Selective Synthesis of Multifunctionalized 2,3-Dihydroinden-1-ones

Article Cite This: J. Org. Chem. 2018, 83, 8971−8983

pubs.acs.org/joc

Selective Synthesis of Multifunctionalized 2,3-Dihydroinden-1-ones and 1,3-Dihydroisobenzofurans from the Reaction of o‑Alkynylbenzaldehydes with Imines Steered by N‑Heterocyclic Carbene/Copper(II) and N‑Heterocyclic Carbene/Base Cascade Catalysis J. Org. Chem. 2018.83:8971-8983. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 08/17/18. For personal use only.

Ya-Li Ding, Shi-Ning Li, and Ying Cheng* College of Chemistry, Beijing Normal University, Beijing 100875, China S Supporting Information *

ABSTRACT: We report in this paper the N-heterocyclic carbene/transition metal and N-heterocyclic carbene/base cascade catalysis in the reaction of o-alkynylbenzaldehydes with N-acylimines, demonstrating the example of reaction pathways steered by catalysts. Under the catalysis of a thiazole carbene/Et3N followed by Cu(OAc)2 in acetonitrile at ambient temperature, oalkynylbenzaldehydes underwent reaction with N-acylimines that were generated in situ from N-((aryl)(tosyl)methyl)amides to produce a pair of Z- and E-2-amido-3-benzylidene-1-indanones in 47−92% total yields. The reaction of the same substrates in the presence of a thiazole carbene and Cs2CO3, on the other hand, afforded (1E,3Z)-1-amidobenzylidene-3-benzylidene-1,3dihydroisobenzofurans in 54−89% yields.

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INTRODUCTION 1-Indanone scaffold occurs widely in natural products and pharmaceutically active substances.1 1-Indanone derivatives have been demonstrated to have a broad spectrum of pharmacological activities including anticancer,2a,b anti-Alzheimer’s disease,2c antiinflammatory2d and antimicrobial2e activities (Figure 1). Due to their biological, pharmaceutical and synthetic importance, the synthesis of 1-indanones and their derivatives has attracted great attention.1−7 The known methods for the construction of 1-indanone core include the acid-catalyzed intramolecular Friedel−Craft acylation of 3arylpropanoic acids and their derivatives,3 the transition metalcatalyzed intramolecular hydroacylation of o-alkenyl aromatic aldehydes4 and carbonylative cyclization of o-holagenstyrenes,5 the acid or metal-promoted intramolecular cyclization of chalcone derivatives,6 and the [2 + 2 + 2] cyclotrimerization of alkynes,7 etc. Noticeably, these methods generally provide the relatively simple indanone compounds. Further chemical manipulations are often required to synthesize the biological and pharmacological active 1-indanone derivatives.1 Therefore, the development of efficient approaches to the multifunctionalized 1-indanones with particularly unsaturated groups amenable to further transformations represents an unconquered and challenging task for organic chemists. © 2018 American Chemical Society

On the other hand, 1,3-dihydroisobenzofuran nucleus is also present in a large number of natural products and synthetic compounds with various biological activities. Some 1,3dihydroisobenzofuran derivatives, for instance, are able to inhibit cholinesterase,8a cancer cell proliferation8b and peptide deformylase,8c and act as antimicrobial8c and antidepression agents8d (Figure 2). Moreover, 1,3-dihydroisobenzofuran derivatives, especially the 3-alkylidene-1,3-dihydroisobenzofurans, are also versatile building blocks in organic synthesis. For example, they have been used to construct functionalized phenanthrofurans,9a isoquinolinones,9b and chroman spiroketals.9c As a result, a variety of strategies for the synthesis of 1,3dihydroisobenzofurans have been developed. Most of the known methods are based on the transition metal-catalyzed cyclization reactions of prefunctionalized substrates.10−14 For example, Au- and Pd-catalyzed cyclization of o-alkynylbenzyl alcohols,10 Ag-catalyzed cyclization of o-alkynylacetophenones,11 Pd-catalyzed cyclization of o-alkynyl arylaldehydes and arylketones,12 Rh-catalyzed tandem reactions of 2-triazolearylaldehydes and -arylketones,13 Pd-catalyzed tandem reaction between bispropargyl ethers with 3-iodocyclohex-2-enones14a and Cu-catalyzed cyanoalkylative cycloetherification of alkeReceived: May 7, 2018 Published: June 12, 2018 8971

DOI: 10.1021/acs.joc.8b01163 J. Org. Chem. 2018, 83, 8971−8983

Article

The Journal of Organic Chemistry

Figure 1. Examples of biologically active 1-indanone derivatives.

Figure 2. Examples of biologically active 1,3-dihydroisobenzofuran derivatives.

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nes14b have been documented in literature. Some metal-free syntheses of 1,3-dihydroisobenzofurans, like I2/base-catalyzed cyclization of o-alkynylbenzyl alcohols,15a chiral phosphoric acid- and squaramide-catalyzed reactions of o-formylchalcones with boronates15b,c have also been reported. In view of the importance of 1,3-dihydroisobenzofuran motif in organic and medicinal chemistry, the development of highly efficient, regioand steroselective reactions for the construction of multifunctionalized 1,3-dihydroisobenzofurans employing costeffective catalysts is highly desirable. In recent decades, the strategies of cascade, relay and sequential catalysis have been attracting ever increasing attention as it can enable the development of unprecedented and diverse transformations that are not conceivable under the conditions using a single catalyst.16 We have been interested for many years in the development of new multicatalytic systems involving N-heterocyclic carbenes (NHC) because of their unique catalytic activity.17 We have achieved the divergent synthesis of complex molecules from simple starting materials using N-heterocyclic carbene catalysts in combination with Lewis acid, Brønsted bases or transition metal.18 Since the NHCs are able to catalyze azabenzoin reactions,19 we envisioned that, in the presence of other different catalysts, the (α-amidoalkyl)arylketones derived from the NHC-catalyzed azabenzoin reaction of o-alkynyl benzaldehydes with Nacylimines would undergo subsequent intramolecular O-, Cor N-addition to alkynyl group to form 1,3-dihydroisobenzofuran, 1-indanone or 2,3-dihydroisoquinolin-4-one derivatives, respectively (Scheme 1). We report herein the study on the cascade catalysis for the reactions between o-alkynyl benzaldehydes and N-acylimines, demonstrating the example of catalyst-regulated selectivie synthesis of highly functionalized 1-indanone and 1,3-dihydroisobenzofuran derivatives.

RESULTS AND DISCUSSION We commenced our study by investigating the reaction of 2(phenylethynyl)benzaldehyde 1a with N-benzoyl(phenylmethan)imine 2a′, which was generated in situ from the treatment of N-(phenyl(tosyl)methyl)benzamide 2a with a base. First, as a prelude to explore the cascade catalytic reaction, N-heterocyclic carbene catalysts were screened to trigger the azabenzoin reaction of aldehyde 1a with 2a. A series of heterocyclic azolium salts including imidazolium 3a, imidazolinium 3b, triazoliums 3c−3f and thiazolium salts 3g−3i were employed as NHC precursors. In the presence of DIPEA (1.5 equiv) in acetonitrile at ambient temperature, the imidazolium, imidazolinium and triazoliums 3a−3f were found to be virtually ineffective toward the azabenzoin reaction of 1a with 2a. On the contrary, the thiazoliums 3g−3i (20 mol %) were able to promote this reaction to give 2-benzamido-2phenyl-1-(2-(phenylethynyl)phenyl)ethanone 4aa in 10−57% yields. The highest yield of 4aa was obtained from the reaction catalyzed by thiazolium salt 3i (Scheme 2). Having optimized Scheme 2. Screening of NHC Catalysts

thiazolium salt 3i as the proper NHC precatalyst for the azabenzoin reaction of o-alkynyl benzaldehydes with Nacylimines, we then surveyed the transition metal-catalyzed transformation of o-alkynylphenyl-α-amidoketone 4aa. Since Cu(II), Pd(II), Pd(0) and Ag(I) catalysts are known to catalyze the intramolecular addition of N- and O-atom of amides or α-C- and O-atom of ketones to alkynyl groups,20 Cu(OAc)2, Pd(OAc)2, PdCl2, Pd(PPh3)4 Pd(OAc)2(PPh3)2, Pd(OAc)2/Ag2CO3 and AgOTf were tested to promote the transformation of 4aa. We were delighted to discover that the reaction of 4aa catalyzed by Cu(OAc)2 and DIPEA produced a pair of Z/E-2-benzamido-3-benzylidene-1-indanones 5aa and

Scheme 1. Proposed Cascade Catalysis for the Reactions between o-Alkynyl Benzaldehydes and N-Acylimines

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The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditions for the Synthesis of 1-Indanone Derivatives from 2(Phenylethynyl)benzaldehyde and N-Benzoylimine

yield (%)a entry c

1 2c 3c 4c 5c 6c 7c 8c 9c 10c 11d 12e 13e 14e 15e 16e 17e 18e 19e 20e 21e 22e 23e 24e 25e 26e

3 (mol %) 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i 3i

(20) (10) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30) (30)

base (equiv) DIPEA (1.5) DIPEA (1.5) DIPEA (1.5) DIPEA (2) DIPEA (2.5) DIPEA (3) DABCO (2.5) Et3N (2.5) DBU (2.5) Cs2CO3 (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5) Et3N (2.5)

CuLn (mol %) Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

(50) (50) (50) (50) (50) (50) (50) (50)

Cu(OAc)2 (50) Cu(OAc)2 (50) Cu(OAc)2 (30) Cu(OAc)2 (100) Cu(OTf)2 (50) CuBr2 (50) Cu(acac)2 (50) CuI (50) Cu(CH3CN)4BF4 (50) Cu(OAc)2 (50) Cu(OAc)2 (50) Cu(OAc)2 (50) Cu(OAc)2 (50) Cu(OAc)2 (50) Cu(OAc)2 (50) Cu(OAc)2 (50)

solvent

temp (°C)

T1/T2 (h)

5aa

6aa

7aa

5aa:6aab

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF dioxane DCM DMF CH3CN CH3CN CH3CN

