NHC-Catalyzed Hetero-Diels–Alder Reaction of Allenoate with

Feb 12, 2018 - An NHC-catalyzed hetero-Diels–Alder and isomerization process of chalcones with allenoates was discovered, which furnished highly ...
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NHC-Catalyzed Hetero-Diels−Alder Reaction of Allenoate with Chalcone: Synthesis of Polysubstituted Pyranyl Carboxylate Yong Hu, Sha Li, Zhanlin Wang, Yibiao Yao, Tuanjie Li, Chenxia Yu, and Changsheng Yao* Jiangsu Key Lab of Green Synthetic Chemistry for Functional Materials, School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou, Jiangsu 221116, P. R. China S Supporting Information *

ABSTRACT: An NHC-catalyzed hetero-Diels−Alder and isomerization process of chalcones with allenoates was discovered, which furnished highly functionalized multisubstituted pyranyl carboxylates successfully. This method features a convergent assembly, mild reaction conditions, moderate to good yields, and high atom economy.

P

Scheme 1. Profiles of Phosphine-Catalyzed [3+2], [4+2], and [4+1] Annulation of Allenes

yran has attracted wide synthetic interest due to its rich appearance as an important skeleton in bioactive active molecules and natural products.1 Some molecules containing this privileged scaffold are associated with interesting biological and pharmacological activities, such as antiviral,1a−c anticancer,1d and anticonvulsant activities.1e In 2015, Das’s group2a reported a ZnI2-catalyzed highly diastereoselective reaction of β,γ-unsaturated α-ketothioesters and olefins to afford highly substituted 3,4-dihydro-2H-pyrans. Very recently, List et al.2b put forward a general and highly enantioselective catalytic [4+2] cyclization of unactivated dienes with aldehydes enabled by chiral Brønsted acids to give enantiomerically enriched dihydropyrans. Therefore, the development of efficient and mild accesses to this skeleton is an active research area.2e The past decade has witnessed spectacular growth of allene chemistry.3 In particular, the Lewis base-catalyzed transformations of allenoates have received considerable interest due to their potential for the facile generation of structurally complex molecules.4 In 1995, Lu et al.5 pioneered a phosphinecatalyzed [3+2] cyclization of allenoates with electron-deficient olefins for the syntheses of cyclopentenes. In this context, phosphine-triggered allenes-involved reactions, such as [3+2],6 [4+1],7 and [4+2]8 cyclization, have now been firmly established as the effective synthetic strategies to construct a wide variety of five- or six-membered cyclic scaffolds and have found broad applications in the preparation of biologically active natural compounds (Scheme 1).9 In addition to phosphines, amines have also been tremendously utilized as nucleophilic catalysts to facilitate numerous novel conversions of allenoates. In 1993, Tsuboi et al.10 reported the DABCOcatalyzed Morita−Baylis−Hillman reactions (MBH reaction) of allenoates with aldehydes. Subsequently, similar aminecatalyzed domino reactions of allenes have been successfully © 2018 American Chemical Society

disclosed for the convenient assembly of a pyran unit by the groups of Shi, Tong, Borhan, Loh, Cheng, and others.11 N-Heterocyclic carbenes (NHCs) have been demonstrated as a kind of powerful organocatalysts for various carbon− carbon and carbon−heteroatom bond-forming reactions.12 An attractive catalytic feature of NHCs is to reverse the polarity of aldehyde (umpolung) to provide a new fashion for organic synthesis (Scheme S1, Supporting Information). For instance, a1-d1 umpolung of aldehydes (carbonyl carbon of aldehyde featuring an inverted, nucleophilic reactivity) participates in the benzoin condensation and Stetter addition and a3-d3 polarity reversal of enals (enals = α,β-unsaturated aldehydes). The homoenolates generated from the reactions of NHCs and enals could be considered as d3-nucleophiles and thus constitute an a3-d3 umpolung and could be accomplished by a NHC Received: December 17, 2017 Published: February 12, 2018 3361

