Microwave-Assisted N-Allylation/Homoallylation-RCM Approach: Access to Pyrrole-, Pyridine-, or Azepine-Appended (Het)aryl Aminoamides

Abstract

A facile and diversity-oriented approach has been developed for the synthesis of pyrrole-, pyridine-, or azepine-appended (het)aryl aminoamides via the N-allylation/homoallylation-ring-closing metathesis (RCM) strategy. Microwave condition was efficiently utilized for N-allylation of (het)aryl aminoamides to synthesize di-, tri-, and tetra-allyl/homoallylated RCM substrates in good yields. All of the RCM substrates were successfully converted to respective pyrroles 6a–h, 13a,b, 15a,b, pyridines 11a–d, 13c, and azepines 7a,b via RCM. All of the five-, six-, and seven-membered N-heterocycles were synthesized in shorter reaction times with excellent yields without isomerization products. A one-pot reaction to synthesize compounds 6a and 6b without isolating corresponding RCM substrates was achieved successfully. The synthetic utility of the compound 6b has been demonstrated by synthesizing biaryl derivatives 17a,b under the microwave Suzuki coupling reaction condition.

Introduction

Among the various N-heterocycle compounds, pyrroles, pyridines, and azepines are the most predominant constituents in many natural products, pharmaceuticals, and functionalized organic molecules.¹⁻⁶

Particularly, many drug molecules and alkaloids possess dihydro pyrroles, tetrahydro pyridines, and tetrahydroazepines as their core moiety (Figure 1).⁷⁻¹³

Figure 1.

Biologically important compounds with pyrrole, pyridine, and azepine heterocycles as cores.

Thus, various expedient routes have been developed for their synthesis. Individually, dihydro pyrroles have been synthesized from intramolecular hydroamination of homoallylic aminols,¹⁴ cyclization of 4-amino butynols,¹⁵ amines with 1,4-dichloro-2-butene under microwave (MW) condition,¹⁶ reaction of Huisgen zwitter ion with benzoyl chlorides,¹⁷ and Nb-catalyzed ring-closing metathesis (RCM) of N,N-diallyl-sulfonamides,¹⁸ as well as from allyl alcohols with amines followed by RCM.¹⁹

On the other hand, tetrahydro pyridines have been synthesized via the reaction of vinyl silanes with iminium/acyl iminium ion,²⁰ alkyne-aza-Prins cyclization of tosyl amines and aldehydes,²¹ radical cyclization of 1,6-enynes,²² reaction of amine aldehyde and esters via the multicomponent reaction (MCR) approach,^23,24 and chemoenzymatic one-pot cascade approach of diallylamines,²⁵ as well as from diallyl aniline using additives via RCM.²⁶

Tetrahydroazepines have been synthesized from cyclohexanone oxime,²⁷ Overman rearrangement–RCM pathway of allylic alcohols,¹³ vinylation of imine–RCM pathway,²⁸ and the reaction of methyl acrylate and allyl amine via RCM.²⁹

In recent years, the microwave (MW) irradiation method has emerged as a complementary tool to classical synthesis.^30,31 And the ring-closing metathesis (RCM)³²⁻³⁵ has been proved as a key step in synthesizing five- and six-membered N-heterocycles. The methods developed for the synthesis of five-, six-, and seven-membered nitrogen heterocycles¹⁴⁻²⁹ require longer and harsh reaction conditions, and more importantly, they suffer isomerization of the product, which impacts the yield of the desired product. To overcome these difficulties and also in continuation to our previous efforts,³⁶ we have developed the microwave-assisted N-allylation/homoallylation-RCM approach to synthesize five-, six-, and seven-membered nitrogen heterocycles. The details of the study are presented in this manuscript.

Results and Discussion

Initially, a mixture of 1 equiv of 2-aminobenzamide (1a) and 2.2 equiv of allyl bromide (2a), with Et₃N as base in CH₃CN was microwave-irradiated (100 W) for 4 min. The reaction afforded 2-(diallylamino)benzamide (3a) in 60% yield (Table 1, entry 1).

