Letter Cite This: Org. Lett. 2018, 20, 7947−7952
pubs.acs.org/OrgLett
Expanding the Reactivity of Donor−Acceptor Cyclopropanes: Synthesis of Benzannulated Five-Membered Heterocycles via Intramolecular Attack of a Pendant Nucleophilic Group Olga A. Ivanova,*,† Vladimir A. Andronov,† Vladimir S. Vasin,‡ Alexey N. Shumsky,§ Victor B. Rybakov,† Leonid G. Voskressensky,∥ and Igor V. Trushkov*,‡,∥ †
Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991, Russian Federation Laboratory of Chemical Synthesis, Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology, and Immunology, Samory Mashela 1, Moscow 117997, Russian Federation § N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygina 4, Moscow 119334, Russian Federation ∥ Faculty of Science, RUDN University, Miklukho-Maklaya 6, Moscow 117198, Russian Federation
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‡
S Supporting Information *
ABSTRACT: Lewis-acid-induced domino transformations of donor−acceptor cyclopropanes, possessing a nucleophilic center embedded in a donor group, into functionalized 2,3dihydrobenzo[b]furans and 2,3-dihydrobenzo[b]thiophenes are reported herein. An unusual switch of the electrophilic center in the three-membered ring, from the atom bearing a donor substituent to an unsubstituted carbon atom, was achieved by a judicious choice of Lewis acid, which induces the isomerization of a cyclopropane to an electrophilic alkene, and the length of linker, connecting a nucleophilic moiety and the small ring.
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promising platforms for synthesizing diverse ring systems in a single operation with controllable reactivity and selectivity. Some interesting transformations of that type of DA cyclopropanes have been recently reported demonstrating their utility toward rapidly accessing structurally diverse products.11−13 In these processes, the C(2) atom of cyclopropane, connected to the donor substituent, typically behaves as an electrophilic center, while the donor substituent contains the appropriate nucleophilic center. We and others have reported two principal methods for forming of carbo- or heterocycles with the participation of the aforementioned centers. The first strategy includes a reaction with some external species (alkene, alkyne, the second molecule of DA cyclopropane, and so on, Scheme 1a).8c,e,11 The second approach is based on a direct intramolecular reaction between these functionalities if they are separated by a linker containing three, four, or five atoms to afford five-, six-, or seven-membered rings, respectively (Scheme 1b).2k,12 Here, we report a new face of DA cyclopropane reactivity when the three-membered ring is attacked by a nucleophilic site in the donor substituent separated by only two atoms (Scheme 1c). This reaction was designed by exploiting the recently disclosed capacity of DA cyclopropanes to react as
ultifunctional building blocks are widely used in modern organic synthesis, and the development of efficient transformations of such compounds into diverse carbo- and heterocycles still remains a challenging goal for synthetic and medicinal chemists.1 In this regard, donor− acceptor (DA) cyclopropanes constitute an important class of building blocks with an amazingly wide variety of reactivity.2,3 Their synthetic potential arises primarily from the ability to react as the synthetic equivalents of all-carbon 1,3-zwitterions, which are otherwise difficult to generate. This is manifested in nucleophilic3a,4 and electrophilic5 ring opening, 1,3-difunctionalizations,6 and (3 + n)-cycloadditions,7 providing efficient pathways for forming diverse valuable acyclic and cyclic compounds. In addition to these mainstream applications, DA cyclopropanes have been incorporated into diverse processes based on their ability to react as isomeric alkenes conjugated with either donor8 or acceptor group(s).8c,9 Nevertheless, the great possibilities inherent to using DA cyclopropanes as flexible building blocks provided by the reactive synergy of the three-membered ring and activating group (donor or acceptor10 moiety) remain underexplored. In this line, we focus our attention on DA cyclopropanes, in which the donor group not only contributes to polarization of the C(1)−C(2) bond between the atoms bearing acceptor and donor substituents (facilitating this bond cleavage) but also provides an additional reactive site for constructing cyclic molecules. Such substrates, that can be referred to as “DA cyclopropanes in which donor is not donor only”, are © 2018 American Chemical Society
Received: November 3, 2018 Published: December 5, 2018 7947
DOI: 10.1021/acs.orglett.8b03491 Org. Lett. 2018, 20, 7947−7952
Letter
