(Diacetoxy)iodobenzene-Mediated Oxidative C–H Amination of

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(Diacetoxy)iodobenzene-Mediated Oxidative C−H Amination of Imidazopyridines at Ambient Temperature Susmita Mondal, Sadhanendu Samanta, Sourav Jana, and Alakananda Hajra* Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India S Supporting Information *

ABSTRACT: (Diacetoxy)iodobenzene (PIDA)-mediated direct oxidative C−H amination for the synthesis of 3-amino substituted imidazopyridines has been achieved under metalfree conditions at room temperature in short reaction times. This methodology is also applicable for the regioselective amination of indolizines. Experimental results suggest that the reaction likely proceeds through a radical pathway.

T

oxidant at room temperature in short reaction time (Scheme 1).

he development of efficient and sustainable methods for the construction of C−N bond have a great importance in organic synthesis due to the wide occurrence of nitrogencontaining molecules in natural products, synthetic intermediates, pharmaceutical agents, and biologically active compounds.1 There are a number of methodologies for the C(sp2)−N bond formation employing well-known strategies like Ullmann−Goldberg, Buchwald−Hartwig, and Chan−Lam aminations.2 However, transition-metal catalysts and preactivated substrates are the necessities for these methodologies. As a consequence, recently much attention has been paid on the direct C−H amination of C(sp2)−H bond due to its straightforwardness.3 In this context iodine(III)-mediated oxidative C(sp2)−H amination has emerged as an important strategy.4 Intramolecular oxidative amination of aromatic C−H bonds using hypervalent iodine have been found to construct various heterocyclic compounds,5 however the intermolecular amination of arenes and heteroarenes under metal-free conditions have been less explored. Recently Chang et al.,6a DeBoef et al.,6b and Antonchick et al.6c have developed iodine(III) mediated intermolecular oxidative amination of arenes. Imidazo[1,2-a]pyridine, an important class of biologically active7 nitrogen containing fused heterocycles, has a wide application in pharmaceutical chemistry as well as in material sciences.8 There are several marketed drugs, such as alpidem, zolpidem, necopidem, saripidem, olprinone, zolimidine, etc., that contain this scaffold. As a consequence this moiety has gained much interest of the synthetic chemists.9,10 Among the various functionalized imidazopyridines, 3-aminoimidazo[1,2a]pyridines are very important in medicinal chemistry. Very recently Charette et al. reported a facile method for the synthesis of 3-aminoimidazo[1,2-a]pyridine from N-Bocprotected 2-aminopyridine-containing amides via cyclodehydration-aromatization.11 However, to the best of our knowledge, there is no method for the direct intermolecular oxidative amination of imidazo[1,2-a]pyridines. Herein, we report a direct C−H amination of imidazopyridines using PIDA as an © 2017 American Chemical Society

Scheme 1. Direct Oxidative Amination of Imidazopyridines

For the optimization of the reaction conditions, we started our study by taking 2-phenylimidazo[1,2-a]pyridine 1a and morpholine 2a as model substrates using PIDA in different solvents (Table 1). Initially we carried out the reaction using 2 equiv of PIDA in THF at room temperature (Table 1, entry 1). Gratifyingly, the coupling product 4-(2-phenylimidazo[1,2a]pyridin-3-yl)morpholine (3aa) was obtained in 67% yield after 10 min. Inspired by this initial result, we checked the effect of different solvents such as DCM, acetonitrile, toluene, 1,4dioxane, 1,2-dichloroethane, ethanol, chlorobenzene, and DMF (Table 1, entries 2−9). The best result was obtained in 1,4dioxane affording 76% of the desired product (Table 1, entry 5). No formation of the product was obtained in the presence of bis(trifluoroacetoxy)iodobenzene (PIFA) (Table 1, entry 10). Trace amount of product was obtained by using catalytic amount of PIDA (0.1 equiv) in the presence of other oxidant, such as K2S2O8, TBHP (Table 1, entries 11 and 12). The yield was decreased with decreasing the amount of PIDA but remained same by using 3 equiv PIDA (Table 1, entries 13 and 14). No significant increment of the yield was observed on increasing the temperature even after 1 h (Table 1, entry 15). Thus, the optimized reaction conditions were obtained in the Received: March 9, 2017 Published: April 6, 2017 4504

DOI: 10.1021/acs.joc.7b00564 J. Org. Chem. 2017, 82, 4504−4510

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The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa

entry

oxidant (equiv)

solvent

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

PIDA (2) PIDA (2) PIDA (2) PIDA (2) PIDA (2) PIDA (2) PIDA (2) PIDA (2) PIDA (2) PIFA (2) K2S2O8 (2) TBHP (2) PIDA (1) PIDA (3) PIDA (2)

THF DCM CH3CN toluene 1,4-dioxane 1,2-DCE EtOH chlorobenzene DMF 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane

67 59 48 67 76 32 25 71 trace nd traceb traceb 62 78 74c

efficiently reacted with morpholine to afford the desired coupling products with good yields (3ba and 3ca). Presence of electron-donating substituent like −Me, −OMe group at the phenyl ring of imidazo[1,2-a]pyridines also worked well (3da− 3fa). Halogens (−Cl, − F) containing imidazopyridines afforded the corresponding products with moderate to good yields (3ga and 3ha). A strong electron-withdrawing group, such as −CF3, also produced the product (3ia) with 72% yield. It is also notable that the marketed drug zolimidine reacted well to give the desired product (3ja). Naphthalene and thiophene substituted imidazo[1,2-a]pyridines also produced the desired product in excellent yields under the optimized reaction conditions (3ka and 3la). Aliphatic substituted (C-2) imidazo[1,2-a]pyridines produced a nonseparable mixtures with morpholine. The single crystal X-ray analysis of 3aa was performed to confirm the structure of the 4-(2-phenylimidazo[1,2-a]pyridin-3-yl)morpholine.13 To extend the scope of the present methodology, we investigated the other cyclic amines like thiomorpholine and piperidine (Scheme 3). Both thiomorpholine and piperidine efficiently reacted with imidazo[1,2-a]pyridines to produce the desired coupling products. Imidazo[1,2-a]pyridine containing both electron-donating, like −OMe, and electron-withdrawing group, such as −F, −Br, and −CN, on the phenyl ring of imidazo[1,2-a]pyridine reacted with thiomorpholine to afford the desired products with moderate to good yields (4fb, 4hb, 4mb, and 4nb). Thiomorpholine also reacted well with both naphthyl and heteroaryl substituted imidazo[1,2-a]pyridine derivatives (4kb and 4ob). Imidazo[1,2-a]pyridines bearing −Cl and −Me substituent on the pyridine ring efficiently reacted with thiomorpholine to afford the desired products (4pb, 4bb, and 4cb). Piperidine also reacted smoothly with different substituted imidazo[1,2-a]pyridines (4ac, 4bc, 4 fc,

a Reaction conditions: 0.2 mmol of 1a and 0.4 mmol of 2a in the presence of 2 equiv PIDA in 2 mL 1,4-dioxane. b0.1 equiv PIDA. c Reaction temperature 60 °C for 1 h. nd = not detected.

presence of 2 equiv of PIDA in 1,4-dioxane at room temperature for 10 min (Table 1, entry 5). With the optimized reaction conditions in hand, we checked the substrate scopes of this protocol to show the generality of this methodology (Scheme 2). Imidazo[1,2-a]pyridines bearing methyl substituent on pyridine ring at different positions Scheme 2. Substrate Scopes of the Present Methoda

a

Reaction conditions: 0.2 mmol of 1 and 0.4 mmol of 2a in the presence of 2 equiv PIDA in 2 mL 1,4-dioxane at room temperature for 10 min. 4505

DOI: 10.1021/acs.joc.7b00564 J. Org. Chem. 2017, 82, 4504−4510

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The Journal of Organic Chemistry Scheme 3. Substrate Scopesa

2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). However, 2,6di-tert-butyl-4-(morpholinomethyl)phenol (7) was obtained under the optimized reaction conditions in absence of 2phenylimidazo[1,2-a]pyridine (1a) by the reaction of morpholine (2a) with BHT in 68% yield (Scheme 5, eq B). These results signify that the reaction proceeds through a radical pathway. Based on the literature reports 12 and our previous experiences on functionalization of imidazo[1,2-a]pyridines, here we proposed a radical mechanism for this coupling reaction (Scheme 6). Initially N-iodoamido species (A) is formed from the morpholine (2a) which subsequently give morpholine radical (B). The resulting morpholine radical (B) reacts with imidazo[1,2-a]pyridine moiety (1a) to produce the radical intermediate (C) which consequently affords the product (3aa) through the elimination of AcOH. In conclusion, we have developed a direct and straightforward method for the intermolecular oxidative amination of imidazopyridines through C(sp2)−H functionalization employing PIDA as an oxidant. Mild and ambient reaction conditions, short reaction times, and broad substrate scopes are the notable advantages of this methodology. Experimental results suggest that the reaction likely proceeds through a radical pathway. To the best of our knowledge this is the first report for the direct intermolecular amination of imidazopyridines. The present methodology is also applicable for the regioselective amination of indolizine derivatives. We believe this metal-free C−H amination strategy will gain much importance in organic synthesis, medicinal chemistry, as well as in material sciences.

a

Reaction conditions: 0.2 mmol of 1 and 0.4 mmol of 2 in the presence of 2 equiv PIDA in 2 mL 1,4-dioxane at room temperature for 10 min. bReaction time 30 min.