Table 1. Optimization of the Synthesis of Compound 3a^a,ba.

entry	base	solvent	MW power (W)	irradiation time (min)	% yield 3ac
1	Et3N	CH3CN	100	4	60
2	Et3N	CH3CN	100	6	75
3	Et3N	CH3CN	100	8	65
4	Et3N	CH3CN	200	2	60
5	Et3N	CH3CN	200	4	85
6	Et3N	CH3CN	200	6	82
7	Et3N	CH3CN	300	2	65
8	Et3N	CH3CN	300	4	80
9	K2CO3	CH3CN	200	4	92d
10	Na2CO3	CH3CN	200	4	87
11	CaH2	CH3CN	200	4	85
12	K2CO3	DMF	200	4	90
13	K2CO3	toluene	200	4	90
14	K2CO3	CH3CN			83e

^aReaction conditions: All of the reactions were carried out on a CEM Discover-300 microwave synthesizer.

^bPower mode, 50 psi.

^cIsolated yield.

^dOptimized condition.

^eReflux for 12 h.

The structure of compound 3a (N₁,N₁-diallylated product) was confirmed after thorough characterization by the spectroscopic method. It should be noted that the other possible N₁,N₂-diallylated and N₁/N₂-monoallylated products were not observed under this condition.

To improve the yield of 3a, an optimization study was undertaken and the parameters such as microwave power, irradiation time, base, and solvent were considered. Thus, a reaction of compounds 1a and 2a in a 1:2.2 ratio was microwave-irradiated at 100 W for 6 min showed a slight improvement of yield of 3a (75%) (Table 1, entry 2). However, upon prolonging the irradiation time to 8 min, a decreased yield of 3a was noted (Table 1, entry 3). Further, improved yields of 3a up to 80% were observed by increasing the microwave power level to 200 and 300 W (Table 1, entries 4–8). Significantly, screening the base afforded compound 3a in excellent yield of up to 92% (Table 1, entries 9–11). The solvent effect in improving the yield of 3a was minimal (Table 1, entries 12 and 13). A reaction under conventional heating yielded the desired product 3a in 83% yield in a longer reaction of 12 h (Table 1, entry 14). Thus, conditions shown in entry 9 of Table 1 were found to be optimum.

Encouraged by the preliminary results, and to expand the scope and diversity of the reaction, various (het)aryl aminoamides 1a–h and alkyl halides 2a–c were screened and the reaction afforded respective diallylated/homoallylated products 3a–h, 4a,b, and 5a (Figure 2). Aminoamides 1a–h with allyl bromide 2a afforded diallylated products 3a–h in good to excellent yields, whereas the reaction with 2b and 2c afforded products 4a,b and 5a in relatively lower yields. This may be due to the reactivity and stability of the corresponding carbocation of allylation/homoallylation reagents 2a–c. Variable yields were observed for the products 3a, 3f, and 3g as the position of the amine group in the substrate is changed. Thus, the allylation of substrates 1a (ortho-NH₂) and 1g (para-NH₂) afforded 3a (92%) and 3g (91%), respectively. While the allylation of 1f (meta-NH₂) afforded product 3f in a slightly decreased yield of 80% (Figure 2). All of the synthesized compounds were thoroughly characterized by spectroscopic data, including single-crystal X-ray diffraction (XRD) data of representative compound 3d (Figure 3).³⁷

Figure 2.

Screened aminoamides 1a–1h and alkylbromides 2a–c and N₁,N₁-dialkylated products 3a–3h, 4a,b, and 5a.

Figure 3.

ORTEP diagram of compound 3d (CCDC 1838002).

