (d, J = 4.9 Hz, 1H), 8.10 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.26 – 7.07 (m, 1H), 3.72 (s, 3H).

3-Methyl-3H-imidazo[4,5-b]pyridine (1q)

Under N₂, at 0°C, to a solution of 1H-imidazo[4,5-b]pyridine (500 mg, 4.20 mmol, 1.0 equiv) in dry DMF (2 mL) was added NaH (60% w/w in oil, 252 mg, 6.30 mmol, 1.50 equiv) in one portion. The reaction mixture was stirred at 0 °C for 10 min, then neat MeI (0.40 mL, 6.30 mmol, 1.5 equiv) was added dropwise. The resulting solution stirred at rt for 16 h. The reaction mixture was then poured onto water, EtOAc was added, the phases were separated, and the organic phase was washed twice more with water. The organic phase was dried over Na₂SO₄ and concentrated in vacuo to give a red oil. Purification by flash chromatography over silica gel (80% acetone/petroleum ether) gave the desired product 1q as a pale yellow amorphous solid (275 mg, 2.07 mmol, 49% yield). ¹H NMR matched the reported data.^{20 1}H NMR (600 MHz, D₂O) δ 8.13 (d, J = 5.0 Hz, 1H), 8.09 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.19 (dd, J = 7.6, 5.0 Hz, 1H), 3.70 (s, 3H).

6-(Benzyloxy)-3-methyl-3H-imidazo[4,5-b]pyridine (1r)

3-Methyl-3H-imidazo[4,5-b]pyridin-6-ol (250 mg, 1.68 mmol, 1.0 equiv) and K₂CO₃ (394 mg, 2.85 mmol, 1.7 equiv) were weighted in a 20 mL Biotage microwave vial (#354833, HxD = 8x2.8 cm), followed by MeCN (12 mL). Benzyl bromide (0.30 mL, 2.5 mmol, 1.5 equiv) was added, the vial was sealed with a teflon-lined cap and heated at 80 °C in a Biotage Initiator+ microwave reactor for 5 h. The reaction mixture was filtered over cotton-wool, and the filtrate was concentrated in vacuo. Purification by flash chromatography over silica gel (60% acetone/petroleum ether) gave the desired product 1r as a white amorphous solid (170 mg, 0.710 mmol, 42% yield). mp 119–120 °C; IR (neat) 3079, 2922, 1595, 1512, 1453, 1321, 1221, 1116, 1009, 898, 743, 701 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.26 (d, J = 2.5 Hz, 1H), 7.96 (s, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.46 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 5.15 (s, 2H), 3.89 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 152.4, 145.0, 142.5, 136.5, 136.0, 135.6, 128.8, 128.3, 127.8, 112.4, 71.5, 30.0; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₄H₁₄N₃O⁺: 240.1131, found: 240.1132.

Ethyl 3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate (1s)

3-Methylimidazo[4,5-b]pyridine-6-carboxylic acid (0.126 g, 0.710 mmol, 1.0 equiv) was heated in SOCl₂ (15 mL) at 80 °C for 2 h. The excess of SOCl₂ was removed in vacuo. The remaining residue was dissolved in EtOH (10 mL) and was heated at reflux for 1 h. EtOH was then removed in vacuo. Purification by flash chromatography over silica gel (100% EtOAc) gave the desired product 1s as a white amorphous solid (79 mg, 0.38 mmol, 54% yield). mp 89–90 °C; IR (neat) 3058, 2993, 2928, 1700, 1603, 1403, 1297, 1240, 1180, 1026, 784, 637 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 9.10 (s, 1H), 8.69 (s, 1H), 8.13 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 166.1, 150.1, 146.7, 146.5, 134.8, 129.7, 121.6, 61.4, 30.1, 14.5; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₀H₁₂N₃O₂⁺: 206.0924, found: 206.0930.

General Procedure for Branched Alkylation

In a N₂-filled glovebox, an oven-dried Biotage microwave vial (#352016, HxD = 8x1.5 cm) was charged with [Rh(cod)Cl]₂ (0.05 equiv), 1,2-bis(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)ethane (dAr^Fpe) (0.125 equiv), potassium phosphate (0.25 equiv) and the azole (1.0 equiv). Toluene was then added (c = 0.6 M), and the reaction mixture was stirred for 5 min to give a yellow-red suspension. The alkene was then added (4.0 equiv). The vial was sealed with a teflon-lined septum, taken out of the glovebox and heated for 24 h at 120 °C in a pre-equilibrated oil bath. The reaction mixture was then filtered over a short pad of silica gel (ca. 2 cm) in a pasteur pipette, followed by washing with acetone until the filtrate came out clear. The filtrate was then concentrated in vacuo, and the products were purified by the indicated chromatography techniques.

