Microwave-Assisted, Metal-Free, Chemoselective N-Formylation of Amines using 2-Formyl-1,3-dimethyl-1H-imidazol-3-ium Iodide and In Situ Synthesis of Benzimidazole and Isocyanides

Abstract

An efficient, environmentally benign, chemoselective, microwave-assisted N-formylation protocol of aromatic, aliphatic, alicyclic, benzylic amines, inactivated aromatic amines and sterically demanding heterocyclic amines using 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide has been developed. This affords a series of N-substituted formamides with good to excellent yields (23 examples, 53–96% yield) and can be readily scaled. The methodology can be further extended to synthesize benzimidazole and isocyanide derivatives.

Key words

N -formylation - N-formamide - microwave-assisted synthesis - 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide - isocyanide - benzimidazole

Formamides are an important class of organic compounds having diverse applications in synthetic organic chemistry[1] and medicinal chemistry.[2] Pharmaceuticals containing the N-formamide group are on the market and others are in clinical trials (Figure [1]).

Figure 1 Structures of N-formyl group containing pharmaceutical drugs

The formyl group is widely used as a protecting group for amines in peptide synthesis because the amine can be readily deprotected under acidic or basic conditions.[3] [4] Furthermore, N-formamides are important precursors in the preparation of isocyanides,[5,6] formamides,[7] oxazolidinones,[8] [9] [10] benzimidazoles, and quinazolinones.[11] Formamides play an important role in the fields of biochemistry and molecular biology, especially in the area of nucleotides and polynucleotides.[12] [13] [14] [15]

Direct N-formylation of various amines can be achieved using different formylating reagents such as formic acetic anhydride,[16] formic acid in the presence of coupling reagents such as T3P[17] and DCC,[18] Weinreb formamide,[19] methanol,[20] formyloxyacetoxyphenylmethane (FAPM),[21] carbon monoxide,[22] carbon dioxide,[23] [24] [25] ammonium formate,[26] N-formylbenzotrizole,[27] and organic and inorganic catalysis.[28] [29] [30]

However, many of these methods have limitations such as long reaction times, harsh reaction conditions, low yields, expensive reagents, lack of selectivity or generality, and decrease in turnover number of the catalyst. In continuation of our research in the area of development of novel methods for the synthesis of amides,[31] o-uredobenzonitriles,[32] bioactive heterocyclic small molecules,[33] and synthetic applications of T3P[34] [35] [36] [37] [38] [39] and dithioesters,[40] we have developed a microwave-assisted N-formylation protocol for various amines including poorly reactive amines using 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide to overcome many of the challenges with existing formylating reagents.

Our group has also identified several benzimidazole-based anticancer agents;[41] [42] [43] hence, we examined this N-formylation protocol for the synthesis of benzimidazole derivatives as well as for production of isocyanides.

In initial studies (Table [1]), we chose benzylamine 1a (1.0 mmol) and 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide 2 (1.0 mmol), synthesized by using the reported procedure with slight modifications,[44] [45] [46] as model substrates to identify optimal reaction conditions. To begin with, we performed the reaction in the presence of THF as a solvent at 30 °C (entry 1) under microwave irradiation, but obtained very little product. However, we observed an increased yield of product when the reaction was carried out at 40 °C for 60 minutes (entry 2). Upon increasing the temperature to 50 °C and 60 °C, a gradual improvement of yield was observed (entries 3 and 4). When the reaction was carried out at 70 °C under microwave irradiation, we observed complete conversion of starting materials with good yield of product (entry 5). With a further increase in temperature to 80 °C, no improvement in the yield was observed (entry 6). The effect of solvent in terms of the yield was screened (entries 7–11). Upon increasing the amount of formylating agent to 1.1 and 1.2 equivalents, no improvement in the yield was observed (entries 12 and 13). Thus, the optimized conditions for the reaction use benzylamine 1a (1.0 mmol) and formylating agent 2 (1.0 mmol) in THF for 20 minutes at 70 °C under microwave irradiation (entry 5).

Table 1 Optimization of the Reaction Conditions for the Synthesis of 3a

Entry	Solvent	Reagent (equiv)	Temp (°C)	Time (min)	Yield (%)
1	THF	1.0	30	60	15
2	THF	1.0	40	60	20
3	THF	1.0	50	60	30
4	THF	1.0	60	30	86
5a	THF	1.0	70	20	95
6	THF	1.0	80	20	91
7	methanol	1.0	65	30	12
8	DCM	1.0	40	30	38
9	acetonitrile	1.0	82	30	43
10	1,4-dioxane	1.0	100	30	63
11	DMF	1.0	150	30	60
12	THF	1.1	70	20	95
13	THF	1.2	70	20	93

^a Reaction conditions (General procedure A): 1a (1.0 mmol), 2 (1.0 mmol), THF (13 vol), 70 °C, 20 min, MW.