DOI: 10.1021/acs.joc.7b03173 J. Org. Chem. 2018, 83, 3361−3366

Note

The Journal of Organic Chemistry readily.13 Now NHCs have been fully proved as the robust catalysts for reactions involving esters14 and other carboxylic acid derivatives.15,16 Nevertheless, catalytic reactions triggered by the addition of NHCs to unsaturated CC bonds are far less explored due to the stability of the NHC-substrate adducts,17 and there were only a handful of examples concerning the reactions of NHCs and CC bonds.18 Allenoates are important synthons that can undergo synthetically useful transformations to a wealth of valuable heterocycles. Compared with the well-established phosphineor amine-catalyzed cycloadditions of allenoates, in sharp contrast, the potential of the NHC-catalyzed reaction of allenoates remains largely underexplored. Thus, we envisaged that a formal [3+2] annulation may be realized through NHC catalysis by employing allenoates and highly activated olefins as C3 and C2 synthons, respectively. Then allenoate 1 and chalcone 2 were deployed as standard substrates in the presence of NHCs to search for a suitable condition for the creation of cyclopentenes 3 (Scheme 2a). To our surprise, this

Table 1. Survey on Reaction Conditions for the Formation of 4aaa

Scheme 2. Our Investigation on Employing Allenoates as a C3 Synthon

entry

catalyst (0.2 equiv)

base (x equiv)

solvent

yield (%)b

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

5a 5b 5c 6a 6b 5a 5a 5a 5a DBU

K2CO3 (0.5) K2CO3 (0.5) K2CO3 (0.5) K2CO3 (0.5) K2CO3 (0.5) K2CO3 (0.25) Cs2CO3 (0.25) Cs2CO3 (0.25) Cs2CO3 (0.25)

THF THF THF THF THF THF THF ACN ACN ACN

31 ND ND trace trace 39 46 62 67 trace

a Reactions were performed with 1a (0.30 mmol, 34 mg, 35 μL), 2a (0.10 mmol, 21 mg), catalyst (0.02 mmol), and base (x equiv) in solvent (1.0 mL) under N2 at 25 °C. bIsolated yields. cAt 30 °C. dAt 30 °C. ND = not detected.

the [4+2] annulation between 1 and 2. The results were tabulated in Table 2. In general, various chalcones 2 with a broad range of electron properties of phenyl groups (e.g., electron-rich or electron-deficient phenyl ring) were subjected to the NHC-catalyzed annulation, and the corresponding products 4ab−4an were obtained in good yields in most cases. The electronic nature of the phenyl group in substrates 2 affected the reaction performance strongly in terms of isolated yields. The reaction of electron-deficient chalcones 2b−2f with 1a occurred smoothly. However, the reactions involving substrates 2 with methyl and methoxyl substituents gave products 4ag and 4ah in somewhat lower yields. 1-Naphthyland 2-thiophenyl-containing substrates 2k−2n could also be employed for the syntheses of 4ak−2an along with good yields. Next, the substrate scope with regard to the allenic ester structures was also evaluated. Different linear/branched alkylor aryl-substituted allenic esters 1 were well-tolerated, and the expected [4+2] coupling compounds 4ba−4da were acquired in good yields. These results highlighted the broad substrate scope of this NHC-catalyzed annulation protocol.19 Thus, this protocol provided a nonmetal-catalyzed alternative for the construction of a pyran unit compared to the previous study.2f,g Moreover, it also demonstrated a new reactive mode of annulation of allenoates with chalcones, which was catalyzed by phosphine and tertiary amine previously.6c,11a On the basis of the related NHC-catalyzed reactions of allenoate,18d,e we proposed two possible pathways of this annulation of 1 and 2 (Scheme 3): (a) NHC may attack the center carbon atom of allenaoate 1, and intermediate A was formed. Then it could undergo a 1,4-addition with chalcone 2, affording an enolate anion intermediate B. Then the double bond in B would be isomerized into the conjugated position with the ester. The subsequent cyclic conjugate addition gave the final product 4 with the release of the NHC catalyst. (b) Intermediate B underwent a proton transfer process to afford intermediate E, and then the elimination of NHC gave rise to

