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Article pubs.acs.org/joc

Transition-Metal-Free Cascade Approach toward 2‑Alkoxy/2Sulfenylpyridines and Dihydrofuro[2,3‑b]pyridines by Trapping In Situ Generated 1,4-Oxazepine Guolin Cheng,*,† Lulu Xue,‡ Yunxiang Weng,‡ and Xiuling Cui*,‡ †

College of Materials Science & Engineering, Huaqiao University, Xiamen 361021, China Engineering Research Center of Molecular Medicine, Ministry of Education, Key Laboratory of Molecular Medicine of Fujian Province, Key Laboratory of Xiamen Marine and Gene Drugs, Institutes of Molecular Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China

‡

S Supporting Information *

ABSTRACT: An efficient cascade reaction via trapping in situ generated active intermediate 1,4-oxazepine, formed from base-promoted 7-exo-dig cyclization reaction of N-propargyl enaminone, has been developed. Alcohols/thiols and aldehydes were used as trapping agents, providing 2-alkoxy/2sulfenylpyridines and dihydrofuro[2,3-b]pyridines in moderate to high yields. This cascade reaction was completed within 30 min at room temperature, generating 1 equiv of H2O as the sole byproduct.

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derivatives.7,8 Considering that 1,4-oxazepines 6 might be derived from the protonation reaction of 1,4-oxazepine anions I, we proposed that intermediate I could be trapped by a suitable electrophile, such as aldehyde, to form intermediate II, and then further transformed to dihydrofuro[2,3-b]pyridines 5 (Scheme 1).9 In our continuing interest in transformation of

INTRODUCTION As one of the most important nitrogen-containing heterocycles, pyridines have been considered as a privileged structure in natural products, pharmaceuticals, and advanced functional materials.1 Especially, 2-alkoxy/2-sulfenylpyridines and furo[2,3-b]pyridines have attracted much research interest, due to being key structural elements in some pharmacological agents (Figure 1).2

Scheme 1. Capture of In Situ Generated 1,4-Oxazepine Anions by Alcohols/Thiols or Aldehydes

Figure 1. Biologically active compounds containing 2-alkoxy/2sulfenylpyridines or furo[2,3-b]pyridine.

enaminones to heterocycles,10 herein we disclose a cascade reaction model of 1,4-oxazepines generation/inter- or intramolecular 1,4-oxazepines capture to provide an efficient method for preparing 2-alkoxy/sulfenylpyridines 4 or dihydrofuro[2,3-b]pyridines 5.

The development of cascade reactions for the synthesis of complicated molecular scaffolds from simple starting materials in a one-pot pattern is strongly demanded in organic chemistry.3 In this context, the capture of reactive species by other functionalities has emerged as a valuable strategy for the discovery of new cascade reactions with unmatched efficiency.4 Fully unsaturated monocyclic 1,4-oxazepines 6 are unstable and difficult to be obtained by traditional synthetic methods due to their antiaromatic character.5 We have recently documented that 1,4-oxazepines 6 could be formed under mild reaction conditions from N-propargyl enaminones 1 via 7-exo-dig cyclization reaction,6 and it could be further used as masked pyridine cores to provide straightforward access to pyridine © 2017 American Chemical Society

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RESULTS AND DISCUSSION We commenced our studies by exploring the reaction of 1,3diphenyl-3-(propargylamino)-2-propen-1-one 1a11 with benzyl alcohol 2a to optimize the reaction conditions (Table 1). First, Received: June 21, 2017 Published: August 21, 2017 9515

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524

Article

The Journal of Organic Chemistry Scheme 2. Scope of Alcohols and Enaminonesa

Table 1. Optimization of the Reaction Conditions for the Cascade Reaction of Benzyl Alcohol 2a and 1,3-Diphenyl-3(propargylamino)-2-propen-1-one 1aa

entry

base

solvent

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11c 12d

Et3N K2CO3 NaOH KOH NaOtBu KOtBu NaOH NaOH NaOH NaOH NaOH NaOH

DMSO DMSO DMSO DMSO DMSO DMSO DMF NMP toluene 1,4-dioxane DMSO DMSO

1 1 0.5 0.5 0.5 0.5 0.5 0.5 1 1 0.5 0.5

0 0 94 90 90 75 87 89 0 0 86 95

a

Reaction conditions: 1a (0.5 mmol), 2a (2 equiv), base (1 equiv), and solvent (1 mL) at room temperature under an air atmosphere. b Isolated yields based on 1a. c1.5 equiv of 2a. d2.5 equiv of 2a. DMSO = dimethyl sulfoxide, DMF = N,N-dimethylformamide, and NMP = Nmethyl-2-pyrrolidone.

a

Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), and NaOH (0.5 mmol) in DMSO (1 mL) at room temperature under air atmosphere. Yield based on 1.

the influence of the base was investigated. Et3N and K2CO3 were both ineffective (entries 1 and 2). However, to our delight, NaOH efficiently promoted the cascade reaction of 1a and 2a, affording 4aa in excellent yield (94%; entry 3). Other strong bases, such as KOH, NaOtBu, and KOtBu, were also effective for this reaction but provided 4aa in slightly lower yield (entries 4−6). The influence of the solvents was then studied using NaOH as the base. Polar solvents (DMSO, DMF, and NMP) favored this transformation (entries 3, 7, and 8, respectively), while no desired product was observed when toluene and 1,4-dioxane were used as solvent (entries 9 and 10, respectively). Further investigation showed that the optimal amount of benzyl alcohol is 2 equiv (entries 3, 11, and 12). Therefore, the optimized reaction conditions were found as follows: 1a and 2a in a molar ratio of 1:2 and NaOH (1 equiv) as the base at room temperature under an air atmosphere (entry 3). With optimal reaction conditions in hand, we then explored the scope of alcohols (Scheme 2, top). Both electron-deficient and electron-rich benzyl alcohols could be applied in this reaction, giving the corresponding products in good to excellent yields (4ab−4ah), and the former (4ab−4af) showed higher reactivity than later ones (4ag and 4ah). Other alcohols, such as alkyl alcohols 4ai−al, allyl alcohols 4am−4ao, and cinnamyl alcohol 4ap, were also compatible substrates, affording the desired products in good yields. Notably, heteroaryl, 1naphthyl, and terminal alkynyl substituents (4aq, 4ar, and 4as) were proved to be well-tolerated under the standard reaction conditions. Significantly, 4-methoxyl phenol 4at, pyridin-2-ol 4au, and benzenethiols 4av−4aw were mendable to this procedure, although exhibiting relatively low reactivity. In the case of 2-amino benzenethiol (2w), compound 4aw was obtained in 70% yield, showing good chemoselectivity of benzenethiol over aniline. It is worth noting that pyridines containing bromide (4ad), iodide (4ae), terminal alkyne (4as),

and amino group (4aw) are difficult to be obtained from transition-metal-catalyzed reactions.8 Furthermore, we explored the scope of enaminones (Scheme 2, bottom). Various enaminones with aryl substituents were used in the cascade reaction to react with benzyl alcohol 2a. The corresponding pyridines 4ba−bp were obtained in good to excellent yields with good functional group tolerance, e.g., halogen, trifluoromethyl, and thienyl groups were all tolerated. Unfortunately, 1-alkyl-substituted enaminone failed to provide the desired product. Encouraged by these exciting results, we further explored other trapping reagents. To our delight, a wide variety of aromatic aldehydes could also be used as electrophiles to trap the proposed 1,4-oxazepine anion intermediates I, delivering the corresponding dihydrofuro[2,3-b]pyridine nucleus (5aa− 5am) in moderate to good yields (Scheme 3). The reaction could be applied to benzaldehydes with either electrondonating or electron-withdrawing groups on the phenyl rings, such as halogen, methylsulfonyl, and methylthio groups. The substituents at ortho-, meta-, or para-position have no significant influence on this transformation. Fused aromatics as well as heteroaromatics, such as naphthylaldehyde 5an and 5ao, 2-pyridylaldehyde 5ap, 2-furylaldehyde 5aq, and 2thienylaldehyde 5ar, afforded the desired dihydrofuro[2,3b]pyridine derivatives in modest to good yields. However, only a trace of product was observed when aliphatic aldehyde was used as the trapping agent, probably because the undesired aldol condensation of aliphatic aldehyde proceeded under the reaction conditions. Furthermore, the scope of enaminones was explored. Enaminones containing electron-rich phenyl (5bf− 5bh and 5bo−5bp), electron-deficient phenyl (5ba−5be and 9516

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524

Article

The Journal of Organic Chemistry Scheme 3. Scope of Aldehydes and Enaminonesa

idine 8 was isolated in 65% yield after 5 min, and it could be aromatized to 4ai in almost quantitative yield under standard reaction conditions (eq 3). The configuration of (±)-trans-8 was determined by single-crystal X-ray diffraction analysis. When the reaction of benzaldehyde and 1a was quenched by water after 5 min, the putative intermediate 9 was detected by HRMS (see Supporting Information, Figure S1) (Scheme 4a). Scheme 4. Potential Pathways for Product Formation

a

Reaction conditions: 3 (1 mmol) and NaOH (1 mmol) were resolved in DMSO (1 mL) at room temperature under an air atmosphere; then a solution of 1 (0.5 mmol) in DMSO (1 mL) was slowly added using a syringe pump within 15 min. Isolated yields based on 1.

However, the reaction of 1,4-oxazepine 6 and benzaldehyde under standard conditions did not give dihydrofuro[2,3b]pyridine 5aa, which suggested that 1,4-oxazepine 6 was not involved in the formation of 5aa (Scheme 4b). In an alternative scenario, the reaction would begin with an alkynylation reaction of aldehyde 3 and N-propargyl enaminone 1.13 The putative enaminone intermediate 10 was independently prepared and resubmitted to the standard reaction conditions. The desired product 5aa was not detected (Scheme 4c). On the basis of the above results, we proposed that the reaction would proceed as discussed in the introduction (Scheme 1). Namely, intermediate II was formed via trapping in situ generated 1,4oxazepine anion intermediate I with aldehyde. A proposed reaction mechanism is depicted in Scheme 5. Initial propargyl−allenyl isomerization followed by enolization of 1 would provide iminoenolate intermediates III, which might take a 7-exo-dig cyclization to afford 1,4-oxazepine anion I. Then trapping I with aldehydes would generate intermediates II, which could isomerize to epoxide intermediates IV via a tandem 6π-electrocyclization/walk rearrangement. Intramolecular SN2 substitution (epoxide ring-opening reaction) of IV was then followed by protonation of V, generating tetrahydrofuro[2,3-b]pyridine intermediates VI. Finally, dehydrative aromatization of VI led to dihydrofuro[2,3-b]pyridines 5. On the other hand, protonation of I would give 1,4-oxazepine 6, which would be further trapped with alcohols, leading to pyridines 4.

5bl−5bn), and heteroaromatic (5bj and 5bk) were all tolerated and resulted in the desired dihydrofuro[2,3-b]pyridines in moderate to good yields. Furo[2,3-b]pyridines represent an essential part of the heterocyclic scaffolds in numerous pharmaceuticals with a broad range of biological activities.2a,12 The versatility of these cascade reactions was further exemplified by synthesizing furo[2,3-b]pyridine 7 from oxidation of dihydrofuro[2,3b]pyridine 5ag with DDQ (DDQ = 2,3-dichloro-5,6dicyanobenzo-1,4-quinone, eq 1).

