Styrylmalonates as an Alternative to Donor–Acceptor Cyclopropanes

Jun 29, 2017 - ... V. TkachevVictor A. KorolevEvgeny V. ShulishovYury V. Tomilov ... Valentine P. Ananikov , Dmitry B. Eremin , Sergey A. Yakukhnov ...
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Styrylmalonates as an Alternative to Donor−Acceptor Cyclopropanes in the Reactions with Aldehydes: A Route to 5,6Dihydropyran-2-ones Denis D. Borisov,† Roman A. Novikov,†,‡ Anna S. Eltysheva,† Yaroslav V. Tkachev,‡ 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 S Supporting Information *

ABSTRACT: A new strategy for modifying the reactivity of donor− acceptor cyclopropanes (DAC) has been suggested. It involves the use of isomeric styrylmalonates as alternative sources of reactive intermediates. The efficiency of the approach has been demonstrated in reactions with aromatic aldehydes. As a result, a new process for construction of the 5,6-dihydropyran-2-one skeleton has been developed. It efficiently occurs with high diastereoselectivity in the presence of BF3·Et2O; the products can be easily isolated by crystallization. The subsequent use of the resulting dihydropyranones in syntheses providing convenient access to various classes of compounds with broad molecular diversity has been demonstrated.

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Scheme 1. Styrylmalonate Strategy and Its Application for Reactions with Aromatic Aldehydes

n recent decades, donor−acceptor cyclopropanes (DAC) have become popular in organic synthesis as versatile building blocks for constructing various structures ranging from aliphatic to polycyclic ones.1 This is evident from the ever increasing number of publications on DAC chemistry in the most prestigious journals.2 2-Arylcyclopropane-1,1-dicarboxylates (ACDC) are the most popular and versatile DAC representatives. Despite the wide variety of chemical reactions of DAC, they can be subdivided into two main types in terms of reactivity (Scheme 1): the classical 1,3-zwitterionic1,2 and recently found 1,2-zwitterionic ones.3 Other reactivity types are usually attributed to the former two types, with further subdivision depending on the specifics of the process, substrates and substituents in the DAC. These processes often involve substituents in the DAC, which considerably expands the diversity of this “chemical construction set”.1 For example, the main classical direction of DAC reactions with aldehydes is formal [3 + 2]-cycloaddition that occurs with a broad range of substrates to give tetrahydrofurans (Scheme 1a).4 Other reaction pathways, e.g. [3 + 2]-6 and [3 + 8]-annulations,5 are also known. Our team recently developed yet another approach that involves generation of 1,2-zwitterionic intermediates using GaCl3 (Scheme 1b).6 In the same study, we used styrylmalonates as an alternative to ACDC for increasing the yields of the target products.6 In this study we use the reactions of styrylmalonates 1 with aldehydes 2 to demonstrate yet another approach to the use of ACDC in organic synthesis giving the dihydropyranone skeleton 3 (Scheme 1c). The idea of this strategy is quite simple and involves the use of isomeric styrylmalonates instead of ACDC in the same reactions. In this case, the corresponding styrylmalonates can be easily obtained by isomerization of ACDCs.7 In the © 2017 American Chemical Society

current project, the used styrylmalonates 1 were prepared as single E-isomers through isomerization of corresponding ACDCs by action of TMSOTf in PhCl at 135 °C.7a Surprisingly, in spite of the simplicity of this approach, it was not used before in organic synthesis, though styrylmalonates have Received: May 22, 2017 Published: June 29, 2017 3731

DOI: 10.1021/acs.orglett.7b01556 Org. Lett. 2017, 19, 3731−3734

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Organic Letters

benzaldehyde in the presence of GaCl3.6 However, GaCl3 was found to be quite an unsuitable Lewis acid in this synthesis, since dihydrapyranones readily underwent decomposition in the presence of this compound even under mild conditions, so the target product could not be obtained in a preparative amount. Other Lewis acids either had low activity (Yb(OTf)3, In(OTf)3, Sn(OTf)3) or caused strong oligomerization (TiCl4, EtAlCl2, TMSOTf), or mainly caused the formation of indenylmalonate 4a (InCl3, SnCl4, Sc(OTf)3). BF3·Et2O was found to be an efficient Lewis acid for the synthesis of dihydropyranone 3a. Though the conversion of the starting styrylmalonate in the presence of this compound was not high, the reaction was quite selective. To create an efficient methodology for synthesizing compounds of type 3, we performed an optimization of the reaction conditions, including a variation of the benzaldehyde−BF3·Et2O ratio, reaction temperature and time, solvent, and method of product isolation. It was found that the conversion of 1a under mild conditions was too low, while the formation of indene 4a prevailed under drastic conditions, because the electrophilic attack is more preferable in the last case6 (Table 1). As a result, we found very good conditions where dihydropyranone 3a was the major reaction product (Table 1, entries 15−17). Unfortunately, the conversion of 1a was ca. 60% under these conditions. Any attempts to increase the conversion of 1a only decreased the yields of 3a due to the formation of indene 4a and partial oligomerization. On the other hand, the process for the isolation of dihydropyranone 3a proved to be rather simple and efficient. Compound 3a could be isolated almost completely from the reaction mixture by crystallization from EtOH or Et2O, while the nonreacted styrylmalonate was regenerated by flash chromatography.