25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 0 50 reflux

24/2 24/2 24/2 12/2 12/2 12/2 12/2 12/2 12 12 12/2 12/2 12/2 12/2 12/2 12/2 12/2 12/2 12/2 12/2 12/2 12/2 12/2 12/2 12/2 12/2

30 17 39 34 46 41 31 52 − − 52 56 11 55 29 28 mess − − 18 17 30 35 19 55 44

17 13 26 24 34 18 23 36 − − 34 36 8 35 19 23

− − − − − − − − 42f 64 − − − − − −

1.8:1 1.3:1 1.5:1 1.4:1 1.4:1 1.5:1 1.4:1 1.4:1

1.5:1 1.6:1 1.4:1 1.5:1 1.5:1 1.2:1

− − 13 7 24 21 11 34 33

− − − − − − − −

1.4:1 2.4:1 1.3:1 1.7:1 1.7:1 1.6:1 1.3:1

a Isolated yields. bThe ratios of 5aa/6aa were calculated on the basis of the isolated yields of 5aa and 6aa. c1a/2a = 1/1. d1a/2a = 1/1.5. e1a/2a = 1.5/1. fThe intermediate 4aa was isolated in 8% yield.

catalyst. The resulting mixture was kept stirring for another 2 h at room temperature. As summarized in Table 1, the reaction of 1a with 2a catalyzed sequentially by thiazolium 3i (20 mol %)/DIPEA (1.5 equiv) and Cu(OAc)2 (50 mol %) in acetonitrile at 25−30 °C produced a pair of Z- and E-2benzamido-3-benzylidene-1-indanones 5aa and 6aa in 30% and 17% yields, respectively. X-ray diffraction analysis confirmed that the products 5aa and 6aa were respectively Z- and E-stereoisomers (see Supporting Information). Increasing the loading of thiazolium 3i to 30 mol % improved the yields to 39% (5aa) and 26% (6aa). Lower yields were obtained when 10 mol % of NHC catalyst was used (Table 1, entries 1−3). The change of the loading of DIPEA from 1.5 to 2, 2.5, and 3 equiv also caused the variation of chemical yields, with the highest yields of 5aa (46%) and 6aa (34%) being achieved from the reaction utilizing 2.5 equiv of DIPEA (Table 1, entries 3−6). It was worth noting that the type of the base used in this cascade catalysis was crucial not only to the efficiency but also to the regioselectivity as well. For example, replacement of DIPEA by Et3N increased the yields of 1indanones 5aa and 6aa to 52% and 36%, respectively, while the use of DABCO instead led to reduced yields (Table 1, entries 7 and 8). Intriguingly, in the absence of Cu(OAc)2, the

6aa in 65% total yield. However, 1,3-dibenzylidene-1,3dihydroisobenzofuran derivative 7aa was generated in 36− 61% yields when Pd(OAc)2(PPh3)2 and PdCl2 were employed as catalysts. Other metal catalysts examined either did not promote the transformation of 4aa or gave a complex mixture. Encouraged by the outcomes of both NHC-catalyzed azabenzoin condensation of 1a with 2a and the transition metal-catalyzed divergent cyclization reactions of 4aa aforementioned, we began a systematical study of the reaction between 1a and 2a under cascade catalytic conditions. Aimed at the synthesis of 1-indanone products, the one-pot reaction of 2-(phenylethynyl)benzaldehyde 1a with N-((phenyl)(tosyl)methyl)benzamide 2a was carried out using combined thiazole carbene and copper catalysts. When the substrates 1a and 2a, NHC precursor thiazolium 3i (20 mol %), Cu(OAc)2 (50 mol %) and DIPEA (1.5 equiv) were mixed together in acetonitrile and stirred for several hours at 25−30 °C, unfortunately, no reaction took place at all. After considering the probable inhibition of the NHC catalysis by copper ion, we then conducted an NHC/copper sequential catalytic reaction of 1a with 2a. In practice, the aldehyde 1a, imine precursor 2a, thiazolium 3i and a base were dissolved in a solvent and kept stirring for 12−24 h followed by the addition of a Cu(II) 8973


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The Journal of Organic Chemistry Table 2. Scope of the NHC/Cu(OAc)2-Catalyzed Reaction between o-Alkynylbenzaldehydes and Imines

yield (%)a entry

1: X, Ar

2: Ar , R

T1/T2 (h)

5

6

5:6b

total yield (%)

1 2 3 4 5 6 7 8 9 10 12 13 14 15 16 17 18 19

1a: H, Ph 1b: 4-F, Ph 1c: 4-Me, Ph 1d: 4-OMe, Ph 1e: 3-F, Ph 1f: 3-Me, Ph 1g: 3-OMe, Ph 1h: H, p-C6H4F 1i: H, p-C6H4Me 1j: H, p-C6H4OMe 1a: H, Ph 1a: H, Ph 1a: H, Ph 1a: H, Ph 1a: H, Ph 1a: H, Ph 1g: 3-OMe, Ph 1g: 3-OMe, Ph

2a: Ph, Ph 2a: Ph, Ph 2a: Ph, Ph 2a: Ph, Ph 2a: Ph, Ph 2a: Ph,Ph 2a: Ph, Ph 2a: Ph, Ph 2a: Ph, Ph 2a: Ph, Ph 2b: p-C6H4F, Ph 2c: p-C6H4Me, Ph 2d: p-C6H4OMe, Ph 2e: m-C6H4Me, Ph 2f: o-C6H4Me, Ph 2g: Ph, Me 2g: Ph, Me 2h: Ph, t-BuO

12/2 12/4 12/4 12/4 12/12 12/7 12/4 12/3 12/3 12/5 12/3 12/4 12/5 12/12 24/12 12/2 12/2 12/2

5aa: 56 5ba: 58 5ca: 56 5da: 33 5ea: 40 5fa: 50 5ga: 43 5ha: 54 5ia: 51 5ja: 49 5ab:49 5ac: 50 5ad: 46 5ae: 43 5af: 28 5ag: 40c 5gg: 38c 5gh: 41c

6aa: 36 6ba: 32 6ca: 36 6da: 21 6ea: 21 6fa: 35 6ga: 39 6ha: 28 6ia: 34 6ja: 31 6ab: 32 6ac: 31 6ad: 26 6ae: 28 6af: 19 6ag: 26c 6gg: 29c 6gh: 28c

1.6:1 1.8:1 1.6:1 1.6:1 1.9:1 1.4:1 1.1:1 1.9:1 1.5:1 1.6:1 1.5:1 1.6:1 1.8:1 1.5:1 1.5:1 1.5:1d 1.3:1d 1.5:1d

92 90 92 54 61 85 82 82 85 80 81 81 72 71 47 66 67 69

1

2

a Isolated yields. bThe ratios of 5:6 were calculated on the basis of the isolated yields of 5 and 6. cThe yields of 5ag, 6ag, 5gg, 6gg, 5gh and 6gh were calculated on the basis of the total yields and the ratios of 5/6, due to the two isomers not being separated by chromatography. dDetermined by 1H NMR in the crude products.

optimal for the selective synthesis of 1-indanone derivatives from the 2-(phenylethynyl)benzaldehyde and N-benzoylimine. With the optimized conditions established, we examined the substrate scope for the synthesis of 2-amido-3-(arylvinyl)-1indanones by employing various o-alkynyl benzaldehydes 1 and N-((aryl)(tosyl)methyl)amides 2 (Table 2). It was revealed that this sequential catalytic reaction tolerated both electrondonating and electron-withdrawing groups on both substrates 1 and 2. However, the reaction efficiency was influenced by the electronic nature and substitution pattern of substituents. For example, o-(phenylethynyl)-benzaldehyde 1a, -4-methylbenzaldehyde 1b and -4-fluorobenzaldehyde 1c underwent reaction with 2a highly efficiently to produce 1-indanone products in 90−92% total yields (5aa−5ca: 56−58%, 6aa−6ca: 32−36%, 5/6 = 1.6−1.8) (Table 2, entries 1−3). The reaction of 2a with o-(phenylethynyl)-3-methylbenzaldehyde 1f and -3methoxybenzaldehyde 1g also provided two indanones in satisfactory total yields (82−85%, 5fa−5ga: 43−50%, 6fa− 6ga: 35−39%, 5/6 = 1.1−1.4) (Table 2, entries 6 and 7). However, only moderate yields (54−61%) were obtained when o-(phenylethynyl)-4-methoxybenzaldehyde 1d and -3fluorobenzaldehyde 1e were used as substrates (5da−5ea: 33− 40%, 6da−6ea: 21%, 5/6 = 1.6−1.9) (Table 2, entries 4 and 5). Notably, the substituents attached to arylethynyl group of substrates 1 have a negligible effect to the outcomes of the reaction, as the reaction of 2a with all p-fluorophenylethynyl-, p-methylphenylethynyl- and p-methoxyphenylethynyl-benzaldehydes 1h−1j provided indanone products in 80−85% total yields (5ha−5ja: 49−54%, 6ha−6ja: 28−34%, 5/6 = 1.5−1.9) (Table 2, entries 8−10). Furthermore, in the case of imine precursors 2, the electronic nature of the aryl (Ar2) of 2 only slightly affected the efficiency of their reactions with aldehyde

reactions employing DBU and Cs2CO3 as base catalysts produced the 1,3-dibenzylidene-1,3-dihydroisobenzofuran 7aa in 42−64% yields (Table 1, entries 9 and 10). Under the cascade catalysis of thiazolium 3i, DBU or Cs2CO3, and Cu(OAc)2, the reactions gave a dark mixture, from which only a trace amount of desired 1-indanone products was identified. Therefore, with the use of thiazolium 3i, Et3N and Cu(OAc)2 as catalysts, other parameters were further optimized to improve the yields of 1-indanones. First of all, the change of a substrate ratio to 1a:2a = 1:1.5 did not benefit to the reaction, while the use of 1.5 equiv of aldehyde 1a slightly increased the formation of 5aa (Table 1, entries 8, 11 and 12). Second, the use of a lower loading of Cu(OAc)2 (30 mol %) dramatically decreased the yield of 5aa and 6aa. However, increasing Cu(OAc)2 to 100 mol % did not improve the yields of products either (Table 1, entries 12−14). Additionally, to seek an optimal metal catalyst, a range of Cu catalysts with different counterions were then examined. Altering Cu(OAc)2 to Cu(OTf)2 and CuBr2 led to the formation of products in diminished yields. Cu(acac)2, Cu(CH3CN)4BF4 and CuI were totally inefficient catalysts in this reaction (Table 1, entries 15−19). Furthermore, the reaction media and temperature played decisive roles on the cascade catalysis in question. The change of solvent from CH3CN to THF, 1,4-dioxane, CH2Cl2 and DMF, for instance, greatly decreased the yield of products (Table 1, entries 20−23). In acetonitrile, similar results were observed in the reactions conducted at 25 and 50 °C (Table 1, entries 12 and 25). Either a lower temperature (0 °C) or a higher temperature (80 °C) provided products in lower yields (Table 1, entries 24 and 26). Thus, sequential catalytic reaction using thiazolium 3i (30 mol %)/Et3N (2.5 equiv) and Cu(OAc)2 (50 mol %) in acetonitrile at 25−30 °C appears 8974