To gain mechanistic insights into these transformations, several control experiments were conducted. Enaminone 1a was subjected to the standard reaction conditions in the absence of MeOH, and the crucial intermediate 1,4-oxazepine 6 was isolated in 63% yield after 7 min. Pyridine 4ai could be obtained directly from the reaction of 6 with methanol in 95% yield (eq 2). Fortunately, the key intermediate 2,3-dihydropyr-

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CONCLUSION In conclusion, we have developed a highly attractive and operationally simple cascade reaction involving inter- or intramolecular capture of in situ generated 1,4-oxazepines to construct 2-alkoxy/2-sulfenylpyridines and dihydrofuro[2,3b]pyridines with readily available substrates. This transformation showed a wide range of functional group tolerance, such as iodide, terminal alkyne, and amino groups. This environmental-friendly procedure proceeded under transitional-metal-free reaction conditions and generated H2O as the sole byproduct. 9517

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524

Article

The Journal of Organic Chemistry Scheme 5. Proposed Mechanistic Pathwaya

129.2, 129.2, 129.0, 128.9, 128.8, 128.2, 128.2, 127.1, 126.3, 118.2, 115.8, 100.2; HRMS m/z (ESI): calcd for C25H17ClNO (M + H)+, 382.0993; found, 382.0995. Preparation of trans-2-Methoxy-3-methyl-4,6-diphenyl-2,3-dihydropyridin-3-ol 8. A mixture of 1a (131 mg, 0.5 mmol), MeOH (32 mg, 1 mmol), and NaOH (20 mg, 0.5 mmol) in DMSO (1 mL) was stirred at room temperature under air for 5 min. Then, the reaction was quenched with H2O (4 mL) and extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts were dried over Na2SO4 and concentrated. Then solvent was evaporated and the residue was purified by chromatography (silica gel, 20% EtOAc in PE) to give 8 (95 mg, 65%). White solid; mp 149−151 °C; 1H NMR (400 MHz, CDCl3) δ 7.98−7.89 (m, 2H), 7.66 (dd, J = 6.4, 2.7 Hz, 2H), 7.43 (m, 6H), 6.62 (s, 1H), 4.80 (s, 1H), 3.76 (s, 3H), 2.49 (s, 1H), 1.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 156. 8, 137.5, 135.6, 130. 6, 129.1, 128.5, 128.2, 126.8, 116.8, 97.7, 73.6, 55.8, 19.4; HRMS m/z (ESI): calcd for C19H20NO2 (M + H)+, 294.1489; found, 294.1494. Preparation of (Z)-3-((4-Hydroxy-4-phenylbut-2-yn-1-yl)amino)1,3-diphenylprop-2-en-1-one 10. A mixture of 11 (161 mg, 1 mmol) and 12 (206 mg, 1 mmol) in MeOH (2 mL) was stirred at room temperature under air for 24 min. Then, the reaction was quenched with H2O (8 mL) and extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts were dried over Na2SO4 and concentrated. Then solvent was evaporated and the residue was purified by chromatography (silica gel, 20% EtOAc in PE) to give 10 (312 mg, 85%). Yellow oil; mp 76−78 °C; IR (KBr): ν 1596, 1565, 1331, 1057, 752, 699 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.31 (s, 1H), 7.94−7.84 (m, 2H), 7.58−7.27 (m, 13H), 5.83 (s, 1H), 5.46 (s, 1H), 4.02 (dd, J = 6.2, 1.8 Hz, 2H), 2.64 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 189.1, 166.0, 140.4, 139.8, 134.8, 130.9, 129.8, 128.6, 128.5, 128.2, 128.2, 127.8, 127.1, 126.5, 94.6, 84.2, 82.3, 64.3, 34.6; HRMS m/z (ESI): calcd for C25H22NO2 (M + H)+, 368.1645; found, 368.1647. General Procedure for the Preparation of Pyridines 4aa−4aw and 4ba−4bq. A mixture of 1 (0.5 mmol), 2 (1 mmol), and NaOH (20 mg, 0.5 mmol) in DMSO (1 mL) was stirred at room temperature under air for 30 min. After 1 was exhausted completely (monitored by TLC), the residue was dissolved in H2O (4 mL) and extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts were dried over Na2SO4 and concentrated. Then solvent was evaporated and the residue was purified by chromatography (silica gel, 5% EtOAc in PE) to give 4aa−4aw and 4ba−4bq. 2-(Benzyloxy)-3-methyl-4,6-diphenylpyridine 4aa. White solid; yield (165 mg, 94%); mp 81−82 °C; IR (KBr): ν 1597, 1555, 1345, 1159, 1012, 751, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09−7.97 (m, 2H), 7.54 (d, J = 7.3 Hz, 2H), 7.48−7.25 (m, 12H), 5.60 (s, 2H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 151.8, 150.9, 139.9, 139.2, 138.3, 128.8, 128.6, 128.4, 127.7, 127.5, 126.5, 116.9, 114.7, 67.5, 12.8; HRMS m/z (ESI): calcd for C25H22NO (M + H)+, 352.1696; found, 352.1700. 2-((2-Fluorobenzyl)oxy)-3-methyl-4,6-diphenylpyridine 4ab. White solid; yield (172 mg, 93%); mp 92−93 °C; IR (KBr): ν 1555, 1493, 1353, 1159, 1023, 752 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.4 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.49−7.32 (m, 8H), 7.28 (d, J = 6.9 Hz, 2H), 7.19−7.03 (m, 2H), 5.67 (s, 2H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 160.9 (d, J = 247.3 Hz), 151.9, 150.9, 139.9, 139.1, 130.0 (d, J = 4.1 Hz), 129.3 (d, J = 8.1 Hz), 128.8, 128.6, 128.5, 128.4, 127.8, 126.5, 125.4 (d, J = 14.5 Hz), 124.0 (d, J = 3.5 Hz), 116.9, 115.3 (d, J = 21.3 Hz), 114.8, 61.6 (d, J = 4.4 Hz), 12.8; HRMS m/z (ESI): calcd for C25H21FNO (M + H)+, 370.1602; found, 370.1602. 2-((4-Chlorobenzyl)oxy)-3-methyl-4,6-diphenylpyridine 4ac. White solid; yield (181 mg, 94%); mp 65−67 °C; IR (KBr): ν 1555, 1340, 1158, 1090, 1007, 812, 699 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 2H), 7.50−7.30 (m, 12H), 7.28 (s, 1H), 5.54 (s, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 151.9, 150.9, 139.8, 139.0, 136.7, 133.3, 129.1, 128.7, 128.5, 128.5, 128.3, 127.75 126.4, 116.7, 114.8, 66.7, 12.7; HRMS m/z (ESI): calcd for C25H21ClNO (M + H)+, 386.1306; found, 386.1310.

a

Step 1, propargyl−allenyl isomerization/enolization; step 2, 7-exo-dig cyclization; step 3, nucleophilic addition; step 4, 6π-electrocyclization; step 5, walk rearrangement; step 6, epoxide ring-opening/protonation; step 7, dehydrative aromatization.

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EXPERIMENTAL SECTION

General Information. All reagents were used directly without further purification. Silica gel was purchased from Qing Dao Hai Yang Chemical Industry Co. All melting points were determined on a Beijing Science Instrument Dianguang Instrument Factory XT4B melting point apparatus and are uncorrected. 1H and 13C NMR spectra were measured on a 400 MHz Bruker spectrometer (1H 400 MHz, 13C 100 MHz), using CDCl3 as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature. HRMS ESI spectra were obtained on Q-TOF spectrometer. IR data were recorded on a Nicolet iS10 spectrometer. The products listed below were determined by 1H, 13 C NMR. PE is petroleum ether (60−90 °C). Preparation of 2-Methyl-5,7-diphenyl-1,4-oxazepine 6. A mixture of 1a (131 mg, 0.5 mmol) and NaOH (20 mg, 0.5 mmol) in DMSO (1 mL) was stirred at room temperature under air for 7 min. Then, the reaction was quenched with H2O (4 mL) and extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts were dried over Na2SO4 and concentrated. Then solvent was evaporated and the residue was purified by chromatography (silica gel, 5% EtOAc in PE) to give 6 (82 mg, 63%). Yellow solid; mp 76−78 °C; IR (KBr): ν 1629, 1173, 842, 766, 694 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.87 (m, 2H), 7.83−7.75 (m, 2H), 7.43 (m, 6H), 6.65 (s, 2H), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.5, 158.2, 144.8, 139.6, 133.7, 130.1, 130.0, 128.7, 128.4, 127.1, 126.3, 126.1, 106.6, 18.7; HRMS m/z (ESI): calcd for C18H16NO (M + H)+, 262.1226; found, 262.1228. Preparation of 2-(4-Chlorophenyl)-4,6-diphenylfuro[2,3-b]pyridine 7. To a solution of 5ag (192 mg, 0.5 mmol) in anhydrous 1,4-dioxane (2 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (341 mg, 1.5 mmol, 3.0 equiv), and the reaction mixture was stirred under reflux for 3 h. Then it was quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated. Then solvent was evaporated and the residue was purified by chromatography (silica gel, 5% EtOAc in PE) to give 7 (149 mg, 78%). White solid; mp 206−208 °C; ν 1607, 1391, 1226, 1056, 683 cm−1; 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.6 Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H), 7.80 (s, 1H), 7.75 (d, J = 7.3 Hz, 2H), 7.58 (t, J = 7.4 Hz, 2H), 7.55−7.47 (m, 3H), 7.46−7.41 (m, 3H), 7.19 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 162.7, 154.8, 152.9, 143.9, 138.9, 137.9, 135.1, 9518