N,N-Dimethyl-2-(1-methyl-1H-benzo[d]imidazol-2-yl)propanamide (3a)

0.4 mmol scale: Prepared according to the General Procedure from 1-methyl-1H-benzo[d]imidazole 1a (53 mg, 0.40 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (50% acetone/CH₂Cl₂), followed by further purification by preparative TLC (5% MeOH/CH₂Cl₂) gave the desired product 3a as an off-white solid (63 mg, 0.27 mmol, 68% yield). 7.6 mmol scale: Prepared according to the General Procedure from 1-methyl-1H-benzo[d]imidazole 1a (1.00 g, 7.57 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv) using a 10–20 mL Biotage vial (#354833, HxD = 8x2.8 cm). Purification by flash chromatography over silica gel (20% acetone/CH₂Cl₂+1% aqueous NH₄OH) followed by trituration with 10% Et₂O/pentane gave the desired product 3a as an off-white amorphous solid (1.32 g, 5.71 mmol, 75% yield). mp 104–105 °C; IR (neat) 2941, 1631, 1495, 1458, 1432, 1390, 1369, 1305, 1283, 1261, 1132, 1072, 769 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.73 (m, 1H), 7.37 – 7.22 (m, 3H), 4.44 (q, J = 7.2 Hz, 1H), 3.80 (s, 3H), 3.01 (s, 3H), 2.98 (s, 3H), 1.68 (d, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.5, 153.2, 142.2, 136.6, 122.7, 122.2, 119.7, 109.3, 39.4, 37.4, 36.4, 30.5, 16.1; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₃H₁₈N₃O⁺: 232.1444, found: 232.1449.

N,N-dimethyl-2-(1-phenyl-1H-benzo[d]imidazol-2-yl)propanamide (3b)

Prepared according to the General Procedure from 1b (78.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (30% acetone/CH₂Cl₂) gave the desired product 3b as a pale yellow amorphous solid (108 mg, 0.368 mmol, 92% yield). mp 135–137 °C. IR (neat) 3059, 2937, 1642, 1595, 1501, 1454, 1395, 1267, 1148, 1089, 752, 699 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.84 (d, J = 7.9 Hz, 1H), 7.63 – 7.50 (m, 3H), 7.39 – 7.31 (m, 2H), 7.31 – 7.22 (m, 1H), 7.19 (td, J = 7.7, 1.1 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 4.10 (q, J = 7.0 Hz, 1H), 2.80 (s, 3H), 2.66 (s, 3H), 1.66 (d, J = 7.0 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 171.0, 153.8, 142.5, 137.2, 135.8, 130.0, 129.5, 128.1, 123.1, 122.4, 120.0, 110.0, 37.1, 37.0, 36.0, 16.4; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₈H₂₀N₃O⁺: 294.1601, found: 294.1609.

2-(1-((Benzyloxy)methyl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpropanamide (3c)

Prepared according to the General Procedure from 1c (95.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (30% acetone/CH₂Cl₂) gave the desired product 1c as a yellow amorphous solid (129 mg, 0.382 mmol, 96% yield). mp 55–56 °C; IR (neat) 2934, 1648, 1507, 1454, 1394, 1358, 1298, 1137, 1052, 768 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.77 (m, 1H), 7.39 – 7.31 (m, 4H), 7.30 – 7.26 (m, 4H), 5.67 (d, J = 11.0 Hz, 1H), 5.56 (d, J = 11.0 Hz, 1H), 4.51 (s, 2H), 4.44 (q, J = 7.1 Hz, 1H), 2.96 (s, 3H), 2.93 (s, 3H), 1.69 (d, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.7, 153.9, 142.4, 136.8, 135.9, 128.7, 128.3, 127.9, 123.3, 122.7, 120.0, 109.8, 72.5, 70.6, 38.6, 37.4, 36.3, 16.7; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₂₀H₂₄N₃O₂⁺: 338.1863, found: 338.1869.