reaction did not proceed in the manner of the desired [3+2] annulation to afford the anticipated products 3. On the contrary, a formal [4+2] reaction occurred, which produced a class of unforeseen products 4 with modest yields (Scheme 2b). Herein, we shall report our preliminary results of this unexpected reaction mode of allenoates catalyzed by a NHC. Our investigation commenced with the screening of NHC catalysts for the model reaction of 1a and 2a (Table 1). After several attempts, we found that catalyst 5a was able to deliver product 4aa in 31% yield at 25 °C in THF presented by K2CO3 (Table 1, entry 1). With the replacement of the bulky tert-butyl group of 5a with a phenyl group or an isopropyl substituent respectively, neither 5b nor 5c could push this reaction forward (Table 1, entries 2 and 3). Triazolium salts 6a and 6b were found to be poor catalysts (Table 1, entries 4 and 5). Further efforts to improve the yield of cycloadduct 4aa by decreasing the base loading from 0.5 equiv to 0.25 equiv gave a better result with the yield modestly up to 39% (Table 1, entry 6). The following studies unraveled that inorganic bases were more competent than their organic counterparts and that the use of the stronger base Cs2CO3 furnished a better yield of the product 4aa (Table 1, entry 7). The solvent effect was also examined by screening DCM, toluene, DME, and ACN; ACN was identified as the best choice (Table 1, entry 8). When the reaction was performed in ACN at 30 °C in the presence of 5a, 4aa was obtained in 67% yield (Table 1, entry 9), which should be the optimal reaction condition. Notably, only a trace amount of the product 4aa was detected if the catalyst 5a was replaced by DBU. (For details of the optimization of reaction condition, please see Table S1, Supporting Information.) With the optimized reaction conditions established (Table 1 entry 9), we turned our attention to test the substrate scope of 3362

DOI: 10.1021/acs.joc.7b03173 J. Org. Chem. 2018, 83, 3361−3366

Note

The Journal of Organic Chemistry Table 2. NHC-Catalyzed Annulations of Allenoates with Chalcones to Form Pyranyl Carboxylatesa,b

a

Reactions were performed with 1a (0.30 mmol), 2a (0.10 mmol), 5a (0.02 mmol, 4.3 mg), and Cs2CO3 (0.025 equiv, 8.1 mg) in ACN (1.0 mL) under N2 at 30 °C. bIsolated yields.

■

Scheme 3. Plausible Reaction Mechanism

EXPERIMENTAL SECTION

General Methods and Materials. Unless otherwise mentioned, all reactions were carried out under an atmosphere of nitrogen in dry glassware and were monitored by analytical thin-layer chromatography (TLC), which was visualized by ultraviolet light (254 nm). All solvents were obtained from commercial sources and were purified according to standard procedures. Substrates 2 were prepared according to a known method.20 Purification of the products was accomplished by flash chromatography using silica gel (200−300 mesh). Melting points were determined in open capillaries and were uncorrected. IR spectra were taken on a FT-IR spectrometer in KBr pellets and reported in cm−1. 1H NMR spectra were measured on a 400 MHz spectrometer in CDCl3 (100 MHz, 13C NMR) or DMSO-d6 with a chemical shift (δ) given in ppm relative to TMS as an internal standard. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration. High-resolution mass spectra (HRMS) were obtained on a HRMS/MS instrument with the technique of electrospray ionization. General Procedure for Syntheses of Pyranyl Carboxylates 4. An oven-dried 10 mL Schlenk tube equipped with a magnetic stir bar was charged with 1 (0.3 mmol), 2 (0.1 mmol), imidazolium salt 5a (0.02 mmol, 4.3 mg), and Cs2CO3 (0.025 mmol, 8.1 mg). The tube was closed with a septum, evacuated, and refilled with nitrogen. Freshly distilled ACN (1.0 mL) was added into the mixture with a syringe. Then the mixture was stirred at 30 °C until completion (monitored by TLC). After the removal of the solvent under reduced pressure, the resulting crude residue was purified by column chromatography (silica gel, mixtures of petroleum ether/ethyl acetate, 80:1 to 40:1, v/v) to afford the desired product 4. Ethyl 2-Methyl-4,6-diphenyl-4H-pyran-3-carboxylate (4aa): yield = 67% (21.5 mg); white solid; mp = 57.0−57.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.64−7.60 (m, 2H), 7.41−7.31 (m, 7H), 7.26− 7.20 (m, 1H), 5.66 (d, J = 5.1 Hz, 1H), 4.56 (d, J = 5.1 Hz, 1H), 4.16− 4.00 (m, 2H), 2.52 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.4, 159.8, 146.4, 146.2, 133.1, 128.5, 128.4, 128.3, 128.1, 126.5, 124.4, 105.2, 103.1, 60.0, 38.9, 19.2, 14.0; IR (KBr) (v, cm−1) 2905, 1713, 1680, 1633, 1496, 1450, 1213, 828; HRMS (ESI) m/z calcd for [M + H]+ C21H21O3 321.1491; found 321.1464. Ethyl 6-(4-Fluorophenyl)-2-methyl-4-phenyl-4H-pyran-3carboxylate (4ab): yield = 79% (26.7 mg); white solid; mp =