■

and 4qc). Other cyclic and acyclic amines, such as pyrrrolidine, dibenzylamine, aniline, diisopropylamine, were unable to produce the desired coupling products. This methodology is also applicable for the regioselective amination of indolizines (Scheme 4). Morpholine, thiomorpholine, and piperidine reacted smoothly with indolizines affording moderate to good yields of the desired products (6aa, 6bb, and 6cc). Few controlled experiments were carried out to understand the mechanistic pathway of the reaction (Scheme 5). The reaction did not proceed in the presence of radical scavengers, like 2,6-di-tert-butyl-4-methyl phenol (BHT), p-benzoquinone (BQ), 2,3-dichloro-5,6-dicyano-1,p-benzoquinone (DDQ), and

EXPERIMENTAL SECTION

General Information. All reagents were purchased from commercial sources and used without further purification. 1H NMR spectra were determined on 400 MHz spectrometer as solutions in CDCl3. Chemical shifts are expressed in parts per million (δ) and the signals were reported as s (singlet), d (doublet), t (triplet), m (multiplet), and coupling constants (J) were given in Hz. 13C{1H} NMR spectra were recorded at 100 MHz in CDCl3 solution. Chemical shifts as internal standard are referenced to CDCl3 (δ = 7.26 for 1H and δ = 77.16 for 13C{1H} NMR) as internal standard. TLC was done on silica gel coated glass slide. All solvents were dried and distilled before use. Commercially available solvents were freshly distilled before the reaction. All reactions involving moisture sensitive reactants were executed using oven-dried glassware. X-ray single crystal data were collected using Mo Kα (λ = 0.71073 Å) radiation with CCD area detector. All the imidazopyridines were prepared by our reported method.10b Typical Experimental Procedure for Compound 3aa. A mixture of 2-phenylimidazo[1,2-a]pyridine (1a) (0.2 mmol, 39 mg) and morpholine (2a) (0.4 mmol, 35 mg) were taken in a sealed tube. Then 1,4-dioxane (2 mL) was added to it and stirred at room temperature for few seconds. Then PIDA (2 equiv, 129 mg) was added to it and stirred at room temperature for 10 min. After completion of the reaction (TLC), the reaction mixture was quenched with ethyl acetate (5 mL) and water (2 mL). Then the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude residue which was purified by column chromatography on silica gel (60−120 mesh) using petroleum ether:ethyl acetate = 7:3 as an eluent to afford desired product (3aa) (42 mg, 76%) as a white solid. 4-(2-Phenylimidazo[1,2-a]pyridin-3-yl)morpholine (3aa). White solid (76%, 42 mg); Rf. = 0.45 (PE:EA = 70:30); mp 137−138 °C; 1H NMR (400 MHz, CDCl3): δ 8.11−8.09 (m, 1H), 7.86−7.84 (m, 2H), 7.56 (d, J = 8.8 Hz, 1H), 7.47−7.43 (m, 2H), 7.37−7.33 (m, 1H), 7.18−7.14 (m, 1H), 6.83−6.79 (m, 1H), 3.87 (t, J = 4.8 Hz, 4H), 3.16

Scheme 4. Subtrate Scopes of Indolizinesa

a

Reaction conditions: 0.2 mmol of 5 and 0.4 mmol of 2 in the presence of 2 equiv PIDA in 2 mL of 1,4-dioxane at room temperature for 30 min. 4506

DOI: 10.1021/acs.joc.7b00564 J. Org. Chem. 2017, 82, 4504−4510

Note

The Journal of Organic Chemistry Scheme 5. Control Experiments

1H), 6.83−6.79 (m, 1H), 3.87 (t, J = 4.8 Hz, 4H), 3.16 (s, 4H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.6, 137.9, 137.6, 131.6, 129.1, 128.7, 128.3, 124.3, 122.7, 117.8, 111.9, 67.9, 50.3, 21.4; Anal. Calcd for C18H19N3O: C, 73.69; H, 6.53; N, 14.32%; Found: C, 73.88; H, 6.58; N, 14.26%. 4-(2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)morpholine (3fa). White solid (71%, 44 mg); Rf. = 0.45 (PE:EA = 70:30); mp 165−166 °C; 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 6.8 Hz, 1H), 7.80−7.76 (m, 2H), 7.54 (d, J = 9.2 Hz, 1H), 7.16−7.12 (m, 1H),7.00−6.96 (m, 2H), 6.81−6.77 (m, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.85 (s, 3H), 3.15 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.4, 141.5, 137.6, 129.9, 127.9, 127.0, 124.2, 122.7, 117.7, 113.8, 111.8, 67.9, 55.3, 50.2; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H19N3O2 [M+H]+: 310.1556, found [M+H]+: 310.1559. 4-(2-(4-Chlorophenyl)-8-methylimidazo[1,2-a]pyridin-3-yl)morpholine (3ga). White solid (80%, 52 mg); Rf. = 0.50 (PE:EA = 75:25); mp 160−161 °C; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 6.8 Hz, 1H), 7.82−7.80 (m, 2H), 7.43−7.40 (m, 2H), 6.98−6.97 (m, 1H), 6.74 (t, J = 6.8 Hz, 1H), 3.86 (t, J = 4.4 Hz, 4H), 3.14 (s, 4H), 2.61 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.1, 136.1, 133.6, 130.1, 129.0, 128.5, 127.8, 127.2, 123.3, 120.7, 112.1, 67.9, 50.3, 16.8; Anal. Calcd for C18H18ClN3O: C, 65.95; H, 5.53; N, 12.82%; Found: C, 65.81; H, 5.48; N, 12.74%. 4-(2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)morpholine (3ha). White solid (74%, 44 mg); Rf. = 0.50 (PE:EA = 70:30); mp 158−159 °C; 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 6.8 Hz, 1H), 7.86−7.82 (m, 2H), 7.55 (d, J = 8.8 Hz, 1H), 7.20−7.12 (m, 3H), 6.84−6.80 (m, 1H), 3.87 (t, J = 4.8 Hz, 4H), 3.16 (s, 4H); 13 C{1H} NMR (100 MHz, CDCl3): δ 162.6 (JC−F = 245 Hz), 141.7, 136.8, 130.7 (JC−F = 4 Hz), 130.4 (JC−F = 9 Hz), 128.4, 124.5, 122.9, 117.9, 115.3 (JC−F = 21 Hz), 112.0, 67.9, 50.3; Anal. Calcd for C17H16FN3O: C, 68.67; H, 5.42; N, 14.13%; Found: C, 68.83; H, 5.37; N, 14.19%. 4-(2-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)morpholine (3ia). Yellow gummy mass (72%, 50 mg); Rf. = 0.60 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 6.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 9.2 Hz, 1H), 7.24−7.22 (m, 1H), 6.89−6.86 (m, 1H), 3.90 (t, J = 4.8 Hz, 4H), 3.20 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.7, 136.6 (JC−F = 185 Hz), 129.4 (JC−F = 74 Hz), 129.5, 128.6, 126.1 (JC−F = 9 Hz), 125.7, 125.5, 125.3 (JC−F = 8 Hz, 5 Hz), 123.0, 117.9, 112.4, 67.7, 50.0; Anal. Calcd for C18H16F3N3O: C, 62.24; H, 4.64; N, 12.10%; Found: C, 62.40; H, 4.70; N, 12.01%. 4-(2-(4-(Methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)morpholine (3ja). Yellow gummy mass (69%, 49 mg); Rf. = 0.50 (PE:EA = 25:75); 1H NMR (400 MHz, CDCl3): δ 8.15 (t, J = 8.8 Hz, 3H), 8.02 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.24−7.22 (m, 1H), 6.89−6.86 (m, 1H), 3.91 (t, J = 5.2 Hz, 4H), 3.22 (t, J = 4.4 Hz, 4H), 3.11 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.2, 140.0,

