Article Cite This: J. Am. Chem. Soc. 2018, 140, 14381−14390
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Ionic Ga-Complexes of Alkylidene- and Arylmethylidenemalonates and Their Reactions with Acetylenes: An In-Depth Look into the Mechanism of the Occurring Gallium Chemistry Roman A. Novikov,*,†,‡,§ Dmitry A. Denisov,†,§ Konstantin V. Potapov,† Yaroslav V. Tkachev,‡ Evgeny V. Shulishov,† and Yury V. Tomilov*,†
J. Am. Chem. Soc. 2018.140:14381-14390. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/31/18. For personal use only.
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N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospekt, 119991 Moscow, Russian Federation ‡ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, 119991 Moscow, Russian Federation S Supporting Information *
ABSTRACT: A new synthetic concept was suggested in the chemistry of substituted methylidenemalonates that enables their utilization as 1,2zwitterionic synthons. This strategy is to generate liquid ionic Ga complexes from methylidenemalonates and GaHal3 with a strict 3/4 composition and then use them in further synthesis. A number of complexes with different metal halides have been synthesized and studied in detail. The unique properties of gallium among all metals have been demonstrated and explained. On the basis of the discovered new class of gallium complexes of methylidenemalonates, a number of novel reactions with acetylenes have been elaborated, which are unknown in the conventional chemistry of methylidenemalonates. The main demonstrated process is a three-component addition to a triple bond involving halide anions, leading to the formation of polyfunctional vinyl halides with high E-selectivity. The mechanism has been studied experimentally in fine detail. Application of specially optimized 71Ga NMR spectroscopy makes it possible to take an in-depth look into the gallium chemistry in a new light. In particular, the key participation of GaHal4− anions in the occurring transformations has been established.
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INTRODUCTION Donor−acceptor cyclopropanes (DACs)1 are a broad class of substituted three-membered carbocycles.2 They are known for their capability to undergo small ring opening to act as 1,3zwitterionic synthones.3 Owing to this feature, they are currently popular in organic synthesis4 and have become quite ordinary building blocks. However, current challenges of organic synthesis require that ever more sophisticated and nontrivial methods be developed for synthesizing complex polyfunctional structures from simple starting compounds in a minimum number of stages. This is required because of the increasing demands for the creation of new biologically active compounds, pharmaceutical agents, functional materials, catalysts, etc. It might seem that DACs have been studied so well1−4 that their chemistry is already exhausted in the sense of creating something fundamentally new. However, this is by no means true, and new studies currently continue to appear where quite nontrivial ways of their application are considered.5 One of these cutting-edge approaches6 that appeared and was actively developed in the past few years involves the use of DACs as sources of 1,2-zwitterions.7−10 The method is based on the use of gallium compounds and allows the reaction © 2018 American Chemical Society
pathways of DACs 1 with substrates of many types to be altered completely. Using common compounds such as alkenes,7 acetylenes,8 aldehydes,9 diazo ethers,10 etc. in the reactions, diverse carbo- and heterocyclic structures can be assembled on the basis of generated 1,2-zwitterions 2 (Scheme 1). No doubt, the 1,2-zwitterionic chemistry of DAC is already a very important and significant concept in synthesis. Taking into consideration these facts and the obvious structural limitations for generation of 1,2-zwitterions from DACs, an obvious question arises: can such 1,2-zwitterions be generated from the corresponding unsaturated precursors? The answer seems self-evident: substituted methylidenemalonates would be very convenient sources because 1,2-zwitterions are in fact their complexes with a strongly polarized double bond (Scheme 2). Everything appears very simple, but no developments of this kind have been reported in the literature. This concept is certainly rather close to the classical Michael chemistry of alkylidenemalonates, but would these reactions occur in a similar way? Moreover, yet another question arises: Received: August 18, 2018 Published: October 2, 2018 14381
DOI: 10.1021/jacs.8b08913 J. Am. Chem. Soc. 2018, 140, 14381−14390
Article
Journal of the American Chemical Society Scheme 1. Utility of the Gallium 1,2-Zwitterions in D−A Cyclopropane Chemistry
Scheme 3. Formation of the Different Types of Complexes with Metal Halides from DACs and Methylidenemalonates
Scheme 2. Concept of This Work
would gallium halides manifest their unique properties here as well, and if yes, to what extent?