intermediate F. The regenerated NHC could act as a base to deprotonate F to give intermediate G. Enolic intermediate G would undergo an intramolecular 6-exo-dig cyclization to give intermediate H, which would be protonated by a NHC precursor to yield product 4 ultimately. In conclusion, a formal [4+2] annulation between α,βunsaturated ketone and allenoate took place readily to provide a wide range of pyranyl carboxylates in the presence of imidazolium catalyst 5a. The moderate to good yields, mild reaction conditions, and high atom economy make it attractive for the construction of oxygenous six-membered heterocycles. 3363

DOI: 10.1021/acs.joc.7b03173 J. Org. Chem. 2018, 83, 3361−3366

Note

The Journal of Organic Chemistry 69.6−70.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.57−7.50 (m, 2H), 7.30−7.26 (m, 4H), 7.22−7.16 (m, 1H), 7.06−6.99 (m, 2H), 5.54 (d, J = 5.0 Hz, 1H), 4.51 (d, J = 5.0 Hz, 1H), 4.10−3.98 (m, 2H), 2.47 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.3, 162.9 (J = 248.2 Hz), 159.6, 146.1, 145.6, 129.3 (J = 3.3 Hz), 128.4, 128.0, 126.6, 126.3 (J = 8.2 Hz), 115.3 (J = 21.7 Hz), 105.3, 102.9 (J = 1.6 Hz), 60.0, 38.8, 19.2, 14.0; IR (KBr) (v, cm−1) 1715, 1629, 1508, 1213, 1078, 836, 764; HRMS (ESI) m/z calcd for [M + H]+ C21H20FO3 339.1396, found 339.1382. Ethyl 2-Methyl-6-(2-nitrophenyl)-4-phenyl-4H-pyran-3-carboxylate (4ac): yield = 82% (30.0 mg); slight yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.9, 1.3 Hz, 1H), 7.59−7.47 (m, 3H), 7.39−7.31 (m, 4H), 7.28−7.20 (m, 1H), 5.50 (d, J = 5.1 Hz, 1H), 4.58 (d, J = 5.1 Hz, 1H), 4.14−4.02 (m, 2H), 2.34 (d, J = 0.5 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0, 159.8, 148.3, 145.5, 145.2, 132.5, 130.4, 129.8, 128.6, 128.4, 128.2, 126.7, 124.2, 107.5, 105.5, 60.1, 38.9, 18.5, 14.0; IR (KBr) (v, cm−1) 1745, 1623, 1521, 1341, 826, 770; HRMS (ESI) m/z calcd for [M + H]+ C21H20NO5 366.1341, found 366.1321. Ethyl 6-(4-Bromophenyl)-2-methyl-4-phenyl-4H-pyran-3carboxylate (4ad): yield = 76% (30.3 mg); off white solid; mp = 85.6−86.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.49−7.40 (m, 4H), 7.32−7.25 (m, 4H), 7.22−7.16 (m, 1H), 5.61 (d, J = 5.1 Hz, 1H), 4.50 (d, J = 5.1 Hz, 1H), 4.10−3.97 (m, 2H), 2.47 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 159.5, 145.8, 145.4, 131.9, 131.4, 128.4, 128.0, 126.6, 125.9, 122.5, 105.2, 103.6, 60.0, 38.8, 19.2, 14.0; IR (KBr) (v, cm−1) 2980, 1706, 1633, 1488, 1252, 848, 832; HRMS (ESI) m/z calcd for [M + H]+ C21H20BrO3 399.0596, found 399.0569. Ethyl 6-(4-Chlorophenyl)-2-methyl-4-phenyl-4H-pyran-3carboxylate (4ae): yield = 72% (25.5 mg); white solid; mp = 70.4−71.