Scheme 6. Probable Mechanistic Pathway

(s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.6, 137.8, 134.5, 128.8, 128.5, 128.3, 127.8, 124.3, 122.7, 117.9, 111.9, 67.9, 50.3; Anal. Calcd for C17H17N3O: C, 73.10; H, 6.13; N, 15.04%; Found: C, 73.25; H, 6.19; N, 15.13%. 4-(8-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)morpholine (3ba). White solid (84%, 49 mg); Rf. = 0.50 (PE:EA = 90:10); mp 147−148 °C; 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 6.8 Hz, 1H), 7.83−7.81 (m, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.37−7.35 (m, 1H), 6.98−6.96 (m, 1H), 6.74 (t, J = 6.8 Hz, 1H), 3.86 (t, J = 4.4 Hz, 4H), 3.13 (s, 4H), 2.62 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.9, 137.4, 134.9, 129.1, 129.0, 128.3, 127.7, 123.1, 120.6, 111.9, 67.9, 50.5, 16.8; Anal. Calcd for C18H19N3O: C, 73.69; H, 6.53; N, 14.32%; Found: C, 73.85; H, 6.46; N, 14.24%. 4-(7-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)morpholine (3ca). White solid (73%, 43 mg); Rf. = 0.55 (PE:EA = 70:30); mp 148−149 °C; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 6.8 Hz, 1H), 7.85−7.83 (m, 2H), 7.45−7.42 (m, 2H), 7.36−7.31 (m, 2H), 6.65−6.63 (m, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.15 (s, 4H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.1, 137.2, 135.3, 134.6, 128.7, 128.3, 128.1, 127.7, 122.1, 116.2, 114.6, 67.9, 50.3, 21.4; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H19N3O [M+H]+: 294.1606, found [M+H]+: 294.1605. 4-(8-Methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)morpholine (3da). White solid (75%, 46 mg); Rf. = 0.50 (PE:EA = 75:25); mp 120−121 °C; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 6.8 Hz, 1H), 7.72−7.70 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.97−6.95 (m, 1H), 6.72 (t, J = 6.8 Hz, 1H), 3.85 (t, J = 4.4 Hz, 4H), 3.12 (s, 4H), 2.62 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.8, 137.5, 131.9, 129.09, 129.00, 128.7, 127.6, 125.9, 123.0, 120.5, 111.9, 67.9, 50.5, 21.4, 16.8; Anal. Calcd for C19H21N3O: C, 74.24; H, 6.89; N, 13.67%; Found: C, 74.11; H, 6.93; N, 13.75%. 4-(2-(p-Tolyl)imidazo[1,2-a]pyridin-3-yl)morpholine (3ea). White solid (78%, 46 mg); Rf. = 0.60 (PE:EA = 70:30); mp 138−139 °C; 1H NMR (400 MHz, CDCl3): δ 8.11−8.09 (m, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.18−7.14 (m, 4507

DOI: 10.1021/acs.joc.7b00564 J. Org. Chem. 2017, 82, 4504−4510

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The Journal of Organic Chemistry