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524

Article

The Journal of Organic Chemistry

3-Methyl-4,6-diphenyl-2-(2,2,2-trifluoroethoxy)pyridine 4al. Colorless oil; yield (154 mg, 90%); IR (KBr): ν 1600, 1439, 1370, 1274, 1164, 963, 773, 670 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.12−7.96 (m, 2H), 7.56−7.28 (m, 9H), 4.97 (q, J = 8.6 Hz, 2H), 2.22 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 160.0, 152.7, 150.9, 139.4, 138.5, 128.8, 128.7, 128.6, 128.4, 128.0, 126.4, 124.1 (q, J = 277.5 Hz), 116.9, 115.9, 62.52 (q, J = 35.7 Hz), 12.4; HRMS m/z (ESI): calcd for C20H17F3NO (M + H)+, 344.1257; found, 344.1261. 2-(Allyloxy)-3-methyl-4,6-diphenylpyridine 4am. Colorless oil; yield (104 mg, 69%); IR (KBr): ν 1595, 1557, 1437, 1383, 1335, 1160, 1011, 773, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−7.98 (m, 2H), 7.51−7.29 (m, 8H), 7.27 (s, 1H), 6.26−6.14 (m, 1H), 5.47 (dd, J = 17.2, 1.5 Hz, 1H), 5.30−5.21 (m, 1H), 5.09−5.00 (m, 2H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 151.7, 150.8, 139.9, 139.1, 134.2, 128.7, 128.5, 128.4, 128.2, 127.6, 126.4, 116.7, 114.4, 66.5, 12.6; HRMS m/z (ESI): calcd for C21H20NO (M + H)+, 302.1539; found, 302.1542. 3-Methyl-2-((2-methylallyl)oxy)-4,6-diphenylpyridine 4an. Colorless oil; yield (110 mg, 70%); IR (KBr): ν 1595, 1558, 1435, 1339, 1159, 1010, 773, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.4 Hz, 2H), 7.47−7.38 (m, 5H), 7.37−7.32 (m, 3H), 7.27 (s, 1H), 5.17 (s, 1H), 4.97 (d, J = 6.4 Hz, 3H), 2.19 (s, 3H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.7, 151.6, 150.8, 141.8, 139.9, 139.1, 128.7, 128.5, 128.4, 128.2, 127.6, 126.4, 116.7, 114.4, 111.6, 69.1, 19.8, 12.6; HRMS m/z (ESI): calcd for C22H22NO (M + H)+, 316.1696; found, 316.1700. (E)-2-(But-2-en-1-yloxy)-3-methyl-4,6-diphenylpyridine 4ao. Colorless oil; yield (110 mg, 70%); IR (KBr): ν 1594, 1557, 1435, 1343, 1158, 1003, 773, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.4 Hz, 2H), 7.46−7.31 (m, 8H), 7.25 (d, J = 6.1 Hz, 1H), 5.98− 5.82 (m, 2H), 4.97 (d, J = 4.9 Hz, 2H), 2.16 (s, 3H), 1.77 (d, J = 5.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 151.6, 150.7, 140.0, 139.2, 129.5, 128.7, 128.5, 128.3, 128.2, 127.6, 127.14, 126.4, 116.7, 114.2, 66.6, 17.9, 12.7; HRMS m/z (ESI): calcd for C22H22NO (M + H)+, 316.1696; found, 316.1701. 2-(Cinnamyloxy)-3-methyl-4,6-diphenylpyridine 4ap. Colorless oil; yield (162 mg, 86%); IR (KBr): ν 1595, 1556, 1435, 1345, 1157, 1005, 751, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10−8.04 (m, 2H), 7.48−7.40 (m, 7H), 7.39−7.33 (m, 4H), 7.33−7.28 (m, 3H), 7.28−7.20 (m, 2H), 6.82 (d, J = 15.9 Hz, 1H), 6.59 (dt, J = 15.9, 6.0 Hz, 1H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 151.7, 150.8, 139.9, 139.1, 136.8, 132.6, 128.7, 128.5, 128.4, 128.2, 127.6, 126.5, 126.4, 125.6, 116.7, 114.5, 66.5, 12.7; HRMS m/z (ESI): calcd for C27H24NO (M + H)+, 378.1852; found, 378.1858. 3-Methyl-4,6-diphenyl-2-(thiophen-2-ylmethoxy)pyridine 4aq. Colorless oil; yield (161 mg, 90%); IR (KBr): ν 1595, 1556, 1437, 1332, 1154, 1007, 772, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.5 Hz, 2H), 7.43 (t, J = 7.3 Hz, 4H), 7.39−7.31 (m, 4H), 7.30 (s, 1H), 7.26 (d, J = 4.8 Hz, 1H), 7.19 (s, 1H), 6.98 (s, 1H), 5.76 (s, 2H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 151.9, 150.6, 140.5, 139.8, 138.9, 128.7, 128.5, 128.4, 128.2, 127.7, 126.9, 126.4, 126.0, 116.9, 114.8, 62.2, 12.7; HRMS m/z (ESI): calcd for C23H20NOS (M + H)+, 358.1260; found, 358.1261. 3-Methyl-2-(2-(naphthalen-1-yl)ethoxy)-4,6-diphenylpyridine 4ar. White solid; yield (201 mg, 97%); mp 80−82 °C; IR (KBr): ν 1595, 1455, 1345, 1156, 1014, 773, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 6.8 Hz, 1H), 8.03 (d, J = 7.4 Hz, 2H), 7.84 (d, J = 6.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.50−7.30 (m, 12H), 7.25 (s, 1H), 4.86 (t, J = 7.2 Hz, 2H), 3.64 (t, J = 7.1 Hz, 2H), 2.11 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 161.9, 151.6, 151.0, 139.9, 139.2, 134.9, 133.8, 132.3, 128.7, 128.6, 128.5, 128.3, 128.2, 127.6, 127.1, 127.1, 126.5, 125.9, 125.5, 124.1, 116.8, 114.5, 66.0, 32.9, 12.7; HRMS m/z (ESI): calcd for C30H26NO (M + H)+, 416.2009; found, 416.2011. 3-Methyl-2-(pent-4-yn-1-yloxy)-4,6-diphenylpyridine 4as. Colorless oil; yield (159 mg, 97%); IR (KBr): ν 3300, 1594, 1557, 1434, 1338, 1039, 774, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06−8.01 (m, 2H), 7.46−7.37 (m, 5H), 7.36−7.31 (m, 3H), 7.26 (s, 1H), 4.60 (t, J = 6.1 Hz, 2H), 2.44 (td, J = 7.2, 2.6 Hz, 2H), 2.14 (s, 3H), 2.10 (dq, J = 13.4, 6.6 Hz, 2H), 1.97 (t, J = 2.6 Hz, 1H); 13C NMR (100

2-((4-Bromobenzyl)oxy)-3-methyl-4,6-diphenylpyridine 4ad. White solid; yield (196 mg, 91%); mp 92−94 °C; IR (KBr): ν 1344, 1157, 1007, 806, 672 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.3 Hz, 2H), 7.49 (d, J = 7.3 Hz, 2H), 7.47−7.31 (m, 10H), 7.28 (s, 1H), 5.53 (s, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 151.9, 150.9, 139.8, 139.0, 137.3, 131.5, 129.4, 128.7, 128.5, 128.5, 128.3, 127.7, 126.4, 121.4, 116.7, 114.8, 66.7, 12.7; HRMS m/z (ESI): calcd for C25H21BrNO (M + H)+, 430.0801; found, 430.0802. 2-((4-Iodobenzyl)oxy)-3-methyl-4,6-diphenylpyridine 4ae. White solid; yield (222 mg, 93%); mp 116−117 °C; IR (KBr): ν 1554, 1342, 1155, 1005, 775, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.3 Hz, 2H), 7.69 (d, J = 7.7 Hz, 2H), 7.48−7.32 (m, 8H), 7.27 (d, J = 8.7 Hz, 3H), 5.52 (s, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 151.9, 150.8, 139.8, 138.9, 137.9, 137.4, 129.6, 128.7, 128.5, 128.5, 128.3, 127.7, 126.4, 116.7, 114.8, 92.9, 66.8, 12.7; HRMS m/z (ESI): calcd for C25H21INO (M + H)+, 478.0662; found, 478.0665. 3-Methyl-4,6-diphenyl-2-((4-(trifluoromethyl)benzyl)oxy)pyridine 4af. White solid; yield (178 mg, 85%); mp 61−62 °C; IR (KBr): ν 1327, 1160, 1120, 1066, 1016, 821, 695 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.4 Hz, 2H), 7.63 (s, 4H), 7.48−7.38 (m, 5H), 7.36 (d, J = 6.8 Hz, 3H), 7.30 (s, 1H), 5.64 (s, 2H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 152.1, 151.0, 142.4, 139.8, 139.0, 129.7 (d, J = 32.3 Hz), 128.8, 128.6, 128.4, 127.9, 127. 7, 126.5, 125.4 (q, J = 3.7 Hz, 5H), 124.3 (d, J = 272.0 Hz), 116.8, 115.0, 66.7, 12.8; HRMS m/z (ESI): calcd for C26H21F3NO (M + H)+, 420.1570; found, 420.1574. 3-Methyl-2-((4-methylbenzyl)oxy)-4,6-diphenylpyridine 4ag. White solid; yield (153 mg, 84%); mp 87−89 °C; IR (KBr): ν 1554, 1342, 1154, 1009, 773, 699 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09−7.99 (m, 2H), 7.47−7.31 (m, 10H), 7.27 (s, 1H), 7.18 (d, J = 7.8 Hz, 2H), 5.55 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9, 151.7, 150.9, 139.9, 139.2, 137.2, 135.2, 129.0, 128.8, 128.5, 128.4, 128.3, 127.9, 127.7, 126.5, 116.8, 114.5, 67.5, 21.2, 12.8; HRMS m/z (ESI): calcd for C26H24NO (M + H)+, 366.1852; found, 366.1855. 2-((4-Methoxybenzyl)oxy)-3-methyl-4,6-diphenylpyridine 4ah. White solid; yield (158 mg, 83%); IR (KBr): ν 1514, 1435, 1342, 1248, 1156, 1034, 699 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 2H), 7.50−7.32 (m, 10H), 7.27 (s, 1H), 6.92 (d, J = 7.3 Hz, 2H), 5.53 (s, 2H), 3.80 (s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9, 159.2, 151.7, 150.8, 139.9, 139.2, 130.3, 129.5, 128.7, 128.5, 128.4, 128.3, 127.7, 126.5, 116.8, 114.5, 113.8, 67.3, 55.2, 12.8; HRMS m/z (ESI): calcd for C26H24NO2 (M + H)+, 382.1802; found, 382.1804. 2-Methoxy-3-methyl-4,6-diphenylpyridine 4ai. White solid; yield (118 mg, 86%); mp 69−70 °C; IR (KBr): ν 1592, 1555, 1453, 1353, 1157, 1016, 700 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−8.04 (m, 2H), 7.48−7.38 (m, 5H), 7.38−7.33 (m, 3H), 7.27 (s, 1H), 4.11 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.4, 151.7, 150.9, 139.9, 139.2, 128.8, 128.5, 128.4, 128.3, 127.7, 126.4, 116.7, 114.4, 53.5, 12.7; HRMS m/z (ESI): calcd for C19H18NO (M + H)+, 276.1383; found, 276.1386. 2-Ethoxy-3-methyl-4,6-diphenylpyridine 4aj. Colorless oil; yield (123 mg, 85%); IR (KBr): ν 1595, 1435, 1339, 1160, 1040, 773, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.3 Hz, 2H), 7.47− 7.38 (m, 5H), 7.37−7.32 (m, 3H), 7.25 (s, 1H), 4.57 (q, J = 7.0 Hz, 2H), 2.15 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.1, 151.5, 150.8, 140.1, 139.3, 128.8, 128.5, 128.3, 128.3, 127.6, 126.4, 116.6, 114.1, 61.7, 14.8, 12.7; HRMS m/z (ESI): calcd for C20H20NO (M + H)+, 290.1539; found, 290.1543. 3-Methyl-2-phenethoxy-4,6-diphenylpyridine 4ak. White solid; yield (146 mg, 80%); mp 118−119 °C; IR (KBr): ν 1561, 1431, 1352, 1163, 1016, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.07−7.99 (m, 2H), 7.45−7.36 (m, 5H), 7.36−7.27 (m, 7H), 7.26−7.19 (m, 2H), 4.71 (t, J = 7.0 Hz, 2H), 3.17 (t, J = 7.0 Hz, 2H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9, 151.5, 150.8, 139.9, 139.1, 139.0, 129.1, 128.7, 128.5, 128.3, 128.3, 128.2, 127.6, 126.4, 126.2, 116.7, 114.3, 66.6, 35.7, 12.6; HRMS m/z (ESI): calcd for C26H24NO (M + H)+, 366.1852; found, 366.1855. 9519