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.51−7.46 (m, 2H), 7.32−7.26 (m, 6H), 7.21−7.17 (m, 1H), 5.59 (d, J = 5.1 Hz, 1H), 4.51 (d, J = 5.0 Hz, 1H), 4.09−3.98 (m, 2H), 2.47 (d, J = 0.6 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.3, 159.6, 145.9, 145.4, 134.3, 131.5, 128.5, 128.4, 128.0, 126.6, 125.7, 105.2, 103.5, 60.0, 38.8, 19.2, 13.9; IR (KBr) (v, cm−1) 2977, 1714, 1628, 1492, 1251, 833, 763; HRMS (ESI) m/z calcd for [M + H]+ C21H20ClO3 355.1101, found 355.1103. Ethyl 2-Methyl-4-phenyl-6-(4-(trifluoromethyl)phenyl)-4Hpyran-3-carboxylate (4af): yield = 68% (26.4 mg); white solid; mp = 55.6−56.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.37−7.30 (m, 4H), 7.27−7.21 (m, 1H), 5.76 (d, J = 5.1 Hz, 1H), 4.59 (d, J = 5.0 Hz, 1H), 4.14−4.04 (m, 2H), 2.53 (d, J = 0.6 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 159.5, 145.6, 145.2, 136.4 (J = 1.3 Hz), 130.4 (J = 32.6 Hz), 128.4, 128.1, 126.7, 125.3 (J = 3.8 Hz), 124.6, 122.6, 105.3, 105.2, 60.1, 38.9, 19.2, 14.0; IR (KBr) (v, cm−1) 2997, 1722, 1645, 1488, 848, 764; HRMS (ESI) m/z calcd for [M + H]+ C22H20F3O3 389.1365, found 389.1342. Ethyl 2-Methyl-4-phenyl-6-(p-tolyl)-4H-pyran-3-carboxylate (4ag): yield = 57% (19.1 mg); white solid; mp = 73.6−74.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.3 Hz, 2H), 7.34−7.30 (m, 4H), 7.25−7.17 (m, 3H), 5.60 (d, J = 5.0 Hz, 1H), 4.55 (d, J = 5.1 Hz, 1H), 4.14−4.02 (m, 2H), 2.51 (d, J = 0.6 Hz, 3H), 2.38 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.5, 159.8, 146.4, 146.3, 138.5, 130.3, 129.0, 128.3, 128.1, 126.5, 124.3, 105.2, 102.3, 59.9, 38.8, 21.2, 19.3, 14.0; IR (KBr) (v, cm−1) 2924, 1705, 1676, 1621, 1512, 1251, 819; HRMS (ESI) m/z calcd for [M + H]+ C22H23O3 335.1647, found 335.1637. Ethyl 6-(4-Methoxyphenyl)-2-methyl-4-phenyl-4H-pyran-3carboxylate (4ah): yield = 54% (18.9 mg); white solid; mp = 75.6−76.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.56−7.51 (m, 2H), 7.34−7.30 (m, 4H), 7.24−7.18 (m, 1H), 6.94−6.87 (m, 2H), 5.51 (d, J = 5.0 Hz, 1H), 4.53 (d, J = 4.6 Hz, 1H), 4.12−4.01 (m, 2H), 3.84 (s, 3H), 2.50 (d, J = 0.6 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.5, 159.9, 159.8, 146.4, 146.2, 128.3, 128.1, 126.5, 125.84, 125.80, 113.7, 105.3, 101.4, 60.0, 55.3, 38.9, 19.3, 14.0; IR (KBr) (v, cm−1) 2925, 1708, 1675, 1514, 839, 758; HRMS (ESI) m/z calcd for [M + H]+ C22H23O4 351.1596, found 351.1618.

