Synthesis of 2, 4, 5-Trisubstituted Oxazoles with Complementary

Article Cite This: J. Org. Chem. 2018, 83, 6607−6622

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Synthesis of 2,4,5-Trisubstituted Oxazoles with Complementary Regioselectivity from α‑Oxoketene Dithioacetals and β‑(Methylthio)β-(het)aryl-2-propenones Siripuram Vijay Kumar,§ Anand Acharya,§ and Hiriyakkanavar Ila* New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research(JNCASR), Jakkur, Bangalore 560064, India

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S Supporting Information *

ABSTRACT: An efficient protocol for the synthesis of 2,5-substituted 4-acyloxazoles and the related 2,4-substituted 5-acyloxazoles with complementary regioselectivity from the corresponding α-oxoketene dithioacetals or β-(het)aryl/ (methylthio)enone precursors has been reported. In the first protocol, the α-oxoketene dithioacetals or β-(methylthio)enones were converted to the corresponding α-bromo-β-(methylthio)enones followed by copper catalyzed inter/intramolecular annulation of these intermediates with various primary amides affording 2-(het)aryl/alkyl-4-(het)aroyl-5-(methylthio)/ (het)aryloxazoles via concomitant formation of the C4−N and C5−O bond via enamide intermediates. In the second approach, the starting α-oxoketene dithioacetals or β-(methylthio)-β-(het)arylenones were subjected to base induced conjugate addition− elimination with various primary amides to furnish β-aroylenamides, which, on subsequent iodine catalyzed intramolecular oxidative C−H functionalization/C−O bond formation, afforded the corresponding regioisomeric 2-(het)aryl/alkyl-4(methylthio)/(het)aryl-5-(het)aroyloxazoles in excellent yields. The methodology has also been extended for the synthesis of regioisomeric 4- or 5-aminooxazoles and 4- or 5-(n-butyl)oxazoles from the corresponding 4- or 5-(methylthio)oxazoles.

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INTRODUCTION An oxazole heterocycle represents an important structural motif, which constitutes a key substructure of several potent therapeutics and biologically active naturally occurring compounds,1 isolated from marine invertebrates and microorganisms.2 Many of the oxazole derivatives display antibacterial, antifungal, anti-inflammatory, and antitumor activities, act as enzyme inhibitors and peptidomimetics, and represent valuable synthetic targets in medicinal chemistry and pharmaceuticals.3 Oxazole derivatives have also found applications in functional materials,4 as efficient luminophores for liquids and plastic scintillators, fluorescent probes for biological systems, corrosion inhibitors, components of laser dyes, sensors, receptors, polymers, and ligands for catalysis.5 This has generated considerable interest in the synthesis of this class of heterocycles in recent years with the development of several efficient synthetic methods.6−21 The classical methods for oxazole synthesis include cyclization of acyclic precursors,6 transition metal catalyzed coupling of prefunctionalized oxazoles,6 and dehydrogenation/ dehydroelimination of oxazolines.6,7 Cyclization approaches are much more effective due to diversity of the substrates, among which, Robinson−Gabriel condensation using α-acylaminoketones and its modified versions,3a,6,8 have been frequently utilized earlier to prepare a range of highly substituted oxazoles. However, this method requires the use of Bronsted or Lewis © 2018 American Chemical Society

acid catalysts/reagents, which limits the overall functional group tolerance of the transformation. The other previously reported syntheses include the Cornforth protocol9 improved by Yokoyama,10 catalytic decomposition of diazocarbonyl compounds in the presence of nitriles or amides,11 and photolysis and pyrolysis of N-acylisoxazolones.6 Among recently reported methods, oxidative or photocatalytic [3+2] annulations of benzylamines with prefunctionalized ketones/esters have been well studied as straightforward procedures.12 Other recent examples include cycloaddition of activated methylene isocyanoacetates with α-ketoacids/esters,13a−ecatalytic enantioselective α-addition of isocyanides to alkylidene malonate,13f Pd catalyzed imidoylative cyclization of α-isocyanoacetamides,14 Cu(I) catalyzed cycloaddition of acyl azide with 1-alkynes,15 gold catalyzed three component annulations of benzylimines,16 tandem aza-Wittig reaction of acyl chloride and vinyliminophosphoranes,17 gold catalyzed formal [3+2] cycloadditions of N-ylides,18 or dioxazoles,19a or N-(pivalolyloxy)amides19b with alkynes, catalytic asymmetric carbonyl-ene reaction of β,γunsaturated α-ketoesters with 5-methyleneoxazolines,19c photoredox catalyzed three component cyclization of 2H-azirines,19d methods based on cyclization- isomerization of propargylamides,20 oxidative annulations of enaminoesters/ketones or amides in the Received: April 11, 2018 Published: May 10, 2018 6607

DOI: 10.1021/acs.joc.8b00900 J. Org. Chem. 2018, 83, 6607−6622

Article

The Journal of Organic Chemistry Scheme 1. Various Strategies for the Synthesis of Enamides and Their Conversion to Oxazoles

presence of hypervalent iodine reagents,21 oxidative [2+2+1] cycloannulation of alkynes and nitriles,22a−e and copper mediated oxidative dehydrogenative annulations of aldehydes, amines, and molecular oxygen.22f Among the various methods for oxazole synthesis, cyclization of enamide derivatives provides a facile access to oxazoles through intramolecular carbon−oxygen bond formation. These enamide precursors are generated in several ways. For example, enamides bearing the β-vinylic C-heteroatom bonds (C−Br, C−I, C−OMe) serve as stable, easily accessible starting materials, which are shown to undergo intramolecular cyclization in the presence of various organic or inorganic bases or acids to provide a broad range of oxazoles under milder conditions6,23,24 Thus, Ferreira and co-workers23a,b have reported the synthesis of β-haloenamides via sequential dehydration of N-acyl-βhydroxy amino acids and subsequent halogenations with NBS or iodine, followed by treatment with DBU to afford 2,5-disubstituted oxazole-4-carboxylates (Scheme 1, route a). On the other hand, Reissig25 has described the synthesis of 2,4-disubstituted 5-acetyloxazoles via TFA mediated cyclization of β-alkoxy-β-ketoenamides (Scheme 1, route b). Enamides have also been generated by copper catalyzed amidation of vinyl halides. Thus, Buchwald and co-workers26 have reported the synthesis of 2,4,5-trisubstituted oxazoles via copper catalyzed amidation of vinyl halides to form enamides followed by intramolecular cyclization promoted by iodine (Scheme 1, route c). Glorious and co-workers have developed the synthesis of disubstituted oxazoles via copper catalyzed annulations of 1,2-dibromoolefins with primary amides via intermediacy of β-bromoenamides (Scheme 1, route d).27 However, the reaction affords a mixture of 2,4- and 2,5-substituted oxazoles. Recently, few examples of transition metal catalyzed methods for the direct intramolecular vinylic C−H functionalization/ C−O bond formation of enamides have also been described.28 Thus, Buchwald has reported28a a copper(II) catalyzed oxidative cyclization of enamides to 2,5-disubstituted oxazoles, via vinylic C−H bond functionalization (Scheme 1, route e) as a complement to previous work.26 Stahl and co-workers28b have recently described the synthesis of a series of enamide intermediates prepared via Ru-catalyzed anti-Markonikov hydroamidation of alkynes with amide. These enamides were

subsequently converted to 2,5-disubstituted oxazoles via Cu(II) mediated oxidative cyclization in the presence of air (Scheme 1, route f). Recently Jiang and co-workers have developed an efficient one-step synthesis of trisubstituted oxazoles from amides and enolizable β-diketones involving the palladium catalyzed sequential inter- and intramolecular C−N and C−O bond formation via oxidative sp2 C−H functionalization (Scheme 1, route g).28c The synthesis of 2,5-substituted oxazoles from N-arylethylamides via iodine catalyzed intramolecular C(sp3)-H functionalization has also been reported (Scheme 1, route h).28d Substituted oxazoles have also been obtained via hypervalent iodine reagents mediated intramolecular oxidative cyclization of enamides.28f In this context, as a part of our program to develop new synthetic methods for the construction of a broad range of heterocycles, from organosulfur building blocks,29 our research group has recently reported an efficient protocol for the synthesis of 2-phenyl-5-(methylthio)-4-functionalized oxazoles 3 via nucleophilic ring opening of 4-[(bismethylthio)methylene]5-oxazolones 1A followed by silver carbonate mediated intramolecular 5-endo cyclization of the resulting functionalized enamides 2A (Scheme 2, eq 1).6a We have further elaborated the synthetic scope of this strategy by developing an efficient synthesis of 2-phenyl-5-(het)aryl-4-functionalized oxazoles 4 and related natural products via nucleophilic ring opening of 4-arylidene-5-oxazolones 1B and subsequent copper catalyzed intramolecular cyclization of enamide precursors 2B (Scheme 2, eq 2).6b During the course of these studies, we became interested in developing a [3+2] annulation approach for the synthesis of 2,4,5-trisubstituted oxazoles 5 and 6, with complementary regioselectivity from the common two carbon precursors such as α-oxoketene dithioacetals 7A30a or the corresponding β-(methylthio)-β-(het)arylenones 7B29 and primary amides 8 via intermediacy of enamides 9 and 11, respectively (Scheme 3). Our proposed strategy for the synthesis of oxazoles 5 and 6 from 7A or 7B is shown in the Scheme 3. Thus, it was envisaged to synthesize 4-acyl-5-(het)aryloxazoles 5 via copper catalyzed cross-coupling of various primary amides with 2-bromoalkenes such as 10 (generated by 2-bromination of 7 with N-bromosuccinimide) and subsequent base mediated 6608


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The Journal of Organic Chemistry Scheme 2. Previous Syntheses of Substituted Oxazoles from Enamide Precursors

Scheme 3. Present Strategy for the Synthesis of Regioisomeric Oxazoles 5 and 6

Scheme 4. Synthesis of β-(methylthio)enones 7a−l and α-bromo-β-(methylthio)enones 10a−l

Scheme 5. Synthesis of Oxazole 5a from α-Bromoenone 10a and Amide 8a

intramolecular cyclization of the resulting enamides 9 (Scheme 3). In continuation of these studies, we further conceived of developing synthesis of regioisomeric 5-acyl-4-(het)aryloxazoles 6 from the same β-(methylthio)enone precursors 7A and 7B as shown in Scheme 3. We speculated a two-step approach via base mediated conjugate addition−elimination of primary amides to β-(methylthio)enones 7 furnishing the corresponding enamide precursors 11. Subsequent intramolecular cyclization of 11 through the oxidative vinylic C−H functionalization/ C−O bond formation28 would provide the desired regioisomeric 5-acyloxazoles 6 (Scheme 3). We have successfully

achieved these goals and described, in the present paper, the efficient syntheses of 2,4,5-trisubstituted oxazoles 5 and 6 with a complementary regioselectivity from easily accessible common β-(methylthio)enone precursors 7A and 7B and primary amides.