Ethyl 1-((benzyloxy)methyl)-2-(1-(dimethylamino)-1-oxopropan-2-yl)-1H-benzo[d]imidazole-5-carboxylate (3d)

Prepared according to the General Procedure from 1d (124 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (30% acetone/CH₂Cl₂) gave the desired product 3d as a cream-colored amorphous solid (134 mg, 0.330 mmol, 82% yield). mp 93–94 °C; IR (neat) 3064, 2976, 2939, 1700, 1643, 1618, 1420, 1277, 1216, 1112, 1013, 774, 700 cm^{−1; 1}H NMR (500 MHz, CDCl₃) δ 8.49 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.39 – 7.30 (m, 4H), 7.27 – 7.21 (m, 2H), 5.67 (d, J = 11.0 Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 4.49 (s, 2H), 4.44 (q, J = 7.2 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.98 (s, 3H), 2.93 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 170.6, 167.1, 155.5, 142.0, 139.1, 136.4, 128.8, 128.5, 128.0, 125.3, 124.8, 122.3, 109.5, 72.6, 70.6, 61.0, 38.6, 37.4, 36.3, 16.4, 14.5; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₂₃H₂₈N₃O₄⁺: 410.2074, found: 410.2074.

2-(1-(Dimethylamino)-1-oxopropan-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl propionate (3e)

Prepared according to the General Procedure from ethyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate 1e (82.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (5 to 20% Acetone/CH₂Cl₂) gave the desired product 3e as an orange amorphous solid (87 mg, 0.287 mmol, 72% yield). mp 108–110 °C; IR (neat) 2982, 1705, 1636, 1618, 1453, 1392, 1296, 1247, 1205, 1102, 1083, 907, 773 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.46 (s, 1H), 8.01 (dd, J = 8.6, 1.2 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 4.44 (q, J = 7.2 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.03 (s, 3H), 2.99 (s, 3H), 1.70 (d, J = 7.2 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.3, 167.3, 155.0, 141.8, 139.7, 124.8, 124.3, 122.0, 108.9, 61.0, 39.3, 37.5, 36.4, 30.7, 15.9, 14.5; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₆H₂₂N₃O₃⁺: 304.1656, found: 304.1673.

N,N-Dimethyl-2-(1-methyl-5-methylsulfonyl-benzimidazol-2-yl)propanamide (3f)

Prepared according to the General Procedure from 1f (84.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (0–5% methanol/EtOAc) followed by trituration with 10% Et₂O/pentane gave the desired product 3f as a cream-colored solid (105 mg, 0.34 mmol, 85% yield). mp 176–178 C; IR (neat) 3012, 2997, 2933, 1635, 1421, 1292, 1246, 1143, 974, 774, 620 cm^{−1; 1}H NMR (500 MHz, CDCl₃) δ 8.34 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 4.47 (q, J = 7.2 Hz, 1H), 3.85 (s, 3H), 3.07 (s, 3H), 3.07 (s, 3H), 3.00 (s, 3H), 1.72 (d, J = 7.2 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 170.1, 156.5, 142.0, 139.9, 134.4, 121.5, 120.1, 110.1, 45.3, 39.1, 37.5, 36.4, 30.9, 15.8; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₄H₂₀N₃O₃S⁺: 310.1220, found: 310.1217.

2-(6-Chloro-1-methyl-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpropanamide (3g)

Prepared according to the General Procedure from 1g (82.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (5 to 20% acetone/CH₂Cl₂) gave the desired product 3g as a pale yellow amorphous solid (94 mg, 0.354 mmol, 88% yield. mp 139–140 °C; IR (neat) 3065, 2950, 1644, 1502, 1474, 1392, 1270, 1133, 1052, 922, 821, 671 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.62 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 4.40 (q, J = 7.2 Hz, 1H), 3.75 (s, 3H), 3.02 (s, 3H), 2.99 (s, 3H), 1.68 (d, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.3, 154.1, 140.9, 137.2, 128.5, 122.8, 120.5, 109.5, 39.3, 37.4, 36.4, 30.6, 16.0; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₃H₁₇ClN₃O⁺: 266.1055, found: 266.1055.

