Copper-Promoted Regioselective Intermolecular Diamination of Ynamides: Synthesis of Imidazo[1,2-a]pyridines.

A facile access to 3-heterosubstituted (3-oxazolidinonyl/indolyl/phenoxy) imidazo[1,2-a]pyridines from readily available 2-aminopyridines and electron-rich (internally activated) alkynes like ynamides/ynamines/ynol ethers is achieved via Cu(OTf)2-mediated intermolecular diamination under aerobic conditions. The reaction is highly regioselective, owing to internal electron bias, and thus led to a single regioisomer with heterosubstitution at C3.

Introduction

Over the past 2 decades, ynamides[1] have been featured as one of the utmost versatile building blocks in organic synthesis, pharmaceuticals, agrochemicals, and material science. This is mainly because of the embedded nitrogen atom as an electron donor directly attached to CSP which imposes a strong electronic bias, rendering levels of chemo-, regio-, and stereo-selectivities. Moreover, several pharmaceutically and naturally significant structural motifs that contain nitrogen-embedded heterocycles, such as indoles,[2a,2b] pyridines,[2c−2e] and oxazolones,[2f,2g] were successfully synthesized from ynamides under metal-catalyzed or metal-free conditions.

The imidazo[1,2-a]pyridine[3] skeleton, a class of nitrogen-containing heterocycles composed of pyridine and imidazole rings, shows numerous biological activities,[4] such as antitumor, antiparasitic, antimicrobial, fungicidal, anti-inflammatory, and hypnotic, and thus is present in several marketed drugs[5] such as alpidem, zolpidem, necopidem, saripidem, zolimidine, and olprinone. Owing to such key pharmacological properties, this moiety has earned significant attention from chemists to develop mild and prolific strategies for its synthesis.

Therefore, numerous methods have been developed so far to assemble imidazo[1,2-a]pyridine from intermolecular heteroannulation of 2-aminopyridines with various precursors such as α-halo ketones,[6] α-diazo ketones,[7] carbonyls,[8] nitro olefins,[9] alkenes,[9c] and alkynes[10a,10b] via condensation, multicomponent reaction, aminoxygenation, hydroamination, oxidative coupling, and C–H functionalization of imidazo[1,2-a]pyridines[10c−10f] toward diverse substitutions at 2- and 3-positions.

Intermolecular diamination of alkynes[11] has emerged as a fascinating area of research in current organic synthesis. It involves heteroannulation with multiple C–N bond formations, providing rapid access to various medicinally important heterocycles such as imidazoles,[11a] quinoxalines,[11b,11c] and imidazo[1,2-a]pyridines[11d,11e] employing amidines, 1,2-phenylenediamines, and 2-aminopyridines as amine partners. Most of the reports used terminal alkynes perhaps because they, having an obvious steric bias, would not suffer from regioselectivity issues in the product formation. Few groups successfully used electronically highly biased internal alkynes such as alkynoates, haloalkynes, and ynamides, which not only dictated the regioselection but also introduced a functional group directly on the imidazole ring. Thus, Jiang et al.[12] reported an elegant copper-catalyzed synthesis of 2-halo-substituted imidazo[1,2-a]pyridines (Scheme , eq 1) and Liu et al.[13] reported Cu(II)/Fe(III) cocatalyzed synthesis of imidazo[1,2-a]pyridines with an electron-withdrawing group at the same C2 position (Scheme , eq 2). Furthermore, gold-catalyzed annulation of 2-aminopyridines with ynamide, an electron-rich alkyne, also was studied by Davies et al.[14] (Scheme , eq 3). Activation of 2-aminopyridine was necessary for this annulation to be possible, resulting in the same regioisomer with amino group installation at the C2 position because of gold-catalyzed activation of ynamides and then attack of activated 2-aminopyridine at α carbon.

Scheme 1

Annulation of Electronically Biased Alkynes with Aminopyridines

As a part of our on-going program of activation of functionalized alkynes[15] for discovering novel reactions, herein, we report annulation of inactivated 2-aminopyridines with ynamides with inverse regioselection for the synthesis of imidazopyridines with the amino function installed at the C3 position.

Results and Discussion

We commenced our study with ynamide 1a (1 equiv) and 2-aminopyridine 2a (1.5 equiv) with Cu(OTf)2 (20 mol %) as a catalyst under an O2 atmosphere. Delightfully, the desired imidazo[1,2-a]pyridine, 3a, was obtained, with recovery of more than half of the starting material, in 12% yield after 6 h (Table , entry 1). For further improvement of the yield of 3a, readily available copper catalysts CuCl2, Cu(TFA)2, and Cu(OAc)2 were inspected, but none of them could do better, whereas Cu(OAc)2 was totally ineffective (entries 2–4).