When the reaction was performed with conventional heating at 70 °C for 3 hours, the starting material 1a was completely consumed but the isolated yield of product was lower compared to those observed under microwave conditions. The yield under conventional heating was 78%; whereas under microwave irradiation the yield was 95%.

With the optimized conditions established, we explored the scope and generality of the reaction using various amines; the results are summarized in Scheme [1]. Benzylic, alicyclic, and aliphatic amines resulted in the desired products in good to excellent yields ranging from 53 to 96%. Our results revealed that substrates having an electron-releasing group on the aromatic ring give the respective N-substituted formamides with higher yields, whereas amines having electron-withdrawing groups on the aromatic ring resulted in relatively low yields. We also found that benzylic amines produced N-substituted formamides in better yields compared to aliphatic and alicyclic amines.

We subsequently extended the scope of the reaction to piperidine, pyrrolidine, and dibenzylamine. This protocol is also scalable, with 3a being synthesized at the 1.0 g scale and being obtained in 90% yield, compared to 95% yield when synthesized at 1.0 mmol scale.

Scheme 1 Substrate scope for the synthesis of N-substituted formamides

Table 2 Optimization of the Reaction Conditions for the Synthesis of N-Phenylformamide (5a)

Entry	Solvent	Base	Base (equiv)	Temp (°C)	Time (min)	Yield (%)
1	THF	DIPEA	1.0	70	20	51
2	THF	Et3N	1.0	70	20	56
3	THF	K2CO3	1.0	70	20	40
4	THF	Cs2CO3	1.0	70	20	48
5	THF	Et3N	1.3	70	20	50
6a	THF	Et3N	0.9	70	20	63
7	THF	Et3N	0.8	70	20	60

^a Reaction conditions (General procedure B): 4a (1.0 mmol), 2 (1.0 mmol), Et₃N (0.9 mmol), THF (13 vol), 70 °C, 20 min.

However, aromatic amines produced low yields of the corresponding N-substituted formamides following the optimized conditions. Thus, we further evaluated the best reaction conditions for N-formylation of aromatic amines (Table [2]) using aniline 4a (1.0 mmol) and 2 (1.0 mmol) with different organic and inorganic bases (entries 2–4) under microwave irradiation. We found triethylamine (0.9 mmol) to be the most suitable base.

With these optimized conditions, we explored the scope and generality of the reaction using various aromatic amines; the results are summarized in Scheme [2]. These conditions resulted in the desired products in good to excellent yields ranging from 53 to 72% (seven examples). The results revealed that substrates having electron-donating groups on the aromatic ring gave the respective N-substituted formamides in higher yields compared to substrates having electron-withdrawing groups on the aromatic ring.

Scheme 2 Substrate scope for the synthesis of N-substituted formamides of aryl amines

Substrate Scope

In further efforts to extend the application of this formylation protocol, we developed methods for in situ synthesis of isocyanide (6a, 6b) and benzimidazole (6c) derivatives from the corresponding amines under microwave irradiation.

Isocyanide 6a was obtained by reacting amine 4f in THF with formylating agent 2 in the presence of triethylamine at 70 °C for 20 minutes under microwave irradiation to furnish the corresponding N-formamide intermediate 5f, which was treated with triethylamine and phosphorus oxychloride at 50 °C for 10 minutes under microwave irradiation to give 6a in 58% isolated yield over two steps (Scheme [3]).

Scheme 3 Synthesis of 1-(chlorodifluoromethoxy)-4-isocyanobenzene 6a

Isocyanide 6b was similarly obtained by reacting amine 1h in THF with 2 at 70 °C for 20 minutes under microwave irradiation, giving N-formamide intermediate 3h (Scheme [4]). On treatment with triethylamine and phosphorus oxychloride at 50 °C, 6b was isolated in 66% yield over two steps.

Scheme 4 Synthesis of 2-(isocyanomethyl)pyridine 6b

Equally, benzimidazole derivative 6c was obtained by reacting amine 4g in THF with 2 in the presence of triethylamine at 70 °C for 20 minutes under microwave irradiation to give the corresponding N-formamide intermediate 5g. The in situ generated 5g was then cooled to 0 °C and glacial acetic acid was added. The resulting mixture was heated to 80 °C for 45 minutes under microwave irradiation to give methyl 1-benzyl-1H- benzo[d]imidazole-5-carboxylate 6c in 51% isolated yield over two steps (Scheme [5]).