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RESULTS AND DISCUSSION

The desired α-oxoketene dithioacetal/β-(methylthio)-β-(het)arylenone precursors 7a−l were prepared according to our earlier reported procedures in excellent yields by reacting various 6609


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The Journal of Organic Chemistry Table 1. Synthesis of 2-(Het)aryl/alkyl-4-acyl-5-(methylthio)/(het)aryloxazoles 5a−n from 10a−la

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The Journal of Organic Chemistry Table 1. continued

a

Reaction conditions: 10 (1.0 mmol), 8 (1.1 mmol), Cs2CO3 (2 mmol), CuI (0.1 mmol), and DMEDA (0.2 mmol) in toluene (5 mL) heated at 100 °C for 3−4 h.

(het)arylmethylene ketones 12 with either CS2 (for 7a−e)30a or dithioesters 13 (for 7f−l)29f in the presence of sodium hydride in DMF followed by alkylation with methyl iodide. The corresponding α-bromoketene dithioacetals (10a−e) and α-bromoβ-(methylthio)-β-(het)arylenones (10f−l) were obtained in good yields by bromination of 7a−l with NBS in CCl4 at room temperature according to our previously reported procedure (Scheme 4 and Table 1).30b In the preliminary experiments, α-bromoketene dithioacetal 10a and the amide 8a were selected as model substrates for the optimization of reaction conditions for the formation of oxazole 5a. Screening of various copper catalysts (CuCl, CuBr, CuI, Cu2O, Cu powder), ligands (L-proline, 1,10-phenanthroline, N,N′-dimethylethylenediamine), and bases (Cs2CO3, K2CO3, K3PO4) in the presence of various solvents (toluene, dioxane, DMF, DMSO) revealed that the best results were obtained using 10 mol % CuI as a catalyst and 20 mol % DMEDA as a ligand in the presence of 2 equiv of Cs2CO3 as a base in refluxing toluene, furnishing the desired 2-(4-methoxyphenyl)4-(4-methoxybenzoyl)-5-(methylthio)oxazole 5a in 90% yield (Scheme 5). As is evident from these results, the reaction appears to proceed by initial copper catalyzed intermolecular cross-coupling of α-bromoenone 10a and the amide 8a to give intermediate enamide 9a, which undergoes, in situ, base mediated intramolecular cyclization yielding oxazole 5a in a twostep, one-pot process (Scheme 5). However, our attempts to isolate enamide 9a under varying reaction conditions were not successful. With the established optimized reaction conditions in hand, we next evaluated the generality and scope of this reaction with respect to a range of substrates 10 and amides 8, these results are presented in Table 1. Thus, the reaction was found to be equally efficient with other α-aroyl (10b), (het)aroyl (10c), and ferrocenoyl (10d) ketene dithioacetals, which afforded the respective 2-aryl/alkyl-4-acyl-5-(methylthio)oxazoles 5b−d in excellent yields on copper catalyzed annulations with various substituted aromatic and aliphatic amides 8b−d (Table 1, entries 2−4). Similarly, the reaction was found to be equally effective with various 2-bromo-3-(methylthio)-3-(het)arylenones 10f−k affording the corresponding 2,5-bis(het)-

aryl-4-(het)aroyloxazoles 5f−k in excellent yields on cyclization with various primary amides 8f−k under identical conditions (entries 6−11, Table 1). Entries 5 and 7 represent the introduction of sterically incumbent pivaloyl and pyrenoyl groups at the 4-position of oxazoles 5e and 5g, respectively. Similarly it was possible to introduce a 2-alkyl- and 2-styryl group in oxazoles 5l−m by using an aliphatic amide like propionamide 8l and cinnamamide 8m, respectively, as cyclization partners (Table 1, entries 12 and 13). On the other hand, cyclization of 10i with benzyl carbamate 8n did not furnish the expected 2-benzyloxyoxazole 5n, and the product isolated was characterized as 2-hydroxyoxazole 5n′, which is apparently formed by cleavage of the benzyl group under the reaction conditions (Table 1, entry 14). The structures of these newly synthesized oxazoles 5a−n′ were confirmed with the help of spectral (1H and 13C NMR) and analytical data; besides, regiochemistry was further confirmed by X-ray crystallographic data of two of the oxazoles 5e (Figure 1) and 5j (Supporting Information).

Figure 1. ORTEP X-ray crystal structure display of 5e; ellipsoids are drawn at a 50% probability level.

Having successfully accomplished the synthesis of 2-(het)aryl/alkyl-5-(methylthio)/(het)aryl-4-acyloxazoles 5a−l (Table 1), we further conceived of synthesizing the substituted 5-acyloxazoles 6 with complementary regiochemistry at 4,5-positions (Scheme 3). 6611


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The Journal of Organic Chemistry In a model experiment as proposed in Scheme 3, we first examined the synthesis of α-(methylthio)-β-aroylenamide 11a via base mediated conjugate addition−elimination of primary amide 8a on ketene dithioacetal 7a (Scheme 6). Thus, treatment

alkylamine such as (3,4-dimethoxyphenyl)ethyl amine or secondary amine like N-benzylpiperazine, at room temperature, furnishing the corresponding 5- or 4-primary or -secondary amino substituted oxazoles 15a−b and 17a−b, respectively, in excellent yields (Scheme 8). In a further elaboration of the reaction, the 4/5-(methylthio) groups in the oxazole 5a or 6a were replaced by the n-butyl group by the treatment with n-butylmagnesium bromide in the presence of copper(I) bromide, yielding the corresponding regioisomeric 4- or 5-(n-butyl) substituted oxazoles 18a and 19a, respectively, in excellent yields (Scheme 9).

Scheme 6. Synthesis of Regioisomeric 4-(Methylthio)-5acyloxazole 6a from α-Oxoketenedithioacetal 7a and Amide 8a via Enamide Precursor 11a

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CONCLUSION We have developed an efficient protocol for the synthesis of 2,5-substituted 4-acyloxazoles 5 (Table 1) and the corresponding 2,4-substituted 5-acyloxazoles 6 (Table 2) with a complementary regioselectivity from the corresponding α-oxoketene dithioacetals or β-(het)aryl/(methylthio)enone precursors by employing two strategies. In the first approach, the α-oxoketene dithioacetals or β-(methylthio)enones were converted to the corresponding α-bromo substituted intermediates by bromination with N-bromosuccinimide. Subsequent copper catalyzed intramolecular annulations of these α-bromoenones with various primary amides afforded 2-(het)aryl/alkyl-4-(het)aroyl-5-(methylthio)/(het)aryloxazoles 5 in excellent yields via the concomitant formation of the C4−N and C5−O bond, without isolation of intermediate enamides (Table 1). In the second approach, the starting α-oxoketene dithioacetals or β-(methylthio)-β-(het)arylenones were subjected to base induced conjugate addition−elimination with various primary amides to furnish β-aroylenamides, which with a subsequent iodine catalyzed intramolecular oxidative cyclization (through C−H functionalization/C−O bond formation) afforded the corresponding regioisomeric 2-(het)aryl/alkyl-4-(methylthio)/(het)aryl-5-(het)aroyloxazoles 6 in excellent yields (Table 2). However, the latter strategy was not successful for the synthesis of a few regioisomeric oxazoles such as 6l−n (Scheme 7) because of our failure to obtain the corresponding enamides 11l−n by the base mediated conjugate addition of the related amides 8l−n to enones 7. The methodology was also extended for the synthesis of 4- or 5-aminooxazoles from the corresponding 4- or 5-(methylthio)oxazoles via the initial m-CPBA mediated oxidation of the methylthio group to the methylsulfonyl group, followed by its replacement with primary or secondary alkylamines. In a further elaboration, 4- or 5-(n-butyl)oxazoles were obtained by replacement of the methylthio group with n-butylmagnesium bromide in the presence of Cu(I) bromide. Further work to explore alternative routes for the synthesis of regioisomeric enamides such as 11l−n and to examine the scope and limitations of these methodologies for the synthesis of biologically important oxazoles is in progress in our laboratory.

of 7a with 8a in the presence of NaH as a base in DMF at 90 °C afforded the corresponding enamide 11a in 87% yield (Scheme 6). Subsequent intramolecular oxidative C−H functionalization/C−O bond formation of enamide 11a was attempted in the presence of various iodine based reagents (I2, PIDA, PIFA, DMP)28 or copper catalysts(CuBr2, CuCl2, Cu(OAc)2, Cu(OTf)2).28a,b The best results were obtained when enamide 11a was reacted with 20 mol % iodine in the presence of t-butylhydroperoxide (TBHP) (1 equiv) as a reoxidant28d in dioxane at 90 °C, furnishing the regioisomeric 2-(4-methoxyphenyl)-4-(methylthio)-5-(4-methoxybenzoyl) oxazole 6a in 85% yield (Scheme 6). The versatility of this novel protocol was established by synthesizing the other regioisomeric 4-(methylthio)-5-(het)aroyloxazoles 6b−e (Table 2, entries 2−5) in excellent yields by employing the appropriate oxoketenedithioacetals 7b−e and amides 8b−e. The oxidative C−H functionalization/C−O bond formation reaction proceeded efficiently, even when the crude enamides 11b−c were used without further purification, yielding the corresponding oxazoles 6b−c in good yields (Table 2, entries 2 and 3). Similarly, the corresponding 2,4bis(het)aryl-5-acyloxazoles 6f−k with a complementary regioselectivity were also obtained in excellent yields by iodine catalyzed intramolecular C−H functionalization/C−O bond formation of enamides 11f−k (obtained from β-methylthio-β(het)arylenones 7f−k and amides 8f−k) (Table 2, entries 6−11). The structure and regiochemistry of newly synthesized 2,4,5trisubstituted oxazoles 6a−k were confirmed with the help of the spectral and analytical data and also by X-ray crystallographic data of two of the regioisomeric oxazoles 6e (Figure 2) and 6j (Supporting Information). However, we failed to obtain the corresponding 2-ethyl-, 2-styryl-, or 2-hydroxyoxazoles 6l−n, since the base mediated addition of propionamide 8l, cinnamamide 8m, or benzyl carbamate 8n to β-(methylthio)enones 7l, 7k, and 7i, respectively, under previously reported conditions, did not afford the desired enamides 11l−n, yielding only an intractable reaction mixture (Scheme 7). The versatility of this new methodology was further demonstrated by the synthesis of regioisomeric 5- or 4-amino substituted oxazoles 15 and 17 as shown in the Scheme 8. Thus, the oxidation of 5- or 4-(methylthio)oxazoles 5c and 6c with m-CPBA in CH2Cl2 afforded the corresponding 5- or 4-(methylsulfonyl)oxazoles 14c and 16c in high yields, which were subjected to the displacement reaction by either primary