Having diallylated products in hand, we then performed a preliminary RCM reaction of the diallylated product 3a in dichloromethane (DCM) with 5 mol % Grubbs I catalyst. The reaction afforded the cyclized product 6a in 87% yield in 5 min (Table 2, entry 1). Further, an optimization study was undertaken by varying the parameters such as catalyst, catalyst loading, temperature, and solvent. Thus, repeating the reaction by increasing the reaction time did not alter the yield (Table 2, entries 2 and 3). Further, the RCM of compound 3a was carried out using Grubbs II catalyst and a slight improvement in the yield was observed (Table 2, entry 4). Subsequent reactions with increased reaction time did not improve the yield of 6a (Table 2, entries 5 and 6). The RCM of 3a was carried out in different solvents such as DCM, toluene, and tetrahydrofuran (THF). The results revealed that toluene was found to be a suitable solvent with an optimum yield of 98% (Table 2, entry 7). The reactions at elevated temperature did not alter the yield, and a slight decrease in the yield was observed after 30 min at 120 °C (Table 2, entry 11). To optimize the catalyst load, RCM reactions with 3 and 10 mol % Grubbs II catalyst were carried out and it was found that 3 mol % catalyst would be sufficient to produce optimum yield (Table 2, entries 12 and 13). Thus, the condition shown in entry 12 of Table 2 was found to be optimum.

Table 2. Optimization of the Synthesis of Compound 6a.

entry	solvent	catalyst (mol %)	time (min)	temp (°C)	% yield 6aa
1	DCM	Grubbs I (5)	5	RT	87
2	DCM	Grubbs I (5)	10	RT	89
3	DCM	Grubbs I (5)	15	RT	89
4	DCM	Grubbs II (5)	3	RT	90
5	DCM	Grubbs II (5)	5	RT	92
6	DCM	Grubbs II (5)	10	RT	92
7	toluene	Grubbs II (5)	3	RT	98
8	THF	Grubbs II (5)	3	RT	93
9	toluene	Grubbs II (5)	5	50	98
10	toluene	Grubbs II (5)	5	100	98
11	toluene	Grubbs II (5)	30	120	92
12	toluene	Grubbs II (3)	3	RT	98b
13	toluene	Grubbs II (10)	3	RT	98

^aIsolated yield.

^bOptimized condition.

To demonstrate the scope of the reaction, under optimized condition, diallylated products 3b–h and 4a,b afforded the corresponding dihydro pyrrole derivatives 6b–h and tetrahydroazepine derivatives 7a,b in excellent yield (Figure 4). The RCM reaction of 2-(di(pent-4-en-1-yl)amino)benzamide 5a was unsuccessful to yield the cyclic product, which might be due to free −NH groups in the substrate.³⁸

Figure 4.

Synthesized 2,5-dihydro-1H-pyrrol-1-yl and 2,3,6,7-tetrahydro-1H-azepin-1-yl-substituted aminoamides 6a–h and 7a,b.

After the successful synthesis of five- and seven-membered N-heterocycles via a two-step procedure, we then explored the possibility of one-pot procedure to synthesize 6a,b directly from 1a,b. Thus, the reaction of 1a/1b with 2a under optimized condition (Table 1, entry 9) and the crude reaction mixture further subjected to RCM (Table 2, entry 12) afforded compounds 6a and 6b in 55 and 63% yields, respectively (Scheme 1).

Scheme 1. One-Pot Synthesis of Compounds 6a,b from 1a,b.

The fruitful results shown in Scheme 1 prompted us to explore the synthesis of six-membered N-heterocycle from the sequential reaction of 1a with allyl bromide 2a, followed by homoallyl bromide 2b and finally RCM cyclization. To achieve the synthesis of six-membered N-heterocycles, as shown in Scheme 2, we have proposed two synthetic routes for the synthesis of 2-(allyl(but-3-en-1-yl)amino)-benzamide 10a. According to route 1, the first N₁-allylated product 8a was synthesized from 1a and allyl bromide 2a, and then, N₁-allyl,N₁-homoallylated product 10a was synthesized in 90% yield from the reaction of 8a and homoallyl bromide 2b under basic condition. In route 2, N₁-homoallylated product 9a was synthesized from 1a and homoallyl bromide 2b and compound 10a was synthesized in 95% yield from 9a and 2a. In both routes 1 and 2, 1 equiv of alkyl halide 2a/2b was used (Table 1, entry 9). It has been observed that N₁-allyl,N₁-homoallylated product 10a synthesized via route 2 has a slight edge over route 1 in terms of yield. Further, the scope of the reaction was extended by synthesizing N₁-allyl,N₁-homoallylated products 10b,c from 1f, 1g, and 1e via route 2 (Scheme 2).