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524

Article

The Journal of Organic Chemistry MHz, CDCl3) δ 161.9, 151.6, 150.8, 139.9, 139.1, 128.7, 128.4, 128.3, 128.2, 127.6, 126.4, 116.6, 114.3, 83.9, 68.6, 64.3, 28.3, 15.5, 12.6; HRMS m/z (ESI): calcd for C23H22NO (M + H)+, 328.1696; found, 328.1699. 2-(4-Methoxyphenoxy)-3-methyl-4,6-diphenylpyridine 4at. White solid; yield (64 mg, 35%); mp 110−111 °C; IR (KBr): ν 1502, 1362, 1211, 1036, 772, 687 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 6.9 Hz, 2H), 7.50−7.42 (m, 3H), 7.42−7.37 (m, 2H), 7.36 (s, 1H), 7.35−7.26 (m, 3H), 7.18 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.0, 156.0, 152.7, 151.1, 148.1, 139.6, 138.5, 128.7, 128.5, 128.4, 128.3, 127.8, 126.3, 122.3, 117.4, 115.7, 114.2, 55.6, 13.0; HRMS m/z (ESI): calcd for C25H22NO2 (M + H)+, 368.1645; found, 368.1647. 3-Methyl-4,6-diphenyl-2-(pyridin-2-yloxy)pyridine 4au. Colorless oil; yield (113 mg, 67%); IR (KBr): ν1667, 1595, 1532, 1276, 769, 702 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−7.97 (m, 2H), 7.72 (s, 1H), 7.60−7.36 (m, 10H), 6.68 (d, J = 9.3 Hz, 1H), 6.31 (t, J = 6.7 Hz, 1H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 154.8, 153.1, 152.7, 140.3, 138.9, 138.1, 137.2, 129.1, 128.8, 128.7, 128.5, 128.3, 127.0, 126.9, 122.0, 121.7, 106.0, 14.9; HRMS m/z (ESI): calcd for C23H19N2O (M + H)+, 339.1492; found, 339.1494. 3-Methyl-4,6-diphenyl-2-(p-tolylthio)pyridine 4av. White solid; yield (110 mg, 60%); mp 122−123 °C; IR (KBr): ν 1576, 1535, 1491, 1414, 1078, 807, 774, 699 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 4.9 Hz, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.49−7.40 (m, 3H), 7.38 (s, 1H), 7.34 (d, J = 7.3 Hz, 2H), 7.27 (t, J = 7.5 Hz, 5H), 2.44 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 152.9, 150.1, 139.7, 138.5, 138.4, 135.4, 129.5, 128.7, 128.5, 128.4, 127.8, 127.6, 126.4, 126.2, 117.3, 21.3, 15.6; HRMS m/z (ESI): calcd for C25H22NS (M + H)+, 368.1467; found, 368.1471. 2-((3-Methyl-4,6-diphenylpyridin-2-yl)thio)aniline 4aw. Yellow solid; yield (129 mg, 70%); mp 107−108 °C; IR (KBr): ν 1611, 1534, 1481, 1059, 771, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.76−7.71 (m, 2H), 7.52−7.41 (m, 4H), 7.39 (s, 1H), 7.37−7.32 (m, 2H), 7.31−7.24 (m, 4H), 6.89 (d, J = 8.0 Hz, 1H), 6.82 (td, J = 7.6, 1.0 Hz, 1H), 3.07 (brs, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.6, 153.0, 150.3, 149.9, 139.6, 138.3, 137.7, 130.9, 128.7, 128.6, 128.4, 127.9, 126.6, 126.2, 118.6, 117.2, 115.5, 114.6, 15.7; HRMS m/z (ESI): calcd for C24H21N2S (M + H)+, 369.1420; found, 369.1425. 2-(Benzyloxy)-3-methyl-6-phenyl-4-(o-tolyl)pyridine 4ba. White solid; yield (120 mg, 66%); IR (KBr): ν 1559, 1436, 1344, 1159, 1005, 695 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.4 Hz, 2H), 7.55 (d, J = 7.3 Hz, 2H), 7.48−7.31 (m, 6H), 7.28 (t, J = 11.6 Hz, 3H), 7.19 (s, 1H), 7.12 (d, J = 7.1 Hz, 1H), 5.67−5.52 (m, 2H), 2.12 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 151.8, 150.7, 139.5, 139.1, 138.2, 135.3, 130.0, 128.5, 128.5, 128.4, 128.3, 127.8, 127.7, 127.5, 126.4, 125.7, 117.4, 114.4, 67.4, 19.7, 12.3; HRMS m/z (ESI): calcd for C26H24NO (M + H)+, 366.1852; found, 366.1857. 2-(Benzyloxy)-3-methyl-6-phenyl-4-(p-tolyl)pyridine 4bb. White solid; yield (137 mg, 75%); mp 92−94 °C; IR (KBr): ν 1452, 1344, 1158, 1013, 753, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06−7.99 (m, 2H), 7.54 (d, J = 7.4 Hz, 2H), 7.46−7.34 (m, 5H), 7.34−7.29 (m, 1H), 7.26 (d, J = 6.9 Hz, 5H), 5.59 (s, 2H), 2.41 (s, 3H), 2.20 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 161.8, 151.7, 150.8, 139.2, 138.3, 137.5, 136.9, 129.0, 128.6, 128.5, 128.3, 128.3, 127.7, 127.5, 126.4, 116.8, 114.7, 67.5, 21.2, 12.8; HRMS m/z (ESI): calcd for C26H24NO (M + H)+, 366.1852; found, 366.1855. 2-(Benzyloxy)-4-(4-(tert-butyl)phenyl)-3-methyl-6-phenylpyridine 4bc. White solid; yield (153 mg, 75%); IR (KBr): ν 2961, 1597, 1437, 1344, 1159, 1007, 695 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 7.3 Hz, 2H), 7.49−7.35 (m, 7H), 7.31 (d, J = 7.9 Hz, 4H), 5.59 (s, 2H), 2.22 (s, 3H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.8, 151.7, 150.7, 150.7, 139.2, 138.3, 136.9, 128.5, 128.3, 127.7, 127.5, 126.4, 125.2, 116.8, 114.8, 67.5, 34.6, 31.3, 29.6, 12.8; HRMS m/z (ESI): calcd for C29H30NO (M + H)+, 408.2322; found, 408.2324. 2-(Benzyloxy)-4-(4-methoxyphenyl)-3-methyl-6-phenylpyridine 4bd. White solid; yield (152 mg, 80%); mp 104−106 °C; IR (KBr): ν 1513, 1345, 1244, 1155, 1001, 695 cm−1; 1H NMR (400 MHz,

CDCl3) δ 8.03 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 7.3 Hz, 2H), 7.46−7.34 (m, 5H), 7.33−7.25 (m, 4H), 6.97 (d, J = 7.9 Hz, 2H), 5.59 (s, 2H), 3.84 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 159.2, 151.4, 150.8, 139.2, 138.2, 132.2, 130.0, 128.5, 128.3, 128.3, 127.6, 127.4, 126.4, 116.8, 114.7, 113.7, 67.4, 55.2, 12.8; HRMS m/z (ESI): calcd for C26H24NO2 (M + H)+, 382.1802; found, 382.1806. 2-(Benzyloxy)-4-(4-fluorophenyl)-3-methyl-6-phenylpyridine 4be. White solid; yield (151 mg, 82%); mp 107−108 °C; IR (KBr): ν 1603, 1511, 1345, 1159, 1013, 833, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.07−7.98 (m, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.46−7.35 (m, 5H), 7.34−7.29 (m, 3H), 7.24 (s, 1H), 7.13 (t, J = 8.7 Hz, 2H), 5.59 (s, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.4 (d, J = 247.1 Hz), 161.8, 151.0, 150.7, 139.0, 138.1, 135.8, 130.4 (d, J = 8.0 Hz, 12H), 128.5, 128.5, 128.3, 127.7, 127.5, 126.4, 116.8, 115.2 (d, J = 21.5 Hz), 114.5, 67.5, 12.7; HRMS m/z (ESI): calcd for C25H21FNO (M + H)+, 370.1602; found, 370.1605. 2-(Benzyloxy)-4-(4-chlorophenyl)-3-methyl-6-phenylpyridine 4bf. White solid; yield (146 mg, 76%); mp 110−111 °C; IR (KBr): ν 1493, 1345, 1159, 1089, 1012, 828, 754, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06−7.99 (m, 2H), 7.53 (d, J = 7.3 Hz, 2H), 7.47−7.35 (m, 7H), 7.34−7.26 (m, 3H), 7.23 (s, 1H), 5.59 (s, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 151.1, 150.5, 138.9, 138.2, 138.1, 133.8, 130.1, 128.5, 128.3, 127.7, 127.5, 126.4, 116.7, 114.3, 67.59 12.7; HRMS m/z (ESI): calcd for C25H21ClNO (M + H)+, 386.1306; found, 386.1310. 2-(Benzyloxy)-3-methyl-6-phenyl-4-(4-(trifluoromethyl)phenyl)pyridine 4bg. White solid; yield (157 mg, 75%); mp 118−119 °C; IR (KBr): ν 1334, 1163, 1124, 1070, 1011, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.2 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 7.0 Hz, 2H), 7.49−7.34 (m, 7H), 7.31 (t, J = 7.3 Hz, 1H), 7.24 (s, 1H), 5.60 (s, 2H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 151.2, 150.3, 143.5, 138.8, 138.0, 129.9 (d, J = 32.5 Hz), 129.1, 128.6, 128.6, 128.4, 127.7, 127.6, 126.4, 125.3 (q, J = 3.6 Hz, 7H), 124.1 (d, J = 272.1 Hz), 116.7, 114.1, 67.6, 12.7; HRMS m/z (ESI): calcd for C26H21F3NO (M + H)+, 420.1570; found, 420.1574. 2-(Benzyloxy)-3-methyl-4-(naphthalen-1-yl)-6-phenylpyridine 4bh. White solid; yield (170 mg, 85%); mp 136−137 °C; IR (KBr): ν 1552, 1330, 1148, 1022, 752, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 5.2, 3.4 Hz, 2H), 7.92−7.83 (m, 3H), 7.80 (s, 1H), 7.55 (d, J = 7.1 Hz, 2H), 7.53−7.49 (m, 2H), 7.48−7.34 (m, 7H), 7.34− 7.29 (m, 1H), 5.62 (s, 2H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 151.7, 150.9, 139.1, 138.2, 137.3, 133.1, 132.6, 128.5, 128.4, 128.3, 128.0, 127.8, 127.7, 127.5, 126.8, 126.4, 126.4, 126.3, 117.0, 114.8, 67.5, 12.8; HRMS m/z (ESI): calcd for C29H24NO (M + H)+, 402.1852; found, 402.1856. 2-(Benzyloxy)-3-methyl-6-phenyl-4-(thiophen-2-yl)pyridine 4bi. White solid; yield (130 mg, 73%); mp 101−103 °C; IR (KBr): ν 1558, 1348, 1133, 1009, 750, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06−8.01 (m, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.45−7.30 (m, 8H), 7.21−7.17 (m, 1H), 7.15−7.11 (m, 1H), 5.58 (s, 2H), 2.37 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 162.0, 151.1, 143.9, 140.8, 138.9, 138.1, 128.5, 128.3, 127.7, 127.6, 127.5, 127.3, 126.4, 126.3, 117.0, 114.7, 67.6, 13.0; HRMS m/z (ESI): calcd for C23H20NOS (M + H)+, 358.1260; found, 358.1264. 2-(Benzyloxy)-3-methyl-4-phenyl-6-(o-tolyl)pyridine 4bj. Colorless oil; yield (139 mg, 76%); IR (KBr): ν 1559, 1436, 1344, 1159, 1006, 695 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.07−8.00 (m, 2H), 7.55 (d, J = 7.4 Hz, 2H), 7.46−7.34 (m, 5H), 7.33−7.22 (m, 4H), 7.20 (d, J = 5.2 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 5.66−5.54 (m, 2H), 2.12 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 151.8, 150.7, 139.5, 139.1, 138.2, 135.3, 130.0, 128.5, 128.5, 128.4. 128.3. 127.8, 127.7, 127.5, 126.4, 125.7, 117.4, 114.4, 67.4, 19.7, 12.3; HRMS m/z (ESI): calcd for C26H24NO (M + H)+, 366.1852; found, 366.1855. 2-(Benzyloxy)-3-methyl-4-phenyl-6-(m-tolyl)pyridine 4bk. White solid; yield (157 mg, 86%); mp 70−71 °C; IR (KBr): ν 1560, 1351, 1163, 1019, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.87−7.79 (m, 2H), 7.54 (d, J = 7.4 Hz, 2H), 7.46−7.40 (m, 2H), 7.40−7.29 (m, 7H), 7.26 (s, 1H), 7.19−7.14 (m, 1H), 5.59 (s, 2H), 2.41 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.7, 151.7, 151.0, 139.9, 9520