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EXPERIMENTAL SECTION

General Information. All reagents were purchased from commercial suppliers and used without further purification. Solvents were dried according to the standard procedures. All reactions were monitored by thin layer chromatography using standard TLC silica gel plates and visualized with UV light. Column chromatography was performed using silica gel (100−200 mesh). Nuclear magnetic resonance spectra were recorded on a (400 MHz) FT-NMR spectrometer with CDCl3 or DMSO-d6 as a solvent. Chemical shifts were reported in δ ppm using residual solvent protons as the internal standard (δ 7.26 for CDCl3 and δ 2.50 for DMSO-d6 in 1H NMR, δ 77.16 for CDCl3 and δ 39.52 for DMSO-d6 in 13C NMR). Coupling constants 6612


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The Journal of Organic Chemistry Table 2. Synthesis 2-(Het)aryl/alkyl-4-(methylthio)/(het)aryl-5-acyloxazoles 6a−k from 7a−kb

a Enamides 11 without further purification were used for I2 catalyzed intramolecular cyclization. bReaction conditions: 7 (1.0 mmol), 8 (1.1 mmol), and NaH (2.2 mmol) in DMF heated at 90 °C for 3−8 h and worked up; 11 (1.0 mmol), I2 (0.2 mmol), and TBHP (1.0 mmol) in dioxane heated at 90 °C for 8−10 h.

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Article

The Journal of Organic Chemistry

E/Z = 65:35); mp 110−112 °C; Rf 0.4 (2:3 EtOAc/hexane); IR (neat, cm−1) 1627, 1536, 1481, 1231, 1016, 738; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 3.2 Hz, 0.35H), 7.95 (d, J = 3.2 Hz, 0.65H), 7.62 (d, J = 3.2 Hz, 0.65H), 7.60 (d, J = 3.2 Hz, 0.35H), 7.50 (s, 0.65H), 7.22 (s, 0.35H), 6.92−6.81 (m, 3H), 6.02 (s, 1.3H), 5.99 (s, 0.7H), 2.53 (s, 1.05H), 2.09 (s, 1.95H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.9, 177.1, 170.6, 169.7, 167.2, 166.1, 148.8, 148.6, 147.9, 147.5, 144.5, 144.4, 132.3, 131.3, 126.0, 125.9, 122.4, 122.2, 118.1, 111.9, 109.2, 108.9, 108.5, 108.2, 101.7, 101.5, 17.1, 16.9; HRMS (ESI-QTOF) m/z [M + Na]+ calcd for C14H11NO3S2Na 328.0078, found 328.0062. (E/Z)-1-(Benzo[d][1,3]dioxol-6-yl)-3-(4-(dimethylamino)phenyl)3-(methylthio)prop-2-en-1-one (7i): yellow solid (255 mg, 75%, E/Z = 80:20); mp 126−128 °C; Rf 0.5 (2:3 EtOAc/hexane); IR (neat, cm−1) 1602, 1506, 1248, 806; 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 1.6 Hz, 0.8H), 7.49 (d, J = 1.6 Hz, 0.8H), 7.47 (d, J = 1.6 Hz, 0.2H), 7.34 (d, J = 1.6 Hz, 0.2H), 7.25 (d, J = 8.8 Hz, 1.8H), 6.99 (s, 0.8H), 6.82 (d, J = 8.0 Hz, 0.8H), 6.76 (d, J = 8.0 Hz, 0.4H), 6.73 (d, J = 8.8 Hz, 1.6H), 6.59 (d, J = 8.8 Hz, 0.4H), 6.41 (s, 0.2H), 6.01 (s, 1.6H), 5.98 (s, 0.4H), 3.01 (s, 4.8H), 2.95 (1.2H), 2.41 (s, 0.6H), 2.04 (s, 2.4H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.8, 186.8, 164.6, 161.1, 151.3, 151.0, 150.9, 148.2, 147.9, 134.3, 134.1, 130.1, 129.5, 126.6, 124.8, 124.5, 123.8, 118.6, 114.6, 111.8, 111.4, 108.6, 108.3, 107.9, 107.7, 101.8, 101.7, 40.4, 40.3, 17.2, 16.6; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C19H20NO3S 342.1164, found 342.1158. (E/Z)-1-(4-(Trifluoromethyl)phenyl)-3-(4-methoxyphenyl)-3(methylthio)prop-2-en-1-one (7j): yellow solid (288 mg, 82%, E/Z = 68:32); mp 73−75 °C; Rf 0.5 (1:4 EtOAc/hexane); IR (neat cm−1) 1603, 1495, 1319, 1248, 1065, 809; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1.32H), 7.78 (d, J = 8.0 Hz, 0.68H), 7.61 (d, J = 8.4 Hz, 1.32H), 7.50 (d, J = 8.0 Hz, 0.68H), 7.20 (d, J = 8.8 Hz, 1.32H), 7.16 (d, J = 8.8 Hz, 0.68H), 6.97 (s, 0.66H), 6.89 (d, J = 8.8 Hz, 1.32H), 6.70 (d, J = 8.8 Hz, 0.68H), 6.41 (s, 0.34H), 3.77 (s, 1.98H), 3.67 (s, 1.02H), 2.37 (s, 1.02H), 1.93 (s, 1.98H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.1, 187.1, 166.9, 163.2, 160.9, 160.5, 142.3, 141.8, 134.0, 133.6, 133.3, 133.0, 131.0, 130.3, 129.5, 128.8, 128.4, 125.7, 125,65 125.61, 125.60, 125.34, 125.31, 125.27, 125.24, 122.5, 118.5, 115.3, 114.2, 113.8, 55.5, 55.3, 17.0, 16.6; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H16F3O2S 353.0823, found 353.0819. (E/Z)-3-(1-Methyl-1H-indol-3-yl)-3-(methylthio)-1-(pyridin-3-yl)prop-2-en-1-one (7k): brown semisolid (246 mg, 80%, E/Z = 70:30) Rf 0.4 (2:3 EtOAc/hexane); IR (neat, cm−1) 2920, 1507, 1233, 1017, 741; 1H NMR (400 MHz, CDCl3) δ 9.18 (d, J = 1.6 Hz, 0.7H), 8.97 (d, J = 1.6 Hz, 0.3H), 8.72 (dd, J = 4.8, 1.6 Hz, 0.7H), 8.52 (dd, J = 4.8 Hz, 1.6H), 8.28 (dt, J = 8.0, 1.6 Hz, 0.7H), 7.96 (dt, J = 8.0, 1.6 Hz, 0.3H), 7.80 (d, J = 8.0 Hz, 0.7H), 7.45 (dt, J = 8.0 Hz, 0.8H), 7.41−7.37 (m, 1.7H), 7.33−7.29 (m, 1.4H), 7.24−7.16 (m, 2.0H), 7.14−7.07 (m, 0.6H), 6.54 (s, 0.3H), 3.86 (s, 2.1H), 3.72 (s, 0.9H), 2.52 (s, 0.9H), 2.19 (s, 2.1H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.2, 188.7, 150.9, 149.2, 149.1, 148.2, 136.9, 134.6, 134.2, 133.1, 132.1, 126.0, 123.5, 122.7, 122.0, 121.7, 121.5, 121.4, 120.8, 120.2, 119.2, 112.2, 111.6, 109.6, 33.0, 31.7, 16.7, 16.4; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C18H17N2OS 309.1062, found 309.1055. 4-((Z)-3-(Methylthio)-3-(pyridin-3-yl)acryloyl)benzonitrile (7l): yellow solid (196 mg, 70%); mp 116−118 °C; Rf 0.3 (3:7 EtOAc/ hexane); IR (neat, cm−1) 2924, 2231, 1623, 1521, 1254, 814; 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 8.61 (dd, J = 2.4, 0.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.67 (dt, J = 7.6, 2.0 Hz, 1H), 7.41 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 7.03 (s, 1H), 2.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 163.5, 150.5, 148.4, 141.6, 135.6, 134.5, 132.6, 128.5, 123.5, 119.3, 118.2, 115.8, 16.9; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C16H13N2OS 281.0749, found 281.0744. 1-(Benzo[d][1,3]dioxol-6-yl)-2-bromo-3,3-bis(methylthio)prop-2en-1-one (10b): obtained from 7b, semisolid (328 mg, 95%); Rf 0.5 (1:9 EtOAc/hexane); IR (neat, cm−1) 2920, 1644, 1562, 1457, 1274, 745; 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 8.0, 1.6 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.06 (s, 2H), 2.46

Figure 2. ORTEP X-ray crystal structure display of 6e; ellipsoids are drawn at a 50% probability level.

Scheme 7. Attempted Synthesis of 2-Alkyl/styryl/ hydroxyoxazoles 6l−n

were reported as J values in hertz (Hz). Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), dd (double doublet), dt (doublet of triplet), td (triplet of doublet), ddd (doublet of doublet of doublet), m (multiplet), and br (broad). Infrared spectra of neat samples were recorded in ATR (attenuated total reflectance) mode using a FT-IR instrument and HRMS on a Q-TOF spectrometer. Melting points were recorded using an electrothermal capillary melting point apparatus and are uncorrected. All the (het)aryl dithioesters were prepared according to the literature procedure.31 All amides 8a−l and 8n were purchased commercially except cinnamamide 8m, which was prepared according to the literature procedure.32 The desired α-oxoketene dithioacetal/β-(methylthio)-β-(het)arylenone precursors 7a−l29f,30a and the corresponding α-bromo derivatives 10a−l30b were prepared according to our earlier reported procedures. The spectral and analytical data of the new α-oxoketene dithioacetal/β-(methylthio)-β-(het)arylenone precursors 7g−l and the corresponding new α-bromo derivatives 10b−l are given below. Since 10h and 10i were found to be unstable, they were used as such for the next step without further purification. (E/Z)-3-(3,4,5-Trimethoxyphenyl)-3-(methylthio)-1-(pyren-1-yl)prop-2-en-1-one (7g): yellow solid (398 mg, 85%, E/Z = 55:45); mp 135−137 °C; Rf 0.5 (3:2 EtOAc/hexane); IR (neat, cm−1) 1579, 1411, 1243, 1118, 840; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 9.2 Hz, 0.55H), 8.54 (d, J = 9.2 Hz, 0.45H), 8.30 (d, J = 8.0 Hz, 0.55H), 8.24−8.21 (m, 1.1H), 8.20−8.09 (m, 3.0H), 8.07−8.03 (m, 1.35H), 8.01−7.97 (m, 1.1H), 7.90 (t, J = 8.0 Hz, 0.9H), 7.16 (s, 0.55H), 6.61 (s, 1.1H), 6.55 (s, 0.45H), 6.22 (s, 0.9H), 3.89 (s, 3.3H), 3.89 (s, 1.65H), 3.43 (s, 2.7H), 2.96 (s, 1.35H), 2.49 (s, 1.35H), 2.11 (s, 1.65H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.1, 192.6, 164.1, 161.4, 153.5, 152.1, 138.6, 138.2, 135.0, 134.7, 134.2, 133.4, 132.7, 132.4, 131.3, 131.2, 130.9, 130.7, 129.5, 129.3, 129.1, 128.9, 128.7, 127.3, 127.1, 126.8, 126.5, 126.4, 126.3, 126.2, 126.1, 126.0, 125.8, 125.2, 125.1, 124.8, 124.6, 124.5, 124.4, 124.3, 123.7, 122.2, 106.3, 105.6, 61.1, 60.2, 56.5, 55.7, 16.9, 16.7; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C29H25O4S 469.1474, found 469.1467. (E/Z)-3-(Benzo[d][1,3]dioxol-5-yl)-2-bromo-3-(methylthio)-1(thiazol-2-yl)prop-2-en-1-one (7h): yellow solid (244 mg, 80%, 6614