Organic Letters Scheme 2. Synthesis of Cyclopropanes 1a,b
Scheme 1. Modes of Synergic Reactivity of the ThreeMembered Ring and Donor Group in DA Cyclopropanes
isomeric electrophilic alkenes.9,14,15 Consequently, instead of common nucleophilic ring opening via attack on the donorbearing C(2) atom of cyclopropane, a domino sequence including the generation of this alkene activated by complexation with Lewis acid followed by intramolecular Michael addition is realized. To implement this strategy, we selected DA cyclopropanes 1 bearing 2-hydroxy- or 2-mercaptoaryl groups as a donor substituent due to the high nucleophilicity of the (thio)phenolic moiety. This approach provides a rapid assembly of functionalized benzannulated five-membered heterocycles such as 2,3-dihydrobenzo[b]furans (DHBF) and -thiophenes (DHBT). The persistent interest in efficient approaches to these heterocycles stems from their ubiquity as the core fragment in natural and bioactive compounds (griseofulvin,16 ramelteon,17 rocaglamide,18 zatosetron,19 etc.20). As the starting compounds for the synthesis of 2hydroxyphenyl-derived cyclopropanes 1 we have selected salicyl aldehydes 2. Generally, the hydroxy group should be protected to realize the Knoevenagel condensation−CoreyChaykovsky reaction sequence. The protecting group should be tolerant to alkaline and weakly acidic conditions and easily removed without affecting the small ring or an acceptor substituent. After screening a variety of protecting groups, including Boc and tosyl functionalities, methoxymethyl (MOM) and ethoxymethyl (EOM) were found to be the most suitable for our substrates. The further synthetic sequence includes Knoevenagel condensation of MOM- or EOM-protected salicyl aldehydes 3 with CH acid, CoreyChaykovsky cyclopropanation of the obtained adducts 4, and protecting group removal in products 5.21 It is noteworthy that the deprotection of cyclopropanes 5 should be performed very cautiously to prevent the formation of side products. Under excessively long duration time, products of cyclopropane methanolysis, such as 6a, were detected as an undesired admixture. The optimal reaction time depends significantly on the nature of donor and acceptor substituents. Nevertheless, the careful control of the reaction allowed us to obtain cyclopropanes 1 in reasonable-to-good yields, except for compounds 1n,o with 2-hydroxy-1-naphthyl and 4-methoxyphenyl as donor groups (Scheme 2).
a
Reaction conditions: 1 (0.84−6 mmol, 1 equiv, 0.13 M), CH2Cl2, MeOH (1:2), aq HCl (10 equiv), rt. bIsolated yields. cReaction temperature: 40 °C.
Then, we explored the transformation of cyclopropanes 1 and their protected derivatives into DHBF 7 using 1a as well as its EOM and MOM derivatives 5a,a′ as model compounds. A series of reactions were carried out while varying initiators, reaction temperature, solvent polarity, ratio, and reagent concentration to optimize the reaction conditions. Among various Lewis acids, we have focused on GaCl3 and magnesium halides, which were earlier reported as efficient initiators for DA cyclopropane isomerization into 2-arylethylidenemalonates15 as well as for domino reactions including the aforementioned isomerization as a key step.9,14 Table 1 summarizes representative results. The best yield of 7a was achieved when 1a was heated with MgBr 2 ·OEt 2 in chlorobenzene at 100 °C in the presence of ammonium acetate as a proton source. With the optimized conditions in hand, we have studied the scope of the disclosed reaction and found that this transformation proceeds efficiently for a broad series of 2hydroxyaryl-derived cyclopropanes with various substituents (halogen, alkyl, alkoxy, nitro groups) in the aromatic ring (Scheme 3). The presence of an alkoxy or nitro group at the C(3) atom of the phenyl group in cyclopropane 1 considerably decreased the target product yield. The structure of compound 7b was unambiguously proven by single-crystal X-ray data.22 7948
DOI: 10.1021/acs.orglett.8b03491 Org. Lett. 2018, 20, 7947−7952
Letter
Organic Letters Table 1. Optimization of Reaction Conditions for the Model Cyclopropanes 1a, 5a, and 5a′a,b
entry
initiator (mol %)
R
solvent
temp (°C)
t (h)
yield of 7a (%)
1 2c 3 4 5 6 7 8 9 10 11 12 13 14
GaCl3 (110) GaCl3 (110) MgI2 (20) MgI2 (20) MgI2 (20) Mg(ClO4)2 (20) MgBr2·OEt2 (120) MgBr2·OEt2 (120) MgBr2·OEt2 (120)/NH4OAc (120) MgBr2·OEt2 (120)/DIPEA (120) MgBr2·OEt2 (120)/NH4OAc (120) MgBr2·OEt2 (220)/ NH4OAc (120) MgBr2·OEt2 (120)/NH4OAc (120) MgBr2·OEt2 (220)/NH4OAc (200)
H H H H H H H H H H MOM MOM EOM EOM
CH2Cl2 CH2Cl2 CH2Cl2 PhCl CH3NO2 CH3NO2 C2H5NO2 PhCl PhCl PhCl PhCl PhCl PhCl PhCl
0 −25 20 100 100 100 100 100 100 100 60 80 110 120
0.3 0.3 24 1 1 1 1.5 1.5 1.5 2.5 2 2 4 2.5
10 traces 42 46