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524

Article

The Journal of Organic Chemistry

CDCl3) δ 8.11−8.03 (m, 2H), 7.63 (td, J = 7.6, 1.4 Hz, 1H), 7.59− 7.53 (m, 2H), 7.52−7.36 (m, 7H), 7.33−7.27 (m, 1H), 7.16 (td, J = 7.6, 1.0 Hz, 1H), 7.11−7.04 (m, 1H), 6.18−6.06 (m, 1H), 3.99−3.86 (m, 1H), 3.33 (dd, J = 16.4, 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5, 159.5 (d, J = 246.2 Hz), 155.9, 147.7, 138.8, 137.9, 129.5 (d, J = 8.1 Hz), 128.9, 128.9, 128.8, 128.6, 127.7, 126.9, 126.8 (d, J = 4.0 Hz), 124.3 (d, J = 3.4 Hz), 115.5, 115.1 (d, J = 24.9 Hz), 113.7, 76.6 (d, J = 3.4 Hz), 36.4; HRMS m/z (ESI): calcd for C25H19FNO (M + H)+, 368.1445; found, 368.1447. 4,6-Diphenyl-2-(o-tolyl)-2,3-dihydrofuro[2,3-b]pyridine 5ac. White solid; yield (118 mg, 65%); mp 183−185 °C; IR (KBr): ν 1601, 1400, 1229, 984, 769, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 2H), 7.61−7.55 (m, 1H), 7.55−7.50 (m, 2H), 7.49−7.37 (m, 7H), 7.23−7.15 (m, 3H), 6.04 (dd, J = 9.4, 7.7 Hz, 1H), 3.83 (dd, J = 16.3, 9.5 Hz, 1H), 3.23 (dd, J = 16.3, 7.6 Hz, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 155.9, 147.5, 139.5, 138.8, 138.0, 133.8, 130.4, 128.7, 128.6, 128.5, 127.7, 127.6, 126.8, 126.2, 124.7, 115.0, 113.4, 79.4, 36.0, 19.1; HRMS m/z (ESI): calcd for C26H22NO (M + H)+, 364.1696; found, 364.1699. 2-(3-Fluorophenyl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5ad. White solid; yield (70 mg, 38%); mp 104−106 °C; IR (KBr): ν 1600, 1393, 1240, 874, 765, 694 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10−8.02 (m, 2H), 7.57−7.51 (m, 2H), 7.51−7.30 (m, 8H), 7.24− 7.16 (m, 2H), 7.04−6.95 (m, 1H), 5.91−5.82 (m, 1H), 3.83 (dd, J = 16.3, 9.5 Hz, 1H), 3.34 (dd, J = 16.3, 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5, 163.0 (d, J = 246.7 Hz), 156.1, 147.7, 144.0 (d, J = 7.1 Hz, 3H), 138.8, 137.9, 130.3 (d, J = 8.2 Hz), 128.9, 128.8 (d, J = 11.7 Hz), 128.6, 127.7, 126.9, 121.0 (d, J = 3.0 Hz), 115.0, 114.8 (d, J = 4.3 Hz), 113.7, 112.6, 112.4, 80.9 (d, J = 1.8 Hz), 37.1; HRMS m/z (ESI): calcd for C25H19FNO (M + H)+, 368.1445; found, 368.1450. 4,6-Diphenyl-2-(m-tolyl)-2,3-dihydrofuro[2,3-b]pyridine 5ae. White solid; yield (98 mg, 54%); mp 110−112 °C; IR (KBr): ν 1600, 1392, 1224, 1079, 774, 699 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.9 Hz, 2H), 7.56 (d, J = 7.8 Hz, 2H), 7.52−7.36 (m, 7H), 7.31 (s, 1H), 7.26 (t, J = 6.2 Hz, 2H), 7.13 (d, J = 6.5 Hz, 1H), 5.85 (t, J = 8.6 Hz, 1H), 3.80 (dd, J = 16.4, 9.4 Hz, 1H), 3.37 (dd, J = 16.3, 7.9 Hz, 1H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 155.7, 147.3, 141.2, 138.8, 138.3, 137.9, 128.7, 128.6, 128.5, 127.6, 126.7, 126.0, 122.4, 115.2, 113.3, 81.7, 37.0, 21.3; HRMS m/z (ESI): calcd for C26H22NO (M + H)+, 364.1696; found, 364.1699. 2-(4-Fluorophenyl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5af. White solid; yield (123 mg, 67%); mp 128−130 °C; IR (KBr): ν 1603, 1510, 1391, 1225, 950, 834 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.7 Hz, 2H), 7.50−7.35 (m, 9H), 7.05 (t, J = 8.4 Hz, 2H), 5.84 (t, J = 8.5 Hz, 1H), 3.80 (dd, J = 16.3, 9.3 Hz, 1H), 3.33 (dd, J = 16.3, 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.6, 162.5 (d, J = 246.6 Hz), 156.0, 147.6, 138.8, 138.0, 137.1, 128.9, 128.8, 128.6, 127.7, 127.3 (d, J = 8.2 Hz), 126.8, 115.6 (d, J = 21.6 Hz), 115.0, 113.6, 81.2, 37.1; HRMS m/z (ESI): calcd for C25H19FNO (M + H)+, 368.1445; found, 368.1450. 2-(4-Chlorophenyl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5ag. White solid; yield (111 mg, 58%); mp 113−115 °C; IR (KBr): ν 1602, 1390, 1227, 1086, 693 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−8.03 (m, 2H), 7.56−7.51 (m, 3H), 7.50−7.30 (m, 11H), 5.89− 5.81 (m, 1H), 3.82 (dd, J = 16.3, 9.4 Hz, 1H), 3.32 (dd, J = 16.3, 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5, 156.0, 147.6, 139.8, 138.7, 137.9, 133.9, 128.9, 128.8, 128.8, 128.7, 128.6, 127.6, 126.8, 126.8, 114.8, 113.6, 81.0, 37.0; HRMS m/z (ESI): calcd for C25H19ClNO (M + H)+, 384.1150; found, 384.1154. 2-(4-Bromophenyl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5ah. White solid; yield (90 mg, 42%); mp 149−151 °C; IR (KBr): ν 1602, 1388, 1225, 949, 822, 694 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.2 Hz, 2H), 7.58−7.36 (m, 11H), 7.33 (d, J = 8.4 Hz, 2H), 5.83 (t, J = 8.5 Hz, 1H), 3.82 (dd, J = 16.3, 9.4 Hz, 1H), 3.31 (dd, J = 16.3, 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5, 156.0, 147.6, 140.3, 138.7, 137.9, 131.8, 128.9, 128.8, 128.7, 128.6, 127.6, 127.1, 126.8, 121.9, 114.8, 113.6, 81.0, 37.0; HRMS m/z (ESI): calcd for C25H19BrNO (M + H)+, 428.0645; found, 428.0646. 2-(4-Iodophenyl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5ai. White solid; yield (95 mg, 40%); mp 162−164 °C; IR (KBr): ν

139.1, 138.3, 138.0, 129.2, 128.7, 128.4, 128.3, 128.2, 127.7, 128.6, 127.4, 127.1, 123.6, 116.6, 114.7, 67.5, 21.5, 12.7; HRMS m/z (ESI): calcd for C26H24NO (M + H)+, 366.1852; found, 366.1854. 2-(Benzyloxy)-3-methyl-4-phenyl-6-(p-tolyl)pyridine 4bl. White solid; yield (146 mg, 80%); mp 76−79 °C; IR (KBr): ν 1560, 1443, 1350, 1162, 1014, 818, 740, 695 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.47−7.41 (m, 2H), 7.41−7.33 (m, 5H), 7.30 (t, J = 7.3 Hz, 1H), 7.26−7.19 (m, 3H), 5.59 (s, 2H), 2.38 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.7, 151.7, 150.9, 140.0, 138.3, 136.4, 129.2, 128.7, 128.3, 128.2, 127.7, 127.6, 127.4, 126.3, 116.3, 114.2, 67.4, 21.2, 12.7; HRMS m/z (ESI): calcd for C26H24NO (M + H)+, 366.1852; found, 366.1855. 2-(Benzyloxy)-6-(4-fluorophenyl)-3-methyl-4-phenylpyridine 4bm. White solid; yield (142 mg, 77%); mp 111−113 °C; IR (KBr): ν 1443, 1351, 1221, 1161, 1022, 838, 730 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04−7.95 (m, 2H), 7.53 (d, J = 7.3 Hz, 2H), 7.48−7.42 (m, 2H), 7.42−7.28 (m, 6H), 7.22 (d, J = 3.6 Hz, 1H), 7.10 (t, J = 8.7 Hz, 2H), 5.57 (s, 2H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.19 (d, J = 247.7 Hz), 161.8, 151.8, 149.9, 139.8, 138.1, 135.2, 128.7, 128.4, 128.2, 128.1 (d, J = 8.1 Hz), 127.7, 127.6, 127.5, 116.7, 115.3 (d, J = 21.5 Hz), 114.3, 67.5, 12.7; HRMS m/z (ESI): calcd for C25H21FNO (M + H)+, 370.1602; found, 370.1605. 2-(Benzyloxy)-6-(4-chlorophenyl)-3-methyl-4-phenylpyridine 4bn. White solid; yield (175 mg, 91%); mp 110−120 °C; IR (KBr): ν 1350, 1160, 1012, 672 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 7.3 Hz, 2H), 7.52−7.32 (m, 10H), 7.28 (s, 1H), 5.61 (s, 2H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 151.8, 149.6, 139.7, 138.1, 137.5, 134.3, 128.7, 128.6, 128.3, 128.3, 127.7, 127.7, 127.6, 127.5, 117.2, 114.4, 67.5, 12.7; HRMS m/z (ESI): calcd for C25H21ClNO (M + H)+, 386.1306; found, 386.1310. 2-(Benzyloxy)-6-(4-bromophenyl)-3-methyl-4-phenylpyridine 4bo. White solid; yield (157 mg, 73%); mp 108−110 °C; IR (KBr): ν 1558, 1441, 1349, 1162, 1012, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2H), 7.57−7.49 (m, 4H), 7.47−7.41 (m, 2H), 7.41−7.27 (m, 6H), 7.23 (s, 1H), 5.56 (s, 2H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 151.8, 149.6, 139.6, 138.0, 138.0, 131.6, 128.7, 128.3, 128.3, 128.0, 127.8, 127.6, 127.5, 122.6, 117.3, 114.4, 67.6, 12.8; HRMS m/z (ESI): calcd for C25H21BrNO (M + H)+, 430.0801; found, 430.0803. 2-(Benzyloxy)-3-methyl-4-phenyl-6-(thiophen-2-yl)pyridine 4bp. White solid; yield (143 mg, 80%); mp 92−93 °C; IR (KBr): ν 1594, 1450, 1351, 1161, 1020, 703 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.1 Hz, 2H), 7.51 (dd, J = 3.6, 1.0 Hz, 1H), 7.47−7.41 (m, 2H), 7.40−7.27 (m, 7H), 7.16 (s, 1H), 7.05 (dd, J = 5.0, 3.7 Hz, 1H), 5.54 (s, 2H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.4, 151.7, 146.4, 145.2, 139.6, 138.0, 128.6, 128.3, 128.0, 127.8, 127.7, 127.5, 126.4, 123.6, 116.6, 113.0, 67.6, 12.7; HRMS m/z (ESI): calcd for C23H20NOS (M + H)+, 358.1260; found, 358.1265. General Procedure for the Preparation of Pyridines 5aa−5ar and 5ba−5bp. A mixture of 3 (1 mmol) and NaOH (40 mg, 1 mmol) in DMSO (1 mL) was stirred at room temperature under air; then a solution of 1 (0.5 mmol) in DMSO (1 mL) was slowly added using a syringe pump for 15 min. After 1 was exhausted completely (monitored by TLC), the residue was dissolved in H2O (8 mL) and extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts were dried over Na2SO4 and concentrated. Then solvent was evaporated and the residue was purified by chromatography (silica gel, 5% EtOAc in PE) to give 5aa−5ar and 5ba−5bp. 2,4,6-Triphenyl-2,3-dihydrofuro[2,3-b]pyridine 5aa. White solid; yield (99 mg, 57%); mp 143−145 °C; IR (KBr): ν 1602, 1397, 1359, 1228, 768, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 7.4 Hz, 2H), 7.50−7.34 (m, 12H), 5.92−5.85 (m, 1H), 3.82 (dd, J = 16.4, 9.4 Hz, 1H), 3.37 (dd, J = 16.4, 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.7, 155.9, 147.4, 141.3, 138.8, 138.0, 128.8, 128.7, 128.6, 128.5, 128.0, 127.7, 126.8, 125.4, 115.2, 113.5, 81.8, 37.1; HRMS m/z (ESI): calcd for C25H20NO (M + H)+, 350.1539; found, 350.1543. 2-(2-Fluorophenyl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5ab. White solid; yield (80 mg, 43%); mp 140−142 °C; IR (KBr): ν 1600, 1576, 1400, 1227, 1032, 779 cm−1; 1H NMR (400 MHz, 9521

