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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 J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 02 Jul 2018 Downloaded from http://pubs.acs.org on July 2, 2018
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GaCl3–Mediated
The Journal of Organic Chemistry
“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
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 three-carbon 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.
INTRODUCTION Donor-acceptor cyclopropanes (DACs)1 proved themselves as unique building blocks in organic synthesis,2 mainly as sources for generation of 1,3zwitterions. 2-Arylcyclopropane-1,1-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 rising 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 1,2zwitterions 2 from them in the presence of gallium compounds (Scheme 1) developed in our scientific group.7,8 The 1,2-zwitterionic path of reactivity is of general nature and can be implemented with various substrates.7–12 It opens access to an extensive class of unique processes that allow various carbo- and 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 of certain substrate combinations have been developed and reported.10b,12,13 It should be noted that formal [2+2]-cycloaddition of gallium 1,2zwitterionic complexes to alkenes to give cyclobutanes was never implemented. Clearly, the 1,2-zwitterionic type of DAC reactivity is yet a very young chapter 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 focus on substrates with multiple C–C bonds. It should be noted that reactions of DACs with alkenes have been studied pretty well by now.9,14,15 The formal [3+2]-cycloaddition (Scheme 2),14 in which DACs serve as sources of 1,3-zwitterionic intermediates, have been studied most thoroughly. Moreover, the [3+2]-annulation (Scheme 2)15 and the
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aforementioned [4+2]-annulation (Scheme 1) are also well known.9 Scheme 1. 1,2-Zwitterionic reactivity of DACs and its reactions with different substrates.
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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 block in this process, while an alkene serves as a three-carbon block (i.e., as an allylic system). It should be noted that in the literature the single example of similar process is known, realized by Snider’s group (1986).14e Reaction of cyclopropanedicarboxylate with methylenecyclohexane in the presence of EtAlCl2 (2 equiv.) leads to the formation of product of formal [3+2]-cycloaddition (Scheme 3). RESULTS AND DISCUSSION The first group of “inverted” formal [3+2]cycloaddition processes was developed for tetramethylethylene 3 (TME). In 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-1,1dicarboxylate 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 2. Known reactions of DACs with alkenes to form five-member cycle.
Scheme 3. Known example of formal [3+2]cycloaddition of cyclopropanedicarboxylate to methylenecyclohexane.
As a result, DACs are widely used as convenient precursors to assemble functionally substituted fivemembered 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.
Table 1. Optimization of reaction conditions for reaction 1a with tetramethylethylene (TME). a
Entry
Concentration of 1a (mM)
TME, 3 (equiv.) b
T (oC)
4a Yield (%)
1
286
3
20
23 c
2
286
3
40
41
3
133
1
40