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The Journal of Organic Chemistry 1a. This has been exemplified by the reactions of 1a with pfluorophenyl-, p-methylphenyl- and p-methoxyphenyl substituted N-(tosylmethyl)amides 2b−2d, which produced the corresponding indanone products in 72−81% total yields (5ab−5ad: 46−50%, 6ab−6ad: 26−32%, 5/6 = 1.5−1.8) (Table 2, entries 12−14). In sharp contrast to the electronic effect, the position of the substituents on the aryl of 2 strongly influenced the reactivity although not the stereoselectivity of reaction. For example, the reactions of aldehyde 1a with pmethylphenylimine, m-methylphenylimine and o-methylphenylimine gave the indanones 5 and 6 in 81%, 71% and 47% total yields respectively, with 5/6 of 1.5−1.6 (Table 2, entries 13, 15 and 16). Finally, it was found that the N-acetyl- and Nboc-2-phenylimine precursors 2g and 2h were also able to undergo reaction with aldehydes 1a and 1g affording indanone products 5ag, 5gg, 5gh and 6ag, 6gg, 6gh in 66−69% total yields (5/6 = 1.3−1.5). Unfortunately, however, the corresponding Z- and E-isomers could not be separated by chromatography because they have very similar polarity. The pure compounds 5ag, 5gh, 6ag and 6gg were obtained from the mixtures of Z- and E-isomers by repeat recrystallization. No pure products 5gg and 6gh were obtained in this way. Although PdCl2 was able to catalyze the conversion of 4aa into 1-benzamidobenzylidene-3-benzylidene-1,3-dihydroisobenzofuran 7aa, the combination of thiazolium salt 3i, Et3N and PdCl2 did not catalyze desired one-pot cascade reaction of 2-(phenylethynyl)benzaldehyde with N-benzoylimine. Only a very small amount of 7aa (∼10%) was isolated from the reaction mixture. As indicated by the results compiled in Table 1, the reaction of 2-(phenylethynyl)benzaldehyde 1a with Nbenzoylimine 2a′ in the presence of thiazolium salt 3i and Cs2CO3 produced (1E,3Z)-1-benzamidobenzylidene-3-benzylidene-1,3-dihydroisobenzofuran 7aa in 64% yield (see Table 1, entry 10). Because Cs2CO3 is much cheaper than PdCl2, and the use of Cs2 CO3 would give higher yield of 1,3dihydroisobenzofuran product in the one-pot reaction fashion, we then set to optimize the conditions for the selective synthesis of 1-amidoarylvinylidene-3-arylvinylidene-1,3-dihydroisobenzofurans 7 from o-alkynylbenzaldehydes 1 and Nacylimines by means of the cascade catalysis using thiazolium salt 3i and a base. We soon discovered that the 1,3-dihydroisobenzofurans 7 derived from aldehydes 1 and N-benzoylimines are sparingly soluble in most common organic solvents, causing problem in purification by chromatography. To circumvent this problem, N-acetylimine was employed instead of N-benzoylimine in optimization of reaction conditions. As summarized in Table 3, 2-(phenylethynyl)benzaldehyde 1a reacted with N-(phenyl(tosyl)methyl)acetamide 2g (1a:2g = 1:1) in the presence of thiazolium salt 3i (30 mol %) and Cs2CO3 (2.5 equiv) in acetonitrile at 25−30 °C to form (1E,3Z)-1-acetamidobenzylidene-3-benzylidene-1,3-dihydroisobenzofuran 7ag in 79% yield. The structure was 7ag was determined by X-ray crystallography (Supporting Information). The variation of the loading of Cs2CO3 from 2.5 to 2 and 1.5 equiv slightly affected the outcomes, and the highest yield of 7ag (84%) was obtained when 2 equiv of Cs2CO3 was applied (Table 3, entries 1, 2 and 4). Increasing the ratio of substrates 1a:2g from 1:1 to 1.5:1 has a negligible effect (Table 3, entries 2 and 3). Furthermore, replacement of Cs2CO3 by DBU, TDB and NaH all led to reduced yields of product 7ag (40−63%) (Table 3, entries 5−7). DIPEA was inefficient to catalyze the transformation of 4ag. Moreever, the change of solvent from

Table 3. Optimization of Reaction Conditions for the Formation of 1,3-Dihydroisobenzofurans

entry

base (equiv)

solvent

T (°C)

yield of 7ag (%)a,b

c

Cs2CO3 (2.5) Cs2CO3 (2) Cs2CO3 (2) Cs2CO3 (1.5) DBU (2) NaH (2) TBD (2) DIPEA (2) Cs2CO3 (2) Cs2CO3 (2) Cs2CO3 (2) Cs2CO3 (2) Cs2CO3 (2) Cs2CO3 (2)

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DMF THF DCM CH3CN CH3CN CH3CN

25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 25−30 50 reflux 0

79 84 82 71 40 52 63 −e 78 70 35 87 72 tracef

1 2c 3d 4c 5c 6c 7c 8c 9c 10c 11c 12c 13c 14c a

Isolated yields. bThe ratios of 7ag/minor isomers in the mixtures of products are in the range of 10:1−50:1 determined by 1H NMR in DMSO-d6. c1a/2g = 1/1. d1a/2g = 1.5/1. eThe intermediate 4ag was isolated in 43% yield. f4ag was isolated in 32% yield.

CH3CN to DMF and to THF gave similar results, whereas CH2Cl2 had a detrimental effect (Table 3, entries 9−11). Finally, a slight increase of the yield of 7ag (87%) was obtained from the reaction conducted in acetonitrile at 50 °C (Table 3, entry 12). Increasing the reaction temperature further to the boiling point of acetonitrile, however, did not have a beneficial effect. It should also be addressed that only a trace amount of 7ag was generated in addition to the formation of 4ag in 32% yield from the reaction conducted at 0 °C (Table 3, entry 14). A trace amount of isomers of 7ag were also detected by 1H NMR and HPLC−MS analysis. The ratios of 7ag over its isomers, which were determined by 1H NMR in DMSO-d6, are in the range of 10:1−50:1. The NHC/Cs2CO3 cascade catalytic reaction was applicable to a broad substrate scope. Under the optimized conditions, this cascade catalysis was compatible with both substrates which contain either an electron-donating or electron-withdrawing group. As illustrated in Table 4, when N-(phenyl(tosyl)methyl)acetamide 2g reacted with a series of o(arylethynyl)benzaldehydes 1 bearing a p-fluoro-, p-methyland p-methoxy group either on the benzaldehyde or phenylethynyl moiety, the corresponding products 7 were obtained in high yields (83−89%) except o-(phenylethynyl)-4-methoxybenzaldehyde 1d which gave a moderated yield of 7dg (54%). Similarly, the reactions of aldehyde 1a with p-fluorophenyl-, pmethylphenyl- and p-methoxyphenyl-substituted N(tosylmethyl)acetamides 2i−2k also afforded good yields of products 7ai−7ak (79−86%). N-(Tosylmethyl)benzamide 2a underwent equally well reactions with aldehydes 1h−1j, furnishing dihydroisobenzofurans 7ha−7ja in 65−72% yields. It should be pointed out that, in addition to the major products 7, a trace amount of minor isomers was also detected in the mixture of products. The ratios of major isomers 7 over minor ones range from 7:1 to 50:1 as determined by 1H NMR spectra in DMSO-d6. It was worth noting that the product 7 8975


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The Journal of Organic Chemistry Table 4. Scope of the NHC/Base Cascade Catalyzed Reaction between o-Alkynylbenzaldehydes and Iminesa,b

a

Isolated yields. bThe ratios of 7/minor isomers in the crude products were determined by 1H NMR in DMSO-d6.

