Lewis Acid-Catalyzed Selective [2 + 2]-Cycloaddition and

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Lewis Acid-Catalyzed Selective [2 + 2]-Cycloaddition and Dearomatizing Cascade Reaction of Aryl Alkynes with Acrylates Liang Shen,‡ Kai Zhao,†,‡ Kazuki Doitomi,§ Rakesh Ganguly,‡ Yong-Xin Li,‡ Zhi-Liang Shen,*,†,‡ Hajime Hirao,‡,§ and Teck-Peng Loh*,†,‡ †

Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing, Jiangsu, P. R. China, 210009 ‡ Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 637371 § Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China S Supporting Information *

ABSTRACT: Combined Lewis acid, consisting of two or more Lewis acids, sometimes shows unique catalytic ability, and it may promote reactions which could not be catalyzed by any of the Lewis acids solely. On the other hand, the development of efficient methods for the facile synthesis of cyclobutenes and densely functionalized decalins is an attractive target for synthetic chemists due to their versatile synthetic utilities and widespread occurrence in natural products. Herein, we wish to report an efficient method for the assembly of cyclobutenes and densely functionalized decalin skeletons through In(tfacac)3TMSBr catalyzed selective [2 + 2]-cycloaddition and dearomatizing cascade reaction of aryl alkynes with acrylates with high chemo- and stereoselectivity. The obtained cyclobutene could be easily converted into cyclobutane as well as synthetically useful 1,4- and 1,5-diketones with high chemo- and stereoselectivity. On the basis of mechanistic studies, plausible reaction mechanisms were proposed for both the [2 + 2]-cycloaddition and the dearomatizing cascade reaction. Finally, the computational studies of reaction mechanisms were conducted, and the results suggest that the combined Lewis acid could efficiently promote both reactions.

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INTRODUCTION

cyclobutenes, [2 + 2]-cycloaddition of an alkyne with an alkene represents one of the most straightforward routes.6−12 The Lewis acid-catalyzed reactions usually require an electronic imbalance between two coupling partners, a combination of electron-rich alkynes and electron-deficient alkenes or vice versa.7−10 For the former class of substrates, several elegant and seminal works have been reported by Narasaka,8 Kozmin,9 Hsung,10 and others; nonetheless, their applications are mainly limited to more reactive alkynes bearing a heteroatom substituent, reflecting the synthetic hurdle in using nonactivated alkynes such as aryl alkynes as substrates. Especially noteworthy is that cyclobutanes bearing aryl and ester functionalities are prevalent molecular frameworks in a myriad of natural products as well as bioactive intermediates (Figure 1).3 In this regard, direct [2 + 2]-cycloaddition of unactivated aryl alkynes with easily accessible acrylates followed by hydrogenation will provide an easy entry to the abovementioned cyclobutanes, and to the best of our knowledge, there is no precedent report on employment of a Lewis acid catalyst system for this reaction.11

The development of efficient methods which could rapidly increase molecular complexity or assemble highly strained cyclic ring systems is the continuing aim of organic chemists.1 In this regard, cyclobutane and decalin rings are very attractive targets mainly due to their widespread occurrence in terpenes, steroids, and other natural products (Figure 1).2,3 Lewis Acid-Catalyzed [2 + 2]-Cycloaddition of Aryl Alkyne with Alkene. Synthetic strategies to assemble cyclobutene rings have been intensively investigated because of the profound synthetic values associated with their inherent ring strain.4,5 Among the methods developed to access

Figure 1. Representative compounds containing cyclobutane moieties or a functionalized decalin ring.2,3 © 2017 American Chemical Society

Received: July 29, 2017 Published: September 7, 2017 13570

DOI: 10.1021/jacs.7b07997 J. Am. Chem. Soc. 2017, 139, 13570−13578

Article

Journal of the American Chemical Society Dearomatization Diels−Alder Reaction of Styrene with Alkene. Among the methods developed for the preparation of functionalized alicyclic compounds, the simple yet efficient strategies granted by dearomatization reaction of arenes are particularly attractive in view of their prevalence, low cost, and susceptibility for synthetic derivatizations.1,12 Considering the easy access of styrene derivatives and the desire to develop atom-economic reactions, the dearomatizing [4 + 2]-cycloaddition of a styrene with an olefin has been considered as an ideal method for decalin formation. However, there is no widely applicable method that has been developed in this area for two reasons: first, the associated loss of aromatic character requires either extremely reactive dienophiles or harsh reaction conditions; second, the dearomatization product (1:1 Diels−Alder adduct) is unstable so that it will decompose or undergo further reaction to give the mixture of double Diels− Alder adduct 1 as well as rearomatized products 2 and 3 (Scheme 1).13 Harman has reported an elegant Diels−Alder