We propose that the lone pair of electrons present on the nitrogen of the amine attacks the carbonyl carbon of formylating agent 2, eliminating C (Scheme [6]). Subsequent charge neutralization leads to the formation of N-substituted formamide and by-product D. In the case of aromatic amines, triethylamine was necessary to facilitate the attack on 2. We isolated the highly hygroscopic by-product D, and its structure was confirmed by ¹H NMR and ¹³C NMR analysis.

Scheme 5 Synthesis of methyl 1-benzyl-1H-benzo[d]imidazole-5-carboxylate 6c

Scheme 6 Proposed reaction mechanism of N-formylation

In conclusion, we have developed an efficient microwave-assisted protocol for N-formylation of amines, including aromatic amines, with a diversity of functional groups using a novel formylating agent 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide. This method provides rapid access to N-formylated products under metal-free, chemoselective, mild conditions with good to excellent yields and broad substrate scope. We have also demonstrated the synthesis of benzimidazole derivatives and substituted isocyanides via in situ generated N-substituted formamides.

Starting materials, reagents, and solvents were purchased from commercial sources and used as received unless stated otherwise. Moisture- or air-sensitive reactions were conducted under a nitrogen atmosphere in oven-dried glass apparatus. The microwave instrument used was an Anton Paar, Monowave 200. Reaction progress was monitored by thin-layer chromatography (TLC) on pre-coated silica gel plates (Silica gel 60 F₂₅₄; Merck) and visualization was accomplished with UV light or potassium permanganate followed by heating. Solvents were removed under reduced pressure using a rotary evaporator. Purification of intermediates and final compounds was carried out using silica gel 230–400 mesh (particle size 40–63 μm) column chromatography. NMR spectra were recorded with Bruker 400 MHz, 300 MHz and 100 MHz spectrometers (DMSO-d ₆ and CDCl₃). Chemical shifts are reported in ppm using the TMS as internal standard. Multiplicities are reported as, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, with coupling constants in Hz. LCMS analyses were performed with an Agilent Technologies Infinity 1290. HRMS analyses were performed with a Waters SYNAPTG2. HPLC analyses were performed with an Agilent, Infinity II LC System.

Synthesis of N-Substituted Formamides 3a–p; General Procedure A

To a solution of 1a–p (1.0 equiv) in THF in a 5 mL microwave reaction vial was added 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide 2 (1.0 equiv) at room temperature under nitrogen atmosphere. The resulting reaction mixture was sealed, pre-stirred for 3 minutes and then heated at 70 °C for 20 minutes under microwave irradiation (ca. 100 W of initial power). Subsequently, the reaction mixture was cooled to room temperature, quenched with water and the organic phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (silica gel 230–400 mesh, eluting with 1–6% methanol in dichloromethane) to obtain pure compounds 3a–p.

Synthesis of Compounds 5a–g; General Procedure B

To a solution of the aromatic amine 4a–g (1.0 equiv) in THF in a 5 mL microwave reaction vial were added triethylamine (0.9 equiv) and 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide 2 (1.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was sealed, pre-stirred for 3 minutes and then heated at 70 °C for 20 minutes under microwave irradiation (ca. 100 W of initial power). Then, the reaction mixture was cooled to room temperature, quenched with water and the organic phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (silica gel 230–400 mesh, eluting with 1–3% MeOH in dichloromethane) to obtain pure compounds 5a–g.

N-Benzylformamide 3a

Yield: 94%; off-white solid; TLC R_f = 0.44 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.50 (s, 1 H, N-H), 8.13–8.14 (t, J = 0.8 Hz,1 H, -CHO), 7.23–7.25 (m, 5 H, Ar-H), 4.29–4.31 (d, J = 6.0 Hz, 2 H, -CH₂)

¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.50, 139.45, 128.91, 128.74, 127.82, 127.76, 127.34, 41.17.

MS (ESI): m/z [M + H]⁺ calcd for C₈H₉NO: 136.06; found: 136.2.

LCMS purity = 98.802%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₉NO: 136.0684; found: 136.1210.

N-(4-Methoxybenzyl)formamide 3b

Yield: 96%; pale-yellow solid; TLC R_f = 0.38 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.42 (s, 1 H, -NH), 8.10 (s, 1 H, -CHO), 7.18–7.20 (d, J = 8.40 Hz, 2 H, Ar-H), 6.88–6.92 (t, J = 8.60 Hz, 2 H, Ar-H), 4.22–4.23 (d, J = 6.0 Hz, 2 H, -CH₂), 3.73 (s, 3 H, -OCH₃).