Scheme 3. Plausible Mechanisms for the Formations of 2-Amido-3-benzylidene-1-indanones and 1-Amidobenzylidene-3benzylidene-1,3-dihydroisobenzofurans from o-Alkynyl Benzaldehydes and N-Acylimines

To account for the formations of 2-amido-3-benzylidene-1indanones 5, 6 and 1-amidobenzylidene-3-benzylidene-1,3dihydroisobenzofurans 7 from o-alkynyl benzaldehydes and Nacylimines, two cascade reaction pathways were proposed which were depicted in Scheme 3. The addition of an NHC catalyst to o-alkynylbenzaldehydes 1 forms the Breslow

underwent tautomerization with an isomer which has lower polarity than 7 in some deuterated solvents. For example, when the pure 7bg was dissolved in DMSO-d6 and CDCl3, the ratios of 7bg over this isomer were 21:1 and 1:2, respectively. Unfortunately, however, the pure minor isomers could not be obtained. 8976


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E-2-Benzamido-3-benzylidene-2-phenyl-1-indanone 6aa. White solid, 75 mg, 36%, mp 202−203 °C (recrystallization from CH2Cl2/nhexane); IR v (cm−1) 3293, 1730, 1661, 1640; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.66 (s, 1H, NH), 8.03 (d, J = 7.5 Hz, 2H), 7.78 (d, J = 7.0 Hz, 2H), 7.70 (d, J = 7.2 Hz, 1H), 7.43−7.56 (m, 10H), 7.33−7.40 (m, 4H), 7.17 (s, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 198.0, 165.9, 145.7, 139.9, 137.4, 136.9, 134.5, 134.4, 133.2, 131.9, 129.5, 129.2, 128.9, 128.7, 128.6, 128.5, 127.9, 127.3, 127.2, 126.6, 124.8, 124.7, 70.4; HRMS (TOF-ESI) [M + H]+ calcd for C29H22NO2: 416.1645, found 416.1649. Z-2-Benzamido-3-benzylidene-5-fluoro-2-phenyl-1-indanone 5ba. White solid, 126 mg, 58%, mp 210−211 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3437, 1734, 1664, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.14 (s, 1H, NH), 7.93 (dd, J = 9.5, 2.2 Hz, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 2H), 7.74 (dd, J = 8.4, 5.4 Hz, 1H), 7.68 (s, 1H), 7.33−7.50 (m, 8H), 7.29 (dd, J = 8.7, 2.0 Hz, 1H), 7.18−7.25 (m, 5H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 196.0, 167.5 (d, J = 252 Hz), 165.9, 152.3 (d, J = 10.5 Hz), 137.6 (d, J = 2.8 Hz), 136.4, 135.3, 133.7, 131.1, 129.7, 129.2, 129.0, 128.7, 128.3, 127.92, 127.88, 127.7, 127.3, 126.9 (d, J = 10.5 Hz), 126.3, 117.2 (d, J = 23.9 Hz), 107.7 (d, J = 23 Hz), 70.1; HRMS (TOF-ESI) [M + H]+ calcd for C29H21FNO2: 434.155, found 434.1547. E-2-Benzamido-3-benzylidene-5-fluoro-2-phenyl-1-indanone 6ba. White solid, 70 mg, 32%, mp 182−183 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3302, 1732, 1663, 1636, 1607; 1 H NMR (400 MHz, CD3COCD3) δ (ppm) 8.70 (s, 1H, NH), 8.03 (d, J = 7.4 Hz, 1H), 7.78 (d, J = 6.3 Hz, 2H), 7.76 (d, J = 6.5 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.33−7.50 (m, 10H), 7.24−7.28 (m, 1H), 7.26 (s, 1H), 7.06 (dd, J = 9.9, 2.2 Hz, 1H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 195.4, 166.0 (d, J = 250 Hz), 165.9, 147.7 (d, J = 11 Hz), 140.4 (d, J = 3 Hz), 137.1, 136.6, 133.5, 131.4, 131.2, 128.8, 128.4, 128.3, 128.1, 128.03, 127.99, 127.8, 127.7, 127.5, 126.5 (d, J = 10 Hz), 117.2 (d, J = 24 Hz), 110.6 (d, J = 24 Hz), 70.5; HRMS (TOF-ESI) [M + H]+ calcd for C29H21FNO2: 434.155, found 434.1549. Z-2-Benzamido-3-benzylidene-5-methyl-2-phenyl-1-indanone 5ca. White solid, 120 mg, 56%, mp 223−224 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3453, 1726, 1670, 1599; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.0 (s, 1H), 7.93 (s, 1H, NH), 7.76 (dd, J = 7.6, 1.2 Hz, 2H), 7.58 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.30−7.42 (m, 9H), 7.21 (t, J = 7.8 Hz, 2H), 7.15−7.19 (m, 3H), 2.55 (s, 3H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 196.9, 165.7, 149.7, 146.2, 138.8, 137.0, 135.8, 133.9, 131.0, 130.59, 130.56, 129.5, 128.9, 128.5, 128.2, 127.9, 127.6, 127.5, 127.3, 124.3, 124.1, 121.3, 70.1, 21.4; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1802. E-2-Benzamido-3-benzylidene-5-methyl-2-phenyl-1-indanone 6ca. White solid, 77 mg, 36%, mp 195−196 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3335, 1717, 1657, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.61 (s, 1H, NH), 8.03 (d, J = 7.3 Hz, 2H), 7.77 (dd, J = 8.3, 1.6 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.43−7.56 (m, 7H), 7.29−7.40 (m, 6H), 7.14 (s, 1H), 2.26 (s, 3H); 13 C NM R (100 MHz, CDCl3) δ (ppm) 197.7, 165.9, 146.1, 145.6, 140.0, 137.8, 137.0, 133.4, 132.3, 132.0, 130.9, 129.2, 128.9, 128.7, 128.68, 128.62, 128.0, 127.4, 127.3, 126.4, 125.1, 124.8, 70.7, 22.4; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1797. Z-2-Benzamido-3-benzylidene-5-methoxy-2-phenyl-1-indanone 5da. White solid, 74 mg, 33%, mp 203−204 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3453, 1719, 1670, 1595; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 7.92 (s, 1H, NH), 7.76 (dd, J = 8.2, 1.8 Hz, 2H), 7.68 (d, J = 2.2 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.34−7.42 (m, 4H), 7.30−7.33 (m, 4H), 7.21 (t, J = 7.4 Hz, 2H), 7.15−7.19 (m, 3H), 7.07 (dd, J = 8.5, 2.2 Hz, 1H), 4.04 (s, 3H); 13C NMR (100 MHz, CD3OD) δ (ppm) 197.6, 168.2, 166.4, 152.3, 137.9, 136.5, 135.5, 133.3, 131.0, 129.0, 128.6, 128.4, 127.9, 127.6, 127.4, 127.2, 126.9, 125.9, 125.4, 124.9, 117.7, 103.5, 70.5, 55.1; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO3: 446.175, found 446.1753.

intermediates 8 which undergo azabenzoin reaction with imines 2′ to give (α-amidoalkyl)(o-alkynylaryl)ketone intermediates 4. The resulting intermediates 4 undergo distinct reactions depending on the second catalyst in presence. Under the catalysis of a weak base and Cu(OAc)2, complexation of copper with o-alkynylketones 4 occurs followed by α-H deprotonation to form carbanion intermediates 10. The intramolecular nucleophilic addition of 10 to Cu-alkynyl complexes leads to the formation of 3-(arylvinyl)-1-indanone intermediates 11. Protolysis of carbon−copper bond of 11 affords finally a pair of 2-amido-3-(arylvinyl)-1-indanones 5 and 6. In the presence of only a strong base Cs2CO3, however, the intermediates 4 are deprotonated to form enolates 12. The subsequent intramolecular O-nucleophilic addition to alkynyl group proceeds selectively to produce dihydroisobenzofurans 7. The intriguing divergence of reaction pathways steered by catalysts remains unclear at the current stage. It is probably the complexation of the carbonyl oxygen and the amido nitrogen with copper to form 10′, prohibiting the O-nucleophilic addition to the triple bond.

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CONCLUSION In summary, we have developed novel and efficient NHC/ Cu(II) and NHC/base cascade catalytic methods for the selective synthesis of 2-amido-3-benzylidene-1-indanones and 1-amidobenzylidene-3-benzylidene-1,3-dihydroisobenzofurans from the reaction of o-alkynylbenzaldehydes with Nacylimines. This work not only provided simple and efficient methods for the highly selective synthesis of multifunctionalized 1-indanones and 1,3-dihydroisobenzofuran derivatives from the same reactants, but also demonstrated a remarkable example of catalyst-steered divergent synthesis based on the cascade catalytic strategy using N-heterocyclic carbenes and other catalysts.

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EXPERIMENTAL SECTION

1. General Procedure for the Synthesis of 2-Amido-3benzylidene-1-indanones 5 and 6 from NHC and Cu(OAc)2 Sequentially Catalyzed Reaction of o-Alkynylbenzaldehydes with Imines. At 25−30 °C, N-((aryl)(tosyl)methyl)amides 2 (0.5 mmol), triazolium salt 3i (40.5 mg, 0.15 mmol, 30 mol %) were added to an oven-dried Schlenk tube. The test tube was then evacuated and backfilled with nitrogen. The dry acetonitrile (5 mL) followed by a solution of o-alkynylbenzaldehydes 1 (0.75 mmol) in acetonitrile (5 mL) were added using a syringe. After stirring for 5 min, Et3N (1.25 mmol, 173 μL) was injected with a microsyringe. In the sealed Schlenk tube, the reaction mixture was stirred for 12 h (24 h for the reaction of 1a with 2f) at 25−30 °C. Cu(OAc)2 (50 mol %) was then added under nitrogen protection. The test tube was sealed again and the resulting mixture was kept stirring for another 2−12 h at 25−30 °C. After removal of the solvent, the residue was chromatographed on a silica gel column eluting with a mixture of petroleum ether and ethyl acetate (PE:EA from 8:1 to 5:1) to give products 5 in 28−58% and 6 in 19−39% yields. Z-2-Benzamido-3-benzylidene-2-phenyl-1-indanone 5aa. White solid, 116 mg, 56%, mp 196−197 °C (recrystallization from AcOEt/nhexane); IR v (cm−1) 3447, 1734, 1665, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.19 (d, J = 7.9 Hz, 1H), 8.08 (s, 1H, NH), 7.82 (d, J = 7.4 Hz, 1H), 7.77−7.79 (m, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.63 (s, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.31−7.42 (m, 8H), 7.20−7.24 (m, 5H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.6, 165.8, 149.4, 138.7, 136.7, 135.7, 135.2, 133.8, 132.7, 131.1, 129.6, 129.4, 129.0, 128.7, 128.3, 127.9, 127.7, 127.6, 127.3, 124.7, 124.2, 121.2, 70.0; HRMS (TOF-ESI) [M + H]+ calcd for C29H22NO2: 416.1645, found 416.1648. 8977