been known for a long time. However, their reactions have almost not been studied. Of the chemical reactions involving styrylmalonates, only a few are known where they manifest the usual reactivity.8,9 The reactions occurred either by the double bond or by the malonyl moiety. Furthermore, a few ACDC reactions are known that occur via intermediate formation of styrylmalonates that subsequently react as alkenes.3c,7b,9 A single example of the [3 + 2]-annulation of styrylmalonate with Nbenzylic sulfonamide is known.10 The substituted 5,6-dihydropyran-2-ones that became accessible using our methodology contain various functional groups and are of practical interest. They can be used in further syntheses involving modifications of both the dihydropyranone ring and the functional groups, with retention of the stereocenters of the original dihydropyranones (see below). The dihydropyranone skeleton is found in various natural compounds (Figure 1) demonstrating a broad spectrum of biological activity, such as antiplasmodial, immunosuppressant, antitumor, neuroregulatoric, cytotoxic activities, etc.11

Figure 1. Examples of natural compounds incorporating the dihydropyranone skeleton.

We were the first to observe that dihydropyranones could be formed in a study on the reaction of styrylmalonate 1a with Table 1. Optimization of the Reaction Conditions for 3a

entrya 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15d 16d 17f 18 19h

2a (equiv) 2.5 1.5 1.5 2.5 4 2.5 1.5 2.5 1.5 2.5 2.5 2.5 2.5 4 6 6 6 6 2.5

LA (equiv) 1 1 1 1 1 1 1 1 1 0.5 2 2 3 3.5 2 2 2 2 1

temp (°C) rt 40 60 60 60 60 80 80 80 80 40 60 40 60 60 60 60 60 60

time (h) 22 3 3 3 3 8 0.5 1.5 3 2 5 3 5 3 3 3 3 6 3

conversion (%) 5 32 51 47 60 74 37 55 93 61 42 38 26 100 62 56 61 89 45

yieldb,c 3a (%) c

n.d. 16 24 35 34 37 8 18 n.d. 17 31 30 17 10 55 (89)e 53 53g (86)e 51 20

yieldb,c 4a (%) n.d. n.d. 6 4 5 14 7 16 45 21 2 2 n.d. 47 4 n.d. 4 26 5

a

General conditions: 0.40 mmol of 1a in 3.5 mL of 1,2-dichloroethane (DCE). bNMR yields. cn.d. = not detected. dTwo identical experiments for reproducibility check. eYield based on recovered starting styrylmalonate 1a (brsm) is indicated in parentheses. f850 mg (3.65 mmol) loading of 1a were used. gIsolated yield. hMS 4 Å were added. 3732

DOI: 10.1021/acs.orglett.7b01556 Org. Lett. 2017, 19, 3731−3734

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complete regeneration of these compounds by flash chromatography followed by reuse in the reaction. The composition and configuration of the all compounds obtained were uniquely determined by 1H, 13C, 14N, and 19F NMR spectroscopy. A full set of modern 2D NMR experiments, such as COSY, NOESY, HSQC, HMBC et al., were used. For compounds 3a and 3t (Figure 2), X-ray analysis was carried out.

Further, we performed this process with a number of other aromatic aldehydes 1b−u and substituted styrylmalonates 2b−e in the presence of BF3·Et2O and obtained a representative series of dihydropyranones 3 (Scheme 2). However, it was found that Scheme 2. Scope of the Reaction for Dihydropyranones 3

Figure 2. Crystal structure of compound 3t (50% ellipsoid probability).