Scheme 2. Selective Dearomatizing Cascade Reaction and [2 + 2]-Cycloaddition of Aryl Alkyne with Acrylate

temperature (Table 1). However, no reaction occurred under the above condition (entry 1). Increasing the loading of InBr3 Table 1. Optimization of In(III)-TMSBr-Catalyzed [2 + 2]Cycloaddition of 1c with 2aa

Scheme 1. Dearomatizing [4 + 2]-Cycloaddition of Styrene with Alkene

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

reaction of metal-complex-activated styrene with dienophiles with good selectivity.14 To date, there has been no catalytic system which can catalyze the dearomatizing [4 + 2] reaction of styrene with common dienophiles to give a stable dearomatization product under mild conditions with good chemoselectivity. Combination of In(III) Salt and Trimethylsilyl Halide. Indium(III) salts have found widespread applications as effective Lewis acids in organic synthesis in recent decades.15 Given their relatively weak strength as Lewis acid compared with other group IIIA elements such as aluminum and boron, trimethylsilyl halide is often employed together with indium salts as a robust combined Lewis acid catalyst. This combined Lewis acid system has been utilized in various reactions developed by Baba,16 Lee,17 Corey,18 our group,19 and others. This Work. In continuation of our research interest in the application of indium in organic synthesis,19,20 herein we wish to report the first example of In(III)-TMSBr-catalyzed selective [2 + 2]-cycloaddition and dearomatizing cascade reaction of aryl alkyne with acrylate to access a series of densely functionalized decalin derivatives and cyclobutenes bearing aryl and carbonyl substituents at room temperature with high chemo- and stereoselectivity (Scheme 2). It is noteworthy that the obtained cyclobutene could be easily converted into cyclobutane as well as 1,4- and 1,5-diketones with high chemo- and stereoselectivity and the dearomatizing cascade reaction involves the formation of a 1:1 Diels−Alder adduct as an intermediate.

catalyst InBr3 InBr3 InBr3 InBr3 InF3 InCl3 InI3 In(acac)3 In(tfacac)3 In(tfacac)3 In(tfacac)3 In(tfacac)3

solvent CH2Cl2 CH2Cl2 DCE CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 DCE DCE DCE

TMSX

yieldb (%)

TMSBr TMSBr TMSBr TMSBr TMSBr TMSBr TMSBr TMSBr TMSCl TMSI

0 0c 0d 54 0 54 24 49 0 68 81 33 38

a Unless otherwise noted, all reactions were performed with 1c (0.4 mmol), 2a (1.6 mmol), catalyst (20 mol %), TMSX (3 equiv), 0 °C-rt, 2 h, N2. bIsolated yields. c1.0 equiv of InBr3 was added. dThe reaction temperature was 80 °C.

to 1 equiv or heating the reaction mixture to 80 °C did not affect the reaction, either (entries 2−3).11 Gratifyingly, the desired cyclobutene product 3ca could be obtained in 54% yield when 3 equiv of TMSBr was added as an additive (entry 4). With this promising result in hand, optimization of the reaction conditions was subsequently carried out. Among the different indium catalysts studied (entries 6−10), In(tfacac)3 was also found to exhibit the best catalytic activity to afford the desired product 3ca in 68% yield (entry 10). In sharp contrast, the similar catalyst of indium(III) acetylacetonate [In(acac)3] could not catalyze the reaction, providing no desired product 3ca (entry 9). Other common Lewis acid catalysts (e.g., AlBr3, ZnCl2, and TiCl4) were also screened, which mostly resulted in no product formation or in inferior yields (see Table SI-1 in the Supporting Information for details). In addition, this reaction was found to work only in chlorinated solvents such as CH2Cl2 or DCE, with the latter giving a higher yield of 81% (entry 10 vs entry 11). In comparison, when TMSBr was replaced by TMSCl or TMSI, the product yields were eroded significantly to 33 and 38% (entries 12−13). An attempt to decrease the