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from CH2Cl2/n-hexane); IR v (cm−1) 3316, 1719, 1659, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.61 (s, 1H, NH), 8.03 (d, J = 7.4 Hz, 2H), 7.77 (d, J = 6.8 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.41−7.49 (m, 6H), 7.31−7.39 (m, 4H), 7.14 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 7.01 (s, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 198.0, 165.9, 160.9, 139.6, 139.3, 137.5, 137.1, 136.0, 133.2, 131.9, 129.1, 128.8, 128.64, 128.61, 128.56, 127.7, 127.3, 127.2, 125.9, 124.2, 123.7, 105.9, 70.8, 55.6; HRMS (TOFESI) [M + H]+ calcd for C30H24NO3: 446.175, found 446.1749. Z-2-Benzamido-3-(p-fluorobenzylidene)-2-phenyl-1-indanone 5ha. White solid, 117 mg, 54%, mp 211−212 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3449, 1732, 1665, 1599; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.17 (d, J = 7.9 Hz, 1H), 8.11 (s, 1H, NH), 7.82 (d, J = 7.2 Hz, 1H), 7.77 (dd, J = 8.2, 2.1 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.37−7.44 (m, 8H), 7.26 (t, J = 7.7 Hz, 2H), 6.93 (t, J = 8.8 Hz, 2H); 13 C NMR (100 MHz, CD3COCD3) δ (ppm) 197.6, 165.7, 162.1 (d, J = 245 Hz), 149.3, 138.4, 136.3, 135.2, 133.6, 132.6, 132.0, 131.7, 131.6, 131.3, 129.4, 129.0, 128.8, 128.0, 127.7, 127.3, 123.9 (d, J = 63.3 Hz), 121.2, 115.0 (d, J = 22 Hz), 70.0; HRMS (TOF-ESI) [M + H]+ calcd for C29H21FNO2: 434.155, found 434.1553. E-2-Benzamido-3-(p-fluorobenzylidene)-2-phenyl-1-indanone 6ha. White solid, 60 mg, 28%, mp 199−200 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3298, 1738, 1641, 1603; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.66 (s, 1H, NH), 8.03 (d, J = 7.4 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 7.3 Hz, 1H), 7.44−7.57 (m, 8H), 7.33−7.39 (m, 3H), 7.22 (t, J = 8.8 Hz, 2H), 7.13 (s, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 198.0, 166.0, 162.5 (d, J = 246 Hz), 145.5, 140.3, 137.3, 134.6, 134.5, 133.2, 132.9, 132.1, 130.44, 130.37, 129.7, 129.3, 129.0, 128.7, 127.4, 127.3, 125.3 (d, J = 40.2 Hz), 124.7, 115.8 (d, J = 21 Hz), 70.5; HRMS (TOF-ESI) [M + H]+ calcd for C29H21FNO2: 434.155, found 434.1547. Z-2-Benzamido-3-(p-methylbenzylidene)-2-phenyl-1-indanone 5ia. White solid, 110 mg, 51%, mp 235−236 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3457, 1727, 1669, 1599; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.17 (d, J = 7.9 Hz, 1H), 8.0 (s, 1H, NH), 7.81 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.37−7.42 (m, 4H), 7.33 (d, J = 7.4 Hz, 2H), 7.21−7.25 (m, 4H), 7.0 (d, J = 7.9 Hz, 2H), 2.26 (s, 3H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.6, 165.7, 149.6, 137.9, 137.5, 136.8, 135.1, 133.8, 132.9, 132.6, 131.1, 129.6, 129.2, 128.9, 128.8, 128.6, 127.9, 127.7, 127.3, 124.7, 124.2, 121.1, 69.9, 20.4; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1799. E-2-Benzamido-3-(p-methylbenzylidene)-2-phenyl-1-indanone 6ia. White solid, 73 mg, 34%, mp 223−224 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3308, 1736, 1645, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.63 (s, 1H, NH), 8.02 (d, J = 7.5 Hz, 2H), 7.77 (d, J = 7.0 Hz, 2H), 7.70 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.52 (t, J = 7.2 Hz, 2H), 7.43−7.47 (m, 3H), 7.33− 7.40 (m, 5H), 7.26 (d, J = 7.8 Hz, 2H), 7.12 (s, 1H), 2.38 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ (ppm) 198.2, 165.9, 145.9, 139.4, 137.9, 137.6, 134.5, 134.4, 133.9, 133.3, 132.0, 129.5, 129.4, 129.2, 128.9, 128.7, 128.5, 127.5, 127.3, 126.9, 124.9, 124.8, 70.5, 21.5; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1801. Z-2-Benzamido-3-(p-methoxybenzylidene)-2-phenyl-1-indanone 5ja. White solid, 110 mg, 49%, mp 217−218 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3351, 1723, 1653, 1599; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.14 (d, J = 7.9 Hz, 1H), 8.07 (s, 1H, NH), 7.77−7.81 (m, 3H), 7.66 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.38−7.43 (m, 6H), 7.31 (d, J = 8.7 Hz, 2H), 7.25 (t, J = 7.6 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.9, 165.7, 159.5, 149.9, 136.6, 136.4, 135.1, 133.8, 132.4, 131.2, 131.1, 128.94, 128.91, 128.6, 128.0, 127.9, 127.7, 127.4, 124.5, 124.2, 121.0, 113.7, 69.9, 54.8; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO3: 446.175, found 446.1749. E-2-Benzamido-3-(p-methyoxybenzylidene)-2-phenyl-1-indanone 6ja. White solid, 70 mg, 31%, mp 196−197 °C (recrystallization

E-2-Benzamido-3-benzylidene-5-methoxy-2-phenyl-1-indanone 6da. White solid, 47 mg, 21%, mp 209−210 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3350, 1715, 1655, 1595; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.56 (s, 1H, NH), 8.03 (d, J = 7.4 Hz, 2H), 7.77 (d, J = 7.0 Hz, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.44−7.58 (m, 7H), 7.31−7.41 (m, 4H), 7.18 (s, 1H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 196.5, 165.9, 164.8, 148.1, 140.1, 138.0, 137.0, 133.5, 132.0, 129.2, 128.9, 128.8, 128.7, 128.0, 127.9, 127.3, 127.26, 126.8, 126.5, 118.1 107.7, 70.6, 55.4; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO3: 446.175, found 446.1752. Z-2-Benzamido-3-benzylidene-6-fluoro-2-phenyl-1-indanone 5ea. White solid, 86 mg, 40%, mp 216−217 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3445, 1734, 1669, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.25 (dd, J = 8.6, 4.6 Hz, 1H), 8.11 (s, 1H, NH), 7.78 (d, J = 7.9 Hz, 2H), 7.62 (dd, J = 8.9, 2.4 Hz, 1H), 7.59 (s, 1H), 7.30−7.42 (m, 9H), 7.23 (d, J = 7.5 Hz, 2H), 7.18−7.20 (m, 3H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 196.6, 165.9, 163.4 (d, J = 248 Hz), 162.2, 145.6, 137.6, 136.2, 135.5, 134.4 (d, J = 8 Hz), 133.5, 131.1, 129.4, 128.9, 128.7, 128.2, 127.8, 127.6, 127.5, 124.6, 123.4 (d, J = 8 Hz), 122.7 (d, J = 24 Hz), 109.6 (d, J = 22 Hz), 70.1; HRMS (TOF-ESI) [M + H]+ calcd for C29H21FNO2: 434.155, found 434.1548. E-2-Benzamido-3-benzylidene-6-fluoro-2-phenyl-1-indanone 6ea. White solid, 46 mg, 21%, mp 217−218 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3302, 1742, 1638, 1602; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.72 (s, 1H, NH), 8.03 (d, J = 7.4 Hz, 1H), 7.78 (d, J = 6.8 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.44−7.52 (m, 7H), 7.35−7.40 (m, 5H), 7.31 (dd, J = 8.8, 2.5 Hz, 1H), 7.15 (s, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 197.2, 166.0, 163.3 (d, J = 251 Hz), 141.9, 139.1 137.0, 136.8, 136.5 (d, J = 6.7 Hz), 133.0, 132.2, 129.4, 129.2, 128.9, 128.8, 128.5, 128.1, 127.4, 127.3, 126.7 (d, J = 7.7 Hz), 126.2, 122.3 (d, J = 23 Hz), 110.9 (d, J = 22 Hz), 70.8; HRMS (TOF-ESI) [M + H]+ calcd for C29H21FNO2: 434.155, found 434.1552. Z-2-Benzamido-3-benzylidene-6-methyl-2-phenyl-1-indanone 5fa. White solid, 108 mg, 50%, mp 225−226 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3457, 1730, 1659, 1602; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.06 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H, NH), 7.76 (dd, J = 8.2, 1.8 Hz, 2H), 7.63 (dd, J = 8.0, 1.0 Hz, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.35−7.42 (m, 4H), 7.30−7.33 (m, 4H), 7.23 (t, J = 7.4 Hz, 2H), 7.16−7.20 (m, 3H), 2.44 (s, 3H); 13 C NMR (100 MHz, CD3COCD3) δ (ppm) 197.4, 165.7, 147.0, 139.7, 138.7, 136.9, 136.2, 135.8, 133.8, 132.8, 130.9, 129.4, 128.8, 128.4, 128.1, 127.8, 127.5, 127.3, 127.2, 124.0, 123.5, 120.9, 70.1, 20.4; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1804. E-2-Benzamido-3-benzylidene-6-methyl-2-phenyl-1-indanone 6fa. White solid, 76 mg, 35%, mp 217−218 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3317, 1717, 1657, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.62 (s, 1H, NH), 8.03 (d, J = 7.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.31−7.48 (m, 13H), 7.09 (s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 198.2, 165.9, 143.4, 140.1, 140.0, 137.7, 137.2, 135.8, 134.6, 133.3, 132.0, 129.2, 128.9, 128.7, 128.6, 127.9, 127.4, 127.3, 125.6, 124.9, 124.6, 70.7, 21.4; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1798. Z-2-Benzamido-3-benzylidene-6-methoxy-2-phenyl-1-indanone 5ga. White solid, 95 mg, 43%, mp 237−238 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3360, 1713, 1665, 1607; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.08 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H, NH), 7.77 (dd, J = 8.2, 1.8 Hz, 2H), 7.45 (s, 1H), 7.36− 7.43 (m, 5H), 7.28−7.31 (m, 4H), 7.22 (t, J = 7.6 Hz, 2H), 7.16− 7.17 (m, 3H), 7.11 (d, J = 2.5 Hz, 1H), 3.90 (s, 3H); 13C NMR (100 MHz, CD3OD) δ (ppm) 197.3, 165.8, 161.2, 142.8, 138.5, 136.9, 136.0, 134.1, 133.9, 131.0, 129.4, 128.9, 128.6, 128.2, 127.9, 127.7, 127.3, 127.2, 124.1, 122.5, 122.4, 105.5, 70.2, 55.3; HRMS (TOFESI) [M + H]+ calcd for C30H24NO3: 446.175, found 446.1752. E-2-Benzamido-3-benzylidene-6-methoxy-2-phenyl-1-indanone 6ga. White solid, 88 mg, 39%, mp 232−233 °C (recrystallization 8978