2-(5-Cyano-1-methyl-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpropanamide (3h)

Prepared according to the General Procedure from 1h (63 mg, 0.40 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv). Purification by reverse-phase flash chromatography over C18 silica gel (10 to 20% MeCN+0.1% TFA/H₂O+0.1% TFA) gave the desired product as its TFA salt, which was treated with an aqueous saturated solution of NaHCO₃. Extraction with EtOAc, followed by drying with Na₂SO₄ and in vacuo concentration led to the desired product 3h as a white amorphous solid (51 mg, 0.20 mmol, 50% yield). mp 150 °C (decomp); IR (neat) 3083, 2994, 2945, 2216, 1634, 1615, 1483, 1388, 1297, 1075, 915, 823, 636 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.04 (s, 1H), 7.53 (dd, J = 8.4, 1.5 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 4.44 (q, J = 7.2 Hz, 1H), 3.82 (s, 3H), 3.06 (s, 3H), 3.00 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 170.0, 156.1, 141.9, 139.3, 126.2, 124.7, 120.1, 110.4, 105.5, 39.9, 37.5, 36.4, 30.8, 15.8; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₄H₁₇N₄O⁺: 257.1397, found: 257.1405.

N,N-Dimethyl-2-(1-methyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propanamide (3i)

Prepared according to the General Procedure from 1i (80.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (35% acetone/CH₂Cl₂) gave the desired product 3i as a pale yellow amorphous solid (101 mg, 0.337 mmol, 85% yield). mp 112–114 °C; IR (neat) 2993, 1641, 1528, 1461, 1388, 1284, 1215, 1169, 1108, 1089, 957, 805, 750 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.94 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.29 (t_app, J = 7.9 Hz, 1H), 4.40 (q, J = 7.2 Hz, 1H), 3.88 (q, J = 1.7 Hz, 3H), 3.023 (s, 3H), 3.02 (s, 3H), 1.72 (d, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.4, 155.6, 144.4, 132.2, 124.3, 124.0 (q, J = 271 Hz), 121.22 (q, J = 6 Hz), 121.18, 113.7 (q, J = 33 Hz), 39.1, 37.4, 36.5, 32.5 (q, J = 6 Hz), 16.0; ¹⁹F NMR (470 MHz, CDCl₃) δ -53.94; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₄H₁₇F₃N₃O⁺: 300.1318, found: 300.1324

N,N-Dimethyl-2-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propanamide (3j)

Prepared according to the General Procedure from 1j (80.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (35% acetone/CH₂Cl₂) gave the desired product 3j as a pale yellow oil (111 mg, 0.371 mmol, 93% yield). mp 128–130 °C; IR (neat) 2945, 1647, 1471, 1391, 1341, 1307, 1278, 1154, 1107, 1048, 923, 832, 666 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.80 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 7.51 (d, J = 8.3 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 3.84 (s, 3H), 3.03 (s, 3H), 3.00 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.1, 155.9, 144.5, 136.0, 125.0 (q, J = 32 Hz), 124.9 (q, J = 272 Hz), 120.0, 119.2 (q, J = 4 Hz), 107.1 (q, J = 4 Hz), 39.3, 37.5, 36.4, 30.7, 15.9; ¹⁹F NMR (470 MHz, CDCl₃) δ -60.66; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₄H₁₇F₃N₃O⁺: 300.1318, found: 300.1313.

N,N-Dimethyl-2-(1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propanamide (3k)

Prepared according to the General Procedure from 1k (80.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (35% acetone/CH₂Cl₂) gave the desired product 3k as a pale yellow oil (105 mg, 0.351 mmol, 88% yield). mp 148–149°C; IR (neat) 2944, 1646, 1629, 1495, 1391, 1326, 1256, 1228, 1098, 1049, 925, 816, 707 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.01 (s, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 4.46 (q, J = 7.1 Hz, 1H), 3.83 (s, 3H), 3.04 (s, 3H), 2.99 (s, 3H), 1.70 (d, J = 7.1 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 170.2, 155.3, 141.7, 138.5, 125.0 (q, J = 272 Hz), 124.8 (q, J = 32 Hz), 119.7 (q, J = 4 Hz), 117.4 (q, J = 4 Hz), 109.7, 39.3, 37.5, 36.4, 30.8, 15.9; ¹⁹F NMR (470 MHz, CDCl₃) δ -60.66; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₄H₁₇F₃N₃O⁺: 300.1318, found: 300.1331.