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RESULTS AND DISCUSSION Optimization of In(III)-TMSBr-Catalyzed [2 + 2]-Cycloaddition of Aryl Alkyne with Acrylate. At the outset, 1phenyl-1-pentyne (1c) and methyl acrylate (2a) were chosen as the model substrates to attempt the reaction with a catalytic amount of InBr3 (20 mol %) in CH2Cl2 from 0 °C to room 13571

DOI: 10.1021/jacs.7b07997 J. Am. Chem. Soc. 2017, 139, 13570−13578

Article

Journal of the American Chemical Society

products 3sa and 3ta, respectively, both in 65% yield. The R1 substituent also could be ring motifs (e.g., cyclopropyl, cyclohexyl, and phenyl), and the corresponding tricylic cyclobutene products 3ua-wa were obtained in moderate yields. The obtained diphenyl substituted cyclobutene 3wa possesses the main skeleton of the unnamed norlignan shown in Figure 1.3b Substrate Scope of Acrylates for Indium(III)-TMSBrCatalyzed [2 + 2]-Cycloaddition. Next, compatibility of different acrylates 2 to the present reaction protocol was investigated using 1-phenyl-1-pentyne (1c) as a standard coupling partner (Table 2b). Reactions of acrylates containing longer O-alkyl substituents proceeded smoothly to give cyclobutenes 3cb-ce, albeit in relatively low yields (13−61%) as compared to methyl acrylate (3ca). Acrylates tethered with other substituents aside from a simple aliphatic chain, such as chloroethyl, bromoethyl, phenyl, phenoxyethyl, and trifluoroethyl group, readily underwent the reaction to afford the corresponding cyclobutenes 3cf-cj in moderate to good yields (32−75%). Functional Group Transformation of Cyclobutenes. The existence of ester and alkene functionalities in the cyclobutene product granted diversified chemical transformations of these products (Scheme 3). The ester group could

amount of TMSBr or methyl acrylate (2a) was observed to have a detrimental impact on reaction efficiency (see Table SI-1 in the Supporting Information for details). Substrate Scope of Aryl Alkynes for Indium(III)TMSBr-Catalyzed [2 + 2]-Cycloaddition. With the optimized reaction conditions in hand (Table 1, entry 11), we went on to probe the generality of alkyne substrate scope of this [2 + 2]-cycloaddition with respect to 2a, and the results are summarized in Table 2a. Both internal alkynes and terminal Table 2. Substrate Scope for In(III)-TMSBr-Catalyzed [2 + 2]-Cycloadditiona,b

Scheme 3. Functional Group Transformations of Cyclobutenes

a Unless otherwise noted, all reactions were performed with 1 (0.4 mmol), 2 (1.6 mmol), In(tfacac)3 (20 mol %), TMSBr (3 equiv), 0 °C-rt, N2. bIsolated yields.

either be reduced by LiAlH4 to afford the desired alcohol 3ca-1 or be hydrolyzed in the presence of aqueous NaOH to deliver the corresponding carboxylic acid 3ca-2 (Scheme 3a). Moreover, the C−C double bond of 3ca could be diastereoselectively hydrogenated by H2 in the presence of Pd/C to give cyclobutane 3ca-3 and be oxidized by m-CPBA to generate epoxide 3ca-4 as single diastereomers (Scheme 3b).21 Notably, 3ca-3 closely resembles the key cyclobutane skeleton shown in Figure 1.3 Encouragingly, the four-membered ring moiety survived under these reaction conditions and remained intact during the course of these transformations. The cyclobutene structure was unambiguously confirmed by the X-ray diffraction analysis of 3xa-1, which was prepared by the saponification of ester 3xa followed by esterification with 6-Br-naphthol in the presence of HATU and DMAP (Scheme 3c).22 Acid- and O2-Mediated Selective Cleavage of the C C/CC Bond of Cyclobutene 3ca. In addition to the abovementioned versatile functional group transformations, the

alkynes were proven to be suitable substrates for this reaction protocol to produce respective products 3aa-wa and 3xa-za in moderate to good yields. Analogously, alkynes bearing linear alkyl substituents underwent the transformation smoothly to afford 3aa-da in 73−85% isolated yields. The presence of sterically more demanding substituents on alkynes, for example, iso-butyl and tert-butyl groups, furnished cyclobutenes 3ea and 3fa in reasonable yields. When halogen substituents or a phenyl group are present on the phenyl ring, the reactions worked equally well to deliver the corresponding products 3ga-ja and 3qa in moderate to good yields, rendering these products amenable for downstream chemical modifications. Notably, alkynes possessing an allyl or benzyl group are compatible with the mild reaction conditions, leading to the anticipated 13572

