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Article

Dimerization/Elimination of β-Styrylmalonates under Action of TiCl4

by
D. D. Borisov
,
G. R. Chermashentsev
,
K. V. Potapov
,
R. A. Novikov
* and
Yu. V. Tomilov
*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(1), 270; https://doi.org/10.3390/molecules28010270
Submission received: 8 December 2022 / Revised: 26 December 2022 / Accepted: 27 December 2022 / Published: 29 December 2022
(This article belongs to the Special Issue Feature Papers in Organic Chemistry)
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Abstract

:
A new type of dimerization of dimethyl (β-styryl)malonates in the presence of TiCl4 accompanied by elimination of a methanol molecule was discovered. Selective methods for the synthesis of substituted trimethyl 4-hydroxy-[1,1′-biaryl]-3,3,5(2H)-tricarboxylates and trimethyl 7-hydroxy-9,10-dihydro-5,9-methanobenzo[8]annulene-6,8,8(5H)-tricarboxylates were developed. The regularities of the occurring processes were determined and a similar reaction of β-styrylmalonate with benzylidenemalonate in the presence of TiCl4 was performed in the scope of the suggested mechanism.

1. Introduction

β-Styrylmalonates 1 are isomers of 2-arylcyclopropane-1,1-dicarboxylates (ACDC, 2) which, in turn, are the most common and accessible class of donor-acceptor cyclopropanes (DAC). The latter are widely used as versatile building blocks that make it possible to involve a three-membered ring along with donor and acceptor substituents [1,2,3,4,5,6,7,8]. To date, DACs proved to be useful synthons in complete syntheses of natural compounds. DACs can be used to obtain various functionally substituted compounds that have a wide range of chemical and biological types of activity [9,10,11,12,13,14,15,16,17,18,19,20,21]. In this context, the study of the chemical reactions of β-styrylmalonates can become a continuation of studies on ACDC chemistry and a relevant area of organic chemistry, since their behavior often differs from the reactions of ACDCs themselves. The efforts of our team allowed us to publish a series of works dealing with reactions of β-styrylmalonates 1 with aromatic aldehydes in the presence of various Lewis acids and under various reaction conditions. [22,23,24,25].
Similar to ACDCs themselves, β-styrylmalonates are highly reactive substrates. If no other substrates are present, ACDCs can undergo dimerization and oligomerization reactions [18,26,27,28,29,30,31,32,33,34,35,36]. As a rule, these processes are accompanied by partial isomerization of an ACDC into a styrylmalonate which, in turn, reacts with an activated ACDC molecule by generation of 1,3- or 1,2-zwitter-ionic intermediates [18,26,27,31,32]. It should be noted that dimerization is an interesting process in organic synthesis. As a rule, these reactions occur with high regio- and diastereoselectivity and in a single synthetic stage, which allows a range of both new and known compounds to be obtained. As of now, there are many works in literature that deal with ACDC dimerizations that can give both cyclization and annulation products (Scheme 1) [18,26,27,28,29,30] and acyclic compounds [31,32,33]. In some cases, the cyclization process is accompanied by elimination of an alkoxy moiety, thus representing a dimerization/elimination reaction. Analysis of the structure of dimers shows that a styrylmalonate molecule is actually or formally involved in the formation of some of these dimers as active intermediates (there are even a few examples of cross-dimerization in reactions of ACDCs with styrylmalonate [28,34,35,36]). However, there is still no information on the possibility of any dimerization of β-styrylmalonates themselves. All starting β-styrylmalonates 1 were synthesized by a known method [37].