N,N-Dimethyl-2-(1-methyl-4-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propanamide (3l)

Prepared according to the General Procedure from 1l (80.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (5 to 20% acetone/CH₂Cl₂) gave the desired product 3l as a pale yellow oil (15 mg, 0.050 mmol, 12% yield). IR (neat) 2926, 1642, 1464, 1428, 1393, 1318, 1212, 1119, 1101, 936, 754 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.53 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.33 (t_app, J = 7.8 Hz, 1H), 4.65 (q, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.08 (s, 3H), 2.97 (s, 3H), 1.68 (d, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.2, 154.7, 139.0 (q, J = 1 Hz), 137.8, 124.1 (q, J = 273 Hz), 121.8, 120.7 (q, J = 32 Hz), 119.6 (q, J = 5 Hz), 113.2, 39.8, 37.6, 36.5, 31.0, 16.0; ¹⁹F NMR (470 MHz, CDCl₃) δ -60.77; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₄H₁₇F₃N₃O⁺: 300.1318, found: 300.1324.

2-(1-((Benzyloxy)methyl)-6-methoxy-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpropanamide (3m)

Prepared according to the General Procedure from 1m (107 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (20 to 40% acetone/CH₂Cl₂) gave the desired product 3m as a pale yellow oil (124 mg, 0.337 mmol, 84% yield). IR (neat) 2936, 1644, 1486, 1454, 1393, 1207, 1139, 1074, 1056, 816, 733 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.63 (d, J = 8.7 Hz, 1H), 7.38 – 7.27 (m, 5H), 6.89 (dd, J = 8.7, 2.3 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 5.61 (d, J = 11.0 Hz, 1H), 5.50 (d, J = 11.0 Hz, 1H), 4.50 (s, 2H), 4.40 (q, J = 7.2 Hz, 1H), 3.81 (s, 3H), 2.96 (s, 3H), 2.93 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.8, 157.0, 152.8, 136.8 (2C), 136.5, 128.7, 128.3, 128.0, 120.4, 111.7, 93.8, 72.4, 70.3, 56.0, 38.7, 37.3, 36.3, 16.6; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₂₁H₂₆N₃O₃⁺: 368.1969, found: 368.1970.

2-(1-((Benzyloxy)methyl)-5-methoxy-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpropanamide (3n)

Prepared according to the General Procedure from 1n (107 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (20 to 40% acetone/CH₂Cl₂) gave the desired product 3n as a pale yellow oil (139 mg, 0.378 mmol, 95% yield). IR (neat) 2938, 1643, 1487, 1441, 1394, 1276, 1197, 1151, 1057, 949, 736 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.38 – 7.29 (m, 3H), 7.28 – 7.26 (m, 3H), 7.22 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.3 Hz, 1H), 5.62 (d, J = 11.0 Hz, 1H), 5.52 (d, J = 11.0 Hz, 1H), 4.49 (s, 2H), 4.39 (q, J = 7.2 Hz, 1H), 3.85 (s, 3H), 2.95 (s, 3H), 2.93 (s, 3H), 1.68 (d, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.6, 156.3, 154.0, 143.0, 136.5, 130.1, 128.5, 128.1, 127.8, 112.8, 110.0, 102.2, 72.3, 70.3, 55.7, 38.2, 37.1, 36.1, 16.5; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₂₁H₂₆N₃O₃⁺: 368.1969, found: 368.1959.

2-(1-((Benzyloxy)methyl)-5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-N,N-dimethylpropanamide (3o)

Prepared according to the General Procedure from 1o (107 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (30% acetone/CH₂Cl₂) gave the desired product 3o as a cream-colored amorphous solid (85 mg, 0.23 mmol, 58% yield). mp 121–123 °C; IR (neat) 2982, 2948, 2844, 1651, 1466, 1382, 1069, 1026, 852, 743, 697 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.51 (s, 1H), 7.38 – 7.27 (m, 5H), 7.08 (s, 1H), 5.62 (d, J = 11.0 Hz, 1H), 5.51 (d, J = 11.0 Hz, 1H), 4.50 (s, 2H), 4.39 (q, J = 7.2 Hz, 1H), 2.93 (s, 3H), 2.92 (s, 3H), 2.36 (s, 6H), 1.66 (d, J = 7.2 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 170.8, 153.0, 141.0, 136.9, 134.4, 132.3, 131.5, 128.7, 128.3, 128.0, 120.1, 110.1, 72.4, 70.4, 38.8, 37.3, 36.4, 20.7, 20.4, 16.8; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₂₂H₂₈N₃O₂⁺: 366.2176, found: 366.2186.