¹³C NMR (100 MHz, DMSO-d₆ ): δ = 161.35, 158.74, 131.40, 129.12, 128.82, 114.31, 114.20, 55.52, 40.02.

MS (ESI): m/z [M + H]⁺ calcd for C₉H₁₁NO₂: 166.08; found: 166.1.

LCMS purity = 99.6%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₁NO₂: 166.0790; found 166.1051.

N-Benzyl-N-methylformamide 3c

Yield: 93%; colorless oil; TLC R_f = 0.33 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ (mixture of cis-trans-rotamers, 1: 0.65) = 8.29 (s, 1 H, -CHO), 7.30–7.40 (m, 5 H, Ar-H), 4.45 (s, 2 H, -CH₂), 2.50 (s, 3 H, -CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.27, 137.38, 129.13, 129.01, 128.16, 128.14, 52.57, 34.10.

MS (ESI): m/z [M + H]⁺ calcd for C₉H₁₁NO: 150.08; found: 150.1.

LCMS purity = 99.3%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₁NO: 150.0841; found: 150.1369.

HPLC (0.1% TFA in Water: Acetonitrile): R_t = 10.062 min.

N,N-Dibenzylformamide 3d

Yield: 92%; white solid; TLC R_f = 0.58 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.47 (s, 1 H, -CHO), 7.34–7.40 (m, 5 H, Ar-H), 7.31–7.33 (m, 1 H, Ar-H), 7.25–7.30 (m, 2 H, Ar-H), 7.17–7.23 (m, 2 H, Ar-H), 4.36 (s, 2 H, -CH₂), 4.28 (s, 2 H, -CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.70, 137.14, 137.01, 129.16, 128.99, 128.28, 128.17, 127.72, 50.14, 44.64.

MS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₅NO: 226.12; found: 226.1.

LCMS purity = 99.9%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₅NO: 226.1154; found: 226.1756.

N-(3-Bromobenzyl)formamide 3e

Yield: 86%; off-white solid; TLC R_f = 0.33 (petroleum ether/ethyl acetate­ 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.54 (s, 1 H, -NH), 8.14–8.15 (d, J = 1.6 Hz, 1 H, -CHO), 7.44–7.49 (m, 2 H, Ar-H), 7.26–7.32 (m, 2 H, Ar-H), 4.29–4.33 (d, J = 15.2 Hz, 2 H, -CH₂).

¹³C NMR (100 MHz, CDCl₃): δ = 161.07, 139.93, 130.78, 130.69, 130.34, 126.33, 122.78, 41.48.

¹³C NMR-DEPT135 (400 MHz, DMSO-d ₆): δ = 40.60 (CH₂).

MS (ESI): m/z [M + H]⁺ calcd for C₈H₈BrNO [⁷⁹Br]: 213.98; found: 214.0.

LCMS purity = 99.99%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₈BrNO [⁷⁹Br] [M + H]⁺: 213.9789, C₈H₈BrNO [⁸¹Br] [M + H]⁺²: 215.9789; found: 213.9573 [⁷⁹Br] [M + H]⁺, 215.8934 [⁸¹Br] [M + H]⁺².

N-(3-Chlorobenzyl)formamide 3f

Yield: 84%; off-white solid; TLC R_f = 0.26 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.54 (s, 1 H, -NH), 8.152–8.155 (t, J = 0.6 Hz, 1 H, -CHO), 7.30–7.39 (m, 3 H, Ar-H), 7.22–7.26 (m, 1 H, Ar-H), 4.30–4.34 (d, J = 14.8 Hz, 2 H, -CH₂).

¹³C NMR (100 MHz, CDCl₃): δ = 161.16, 139.68, 134.58, 130.07, 127.81, 127.74, 125.82, 41.52.

MS (ESI): m/z [M + H]⁺ calcd for C₈H₈ClNO: 170.03; found: 170.1.

LCMS purity = 99.91%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₈ClNO: 170.0294; found: 170.0378.

N-(4-Methylbenzyl)formamide 3g

Yield: 96%; white solid; TLC R_f = 0.25 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.45 (s, 1 H, -NH), 8.114–8.118 (t, J = 0.8 Hz, 1 H, -CHO), 7.12–7.16 (m, 4 H, Ar-H), 4.24–4.25 (d, J = 6.0 Hz, 2 H, -CH₂), 2.27 (s, 3 H, -CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.39, 136.40, 129.32, 127.75, 40.28, 21.11.