Table 1

Optimization Studiesa

s.no.	[Cu]	mol %	additive	solvent	yield %b	conversion %
1	Cu(OTf)2	20		MeCN	12	20
2	CuCl2	20		MeCN	8	12
3	Cu(OAc)2	20		MeCN	n.d.	c
4	Cu(TFA)2	20		MeCN	10	18
5d	Cu(OTf)2	20	Phl(OAc)2	MeCN	n.d.e	c
6d	Cu(OTf)2	20	K2S2O8	MeCN	n.d.	c
7	Cu(OTf)2	100		MeCN	62	100
8	CuCl	100		MeCN	48	85
9	Cul	100		MeCN	51	90
10	CuOTf	100		MeCN	55	90
11f	Cu(OTf)2	100	Pd(TFA)2	MeCN	40	82
12	Cu(OTf)2	100		toluene	50	75
13	Cu(OTf)2	100		dimethylformamide (DMF)	42	52
14	Cu(OTf)2	100		dimethyl sulfoxide (DMSO)	n.d.	c

Reaction conditions: 1 mmol 1a, 3.5 mmol 2a, 100 mol % Cu(OTf)2 in CH3CN (0.1 M) in air for 12 h.

Isolated yields.

Starting material decomposed.

Additive (2 equiv).

n.d. = not detected.

Additive (20 mol %).

Increasing temperature or prolonged reaction time was inadequate to improve the yield. Employing various acid and base additives, such as K2CO3, Na2CO3, K3PO4, PivOH, pTSA, and NaOAc, proved to be detrimental to the reaction. Oxidants such as PhI(OAc)2 and K2S2O8 led to the decomposition of the starting material (Table , entries 5–6). Pleasingly, use of equimolar (100 mol %) Cu(OTf)2 at 60 °C in air furnished the desired annulated adduct imidazo[1,2-a]pyridine, 3a, in 62% yield (Table , entry 7). Other copper(I) salts such as CuCl, CuI, and CuOTf in similar quantities could not afford the desired product (Table , entries 8–10) superior to Cu(OTf)2. Employing Pd(TFA)2 as the cocatalyst also offered a lesser yield than that from Cu(OTf)2 alone (Table , entry 11). Other solvents such as toluene and DMF were less effective, whereas DMSO was totally unproductive (Table , entries 12–14), leaving MeCN as the best option as the solvent.

Summarizing the observations based on optimization studies, the optimal condition for intermolecular diamination of ynamide was 1 equiv ynamide, 3.5 equiv 2-aminopyridine, and 100 mol % Cu(OTf)2 in 0.1 M MeCN at 60 °C in air for 12 h.

The scope of the transformation was investigated under observed optimal conditions (Table ). As is evident from Tables , 3, and 4, a huge variety of substituted ynamides were converted to the corresponding imidazo[1,2-a]pyridines in moderate to good yields. Electron-rich aryl ynamides, such as 4-methyl (1b), 4-ethyl (1c), 4-t-butyl (1d), and 4-methoxyphenyl ynamide (1e), were successfully converted to the desired annulated products, 3b–e, but in moderate yields (54–58%). In contrast, electron-deficient aryl ynamides showed a relatively better productivity. Thus 3-chloro- (1f), 3-fluoro- (1g), 3,5-difluoro- (1h) phenyl ynamides afforded the products, 3f–h, in 64–73% yields.

Table 2

Synthesis of Various Imidazo[1,2-a]pyridine Derivativesa

Reaction conditions: 1 (1 equiv), 2 (3.5 equiv), Cu(OTf)2 (1 equiv), and solvent (0.1 M).

Table 3

Synthesis of Indole-Based Imidazo[1,2-a]pyridine Derivativesa

Reaction Conditions: 4 (1 equiv), 2a (3.5 equiv), Cu(OTf)2 (1 equiv), and solvent (0.1 M).

Table 4

Extended Scope of Electron-Rich Alkynesa

Reaction conditions: 6 (1 equiv), 2 (3.5 equiv), Cu(OTf)2 (1 equiv), and solvent (0.1 M).

Furthermore, 4-chloro- (1i), 4-fluoro- (1j), 4-cyano- (1k), 4-trifluoromethyl (1l), and 4-methylcarboxyl (1m) phenyl ynamides could be annulated with 2-aminopyridines under standard conditions to give imidazopyridine adducts 3i–m in 52–63% yields. Next, we examined some variation of substitution on 2-aminopyridines. Therefore, few commercially available methyl 2-aminopyridines were chosen for the study. Thus, 4-methyl- and 5-methyl-2-aminopyridines 2n–o reacted smoothly with ynamide 1a under standard conditions to afford the annulated adducts, 3n-o, in 58–63% yields. Whereas 3-methyl- and 6-methyl-2-aminopyridines 2p–q reacted very slowly (24 h), perhaps due to steric crowding, but gave the products (3p–q) in acceptable yields (43–48%).

Furthermore, alkylphenyl and fluorophenyl ynamides were also annulated with these methyl-substituted 2-aminopyridines with equal ease (3r–u in 51–67%). Next, 5-bromo-2-aminopyridine 2v with ynamide 1a gave 3v in 45% yield, whereas thiophenyl ynamide 1w with 4-methyl-2-aminopyridine delivered 3w in 69% yield. A single regioisomer was isolated in all cases, and the structure of 3u was unambiguously confirmed by single X-ray crystallography.

