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[4+2]-Annulation of Donor-Acceptor Cyclopropanes with Acetylenes using 1,2-Zwitterionic Reactivity Roman A. Novikov, Anna V. Tarasova, Dmitry A. Denisov, Denis D. Borisov, Victor A. Korolev, Vladimir P. Timofeev, and Yury V. Tomilov J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00209 • Publication Date (Web): 13 Feb 2017 Downloaded from http://pubs.acs.org on February 14, 2017
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[4+2]-Annulation of Donor-Acceptor Cyclopropanes with Acetylenes using 1,2Zwitterionic Reactivity Roman A. Novikov,†,‡ Anna V. Tarasova,† Dmitry A. Denisov,† Denis D. Borisov,† Victor A. Korolev,† Vladimir P. Timofeev,‡ and Yury V. Tomilov*† †
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp.,
119991 Moscow, Russian Federation ‡
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov st., 119991
Moscow, Russian Federation Keywords: Donor-acceptor cyclopropane, 1,2-zwitterion, gallium trichloride, annulation, acetylenes, dihydronaphthalenes.
Abstract: A new process for the [4+2]-annulation of donor-acceptor cyclopropanes (DACs) with acetylenes under the effect of anhydrous GaCl3 using 1,2-zwitterion reactivity has been elaborated. The reaction opens access to substituted dihydronaphthalenes, naphthalenes and other fused carbocycles. The direction of the reaction can be efficiently controlled by temperature. Introduction Cyclopropanes with donor and acceptor substituents in vicinal position (donor-acceptor cyclopropanes, DACs) are remarkable building blocks widely used in contemporary organic synthesis to assemble diverse carbo- and heterocyclic systems.1,2 DACs have a great synthetic potential that stimulates researchers to intensify studies on their chemistry.3 Most commonly, DACs are used as sources of 1,3-zwitterion intermediates,1,2 which are then used in reactions with a broad range of substrates. Reactions of this kind have been studied most thoroughly. However, DACs are ACS Paragon Plus Environment
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multifunctional substrates and their application is not limited to 1,3-zwitterionic reactivity. The use of DACs as sources for generation of 1,2-zwitterions4 (Scheme 1, top) employs quite a different type of reactivity of DAC, 2-arylcyclopropane-1,1-dicarboxylates (ACDC) in particular. This type of reactivity was recently discovered by our team. Currently it is under intense development and is gaining popularity.4–10 A distinctive feature of this approach is that gallium compounds are used for complexation and opening of the three-membered ring with displacement of the carbocationic center.4,5a To date, the use of ACDC as 1,2-zwitterions has been studied for isomerization,6 dimerization,5 fragmentation,7 reactions with alkenes (Scheme 1, a),8 aldehydes,9 and addition of nucleophiles.10 In this work we expanded the 1,2-zwitterionic type of reactivity to reactions with acetylenes. In total, reactions of DACs with acetylenes have been studied rather poorly in comparison with other substrates.1,2,11 In fact, two pathways of reactions with acetylenes11 are known for the most popular ACDC that are commonly used as model substrates, namely, formal [3+2]-cycloaddition12 and [3+2]annulation13 to give cyclopentene and indene structures, respectively (Scheme 1, b). In this study, we succeeded in development of new ACDC reactions with acetylenes that occur by [4+2]-annulation type to give the dihydronaphthalene frame (Scheme 1, c) and performed some reactions involving these compounds.
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Scheme 1. The strategy of this study.
Dihydronaphthalene derivatives belong to important classes of organic compounds. The dihydronaphthalene frame is part of various natural compounds (Figure 1).14 Its derivatives both natural and synthetic show a very broad spectrum of biological activity, such as cytotoxic, antimicrobial, antimalarial, antiestrogenic, antiinflammatory activities, etc. as well as lipoxygenase enzyme inhibition, anti-HIV and anti-cancer properties.14,15 They also serve as versatile building blocks in the construction of biologically important compounds.16 Also dihydronaphthalenes are used as compounds with luminescent, phosphorescent and other properties.17 ACS Paragon Plus Environment
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Figure 1. Dihydronaphthalene skeleton in nature. Results and discussion The two-stage approach, which involved preliminary in situ generation of 1,2-zwitterionic gallium complex 1 immediately brought into a reaction with acetylene, was found to be the most efficient way to use ACDC in the function of 1,2-zwitterions. This approach was found to be quite efficient and allowed the pathway of reactions with acetylenes to be totally changed in the desired direction. However, a detailed optimization of the process conditions was required to obtain high product yields (Table 1); it was carried out using ACDC 2a and phenylacetylene 3a as the model compounds. During the optimization, we found that the conditions of ACDC reactions with acetylenes differed principally from similar reactions of ACDC with alkenes or dimerization reactions studied previously. In fact, acetylenes turned out to be much more efficient than alkenes, and their reactions with ACDC occurred at lower temperatures. Furthermore, the [4+2]-annulation product, i.e., dihydronaphthalenylmalonate 4aa, readily eliminated a dimethylmalonate moiety in the presence of gallium trichloride even at reduced temperatures, which resulted in its aromatization to give naphthalene 5aa (Table 1). All this complicated the implementation of the target [4+2]-annulation considerably. However, we managed to turn the drawbacks of the process into advantages and to develop, in addition to the target reaction, ACS Paragon Plus Environment
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new pathways of the ACDC reaction with acetylenes that can be carried out with high selectivity. Temperature is the main condition for easy control of the process direction (apart from generation of 1,2-zwitterion 1a). For example, selective synthesis of dihydronaphthalene 4aa requires that the second reaction stage be carried out at temperatures not higher than –70 °C to prevent subsequent fragmentation of the product (Table 1, Entries 10,11). Furthermore, ingress of moisture at reduced temperatures should be avoided as it can decrease the yield of the target product considerably (Entry 9). Conversely, selective synthesis of naphthalene 5aa requires that the temperature be increased to 40 °C (Entry 3). Table 1. Optimization of the reaction conditions. CO2Me Ph
CO2Me
GaCl3 (1 eq) 0 °C, 10 min CH2Cl2
MeO O GaCl3
Step 1
Ph
O MeO
2a
1,2-zwitterion, 1a Step 2 Optimal Temp.
–70 °C
Ph C CH 3a +40 °C
CO2Me CO2Me or
Ph
Ph
4aa
5aa
Entrya 3a (eq)
Step 2 T, °C
t, min
Yields, %b,c 5aa 4aa
1 2 3 4 5 6 7 8 9d 10 11e
40 40 40 0 –30 –70 –70 –70 –70 –70 –70
30 5 30 30 30 30 30 120 30 30 30
70b 67b 85 71b 62b