MS (ESI): m/z [M + H]⁺ calcd for C₉H₁₁NO: 150.08; found: 150.1.

LCMS purity = 98.25%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₁NO: 150.0841; found: 150.1778.

N-(Pyridin-2-ylmethyl)formamide 3h

Yield: 78%; pale-yellow liquid; TLC R_f = 0.30 (dichloromethane/methanol 9:1 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.59 (s, 1 H, -NH), 8.50–8.53 (t, J = 6.4 Hz, 1 H, -CHO), 8.17 (s, 1 H, Ar-H), 7.75–7.80 (m, 1 H, Ar-H), 7.26–7.31 (m, 2 H, Ar-H), 4.39–4.41 (d, J = 6.4 Hz, 2 H, -CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.73, 158.40, 149.34, 137.24, 122.67, 121.58, 43.22.

MS (ESI): m/z [M + H]⁺ calcd for C₇H₈N₂O: 137.06; found: 137.0.

LCMS purity = 99.81%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₇H₈N₂O: 137.0637; found: 137.1333.

N-(4-Cyanobenzyl)formamide 3i

Yield: 90%; off-white solid; TLC R_f = 0.48 (dichloromethane/methanol 9:1 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.62 (s, 1 H, -NH), 8.184–8.188 (d, J = 1.6 Hz, 1 H, -CHO), 7.80–7.83 (m, 2 H, Ar-H), 7.45–7.47 (d, J = 8.8 Hz, 2 H, Ar-H), 4.38–4.40 (d, J = 6.4 Hz, 2 H, -CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.83, 145.41, 132.78, 128.52, 119.32, 110.10, 40.19.

MS (ESI): m/z [M – H]^– calcd for C₉H₈N₂O: 159.06; found: 159.0.

LCMS purity = 99.71%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₈N₂O: 161.0637; found: 161.1165.

N-(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl)formamide 3j

Yield: 81%; pale-yellow solid; TLC R_f = 0.27 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.33 (s, 1 H, -NH), 7.95 (s, 1 H, -CHO), 6.97–7.00 (d, J = 14.4 Hz, 2 H, Ar-H), 4.46–4.51 (m, 1 H, -CH), 3.08–3.14 (m, 2 H, -CH₂), 2.66–2.72 (m, 2 H, -CH₂), 2.53–2.59 (m, 4 H, -2CH₂), 1.15–1.11 (t, J = 7.6 Hz, 6 H, -2CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.17, 139.94, 139.87, 138.99, 138.72, 124.96, 124.69, 49.24, 40.12, 27.28, 25.34, 16.10.

MS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₉NO: 218.15; found: 218.2.

LCMS purity = 97.47%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₉NO: 218.1467; found: 218.1622.

N-(Cyclopentylmethyl)formamide 3k

Yield: 64%; pale-yellow liquid; TLC R_f = 0.26 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.02 (s, 1 H, -NH), 7.91 (s, 1 H, -CHO), 4.06–4.01 (m, 1 H, -CH), 1.81–1.77 (m, 2 H, -CH₂), 1.60–1.64 (m, 4 H, –2CH₂), 1.52–1.51 (m, 2 H, -CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.78, 49.33, 32.75, 32.72, 23.83, 23.80.

MS (ESI): m/z [M + H]⁺ calcd for C₆H₁₁NO: 114.08; found: 114.2.

LCMS purity = 99.93%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₆H₁₁NO: 114.0841; found: 114.1295.

N-Hexylformamide 3l

Yield: 69%; colorless liquid; TLC R_f = 0.29 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.97 (s, 2 H, -NH and -CHO), 3.02–3.08 (m, 2 H, -CH₂), 1.36–1.38 (d, J = 6.3 Hz, 2 H, -CH₂), 1.24 (s, 6 H, -3CH₂), 0.83–0.86 (d, J = 6.6 Hz, 3 H, -CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.27, 37.50, 31.37, 29.42, 26.47, 22.49, 14.32.

MS (ESI): m/z [M + H]⁺ calcd for C₇H₁₅NO: 130.12; found: 130.2.

LCMS purity = 100%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₇H₁₅NO: 130.1154; found: 130.1651.