At this point, keeping in mind the pharmacological significance of indoles and to evaluate the substrate scope with respect to substitution on the nitrogen terminal of ynamide, we examined some indole-tethered alkynes anticipating indolyl imidazo[1,2-a]pyridines. Delightfully, the readily synthesizable ynamines based on methyl indole-2-carboxylate (4a), ethyl indole-2-carboxylate (4b), and 3-acetyl indole (4c) were transformed through the reaction successfully to deliver the corresponding products (5a–5c) in 59–71% yields. The structure of 5b was confirmed by X-ray crystallography study.

After successfully testing the title reaction on ynamides/ynamines, we turned our focus to test it on their oxygen counterparts, that is, ynol ethers. Applying optimized conditions with ynol ether 6a, delightfully, the desired product, 7a, was afforded in 68% yield. 3- and 5-Methyl-substituted 2-aminopyridines (7b in 56% and 7c in 58%) and tolyl-ynol ether (7d, 64%) were also transformed to the anticipated products with equal ease.

On the basis of previous reports, a putative mechanism of this copper-mediated diamination of ynamides with 2-aminopyridines is proposed in Scheme . It is proposed that the reaction starts with coordination of the copper salt with the pyridyl nitrogen and ynamide while forming a covalent bond with the amino group of 2-aminopyridine, as indicated in intermediate A. This A upon ynamide N-assisted nucleophilic displacement leads to Cu-ketenimine complex B, which after intramolecular pyridine attack on the electrophilic central carbon forms a 6-membered cuprous metellacycle, C. Reductive elimination of Cu(0) from C led to the final product.

Scheme 2

Probable Reaction Mechanism

In conclusion, we have demonstrated a protocol for the regioselective annulation of electron-rich alkynes, ynamides/ynamines and ynol ethers, with readily available 2-aminopyridines to access the biologically interesting imidazo[1,2-a]pyridines with 3-heterosubstitution. The reaction is mediated by Cu(OTf)2 and is conducted in open air. The mechanism is postulated to involve at the end the reduction of Cu(II) to Cu(0); hence, it is required in stoichiometric amount.

Experimental Section

General Information

All reagents and solvents were purchased from commercial sources and used without purification. NMR spectra were recorded with a 400 or 500 MHz spectrometer for 1H NMR and with a 100 or 125 MHz spectrometer for 13C NMR spectroscopy. Chemical shifts are reported relative to the residual signals of tetramethylsilane in CDCl3 or deuterated solvent CDCl3 for 1H and 13C NMR spectroscopy. High-resolution mass spectrometry (HRMS) spectra were recorded using a quadrupole time-of-flight mass spectrometer. Column chromatography was performed with silica gel (230–400 mesh) as the stationary phase. All reactions were monitored using thin-layer chromatography (TLC).

General Procedure for the Synthesis of 3/5/7

A mixture of ynamide/ynamine/ynol ether substrate 1/4/6 (1.0 mmol), 2-aminopyridines 2 (3.5 mmol), and Cu(OTf)2 (1.0 mmol) was added in 0.1 M CH3CN at 60 °C for 12–24 h. Upon completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography.

Characteristic Data of Final Compounds

3-(2-Phenylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3a)

Off-white solid; mp 223–225 °C; R = 0.46 (70% ethyl acetate/hexanes); yield = 173 mg (62%); 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 7.1 Hz, 2H), 7.67 (d, J = 9.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.33–7.25 (m, 1H), 6.95–6.88 (m, 1H), 4.64 (t, J = 7.9 Hz, 2H), 3.87 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.6, 143.3, 140.4, 132.8, 128.9, 128.5, 127.2, 125.6, 122.4, 118.0, 114.0, 112.9, 63.2, 45.3 ppm; IR (KBr) ν 3583, 1756, 1412, 1252, 1081, 665 cm–1; HRMS (electrospray ionization (ESI)) calcd for C16H14N3O2 [M + H] 280.1086 found 280.1074.

3-(2-(p-Tolyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3b)

Off-white solid; mp 110–112 °C; R = 0.46 (70% ethyl acetate/hexanes); yield = 170 mg (58%); 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 6.7 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 8.1 Hz, 3H), 6.92 (t, J = 6.6 Hz, 1H), 4.65 (t, J = 7.9 Hz, 2H), 3.88 (t, J = 7.9 Hz, 2H), 2.43 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.6, 143.3, 140.6, 138.7, 129.9, 129.6, 127.1, 125.5, 122.3, 118.0, 112.8, 63.2, 45.3, 21.3 ppm; IR (KBr) ν 3665, 2305, 2037, 1486, 1248, 1080, 666 cm–1; HRMS (ESI) calcd for C17H16N3O2 [M + H] 294.1243 found 294.1238.

3-(2-(4-Ethylphenyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3c)

White solid; mp 178–179 °C; R = 0.40 (70% ethyl acetate/hexanes); yield = 169 mg (55%); 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 6.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 9.0 Hz, 1H), 7.38–7.17 (m, 3H), 6.88 (t, J = 6.6 Hz, 1H), 4.63 (t, J = 7.9 Hz, 2H), 3.86 (t, J = 7.9 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.6, 144.9, 143.4, 140.7, 130.2, 128.5, 127.3, 125.6, 122.4, 118.2, 113.8, 113.0, 63.3, 45.5, 28.8, 15.4 ppm; IR (KBr) ν 3583, 3392, 1755, 1390, 1084, 665 cm–1; HRMS (ESI) calcd for C18H18N3O2 [M + H] 308.1399 found 308.1390.