Article

The Journal of Organic Chemistry from CH2Cl2/n-hexane); IR v (cm−1) 3310, 1730, 1638, 1605; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.61 (s, 1H, NH), 8.02 (d, J = 7.4 Hz, 2H), 7.76 (d, J = 6.9 Hz, 2H), 7.69 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.3 Hz, 2H), 7.43−7.47 (m, 5H), 7.32−7.38 (m, 3H), 7.09 (s, 1H), 7.0 (d, J = 8.5 Hz, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 198.2, 165.8, 159.4, 146.0, 138.9, 137.5, 134.4, 134.3, 133.2, 131.9, 129.9, 129.3, 129.12, 129.08, 128.8, 128.6, 127.3, 127.2, 126.5, 124.9, 124.6, 114.0, 70.4, 55.3; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO3: 446.175, found 446.1748. Z-2-Benzamido-3-benzylidene-2-(p-fluorophenyl)-1-indanone 5ab. White solid, 106 mg, 49%, mp 183−184 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3362, 1734, 1640, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.19 (d, J = 7.9 Hz, 1H), 8.16 (s, 1H, NH), 7.81−7.84 (m, 3H), 7.69 (d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.36−7.40 (m, 3H), 7.32 (d, J = 7.3 Hz, 2H), 7.16−7.24 (m, 7H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.5, 165.8, 162.9 (d, J = 244 Hz), 149.3, 138.4, 135.5, 135.2, 133.7, 132.6 (d, J = 2.8 Hz), 132.5, 131.1, 130.1 (d, J = 8.6 Hz), 129.6, 129.5, 128.3, 127.9, 127.6, 127.3, 125.0, 124.2, 121.3, 115.6 (d, J = 22 Hz), 69.3; HRMS (TOF-ESI) [M + H]+ calcd for C29H21FNO2: 434.155, found 434.1551. E-2-Benzamido-3-benzylidene-2-(p-fluorophenyl)-1-indanone 6ab. White solid, 69 mg, 32%, mp 239−240 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3296, 1724, 1637, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.69 (s, 1H, NH), 8.00 (d, J = 7.5 Hz, 2H), 7.84 (dd, J = 8.7, 5.4 Hz, 2H), 7.72 (d, J = 6.9 Hz, 1H), 7.43−7.56 (m, 10H), 7.39 (t, J = 7.1 Hz, 1H), 7.18 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 198.0, 166.0, 163.1 (d, J = 247 Hz), 145.6, 139.8, 136.8, 134.7, 134.2, 133.1, 132.1, 129.8, 129.5 (d, J = 7.7 Hz), 128.83, 128.76, 128.6, 128.1, 127.3, 126.9, 125.0, 124.8, 116.2 (d, J = 21.1 Hz), 69.9; HRMS (TOF-ESI) [M + H]+ calcd for C29H21FNO2: 434.155, found 434.1548. Z-2-Benzamido-3-benzylidene-2-(p-methylphenyl)-1-indanone 5ac. White solid, 108 mg, 50%, mp 218−219 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3455, 1732, 1667; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.18 (d, J = 7.9 Hz, 1H), 7.99 (s, 1H, NH), 7.81 (t, J = 7.7 Hz, 1H), 7.64−7.68 (m, 3H), 7.61 (s, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.35−7.39 (m, 3H), 7.33 (d, J = 7.3 Hz, 2H), 7.19−7.24 (m, 7H), 2.32 (s, 3H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.7, 165.7, 149.4, 138.8, 138.5, 135.7, 135.1, 133.8, 133.7, 132.7, 131.1, 129.62, 129.57, 129.3, 128.2, 127.9, 127.6, 127.5, 127.3, 124.6, 124.2, 121.2, 69.7, 20.3; HRMS (TOFESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1809. E-2-Benzamido-3-benzylidene-2-(p-methylphenyl)-1-indanone 6ac. White solid, 67 mg, 31%, mp 206−207 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3379, 1721, 1655; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.54 (s, 1H, NH), 8.03 (d, J = 7.6 Hz, 2H), 7.7 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.43−7.50 (m, 9H), 7.38 (t, J = 7 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.15 (s, 1H), 2.3 (s, 3H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.0, 165.7, 145.3, 141.2, 137.9, 137.3, 134.8, 134.4, 133.9, 133.7, 131.3, 129.3, 129.0, 128.5, 128.1, 128.07, 127.62, 127.58, 127.4, 125.9, 124.3, 123.9, 70.1, 19.9; HRMS (TOFESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1807. Z-2-Benzamido-3-benzylidene-2-(p-methoxyphenyl)-1-indanone 5ad. White solid, 103 mg, 46%, mp 206−207 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3445, 1730, 1665, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.16 (d, J = 7.9 Hz, 1H), 7.99 (s, 1H, NH), 7.80 (td, J = 8.2, 1.1 Hz, 1H), 7.68 (d, J = 9.0 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.31−7.40 (m, 5H), 7.19−7.21 (m, 5H), 7.94 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.6, 165.6, 160.1, 149.2, 138.7, 135.7, 135.0, 133.8, 132.7, 131.0, 129.6, 129.2, 129.0, 128.2, 128.1, 127.8, 127.4, 127.2, 124.5, 124.1, 121.1, 114.2, 69.2, 54.7; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO3: 446.175, found 446.1749. E-2-Benzamido-3-benzylidene-2-(p-methoxyphenyl)-1-indanone 6ad. White solid, 59 mg, 26%, mp 237−228 °C (recrystallization

from CH2Cl2/n-hexane); IR v (cm−1) 3291, 1730, 1638, 1603; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.56 (s, 1H, NH), 8.02 (d, J = 7.4 Hz, 2H), 7.70 (d, J = 6.7 Hz, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.43−7.56 (m, 10H), 7.38 (t, J = 7.1 Hz, 1H), 7.15 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.7, 166.4, 159.8, 145.3, 141.8, 137.1, 134.9, 134.6, 133.5, 132.1, 130.2, 129.5, 129.3, 129.2, 128.7, 128.6, 128.4, 128.3, 126.4, 124.6, 124.4, 114.4, 70.0, 55.7; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO3: 446.175, found 446.1747. Z-2-Benzamido-3-benzylidene-2-(m-methylphenyl)-1-indanone 5ae. White solid, 92 mg, 43%, mp 262−263 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3445, 1734, 1665, 1599; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.17 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H, NH), 7.81 (t, J = 8.0 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.51−7.55 (m, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.32−7.34 (m, 2H), 7.18−7.29 (m, 9H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 197.3, 165.6, 149.4, 138.9, 138.5, 136.8, 135.8, 135.0, 133.8, 132.8, 131.0, 129.4, 129.22, 129.19, 128.7, 128.1, 127.9, 127.8, 127.4, 127.1, 124.5, 124.4, 124.1, 121.0, 69.8, 20.6; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1805. E-2-Benzamido-3-benzylidene-2-(m-methylphenyl)-1-indanone 6ae. White solid, 61 mg, 28%, mp 189−190 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3329, 1732, 1636, 1603; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.60 (s, 1H, NH), 8.03 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.1 Hz, 1H), 7.64 (s, 1H), 7.44−7.54 (m, 11H), 7.38 (t, J = 7.0 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.15 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 198.8, 168.3, 145.8, 141.0, 138.3, 137.1, 136.8, 134.4, 134.3, 133.3, 131.6, 129.3, 128.9, 128.5, 128.2, 128.1, 128.0, 127.9, 127.6, 127.3, 126.5, 124.5, 124.3, 124.1, 70.6, 20.2; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1808. Z-2-Benzamido-3-benzylidene-2-(o-methylphenyl)-1-indanone 5af. White solid, 60 mg, 28%, mp 246−247 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3449, 1736, 1663, 1597; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.15 (d, J = 7.9 Hz, 1H), 7.81 (td, J = 8.3, 1.1 Hz, 1H), 7.74 (s, 1H, NH), 7.68 (d, J = 7.9 Hz, 2H), 7.53 (s, 1H), 7.53 (t, J = 8.5 Hz, 1H), 7.38 (td, J = 7.3, 1.2 Hz, 1H), 7.30− 7.33 (m, 3H), 7.21−7.27 (m, 5H), 7.11−7.17 (m, 4H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 196.5, 164.5, 149.0, 140.3, 138.6, 136.0, 135.0, 134.3, 133.9, 133.6, 132.9, 131.0, 129.6, 129.3, 129.1, 128.4, 128.2, 127.9, 127.3, 126.9, 126.2, 124.3, 124.2, 121.0, 71.6, 21.3; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1805. E-2-Benzamido-3-benzylidene-2-(o-methylphenyl)-1-indanone 6af. White solid, 41 mg, 19%, mp 187−188 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3364, 1732, 1663, 1601; 1H NMR (600 MHz, CD3COCD3) δ (ppm) 8.81 (s, 1H, NH), 8.05 (dd, J = 9.0, 2.4 Hz, 2H), 7.65 (d, J = 6.6 Hz, 1H), 7.52 (tt, J = 7.8, 1.8 Hz, 1H), 7.39−7.49 (m, 10H), 7.32−7.36 (m, 1H), 7.22 (d, J = 6.6 Hz, 1H), 7.15 (td, J = 7.8, 1.8 Hz, 1H), 7.04 (td, J = 8.4, 1.8 Hz, 1H), 7.02 (s, 1H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 196.6, 165.1, 145.4, 143.8, 139.6, 137.5, 135.0, 134.8, 134.1, 134.0, 133.4, 131.5, 129.6, 129.5, 128.8, 128.4, 128.22, 128.18, 127.8, 127.6, 126.0, 125.7, 124.4, 124.3, 72.5, 21.6; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1804. Z-2-Acetamido-3-benzylidene-2-phenyl-1-indanone 5ag. White solid, 40% (calculated yield), mp 214−215 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3406, 1726, 1678, 1599; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.14 (d, J = 7.9 Hz, 1H), 7.77 (td, J = 8.2, 1.2 Hz, 1H), 7.74 (s, 1H, NH), 7.68 (dd, J = 8.3, 1.8 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.32− 7.39 (m, 3H), 7.25−7.28 (m, 2H), 7.19−7.20 (m, 3H), 1.51 (s, 3H); 13 C NMR (100 MHz, CD3OD) δ (ppm) 199.5, 170.5, 149.6, 137.5, 135.9, 135.4, 135.1, 132.0, 129.02, 128.97, 128.6, 128.4, 127.7, 127.3, 127.2, 124.6, 123.9, 120.8, 69.8, 19.8; HRMS (TOF-APCI+) [M + H]+ calcd for C24H20NO2: 354.1488, found 354.1492. E-2-Acetamido-3-benzylidene-2-phenyl-1-indanone 6ag. White solid, 26% (calculated yield), mp 255−256 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3239, 1730, 1649, 1599; 1H NMR 8979