Piperidine-1-carbaldehyde 3m

Yield: 73%(145 mg); colorless liquid; TLC R_f = 0.2 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.95 (s, 1 H, -CHO), 3.28–3.35 (m, 4 H, -2CH₂), 1.58–1.63 (m, 2 H, -CH₂), 1.46–1.50 (m, 2 H, -CH₂), 1.38–1.44 (m, 2 H, -CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.04, 46.21, 26.69, 25.35, 24.69.

MS (ESI): m/z [M + H]⁺ calcd for C₆H₁₁NO: 114.08; found: 114.1.

LCMS purity = 99.83%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₆H₁₁NO: 114.0841; found: 114.1295.

Pyrrolidine-1-carbaldehyde 3n

Yield: 70%; colorless liquid; TLC R_f = 0.65 (dichloromethane/methanol 9:1 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.17 (s, 1 H, -CHO), 3.43–3.46 (t, J = 6.2 Hz, 2 H, -CH₂), 3.20–3.24 (t, J = 6.6 Hz, 2 H, -CH₂), 1.77–1.83 (t, J = 12 Hz, 4 H, -2CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.06, 45.81, 43.13, 24.91, 24.23.

MS (ESI): m/z [M + H]⁺ calcd for C₅H₉NO: 100.07; found: 100.3.

LCMS purity = 99.82%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₅H₉NO: 100.0684; found: 100.1117.

N-tert-Butylformamide 3o

Yield: 53%; colorless liquid; TLC R_f = 0.29 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.847–7.843 (d, J = 1.6 Hz, 1 H, -CHO), 7.69 (s, 1 H, -NH), 7.26 (s, 9 H, -3CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.79, 50.26, 28.99.

MS (ESI): m/z [M + H]⁺ calcd for C₅H₁₁NO: 102.08; found: 102.3.

LCMS purity = 99.34%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₅H₁₁NO: 102.0841; found: 102.0932.

N,N-Dimethylformamide 3p

Yield: 58%; colorless liquid; TLC R_f = 0.74 (dichloromethane/methanol 9:1 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.95 (s, 1 H, -CHO), 2.89 (s, 3 H, -CH₃), 2.737–2.738 (d, 3 H, -CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.76, 36.22, 31.21.

MS (ESI): m/z [M + H]⁺ calcd for C₃H₇NO: 74.05; found: 147.2 [M + H × 2, dimer mass]⁺.

LCMS purity = 97.31%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃H₇NO: 74.0528; found: 74.0906.

N-Phenylformamide 5a

Yield: 63%; off-white solid; TLC R_f = 0.45 (petroleum ether/ethyl acetate­ 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.18 (s, 1 H, -NH), 8.27–8.28 (d, J = 1.6 Hz, 1 H, -CHO), 7.58–7.60 (d, J = 7.6 Hz, 2 H, Ar-H), 7.30–7.34 (t, J = 8.0 Hz, 2 H, Ar-H), 7.06–7.11 (m, 1 H, -Ar-H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.04, 138.71, 129.33, 124.07, 119.59.

MS (ESI): m/z [M + H]⁺ calcd for C₇H₇NO: 122.05; found: 122.2.

LCMS purity = 99.88%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₇H₇NO: 122.0528; found: 122.1004.

N-(4-Methoxyphenyl)formamide 5b

Yield: 71%; pale-brown solid; TLC R_f = 0.32 (petroleum ether/ethyl acetate­ 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.00 (s, 1 H, -NH), 8.19–8.20 (d, J = 2.0 Hz, 1 H, -CHO), 7.48–7.52 (m, 2 H, Ar-H), 6.87–6.91 (m, 2 H, Ar-H), 3.72 (s, 3 H, -OCH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.50, 155.86, 131.92, 120.16, 114.43, 55.63.

MS (ESI): m/z [M + H]⁺ calcd for C₈H₉NO₂: 152.06; found: 152.2.

LCMS purity = 99.81%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₉NO₂: 152.0633; found: 152.1145.

N-p-Tolylformamide 5c

Yield: 72%; pale-brown solid; TLC R_f = 0.45 (petroleum ether/ethyl acetate­ 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.07 (s, 1 H, -NH), 8.222–8.227 (d, J = 2.0 Hz, 1 H, -CHO), 7.45–7.48 (m, 1 H, Ar-H), 7.05–7.12 (m, 3 H, Ar-H), 2.24 (s, 3 H, -CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.77, 136.22, 133.15, 132.97, 129.66, 119.55, 20.89.

MS (ESI): m/z [M + H]⁺ calcd for C₈H₉NO: 136.07; found: 136.1.

LCMS purity = 99.94%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₉NO: 136.0684; found: 136.1183.