3-(2-(4-(tert-Butyl)phenyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3d)

Brown solid; mp 114–116 °C; R = 0.40 (70% ethyl acetate/hexanes); yield = 168 mg (56%); 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 6.6 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.36–7.20 (m, 1H), 6.90 (t, J = 6.7 Hz, 1H), 4.66 (t, J = 7.9 Hz, 2H), 3.90 (t, J = 7.9 Hz, 2H), 1.38 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.5, 151.6, 143.3, 140.4, 129.8, 126.8, 125.8, 125.4, 122.3, 118.0, 113.7, 112.8, 63.2, 45.3, 34.7, 31.2 ppm; IR (KBr) ν 3211, 1751, 1628, 1416, 1081, 843, 637 cm–1; HRMS (ESI) calcd for C20H22N3O2 [M + H] 336.1712 found 336.1694.

3-(2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3e)

White solid; mp 114–116 °C; R = 0.44 (70% ethyl acetate/hexanes); yield = 173 mg (56%); 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 6.6 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 9.0 Hz, 1H), 7.32–7.21 (m, 1H), 7.01 (d, J = 8.6 Hz, 2H), 6.88 (t, J = 6.6 Hz, 1H), 4.62 (t, J = 7.9 Hz, 2H), 3.86 (s, 5H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.0, 156.7, 143.3, 140.4, 128.7, 125.7, 125.2, 122.4, 117.9, 114.5, 113.4, 113.0, 63.3, 55.4, 45.4 ppm; IR (KBr) ν 3012, 2840, 1759, 1613, 1512, 1302, 1146, 754, 664 cm–1; HRMS (ESI) calcd for C17H16N3O3 [M + H] 310.1192 found 310.1176.

3-(2-(3-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3f)

Light yellow solid; mp 116–118 °C; R = 0.44 (70% ethyl acetate/hexanes); yield = 200 mg (64%); 1H NMR (400 MHz, CDCl3): δ 7.99–7.84 (m, 2H), 7.76–7.61 (m, 2H), 7.46–7.33 (m, 2H), 7.33–7.27 (m, 1H), 6.92 (t, J = 6.6 Hz, 1H), 4.66 (t, J = 7.9 Hz, 2H), 3.88 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.4, 143.4, 139.0, 134.9, 134.6, 130.2, 128.5, 127.3, 126.0, 125.1, 122.4, 118.2, 114.3, 113.2, 63.3, 45.4 ppm; IR (KBr) ν 3020, 2960, 1762, 1579, 1481, 1357, 1215, 1081, 755, 664 cm–1; HRMS (ESI) calcd for C16H13ClN3O2 [M + H] 314.0696 found 314.0690.

3-(2-(3-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3g)

Brown solid; mp 106–108 °C; R = 0.44 (70% ethyl acetate/hexanes); yield = 205 mg (69%); 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 6.7 Hz, 1H), 7.74–7.58 (m, 3H), 7.50–7.41 (m, 1H), 7.35–7.26 (m, 1H), 7.16–7.06 (m, 1H), 6.94 (t, J = 6.7 Hz, 1H), 4.68 (t, J = 7.9 Hz, 2H), 3.91 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 163.2 (d, J = 246.0 Hz), 156.4, 143.3, 139.3, 135.0 (d, J = 8.0 Hz), 130.5 (d, J = 8.2 Hz), 125.9, 122.7, 122.4, 118.2, 115.4 (d, J = 21.0 Hz), 114.2 (d, J = 22.8 Hz), 113.2, 63.2, 45.4 ppm; IR (KBr) ν 3018, 1759, 1617, 1441, 1277, 1079, 664 cm–1; HRMS (ESI) calcd for C16H13FN3O2 [M + H] 298.0992 found 298.0981.

3-(2-(3,5-Difluorophenyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3h)

Off-white solid; mp 154–156 °C; R = 0.44 (70% ethyl acetate/hexanes); yield = 230 mg (73%); 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 6.8 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.45–7.38 (m, 2H), 7.35–7.27 (m, 1H), 6.93 (t, J = 6.7 Hz, 1H), 6.88 (m, 1H), 4.68 (t, J = 7.9 Hz, 2H), 3.91 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 163.3 (dd, J = 248.0, 12.7 Hz), 156.3, 143.3, 138.2, 136.0 (t, J = 10.1 Hz), 126.2, 122.4, 118.3, 114.5, 113.4, 109.9 (dd, J = 19.2, 7.4 Hz), 103.8 (t, J = 25.3 Hz), 63.2, 45.4 ppm; IR (KBr) ν 3214, 1657, 1521, 1400, 962, 664 cm–1; HRMS (ESI) calcd for C16H12F2N3O2 [M + H] 316.0898 found 316.0892.

