Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Cu(I)-Catalyzed Intramolecular Tandem Cyclization of N‑IndoleTethered Cyclopropenes: Synthesis of Functionalized Hydrogenated Diazabenzo[a]cyclopenta[cd]azulene Derivatives Peng-Hua Li,† Song Yang,† Tong-Gang Hao,† Qin Xu,† and Min Shi*,†,‡
Org. Lett. Downloaded from pubs.acs.org by IDAHO STATE UNIV on 04/17/19. For personal use only.
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Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, People’s Republic of China ‡ State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China S Supporting Information *
ABSTRACT: A Cu(I)-catalyzed [3 + 2] intramolecular cycloaddition reaction of N-indole-tethered cyclopropenes is presented in this paper. This reaction starts from the formation of π-allyl cationic intermediate or its resonance-stabilized metal carbenoid intermediate upon activation of cyclopropene with Cu(I) catalyst and a Friedel−Crafts-type cyclization to give functionalized hydrogenated diazabenzo[a]cyclopenta[cd]azulenes in good to excellent yields along with moderate to good dr values. The asymmetric variant of this cycloaddition reaction can be realized, giving the desired products with moderate ee values.
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highly strained carbocycles are readily accessible and can be involved in transition-metal-catalyzed reactions through various reaction modes due to their unique characteristics. First, vinyl carbenoid metal complex, resulting from the ringopening process of cyclopropenes, can be formed upon transition-metal catalysis, which further undergo intramolecular 1,5- or 1,6-C(sp3)-H insertion reactions or the nucleophilic additions by oxygen atom to afford the corresponding cyclized products.4 In addition, cycloaddition reactions with unsaturated moieties are the other important reaction mode. Namely, these vinyl carbenoid metal complexes can undergo intramolecular [1 + 2] cyclopropanation with olefins to achieve cyclizations (Scheme 1, eq 1).5 Moreover, cyclopropenes can act as the three-carbon synthon to undergo [3 + 2] cycloaddition reactions with olefins or [3 + 4] cycloaddition reactions with 2H-pyran-2-ones in the presence of metal catalysts or under heating conditions (Scheme 1, eq 1).6 On the other hand, highly substituted cyclopropane derivatives can be produced when the ring-opening process of cyclopropenes is not involved in these cycloaddition reactions. For instance, substituted cyclopropenes can be used as dipolarophiles in the cycloaddition reactions with azomethine ylides.7 In 2018, Stepakov and coworkers disclosed such an example in the cycloaddition reaction of 1,2-diphenylcyclopropene with azomethine ylide generated from ketone and proline, producing formal [3 + 2] cycloadduct without cyclopropene ring-opening (Scheme 1, eq 2).7b Furthermore, as for
ultiple parallel cyclic structures containing sevenmembered aza-heterocyclic rings are valuable intermediates in organic synthesis. As its subunits, these frameworks, containing aza-azulene or cyclopenta-azepine motifs and existing in a great number of bioactive natural products and pharmaceuticals, frequently displayed significant activity against rubrum and subtilis and have been used in traditional medicine to treat carbuncle abscess in folk medicine and others and as an insecticide (Figure 1).1 Thus, the exploration of new synthetic approaches to directly construct this pivotal skeleton and their derivatives is an important objective in the area of synthetic organic chemistry and medicinal chemistry.2 Cyclopropenes, which have a fascinating versatile reactivity, have captured the attention of organic chemists in the area of transition-metal catalysis for more than half a century.3 These
Figure 1. Selected examples of nature products with aza-azulene or cyclopenta-azepine motifs © XXXX American Chemical Society
Received: March 10, 2019
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DOI: 10.1021/acs.orglett.9b00864 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. General Reaction Modes of Cyclopropene Derivatives and This Work
Table 1. Optimization of the Reaction Conditions for Transition-Metal-Catalyzed Cycloaddition Reactions
entrya
catalyst
solvent
yield (%)/(2a:2a′)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
AgOTf PtCl2 Rh2(OAc)4 PPh3AuNTf2 IPrAuNTf2 [JohnPhosAu](MeCN)SbF6 DppmAu(MeCN)SbF6 [JackiePhosAu](MeCN)OTf [tBuXPhosAu](MeCN)NTf2 [tBuBrettPhosAu](MeCN)OTf [Me4tBuXPhosAu](MeCN)OTf Cu(MeCN)4BF4 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6
DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCE CHCl3 THF
25 (1.5:1) 74 (9.9:1) 25 (5.0:1) 88 (1.5:1) 93 (1.3:1) 98 (3.0:1) 88 (2.0:1) 78 (1.7:1) 71 (2.0:1) 25 (1.0:1) 12 (1.4:1) 63 (6.0:1) (86c)(12:1) 74 (10:1) 82 (1.1:1) 64 (3.2:1)
a
Reaction was run under the following conditions: a solution of 1a (0.05 mmol) and catalyst (0.005 mmol) in dry solvent (1.0 mL) was stirred at room temperature under nitrogen atmosphere. bYields and dr values were determined by 1H NMR spectroscopic analysis of the crude mixture. cIsolated yield of 2a after purification by flash chromatography.
cyclopropenes containing an ester group at C3 position, the coordination between metal catalyst and cyclopropene can generate metal-activated cyclopropenes, which can be attacked by the tethered nucleophiles to give functionalized cyclopropanes (Scheme 1, eq 3).8 In the field of chemical transformations of cyclopropenes, we investigated a series of reactions of functionalized cyclopropenes with indoles or propargylic esters.9 As our ongoing efforts on the exploration of transition-metal-catalyzed or mediated new reactions of indoles10 and cyclopropenes, we designed a new type of N-indole-tethered cyclopropenes to realize the rapid construction of polyheterocyclic frameworks. Herein, we report a copper(I)-catalyzed transformation of these functionalized cyclopropenes to hydrogenated diazabenzo[a]cyclopenta[cd] azulene derivatives via a tandem cycloaddition accompanied by a cyclopropene ring-opening process (Scheme 1, eq 4). To clarify the feasibility of our working hypothesis, we initially investigated the reaction of N-(2-(1H-indol-1-yl)ethyl)-N-((2-butylcycloprop-2-en-1-yl)methyl)-4-methylbenzenesulfonamide 1a in the presence of various metal catalysts (10 mol %), and the results are summarized in Table 1 (for more details, see Table S1 in the Supporting Information). To our delight, the desired formal [3 + 2] cycloaddition took place smoothly in dichloromethane (DCM) at room temperature in the presence of AgOTf for 20 h, affording the cycloadducts 2a and 2a′ in total 25% yield along with 1.5:1 dr value (Table 1, entry 1). Next, we optimized the reaction conditions by screening various transition-metal catalysts. When PtCl2 was employed as the catalyst, the diazabenzo[a]cyclopenta[cd]azulene 2a was obtained in 74% yield along with the 9.9:1 dr value (Table 1, entry 2). When Rh2(OAc)4 was used as the catalyst, 2a was produced in only 25% yield along with a moderate dr value (5.0:1) (Table 1, entry 3). Notably, the use of PPh3AuNTf2 as the catalyst gave the desired product 2a in good yield up to 88% but with lower dr value (1.5:1) (Table 1, entry 4). On the basis of this finding, several other gold
catalysts coordinated with different ligands were investigated, and we found that when IPrAuNTf2, [JohnPhosAu](MeCN)SbF6, or DppmAu(MeCN)SbF6 was used as the catalyst, the desired product 2a was given in excellent yields but with lower dr values (>88% yields and