Article

The Journal of Organic Chemistry (400 MHz, CD3COCD3) δ (ppm) 8.14 (s, 1H, NH), 7.67 (dd, J = 8.2, 1.8 Hz, 2H), 7.64 (d, J = 7.2 Hz, 1H), 7.37−7.50 (m, 8H), 7.27− 7.35 (m, 3H), 6.99 (s, 1H), 2.02 (s, 3H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.5, 168.4, 145.5, 141.2, 137.7, 137.4, 134.8, 134.0, 129.4, 128.7, 128.4, 128.3, 128.2, 127.7, 127.6, 125.9, 124.5, 123.9, 70.1, 21.3; HRMS (TOF-APCI+) [M + H]+ calcd for C24H20NO2: 354.1488, found 354.1491. E-2-Acetamido-3-benzylidene-6-methoxy-2-phenyl-1-indanone 6gg. White solid, 29% (calculated yield), mp 227−228 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3237, 1728, 1638, 1601; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.15 (s, 1H, NH), 7.66 (d, J = 6.6 Hz, 2H), 7.48 (d, J = 7.1 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.30−7.39 (m, 5H), 7.07 (d, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.6, 2.5 Hz, 1H), 6.84 (s, 1H), 3.85 (s, 3H), 2.02 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 197.7, 169.1, 160.8, 141.0, 138.6, 137.5, 137.2, 136.1, 129.0, 128.8, 128.51, 128.45, 128.0, 127.8, 125.5, 123.4, 123.2, 106.3, 70.5, 55.9, 22.1; HRMS (TOF-ESI) [M + H]+ calcd for C25H22NO3: 384.1594, found 384.1598. Z-2-(t-Butyl carbamate)-3-benzylidene-6-methoxy-2-phenyl-1indanone 5gh. Pale yellow solid, 41% (calculated yield), mp 174− 175 °C (recrystallization from CH2Cl2/n-hexane); IR v (cm−1) 3320, 1740, 1701, 1609; 1H NMR (400 MHz, CD3COCD3) δ (ppm) 8.10 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 7.0 Hz, 2H), 7.47 (s, 1H), 7.34−7.42 (m, 4H), 7.19−7.27 (m, 5H), 7.10 (s, 1H), 6.31 (brs, 1H, NH), 3.91 (s, 3H), 1.11 (brs, 9H); 13C NMR (100 MHz, CD3COCD3) δ (ppm) 197.9, 161.1, 153.5, 143.1, 138.9, 137.4, 135.6, 133.8, 129.0, 128.7, 128.1, 127.7, 126.94, 126.90, 124.0, 122.1, 105.4, 78.5, 69.6, 55.0, 27.2; HRMS (TOF-ESI) [M + H]+ calcd for C28H28NO4: 442.2012, found 442.2017. 2. General Procedure for the Synthesis of 1-Amidobenzylidene-3-benzylidene-1,3-dihydroisobenzofurans 7 from NHC and Cs2CO3 Catalyzed Reaction of o-Alkynylbenzaldehydes with Imines. At ambient temperature, N-((aryl)(tosyl)methyl)amides 2 (0.5 mmol) and triazolium salt 3i (40.5 mg, 0.15 mmol, 30 mol %) were added to an oven-dried Schlenk tube. The test tube was then evacuated and backfilled with nitrogen. The dry acetonitrile (5 mL) followed by a solution of o-alkynylbenzaldehydes 1 (0.5 mmol) in acetonitrile (5 mL) were added using a syringe. After stirring for 5 min, Cs2CO3 (1 mmol, 326 mg) was added under nitrogen atmosphere. The resulting mixture was then stirred at 50 °C under nitrogen. During the process of the reaction, the yellow products 7 precipitated from acetonitrile. After stirring for 12 h at 50 °C, the reaction mixture was cooled to room temperature. The precipitated yellow products 7 and Cs2CO3 solid were separated by filtration. The solids were washed with ethyl acetate (5 × 3 mL). The obtained solid mixture and the combined filtrate were then worked up in the following procedures. The solid mixture was dissolved in a biphasic mixture of dichloromethane (50 mL) and water (10 mL). If the solids did not dissolved entirely, THF was added until all solids were dissolved to give two clear layers. The organic layer was separated from water using a separating funnel, and the water layer was extracted with dichloromethane (30 × 3 mL). The combined organic layer was dried with anhydrous MgSO4. After removal of MgSO4 and organic solvents, most of the pure products 7 were obtained. On the other hand, the combined filtrate was concentrated under vacuum. The residue was chromatographed on a silica gel column eluting with a mixture of dichloromethane and ethyl acetate (DCM:EA from 60:1 to 40:1) to give another small portion of products 7. The total yields of 7 were 54−89%. (1E,3Z)-1-(2-Acetamidobenzylidene)-3-benzylidene-1,3-dihydroisobenzofuran 7ag. Yellow solid, 154 mg, 87%, mp 213-214 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3220, 1653, 1637; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.64 (s, 1H, NH), 7.91−7.94 (m, 1H), 7.72−7.78 (m, 5H), 7.50−7.53 (m, 2H), 7.46 (t, J = 8.0 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.51 (s, 1H), 2.14 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ (ppm) 170.3, 151.0, 149.5, 136.6, 135.1, 134.6, 132.0, 130.5, 130.4, 129.1, 128.6, 128.5, 128.0, 127.8, 127.1, 124.3, 120.8, 113.4, 99.9, 23.5; HRMS (TOF-ESI) [M + H]+ calcd for C24H20NO2: 354.1488, found 354.1484.

(1E,3Z)-1-(2-Acetamidobenzylidene)-3-benzylidene-5-fluoro-1,3dihydroisobenzofuran 7bg. Yellow solid, 166 mg, 89%, mp 235−236 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3259, 1655; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.63 (s, 1H, NH), 7.84 (d, J = 9.2 Hz, 1H), 7.73−7.76 (m, 5H), 7.46 (t, J = 7.2 Hz, 2H), 7.29−7.39 (m, 4H), 7.21 (t, J = 7.6 Hz, 1H), 6.59 (s, 1H), 2.14 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ (ppm) 170.3, 163.4 (d, J = 245.7 Hz), 150.1, 148.8, 136.9 (d, J = 10.1 Hz), 136.4, 134.8, 129.2, 128.6, 128.5, 128.0, 127.8, 127.5, 126.53, 126.47, 118.3 (d, J = 24.3 Hz), 113.1, 107.3 (d, J = 25.8 Hz), 101.1, 23.5; HRMS (TOFESI) [M + H]+ calcd for C24H19FNO2: 372.1394, found 372.1395. (1E,3Z)-1-(2-Acetamidobenzylidene)-3-benzylidene-5-methyl1,3-dihydroisobenzofuran 7cg. Yellow solid, 154 mg, 84%, mp 227− 228 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3213, 1639; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.59 (s, 1H, NH), 7.73−7.78 (m, 5H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.30−7.35 (m, 4H), 7.19 (t, J = 7.2 Hz, 1H), 6.46 (s, 1H), 2.41 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 170.3, 151.0, 149.7, 140.4, 136.7, 135.2, 134.9, 131.6, 129.7, 129.1, 128.6, 128.5, 127.8, 127.7, 127.1, 124.0, 120.7, 112.5, 99.7, 23.4, 21.7; HRMS (TOF-ESI) [M + H]+ calcd for C25H22NO2: 368.1645, found 368.1642. (1E,3Z)-1-(2-Acetamidobenzylidene)-3-benzylidene-5-methoxy1,3-dihydroisobenzofuran 7dg. Yellow solid, 104 mg, 54%, mp 216− 217 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3250, 1654, 1641; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.55 (s, 1H, NH), 7.77 (d, J = 7.6 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.10 (dd, J = 8.8, 2.4 Hz, 1H), 6.56 (s, 1H), 3.87 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 170.3, 161.4, 150.9, 149.6, 136.8, 136.5, 135.2, 129.2, 128.6, 128.5, 127.6, 127.5, 127.1, 125.5, 125.1, 119.1, 111.4, 103.6, 100.1, 56.3, 23.4; HRMS (TOFESI) [M + H]+ calcd for C25H22NO3: 384.1594, found 384.1589. (1E,3Z)-1-(2-Acetamidobenzylidene)-3-(p-fluorobenzylidene)1,3-dihydroisobenzofuran 7hg. Yellow solid, 159 mg, 85%, mp 233− 234 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3164, 1650; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.63 (s, 1H, NH), 7.88−7.91 (m, 1H), 7.72−7.82 (m, 6H), 7.51−7.53 (m, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.17 (t, J = 8.8 Hz, 2H), 6.52 (s, 1H), 2.14 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ (ppm) 170.3, 161.3 (d, J = 243.4 Hz), 150.6, 149.5, 136.6, 134.4, 131.9, 131.7 (d, J = 2.9 Hz), 130.5, 130.4, 130.3, 128.7, 128.0, 127.7, 124.3, 120.7, 116.0 (d, J = 21 Hz), 113.4, 98.7, 23.4; HRMS (TOFESI) [M + H]+ calcd for C24H19FNO2: 372.1394, found 372.1396. (1E,3Z)-1-(2-Acetamidobenzylidene)-3-(p-methylbenzylidene)1,3-dihydroisobenzofuran 7ig. Yellow solid, 156 mg, 85%, mp 245− 246 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3248, 1653; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.62 (s, 1H, NH), 7.88−7.91 (m, 1H), 7.73−7.76 (m, 3H), 7.67 (d, J = 8 Hz, 2H), 7.49−7.52 (m, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 2.28 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 170.3, 150.3, 149.6, 136.7, 136.6, 134.7, 132.3, 131.9, 130.33, 130.25, 129.8, 128.6, 128.5, 127.9, 127.7, 124.3, 120.6, 113.1, 100.0, 23.5, 21.4; HRMS (TOF-ESI) [M + H]+ calcd for C25H22NO2: 368.1645, found 368.1649. (1E,3Z)-1-(2-Acetamidobenzylidene)-3-(p-methoxybenzylidene)1,3-dihydroisobenzofuran 7jg. Yellow solid, 160 mg, 83%, mp 222− 223 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3221, 1655; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.60 (s, 1H, NH), 7.86−7.88 (m, 1H), 7.71−7.76 (m, 5H), 7.45−7.50 (m, 4H),7.30 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 2H), 6.46 (s, 1H), 3.76 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 170.3, 158.7, 149.7, 149.3, 136.7, 134.8, 131.7, 130.3, 129.98, 129.95, 128.7, 127.8, 127.7, 127.6, 124.3, 120.4, 114.7, 112.7, 99.8, 55.7, 23.5; HRMS (TOF-ESI) [M + H]+ calcd for C25H22NO3: 384.1594, found 384.1601. (1E,3Z)-1-(2-Acetamido-p-fluorobenzylidene)-3-benzylidene-1,3dihydroisobenzofuran 7ai. Yellow solid, 160 mg, 86%, mp 255−256 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 8980