3-(2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3i)

Off-white solid; mp 56–58 °C; R = 0.42 (70% ethyl acetate/hexanes); yield = 188 mg (60%); 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 6.8 Hz, 1H), 7.80 (dd, J = 6.7, 1.8 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.47–7.43 (m, 2H), 7.32–7.27 (m, 1H), 6.95–6.90 (m, 1H), 4.65 (t, J = 7.9 Hz, 2H), 3.86 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.4, 134.5, 131.3, 129.2, 128.5, 125.9, 122.3, 118.2, 113.2, 63.2, 45.4 ppm; IR (KBr) ν 3021, 2401, 1630, 1417, 1030, 928, 667 cm–1; HRMS (ESI) calcd for C16H13ClN3O2 [M + H] 314.0696 found 314.0688.

3-(2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3j)

White solid; mp 144–146 °C; R = 0.44 (70% ethyl acetate/hexanes); yield = 178 mg (60%); 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 6.6 Hz, 1H), 7.90–7.79 (m, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.33–7.25 (m, 1H), 7.18 (t, J = 8.5 Hz, 2H), 6.91 (t, J = 6.6 Hz, 1H), 4.65 (t, J = 7.9 Hz, 2H), 3.86 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 162.9 (d, J = 248.0 Hz), 156.5, 143.3, 139.8, 129.1 (d, J = 8.2 Hz), 125.8, 122.3, 118.1, 115.9 (d, J = 21.5 Hz), 113.7, 113.0, 63.2, 45.4 ppm; IR (KBr) ν 3017, 2961, 1758, 1634, 976, 664 cm–1; HRMS (ESI) calcd for C16H13FN3O2 [M + H] 298.0992 found 298.0985.

4-(3-(2-Oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)benzonitrile (3k)

White solid; mp 145–147 °C; R = 0.44 (70% ethyl acetate/hexanes); yield = 191 mg (63%); 1H NMR (400 MHz, CDCl3): δ 8.12–7.91 (m, 3H), 7.79 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 9.2 Hz, 1H), 7.45–7.32 (m, 1H), 6.99 (t, J = 6.6 Hz, 1H), 4.71 (t, J = 7.9 Hz, 2H), 3.92 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.5, 144.1, 137.4, 132.9, 127.8, 126.6, 122.6, 118.8, 118.5, 113.8, 112.1, 63.4, 45.7 ppm; IR (KBr) ν 3321, 1695, 1520, 1479, 1021, 660 cm–1; HRMS (ESI) calcd for C17H13N4O2 [M + H] 305.1039 found 305.1026.

3-(2-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3l)

Off-white solid; mp 199–201 °C; R = 0.40 (70% ethyl acetate/hexanes); yield = 180 mg (52%); 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.9 Hz, 2H), 7.93 (d, J = 6.4 Hz, 1H), 7.73 (d, J = 7.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 1H), 7.37–7.28 (m, 1H), 6.93 (t, J = 6.6 Hz, 1H), 4.66 (t, J = 7.9 Hz, 2H), 3.87 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.5, 143.5, 137.7 (d, J = 260 Hz), 130.2 (q, J = 32 Hz), 127.5, 126.2, 125.9, 125.3, 122.8, 122.5, 118.3, 114.8, 113.4, 63.3, 45.3 ppm; IR (KBr) ν 3394, 1622, 1414, 1246, 1165, 1083, 976, 755 cm–1; HRMS (ESI) calcd for C17H13F3N3O2 [M + H] 348.0960 found 348.0946.

Methyl 4-(3-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)benzoate (3m)

White solid; mp 154–156 °C; R = 0.46 (70% ethyl acetate/hexanes); yield = 199 mg (59%); 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 2H), 8.01–7.92 (m, 3H), 7.70 (d, J = 9.0 Hz, 1H), 7.38–7.31 (m, 1H), 6.97 (t, J = 6.8 Hz, 1H), 4.68 (t, J = 7.9 Hz, 2H), 3.97 (s, 3H), 3.90 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.9, 160.0, 156.5, 130.3, 130.1, 127.2, 126.2, 122.6, 118.5, 113.5, 63.4, 52.3, 45.6 ppm; IR (KBr) ν 3583, 2921, 1611, 1358, 1280, 756 cm–1; HRMS (ESI) calcd for C18H16N3O4 [M + H] 338.1141 found 338.1127.

3-(7-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3n)

Off-white solid; mp 163–165 °C; R = 0.40 (70% ethyl acetate/hexanes); yield = 184 mg (63%); 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 7.3 Hz, 2H), 7.78 (d, J = 6.9 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.42–7.33 (m, 2H), 6.71 (d, J = 6.0 Hz, 1H), 4.61 (t, J = 7.9 Hz, 2H), 3.83 (t, J = 7.9 Hz, 2H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.7, 143.9, 140.2, 136.9, 133.0, 129.0, 128.5, 127.3, 121.7, 116.6, 115.7, 113.6, 63.3, 45.6, 21.5 ppm; IR (KBr) ν 3321, 1583, 1456, 1387, 1120, 664 cm–1; HRMS (ESI) calcd for C17H16N3O2 [M + H] 294.1243 found 294.1238.