126.8, 124.7, 123.0, 122.6, 118.1, 112.2, 52.5, 29.0; Anal. Calcd for C17H16BrN3S: C, 54.55; H, 4.31; N, 11.23%; Found: C, 54.71; H, 4.24; N, 11.31%. 4-(3-Thiomorpholinoimidazo[1,2-a]pyridin-2-yl)benzonitrile (4nb). White solid (62%, 40 mg); Rf. = 0.50 (PE:EA = 70:30); mp 184−185 °C; 1H NMR (400 MHz, CDCl3): δ 8.09−8.05 (m, 3H), 7.75−7.72 (m, 2H), 7.57−7.55 (m, 1H), 7.23−7.19 (m, 1H), 6.87− 6.83 (m, 1H), 3.44 (t, J = 5.2 Hz, 4H), 2.84 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.0, 138.9, 135.2, 132.2, 130.8, 128.5, 125.1, 123.1, 119.0, 118.2, 112.5, 111.0, 52.3, 28.9; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H16N4S [M+H]+: 321.1174, found [M+H]+: 321.1193. 4-(2-(Naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)thiomorpholine (4kb). Yellow gummy mass (78%, 54 mg); Rf. = 0.45 (PE:EA = 70:30); 1 H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 8.11−8.09 (m, 1H), 8.05−8.02 (m, 1H), 7.96−7.93 (m, 2H), 7.89−7.86 (m, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.52−7.49 (m, 2H), 7.22−7.18 (m, 1H), 6.86−6.82 (m, 1H), 3.47 (s, 4H), 2.84 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.7, 137.3, 133.4, 133.0, 131.6, 130.1, 128.5, 128.0, 127.8, 127.6, 126.5, 126.3, 126.2, 124.6, 122.8, 117.9, 112.1, 52.7, 29.0; Anal. Calcd for C21H19N3S: C, 73.01; H, 5.54; N, 12.16%; Found: C, 73.18; H, 5.60; N, 12.25%. 4-(2-(Furan-2-yl)imidazo[1,2-a]pyridin-3-yl)thiomorpholine (4ob). Yellow gummy mass (81%, 46 mg); Rf. = 0.50 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.11−8.09 (m, 1H), 7.58− 7.57 (m, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.17−7.13 (m, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.80−6.77 (m, 1H), 6.53−6.52 (m, 1H), 3.61 (s, 2H), 3.20 (s, 2H), 3.01 (s, 2H), 2.66 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 149.2, 142.4, 141.5, 130.0, 129.5, 125.0, 122.5, 117.3, 112.0, 111.6, 108.1, 52.7, 29.3; Anal. Calcd for C15H15N3OS: C, 63.13; H, 5.30; N, 14.73%; Found: C, 62.91; H, 5.25; N, 14.64%. 4-(6-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)thiomorpholine (4pb). Light yellow gummy mass (59%, 39 mg); Rf. = 0.50 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 2.0 Hz, 1H), 7.83−7.81 (m, 2H), 7.52−7.45 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 7.15−7.12 (m, 1H), 3.38 (s, 4H), 2.81 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 139.8, 138.8, 134.0, 130.2, 128.6, 128.5, 128.1, 125.7, 120.54, 120.50, 118.4, 52.7, 29.0; Anal. Calcd for C17H16ClN3S: C, 61.90; H, 4.89; N, 12.74%; Found: C, 61.72; H, 4.78; N, 12.63%. 4-(8-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)thiomorpholine (4bb). Yellow gummy mass (86%, 53 mg); Rf. = 0.60 (PE:EA = 90:10); 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 6.8 Hz, 1H), 7.85−7.82 (m, 2H), 7.47−7.43 (m, 2H), 7.36−7.32 (m, 1H), 6.96− 6.94 (m, 1H), 6.72 (t, J = 6.8 Hz, 1H), 3.36 (t, J = 4.8 Hz, 4H), 2.84 (s, 4H), 2.61 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.8, 137.0, 134.7, 130.2, 128.8, 128.4, 127.7, 127.6, 123.1, 120.5, 111.9, 52.8, 29.0, 16.7; Anal. Calcd for C18H19N3S: C, 69.87; H, 6.19; N, 13.58%; Found: C, 69.68; H, 6.14; N, 13.51%. 4-(7-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)thiomorpholine (4cb). Light yellow solid (76%, 47 mg); Rf. = 0.50 (PE:EA = 70:30); mp 145−146 °C; 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 7.2 Hz, 1H), 7.86−7.84 (m, 2H), 7.46−7.42 (m, 2H), 7.35−7.30 (m, 2H), 6.64−6.62 (m, 1H), 3.38 (d, J = 4.0 Hz, 4H), 2.81 (s, 4H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.0, 136.9, 135.3, 134.5, 129.5, 128.5, 128.4, 127.6, 122.0, 116.2, 114.6, 52.7, 29.0, 21.4; Anal. Calcd for C18H19N3S: C, 69.87; H, 6.19; N, 13.58%; Found: C, 70.03; H, 6.13; N, 13.68%. 2-Phenyl-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4ac). Yellow liquid (62%, 34 mg); Rf. = 0.55 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.06−8.04 (m, 1H), 7.86−7.84 (m, 2H), 7.55 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.36−7.32 (m, 1H), 7.16−7.12 (m, 1H), 6.80−6.77 (m, 1H), 3.09 (t, J = 5.2 Hz, 4H), 1.76−1.71 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.5, 135.0, 131.0, 128.9, 128.8, 128.2, 127.5, 124.0, 123.1, 117.8, 111.6, 51.5, 27.1, 24.2; Anal. Calcd for C18H19N3: C, 77.95; H, 6.90; N, 15.15%; Found: C, 78.17; H, 6.80; N, 15.03%. 8-Methyl-2-phenyl-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4bc). Yellow gummy mass (67%, 39 mg); Rf. = 0.55 (PE:EA = 90:10); 1 H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 6.4 Hz, 1H), 7.84−7.82 (m, 2H), 7.45−7.41 (m, 2H), 7.35−7.31 (m, 1H), 6.94−6.92 (m, 1H),