N-(4-Bromophenyl)formamide 5d

Yield: 55%; off-white solid; TLC R_f = 0.41 (petroleum ether/ethyl acetate­ 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.32 (s, 1 H, -NH), 8.293–8.298 (d, J = 2.0 Hz, 1 H, -CHO), 7.54–7.58 (m, 2 H, Ar-H), 7.48–7.52 (m, 2 H, Ar-H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.22, 138.04, 132.15, 121.55, 115.64.

MS (ESI): m/z [M – H]^–2 calcd for C₇H₆BrNO: 199.96; found: 200.1.

LCMS purity = 99.16%.

HRMS (ESI): m/z calcd for C₇H₆BrNO [⁷⁹Br]⁺ [M + H]⁺: 199.9633, [⁸¹Br] [M + H]⁺²: 201.9633; found: 200.0219 [M + H]⁺, 202.0183 [M + H]⁺².

N-(4,6-Dichloropyrimidin-2-yl)formamide 5e

Yield: 48%; off-white solid; TLC R_f = 0.64 (petroleum ether/ethyl acetate­ 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 11.52 (s, 1 H, -NH), 9.06 (S, 1 H, -CHO), 7.38 (S, 1 H, Ar-H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.63, 161.48, 159.06, 107.05.

MS (ESI): m/z calcd for C₅H₃Cl₂N₃O [M + H]⁺: 191.97, C₅H₃Cl₂N₃O [M + H]⁺²: 193.97; found: 192.0 [M + H]⁺, 194.0 [M + H]⁺².

LCMS purity = 97.68%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₅H₃Cl₂N₃O: 191.9653; found: 192.0220.

N-(4-(Chlorodifluoromethoxy)phenyl)formamide 5f

Yield: 66%; pale-yellow solid; TLC R_f = 0.45 (petroleum ether/ethyl acetate­ 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.40 (s, 1 H, -NH), 8.305–8.309 (d, J = 1.6 Hz, 1 H, -CHO), 7.69–7.72 (m, 2 H, Ar-H), 7.31–7.34 (d, J = 8.4 Hz, 2 H, Ar-H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.24, 145.37, 137.92, 125.43, 123.15, 122.58, 120.92, 119.13.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –24.85.

MS (ESI): m/z [M – H]^– calcd for C₈H₆ClF₂NO₂: 220.01; found: 220.0.

LCMS purity = 99.77%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₆ClF₂NO₂: 222.0055; found: 222.0668.

Methyl 4-(Benzylamino)-3-formamidobenzoate 5g

Yield: 54%; pale-brown solid; TLC R_f = 0.47 (petroleum ether/ethyl acetate­ 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.53 (s, 1 H, -NH), 8.306–8.309 (d, J = 1.2 Hz, 1 H, -CHO), 7.86–7.87 (d, J = 2.0 Hz, 1 H, -NH), 7.55–7.58 (m, 1 H, Ar-H), 7.31–7.38 (m, 4 H, Ar-H), 7.22–7.26 (m, 1 H, Ar-H), 6.56–6.59 (m, 1 H, Ar-H), 6.478 (s, 1 H, Ar-H), 4.41–4.43 (d, J = 6.0 Hz, 2 H, -CH₂), 3.74 (s, 3 H, -CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.50, 164.41, 146.47, 139.44, 128.94, 127.54, 127.39, 121.91, 116.42, 110.43, 51.87, 46.34.

MS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₆N₂O₂: 285.12; found: 285.1.

LCMS purity = 99.90%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₆N₂O₂: 285.1161; found: 285.1861.

1-(Chlorodifluoromethoxy)-4-isocyanobenzene 6a

To a solution of compound 4f (150 mg, 0.774 mmol, 1.0 equiv) in THF (2 mL) in a 10 mL microwave reaction vial, 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide 2 (198 mg, 0.785 mmol, 1.0 equiv) and triethylamine (0.1 mL, 0.716 mmol, 0.9 equiv) were added at room temperature under a nitrogen atmosphere. The resulting reaction mixture was pre-stirred for 1 minute and then it was heated at 70 °C for 20 minutes under microwave irradiation. Then the reaction mixture was cooled to 0 °C, triethylamine (0.36 mL, 2.581 mmol, 3.3 equiv) and phosphorus oxychloride (0.08 mL, 0.858 mmol, 1.1 equiv) were added and the mixture was stirred for 1 minute and then heated at 50 °C for 10 minutes under microwave irradiation. After that, the reaction mixture was cooled to room temperature, quenched with ice cold water and the organic phase was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with water and brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography eluting with 15–20% ethyl acetate in petroleum ether to obtain 6a as a dark gum in 58% yield (91 mg).