N,N-Dimethyl-2-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)propanamide (3p)

Prepared according to the General Procedure from 1p (100 mg, 0.751 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.31, 3.0 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (5 to 10% MeOH/CH₂Cl₂) gave the desired product 3p as a beige amorphous solid (148 mg, 0.637 mmol, 85% yield). mp 141–143 °C; IR (neat) 2940, 1637, 1612, 1506, 1445, 1408, 1389, 1274, 1142, 1081, 781, 755, 581 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.52 (dd, J = 4.8, 1.2 Hz, 1H), 7.61 (dd, J = 7.9, 1.2 Hz, 1H), 7.19 (dd, J = 7.9, 4.8 Hz, 1H), 4.55 (q, J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.07 (s, 3H), 2.97 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.2, 155.6, 155.2, 144.9, 128.9, 117.8, 117.2, 39.7, 37.6, 36.4, 30.8, 15.8; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₂H₁₇N₄O⁺: 233.1397, found: 233.1397.

N,N-Dimethyl-2-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)propanamide (3q)

Prepared according to the General Procedure from 1q (53.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (60% acetone/CH₂Cl₂) gave the desired product 3q as a pale yellow amorphous solid (90 mg, 0.387 mmol, 97% yield). mp 105–106 °C; IR (neat) 3029, 2977, 1636, 1601, 1509, 1475, 1448, 1399, 1281, 1132, 1076, 806, 782, 702 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.35 (dd, J = 4.8, 1.4 Hz, 1H), 7.99 (dd, J = 8.0, 1.4 Hz, 1H), 7.21 (dd, J = 8.0, 4.8 Hz, 1H), 4.39 (q, J = 7.2 Hz, 1H), 3.86 (s, 3H), 3.02 (s, 3H), 3.00 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.1, 154.7, 148.9, 143.7, 134.5, 127.1, 118.3, 39.3, 37.4, 36.4, 29.0, 15.7; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₂H₁₇N₄O⁺: 233.1397, found: 233.1406.

2-(6-(Benzyloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-N,N-dimethylpropanamide (3r)

Prepared according to the General Procedure from 1r (96.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (40% acetone/CH₂Cl₂) gave the desired product 3r as an off-white amorphous solid (125 mg, 0.369 mmol, 92% yield). mp 128–129 °C; IR (neat) 2941, 1636, 1498, 1453, 1393, 1258, 1174, 1028, 869, 731, 692 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.19 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 7.2 Hz, 2H), 7.38 (t_app, J = 7.3 Hz, 2H), 7.32 (m, 1H), 5.13 (s, 2H), 4.33 (q, J =7.2 Hz, 1H), 3.81 (s, 3H), 3.00 (s, 6H), 1.67 (d, J =7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.1, 155.0, 152.4, 143.8, 136.6, 134.9, 134.6, 128.8, 128.3, 127.7, 112.0, 71.6, 39.3, 37.4, 36.4, 29.0, 15.7; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₉H₂₃N₄O₂⁺: 339.1816, found: 339.1821.

Ethyl 2-(1-(dimethylamino)-1-oxopropan-2-yl)-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate (3s)

Prepared according to the General Procedure from 1s (82 mg, 0.40 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (20% acetone/CH₂Cl₂) gave the desired product 3s as a pale yellow solid (90 mg, 0.30 mmol, 74% yield). mp 137–138 °C; IR (neat) 3041, 2987, 2942, 1715, 1636, 1602, 1481, 1371, 1293, 1197, 1086, 1009, 789, 621 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 9.04 (d, J = 1.8 Hz, 1H), 8.61 (d, J = 1.8 Hz, 1H), 4.46 – 4.37 (m, 3H), 3.88 (s, 3H), 3.05 (s, 3H), 3.01 (s, 3H), 1.73 (d, J = 7.2 Hz, 3H), 1.42 (t, J = 7.1 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 169.9, 166.2, 156.7, 151.5, 146.0, 133.8, 128.6, 121.6, 61.3, 39.3, 37.5, 36.4, 29.3, 15.5, 14.5; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₅H₂₁N₄O₃⁺: 305.1608, found: 305.1624.