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524

Article

The Journal of Organic Chemistry 1603, 1387, 1226, 949, 820, 695 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09−8.03 (m, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.56−7.51 (m, 2H), 7.51−7.37 (m, 7H), 7.21 (d, J = 8.2 Hz, 2H), 5.88−5.77 (m, 1H), 3.81 (dd, J = 16.3, 9.4 Hz, 1H), 3.31 (dd, J = 16.3, 7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5, 156.0, 147.6, 141.0, 138.7, 137.8, 137.7, 128.8, 128.8, 128.7, 128.5, 127.6, 127.3, 126.8, 114.8, 113.6, 93.5, 81.0, 37.0; HRMS m/z (ESI): calcd for C25H19INO (M + H)+, 476.0506; found, 476.0507. 2-(4-(Methylsulfonyl)phenyl)-4,6-diphenyl-2,3-dihydrofuro[2,3b]pyridine 5aj. White solid; yield (70 mg, 33%); mp 194−196 °C; IR (KBr): ν 2920, 1602, 1304, 1152, 1083, 950, 771 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.56−7.40 (m, 9H), 6.02−5.93 (m, 1H), 3.91 (dd, J = 16.3, 9.6 Hz, 1H), 3.32 (dd, J = 16.3, 7.6 Hz, 1H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 156.2, 147.9, 147.6, 140.1, 138.6, 137.7, 129.0, 128.9, 128.6, 127.8, 127.6, 126.8, 126.2, 114.2, 113.9, 80.5, 44.4, 37.0; HRMS m/z (ESI): calcd for C26H22NO3S (M + H)+, 428.1315; found, 428.1318. 4,6-Diphenyl-2-(o-tolyl)-2,3-dihydrofuro[2,3-b]pyridine 5ak. White solid; yield (91 mg, 50%); mp 79−81 °C; IR (KBr): ν1599, 1394, 1225, 951, 756, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.3 Hz, 2H), 7.55−7.50 (m, 2H), 7.47−7.35 (m, 7H), 7.32 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 5.82 (t, J = 8.6 Hz, 1H), 3.76 (dd, J = 16.4, 9.3 Hz, 1H), 3.33 (dd, J = 16.4, 7.8 Hz, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 155.8, 147.3, 138.9, 138.3, 138.0, 137.8, 129.2, 128.7, 128.6, 128.5, 127.7, 126.8, 125.4, 115.3, 113.4, 81.8, 37.0, 21.1; HRMS m/z (ESI): calcd for C26H22NO (M + H)+, 364.1696; found, 364.1698. 2-(4-Methoxyphenyl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5al. White solid; yield (80 mg, 42%); mp 49−52 °C; IR (KBr): ν1605, 1514, 1395, 1248, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.4 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.50−7.35 (m, 9H), 6.90 (d, J = 8.7 Hz, 2H), 5.83 (t, J = 8.6 Hz, 1H), 3.83−3.72 (m, 4H), 3.37 (dd, J = 16.4, 7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.7, 159.5, 155.8, 147.3, 138.9, 138.0 133.2, 128.8, 128.7, 128.6, 128.5, 127.7, 127.0, 126.8, 115.4, 114.0, 113.4, 81.8, 55.2, 36.9; HRMS m/z (ESI): calcd for C26H22NO2 (M + H)+, 380.1645; found, 380.1649. 2-(4-(Methylthio)phenyl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5am. White solid; yield (142 mg, 72%); mp 124−126 °C; IR (KBr): ν 1602, 1389, 1364, 948, 689 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09−8.04 (m, 2H), 7.57−7.53 (m, 2H), 7.50−7.36 (m, 9H), 7.26 (t, J = 4.2 Hz, 2H), 5.88−5.81 (m, 1H), 3.80 (dd, J = 16.3, 9.3 Hz, 1H), 3.35 (dd, J = 16.3, 7.8 Hz, 1H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.5, 138.8, 138.5, 138.8, 138.5, 138.1, 138.0, 128.8, 128.7, 128.6, 127.7, 126.8, 126.7, 126.0, 115.1, 113.5, 81.5, 37.0, 15.8; HRMS m/z (ESI): calcd for C26H22NOS (M + H)+, 396.1417; found, 396.1420. 2-(Naphthalen-1-yl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5an. White solid; yield (144 mg, 72%); mp 201−203 °C; IR (KBr): ν 1604, 1400, 1236, 988, 775, 697 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.13−8.06 (m, 2H), 7.91−7.75 (m, 4H), 7.54−7.32 (m, 12H), 6.54 (dd, J = 9.4, 7.3 Hz, 1H), 4.02 (dd, J = 16.3, 9.7 Hz, 1H), 3.35 (dd, J = 16.3, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.8, 156.0, 147.8, 138.9, 138.0, 137.0, 133.9, 129.4, 129.1, 128.9, 128.8, 128.7, 128.7, 128.4, 127.7, 126.9, 126.4, 125.7, 125.6, 122.8, 122.3, 115.2, 113.7, 79.5, 37.0; HRMS m/z (ESI): calcd for C29H22NO (M + H)+, 400.1696; found, 400.1700. 2-(Naphthalen-2-yl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5ao. White solid; yield (76 mg, 38%); mp 123−125 °C; IR (KBr): ν 1600, 1263, 1090, 1024, 800 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.11−8.05 (m, 2H), 7.95 (s, 1H), 7.89−7.79 (m, 3H), 7.57−7.50 (m, 3H), 7.50−7.36 (m, 9H), 6.09−6.00 (m, 1H), 3.89 (dd, J = 16.4, 9.4 Hz, 1H), 3.44 (dd, J = 16.4, 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.8, 156.0, 147.6, 138.9, 138.6, 138.0, 133.1, 133.0, 128.8, 128.7, 128.7, 128.6, 128.0, 127.7, 127.7 126.8, 126.3, 126.1, 124.3, 123.2, 115.2, 113.6, 81.9, 37.1; HRMS m/z (ESI): calcd for C29H21NO (M + H)+, 400.1696; found, 400.1701. 4,6-Diphenyl-2-(pyridin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine 5ap. White solid; yield (110 mg, 63%); mp 124−137 °C; IR (KBr): ν 1602,

1393, 1227, 776, 750, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 4.8 Hz, 1H), 8.07−7.99 (m, 2H), 7.72−7.64 (m, 2H), 7.57− 7.51 (m, 2H), 7.48−7.34 (m, 7H), 7.19 (ddd, J = 6.7, 4.9, 2.0 Hz, 1H), 5.96 (dd, J = 9.9, 6.8 Hz, 1H), 3.91 (dd, J = 16.6, 9.9 Hz, 1H), 3.62 (dd, J = 16.6, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5, 160.3, 155.8, 149.3, 147.6, 138.8, 137.85 136.9, 128.8, 128.7, 128.5, 127.7, 126.8, 122.8, 120.3, 115.0, 113.6, 81.5, 35.1; HRMS m/z (ESI): calcd for C24H19N2O (M + H)+, 351.1492; found, 351.1495. 2-(Furan-2-yl)-4,6-diphenyl-2,3-dihydrofuro[2,3-b]pyridine 5aq. White solid; yield (59 mg, 35%); mp 110−112 °C; IR (KBr): ν 1600, 1384, 1342, 751, 695 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.07−8.01 (m, 2H), 7.61−7.55 (m, 2H), 7.50 (t, J = 7.3 Hz, 2H), 7.46−7.40 (m, 5H), 7.40−7.34 (m, 1H), 6.47 (d, J = 3.3 Hz, 1H), 6.36 (dd, J = 3.2, 1.9 Hz, 1H), 5.84 (t, J = 8.5 Hz, 1H), 3.67 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 168.1, 155.8, 152.2, 147.4, 143.1, 138.7, 138.0, 128.8, 128.8, 128.7, 128.5, 127.7, 126.8, 114.9, 113.4, 110.4, 108.7, 75.0, 32.9; HRMS m/z (ESI): calcd for C23H18NO2 (M + H)+, 340.1332; found, 340.1334. 4,6-Diphenyl-2-(thiophen-2-yl)-2,3-dihydrofuro[2,3-b]pyridine 5ar. White solid; yield (78 mg, 44%); mp 58−78 °C; IR (KBr): ν 1603, 1393, 1015, 775, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 7.4 Hz, 2H), 7.51−7.36 (m, 7H), 7.28 (d, J = 5.0 Hz, 1H), 7.14 (d, J = 3.4 Hz, 1H), 7.01−6.94 (m, 1H), 6.06 (t, J = 8.3 Hz, 1H), 3.79 (dd, J = 16.3, 9.1 Hz, 1H), 3.52 (dd, J = 16.3, 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.9, 155.9, 147.5, 143.7, 138.7, 137.9, 128.8, 128.7, 128.5, 127.7, 126.8, 125.6, 125.2, 114.9, 113.6, 78.0, 37.0; HRMS m/z (ESI): calcd for C23H18NOS (M + H)+, 356.1104; found, 356.1106. 4-(3-Fluorophenyl)-2-(naphthalen-1-yl)-6-phenyl-2,3dihydrofuro[2,3-b]pyridine 5ba. White solid; yield (63 mg, 30%); mp 195−198 °C; IR (KBr): ν 1602, 1574, 1401, 985, 778 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.13−8.07 (m, 2H), 7.95−7.86 (m, 2H), 7.82 (dd, J = 7.4, 2.5 Hz, 2H), 7.60−7.35 (m, 8H), 7.31−7.27 (m, 1H), 7.24−7.19 (m, 1H), 7.13−7.06 (m, 1H), 6.61 (dd, J = 9.5, 7.2 Hz, 1H), 4.08 (dd, J = 16.4, 9.7 Hz, 1H), 3.38 (dd, J = 16.4, 7.1 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 168.9, 162.9 (d, J = 247.3 Hz), 156.3, 146.5, 140.1 (d, J = 7.6 Hz), 138.7, 136.7, 133.9, 130.5 (d, J = 8.4 Hz), 129.3, 129.1, 129.0, 128.7, 128.4, 126.9, 126.4, 125.7 (d, J = 23.9 Hz), 123.5 (d, J = 3.0 Hz), 122.7, 122.3, 115.6 (d, J = 21.1 Hz), 115.2, 114.9, 114.6, 113.4, 79.6, 36.8; HRMS m/z (ESI): calcd for C29H21FNO (M + H)+, 418.1602; found, 418.1607. 4-(3-Chlorophenyl)-2-(naphthalen-1-yl)-6-phenyl-2,3dihydrofuro[2,3-b]pyridine 5bb. White solid; yield (82 mg, 38%); mp 202−204 °C; IR (KBr): ν 1591, 1432, 1396, 1236, 776, 695 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.11−8.07 (m, 2H), 7.93−7.85 (m, 2H), 7.81 (dd, J = 7.7, 3.4 Hz, 2H), 7.58−7.33 (m, 11H), 6.59 (dd, J = 9.5, 7.3 Hz, 1H), 4.05 (dd, J = 16.4, 9.7 Hz, 1H), 3.35 (dd, J = 16.4, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.8, 156.2, 146.4, 139.7, 138.6, 136.7, 134.8, 133.8, 130.1, 129.3, 129.1, 129.0, 128.7, 128.6, 128.4, 127.7, 126.9, 126.4, 125.8, 125.7, 125.5, 122.7, 122.3, 115.2, 113.4, 79.5, 36.7; HRMS m/z (ESI): calcd for C29H21ClNO (M + H)+, 434.1306; found, 434.1311. 4-(4-Chlorophenyl)-2-(naphthalen-1-yl)-6-phenyl-2,3dihydrofuro[2,3-b]pyridine 5bc. White solid; yield (87 mg, 40%); mp 201−203 °C; IR (KBr): ν 1592, 1433, 1395, 1230, 779, 694 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 2H), 7.97−7.79 (m, 4H), 7.60−7.39 (m, 10H), 7.26 (s, 1H), 6.74−6.49 (m, 1H), 4.06 (dd, J = 16.3, 9.7 Hz, 1H), 3.37 (dd, J = 16.3, 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.9, 156.3, 146.6, 138.7, 136.8, 136.4, 134.9, 133.9, 129.3, 129.1, 129.1, 129.0, 128.7, 128.4, 126.9, 126.4, 125.8, 125.5, 122.7, 122.3, 115.0, 113.3, 79.5, 36.9; HRMS m/z (ESI): calcd for C29H21ClNO (M + H)+, 434.1306; found, 434.1312. 4-(4-Bromophenyl)-2-(naphthalen-1-yl)-6-phenyl-2,3dihydrofuro[2,3-b]pyridine 5bd. White solid; yield (86 mg, 36%); mp 211−213 °C; IR (KBr): ν 1603, 1409, 1234, 1044, 805 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.11−8.04 (m, 2H), 7.94−7.88 (m, 1H), 7.88−7.79 (m, 3H), 7.59−7.33 (m, 11H), 6.58 (dd, J = 9.5, 7.2 Hz, 1H), 4.03 (dd, J = 16.3, 9.7 Hz, 1H), 3.35 (dd, J = 16.3, 7.1 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 168.8, 156.2, 146.6, 138.6, 136.8, 136.7, 133.8, 132.0, 129.3, 129.2, 129.1, 129.0, 128.6, 128.4, 126.8, 9522