Article

The Journal of Organic Chemistry Scheme 8. Synthesis of 4- or 5-Primary and -Secondary Amino Substituted Oxazoles

(316 mg, 90%, E/Z = 70:30); mp 93−95 °C; Rf 0.7 (1:4 EtOAc/ hexane); IR (neat, cm−1) 2925, 1646, 1458, 1249, 1016, 754; 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 0.3H), 7.47 (d, J = 8.8 Hz, 0.7H), 7.43 (s, 0.7H), 7.32 (d, J = 8.8 Hz, 0.3H), 7.11 (d, J = 8.8 Hz, 1.4 H), 7.00 (d, J = 3.6 Hz, 0.6H), 6.96 (d, J = 8.8 Hz, 0.6H), 6.74 (d, J = 8.8 Hz, 1.4H), 6.59 (dd, J = 2.8, 1.2 Hz, 0.3H), 6.36 (dd, J = 2.8, 1.2 Hz, 0.7H), 3.85 (s, 0.9H), 3.72 (s, 2.1H), 1.94 (s, 2.1H), 1.85 (s, 0.9H); 13 C{1H} NMR (100 MHz, CDCl3) δ 178.4, 178.0, 160.3, 160.1, 150.8, 148.8, 147.8, 147.3, 143.0, 131.9, 130.9, 130.8, 128.3, 127.5, 120.6, 120.3, 114.1, 114.0, 112.8, 112.4, 110.9, 110.2, 55.4, 55.3, 17.3, 16.3; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C15H14BrO3S 352.9847 and 354.9827, found 352.9843 and 354.9829. (E)-2-Bromo-3-(3,4,5-trimethoxyphenyl)-3-(methylthio)-1-(pyren1-yl)prop-2-en-1-one (10g): obtained from 7g, yellow solid (464 mg, 85%); mp 122−124 °C; Rf 0.5 (1:1 EtOAc/hexane); IR (neat, cm−1) 1647, 1582, 1230, 1132, 745; 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 13.6 Hz, 1H), 8.18 (t, J = 7.2 Hz, 2H), 8.11 (d, J = 3.2 Hz, 1H), 8.08 (d, J = 3.2 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.98 (m, 3H), 5.87 (s, 2H), 3.34 (s, 6H), 2.51 (s, 3H), 1.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.7, 164.6, 156.6, 153.2, 140.0, 134.8, 133.8, 131.7, 131.3, 131.0, 130.9, 130.8, 129.9, 129.6, 129.5, 129.3, 127.4, 126.6, 126.5, 126.3, 126.0, 125.1, 124.7, 124.6, 124.5, 116.4, 116.2, 110.3, 105.1, 61.1, 56.4; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C29H24BrO4S 547.0579 and 549.0558, found 547.0567 and 549.0547. (E/Z)-2-Bromo-1-(4-(trifluoromethyl)phenyl)-3-(4-methoxyphenyl)-3-(methylthio) prop-2-en-1-one (10j): obtained from 7j, off-white solid (377 mg, 88%, E/Z = 60:40); mp 115−117 °C; Rf 0.5 (2:3 EtOAc/hexane); IR (neat, cm−1) 1669, 1604, 1321, 1248, 1125, 858; 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 0.4H), 7.77 (d, J = 8.0 Hz, 0.4H), 7.70 (d, J = 8.8 Hz, 1.6H), 7.53−7.49 (m, 2H), 7.01− 6.98 (m, 2H), 6.66 (d, J = 8.8 Hz, 1.6H), 3.86 (s, 0.6 H), 3.68 (s, 2.4H), 1.95 (s, 2.4H), 1.80 (s, 0.6H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.9, 189.0, 160.5, 160.4, 151.6, 143.1, 139.7, 138.2, 134.3, 133.9, 133.6, 133.3, 130.95, 130.93, 129.8, 129.6, 127.8, 127.3, 126.0, 125.93, 125.90, 125.86, 125.22, 125.19, 125.15, 125.11, 125.0, 122.3, 114.2, 111.6, 55.5, 55.3, 17.1, 16.4; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C18H15BrF3O2S 430.9928 and 432.9908, found 430.9924 and 432.9906. (E)-2-Bromo-3-(1-methyl-1H-indol-3-yl)-3-(methylthio)-1-(pyridin-3-yl)prop-2-en-1-one (10k): obtained from 7k, yellow solid (347 mg, 90%); mp 120−122 °C; Rf 0.5 (2:3 EtOAc/hexane); IR (neat, cm−1) 1630, 1504, 1257, 738; 1H NMR (400 MHz, CDCl3)

Scheme 9. Synthesis of 4- or 5-(n-Butyl)oxazoles

(s, 3H), 2.17 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.6, 152.7, 148.5, 137.7, 129.2, 126.9, 118.0, 108.9, 108.1, 102.1, 18.9, 16.3; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C12H12BrO3S2 346.9411 and 348.9391, found 346.9415 and 348.9394. 2-Bromo-1-(furan-2-yl)-3,3-bis(methylthio)prop-2-en-1-one (10c): obtained from 7c, off-white solid (283 mg, 97%); mp 259− 261 °C; Rf 0.6 (1:9 EtOAc/hexane); IR (neat, cm−1) 1640, 1436, 1258, 1031, 784; 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 1.6, 0.8 Hz, 1H), 7.19 (dd, J = 3.6, 0.8 Hz, 1H), 6.57 (dd, J = 3.6, 1.6 Hz, 1H), 2.46 (s, 3H), 2.21 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.2, 150.7, 148.0, 140.3, 120.5, 116.3, 112.8, 19.3, 16.5; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C9H10BrO2S2 292.9306 and 294.9285, found 292.9311 and 294.9290. 2-Bromo-(ferrocen-1-yl)-3,3-bis(methylthio)prop-2-en-1-one (10d): obtained from 7d, brown solid (336 mg, 82%); mp 259− 261 °C; Rf 0.5 (1:4 EtOAc/hexane); IR (neat, cm−1) 1590, 1500, 1353, 1120, 702; 1H NMR (400 MHz, CDCl3) δ 4.77 (t, J = 2.0 Hz, 2H), 4.58 (t, J = 2.0 Hz, 2H), 4.29 (s, 5H), 2.43 (s, 3H), 2.15 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 195.0, 138.1, 118.8, 72.9, 71.0, 70.2, 18.9, 16.5; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C15H16BrFeOS2 410.9175 and 412.9155, found 410.9150 and 412.9148 2-Bromo-4,4-dimethyl-1,1-bis(methylthio)pent-1-en-3-one (10e): obtained from 7e, colorless liquid (253 mg, 90%); Rf 0.6 (1:4 EtOAc/ hexane); IR (neat, cm−1) 2968, 1689, 1477, 1100, 751; 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 2.23 (s, 3H), 1.29 (s, 9H); 13 C{1H} NMR (100 MHz, CDCl3) δ 206.3, 134.0, 118.7, 43.9, 28.5, 18.9, 16.2; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C9H16BrOS2 282.9826 and 284.9805, found 282.9832 and 284.9811. (E/Z)-2-Bromo-1-(furan-2-yl)-3-(4-methoxyphenyl)-3(methylthio)prop-2-en-1-one (10f): obtained from 7f, off-white solid 6615