DOI: 10.1021/jacs.7b07997 J. Am. Chem. Soc. 2017, 139, 13570−13578

Article

Journal of the American Chemical Society existence of phenyl and ester substituents might lead to some new reaction modes. It is commonly known that cyclobutene could be easily transformed to related diene under thermal conditions.4,5 However, when 3ca was refluxed in toluene for 24 h, most of the starting material was recovered and no diene product could be observed (Scheme 4a). After many trials, we

Table 3. Acid- and O2-Mediated Selective Cleavage of the C−C Bond of Cyclobutene

Scheme 4. Acid- and O2-Mediated Selective Cleavage of the CC/CC Bond of 3ca

were pleased to find that cyclobutene 3ca could be selectively converted into 1,5-dicarbonyl compound 4ca or 1,4-dicarbonyl compound 5ca through selective cleavage of the CC or C C bond of 3ca in the presence of InBr3-aq. HBr or atmospheric O2 at room temperature, respectively (Scheme 4b). It should be noted that the present method for the synthesis of 1,5dicarbonyl compound is the first example of acid-mediated conversion of cyclobutene to linear ketone.23 On the other hand, direct cleavage of the CC bond using molecular oxygen instead of ozone is rare; most of the existing methods were reported to work only with acyclic alkenes and should proceed in the presence of catalyst.24 Substrate Scopes of Acid- and O2-Mediated Selective Cleavage of the CC/CC Bond of Cyclobutene. Having recognized the novelty and synthetic value of these CC/CC bond cleavage reactions, we focused on examining the substrate scope felicitous for these transformations, and the results are summarized in Table 3. It was found that both ring-opening reactions proceeded efficiently under mild conditions to produce the desired 1,5- and 1,4dicarbonyl compounds in moderate to good yields in the presence of InBr3-aq. HBr or atmospheric O2, respectively. It should be noted that the effects of the R1 substituent on both ring-opening reactions are similar: as the R1 chain was elongated from one to four carbons, the yields of 1,5-dicarbonyl compounds 4aa-da and 1,4-dicarbonyl compounds 5aa-da decreased accordingly. In contrast, when the R2 alkyl chain length increased from the methyl to n-hexyl group, 4ca-cc was formed in decreased yield, while the formation of 5ca-cd showed the opposite trend. One-Pot Synthesis of Pyrrole and Furan Derivatives from 3ca. Notably, 1,4-dicarbonyl compounds are difficult to prepare by conventional methods but are useful building blocks toward various carbocyclic and heterocyclic structural motifs.25 By employing this protocol, trisubstituted pyrrole 3ca-5 and furan 3ca-6 can be facilely synthesized in a one-pot manner by subjecting cyclobutene 3ca to aforementioned oxygen-mediated cleavage followed by ring closure in the presence of NH4OAc/AcOH or P2O5 (Scheme 5).25a Preliminary Result of In(III)-TMSBr-Catalyzed Dearomatizing Cascade Reaction. This dearomatizing cyclization reaction was serendipitously discovered during our course of studying the application of the combined Lewis acid system

a

Unless otherwise noted, all reactions were performed with 3 (0.1 mmol), InBr3 (1 equiv), 48% aq. HBr (1.5 equiv), DCM (1 mL), 36 h, rt, N2. bIsolated yield. cThe reaction time was 12 h. dUnless otherwise noted, all reactions were performed with 3 (0.1 mmol), O2 ballon, neat, rt, 72 h.