Ethyl 6-(4-Chlorophenyl)-2-methyl-4-(p-tolyl)-4H-pyran-3carboxylate (4ai): yield = 56% (20.7 mg); slight yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.55−7.50 (m, 2H), 7.36−7.31 (m, 2H), 7.20 (d, J = 8.07 Hz, 2H), 7.13 (d, J = 7.95 Hz, 2H), 5.62 (d, J = 5.1 Hz, 1H), 4.51 (d, J = 5.1 Hz, 1H), 4.15−4.01 (m, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.4, 159.4, 145.4, 143.0, 136.2, 134.3, 131.6, 129.1, 128.5, 127.9, 125.6, 105.4, 103.7, 60.0, 38.3, 21.1, 19.2, 14.1; IR (KBr) (v, cm−1) 1791, 1748, 1625, 1478, 1305, 861, 829; HRMS (ESI) m/z calcd for [M + H]+ C22H22ClO3 369.1257, found 369.1229. Ethyl 4,6-Bis(4-chlorophenyl)-2-methyl-4H-pyran-3-carboxylate (4aj): yield = 61% (23.7 mg); white solid; mp = 110.0−111.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.54−7.49 (m, 2H), 7.36−7.32 (m, 2H), 7.31−7.21 (m, 4H), 5.58 (d, J = 5.1 Hz, 1H), 4.53 (d, J = 5.0 Hz, 1H), 4.16−4.01 (m, 2H), 2.50 (d, J = 0.5 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0, 159.9, 145.7, 144.5, 134.5, 132.3, 131.3, 129.4, 128.6, 128.5, 125.7, 105.0, 103.0, 60.2, 38.3, 19.3, 14.1; IR (KBr) (v, cm−1) 2980, 1708, 1625, 1488, 851, 829; HRMS (ESI) m/z calcd for [M + H]+ C21H19Cl2O3 389.0711, found 389.0723. Ethyl 6-(Furan-2-yl)-2-methyl-4-phenyl-4H-pyran-3-carboxylate (4ak): yield = 74% (23.0 mg); yellow solid; mp = 53.8−54.3 °C; H NMR (400 MHz, CDCl3) δ 7.38−7.36 (m, 1H), 7.33−7.29 (m, 4H), 7.25−7.19 (m, 1H), 6.55 (d, J = 3.3 Hz, 1H), 6.44 (dd, J = 3.4, 1.8 Hz, 1H), 5.63 (d, J = 5.0 Hz, 1H), 4.53 (d, J = 5.0 Hz, 1H), 4.13− 4.00 (m, 2H), 2.48 (d, J = 0.7 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.3, 159.4, 147.7, 145.9, 142.5, 139.6, 128.3, 128.0, 126.5, 111.1, 106.6, 105.3, 102.0, 60.0, 38.1, 19.2, 14.0; IR (KBr) (v, cm−1) 1716, 1630, 1527, 1327, 848, 811; HRMS (ESI) m/z calcd for [M + H]+ C19H19O4 311.1283, found 311.1279. Ethyl 2-Methyl-4-phenyl-6-(thiophen-2-yl)-4H-pyran-3-carboxylate (4al): yield = 83% (27.1 mg); white solid; mp = 66.0− 67.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.35−7.30 (m, 4H), 7.27− 7.20 (m, 3H), 7.03 (dd, J = 5.0, 3.7 Hz, 1H), 5.55 (d, J = 5.1 Hz, 1H), 4.53 (d, J = 5.0 Hz, 1H), 4.13−4.03 (m, 2H), 2.50 (d, J = 0.7 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 159.6, 145.8, 142.5, 136.8, 128.4, 128.1, 127.3, 126.6, 125.0, 123.6, 105.4, 102.3, 60.0, 38.7, 19.2, 14.0; IR (KBr) (v, cm−1) 1707, 1623, 1378, 843; HRMS (ESI) m/z calcd for [M + H]+ C19H19O3S 327.1055, found 327.1050. Ethyl 2-Methyl-6-(naphthalen-2-yl)-4-phenyl-4H-pyran-3carboxylate (4am): yield = 87% (32.2 mg); white solid; mp = 84.9−86.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.93− 7.80 (m, 3H), 7.66 (dd, J = 8.7, 1.8 Hz, 1H), 7.49−7.43 (m, 2H), 7.40−7.32 (m, 4H), 7.21−7.17 (m, 1H), 5.81 (d, J = 5.1 Hz, 1H), 4.62 (d, J = 5.0 Hz, 1H), 4.12−3.99 (m, 2H), 2.60 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.4, 159.9, 146.3, 146.2, 133.2, 133.1, 130.2, 128.4, 128.1, 128.0, 127.6, 126.6, 126.4, 126.3, 123.5, 122.1, 105.3, 103.8, 60.0, 39.0, 19.3, 14.0; IR (KBr) (v, cm−1) 1709, 1630, 1454, 845, 759; HRMS (ESI) m/z calcd for [M + H]+ C25H23O3 371.1647, found 371.1667. Ethyl 2-Methyl-6-phenyl-4-(thiophen-2-yl)-4H-pyran-3-carboxylate (4an): yield = 81% (26.4 mg); white solid; mp = 59.7− 60.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.55−7.49 (m, 2H), 7.31− 7.22 (m, 3H), 7.05 (dd, J = 2.51, 3.84 Hz, 1H), 6.83−6.82 (m, 2H), 5.64 (d, J = 5.3 Hz, 1H), 4.78 (d, J = 5.3 Hz, 1H), 4.14−4.01 (m, 2H), 2.37 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 159.8, 150.4, 147.2, 132.8, 128.7, 128.3, 126.6, 124.5, 124.1, 124.0, 105.4, 102.2, 60.1, 33.2, 19.2, 14.1; IR (KBr) (v, cm−1) 2980, 1707, 1622, 763; HRMS (ESI) m/z calcd for [M + H]+ C19H19O3S 327.1055, found 327.1042. Isopropyl 2-Methyl-4,6-diphenyl-4H-pyran-3-carboxylate (4ba): yield = 74% (24.7 mg); white solid; mp = 54.4−55.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.57−7.55 (m, 2H), 7.36−7.25 (m, 7H), 7.21−7.14 (m, 1H), 5.60 (d, J = 4.9 Hz, 1H), 4.96−4.86 (m, 1H), 4.51 (d, J = 4.6 Hz, 1H), 2.47 (d, J = 0.6 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 159.5, 146.2, 146.1, 133.1, 128.4, 128.2, 128.1, 126.4, 124.3, 105.3, 103.1, 67.2, 38.9, 21.9, 21.3, 19.1; IR (KBr) (v, cm−1) 1733, 1677, 1633, 3364