Article

The Journal of Organic Chemistry δ 8.54 (d, J = 1.6 Hz, 1H), 8.13 (dd, J = 4.8, 1.6 Hz, 1H), 7.66−7.64 (m, 1H), 7.47 (dt, J = 8.0, 2.0 Hz, 1H), 7.18−7.15 (m, 2H), 7.02−7.00 (m, 1H), 6.82 (s, 1H), 6.66 (dd, J = 7.6, 4.8 Hz, 1H), 3.53 (s, 3H), 2.09 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.2, 150.9, 149.2, 149.1, 136.9, 134.6, 133.1, 132.1, 125.9, 123.4, 121.7, 121.5, 120.2, 112.2, 111.6, 109.6, 32.9, 16.7; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C18H16BrN2OS 387.0167 and 389.0146, found 387.0163 and 389.0144. 4-((E)-2-Bromo-3-(methylthio)-3-(pyridin-3-yl)acryloyl)benzonitrile (10l): obtained from 7l, off-white solid (303 mg, 85%); mp 130−132 °C; Rf 0.5 (3:7 EtOAc/hexane); IR (neat, cm−1) 2926, 2230, 1658, 1256, 748; 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 0.33H), 8.68 (d, J = 4.0 Hz, 0.33H), 8.46 (d, J = 4.0 Hz, 0.67H), 8.36 (s, 0.67H), 8.08 (d, J = 8.4 Hz, 0.66H), 7.87 (dt, J = 12.0, 2.0 Hz, 0.33H), 7.82 (d, J = 8.4 Hz, 0.66H), 7.76 (d, J = 8.4 Hz, 1.34H), 7.62 (d, J = 8.4 Hz, 1.34H), 7.48 (dt, J = 12.0, 2.0 Hz, 0.67H), 7.44 (dd, J = 7.6, 4.8 Hz, 0.33H), 7.18 (dd, J = 7.6, 4.8 Hz, 0.67H), 1.96 (s, 2.01H), 1.85 (s, 0.99H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.5, 188.2, 150.5, 150.1, 149.3, 148.2, 140.5, 139.5, 138.2, 136.8, 136.6, 132.8, 132.3, 131.5, 129.9, 129.8, 123.7, 123.4, 117.9, 117.8, 117.1, 116.5, 114.3, 113.1, 17.3, 16.4; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C16H12BrN2OS 358.9854 and 360.9833, found 358.9842 and 360.9823. General Procedure for the Synthesis of 2-(Het)aryl/alkyl-4acyl-5-(het)aryloxazoles 5a−n′. To a stirring solution of α-bromo derivatives 10a−l (1.0 mmol) and the corresponding amides 8a−n (1.0 mmol) in toluene (5 mL) were added CuI (0.1 mmol, 19 mg), DMEDA (0.2 mmol, 17 mg), and Cs2CO3 (2.0 mmol, 650 mg) under a N2 atmosphere, and the reaction mixture was heated at 90 °C (monitored by TLC). It was then diluted with saturated a NH4Cl solution (25 mL) and extracted with EtOAc (3 × 25 mL), and the combined organic layer was washed with water (3 × 25 mL) and brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using EtOAc/hexane as an eluent. (4-Methoxyphenyl)(2-(4-methoxyphenyl)-5-(methylthio)oxazol4-yl)methanone (5a): obtained from 10a and amide 8a, off-white solid (320 mg, 90%); mp 104−105 °C; Rf 0.4 (1:4 EtOAc/hexane); IR (neat, cm−1) 2963, 1598, 1467, 1250, 760; 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 7.00−6.97 (m, 4H), 3.88 (s, 3H), 3.87 (s, 3H), 2.69 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 184.2, 163.4, 161.7, 159.8, 156.7, 136.0, 132.8, 130.2, 128.1, 119.6, 114.4, 113.6, 55.53, 55.51, 14.4; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C19H18NO4S 356.0957, found 356.0949. (2-tert-Butyl-5-(methylthio)oxazol-4-yl)(benzo[d][1,3]dioxol-5yl)methanone (5b): obtained from 10b and amide 8b, pale yellow solid (287 mg, 90%); mp 106−108 °C; Rf 0.4 (1:9 EtOAc/hexane); IR (neat, cm−1) 2965, 1581, 1480, 1249, 850; 1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 8.4, 1.6 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.03 (s, 2H), 2.60 (s, 3H), 1.42 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 183.5, 169.3, 156.9, 151.5, 147.7, 134.3, 131.7, 127.1, 110.3, 107.9, 101.7, 34.2, 28.5, 14.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C16H18NO4S 320.0957, found 320.0953. (Furan-2-yl)(5-(methylthio)-2-phenyloxazol-4-yl)methanone (5c): obtained from 10c and amide 8c, off-white solid (236 mg, 83%); mp 130−132 °C; Rf 0.5 (1:9 EtOAc/hexane); IR (neat, cm−1) 1608, 1498, 856, 762; 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 3.6, 0.8 Hz, 1H), 8.05−8.02 (m, 2H), 7.71 (dd, J = 1.6, 0.8 Hz, 1H), 7.50−7.48 (m, 3H), 6.61 (dd, J = 3.6, 1.6 Hz, 1H), 2.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 160.0, 157.3, 151.3, 147.3, 134.4, 130.9, 129.1, 126.7, 126.4, 121.9, 112.3, 14.2; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C15H12NO3S 286.0538, found 286.0526. (2-(3-(Trifluoromethyl)phenyl)-5-(methylthio)oxazol-4-yl)(ferrocen-1-yl)methanone (5d): obtained from 10d and amide 8d, maroon solid (381 mg, 81%); mp 190−192 °C; Rf 0.4 (1:4 EtOAc/ hexane); IR (neat, cm−1) 1606, 1495, 1119, 695; 1H NMR (400 MHz, CDCl3) δ 8.28−8.25 (m, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 5.47 (t, J = 2.0 Hz, 2H), 4.62 (t, J = 2.0 Hz, 2H), 4.19

(s, 5H), 2.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.3, 158.1, 156.0, 136.4, 131.9, 129.7, 129.3, 127.9, 127.1 (J = 3.6 Hz), 123.0, 122.9, 78.4, 72.8, 71.5, 70.2, 14.3; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H17F3FeNO2S 472.0282, found 472.0291. 1-(2-(4-Chlorophenyl)-5-(methylthio)oxazol-4-yl)-2,2-dimethylpropan-1-one (5e): obtained from 10e and amide 8e, off-white solid (247 mg, 80%); mp 97−99 °C; Rf 0.7 (1:4 EtOAc/hexane); IR (neat, cm−1) 2926, 1645, 1482, 1087, 835; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 2.67 (s, 3H), 1.41 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.5, 157.8, 157.1, 136.7, 134.6, 129.3, 127.5, 125.5, 43.8, 26.5, 14.1; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C15H17ClNO2S 310.0669 and 312.0639, found 310.0668 and 312.0637. (2-(2-Chlorophenyl)-5-(4-methoxyphenyl)oxazol-4-yl)(furan-2yl)methanone (5f): obtained from 10f and amide 8f, yellow solid (333 mg, 88%); mp 153−155 °C; Rf 0.4 (1:4 EtOAc/hexane); IR (neat, cm−1) 1634, 1493, 1179, 855, 766; 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 9.2 Hz, 2H), 8.19 (dd, J = 3.2, 0.4 Hz, 1H), 8.14−8.11 (m, 1H), 7.72 (dd, J = 1.2, 0.4 Hz, 1H), 7.58−7.56 (m, 1H), 7.43−7.42 (m, 2H), 7.01 (d, J = 9.2 Hz, 2H), 6.62 (dd, J = 3.2, 1.2 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.1, 161.7, 156.2, 156.1, 152.3, 147.4, 132.9, 132.8, 131.7, 131.6, 130.9, 130.4, 127.2, 125.5, 122.9, 119.8, 114.1, 112.5, 55.6; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C21H15ClNO4 380.0690 and 382.0660, found 380.0674 and 382.0652. (2-(4-Fluorophenyl)-5-(3,4,5-trimethoxyphenyl)oxazol-4-yl)(pyren-1-yl)methanone (5g): obtained from 10g and amide 8g, yellow solid (462 mg, 83%); mp 192−194 °C; Rf 0.4 (2:3 EtOAc/ hexane); IR (neat, cm−1) 1498, 1128, 929, 840; 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 9.6 Hz, 1H), 8.28−8.26 (m, 2H), 8.23 (d, J = 3.2 Hz, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.09−8.04 (m, 4H), 7.40 (s, 2H), 7.16−7.11 (m, 2H), 3.82 (s, 3H), 3.78 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.6, 164.6 (1JC−F = 250 Hz), 158.2, 155.3, 153.3, 140.3, 136.4, 133.8, 133.0, 130.9, 130.3, 129.6, 129.4, 129.2, 128.3, 127.3, 126.5, 126.4, 126.1, 125.0, 124.9, 124.6, 123.8, 123.0, 122.6, 116.4, 116.1, 105.8, 61.1, 56.3; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C35H25FNO5 558.1717, found 558.1699. (2-(Benzo[b]thiophen-2-yl)-5-(benzo[d][1,3]dioxol-5-yl)oxazol-4yl)(thiazol-2-yl)methanone (5h): obtained from 10h and amide 8h, pale yellow solid (367 mg, 85%); mp 179−180 °C; Rf 0.5 (3:7 EtOAc/ hexane); IR (neat, cm−1) 2212, 1609, 1467, 1202, 813; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 7.89−7.86 (m, 2H), 7.81 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.45−7.40 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.06 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 156.6, 154.8, 150.3, 148.1, 144.9, 141.0, 139.5, 133.0, 128.4, 126.9, 126.5, 125.8, 125.3, 125.0, 124.0, 122.7, 120.6, 108.7, 108.5, 101.9; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C22H13N2O4S2 433.0317, found 433.0310. (Benzo[d][1,3]dioxol-5-yl)(2-(4-bromophenyl)-5-(4(dimethylamino)phenyl)oxazol-4-yl)methanone (5i): obtained from 10i and amide 8i, yellow solid (343 mg, 70%): Rf 0.6 (1:4 EtOAc/ hexane); IR (neat, cm−1) 2920, 1609, 1482, 1249, 767; 1H NMR (400 MHz, CDCl3) δ 8.01−7.96 (m, 4H), 7.87 (dd, J = 8.4, 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.8 Hz, 2H), 6.05 (s, 2H), 3.04 (s, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ 186.6, 156.7, 156.5, 151.7, 151.6, 147.8, 132.9, 132.6, 132.2, 129.4, 128.1, 127.4, 126.1, 125.0, 114.8, 111.6, 110.5, 107.9, 101.8, 40.2; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C25H20BrN2O4 491.0606 and 493.0586, found 491.0609 and 493.0579. (4-(Trifluoromethyl)phenyl)(2-(furan-2-yl)-5-(4-methoxyphenyl)oxazol-4-yl)methanone (5j): obtained from 10j and amide 8j, offwhite solid (351 mg, 85%); mp 140−142 °C; Rf 0.5 (1:4 EtOAc/ hexane); IR (neat, cm−1) 2932, 1605, 1358, 764; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.61 (dd, J = 1.6, 0.8 Hz, 1H), 7.14 (dd, J = 3.2, 0.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.58 (dd, J = 3.2, 1.6 Hz, 1H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.4, 161.8, 155.8, 6616