Scheme 5. One-Pot Synthesis of Pyrrole and Furan Derivatives from 3caa,b

a

Reaction conditions: (a) (1) 3ca (0.1 mmol), O2, rt, 72 h; (2) NH4OAc (5 equiv), AcOH (0.3 mL), 90 °C, 24 h. (b) (1) 3ca (0.1 mmol), O2, rt, 72 h; (2) P2O5 (3 equiv), toluene, 100 °C, 24 h. b Isolated yield.

of InX3-TMSBr in an attempted dearomatizing [4 + 2]cycloaddition between α-aryl vinyl bromide and acrylate under ambient conditions. Considering the relative instability of α-aryl vinyl bromide, we speculated that this Diels−Alder reaction could be realized in a one-pot manner by in situ generation of α-aryl vinyl bromide c from aryl alkyne a in the presence of a proton source,26 followed by a [4 + 2]-cycloaddition with Lewis acid-activated acrylate b to give 1:1 Diels−Alder product d that could presumably undergo further reaction (Scheme 6a). To test this hypothesis, a reaction using 4-ethynyltoluene (6a) and methyl acrylate (2a) as model substrates was performed in the presence of InBr3 (20 mol %), TMSBr (4 equiv; which could serve as both additive and bromine source), and H2O (1.0 equiv; which could serve as proton source) in CH2Cl2. When the reaction mixture was stirred at 0 °C to room temperature for 30 min, no hypothesized 1:1 Diels−Alder product int-7aa was obtained. To our surprise, a polycyclic ene 7aa was obtained in 37% yield with >20:1 d.r., along with 13573

DOI: 10.1021/jacs.7b07997 J. Am. Chem. Soc. 2017, 139, 13570−13578

Article

Journal of the American Chemical Society Scheme 6. Originally Proposed Dearomatizing [4 + 2]Cycloaddtion of α-Aryl Vinyl Bromide with Acrylate

Table 4. Optimization of In(III)-Catalyzed Dearomatizing Cascade Reaction of 6a with 2aa

formation of 7aa-1 in 4% yield (Scheme 6b). The structure of product 7aa was unequivocally confirmed by single crystal Xray diffraction analysis.22 After meticulous structural examination of 7aa and 7aa-1, we tentatively proposed that the initially postulated [4 + 2]-cycloaddition could have occurred to give 1:1 Diels−Alder adduct int-7aa as a reaction intermediate. The expected high reactivity of int-7aa could have allowed it to participate in tandem reactions through interception by another molecule of aryl alkyne 6a to generate 7aa or undergo rearomatization to give 7aa-1. To the best of our knowledge, this is the first example of interception of 1:1 Diels−Alder adduct through a nucleophilic attack of alkyne. While in another reported case, it was observed that the 1:1 Diels−Alder adduct could react with another molecule of dienophile to give either a double Diels−Alder product or a Diels−Alder-ene product (Scheme 1).13 Optimization of In(III)-TMSBr-Catalyzed Cascade Dearomatization Reaction of 6a with 2a. Intrigued by the efficient and elegant construction of complex molecular architectures from simple substrates under an operationally simple procedure, we commenced the optimization studies of this reaction using 4-ethynyltoluene (6a) and methyl acrylate (2a) as model substrates (Table 4). It was found that indium catalyst, TMSBr, and H2O were indispensable for product formation: reactions performed in the absence of indium catalyst, H2O, or TMSBr resulted in an almost negligible formation of the desired product 7aa (entries 1−3). Among the different indium catalysts evaluated (entries 4−9), indium(III) trifluoroacetylacetonate [In(tfacac)3] was found to exhibit the best catalytic activity to afford the desired product 7aa in 66% yield (entry 9). Common Lewis acid catalysts (e.g., AlBr3, ZnCl2, and TiCl4) were also screened, which mostly resulted in no product formation (see Table SI-2 in the Supporting Information for details). In addition, this reaction was found to be highly solvent-dependent and worked only in chlorinated solvents such as CH2Cl2 or 1,2-dichloroethane (DCE), albeit in relatively low yield with DCE (entry 9 vs entry 10). On the other hand, when TMSBr was replaced by TMSCl, only a trace amount of the corresponding product could be detected in the crude NMR spectrum (entry 11). We also found that the amount of H2O critically affected the product yield: decreasing or increasing the amount of H2O to 0.5 or 2.0 equiv hampered the yield significantly or even inhibited the product formation

entry

catalyst

solvent

TMSX

yieldb (%)

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

InBr3 InBr3 InBr3 InF3 InCl3 InI3 In(OTf)3 In(tfacac)3 In(tfacac)3 In(tfacac)3 In(tfacac)3 In(tfacac)3

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 DCE CH2Cl2 CH2Cl2 CH2Cl2

TMSBr TMSBr

0