Article

The Journal of Organic Chemistry 3214, 1639; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.66 (s, 1H, NH), 7.91−7.93 (m, 1H), 7.73−7.78 (m, 5H), 7.51−7.54 (m, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.30 (t, J = 8.8 Hz, 2H), 7.20 (t, J = 7.6 Hz, 1H), 6.51 (s, 1H), 2.14 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 170.3, 161.7 (d, J = 244 Hz), 150.9, 149.4, 135.1, 134.5, 133.1 (d, J = 2.9 Hz), 131.9, 130.4 (d, J = 6.7 Hz), 129.9, 129.8, 129.2, 128.5, 127.1, 124.2, 120.8, 115.6 (d, J = 22 Hz), 112.4, 100.0, 23.4; HRMS (TOF-ESI) [M + H]+ calcd for C24H19FNO2: 372.1394, found 372.1401. (1E,3Z)-1-(2-Acetamido-p-methylbenzylidene)-3-benzylidene1,3-dihydroisobenzofuran 7aj. Yellow solid, 150 mg, 82%, mp 256− 257 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3219, 1653; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.58 (s, 1H, NH), 7.90−7.93 (m, 1H), 7.78 (d, J = 7.2 Hz, 2H),7.71−7.74 (m, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.50−7.52 (m, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 6.50 (s, 1H), 2.35 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 170.1, 150.9, 149.0, 137.4, 135.1, 134.3, 133.6, 132.0, 130.3, 130.1, 129.2, 129.1, 128.4, 127.6, 127.0, 124.1, 120.7, 113.4, 99.6, 23.4, 21.4; HRMS (TOF-ESI) [M + H]+ calcd for C25H22NO2: 368.1645, found 368.1644. (1E,3Z)-1-(2-Acetamido-p-methoxybenzylidene)-3-benzylidene1,3-dihydroisobenzofuran 7ak. Yellow solid, 151 mg, 79%, mp 249− 250 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3259, 1648; 1H NMR (600 MHz, DMSO-d6) δ (ppm) 9.57 (s, 1H, NH), 7.90−7.91 (m, 1H), 7.77 (d, J = 6.6 Hz, 2H), 7.69−7.71 (m, 1H), 7.70 (d, J = 9 Hz, 2H), 7.49−7.51 (m, 2H), 7.35 (t, J = 8.4 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 9 Hz, 2H), 6.48 (s, 1H), 3.81 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 170.2, 159.2, 151.1, 148.4, 135.3, 134.3, 132.2, 130.4, 130.0, 129.2, 129.0, 128.9, 128.4, 127.0, 124.0, 120.7, 114.1, 113.4, 99.4, 55.8, 23.5; HRMS (TOF-ESI) [M + H]+ calcd for C25H22NO3: 384.1594, found 384.1594. (1E,3Z)-1-(2-Benzamidobenzylidene)-3-benzylidene-1,3-dihydroisobenzofuran 7aa. Yellow solid, 152 mg, 73%, mp 238−239 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3269, 1656, 1640; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.3 (s, 1H, NH), 8.10 (d, J = 7.2 Hz, 2H), 7.97 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8 Hz, 4H), 7.63−7.68 (m, 2H) 7.58 (t, J = 7.7 Hz, 2H), 7.43−7.54 (m, 4H), 7.32−7.39 (m, 3H), 7.23 (t, J = 7.4 Hz, 1H), 6.57 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 166.8, 150.9, 149.9, 136.6, 135.0, 134.6, 134.0, 132.5, 131.9, 130.42, 130.37, 129.2, 129.1, 128.7, 128.5, 128.1, 128.0, 127.6, 127.1, 123.8, 120.9, 113.3, 100.1; HRMS (TOF-ESI) [M + H]+ calcd for C29H22NO2: 416.1645, found 416.1651. (1E,3Z)-1-(2-Benzamidobenzylidene)-3-(p-fluorobenzylidene)1,3-dihydroisobenzofuran 7ha. Yellow solid, 142 mg, 65%, mp 241− 242 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3267, 1656, 1645; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.3 (s, 1H, NH), 8.09 (d, J = 8 Hz, 2H), 7.92 (d, J = 8 Hz, 1H), 7.83 (t, J = 6.8 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.63 (t, J = 8.8 Hz, 2H), 7.56 (t, J = 7.2 Hz, 2H), 7.47−7.51 (m, 3H), 7.43 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.57 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 166.9, 161.3 (d, J = 244.4 Hz), 150.6, 149.9, 136.7, 134.5, 134.2, 132.6, 132.0, 131.7 (d, J = 1.9 Hz), 130.5, 130.45, 130.4, 129.3, 128.8, 128.2, 128.1, 127.7, 123.7, 120.9, 116.1 (d, J = 21 Hz), 113.4, 99.0; HRMS (TOF-ESI) [M + H]+ calcd for C29H21FNO2: 434.155, found 434.1552. (1E,3Z)-1-(2-Benzamidobenzylidene)-3-(p-methylbenzylidene)1,3-dihydroisobenzofuran 7ia. Yellow solid, 153 mg, 71%, mp 244− 245 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3272, 1652, 1641; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.2 (s, 1H, NH), 8.09 (dd, J = 8.4, 1.6 Hz, 2H), 7.92 (d, J = 7.6 Hz, 1H), 7.81 (dd, J = 8, 0.8 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.63 (t, J = 8.4 Hz, 2H), 7.56 (t, J = 7.2 Hz, 2H), 7.45−7.51 (m, 3H), 7.41 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 8 Hz, 2H), 6.51 (s, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 166.9, 150.3, 150.0, 136.74, 136.71, 134.8, 134.2, 132.5, 132.3, 131.9, 130.5, 130.2, 129.8, 129.3, 128.7, 128.6, 128.2, 128.0, 127.7, 123.8, 120.8,

113.1, 100.2, 21.4; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO2: 430.1801, found 430.1803. (1E,3Z)-1-(2-Benzamidobenzylidene)-3-(p-methoxybenzylidene)1,3-dihydroisobenzofuran 7ja. Yellow solid, 160 mg, 72%, mp 231− 232 °C (recrystallization from THF/CH2Cl2/n-hexane); IR v (cm−1) 3274, 1649; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.2 (s, 1H, NH), 8.09 (d, J = 6.8 Hz, 2H), 7.89 (d, J = 8 Hz, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 9.2 Hz, 2H), 7.62 (t, J = 8 Hz, 2H), 7.56 (t, J = 8 Hz, 2H), 7.48 (t, J = 7.6 Hz, 3H), 7.39 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.50 (s, 1H), 3.77 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ (ppm) 166.9, 158.8, 150.1, 149.3, 136.8, 134.9, 134.2, 132.5, 131.7, 130.4, 130.03, 129.98, 129.3, 128.8, 128.2, 127.9, 127.7, 127.6, 123.8, 120.6, 114.8, 112.7, 100.1, 55.7; HRMS (TOF-ESI) [M + H]+ calcd for C30H24NO3: 446.175, found 446.1748.

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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.8b01163. Copies of 1H NMR and 13C NMR spectra for the products 5, 6, and 7 (PDF) Crystallographic data of 5aa (CIF) Crystallographic data of 6aa (CIF) Crystallographic data of 7ag (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ying Cheng: 0000-0002-2598-2974 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 21772015). REFERENCES

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Selective Synthesis of Multifunctionalized 2,3-Dihydroinden-1-ones

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