139.3, 129.1, 128.2, 127.8, 127.5, 125.3, 123.3, 118.3, 112.6, 67.8, 50.0, 44.7; Anal. Calcd for C18H19N3O3S: C, 60.49; H, 5.36; N, 11.76%; Found: C, 60.30; H, 5.31; N, 11.84%. 4-(2-(Naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)morpholine (3ka). Yellow gummy mass (77%, 51 mg); Rf. = 0.45 (PE:EA = 70:30); 1 H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 8.15−8.13 (m, 1H), 8.04−8.02 (m, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.88−7.86 (m, 1H), 7.64−7.61 (m, 1H), 7.53−7.47 (m, 2H), 7.22−7.18 (m, 1H), 6.86− 6.82 (m, 1H), 3.90 (t, J = 4.8 Hz, 4H), 3.23 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.8, 137.6, 133.4, 133.0, 131.8, 128.8, 128.5, 127.9, 127.8, 127.7, 126.7, 126.3, 126.2, 124.6, 122.9, 117.9, 112.1, 67.9, 50.3; Anal. Calcd for C21H19N3O: C, 76.57; H, 5.81; N, 12.76%; Found: C, 76.41; H, 5.88; N, 12.85%. 4-(2-(Thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)morpholine (3la). Yellow gummy mass (81%, 46 mg); Rf. = 0.50 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.11−8.09 (m, 1H), 7.63−7.62 (m, 1H), 7.55−7.53 (m, 1H), 7.35−7.33 (m, 1H), 7.17−7.10 (m, 2H), 6.80− 6.77 (m, 1H), 3.94 (t, J = 4.4 Hz, 4H), 3.28 (t, J = 4.8 Hz, 4H); 13 C{1H} NMR (100 MHz, CDCl3): δ 142.0, 136.6, 133.6, 127.44, 127.41, 125.8, 125.6, 124.7, 123.3, 117.9, 112.1, 67.8, 49.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H15N3OS [M+H]+: 286.1014, found [M+H]+: 286.1021. Typical Experimental Procedure for Compound 4ab. A mixture of 2-phenylimidazo[1,2-a]pyridine (1a) (0.2 mmol, 39 mg) and thiomorpholine (2b) (0.4 mmol, 41 mg) were taken in a sealed tube. Then 1,4-dioxane (2 mL) was added to it and stirred at room temperature for few seconds. Then PIDA (2 equiv, 129 mg) was added to it and stirred at room temperature for 10 min. After completion of the reaction (TLC), the reaction mixture was quenched with ethyl acetate (5 mL) and water (2 mL). Then the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude residue which was purified by column chromatography on silica gel (60−120 mesh) using petroleum ether:ethyl acetate = 7:3 as an eluent to afford desired product (4ab) (46 mg, 78%) as a yellow gummy mass. 4-(2-Phenylimidazo[1,2-a]pyridin-3-yl)thiomorpholine (4ab). Yellow gummy mass (78%, 46 mg); Rf. = 0.50 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.07−8.05 (m, 1H), 7.88−7.85 (m, 2H), 7.56 (d, J = 9.2 Hz, 1H), 7.48−7.44 (m, 2H), 7.38−7.34 (m, 1H), 7.19− 7.15 (m, 1H), 6.84−6.80 (m, 1H), 3.41 (t, J = 5.2 Hz, 4H), 2.81 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.5, 137.4, 134.3, 129.9, 128.6, 128.4, 127.8, 124.5, 122.7, 117.9, 112.0, 52.7, 29.0; Anal. Calcd for C17H17N3S: C, 69.12; H, 5.80; N, 14.22%. Found: C, 68.93; H, 5.75; N, 14.14%. 4-(2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)thiomorpholine (4fb). Colorless liquid (72%, 47 mg); Rf. = 0.50 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 6.8 Hz, 1H), 7.81−7.79 (m, 2H), 7.55 (d, J = 8.8 Hz, 1H), 7.18−7.13 (m, 1H), 7.01−6.99 (m, 2H), 6.82−6.79 (m, 1H), 3.86 (s, 3H), 3.41−3.39 (m, 4H), 2.79 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.4, 141.4, 137.3, 129.8, 129.2, 126.9, 124.2, 122.6, 117.7, 113.8, 111.8, 55.4, 52.6, 29.0; Anal. Calcd for C18H19N3OS: C, 66.43; H, 5.89; N, 12.91%; Found: C, 66.25; H, 5.94; N, 12.97%. 4-(2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)thiomorpholine (4hb). Yellow gummy mass (73%, 46 mg); Rf. = 0.60 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.06−8.04 (m, 1H), 7.87− 7.82 (m, 2H), 7.56−7.53 (m, 1H), 7.19−7.12 (m, 3H), 6.83−6.80 (m, 1H), 3.39 (t, J = 5.2 Hz, 4H), 2.81 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 162.6 (JC−F = 246.0 Hz), 141.6, 136.5, 130.5 (JC−F = 3.0 Hz), 130.2 (JC−F = 8.0 Hz), 129.7, 124.5, 122.8, 117.9, 115.4 (JC−F = 22 Hz), 112.1, 52.7, 29.0; Anal. Calcd for C17H16FN3S: C, 65.15; H, 5.15; N, 13.41%; Found: C, 65.31; H, 5.21; N, 13.52%. 4-(2-(3-Bromophenyl)imidazo[1,2-a]pyridin-3-yl)thiomorpholine (4mb). Yellow gummy mass (71%, 53 mg); Rf. = 0.50 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 8.05 (d, J = 6.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.20−7.15 (m, 1H), 6.82 (t, J = 6.8 Hz, 1H), 3.41 (t, J = 5.2 Hz, 4H), 2.83 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.7, 136.4, 135.8, 131.3, 130.7, 130.1, 129.9, 4508