3-(6-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3o)

Off-white solid; mp 154–156 °C; R = 0.40 (70% ethyl acetate/hexanes); yield = 167 mg (57%); 1H NMR (400 MHz, CDCl3): δ 7.96–7.72 (m, 3H), 7.55–7.31 (m, 4H), 6.71 (d, J = 5.9 Hz, 1H), 4.60 (t, J = 7.9 Hz, 2H), 3.83 (t, J = 7.9 Hz, 2H), 2.41 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.7, 136.9, 129.0, 128.5, 127.3, 127.2, 123.0, 121.7, 120.1, 117.5, 116.5, 115.7, 63.3, 45.5, 21.4 ppm; IR (KBr) ν 3214, 2851, 1721, 1547, 1394, 953, 664 cm–1; HRMS (ESI) calcd for C17H16N3O2 [M + H] 294.1243 found 294.1240.

3-(8-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3p)

Off-white solid; mp105–107 °C; R = 0.40 (70% ethyl acetate/hexanes); yield = 170 mg (58%); 1H NMR (400 MHz, CDCl3): δ 7.92–7.82 (m, 2H), 7.78 (d, J = 6.7 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.42–7.32 (m, 1H), 7.06 (d, J = 6.8 Hz, 1H), 6.80 (t, J = 6.8 Hz, 1H), 4.60 (t, J = 7.9 Hz, 2H), 3.83 (t, J = 7.9 Hz, 2H), 2.65 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.7, 143.8, 140.2, 133.2, 129.0, 128.4, 128.3, 127.5, 124.4, 120.2, 114.4, 113.1, 63.2, 45.6, 16.7 ppm; IR (KBr) ν 3131, 2965, 1860, 1774, 1091, 931, 666 cm–1; HRMS (ESI) calcd for C17H16N3O2 [M + H] 294.1243 found 294.1222.

3-(5-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3q)

Off-white solid; mp 154–156 °C; R = 0.40 (70% ethyl acetate/hexanes); yield = 146 mg (50%); 1H NMR (400 MHz, CDCl3): δ 7.87–7.76 (m, 2H), 7.59–7.45 (m, 3H), 7.45–7.37 (m, 1H), 7.18 (dd, J = 8.9, 6.9 Hz, 1H), 6.61 (d, J = 6.8 Hz, 1H), 4.63–4.41(m, 2H), 3.89–3.66(m, 2H), 2.79(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 158.5, 135.2, 133.0, 129.5, 129.0, 128.7, 128.3, 127.7, 126.1, 116.3, 114.5, 62.7, 48.5, 18.3 ppm; IR (KBr) ν 3011, 1854, 1601, 1482, 1125, 633 cm–1; HRMS (ESI) calcd for C17H16N3O2 [M + H] 294.1243 found 294.1240.

3-(2-(4-Butylphenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3r)

Off-white solid; mp 218–220 °C; R = 0.48 (70% ethyl acetate/hexanes); yield = 185 mg (53%); 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.0 Hz, 2H),7.67 (s, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 1H), 4.63 (t, J = 7.9 Hz, 2H), 3.85 (t, J = 7.9 Hz, 2H), 2.65 (t, J = 7.8 Hz, 2H), 2.35 (s, 3H), 1.67–1.60 (m, 2H), 1.42–1.35 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 151.8, 138.5, 126.1, 125.5, 124.2, 123.9, 122.2, 117.9, 115.2, 112.6, 58.4, 40.6, 30.7, 28.7, 17.6, 13.5, 9.2 ppm; IR (KBr) ν 3014, 2130, 1692, 1300, 903, 651 cm–1; HRMS (ESI) calcd for C21H24N3O2 [M + H] 350.1869 found 350.1864.

3-(2-(4-(tert-Butyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3s)

Off-white solid; mp 231–233 °C; R = 0.48 (70% ethyl acetate/hexanes); yield = 188 mg (54%); 1H NMR (400 MHz, CDCl3): δ 7.82–7.74 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 6.71 (d, J = 6.9 Hz, 1H), 4.63 (t, J = 7.9 Hz, 2H), 3.87 (t, J = 7.9 Hz, 2H), 2.41 (s, 3H), 1.35 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.6, 151.4, 143.7, 140.0, 136.6, 129.9, 126.7, 125.8, 121.5, 116.2, 115.4, 113.2, 63.1, 45.4, 34.6, 31.2, 21.3 ppm; IR (KBr) ν 3380, 2033, 1487, 1312, 943, 681 cm–1; HRMS (ESI) calcd for C21H24N3O2 [M + H] 350.1869 found 350.1852.