Article

The Journal of Organic Chemistry 151.3, 145.2, 142.1, 140.9, 134.2, 133.8, 133.2, 130.8, 130.1, 125.3 (q, J = 3.6 Hz), 119.5, 114.2, 112.9, 112.2, 55.6; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H15F3NO4 414.0953, found 414.0947. (5-(1-Methyl-1H-indol-3-yl)-2-(thiophen-2-yl)oxazol-4-yl)(pyridin3-yl)methanone (5k): obtained from 10k and amide 8k, yellow solid (346 mg, 90%); mp 133−135 °C; Rf 0.4 (3:7 EtOAc/hexane); IR (neat, cm−1) 1643, 1603, 1386, 880, 705; 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 9.16 (s, 1H), 8.78 (s, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.34 (t, J = 4.8 Hz, 1H), 7.84 (d, J = 3.2 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.47−7.36 (m, 4H), 7.19 (t, J = 4.0 Hz, 1H), 3.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.4, 155.9, 153.3, 152.4, 151.8, 137.8, 137.4, 135.1, 134.4, 131.8, 129.4, 128.8, 128.3, 128.26, 126.1, 123.43, 123.13, 122.1, 121.8, 110.3, 33.8; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H16N3O2S 386.0963, found 386.0960. 4-(2-Ethyl-5-(pyridin-3-yl)oxazole-4-carbonyl)benzonitrile (5l): obtained from 10l and amide 8l, off-white solid (248 mg, 82%); mp 82−83 °C; Rf 0.4 (3:7 EtOAc/hexane); IR (neat, cm−1) 2231, 1660, 1345, 902, 775; 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.68 (d, J = 4.0 Hz, 1H), 8.50 (dt, J = 8.4, 1.6 Hz, 1H), 8.26 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.42 (dd, J = 8.0, 4.8 Hz, 1H), 2.93 (q, J = 7.6 Hz, 2H), 1.43 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.6, 164.5, 153.5, 151.2, 148.9, 140.9, 135.4, 134.7, 132.1, 131.0, 123.88, 123.4, 118.3, 116.2, 21.8, 11.2 HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C18H14N3O2 304.1086, found 304.1076. (E)-(5-(1-Methyl-1H-indol-3-yl)-2-styryloxazol-4-yl)(pyridin-3-yl)methanone (5m): obtained from 10k and amide 8m, off-white solid (319 mg, 79%); mp 125−127 °C; Rf 0.39 (1:4 EtOAc/hexane); IR (neat, cm−1) 2231, 1660, 1345, 902, 775; 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 9.16 (s, 1H), 8.78 (d, J = 3.6 Hz, 1H), 8.54 (dt, J = 8.0, 2.0 Hz, 1H), 8.35 (dd, J = 4.8, 3.2 Hz, 1H), 7.66−7.61 (m, 3H), 7.46−7.37 (m, 7H), 7.04 (d, J = 15.6 Hz, 1H), 3.93 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 185.6, 156.9, 156.1, 152.2, 151.6, 137.8, 137.4, 136.7, 135.5, 135.2, 134.6, 132.1, 129.5, 129.1, 127.4, 126.1, 123.4, 123.2, 122.1, 121.1, 113.5, 110.3, 103.7, 33.8; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C26H20N3O2 406.1556, found 406.1561. Benzo[d][1,3]dioxol-5-yl(5-(4-(dimethylamino)phenyl)-2-hydroxyoxazol-4-yl)methanone (5n′): obtained from 10i and amide 8n, yellow solid (275 mg, 78%); mp 172−174 °C; Rf 0.2 (3:7 EtOAc/ hexane); IR (neat, cm−1) 2231, 1660, 1345, 902, 775; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz, 2H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 6.05 (s, 2H), 3.08 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.5, 183.0, 153.4, 150.9, 148.2, 131.4, 130.7, 129.2, 122.7, 122.4, 111.2, 108.3, 107.2, 101.8, 91.1, 40.2; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C19H17N2O5 353.1127, found 353.1121. Synthesis of (Z)-4-Methoxy-N-(3-(4-methoxyphenyl)-1-(methylthio)-3-oxoprop-1-en-1-yl)benzamide (11a) from Ketene Dithioacetal 7a and Amide 8a. To a stirring solution of oxoketenedithioacetal 7a (1.0 mmol, 254 mg) and amide 8a (1.0 mmol, 151 mg) in DMF (5 mL) was added NaH (60% emulsion in paraffin) (2.0 mmol, 80 mg), and the reaction mixture was heated at 90 °C (monitored by TLC). It was then cooled to room temperature, diluted with a saturated NH4Cl solution (25 mL), and extracted with EtOAc (3 × 25 mL), and the combined organic layer was washed with water (3 × 25 mL) and brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using EtOAc/hexane as an eluent to get pure 11a: off-white solid (310 mg, 87%); mp 91−93 °C; Rf 0.4 (2:3 EtOAc/ hexane); IR (neat, cm−1) 1677, 1558, 1227, 1020, 756; 1H NMR (400 MHz, CDCl3) δ 14.94 (s, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.11 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.2, 165.8, 164.3, 163.4, 163.1, 132.0, 130.3, 129.8, 125.1, 114.3, 114.0, 94.7, 55.59, 55.57, 15.8; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C19H19NO4S 358.1113, found 358.1096. The remaining enamides 11b−e and 11f−k were also prepared by the above general procedure for 11a from the corresponding S,Sacetals 7b−e or β-(methylthio)propenones 7f−k and theamides 8b−k.

The spectral and analytical data for 11d−f and 11i−k are given below, whereas the enamides 11b−c and 11g−h were used as such for the next step without further purification. (Z)-N-(3-Ferrocenyl-1-(methylthio)-3-oxoprop-1-en-1-yl)-3(trifluoromethyl)benzamide (11d): obtained from 7d and amide 8d, reddish-brown solid (381 mg, 81%); mp 212−214 °C; Rf 0.5 (1:4 EtOAc/hexane); IR (neat, cm−1) 1684, 1559, 1425, 1100, 740; 1 H NMR (400 MHz, CDCl3) δ 14.90 (s, 1H), 8.38 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 5.77 (s, 1H), 4.83 (t, J = 1.6 Hz, 2H), 4.56 (t, J = 2.0 Hz, 2H), 4.21 (s, 5H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.2, 164.7, 160.5, 133.9, 131.9, 131.6, 130.7, 129.7, 129.2 (J = 3.6 Hz), 126.0, 125.9, 125.1, 122.4, 97.5, 81.0, 72.6, 70.4, 69.3, 15.8; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H17F3FeNO2S 472.0282, found 472.0259. (Z)-4-Chloro-N-(4,4-dimethyl-1-(methylthio)-3-oxopent-1-en-1yl)benzamide (11e): obtained from 7e and amide 8e, off-white solid (245 mg, 79%); mp 87−89 °C; Rf 0.6 (1:9 EtOAc/hexane); IR (neat, cm−1) 2964, 1683, 1558, 1418, 1012, 843; 1H NMR (400 MHz, CDCl3) δ 14.59, (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 5.70 (s, 1H), 2.36 (s, 3H), 1.22 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.7, 165.1, 163.2, 139.3, 131.2, 129.6, 129.3, 94.7, 43.3, 27.6, 15.7; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C15H19ClNO2S 312.0825 and 314.0796, found 312.0818 and 314.0790. (Z)-2-Chloro-N-(3-(furan-2-yl)-1-(4-methoxyphenyl)-3-oxoprop1-en-1-yl)benzamide (11f): obtained from 7f and amide 8f, pale yellow solid (289 mg, 76%); mp 151−153 °C; Rf 0.5 (1:4 EtOAc/ hexane); IR (neat, cm−1) 1710, 1575, 1451, 1231, 1048, 796; 1H NMR (400 MHz, CDCl3) δ 12.41 (s, 1H), 7.71 (dd, J = 7.2, 2.0 Hz, 1H), 7.59 (dd, J = 1.6, 0.8 Hz, 1H), 7.56 (d, J = 9.2 Hz, 2H), 7.47 (dd, J = 8.0, 1.2 Hz, 1H), 7.41 (td, J = 7.6, 1.6 Hz, 1H), 7.35 (td, J = 7.6, 1.6 Hz, 1H), 7.22 (dd, J = 3.6, 0.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.55 (dd, J = 3.6, 1.6 Hz, 1H), 6.38 (s, 1H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.8, 165.4, 161.5, 155.6, 153.7, 146.5, 135.0, 132.1, 132.0, 130.9, 130.0, 129.4, 127.9, 127.3, 116.8, 113.9, 112.8, 104.9, 55.5; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C21H17ClNO4 382.0846 and 384.0817, found 382.0848 and 384.0813. (Z)-N-(3-(Benzo[d][1,3]dioxol-5-yl)-1-(4-(dimethylamino)phenyl)3-oxoprop-1-en-1-yl)-4-bromobenzamide (11i): obtained from 7i and amide 8i, yellow solid (378 mg, 77%); mp 192−194 °C; Rf 0.5 (1:4 EtOAc/hexane); IR (neat, cm−1) 1692, 1562, 1419, 1152, 780; 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 9.2 Hz, 2H), 7.56 (dd, J = 8.4, 1.6 Hz, 1H), 7.44 (d, J = 2.0, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 9.2 Hz, 2H), 6.64 (s, 1H), 6.04 (s, 2H), 3.07 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.4, 182.9, 153.4, 150.9, 148.2, 131.4, 130.7, 129.2, 122.6, 122.4, 111.2, 110.8, 108.3, 107.2, 101.8, 91.1, 40.2; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C25H22BrN2O4 493.0763 and 495.0742, found 493.0756 and 495.0739. (Z)-N-(1-(4-Methoxyphenyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)furan-2-carboxamide (11j): obtained from 7j and amide 8j, off-white solid (303 mg, 73%); mp 181−183 °C; Rf 0.4 (1:4 EtOAc/hexane); IR (neat, cm−1) 2916, 1694, 1584, 1481, 1315, 1066, 747; 1H NMR (400 MHz, CDCl3) δ 13.17, s, 1H), 8.0 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.69 (dd, J = 1.6, 0.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.27 (dd, J = 3.6, 0.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.58 (dd, J = 3.6, 1.6 Hz, 1H), 6.38 (s, 1H), 3.86 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 190.4, 161.6, 157.2, 156.3, 147.7, 146.0, 141.9, 129.5, 128.3, 128.0, 125.8 (q, J = 3.6 Hz), 125.2, 122.5, 117.4, 113.8, 112.8, 104.5, 55.5; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H17F3NO4 416.1110, found 416.1105. (Z)-N-(1-(1-Methyl-1H-indol-3-yl)-3-oxo-3-(pyridin-3-yl)prop-1en-1-yl)thiophene-2-carboxamide (11k): obtained from 7k and amide 8k, brown solid (290 mg, 75%); mp 196−198 °C; Rf 0.2 (3:7 EtOAc/hexane); IR (neat, cm−1) 1687, 1589, 1456, 1339, 1228, 748; 1 H NMR (400 MHz, CDCl3) δ 13.72 (s, 1H), 9.22 (dd, J = 2.0, 0.8 Hz, 1H), 8.74 (dd, J = 4.8, 2.4 Hz, 1H), 8.27 (dt, J = 8.0, 1.6 Hz, 1H), 8.05 (dd, J = 3.6, 1.2 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.63 (dd, J = 5.2, 0.8 Hz, 1H), 7.41 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.37−7.36 (m, 1H), 7.30 (dt, J = 4.8, 0.8 Hz, 1H), 7.27−7.23 6617