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524

Article

The Journal of Organic Chemistry

122.3, 112.0, 111.6, 110.5, 108.7, 79.5, 37.8; HRMS m/z (ESI): calcd for C27H20NO2 (M + H)+, 390.1489; found, 390.1493. 2-(Naphthalen-1-yl)-6-phenyl-4-(thiophen-2-yl)-2,3-dihydrofuro[2,3-b]pyridine 5bk. White solid; yield (69 mg, 34%); mp 223−225 °C; IR (KBr): ν 1603, 1402, 1240, 1046, 777 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.13−8.06 (m, 2H), 7.97−7.89 (m, 2H), 7.87−7.78 (m, 2H), 7.63−7.38 (m, 9H), 7.12 (dd, J = 5.0, 3.8 Hz, 1H), 6.63 (dd, J = 9.7, 7.0 Hz, 1H), 4.18 (dd, J = 16.3, 9.8 Hz, 1H), 3.46 (dd, J = 16.3, 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.1, 156.0, 140.3, 140.1, 138.8, 136.9, 133.9, 129.4, 129.1, 128.9, 128.6, 128.4, 128.0, 127.3, 126.9, 126.8, 126.4, 125.7, 125.5, 122.8, 122.3, 113.1, 111.4, 79.4, 37.9; HRMS m/z (ESI): calcd for C27H20NOS (M + H)+, 406.1260; found, 406.1265. 6-(4-Fluorophenyl)-2-(naphthalen-1-yl)-4-phenyl-2,3dihydrofuro[2,3-b]pyridine 5bl. White solid; yield (69 mg, 33%); mp 209−211 °C; IR (KBr): ν 1608, 1446, 1404, 1228, 776 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.13−8.04 (m, 2H), 7.95−7.85 (m, 2H), 7.85−7.78 (m, 2H), 7.59−7.36 (m, 9H), 7.16 (t, J = 8.7 Hz, 2H), 6.59 (dd, J = 9.5, 7.3 Hz, 1H), 4.08 (dd, J = 16.4, 9.7 Hz, 1H), 3.39 (dd, J = 16.4, 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.8, 163.4 (d, J = 248.2 Hz), 155.0, 147.9, 137.8, 136.8, 135.0 (d, J = 3.1 Hz), 133.9, 129.4, 129.1, 128.8, 128.8, 128.7 (d, J = 8.3 Hz), 128.4, 127.7, 126.4, 125.7, 125.5, 122.8, 122.2, 115.5 (d, J = 21.5 Hz), 115.1, 113.3, 79.6, 36.9; HRMS m/z (ESI): calcd for C29H21FNO (M + H)+, 418.1602; found, 418.1606. 6-(4-Chlorophenyl)-2-(naphthalen-1-yl)-4-phenyl-2,3dihydrofuro[2,3-b]pyridine 5bm. White solid; yield (108 mg, 51%); mp 242−244 °C; IR (KBr): ν 1601, 1405, 1228, 1084, 775 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10−8.01 (m, 2H), 7.94−7.85 (m, 2H), 7.81 (dd, J = 7.7, 4.4 Hz, 2H), 7.60−7.35 (m, 11H), 6.59 (dd, J = 9.4, 7.3 Hz, 1H), 4.08 (dd, J = 16.4, 9.7 Hz, 1H), 3.39 (dd, J = 16.4, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.8, 154.7, 147.9, 137.7, 137.3, 136.7, 134.9, 133.9, 129.37, 129.1, 128.8, 128.8, 128.4, 128.1, 127.6, 126.4, 125.7, 125.5, 122.7, 122.2, 115.5, 113.5, 79.6, 36.9; HRMS m/z (ESI): calcd for C29H21ClNO (M + H)+, 434.1306; found, 434.1310. 6-(4-Bromophenyl)-2-(naphthalen-1-yl)-4-phenyl-2,3dihydrofuro[2,3-b]pyridine 5bn. White solid; yield (79 mg, 33%); mp 245−247 °C; IR (KBr): ν 1599, 1404, 1358, 1225, 774 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−8.00 (m, 2H), 7.94−7.84 (m, 2H), 7.81 (dd, J = 7.7, 3.8 Hz, 2H), 7.58−7.36 (m, 11H), 6.59 (dd, J = 9.5, 7.3 Hz, 1H), 4.07 (dd, J = 16.4, 9.6 Hz, 1H), 3.39 (dd, J = 16.4, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.8, 154.7, 147.9, 137.7, 137.3, 136.8, 134.9, 133.9, 129.4, 129.1, 128.8, 128.8, 128.4, 128.1, 127.6, 126.4, 125.7, 125.5, 122.7, 122.2, 115.5, 113.5, 79.6, 36.9; HRMS m/z (ESI): calcd for C29H21BrNO (M + H)+, 478.0801; found, 478.0805. 2-(Naphthalen-1-yl)-4-phenyl-6-(p-tolyl)-2,3-dihydrofuro[2,3-b]pyridine 5bo. White solid; yield (97 mg, 47%); mp 255−257 °C; IR (KBr): ν 1595, 1406, 1360, 1225, 775 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.2 Hz, 2H), 7.94−7.85 (m, 2H), 7.82 (dd, J = 7.0, 6.2 Hz, 2H), 7.58−7.35 (m, 9H), 7.28 (d, J = 8.0 Hz, 2H), 6.58 (dd, J = 9.4, 7.3 Hz, 1H), 4.06 (dd, J = 16.3, 9.7 Hz, 1H), 3.38 (dd, J = 16.3, 7.2 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 156.0, 147.8, 138.8, 138.0, 136.9, 136.1, 133.8, 129.4, 129.3, 129.1, 128.8, 128.6, 128.3, 127.7, 126.7, 126.3, 125.7, 125.5, 122.8, 122.3, 114.7, 113.3, 79.5, 36.9, 21.2; HRMS m/z (ESI): calcd for C30H24NO (M + H)+, 414.1852; found, 414.1856. 2-(Naphthalen-1-yl)-4-phenyl-6-(m-tolyl)-2,3-dihydrofuro[2,3-b]pyridine 5bp. White solid; yield (109 mg, 53%); mp 180−182 °C; IR (KBr): ν 1595, 1402, 1230, 1047, 774, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.92−7.78 (m, 5H), 7.56−7.33 (m, 10H), 7.23 (d, J = 7.5 Hz, 1H), 6.58 (dd, J = 9.5, 7.3 Hz, 1H), 4.07 (dd, J = 16.3, 9.7 Hz, 1H), 3.38 (dd, J = 16.3, 7.2 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 156.1, 147.7, 138.8, 138.2, 137.9, 136.9, 133.8, 129.6, 129.3, 129.1, 128.8, 128.6, 128.5, 128.3, 127.6, 127.6, 126.3, 125.7, 125.5, 123.9, 122.7, 122.2, 114.9, 113.6, 79.5, 36.9, 21.5; HRMS m/z (ESI): calcd for C30H23NO (M + H)+, 414.1852; found, 414.1857.

126.4, 125.7, 125.5, 123.0, 122.7, 122.2, 115.0, 113.2, 79.5, 36.8; HRMS m/z (ESI): calcd for C29H21BrNO (M + H)+, 478.0801; found, 478.0802. 4-(3,4-Dichlorophenyl)-2-(naphthalen-1-yl)-6-phenyl-2,3dihydrofuro[2,3-b]pyridine 5be. White solid; yield (72 mg, 31%); mp 204−207 °C; IR (KBr): ν 2921, 1602, 1410, 1236, 1027, 804, 672 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.11−8.06 (m, 2H), 7.94−7.78 (m, 4H), 7.61−7.41 (m, 8H), 7.38−7.31 (m, 2H), 6.60 (dd, J = 9.5, 7.2 Hz, 1H), 4.04 (dd, J = 16.3, 9.7 Hz, 1H), 3.35 (dd, J = 16.3, 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) 13C NMR (100 MHz, CDCl3) δ 168.9, 156.5, 145.4, 138.5, 137.9, 136.6, 133.9, 133.2, 133.0, 130.8, 129.6, 129.3, 129.1, 129.1, 128.7, 128.5, 126.9, 126.9, 126.5, 125.8, 125.5, 122.6, 122.3, 115.1, 113.1, 79.6, 36.7; HRMS m/z (ESI): calcd for C29H20Cl2NO (M + H)+, 468.0916; found, 468.0916. 2-(Naphthalen-1-yl)-6-phenyl-4-(o-tolyl)-2,3-dihydrofuro[2,3-b]pyridine 5bf. White solid; yield (124 mg, 60%); mp 203−205 °C; IR (KBr): ν 2921, 1581, 1407, 1233, 1083, 777 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10−8.04 (m, 2H), 7.91−7.85 (m, 1H), 7.85−7.77 (m, 3H), 7.52−7.37 (m, 6H), 7.28−7.12 (m, 5H), 6.56 (dd, J = 9.6, 7.3 Hz, 1H), 3.76 (dd, J = 16.5, 9.8 Hz, 1H), 3.07 (dd, J = 16.5, 7.2 Hz, 1H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 155.3, 148.8, 138.8, 137.7, 136.9, 134.9, 133.8, 130.4, 129.3, 129.0, 128.8, 128.6, 128.3, 128.3, 128.1, 126.8, 126.2, 125.8, 125.6,125.5, 122.7, 122.2, 116.5, 114.9, 79.5, 36.3, 19.7; HRMS m/z (ESI): calcd for C30H24NO (M + H)+, 414.1852; found, 414.1855. 4-(4-(tert-Butyl)phenyl)-2-(naphthalen-1-yl)-6-phenyl-2,3dihydrofuro[2,3-b]pyridine 5bg. White solid; yield (164 mg, 72%); mp 195−197 °C; IR (KBr): ν 2961, 2920, 1602, 1262, 1088, 1024, 801 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.12−8.07 (m, 2H), 7.91−7.84 (m, 2H), 7.81 (t, J = 8.3 Hz, 2H), 7.55−7.37 (m, 11H), 6.56 (dd, J = 9.4, 7.2 Hz, 1H), 4.08 (dd, J = 16.3, 9.7 Hz, 1H), 3.38 (dd, J = 16.3, 7.1 Hz, 1H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.8, 155.9, 152.0, 147.7, 139.0, 137.0, 135.0, 133.9, 129.4, 129.1, 128.8, 128.6, 128.3, 127.4, 126.9, 126.3, 125.8, 125.7, 125.6, 122.8, 122.3, 115.0, 113.6, 79.5, 37.1, 34.7, 31.2; HRMS m/z (ESI): calcd for C33H30NO (M + H)+, 456.2322; found, 456.2322. 4-(3-Methoxyphenyl)-2-(naphthalen-1-yl)-6-phenyl-2,3dihydrofuro[2,3-b]pyridine 5bh. White solid; yield (144 mg, 67%); mp 221−223 °C; IR (KBr): ν 1600, 1576, 1400, 1227, 1032, 779 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.13−8.06 (m, 2H), 7.94−7.85 (m, 2H), 7.84−7.78 (m, 2H), 7.57−7.38 (m, 7H), 7.35 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.06−7.01 (m, 1H), 6.93 (dd, J = 8.0, 2.3 Hz, 1H), 6.58 (dd, J = 9.4, 7.4 Hz, 1H), 4.07 (dd, J = 16.4, 9.7 Hz, 1H), 3.81 (s, 3H), 3.38 (dd, J = 16.4, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.8, 159.8, 156.0, 147.7, 139.3, 138.8, 136.8, 133.8, 129.9, 129.4, 129.1, 128.8, 128.6, 128.3, 126.9, 126.3, 125.7, 125.5, 122.7, 122.2, 120.1, 115.1, 113.7, 113.7, 113.6, 79.5, 55.3, 36.9; HRMS m/z (ESI): calcd for C30H24NO2 (M + H)+, 430.1802; found, 430.1806. 2,4-Di(naphthalen-1-yl)-6-phenyl-2,3-dihydrofuro[2,3-b]pyridine 5bi. White solid; yield (101 mg, 45%); mp 206−209 °C; IR (KBr): ν 1600, 1406, 986, 777, 692 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.16−8.10 (m, 2H), 7.96 (s, 1H), 7.93−7.79 (m, 7H), 7.61 (dd, J = 8.5, 1.8 Hz, 1H), 7.57−7.39 (m, 9H), 6.60 (dd, J = 9.4, 7.5 Hz, 1H), 4.11 (dd, J = 16.3, 9.6 Hz, 1H), 3.46 (dd, J = 16.3, 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.8, 156.1, 147.8, 138.9, 136.9, 135.3, 133.8, 133.1, 133.0, 129.4, 129.1, 128.9, 128.6, 128.6, 128.3, 128.2, 127.7, 127.1, 126.9, 126.8, 126.6, 126.4, 125.7, 125.5, 125.2, 122.8, 122.3, 115.3, 113.9, 79.6, 37.0; HRMS m/z (ESI): calcd for C33H24NO (M + H)+, 450.1852; found, 450.1854. 4-(Furan-2-yl)-2-(naphthalen-1-yl)-6-phenyl-2,3-dihydrofuro[2,3b]pyridine 5bj. White solid; yield (70 mg, 36%); mp 204−206 °C; IR (KBr): ν 1261, 1093, 1025, 803, 672 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.19−8.03 (m, 2H), 7.98−7.91 (m, 2H), 7.82 (t, J = 7.2 Hz, 2H), 7.66 (s, 1H), 7.63−7.38 (m, 7H), 6.77 (d, J = 3.5 Hz, 1H), 6.63 (dd, J = 9.7, 6.9 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 4.17 (dd, J = 16.7, 9.9 Hz, 1H), 3.46 (dd, J = 16.7, 6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.1, 155.9, 151.1, 143.6, 138.8, 137.1, 136.0, 133.9, 129.4, 129.1, 128.8, 128.6, 128.3, 126.9, 126.4, 125.7, 125.5, 122.8, 9523