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RESULTS AND DISCUSSION As a first step, it was necessary to study the possible formation of methylidenemalonate complexes with various metal halides. It was found that methylidenemalonates 3 are rather good bidentate ligands that readily coordinate metal atoms at the two carbonyls of the ester groups. This causes a polarization of the CC bond, and its strength can be monitored by the downfield shifts of CH in the 1H and 13C NMR spectra.6b In most cases, 1/1 covalent complexes 4 are formed, e.g., with SnCl4, TiCl4, ZnCl2, etc. (Scheme 3). The coordination of the metal in these complexes is not very strong, as the gradual change in the chemical shifts upon varying the reagent ratio confirms. ZnCl2 is coordinated much more weakly. Quite a different picture is observed in the complexation with GaCl3. In this case, ionic complex 5 with a strict 3/4 composition is formed, in which three methylidenemalonate ligands are coordinated to one gallium atom (Scheme 3). They replace three chloride ions at that gallium atom, which then form three GaCl4− anions. The structure of the complex was thoroughly studied using NMR spectroscopy (Figures 1 and 2), including that on 71Ga atoms,11,14 and 2D experiments (see also Supporting Information). Complexes with similar structures have been reported in only a few cases,12,13 and we studied them just recently using model ligands, diethyl
Figure 1. Characteristic NMR spectra for ionic Ga complex 5b (X = Br) in CD2Cl2. 1H NMR spectra of neat 5b and its solution in CD2Cl2 at +30 °C (left). 71Ga NMR spectrum (after deconvolution) of neat 5b demonstrated two types of Ga atoms in the complex (right). Samples of complexes 5a−c in NMR tubes in CD2Cl2 (middle); at the bottom of the tubes, neat liquid Ga complexes can be seen that are analogues of ionic liquids.
malonate and cyclopropanedicarboxylate, as an example.14 It was found that complexes 5 had a surprisingly stable and beneficial structure. They were readily formed upon mixing the reagents even at low temperatures and did not decompose on heating up to 100 °C (we failed to detect the 1/1 intermediate complex at −70 °C by means of spectroscopy). If the reagents are mixed in a smaller ratio than 3/4, then the NMR spectra contain a double set of signals that belong to the individual complex 5 and the free ligand 3. It is interesting to note that pure complex 5 is a liquid; apparently it is some analogue of ionic liquids.15,16 14382
DOI: 10.1021/jacs.8b08913 J. Am. Chem. Soc. 2018, 140, 14381−14390
Article
Journal of the American Chemical Society
Figure 2. 71Ga NMR spectra of complexes 2a (top, ref 6b) and 5a (bottom) demonstrating a fundamental difference in the environment of Ga atoms. Small and highly symmetrical GaCl4− anions have a much narrower signal with a characteristic chemical shift of ca. +250 ppm. Figure 3. 1H NMR spectra for complexes 5a,b (Hal = Cl, Br) at different temperatures in the range from −50 to +30 °C (CHδ+ and CO2Me regions are shown); these spectra show the presence of two stereoisomers A and B in solution at low temperatures, while at temperatures above −20 °C they are averaged due to rotation around the polarized C−C double bond. At the top, isomers A and B are presented, as well as their simplified projection in an orange frame.