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1H), 7.73 (dd, J = 1.6, 0.8 Hz, 1H), 7.57 (dd, J = 7.6, 1.6 Hz, 1H), 7.50−7.41 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.63 (dd, J = 3.6, 1.6 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.8, 161.4, 159.8, 151.4, 148.8, 147.7, 142.5, 133.0, 132.4, 132.3, 131.5, 131.4, 127.3, 125.7, 122.9, 120.7, 113.8, 112.6, 55.5; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C21H14ClNO4 380.0690 and 382.0660, found 380.0684 and 382.0659. (2-(4-Fluorophenyl)-4-(3,4,5-trimethoxyphenyl)oxazol-5-yl)(pyren-1-yl)methanone (6g): obtained from crude 11g, pale yellow solid (306 mg, 55%); mp 203−205 °C; Rf 0.45 (2:3 EtOAc/hexane); IR (neat, cm−1) 2942, 1583, 1498, 1228, 1124, 845; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 9.6 Hz, 1H), 8.26 (t, J = 8.0 Hz, 2H), 8.20−8.17 (m, 2H), 8.15−8.03 (m, 6H), 7.44 (s, 2H), 7.11 (t, J = 4.8 Hz, 2H), 3.76 (s, 3H), 3.71 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.3, 163.8 (1JC−F = 214 Hz), 152.9, 149.5, 144.8, 139.7, 133.7 132.7, 130.9, 130.1, 130.0, 129.8, 129.7, 129.5, 127.5, 127.3, 126.9, 126.5, 126.3, 125.9, 124.9, 124.5, 124.3, 124.0, 122.6, 116.5, 116.3, 107.5, 106.8, 60.9, 56.1; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C35H25FNO5 558.1717, found 558.1712. (2-(Benzo[b]thiophen-2-yl)-4-(benzo[d][1,3]dioxol-6-yl)oxazol-5yl)(thiazol-2-yl) methanone (6h): obtained from 11h, yellow solid (388 mg, 90%); mp 208−210 °C; Rf 0.6 (3:7 EtOAc/hexane); IR (neat, cm−1) 2923, 1584, 1447, 1248, 1040, 834, 744; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.94 (dd, J = 8.4, 1.6 Hz, 1H), 7.92−7.89 (m, 2H), 7.85 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.45−7.41 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.04 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.1, 166.5, 159.1, 151.6, 149.8, 147.8, 145.4, 141.8, 141.7, 139.5, 128.4, 127.9, 126.9, 126.2, 125.4, 125.3, 125.0, 124.2, 122.8, 110.0, 108.3, 101.6; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H13N2O4S2 433.0317, found 433.0312. (Benzo[d][1,3]dioxol-6-yl)(2-(4-bromophenyl)-4-(4(dimethylamino)phenyl)oxazol-5-yl)methanone (6i): obtained from 11i, yellow solid (416 mg, 85%); mp 187−189 °C; Rf 0.7 (1:4 EtOAc/ hexane); IR (neat, cm−1) 1600, 1472, 1257, 760; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 4.4 Hz, 1H), 7.48 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 6.06 (s, 2H), 3.02 (s, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ 181.3, 160.6, 151.7, 151.6, 149.5, 148.1, 142.5, 132.6, 132.4, 130.7, 128.9, 126.3, 126.1, 125.8, 118.1, 111.6, 109.6, 108.0, 101.9, 40.3; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C25H20BrN2O4 491.0606 and 493.0586, found 491.0600 and 493.0583. (4-(Trifluoromethyl)phenyl)(2-(furan-2-yl)-4-(4-methoxyphenyl)oxazol-5-yl)methanone (6j): obtained from 11j, pale yellow solid (363 mg, 88%); mp 172−174 °C; Rf 0.6 (1:4 EtOAc/hexane); IR (neat, cm−1) 1622, 1495, 1315, 852, 765; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.66 (dd, J = 1.6, 0.8 Hz, 1H), 7.25 (dd, J = 3.6, 0.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.61 (dd, J = 3.6, 1.6 Hz, 1H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 181.4, 161.6, 154.6, 150.1, 146.2, 142.1, 141.0, 131.3, 129.9, 125.4 (q, J = 3.6 Hz), 122.6, 115.1, 113.8, 112.6, 55.5; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H15F3NO4 414.0953, found 414.0957. (4-(1-Methyl-1H-indol-3-yl)-2-(thiophen-2-yl)oxazol-5-yl)(pyridin3-yl)methanone (6k): obtained from 11k, brown solid (354 mg, 92%); mp 180−182 °C; Rf 0.45 (3:7 EtOAc/hexane); IR (neat, cm−1) 1629, 1575, 1514, 1326, 1082, 879, 744; 1H NMR (400 MHz, CDCl3) δ 9.30 (dd, J = 2.4, 0.8 Hz, 1H), 9.06 (s, 1H), 8.80−8.76 (m, 2H), 8.31 (dt, J = 8.0, 2.0 Hz, 1H), 7.86 (dd, J = 3.6, 1.2 Hz, 1H), 7.58 (dd, J = 4.8, 1.2 Hz, 1H), 7.46 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.38−7.31 (m, 3H), 7.18 (dd, J = 5.2, 3.6 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.8, 158.8, 152.4, 150.4, 148.6, 141.4, 137.5, 136.7, 135.1, 134.5, 130.9, 130.5, 129.1, 128.5, 127.6, 123.4, 123.2, 122.9, 121.5, 109.7, 105.9, 33.6; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H16N3O2S 386.0963, found 386.0962. General Procedure for Synthesis of 5/4-(Methylsulfonyl)oxazoles 14c and 16c. m-CPBA (1.1 mmol, 190 mg) was added to a stirring solution of oxazole (5c or 6c) (1.0 mmol) in DCM (5 mL), and the reaction mixture was stirred at ambient temperature

(m, 1H), 7.21 (dd, J = 5.2, 4.0 Hz, 1H), 6.67 (s, 1H), 3.83 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ189.5, 160.5, 153.0, 152.6, 149.1, 139.7, 137.4, 135.2, 134.8, 133.6, 132.7, 130.7, 128.4, 126.4, 123.6, 122.9, 121.9, 120.6, 110.4, 109.8, 101.5, 33.5; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C22H18N3O2S 388.1120, found 388.1117. General Procedure for the Synthesis of 2-(Het)aryl/alkyl-5acyl-4-(het)aryloxazoles 6a−k. To a stirring solution of enamide 11a−k in 1,4-dioxane (5 mL) were added iodine (0.2 mmol, 56 mg) and TBHP (70% aq solution, 1.0 mmol), and the reaction mixture was heated at 80 °C (monitored by TLC). It was then cooled to room temperature, diluted with a saturated NH4Cl solution (25 mL), and extracted with EtOAc (3 × 25 mL), and the combined organic layer was washed with water (3 × 25 mL) and brine, dried (Na2SO4), and concentrated under reduced pressure. The crude oxazoles were purified by silica gel column chromatography using EtOAc/hexane as an eluent. (4-Methoxyphenyl)(2-(4-methoxyphenyl)-4-(methylthio)oxazol5-yl)methanone (6a): obtained from 11a, off-white solid (301 mg, 85%); mp 112−114 °C; Rf 0.5 (1:4 EtOAc/hexane); IR (neat, cm−1) 2925, 1583, 1476, 1253, 740; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 7.03−7.00 (m, 4H), 3.90 (s, 3H), 3.88 (s, 3H), 2.69 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 178.5, 163.3, 162.7, 162.4, 152.6, 131.6, 130.0, 129.7, 129.4, 119.0, 114.6, 113.9, 55.6, 55.59, 14.2; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C19H18NO4S 356.0957, found 356.0956. (2-tert-Butyl-4-(methylthio)oxazol-5-yl)(benzo[d][1,3]dioxol-6yl)methanone (6b): obtained from crude 11b, off-white solid (284 mg, 89%); mp 140−142 °C; Rf 0.5 (1:9 EtOAc/hexane); IR (neat, cm−1) 2965, 1480, 1245, 836, 740; 1H NMR (400 MHz, CDCl3) δ7.78 (dd, J = 8.0, 1.2 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.05 (s, 2H), 2.61 (s, 3H), 1.45 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.1, 172.8, 151.5, 151.3, 148.1, 143.3, 131.2, 125.5, 109.3, 108.2, 101.9, 34.5, 28.6, 14.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C16H18NO4S 320.0957, found 320.0952. (Furan-2-yl)(4-(methylthio)-2-phenyloxazol-5-yl)methanone (6c): obtained from 11c, pale yellow solid (230 mg, 81%); mp 151−153 °C; Rf 0.4 (1:9 EtOAc/hexane); IR (neat, cm−1) 1619, 1511, 1461, 1236, 858; 1H NMR (400 MHz, CDCl3) δ 8.18−8.15 (m, 2H), 7.74 (dd, J = 1.6, 0.4 Hz, 1H), 7.61 (dd, J = 3.6, 0.4 Hz, 1H), 7.57−7.51 (m, 3H), 6.65 (dd, J = 3.6, 1.6 Hz, 1H), 2.71 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.2, 162.5, 152.6, 150.8, 147.3, 142.1, 132.2, 129.2, 127.6, 126.3, 119.3, 112.4, 14.0; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C15H12NO3S 286.0538, found 286.0528. (Ferrocen-1-yl)(4-(methylthio)-2-(3-(trifluoromethyl)phenyl)oxazol-5-yl)methanone (6d): obtained from crude 11d, red solid (362 mg, 77%); mp 172−174 °C; Rf 0.65 (1:4 EtOAc/hexane); IR (neat, cm−1) 1592, 1504, 1335, 1130, 692; 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 5.20 (t, J = 2.0 Hz, 2H), 4.66 (t, J = 2.0 Hz, 2H), 4.20 (s, 5H), 2.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 183.2, 159.9, 149.9, 144.0, 132.2, 131.9, 131.6, 130.2, 130.0, 128.2 (q, J = 3.6 Hz), 127.5, 125.1, 124.2, 124.19, 122.4, 77.8, 72.9, 70.4, 70.3, 14.1; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H17F3FeNO2S 472.0282, found 472.0292. 1-(2-(4-Chlorophenyl)-4-(methylthio)oxazol-5-yl)-2,2-dimethylpropan-1-one (6e): obtained from 11e, white solid (262 mg, 85%); mp 118−120 °C; Rf 0.7 (1:9 EtOAc/hexane); IR (neat, cm−1) 2925, 1636, 1471, 1086, 836, 733; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 2.65 (s, 3H), 1.38 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.7, 160.4, 151.8, 142.7, 138.2, 129.5, 128.6, 124.9, 42.9, 26.4, 14.0; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C15H17ClNO2S 310.0669 and 312.0639, found 310.0664 and 312.0632. (2-(2-Chlorophenyl)-4-(4-methoxyphenyl)oxazol-5-yl)(furan-2yl)methanone (6f): obtained from 11f, off-white solid (303 mg, 80%); mp 120−122 °C; Rf 0.5 (1:9 EtOAc/hexane); IR (neat, cm−1) 1630, 1456, 1247, 858, 738; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz, 2H), 8.21 (dd, J = 7.6, 1.6 Hz, 1H), 7.83 (dd, J = 3.6, 0.8 Hz, 6618