2-(1-methyl-1H-benzo[d]imidazol-2-yl)propanal O-methyl oxime (4a)

In a N₂-filled glovebox, a flame-dried Biotage microwave vial (#351521, HxD = 8x1.5 cm) was charged with bis(cyclopentadienyl)zirconium (IV) chloride hydride (62 mg, 0.24 mmol, 1.2 equiv) followed by THF (3 mL). To this suspension was added 3a (46 mg, 0.2 mmol, 1.0 equiv) in THF (2.1 mL), and the vial was sealed with a teflon-lined septum. The mixture was stirred at room temperature for 1.5 h, after which time NH₂-OMe•HCl (50 mg, 0.6 mmol, 3 equiv) was added, and the reaction mixture was stirred for an additional 2 h. The reaction mixture was then concentrated in vacuo. An aqueous saturated solution of NaHCO₃ was added until a pH ~8 was reached, and the resulting mixture was then extracted with EtOAc (3 x 25 mL). The organic phase was dried over Na₂SO₄ and concentrated in vacuo. Purification by flash chromatography over silica gel (15% EtOAc/hexanes + 1% Et₃N) gave a mixture of oxime isomers as a clear oil (38 mg, 0.176 mmol, 88% yield, 3:1 dr). For characterization purposes, stereoisomerically pure samples of each of the isomers were obtained by chromatography over silica gel (1% acetone/CH₂Cl₂ + 1% Et₃N) followed by a second silica gel column (10% EtOAc/Hexanes + 1% Et₃N). (major isomer of 4a): IR (neat) 2991, 2937, 2824, 1615, 1500, 1473, 1279, 1048, 1031, 840, 748 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.36 – 7.23 (m, 3H), 4.03 (p, J = 7.1 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 1.68 (d, J = 7.0 Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 153.9, 150.6, 142.5, 136.0, 122.7, 122.2, 119.7, 109.2, 61.8, 33.7, 30.0, 17.3; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₂H₁₆N₃O⁺: 218.1288, found: 218.1310. (minor isomer of 4a): IR (neat) 2976, 2938, 2833, 1616, 1504, 1468, 1279, 1050, 1031, 872, 743 cm^{−1; 1}H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 6.6 Hz, 1H), 7.34 – 7.23 (m, 3H), 6.91 (d, J = 7.4 Hz, 1H), 4.67 (p, J = 7.1 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 154.5, 150.5, 142.6, 135.8, 122.6, 122.2, 119.8, 109.3, 62.1, 29.7, 28.8, 16.7; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₂H₁₆N₃O⁺: 218.1288, found: 218.1289.

2-(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)propanal O-methyl oxime (4p)

In a N₂-filled glovebox, a flame-dried Biotage microwave vial (#351521, HxD = 8x1.5 cm) was charged with bis(cyclopentadienyl)zirconium (IV) chloride hydride (62 mg, 0.24 mmol, 1.2 equiv) followed by THF (3 mL). To this suspension was added 3p (47 mg, 0.2 mmol, 1.0 equiv) suspended in THF (3.1 mL), and the vial was sealed with a teflon-lined septum. The mixture was stirred at room temperature for 2.5 h, after which time NH₂-OMe•HCl (50 mg, 0.6 mmol, 3 equiv) was added, and the reaction mixture was stirred for an additional 2.5 h. The reaction mixture was the concentrated in vacuo. An aqueous saturated solution of NaHCO₃ was added until a pH ~8 was reached, and the resulting mixture was extracted with EtOAc (3 x 25 mL). The organic phase was dried over Na₂SO₄ and concentrated in vacuo. Purification by flash chromatography over silica gel (80% EtOAc/hexanes + 1% Et₃N) gave a mixture of E- and Z-isomers as a pale yellow oil (29 mg, 0.131 mmol, 66% yield, 3:1 dr). IR (neat) 2987, 2939, 2819, 1612, 1503, 1454, 1408, 1279, 1050, 888, 778, 731 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.51 (d, J = 4.7 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 0.75H), 7.19 (t, J = 8.0, 4.8 Hz, 1H), 6.96 (d, J = 7.3 Hz, 0.25H), 4.68 (p, J = 7.0 Hz, 0.25H), 4.03 (p, J = 7.1 Hz, 0.75H), 3.93 (s, 0.75H), 3.83 (s, 2.25H), 3.80 (s, 2.25H), 3.77 (s, 0.75H), 1.69 (d, J = 7.0 Hz, 2.25H), 1.62 (d, J = 7.0 Hz, 0.75H); ¹³C NMR (151 MHz, CDCl₃) δ 156.9, 156.4, 155.4, 155.3, 150.2, 149.9, 144.6, 144.6, 128.1, 127.9, 117.7, 117.6, 116.99, 116.97, 62.0, 61.7, 33.7, 29.9, 29.7, 28.8, 17.1, 16.6; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₁H₁₅N₄O⁺: 219.1240, found: 219.1247.

