Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 8193−8207
GaCl3‑Mediated “Inverted” Formal [3 + 2]-Cycloaddition of Donor− Acceptor Cyclopropanes to Allylic Systems Maria A. Zotova,§ Roman A. Novikov,*,§ Evgeny V. Shulishov, and Yury V. Tomilov* N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian Federation
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ABSTRACT: A new process of “inverted” formal [3 + 2]cycloaddition of donor−acceptor cyclopropanes (DACs) to allylic systems to give polyfunctionalized cyclopentanes has been developed. Unlike the classical version of formal [3 + 2]cycloaddition, a DAC acts in this process as a two-carbon synthon (1,2-zwitterionic reactivity type), while an alkene acts as a threecarbon synthon. Tetramethylethylene, allylbenzenes, homoallylbenzene, terminal and internal aliphatic alkenes, and methylenecyclobutane were successfully used as alkenes. Furthermore, in order to suppress annulation at the aromatic ring in 2-arylcyclopropane-1,1dicarboxylates and enhance the selectivity of the reaction with the allylic system of alkenes, we suggested a new approach for managing the reactivity of DACs involving substitution at both ortho positions of the aromatic ring. Multinuclear NMR spectroscopy was used to study the structure of the 1,2-zwitterionic gallium complexes generated and their properties and to examine the mechanisms of the occurring reactions.
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INTRODUCTION Donor−acceptor cyclopropanes (DACs)1 proved themselves as unique building blocks in organic synthesis,2 mainly as sources for generation of 1,3-zwitterions. 2-Arylcyclopropane1,1-dicarboxylates 1 are popular DACs3 that are also used in this study. This field of chemistry currently continues to develop rapidly4,5 and opens up new unique pathways of DAC reactivity,6 thus increasing the prospects of this class of compounds in organic chemistry. One of the new key types of DAC 1 reactivity involves the method for generation of formal 1,2-zwitterions 2 from them in the presence of gallium compounds (Scheme 1) developed by our group.7,8 The 1,2zwitterionic path of reactivity is of a general nature and can be implemented with various substrates.7−12 It opens access to an extensive class of unique processes that allow various carboand heterocyclic structures to be constructed, and it continues to be developed rapidly.10b,12 The reaction pathway considerably depends on the substrate, which reacts with the formal 1,2-zwitterion 2 generated (Scheme 1). [4 + 2]-Annulation at the aromatic ring that occurs with various substrates containing multiple bonds,7,9,10 including DAC 1 dimerization processes,7,8 is the most general process. The reaction of formal 1,2-zwitterions with aromatic aldehydes that occurs as [3 + 2]-annulation, as well as more complex cascade processes,11 is yet another general process. Apart from these reactions, a number of other narrower types of processes specific to certain substrate combinations have been developed and reported.10b,12,13 It should be noted that formal [2 + 2]-cycloaddition of gallium 1,2-zwitterionic complexes to alkenes to give cyclobutanes was © 2018 American Chemical Society
never implemented. Clearly, the 1,2-zwitterionic type of DAC reactivity is still a very young topic in the chemistry of cyclopropanes. Taking the above into consideration, in this work we continued a detailed study of the reactivity of formal 1,2zwitterions generated from DACs in the presence of gallium compounds, with a focus on substrates with multiple C−C bonds. It should be noted that reactions of DACs with alkenes have been studied pretty well to date.9,14,15 The formal [3 + 2]cycloaddition (Scheme 2),14 in which DACs serve as sources of 1,3-zwitterionic intermediates, has been studied most thoroughly. Moreover, the [3 + 2]-annulation (Scheme 2)15 and the aforementioned [4 + 2]-annulation (Scheme 1) are also well-known.9 As a result, DACs are widely used as convenient precursors to assemble functionally substituted five-membered carbocycles.16 As the cyclopentane skeleton is widespread in many synthetic and natural biologically active compounds,17 such as prostaglandins, steroids, terpenoids etc., various methods to assemble the cyclopentane skeleton are developed and new variants are searched for. In this work we succeeded in implementing one more rather general pathway of DAC 1 reactions with alkenes and suggested methods for controlling the DAC reactivity. The method that we developed is an example of “inverted” formal [3 + 2]-cycloaddition of DACs to alkenes (Scheme 1). Unlike the classical variant, a DAC serves as a two-carbon building Received: April 16, 2018 Published: July 2, 2018 8193
DOI: 10.1021/acs.joc.8b00959 J. Org. Chem. 2018, 83, 8193−8207
Article
The Journal of Organic Chemistry
this case, DACs were used as sources for generation of gallium 1,2-zwitterionic intermediates 2 in the presence of anhydrous gallium trichloride. We used 2-phenylcyclopropane-1,1-dicarboxylate 1a as the model DAC. It should be noted that TME markedly differs in reactivity from the majority of alkenes and quite poorly undergoes [4 + 2]-annulation typical of these compounds.9 In this case, resinification and oligomerization were the main reaction pathways, which required an optimization of the reaction conditions in order to minimize these processes (Table 1).
Scheme 1. 1,2-Zwitterionic Reactivity of DACs and Its Reactions with Different Substrates
Table 1. Optimization of Reaction Conditions for Reaction 1a with Tetramethylethylenea
Scheme 2. Known Reactions of DACs with Alkenes to Form Five-Member Cycle
entry
concentration of 1a (mM)
TME, 3 (equiv)b
T (°C)
4a yield (%)
1 2 3 4 5 6 7 8
286 286 133 133 133 66 66 66
3 3 1 3 5 1 3 5
20 40 40 40 40 40 40 40
23c 41