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(4-(4-Benzylpiperazin-1-yl)-2-phenyloxazol-5-yl)(furan-2-yl)methanone (17b): obtained from oxazole 16c, yellow semisolid (247 mg, 60%); Rf 0.45 (2:3 EtOAc/hexane); IR (neat, cm−1) 1615, 1541, 1466, 1267, 953, 849, 752; 1H NMR (400 MHz, CDCl3) δ 8.10 (m, 2H), 7.67 (dd, J = 1.6, 0.4 Hz, 1H), 7.54−7.51 (m, 3H), 7.45 (dd, J = 3.6, 0.8 Hz, 1H), 7.36−7.27 (m, 5H), 6.61 (dd, J = 3.6, 1.6 Hz, 1H), 3.92 (t, J = 4.8 Hz, 4H), 3.60 (s, 2H), 2.64 (t, J = 4.8 Hz, 4H); 13 C{1H} NMR (100 MHz, CDCl3) δ 165.9, 161.2, 157.0, 152.2, 146.0, 132.1, 130.1, 129.5, 129.1, 129.0, 128.4, 127.7, 127.4, 126.5, 117.4, 112.0, 63.1, 53.0, 48.6; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C25H23N3O3 414.1818, found 414.1815. General Procedure for the Synthesis of 5/4-(n-Butyl)oxazoles 18a−19a from 5/4-(Methylthio)oxazoles 5a−6a. To a solution of 5/4-(methylthio)oxazoles 5a or 6a (1.0 mmol, 355 mg) in THF (3 mL) was added CuBr (1.0 mmol, 142 mg), and the mixture was cooled to 0 °C. A solution of freshly prepared n-butylmagnesium bromide (1.0 mmol, 160 mg) in 2 mL of THF was added dropwise to the reaction mixture at 0 °C, followed by stirring at the same temperature for 3 h (monitored by TLC). It was then diluted with a saturated NH4Cl solution (25 mL) and extracted with EtOAc (3 × 25 mL), and the combined organic layer was washed with water (3 × 25 mL) and brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using EtOAc/hexane as an eluent. (5-Butyl-2-(4-methoxyphenyl)oxazol-4-yl)(4-methoxyphenyl)methanone (18a): obtained from oxazole 5a, off-white solid (0.335 mg, 92%); mp 83−85 °C; Rf 0.5 (1:4 EtOAc/hexane); IR (neat, cm−1) 2930, 1595, 1501, 1250, 1168, 1027, 909; 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 4H), 3.88 (s, 3H), 3.86 (s, 3H), 3.13 (t, J = 7.6 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H), 1.45 (q, J = 7.6 Hz, 2H), 0.96 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 163.3, 161.5, 160.2, 158.4, 135.2, 132.8, 130.6, 128.1, 119.8, 114.2, 113.4, 55.4, 55.36, 29.9, 26.3, 22.4, 13.8; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H24NO4 366.1705, found 366.1695. (4-Butyl-2-(4-methoxyphenyl)oxazol-5-yl)(4-methoxyphenyl)methanone (19a): obtained from oxazole 6a, colorless liquid (310 mg, 85%); Rf 0.6 (1:4 EtOAc/hexane); IR (neat, cm−1) 2929, 1591, 1251, 1162, 1023, 833; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.03−6.96 (m, 4H), 3.90 (s, 3H), 3.87 (s, 3H), 2.99 (t, J = 8.0 Hz, 2H), 1.76 (quin, J = 8.0 Hz, 2H), 1.46 (q, J = 8.0 Hz, 2H), 0.95 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 181.1, 163.3, 162.2, 161.7, 153.2, 144.3, 131.7, 130.3, 130.1, 129.9, 129.0, 119.3, 114.4, 114.1, 113.8, 113.7, 55.5, 55.4, 30.6, 27.7, 22.6, 13.9; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C22H24NO4 366.1705, found 366.1704.

(monitored by TLC). It was then diluted with water (25 mL) and extracted with DCM (3 × 25 mL), and the combined organic layer was washed with saturated NaHCO3 (3 × 25 mL), water (3 × 25 mL), and brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography using EtOAc/hexane as an eluent. (Furan-2-yl)(5-(methylsulfonyl)-2-phenyloxazol-4-yl)methanone (14c): obtained from oxazole 5c, off-white solid (301 mg, 95%); mp 179−181 °C; Rf 0.45 (2:3 EtOAc/hexane); IR (neat, cm−1) 1645, 1460, 1331, 1147, 861, 714; 1H NMR (400 MHz, CDCl3) δ 8.19−8.17 (m, 2H), 8.04 (d, J = 3.6 Hz, 1H), 7.79 (t, J = 0.8 Hz, 1H), 7.62−7.52 (m, 3H), 6.67 (dd, J = 3.6, 1.6 Hz, 1H), 3.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 162.2, 151.0, 149.9, 149.1, 140.9, 132.8, 129.3, 127.7, 125.2, 124.6, 113.0, 44.2; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C15H12NO5S 318.0436, found 318.0436. (Furan-2-yl)(4-(methylsulfonyl)-2-phenyloxazol-5-yl)methanone (16c): obtained from oxazole 6c, white solid (285 mg, 90%); mp 171−173 °C; Rf 0.4 (2:3 EtOAc/hexane); IR (neat, cm−1) 1637, 1461, 1315, 1148, 717; 1H NMR (400 MHz, CDCl3) δ 8.20−8.17 (m, 2H), 7.83 (dd, J = 1.6, 0.4 Hz, 1H), 7.64 (dd, J = 3.6, 0.4 Hz, 1H), 7.61− 7.53 (m, 3H), 6.72 (dd, J = 4.0, 1.6 Hz, 1H), 3.48 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.1, 161.8, 150.8, 149.2, 146.2, 146.0, 132.9, 129.4, 127.8, 125.1, 122.5, 113.3, 43.0; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C15H12NO5S 318.0436, found 318.0432. General Procedure for the Synthesis of 4/5-Amino Substituted Oxazoles 15a−b and 17a−b. A solution of 5/4(methylsulfonyl)oxazole 14c (or 16c) (1.0 mmol) and corresponding amine (1.1 mmol) in DMF (3 mL) was heated at 90 °C (monitored by TLC). It was then diluted with a saturated NH4Cl solution (25 mL) and extracted with EtOAc (3 × 25 mL), and the combined organic layer was washed with water (3 × 25 mL) and brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using EtOAc/hexane as an eluent. (5-(3,4-Dimethoxyphenethylamino)-2-phenyloxazol-4-yl)(furan2-yl)methanone (15a): obtained from oxazole 14c, yellow solid (0.384 mg, 92%); mp 120−122 °C; Rf 0.4 (2:3 EtOAc/hexane); IR (neat, cm−1) 3308, 1634, 1480, 1233, 1021, 765; 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 3.6, 0.4 Hz, 1H), 7.91 (dd, J = 8.4, 2.0 Hz, 2H), 7.86 (t, J = 6.0 Hz, 1H), 7.64 (dd, J = 1.6, 0.8 Hz, 1H), 7.46−7.40 (m, 3H), 6.80 (s, 2H), 6.74 (s, 1H), 6.58 (dd, J = 3.2, 1.6 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.80 (q, J = 6.8 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.5, 161.9, 151.3, 149.6, 149.3, 148.1, 145.9, 130.7, 129.9, 128.8, 126.9, 125.8, 120.9, 119.6, 113.5, 112.2, 112.0, 111.8, 56.0, 44.9, 36.4; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C24H23N2O5 419.1607, found 419.1601. (5-(4-Benzylpiperazin-1-yl)-2-phenyloxazol-4-yl)(furan-2-yl)methanone (15b): obtained from oxazole 14c, yellow solid (396 mg, 96%); mp 143−145 °C; Rf 0.4 (2:3 EtOAc/hexane); IR (neat, cm−1) 1615, 1541, 1466, 1267, 849, 752; 1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 3.6, 0.8 Hz, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 2H), 7.64 (dd, J = 1.6, 0.8 Hz, 1H), 7.46−7.40 (m, 3H), 7.34−7.31 (m, 4H), 7.29−7.27 (m, 1H), 6.57 (dd, J = 3.2, 1.6 Hz, 1H), 3.83 (t, J = 4.8 Hz, 4H), 3.58 (s, 2H), 2.65 (t, J = 4.8 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 159.8, 152.7, 149.8, 145.9, 137.7, 129.9, 129.3, 128.9, 128.4, 127.4, 127.0, 125.7, 120.2, 115.7, 111.9, 63.1, 52.7, 48.4; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C25H23N3O3 414.1818, found 414.1812. (4-(3,4-Dimethoxyphenethylamino)-2-phenyloxazol-5-yl)(furan2-yl)methanone (17a): obtained from oxazole 16c, yellow semisolid (271 mg, 65%); Rf 0.45 (2:3 EtOAc/hexane); IR (neat, cm−1) 3340, 2920, 1634, 1511, 1231, 1143, 1027, 754; 1H NMR (400 MHz, CDCl3) δ 8.16−8.14 (m, 2H), 7.68 (dd, J = 1.6, 0.8 Hz, 1H), 7.56− 7.51 (m, 3H), 7.45 (dd, J = 3.6, 0.4 Hz, 1H), 7.11 (t, J = 6.0 Hz, 1H), 6.84−6.77 (m, 3H), 6.61 (dd, J = 3.6, 2.0 Hz, 1H), 3.86 (q, J = 4.0 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 2.93 (t, J = 6.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 162.7, 158.4, 150.9, 149.1, 147.8, 145.9, 132.2, 131.5, 129.0, 128.7, 127.8, 126.5, 120.9, 116.9, 112.2, 112.0, 111.6, 56.0, 55.9, 44.5, 36.5; HRMS (ESI-Q-TOF) m/z [M + H]+ calcd for C24H23N2O5 419.1607, found 419.1602.

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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.8b00900. Copies of 1H NMR and 13C NMR spectra for newly synthesized compounds 7g−l, 10b−g, 10j−l, 5a-n′, 11a, 11d−f, 11i−k, 6a−k, 14c, 16c, 15a−b, 17a−b, 18a, and 19a and ORTEP X-ray crystal structures (PDF) Crystallographic data for 5e, 5j, 6e, and 6j (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hiriyakkanavar Ila: 0000-0002-6971-8374 Author Contributions §

S.V.K. and A.A. contributed equally to this work

Notes

The authors declare no competing financial interest. 6619


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ACKNOWLEDGMENTS We thank Professor C. N. R. Rao, FRS, for encouragement and support of our research; JNCASR and the Council of Scientific and Industrial Research (CSIR, New Delhi) for financial assistance; and CSIR−SRF (to S.V.K. and A.A.) and JNCASR for the Hindustan Lever Research Professorship (to H.I.).

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