DOI: 10.1021/acs.joc.7b03173 J. Org. Chem. 2018, 83, 3361−3366

Note

The Journal of Organic Chemistry 1496, 1450, 828; HRMS (ESI) m/z calcd for [M + H]+ C22H23O3 335.1647, found 335.1629. Butyl 2-Methyl-4,6-diphenyl-4H-pyran-3-carboxylate (4ca): yield = 71% (24.7 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.57−7.55 (m, 2H), 7.35−7.27 (m, 7H), 7.20−7.15 (m, 1H), 5.61 (d, J = 5.1 Hz, 1H), 4.51 (d, J = 4.9 Hz, 1H), 4.05−3.93 (m, 2H), 2.48 (d, J = 0.4 Hz, 3H), 1.50−1.38 (m, 2H), 1.22−1.15 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.4, 159.9, 146.2, 146.1, 133.0, 128.4, 128.3, 128.2, 127.9, 126.4, 124.3, 105.0, 103.1, 63.8, 38.8, 30.5, 19.2, 19.0, 13.6; IR (KBr) (v, cm−1) 1754, 1514, 1480, 1445, 848; HRMS (ESI) m/z calcd for [M + H]+ C23H25O3 349.1804, found 349.1811. Benzyl 2-Methyl-4,6-diphenyl-4H-pyran-3-carboxylate (4da): yield = 66% (25.2 mg); white solid; mp = 71.4−72.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.65−7.54 (m, 2H), 7.41−7.36 (m, 4H), 7.34−7.28 (m, 7H), 7.15−7.06 (m, 2H), 5.65 (d, J = 5.1 Hz, 1H), 5.16−5.04 (m, 2H), 4.58 (d, J = 5.0 Hz, 1H), 2.54 (d, J = 0.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 167.2, 160.6, 146.3, 146.1, 136.1, 133.0, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 126.6, 124.4, 104.8, 103.2, 65.9, 38.8, 19.4; IR (KBr) (v, cm−1) 1723, 1691, 1496, 1450, 808; HRMS (ESI) m/z calcd for [M + H]+ C26H23O3 383.1647, found 383.1651.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03173. Some known key intermediates generated from NHCs and aldehydes or alkenes, optimization of the reaction conditions, and 1H and 13CNMR spectra for all pure products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Changsheng Yao: 0000-0002-0185-2366 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support by the National Natural Science Foundation of China (Grant nos. 21242014 and 21372101), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD); TAPP.

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REFERENCES

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DOI: 10.1021/acs.joc.7b03173 J. Org. Chem. 2018, 83, 3361−3366