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524

Article

The Journal of Organic Chemistry

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Holzwarth, M. S.; Rychnovsky, S. D. J. Org. Chem. 2016, 81, 10376− 10382. (8) For recent examples on transition-metal-catalyzed pyridine synthesis: (a) Hille, T.; Irrgang, T.; Kempe, R. Angew. Chem., Int. Ed. 2017, 56, 371−374. (b) Yin, J.; Ye, Q.; Hao, W.; Du, S.; Gu, Y.; Zhang, W.-X.; Xi, Z. Org. Lett. 2017, 19, 138−141. (c) Zhao, M.-N.; Ren, Z.-H.; Yu, L.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2016, 18, 1194−1197. (d) Rohokale, R. S.; Koenig, B.; Dhavale, D. D. J. Org. Chem. 2016, 81, 7121−7126. (e) Hashimoto, T.; Kato, K.; Yano, R.; Natori, T.; Miura, H.; Takeuchi, R. J. Org. Chem. 2016, 81, 5393− 5400. (f) Huang, H.; Cai, J.; Tang, L.; Wang, Z.; Li, F.; Deng, G.-J. J. Org. Chem. 2016, 81, 1499−1505. (9) For recently examples on dihydrofuro[2,3-b]pyridine synthesis: (a) Duret, G.; Quinlan, R.; Martin, R. E.; Bisseret, P.; Neuburger, M.; Gandon, V.; Blanchard, N. Org. Lett. 2016, 18, 1610−1613. (b) Yu, L.Z.; Hu, X.-B.; Xu, Q.; Shi, M. Chem. Commun. 2016, 52, 2701−2704. (c) Barl, N. M.; Sansiaume-Dagousset, E.; Monzon, G.; Wagner, A. J.; Knochel, P. Org. Lett. 2014, 16, 2422−2425. (d) Martin, R. E.; Morawitz, F.; Kuratli, C.; Alker, A. M.; Alanine, A. I. Eur. J. Org. Chem. 2012, 2012, 47−52. (e) Zhou, Q.; Snider, B. B. Org. Lett. 2011, 13, 526−529. (f) While this manuscript was being prepared, the same result was reported by Zhang and co-workers: Yang, X.; Hu, F.; Wang, Y.; Yang, C.; Zou, X.; Liu, J.; Zhang, Q. Chem. Commun. 2017, 53, 7497−7500. (10) (a) Zhu, R.; Cheng, G.; Jia, C.; Xue, L.; Cui, X. J. Org. Chem. 2016, 81, 7539−7544. (b) Shen, J.; Yang, X.; Wang, F.; Wang, Y.; Cheng, G.; Cui, X. RSC Adv. 2016, 6, 48905−48909. (c) Shen, J.; Wang, X.; Lin, X.; Yang, Z.; Cheng, G.; Cui, X. Org. Lett. 2016, 18, 1378−1381. (d) Shen, J.; Cai, D.; Kuai, C.; Liu, Y.; Wei, M. e.; Cheng, G.; Cui, X. J. Org. Chem. 2015, 80, 6584−6589. (e) Yang, X.; Cheng, G.; Shen, J.; Kuai, C.; Cui, X. Org. Chem. Front. 2015, 2, 366−368. (f) Cheng, G.; Zeng, X.; Shen, J.; Wang, X.; Cui, X. Angew. Chem., Int. Ed. 2013, 52, 13265−8. (g) Cheng, G.; Cui, X. Org. Lett. 2013, 15, 1480−1483. (11) (a) Kelgokmen, Y.; Zora, M. RSC Adv. 2016, 6, 4608−4621. (b) Yang, X.; Wang, Y.; Hu, F.; Kan, X.; Yang, C.; Liu, J.; Liu, P.; Zhang, Q. RSC Adv. 2016, 6, 68454−68459. (c) Mikusek, J.; Matous, P.; Matousova, E.; Janousek, M.; Kunes, J.; Pour, M. Adv. Synth. Catal. 2016, 358, 2912−2922. (d) Kumar, R.; Thorat, S. H.; Reddy, M. S. Chem. Commun. 2016, 52, 13475−13478. (e) Goutham, K.; Ashok Kumar, D.; Suresh, S.; Sridhar, B.; Narender, R.; Karunakar, G. V. J. Org. Chem. 2015, 80, 11162−11168. (f) Martins, M. A. P.; Rossatto, M.; Frizzo, C. P.; Scapin, E.; Buriol, L.; Zanatta, N.; Bonacorso, H. G. Tetrahedron Lett. 2013, 54, 847−849. (12) For recently examples on furo[2,3-b]pyridine synthesis: (a) Fumagalli, F.; da Silva Emery, F. J. Org. Chem. 2016, 81, 10339−10347. (b) Li, Z.; Ling, F.; Cheng, D.; Ma, C. Org. Lett. 2014, 16, 1822−1825. (13) (a) Li, C.; Li, X.; Meng, X.; Wang, T.; Li, J.; Chen, B. Synth. Commun. 2011, 41, 1208−1217. (b) Tzalis, D.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 1463−1465. (c) Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo, T.; Saito, S. J. Org. Chem. 2003, 68, 3702−3705.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01541. Copies of 1H NMR and 13C NMR for all synthesized compounds (PDF) X-ray crystallographic data of 8 (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xiuling Cui: 0000-0001-5759-766X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by NSF of China (21672075), Science and Technology Bureau of Xiamen City (3502Z20150054), Xiamen Southern Oceanographic Center (15PYY052SF01), Outstanding Youth Scientific Research Cultivation Plan of Colleges and Universities of Fujian Province (JA14012), and Promotion Program for Young and Middleaged Teacher in Science and Technology Research of Huaqiao University (ZQN-PY120).

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REFERENCES

(1) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627−646. (2) (a) Kung, P.-P.; Rui, E.; Bergqvist, S.; Bingham, P.; Braganza, J.; Collins, M.; Cui, M.; Diehl, W.; Dinh, D.; Fan, C.; Fantin, V. R.; Gukasyan, H. J.; Hu, W.; Huang, B.; Kephart, S.; Krivacic, C.; Kumpf, R. A.; Li, G.; Maegley, K. A.; McAlpine, I.; Nguyen, L.; Ninkovic, S.; Ornelas, M.; Ryskin, M.; Scales, S.; Sutton, S.; Tatlock, J.; Verhelle, D.; Wang, F.; Wells, P.; Wythes, M.; Yamazaki, S.; Yip, B.; Yu, X.; Zehnder, L.; Zhang, W.-G.; Rollins, R. A.; Edwards, M. J. Med. Chem. 2016, 59, 8306−8325. (b) Trist, I. M. L.; Nannetti, G.; Tintori, C.; Fallacara, A. L.; Deodato, D.; Mercorelli, B.; Palu, G.; Wijtmans, M.; Gospodova, T.; Edink, E.; Verheij, M.; de Esch, I.; Viteva, L.; Loregian, A.; Botta, M. J. Med. Chem. 2016, 59, 2688−2703. (c) Rodriguez, A. L.; Williams, R.; Zhou, Y.; Lindsley, S. R.; Le, U.; Grier, M. D.; Weaver, C. D.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2009, 19, 3209−3213. (3) For reviews of cascade reaction: (a) Volla, C. M. R.; Atodiresei, L.; Rueping, M. Chem. Rev. 2014, 114, 2390−2431. (b) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem. Res. 2012, 45, 1278−1293. (c) Climent, M. J.; Corma, A.; Iborra, S. Chem. Rev. 2011, 111, 1072− 1133. (d) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993− 3009. (4) (a) Yu, C.-B.; Huang, W.-X.; Shi, L.; Chen, M.-W.; Wu, B.; Zhou, Y.-G. J. Am. Chem. Soc. 2014, 136, 15837−15840. (b) Guo, X.; Hu, W. Acc. Chem. Res. 2013, 46, 2427−2440. (5) (a) Kurita, J.; Iwata, K.; Tsuchiya, T. Chem. Pharm. Bull. 1987, 35, 3166−3174. (b) Kurita, J.; Iwata, K.; Tsuchiya, T. J. Chem. Soc., Chem. Commun. 1986, 1188−1189. (6) Cheng, G.; Weng, Y.; Yang, X.; Cui, X. Org. Lett. 2015, 17, 3790− 3793. (7) For recent examples on metal-free pyridine synthesis: (a) Zhang, J.; Zhang, Q.; Xia, B.; Wu, J.; Wang, X.-N.; Chang, J. Org. Lett. 2016, 18, 3390−3393. (b) Song, Z.; Huang, X.; Yi, W.; Zhang, W. Org. Lett. 2016, 18, 5640−5643. (c) Lin, Y.; Yang, X.; Pan, W.; Rao, Y. Org. Lett. 2016, 18, 2304−2307. (d) Xiang, J.-C.; Wang, M.; Cheng, Y.; Wu, A.X. Org. Lett. 2016, 18, 24−27. (e) Wang, Y.; Song, L.-J.; Zhang, X.; Sun, J. Angew. Chem., Int. Ed. 2016, 55, 9704−9708. (f) Hilf, J. A.; 9524

DOI: 10.1021/acs.joc.7b01541 J. Org. Chem. 2017, 82, 9515−9524