Ethyl 2-(1-((benzyloxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-methylpropanoate (6c) and Ethyl 3-(1-((benzyloxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-methylpropanoate (6c′)

Prepared according to the General Procedure from 1c (95 mg, 0.400 mmol, 1.0 equiv) and ethyl methacrylate 5 (0.190 mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (5 to 10% diethyl ether/CH₂Cl₂) gave, by order of elution, the desired products 6c as a pale yellow oil (45 mg, 0.128 mmol, 32% yield) and 6c' as a pale yellow oil (48 mg, 0.136 mmol, 34% yield). (6c): IR (neat) 2985, 1728, 1457, 1361, 1247, 1147, 1064, 1025, 909, 728 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.88 – 7.74 (m, 1H), 7.43 – 7.19 (m, 8H), 5.46 (s, 2H), 4.56 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.81 (s, 6H), 1.13 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 175.1, 156.1, 141.7, 136.6, 136.4, 128.7, 128.3, 127.9, 123.4, 122.6, 120.0, 110.1, 73.0, 70.8, 61.7, 44.7, 26.1, 14.1; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₂₁H₂₅N₂O₃⁺: 353.1860, found: 353.1851. (6c'): IR (neat) 2979, 1725, 1519, 1456, 167, 1281, 1178, 1066, 906, 736, 697 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.87 – 7.61 (m, 1H), 7.40 – 7.21 (m, 8H), 5.65 (d, J = 11.3 Hz, 1H), 5.54 (d, J = 11.3 Hz, 1H), 4.49 (s, 2H), 4.17 – 4.04 (m, 2H), 3.39 – 3.28 (m, 2H), 2.93 (q_app, J = 9.6 Hz, 1H), 1.33 (d, J = 6.7 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 175.7, 153.7, 142.7, 136.7, 135.3, 128.7, 128.3, 127.9, 122.8, 122.5, 119.5, 109.5, 71.9, 70.3, 60.7, 38.3, 30.8, 17.7, 14.2; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₂₁H₂₅N₂O₃⁺: 353.1860, found: 353.1847.

Ethyl 2-methyl-2- (1-methyl-6-trifluoromethyl-1H-benzo[d]imidazol-2-yl)propanoate (6j)

Prepared according to the General Procedure from 1j (80.0 mg, 0.400 mmol, 1.0 equiv) and ethyl methacrylate 5 (0.190 mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (10% acetone/CH₂Cl₂) gave the desired product 6j as a pale yellow oil (108 mg, 0.344 mmol, 86% yield). IR (neat) 2987, 1732, 1509, 1469, 1335, 1279, 1151, 1010, 1049, 822, 732 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 7.85 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.69 (s, 3H), 1.78 (s, 6H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 174.8, 158.7, 144.0, 136.3, 125.0 (q, J = 32 Hz), 124.9 (d, J = 272 Hz), 120.2, 119.2 (q, J = 3 Hz), 107.0 (q, J = 4 Hz), 62.0, 44.6, 31.1, 25.5, 14.3; ¹⁹F NMR (470 MHz, CDCl₃) δ -60.63. HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₅H₁₈F₃N₂O₂⁺: 315.1315, found: 315.1310.

Ethyl 2-methyl-2-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)propanoate (6q)

Prepared according to the General Procedure from 1q (53.0 mg, 0.400 mmol, 1.0 equiv) and ethyl methacrylate 5 (0.190 mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over silica gel (10% acetone/CH₂Cl₂) gave the desired product 4q as a pale yellow oil (95 mg, 0.384 mmol, 96% yield). IR (neat) 2982, 1731, 1602, 1500, 1464, 1407, 1387, 1283, 258, 1229, 1147, 1021, 774 cm^{−1; 1}H NMR (600 MHz, CDCl₃) δ 8.36 (dd, J = 4.8, 1.4 Hz, 1H), 8.03 (dd, J = 7.9, 1.4 Hz, 1H), 7.22 (dd, J = 7.9, 4.8 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 1.78 (s, 6H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 174.7, 157.3, 149.3, 143.8, 134.0, 127.2, 118.3, 61.9, 44.8, 29.5, 25.2, 14.3; HRMS (ESI+, m/z): [M+H]⁺ calcd for C₁₃H₁₈N₃O₂⁺: 248.1394, found: 248.1400.