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6.70 (t, J = 6.8 Hz, 1H), 3.05 (t, J = 5.6 Hz, 4H), 2.62 (s, 3H), 1.83 (s, 1H), 1.74−1.68 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.7, 136.6, 135.3, 130.7, 129.1, 128.2, 127.5, 127.4, 122.7, 120.9, 111.6, 51.7, 27.1, 24.2, 16.8; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H21N3 [M+H]+: 292.1814, found [M+H]+: 292.1831. 2-(4-Methoxyphenyl)-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4 fc). Yellow gummy mass (63%, 39 mg); Rf. = 0.50 (PE:EA = 70:30); 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 6.8 Hz, 1H), 7.80−7.78 (m, 2H), 7.53 (d, J = 9.2 Hz, 1H), 7.14−7.10 (m, 1H), 6.99−6.97 (m, 2H), 6.79−6.75 (m, 1H), 3.86 (s, 3H), 3.08 (t, J = 5.6 Hz, 4H), 2.06 (s, 2H), 1.76−1.72 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.2, 141.4, 136.8, 130.0, 127.4, 123.9, 123.1, 117.5, 114.2, 113.7, 111.5, 55.4, 51.5, 27.1, 24.2; Anal. Calcd for C19H21N3O: C, 74.24; H, 6.89; N, 13.67%; Found: C, 74.41; H, 6.85; N, 13.68%. 2-(4-Chlorophenyl)-3-(piperidin-1-yl)imidazo[1,2-a]pyridine (4qc). Yellow gummy mass (65%, 40 mg); Rf. = 0.45 (PE:EA = 70:30); 1 H NMR (400 MHz, CDCl3): δ 8.06−8.04 (m, 1H), 7.85−7.81 (m, 2H), 7.55−7.53 (m, 1H), 7.43−7.39 (m, 2H), 7.17−7.13 (m, 1H), 6.81−6.77 (m, 1H), 3.09 (t, J = 5.6 Hz, 4H), 1.77−1.71 (m, 6H); 13 C{1H} NMR (100 MHz, CDCl3): δ 134.0, 130.8, 129.9, 128.8, 128.6, 128.5, 125.5, 123.3, 117.3, 114.7, 112.6, 51.4, 26.9, 24.1; Anal. Calcd for C18H18ClN3: C, 69.34; H, 5.82; N, 13.48%; Found: C, 69.17; H, 5.90; N, 13.59%. Typical Experimental Procedure for Compound 6aa. A mixture of methyl indolizine-1-carboxylate (5a) (0.2 mmol, 35 mg) and morpholine (2a) (0.4 mmol, 35 mg) were taken in a sealed tube. Then 1,4-dioxane (2 mL) was added to it and stirred at room temperature for few seconds. Then PIDA (2 equiv, 129 mg) was added to it and stirred at room temperature for 30 min. After completion of the reaction (TLC), the reaction mixture was quenched with ethyl acetate (5 mL) and water (2 mL). Then the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude residue which was purified by column chromatography on silica gel (60−120 mesh) using petroleum ether:ethyl acetate = 9:1 as an eluent to afford desired product (6aa) (38 mg, 73%) as a yellow gummy mass. Methyl 3-Morpholinoindolizine-1-carboxylate (6aa). Yellow gummy mass (73%, 38 mg); Rf. = 0.55 (PE:EA = 90:10); 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.03−6.99 (m, 1H), 6.86 (s, 1H), 6.74−6.70 (m, 1H), 3.89−3.86 (m, 7H), 2.98 (t, J = 4.8 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.5, 135.0, 132.6, 122.0, 121.9, 119.9, 112.1, 104.2, 101.3, 67.3, 52.3, 50.9; Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76%; Found: C, 64.77; H, 6.25; N, 10.66%. 3-Thiomorpholinoindolizine-1-carbonitrile (6bb). Yellow gummy mass (71%, 34 mg); Rf. = 0.50 (PE:EA = 85:15); 1H NMR (400 MHz, CDCl3): δ 7.99−7.97 (m, 1H), 7.60−7.57 (m, 1H), 7.04−7.00 (m, 1H), 6.78−6.74 (m, 1H), 6.64 (s, 1H), 3.22 (t, J = 5.2 Hz, 4H), 2.83 (t, J = 4.4 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 135.7, 134.6, 131.8, 122.2, 121.9, 118.1, 117.3, 112.5, 105.7, 54.0, 28.3; Anal. Calcd for C13H13N3S: C, 64.17; H, 5.39; N, 17.27%; Found: C, 64.01; H, 5.47; N, 17.16%. 3-(Piperidin-1-yl)indolizine-1-carbonitrile (6cc). Yellow gummy mass (61%, 27 mg); Rf. = 0.60 (PE:EA = 90:10); 1H NMR (400 MHz, CDCl3): δ 7.98−7.96 (m, 1H), 7.58−7.56 (m, 1H), 7.00−6.96 (m, 1H), 6.75−6.71 (m, 1H), 6.56 (s, 1H), 2.90 (t, J = 5.2 Hz, 4H), 1.77−1.72 (m, 4H), 1.65−1.60 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 134.4, 130.9, 128.8, 122.5, 121.3, 117.8, 117.6, 112.0, 104.0, 53.0, 26.1, 24.0; Anal. Calcd for C14H15N3: C, 74.64; H, 6.71; N, 18.65%; Found: C, 74.80; H, 6.62; N, 18.58%. 2,6-Ditert-butyl-4-(morpholinomethyl)phenol (7).3g (68%, 42 mg): 1H NMR (400 MHz, CDCl3): δ 7.09 (s, 2H), 5.13 (s, 1H), 3.71 (t, J = 4.8 Hz, 4H), 3.42 (s, 2H), 2.44 (t, J = 4.4 Hz, 4H), 1.44 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3): δ 152.9, 135.7, 128.1, 126.0, 67.2, 63.7, 53.6, 34.4, 30.5.