3-(2-(3-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3t)

Off-white solid; mp 110–112 °C; R = 0.44 (70% ethyl acetate/hexanes); yield = 208 mg (67%); 1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.66–7.59 (m, 2H), 7.56 (d, J = 9.2 Hz, 1H), 7.49–7.39 (m, 1H), 7.15 (d, J = 9.2 Hz, 1H), 7.12–7.04 (m, 1H), 4.68 (t, J = 7.9 Hz, 2H), 3.89 (t, J = 7.9 Hz, 2H), 2.37 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 163.1 (d, J = 246.1 Hz), 156.5, 142.4, 139.0, 135.2 (d, J = 8.2 Hz), 130.4 (d, J = 8.2 Hz), 129.1, 123.2, 122.6 (d, J = 2.7 Hz), 120.0, 117.4, 115.2 (d, J = 21.1 Hz), 114.0 (d, J = 23.0 Hz), 63.2, 45.4, 18.2 ppm; IR (KBr) ν 3087, 2471, 1590, 1431, 943, 837, 681 cm–1; HRMS (ESI) calcd for C17H15FN3O2 [M + H] 312.1148 found 312.1144.

3-(2-(4-Fluorophenyl)-8-methylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3u)

White solid; mp 154–156 °C; R = 0.44 (70% ethyl acetate/hexanes); yield = 205 mg (66%); 1H NMR (400 MHz, CDCl3): δ 7.89–7.80 (m, 2H), 7.77 (d, J = 6.6 Hz, 1H), 7.20–7.12 (m, 2H), 7.10–7.03 (m, 1H), 6.81 (t, J = 6.6 Hz, 1H), 4.61 (t, J = 7.9 Hz, 2H), 3.82 (t, J = 7.9 Hz, 2H), 2.64 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 163.0 (d, J = 249.5 Hz), 156.7, 143.8, 139.5, 129.4 (d, J = 8.5 Hz), 128.3, 124.6, 120.2, 116.0 (d, J = 21.5 Hz), 113.3, 63.2, 45.6, 16.7 ppm; IR (KBr) ν 3485, 2928, 1668, 1217, 930, 824, 637 cm–1; HRMS (ESI) calcd for C17H15FN3O2 [M + H] 312.1148 found 312.1136.

3-(6-Bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3v)

White solid; mp 204–206 °C; R = 0.40 (70% ethyl acetate/hexanes); yield = 161 mg (45%); 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.82 (d, J = 7.3 Hz, 2H), 7.55 (d, J = 9.4 Hz, 1H), 7.48 (t, J = 7.3 Hz, 2H), 7.44-7.37 (m, 1H), 7.34 (d, J = 9.4 Hz, 1H), 4.65 (t, J = 7.9 Hz, 2H), 3.85 (t, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.4, 141.7, 141.1, 132.3, 129.0 (t, J = 18.0 Hz), 127.2, 122.6, 118.7, 107.9, 63.3, 45.3 ppm; IR (KBr) ν 3424, 2981, 1579, 1414, 1146, 1088, 918, 664 cm–1; HRMS (ESI) calcd for C16H13BrN3O2 [M + H] 358.0191 found 358.0179.

3-(7-Methyl-2-(thiophen-3-yl)imidazo[1,2-a]pyridin-3-yl)oxazolidin-2-one (3w)

Brown solid; mp 120–122 °C; R = 0.50 (70% ethyl acetate/hexanes); yield = 206 mg (69%); 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.47–7.42 (m, 1H), 7.40 (s, 1H), 6.75 (d, J = 6.8 Hz, 1H), 4.68 (t, J = 7.9 Hz, 2H), 3.92 (t, J = 7.9 Hz, 2H), 2.44 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.7, 143.8, 137.2, 136.7, 133.9, 126.6, 126.3, 123.3, 121.6, 116.3, 115.8, 63.3, 45.6, 21.5 ppm; IR (KBr) ν 3324, 1579, 1502, 1354, 1146, 832, 649 cm–1; HRMS (ESI) calcd for C15H14N3O2S [M + H] 300.0807 found 300.0792.

Methyl 1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-1H-indole-2-carboxylate (5a)

Yellow solid; mp 157–159 °C; R = 0.50 (40% ethyl acetate/hexanes); yield = 246 mg (67%); 1H NMR (400 MHz, CDCl3): δ 7.87–7.82 (m, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.68 (s, 1H), 7.46–7.38 (m, 3H), 7.33–7.27 (m, 3H), 7.25–7.17 (m, 3H), 7.00–6.89 (m, 1H), 6.78 (t, J = 6.6 Hz, 1H), 3.68 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.8, 143.4, 140.4, 139.9, 132.5, 128.9, 128.7, 128.1, 127.0, 126.9, 126.5, 125.6, 123.0, 122.7, 122.5, 117.9, 114.1, 112.8, 111.4, 52.0 ppm; IR (KBr) ν 1634, 1580, 1088, 940, 831, 666 cm–1; HRMS (ESI) calcd for C23H18N3O2 [M + H] 368.1399 found 368.1386.

Ethyl 1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-1H-indole-2-carboxylate (5b)

Yellow solid; mp 151–153 °C; R = 0.46 (40% ethyl acetate/hexanes); yield = 225 mg (59%); 1H NMR (400 MHz, CDCl3): δ 7.84–7.75 (m, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.67 (s, 1H), 7.45–7.32 (m, 3H), 7.32–7.20 (m, 3H), 7.20–7.10 (m, 3H), 6.97–6.83 (m, 1H), 6.83–6.69 (m, 1H), 4.07–3.98 (m, 2H), 0.91 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.4, 143.2, 140.3, 139.8, 132.5, 129.5, 128.7, 128.1, 127.1, 126.9, 126.5, 125.5, 122.9, 122.6, 122.6, 117.9, 114.2, 112.8, 111.4, 60.9, 13.7 ppm; IR (KBr) ν 1764, 1593, 1163, 934, 743, 646 cm–1; HRMS (ESI) calcd for C24H20N3O2 [M + H] 382.1556 found 382.1538.