Scheme 2. Synthesis of N₁-Allyl, N₁-Homoallylated Aminoamides 10a–d.

To achieve six-membered N-heterocycles, the RCM reaction of compounds 10a–d under optimized condition (Table 2, entry 12) was carried out to synthesize 1,2,3,6-tetrahydropyridine-substituted aminoamides 11a–d in very good yields (Scheme 3). All of the new compounds were thoroughly characterized by spectroscopic data including single-crystal XRD data of compound 11b (Figure 5).³⁷

Scheme 3. Synthesis of 5,6-Dihydropyridin-1(2H)-yl-Substituted Aminoamides 11a–d.

Figure 5.

ORTEP diagram of compound 11b (CCDC 1947372).

All of the five-, six-, and seven-membered N-heterocycles were synthesized via diallylated/homoallylated RCM substrates. However, we envisaged the possibility of synthesis of tri- and tetra-allylation substrate followed by the RCM cyclization approach to construct the title compounds. Initially, to achieve the synthesis of triallylated RCM substrates, a reaction of 3a with 1 equiv of compound 2a was carried out, although the expected triallylated product 12a was obtained only in 10% yield. The reaction was optimized by varying base, substrate ratio, and solvent. Among the different conditions explored, the reaction of 3a and 2a in a 1:1.2 ratio in dimethyl sulfoxide (DMSO) using NaH as base and microwave power level of 200 W and 4 min irradiation was found to be optimum with 85% yield of 12a (see Table S1, entry 5).

Under similar conditions, triallylated products 12b,c were obtained from 3e and 10d, respectively. All of the trialkylated RCM substrates 12a–c were converted to N₂-allylated 2,5-dihydro-1H-pyrrol-1-yl-substituted aminoamides 13a,b and N-allyl-2-(5,6-dihydropyridin-1(2H)-yl)benzenesulfonamide 13c under optimized RCM cyclization (Scheme 4). We did not observe other possible cyclized products from cyclization of N₁ and N₂ allyl groups.²¹

Scheme 4. Synthesis of N₂-Allylated 2,5-Dihydro-1H-pyrrol-1-yl and 5,6-Dihydropyridin-1(2H)-yl-Substituted Aminoamides 13a–c.

To begin with, the tetra-allylated RCM substrate 14a was obtained in 20% yield from compounds 3a and 2a (2 equiv) using 1,4-dioxane as solvent and NaH as base. The reaction was carried out at 50 W power level and 50 psi pressure under microwave condition over 5 min (see Table S2, entry 1). To improve the yield of compound 14a, an optimization study was conducted. To begin with, a slight increase in the yield was observed by increasing the irradiation time and equivalence of 2a (see Table S2, entries 2–5). Interestingly, a sharp increase in the yield of compound 14a to 82% was observed when the KOH was used as base (see Table S2, entry 6). Repeating the reaction with base NaOH did not improve the yield (see Table S2, entry 7). Thus, the condition shown in entry 6 of Table S2 (see Supporting Information) was found to be optimum. Similarly, compound 14b was synthesized in 85% yield from substrate 3b. Under optimized RCM condition, the synthesized tetra-allylated RCM substrates 14a,b were converted to respective cyclic (2,5-dihydro-1H-pyrrol-1-yl)(2-(2,5-dihydro-1H-pyrrol-1-yl)aryl)methanones 15a,b in excellent yield. Notably, the diazoninone derivative 15b′ was isolated in 10% yield along with 15b from the RCM reaction of 14b, which might be due to the metathesis of N₁ and N₂ allyl groups (Scheme 5).