The CC double bond in the malonate moiety of complex 5 is strongly polarized, much more strongly than upon coordination of malonate 2 with SnCl4 or TiCl4 (complexes 4), despite the fact that three malonate ligands at once are bound to one gallium atom in complex 5. The strength of polarization matches that in complex 2 formed from a DAC,6b although the structure of this complex differs from that of the GaCl3 complex with methylidenemalonates (5a−e). The complexation of methylidenemalonates 3 with AlCl3 or EtAlCl2 gives rise to a mixture of a few hardly identifiable complexes and is apparently of intermediate nature. In this case, partial formation of AlCl4− anions within the complexes is also observed. There is a very interesting situation with the stereochemistry of complexes 5. The fact is that ligand 3 is not symmetrical in terms of R-substituent. As a result, from the theoretical point of view, complexes 5 can exist as two stereoisomers A and B with different relative positions of the CCH(R) fragments (Figure 3). From statistical considerations the ratio of stereoisomers A and B should be 1/3. These facts are excellently confirmed by detailed studies of the complexes 5 by means of NMR spectroscopy at various temperatures (Figure 3). At temperatures below −20 °C, four signals of each type are observed in the spectra with equal intensities (for both CH fragments and for each of the MeO groups). From the considerations of symmetry, isomer B should give three signals and isomer A gives a single signal with tripled intensity. Taking into account the ratio of the isomers of A and B as 1/3, this gives the observed picture (Figure 3). When heated to +30 °C, all four signals collapse into one for all types of groups. This is a very important fact, because it is evidence of the strong polarization of the CC double bond and its high semidouble character, which allows it to rotate at temperatures above −20 °C. We have also carried out detailed studies of complex 5a by mass spectrometry method (electrospray ionization highresolution mass spectrometry (ESI-HRMS)) (Scheme 4). Unfortunately, it turned out that this method is poorly suited
Scheme 4. Mass Spectrometric Studies of Complex 5a and Its Partial Decomposition by MeCN
for the study of such complexes, because they are unstable under the conditions of the extreme dilution necessary for the recording of mass spectra. Thus, using ESI-HRMS we were able to detect the GaCl4− anions (in negative masses), as well as the free ligand 3a and its dimer in minor amounts (Scheme 4). The cation part of any gallium complexes could not be 14383
DOI: 10.1021/jacs.8b08913 J. Am. Chem. Soc. 2018, 140, 14381−14390
Article
Journal of the American Chemical Society detected (using any solvents including common MeCN and CH2Cl2). Electron ionization MS (EI-MS) failed to detect any species except ligand 3a. To study the nature of the destruction of complexes 5, we have carried out the reaction of 5a with a large excess of acetonitrile. 71Ga NMR studies show the ligand exchange in the cationic part of 5a with preservation of GaCl4− anions (Scheme 4). Herewith, an octahedral cation [Ga3+(MeCN)6] is formed. Benzylmethylidenemalonates (1′) noticeably differ from other substituted methylidenemalonates 3 in their behavior upon reaction with Ga halides and are similar in this to D−A cyclopropanes 1 (Scheme 5). They can form two types of
Scheme 6. Some Reactions of Ionic Ga Complexes 5
Scheme 5. Formation of Complexes with Ga Halides from DACs and Isomeric Benzylmethylidenemalonates
potential of ionic gallium complexes 5. In this case, it is not necessary to generate this complex beforehand: it is sufficient to mix all the reagents at once, which simplifies the synthetic protocol. Apart from GaCl3, it was interesting to study the behavior of other Lewis acids and metal halides in this reaction (Table 1). It should be noted that, despite its simplicity, the Table 1. Screening of Different Metal Chloridesa
entry d
complexes 2 and 5 depending on the conditions, one of the main of which is the used excess of Ga halide. Herewith, the initially formed complexes 2 transform into ionic complexes 5 under certain conditions. The latter precipitate as a thick oil and are not very stable in this state. They are easily dimerized and oligomerized by analogy with D−A cyclopropanes.3g The processes of formation of complexes 2/5 have been studied in detail by NMR spectroscopy on the example of reaction of 1a and 1a′ with GaCl3 (Scheme 5). The previous data6,7b were refined and supplemented. NMR spectra for both complexes are similar to those shown in Figure 2. Benzylmethylidenemalonates 1′ with other aryl substituents react similarly.6,7b Also, we have synthesized the stable ionic complex 5g based on sterically hindered ortho,ortho-Me2-substituted malonate 1b′ and GaBr3 (Scheme 5), used for additional structural assignments. Obtained structural data allowed us to look deeper at the “gallium” reactions of D−A cyclopropanes, which have a significant synthetic utility.7−10 It should be noted that the 1/1 gallium complexes like 2 from other methylidenemalonates are highly unstable and were not detected. The formation of ionic complexes 5 from methylidenemalonates allows their usual reactivity to be changed completely. The next stage involved a study of their new interesting chemistry. In this Article, we focused our attention on the carbocationic processes characteristic of the gallium chemistry of DACs7,8 mainly reactions with acetylenes that allow a number of new processes to be performed (Scheme 6). Apparently, it is just the first chapter of new, interesting gallium chemistry. The reaction with acetylenes 6 was found to be a convenient model process for studying and demonstrating the synthetic
1 2 3 4 5 6 7 8 9 10 11
metal chloride
yield (%)b,c
GaCl3 AlCl3 EtAlCl2 Et2AlCl FeCl3 SnCl4 TiCl4 ZnCl2 InCl3 GeCl4 SbCl5
70 25 37 26 39