Note

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00564. Scanned copies of 1H and 13C{1H} NMR spectra of the synthesized compounds (PDF) X-ray crystallographic data for compound 3aa (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Alakananda Hajra: 0000-0001-6141-0343 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.H. acknowledges the financial support from SERB-DST, (Grant no. EMR/2016/001643). S.M. thanks CSIR-New Delhi (CSIR-JRF) and S.S. thanks UGC-New Delhi (UGC-JRF) for their fellowships.

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REFERENCES

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DOI: 10.1021/acs.joc.7b00564 J. Org. Chem. 2017, 82, 4504−4510

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The Journal of Organic Chemistry (9) (a) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Chem. Commun. 2015, 51, 1555. (b) Pericherla, K.; Kaswan, P.; Pandey, K.; Kumar, A. Synthesis 2015, 47, 887. (c) Koubachi, J.; Kazzouli, S. E.; Bousmina, M.; Guillaumet, G. Eur. J. Org. Chem. 2014, 2014, 5119. (d) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2743. (e) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678. (f) Donthiri, R. R.; Pappula, V.; Reddy, N. N. K.; Bairagi, D.; Adimurthy, S. J. Org. Chem. 2014, 79, 11277. (g) Lei, S.; Mai, Y.; Yan, C.; Mao, J.; Cao, H. Org. Lett. 2016, 18, 3582. (10) (a) Bagdi, A. K.; Hajra, A. Chem. Rec. 2016, 16, 1868. (b) Bagdi, A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2013, 355, 1741. (c) Mondal, S.; Samanta, S.; Santra, S.; Bagdi, A. K.; Hajra, A. Adv. Synth. Catal. 2016, 358, 3633. (11) Règnier, S.; Bechara, W. S.; Charette, A. B. J. Org. Chem. 2016, 81, 10348. (12) (a) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133, 5996. (b) Boursalian, G. B.; Ham, W. S.; Mazzotti, A. R.; Ritter, T. Nat. Chem. 2016, 8, 810. (c) Minisci, F. Synthesis 1973, 1973, 1. (d) Chen, J. R.; Hu, X. Q.; Lu, L. Q.; Xiao, W. J. Chem. Soc. Rev. 2016, 45, 2044. (e) Xiong, T.; Zhang, Q. Chem. Soc. Rev. 2016, 45, 3069. (13) Further information can be found in the CIF file. This crystal was deposited in the Cambridge Crystallographic Data Centre and assigned as CCDC 1535661.

4510

DOI: 10.1021/acs.joc.7b00564 J. Org. Chem. 2017, 82, 4504−4510