Scheme 5. Synthesis of (2,5-Dihydro-1H-pyrrol-1-yl)(2-(2,5-dihydro-1H-pyrrol-1-yl)aryl)methanones 15a,b.

To demonstrate the synthetic utility of the products, the microwave-assisted Suzuki reaction³⁹ of 6b with aryl boronic acids 16a,b was successfully attempted to afford 4-(2,5-dihydro-1H-pyrrol-1-yl)-4′-methyl-[1,1′-biphenyl]-3-carboxamide 17a and 4′-cyano-4-(2,5-dihydro-1H-pyrrol-1-yl)-[1,1′-biphenyl]-3-carboxamide17b in 82 and 78% yields, respectively (Scheme 6).

Scheme 6. Synthesis of 2,5-Dihydro-1H-pyrrole-Substituted [1,1′-biphenyl]-3-carboxamides 17a,b from 6b via Suzuki Coupling.

Conclusions

In conclusion, we have synthesized five-, six-, and seven-membered N-heterocycles via the N-allylation-RCM strategy from (het)aryl aminoamides. Di-, tri-, and tetra-allylated products (3a–h, 4a,b, 5a, 10a–d, 12a–c, 14a,b) were synthesized via N-allylation of (het)aryl aminoamides under variable optimized microwave irradiation conditions. Dihydro pyrrole derivatives 6a–h and tetrahydroazepine derivatives 7a,b were synthesized from dialkylated RCM substrates 3a–h and 4a,b, respectively. A direct one-pot reaction has been demonstrated for the synthesized compounds 6a,b without isolating their corresponding diallylated intermediates. Dihydropyridin-1(2H)-yl derivatives 11a–d were synthesized from N₁-allyl,N₁-homoallylated RCM substrates 10a–d. Trialkylated RCM substrates 12a–c were converted to the corresponding N₂-allylated pyrroles 13a,b and N₂-allylated pyridine 13c derivatives. Tetra-allylated RCM substrates 14a,b were converted to (2,5- dihydro-1H-pyrrol-1-yl)(2-(2,5-dihydro-1H-pyrrol-1-yl)aryl) methanones 15a,b. The synthetic utility of compound 6b has been demonstrated by synthesizing pyrrole-substituted biaryl derivatives 17a,b via Suzuki coupling.

Experimental Section

Materials and Methods

All of the reactions were carried out in oven-dried glassware. A CEM Discover-300 microwave synthesizer was used for all of the microwave irradiation reactions. All of the chemicals, including (het)aryl aminoamides (1a–g), alkyl halides (2a–c), aryl boronic acids (16a,b), Grubbs II catalyst, and palladium reagent were purchased from Sigma-Aldrich and used as received. Thin-layer chromatography (TLC) monitored the progress of the reactions, while purification of crude compounds was done by column chromatography using silica gel (mesh size, 100–200). The nuclear magnetic resonance (NMR) spectra were recorded on a Bruker-400 MHz NMR spectrometer (400 MHz for ¹H NMR and 100 MHz for ¹³C NMR) with CDCl₃ or (CD₃)₂SO as the solvent and tetramethylsilane (TMS) as an internal reference. Integrals are in accordance with assignments; coupling constant (J) was reported in hertz (Hz). All ¹³C NMR spectra reported are proton-decoupled. Multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), br s (broad singlet). High resolution mass spectrometry (HRMS) analyses were conducted using Q-T of a Micro mass spectrometer (different mass analyses based on the availability of instruments). Yields refer to quantities obtained after chromatography. All of the commercial solvents were purified before use.