1-(1-(2-Phenylimidazo[1,2-a]pyridin-3-yl)-1H-indol-3-yl)ethan-1-one (5c)

Light yellow solid; mp 270–272 °C; R = 0.46 (40% ethyl acetate/hexanes); yield = 249 mg (71%); 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.56–7.50 (m, 2H), 7.46–7.38 (m, 2H), 7.37–7.32 (m, 1H), 7.31–7.26 (m, 4H), 6.98 (d, J = 8.2 Hz, 1H), 6.82 (t, J = 6.7 Hz, 1H), 2.54 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 193.3, 143.4, 140.4, 137.5, 135.4, 131.7, 128.8, 128.6, 126.6, 126.3, 126.2, 125.0, 124.0, 123.2, 122.2, 120.9, 118.1, 114.3, 113.4, 110.5, 27.7 ppm; IR (KBr) ν 1698, 1491, 1110, 936, 827, 681 cm–1; HRMS (ESI) calcd for C23H18N3O [M + H] 352.1450 found 352.1431.

3-Phenoxy-2-phenylimidazo[1,2-a]pyridine (7a)

White solid; mp 111–113 °C; R = 0.48 (30% ethyl acetate/hexanes); yield = 194 mg (68%); 1H NMR (400 MHz, CDCl3): δ 8.11–7.98 (m, 2H), 7.73 (d, J = 6.6 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.42–7.34 (m, 2H), 7.33–7.26 (m, 3H), 7.22–7.14 (m,1H), 7.09 (t, J = 7.4 Hz, 1H), 6.99–6.91 (m, 2H), 6.79–6.69 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.2, 140.0, 132.6, 131.3, 130.3, 130.1, 128.7, 127.8, 126.6, 124.4, 123.8, 121.7, 118.0, 115.1, 112.4 ppm; IR (KBr) ν 1587, 1447, 1362, 1274, 1072, 607 cm–1; HRMS (ESI) calcd for C19H15N2O [M + H] 287.1184 found 287.1165.

8-Methyl-3-phenoxy-2-phenylimidazo[1,2-a]pyridine (7b)

White solid; mp 110–112 °C; R = 0.44 (30% ethyl acetate/hexanes); yield = 168 mg (56%); 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 7.3 Hz, 2H), 7.60 (d, J = 6.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.33–7.22 (m, 3H), 7.08 (t, J = 7.4 Hz, 1H), 7.02–6.89 (m, 3H), 6.65 (t, J = 6.8 Hz, 1H), 2.68 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.4, 140.3, 132.9, 130.7, 130.4, 130.2, 128.7, 127.9, 127.6, 126.7, 123.6, 123.0, 119.5, 115.1, 112.4, 16.5 ppm; IR (KBr) ν 3296, 2637, 1846, 1549, 1120, 998, 660 cm–1; HRMS (ESI) calcd for C20H17N2O [M + H] 301.1341 found 301.1330.

6-Methyl-3-phenoxy-2-phenylimidazo[1,2-a]pyridine (7c)

White solid; mp 122–124 °C; R = 0.48 (30% ethyl acetate/hexanes); yield = 174 mg (58%); 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 7.3 Hz, 2H), 7.52 (d, J = 9.6 Hz, 2H), 7.42–7.20 (m, 5H), 7.14–7.05 (m, 1H), 7.05–6.99 (m, 1H), 6.95 (d, J = 8.0 Hz, 2H), 2.25 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.3, 139.1, 132.8, 131.0, 130.2, 129.9, 128.7, 127.7, 127.6, 126.4, 123.6, 122.2, 119.1, 117.3, 115.1, 18.3 ppm; IR (KBr) ν 3582, 2922, 1586, 1390, 1264, 1030, 664 cm–1; HRMS (ESI) calcd for C20H17N2O [M + H] 301.1341 found 301.1324.

3-Phenoxy-2-(p-tolyl)imidazo[1,2-a]pyridine (7d)

Off-white solid; mp 132–134 °C; R = 0.44 (30% ethyl acetate/hexanes); yield = 192 mg (64%); 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 6.6 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.37–7.27 (m, 2H), 7.24–7.14 (m, 3H),7.09 (t, J = 7.3 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 6.6 Hz, 1H), 2.34 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 156.2, 139.8, 137.7, 131.2, 130.3, 129.8, 129.5, 126.5, 124.5, 123.8, 121.6, 117.8, 115.1, 112.4, 21.4 ppm; IR (KBr) ν 3432, 2751, 1635, 1209, 1156, 979, 679 cm–1; HRMS (ESI) calcd for C20H17N2O [M + H] 301.1341 found 301.1319.