The following reaction mechanism can be assumed (Scheme 3). The main role of BF3·Et2O involves activation of the malonyl Scheme 3. Proposed Mechanism

the formation of compound 3a with which we performed the optimization was by far not the best example. The reactions occurred most successfully in the case of aldehydes with electronwithdrawing substituents (NO2, CN, CO2Me, CHO, or CF3) in the aryl moiety. Halo-substituted benzaldehydes, including iododerivatives, reacted quite readily. The reactions occur equally well with ortho-, meta-, and para-substituted benzaldehyde derivatives, including those with a few substituents at the benzene ring. Aldehydes with strong donor substituents at the aromatic ring reacted less readily and with low conversion. It is remarkable that dihydropyranones 3 can also be successfully obtained from heteroaromatic aldehydes, e.g., furan and thiophene derivatives. 5Nitrofuryl- and 5-nitrothienyl-2-carbaldehydes reacted particularly readily to give compounds 3t,u in 92% and 53% yields, respectively. In the case of aliphatic aldehydes the reaction practically does not occur in current conditions. Styrylmalonates substituted at the aromatic ring can also be used to synthesize dihydropyranones. In fact, methyl- and halo-substituted styrylmalonates, including disubstituted ones, and (1-naphthyl)vinylmalonate gave dihydropyranones 3v−z in variable yields. All dihydropyranones 3 were isolated by crystallization (or deposition) from the reaction mixture (from Et2O or an Et2O− petroleum ether mixture) without the use of chromatography. In almost all the cases, the reaction occurred with incomplete conversion of styrylmalonates but with rather good selectivity. The conversion of styrylmalonates was usually a little higher than the yields of the resulting dihydropyranones, but, as in the case of compound 3a, we failed to increase the conversion without losing some amount of products. However, the incomplete conversion of styrylmalonates 2 can be easily compensated by the nearly

moiety (by analogy with DACs)1−3 and hence activation of the double bond due to conjugation. In this process, an HF molecule is eliminated from the malonyl moiety and the complex-bound BF3 to give boron complex I, in which the C(2) atom of the double bond manifests a nucleophilic nature. In turn, the eliminated HF activates the aldehyde molecule (II), providing the formation of a C−C intermolecular bond. Subsequently, the resulting complex III undergoes intramolecular cyclization to give a dihydropyrane ring (IV). The latter undergoes hydrolysis and eliminates methanol to give the final product 3. The process stereochemistry is defined at the step of C−C bond formation and is controlled by steric factors. In this case, the existence of weak intramolecular interactions makes this control very efficient and gives only one diastereomer (Scheme 3). The dihydropyranone derivatives 3 accessible by our methodology contain various functional groups in a molecule and can be used in further reactions involving modifications of either the substituents or the dihydropyranone ring itself. Some examples of rather simple reactions are presented in Scheme 4. For example, 3733

DOI: 10.1021/acs.orglett.7b01556 Org. Lett. 2017, 19, 3731−3734

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Scheme 4. Examples of Utility of Dihydropyrone 3a in Further Synthesis

Yury V. Tomilov: 0000-0002-3433-7571 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The work was supported by the Russian Science Foundation (Grant 14-13-01054-P). High resolution mass spectra were recorded in the Department of Structural Studies of N. D. Zelinsky Institute of Organic Chemistry RAS, Moscow.

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dihydropyranone 3a can be readily oxidized with DDQ to give the corresponding pyranone 5. Reduction can give a series of cyclic or acyclic alcohols 6−9, depending on the conditions. However, the original configuration of the two phenyl substituents is retained in all cases. Compound 3a is decarboxylated under Krapcho reaction conditions to give dienes 10 with incorporation of DMSO, or dienes 11 under more drastic conditions. In general, dihydropyranones 3 are very convenient building blocks for their further transformations. In conclusion, we have developed a new original strategy for using styrylmalonates as an alternative to DAC (using reactions with aldehydes as an example). Surprisingly, styrylmalonates were almost never used in organic synthesis before, though their structure is quite simple. Meanwhile, a combination of donor and acceptor substituents at different ends of the propene moiety can change their properties in comparison with isomeric ACDC. Conceptually, styrylmalonates are new three-carbon building blocks that allow one to change the direction of reactions based on the general principles of chemical reactions of DAC in the presence of Lewis acids. As a result of implementing this approach, we developed a new process for constructing the dihydropyranone skeleton that efficiently occurs in the presence of BF3·Et2O and shows high diastereoselectivity. It has been shown that a broad range of products can be obtained and easily isolated by crystallization. It has been demonstrated that the obtained dihydropyranones can further be used in a number of chemical reactions.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01556. Crystallographic data CCDC 1542829 (4a) (CIF) Crystallographic data CCDC 1542838 (4t) (CIF) Experimental procedures, characterization data, copies of NMR spectra (PDF)

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*E-mail: [email protected]. 3734

DOI: 10.1021/acs.orglett.7b01556 Org. Lett. 2017, 19, 3731−3734