General Experimental Procedure for the Synthesis of N₁,N₁-Dialkylated (Het)aryl aminoamides (3a–h, 4a,b) and 5a

To a solution of (het)aryl aminoamides 1a–h (1 equiv) and alkyl bromide 2a–c (2 equiv) in CH₃CN (1 mL) was added K₂CO₃ (2.5 equiv), and the reaction mixture was microwave-irradiated (power mode) at 200 W for 4 min. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with ethyl acetate and washed with HCl (0.25 M, 10 mL) followed by brine and distilled water, dried over Na₂SO₄, and the solvent was evaporated under reduced pressure. The crude product was purified on a silica gel column to afford the corresponding N,N-dialkylated (het)aryl aminoamides 3a–h in excellent yields, and 4a,b and 5a in good yields (eluent: n-hexane/EtOAc).

Experimental Procedure for the Synthesis of N₁-Monoalkylated Aminoamides (8a and 9a–d)

To a solution of (het)aryl aminoamides 1a–h (1 equiv) and alkyl bromide 2a/2b (1 equiv) in CH₃CN (1 mL) was added K₂CO₃ (2.5 equiv), and the reaction mixture was microwave-irradiated (power mode) at 200 W for 4 min. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with ethyl acetate and washed with HCl (0.25 M, 10 mL) followed by brine and distilled water, dried over Na₂SO₄, and the crude product was purified on a silica gel column to afford the corresponding N₁-monoallylated aminoamides 8a and N₁-mono homoallylated aminoamides 9a–d in good yields (eluent: n-hexane/EtOAc).

Experimental Procedure for the Synthesis of N₁-Allyl,N₁-Homoallylated Aminoamides 10a–d

Synthesis from (Allylamino)benzene Amides (8a)

To a solution of (allylamino)benzene amides 8a (1 equiv) and 4-bromo-1-butene 2b (1 equiv) in CH₃CN (1 mL) was added K₂CO₃ (1.2 equiv), and the reaction mixture was microwave-irradiated (power mode) at 200 W for 4 min. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with ethyl acetate and washed with HCl (0.25 M, 10 mL) followed by brine and distilled water, dried over Na₂SO₄, and the crude product was purified over a column of silica gel to afford the corresponding N₁-allyl,N₁-homoallylated aminobenzamide 10a in good yield (eluent: n-hexane/EtOAc).

Synthesis from (Homoallylamino)Benzene Amides (9a–d)

To a solution of (homoallylamino)benzene amides 13 (1 equiv) and allyl bromide 2a (1 equiv) in CH₃CN (1 mL) was added K₂CO₃ (1.2 equiv), and the reaction mixture was microwave-irradiated (power mode) at 200 W for 4 min. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with ethyl acetate and washed with HCl (0.25 M, 10 mL) followed by brine and distilled water, dried over Na₂SO₄, and the crude product was purified on a silica gel column to afford the corresponding N₁-allyl,N₁-homoallylated aminobenzamides 10a–d in excellent yields (eluent: n-hexane/EtOAc).

Typical Experimental Procedure for the Preparation of Trialkylated Aminoamides 12a–c from 3a/3e/10d

A mixture of N₁,N₁-diallylated aminoamides 3a/3e/10d (1 equiv), allyl bromide 2a (1 equiv), and sodium hydride (1.5 equiv) in 1,4-dioxane (1 mL) was microwave-irradiated (power mode) at 200 W for 4 min. The reaction was quenched with cold water upon completion (monitored by TLC). The crude was extracted with ethyl acetate and washed with dilute HCl (0.25 M, 10 mL) followed by brine and distilled water. The combined organic layer was dried over Na₂SO₄, and the mixture was purified through silica gel column chromatography by gradient elution using EtOAc/hexane as eluent to afford N-allyl-2-(diallylamino)benzamide (12a)/sulfonamide(12b) and N-allyl-2-(allyl(but-3-en-1-yl)amino)benzenesulfonamide (12c) in very good yields.