TLC R_f = 0.92 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.74–7.78 (m, 2 H, Ar-H), 7.50–7.54 (m, 2 H, Ar-H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.82, 149.97, 149.95, 129.11, 127.91, 125.04, 123.34, 122.17.

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –25.27.

MS (ESI): m/z [M + H]⁺ calcd for C₈H₄ClF₂NO: 203.99; found 203.9.

LCMS purity = 96.10%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₄ClF₂NO: 203.9944; found: 204.0218.

2-(Isocyanomethyl)pyridine 6b

To a solution of 1h (150 mg, 1.237 mmol) in THF (2 mL) in a 10 mL microwave reaction vial, 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide 2 (313 mg, 1.241 mmol, 1.0 equiv) was added at room temperature under a nitrogen atmosphere. The resulting reaction mixture was pre-stirred for 1 minute and then it was heated at 70 °C for 20 minutes under microwave irradiation. Then the reaction mixture was cooled to 0 °C, triethylamine (0.58 mL, 4.158 mmol, 3.3 equiv) and phosphorus oxychloride (0.13 mL, 1.394 mmol, 1.1 equiv) were added, the mixture was stirred for 1 minute and then it was heated at 50 °C for 10 minutes under microwave irradiation. After that, the reaction mixture was cooled to room temperature, quenched with ice cold water and the organic phase was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography using 60–70% ethyl acetate in petroleum ether to obtain pure compound 6b as an off-white solid in 66% yield (121 mg).

TLC R_f = 0.26 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, CDCl₃): δ = 8.14 (s, 1 H, Ar-H), 7.93–7.95 (m, 1 H, Ar-H), 7.43–7.47 (m, 2 H, Ar-H), 6.70–6.74 (m, 1 H, -CH₂), 6.55–6.59 (m, 1 H, -CH₂).

¹³C NMR (100 MHz, CDCl₃): δ = 130.28, 127.56, 122.31, 119.79, 119.00, 118.40, 112.73.

MS (ESI): m/z [M + H]⁺ calcd for C₇H₆N₂: 119.05; found: 119.0.

LCMS purity = 92.36%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₇H₆N₂: 119.0531; found: 119.1021.

Methyl 1-Benzyl-1H-benzo[d]imidazole-5-carboxylate 6c

To a solution of 4g (150 mg, 0.585 mmol, 1.0 mmol) in THF (2 mL) in a 10 mL microwave reaction vial, 2-formyl-1,3-dimethyl-1H-imidazol-3-ium iodide 2 (148 mg, 0.587 mmol, 1.0 equiv), and triethylamine (0.08 mL, 0.573 mmol, 1.0 equiv) were added at room temperature under a nitrogen atmosphere. The resulting reaction mixture was pre-stirred for 1 minute and then it was heated at 70 °C for 20 minutes under microwave irradiation. The reaction mixture was cooled to room temperature then glacial acetic acid (1.0 mL) was added. The resulting mixture was stirred for 3 minutes and then heated at 80 °C for 45 minutes under microwave irradiation and then cooled to room temperature. The reaction was quenched with ice cold water, the organic phase was extracted with ethyl acetate (3 × 15 mL) and the combined organic phases were washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography eluting with 30–35% ethyl acetate in petroleum ether to obtain pure 6c as a pale-yellow solid in 51% yield (79 mg).

TLC R_f = 0.52 (petroleum ether/ethyl acetate 5:5 V/V).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.58 (s, 1 H, Ar-H), 8.26–8.27 (d, J = 1.2 Hz, 1 H, Ar-H), 7.84–7.87 (m, 1 H, Ar-H), 7.64–7.66 (m, 1 H, Ar-H), 7.28–7.37 (m, 5 H, Ar-H), 5.56 (s, 2 H, -CH₂), 3.73 (s, 3 H, -OCH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 167.14, 146.93, 143.63, 137.49, 137.05, 129.24, 128.34, 127.88, 123.95, 123.81, 121.70, 111.37, 52.48, 48.27.

MS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₄N₂O₂: 267.11; found: 267.1.

LCMS purity = 94.62%.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₄N₂O₂: 267.1055; found: 267.1755.

Conflict of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

We thank the NMR, LCMS & HRMS Facility, Institute of Excellence, University of Mysore, Manasagangotri, Mysuru-570006, India, for analyses.

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Publication History

Received: 20 March 2022

Accepted after revision: 27 April 2022

Article published online:
08 June 2022