Experimental Procedure for the Synthesis of N,N-Diallyl-2-(diallylamino)-Substituted Benzamides 14a,b

To a mixture of 3a/3b (1 equiv) and allyl bromide 2a (2 equiv) in 1,4-dioxane (1 mL) was added potassium hydroxide (KOH) (2.5 mmol) and microwave-irradiated (power mode) at 50 W for 7 min. The reaction was quenched with cold water upon completion (monitored by TLC). The crude was extracted with ethyl acetate and washed with dilute HCl and distilled water. The combined organic layer was dried over anhydrous Na₂SO₄. The solvent was removed under vacuum, and the crude was purified by silica gel column chromatography to afford pure N,N-diallyl-2-(diallylamino)-substituted benzamides 14a,b in excellent yields.

General RCM Procedure for the Preparation of Compounds 2,5-Dihydro-1H-pyrrole-Substituted Aminoamides (6a–h, 13a,b, and 15a,b), 5,6-Dihydropyridin-1(2H)-yl-Substituted Aminoamides (11a–d) and 2,3,6,7-Tetrahydro-1H-azepine-Substituted Aminoamides (7a,b)

To a solution of RCM substrates (3a–h/4a,b/5a/10a–d/13a–c/14a,b) in toluene, 3 mol % of Grubbs II catalyst (6 mol % Grubbs II catalyst was used for the substrates 14a,b) was added and stirred at RT for 3 min. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using EtOAc/hexane as eluent to afford pure 2,5-dihydro-1H-pyrrole-substituted aminoamides (6a–h, 13a,b, and 15a,b), 5,6-dihydropyridin-1(2H)-yl-substituted aminoamides (11a–d), and 2,3,6,7-tetrahydro-1H-azepine-substituted aminoamides (7a,b) in excellent yields.

General Procedure for the Preparation of 2,5-Dihydro-1H-pyrrole-Substituted [1,1′-biphenyl]-3-carboxamides 17a,b by Suzuki Coupling

A mixture of 2-(2,5-dihydro-1H-pyrrol-1-yl)-5-iodo- benzamide 6b (1 equiv), arylboronic acids 16 (1.5 equiv), Pd(dppf)Cl₂·DCM (10 mol %), and 0.5 N K₂CO₃ (1 mL) in 4 mL of dioxane–methanol (3:1) was microwave-irradiated (power mode) at 200 W for 10 min. After completion of the reaction (TLC), the solvent was removed in vacuo and the residue was extracted with ethyl acetate and washed with HCl (0.25 M, 20 mL) followed by brine. The combined organic layer was dried over Na₂SO₄, and the mixture was purified through silica gel column chromatography by gradient elution using EtOAc/hexane to afford 2,5-dihydro-1H-pyrrole-substituted [1,1′-biphenyl]-3-carboxamides 17a,b in very good yields.

One-Pot Preparation of 2,5-Dihydro-1H-pyrrole-Substituted Aminoamides 6a,b from 1a and 1b

To a solution of (het)aryl aminoamides 1a/1b (1 equiv) and alkyl bromide 2a (2 equiv) in toluene (1 mL) was added K₂CO₃ (2.5 equiv), and the reaction mixture was microwave-irradiated (power mode) at 200 W for 4 min. After 4 min, the reaction mixture was cooled to room temperature and a 3 mol % of Grubbs II catalyst was added and stirred at RT for 3 min. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using EtOAc/hexane as eluent to afford pure 2,5-dihydro-1H-pyrrole-substituted aminoamides 6a,b in good overall yields.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b04038.

• Optimization of synthesis of compounds 12a and 14a; copies of ¹H NMR,¹³C NMR, DEPT-135, and HRMS data for all of the new compounds; basic crystallographic data of compounds 3d and 11b (PDF)

• Single-crystal XRD data for compound 3d (CIF)

• Single-crystal XRD data for compound 11b (CIF)

M.N. thanks UGC (New Delhi) for the award of RGNF, and P.S. thanks financial support from the DST (New Delhi) via Grant No. SB/EMEQ-044/2014.

The authors declare no competing financial interest.