2. Results and Discussion

In this work, we discovered the first example of dimerization of β-styrylmalonates 1 in the presence of titanium tetrachloride accompanied by elimination of one alkoxy group. This process opens a way to substituted trimethyl 4-hydroxy-[1,1′-biphenyl]-3,3,5(2H)-tricarboxylates 2 and trimethyl 7-hydroxy-9,10-dihydro-5,9-methanobenzo[8]annulene-6,8,8(5H)-tricarboxylates 3 that are formed with involvement of one of the ester groups of the starting styrylmalonate. It is important to note that these dimerization/elimination processes can be partially controlled, as follows from the data on the optimization of these processes with styrylmalonate 1a as an example (Table 1). It should be noted that in the presence of other Lewis acids we did not observe such type of the transformations [24]. Usually, we fixed oligomers or (4 + 2)-products in NMR spectra of the reaction mixtures. In fact, the reaction in the presence of 0.5 equiv. TiCl4 in 1,2-dichloroethane under reflux conditions gives almost exclusively cyclohexadienol 2a, whereas the reaction with excess TiCl4 (1.5 equiv.) at a lower temperature (in dichloromethane, reflux conditions) gives substituted dihydro-5,9-methanobenzo[8]annulene 3a, though its maximum yield is as small as 30%. The relatively low yield of compound 3a is explained by competitive side processes, in particular, (4 + 2)-dimerization and oligomerization.
In order to study the effect of electronic and steric factors on the reactions, the dimerization reaction was performed with a number of substituted β-styrylmalonates. It was found that β-styrylmalonates with an acceptor substituent in the aromatic ring as well as various halo-substituted derivatives readily enter the process under study on heating in dichloroethane, while the position of the halogen atoms in the aromatic moiety does not significantly affect the occurring reactions. The process with these substrates occurs quite selectively without significant formation of side products. Moreover, the final compounds, i.e., the corresponding 2-hydroxycyclohexa-2,4-diene-1,1,3-tricarboxylates 2a–e, do not require additional purification after extraction. The sterically hindered β-styrylmalonate and a styrylmalonate with a donor substituent in the aromatic ring underwent this type of dimerization somewhat less readily (Scheme 2). The 1H NMR spectra of the reaction mixtures contained a significant number of dimers 4f,g formed by (4 + 2)-annulation, as we reported previously [18]. Moreover, the donor moiety in styrylmalonate 1f partially favors yet another reaction pathway to give not only compound 2f (Scheme 2) but also a small amount of substituted dihydro-5,9-methanobenzo[8]annulene 3f (Scheme 3).
Subsequently, we studied a deeper transformation of substituted β-styrylmalonates that resulted in dihydro-5,9-methanobenzo[8]annulenes 3. It was found that a narrower range of substrates could be used in this process compared to the formation of cyclohexadienols 2 due to the high sensitivity of the reaction to the position and nature of the substituent in the aromatic part of styrylmalonate. The reaction occurs rather successfully with styrylmalonate 1a itself or with its meta-bromo substituted derivative (Scheme 3). Although the presence of a substituent, e.g., a fluorine atom, at the para-position of the aromatic moiety makes it possible to obtain a certain amount of dihydro-5,9-methanobenzo[8]annulene 3e, the typical formation of the dimeric product of (4 + 2)-annulation 4e is still the main process. A donor substituent in the aromatic moiety, similar to sterically hindered naphthyl, shifts the reaction pathway of these styrylmalonates toward the formation of (4 + 2)-annulation products 4f,g. Nevertheless, the annulated compound 3f was obtained in small yields by the reaction of styrylmalonate 1f with 0.5 equiv. TiCl4 under the conditions used to synthesize cyclohexadienol 2f (Scheme 3). An acceptor substituent at the para position does not favor the formation of fused rings 3, either. For example, the action of TiCl4 (1.5 equiv.) on (4-nitrostyryl)malonate 1c results in intense reddish-brown coloring of the reaction mixture with formation of a significant amount of oligomers among which it was almost impossible to identify any dimerization products. In contrast, though the formation of dihydro-5,9-methanobenzo[8]annulene 3d was not observed in the case of (2-chlorostyryl)malonate 1d, almost no oligomerization processes were observed either, and according to the NMR spectra of the reaction mixture, all the major signals corresponded only to compound 2d.
9,10-Dihydro-5,9-methanobenzo[8]annulenes 3 are formed as a single diastereomer where the aryl substituent is oriented toward the OH group (Figure 1). At the same time, the other diastereomer is not detected in any noticeable amounts.
In addition to the dimerization/elimination of β-styrylmalonates 1 in the presence of titanium tetrachloride, a cross variant of a similar process was carried out by the reaction of β-styrylmalonate 1a with benzylidenemalonate 5 as one of the possible components for the formation of cyclohexadienols 2. In fact, a mixture of two different cyclohexadienols in 1: 2 ratio was obtained in the reaction of malonates 1a and 5 in 1: 2 ratio in the presence of 0.5 equiv. TiCl4 at 80 °C. Cyclohexadienol 2a, a product of formal dimerization/elimination of styrylmalonate 1a described above, was a minor compound, while the related cyclohexadienol 6a formed by the reaction of benzylidenemalonate 5 with styrylmalonate 1a and also with elimination of a methanol molecule was the main compound according to NMR and mass spectra (Scheme 4). It should be noted that due to similarity of the structures of compounds 2a and 6a, we failed to separate them completely and to isolate cyclohexadienol 6a individually even after double chromatography on SiO2. An attempt was made to perform the reaction with a large excess of benzylidenemalonate 5, but even in this case we failed to avoid the formation of homodimer 2a completely.
The same reaction of benzylidenemalonate 5 with (4-methylstyryl)malonate 1f occurred more selectively. According to the 1H NMR spectra of the reaction mixture, the homo-dimerization/elimination product 2f was detected in trace amounts, whereas the cross-coupling product 6f (2f/6f ratio approximately 1:16) predominated (Scheme 4). The total yield of cyclohexadienols 2f and 6f was smaller than in the case of unsubstituted styrylmalonate 1a and was approximately the same as in the homo-dimerization/elimination reaction of (4-methylstyryl)malonate 1f (see Scheme 2), which is still due to the fact that its dimerization to give the (4 + 2)-annulation product 4f occurs more readily.
Finally, we tested the variant of the asymmetric reaction of dimerization/elimination of β-styrylmalonates, for which no asymmetric processes have been described in the literature so far. In fact, this turned out to be not an easy task, since the standard asymmetric catalytic approaches using chiral ligands, which were used for ACDC reactions [38,39,40,41], would hardly work for the processes under consideration under conditions of equimolar amounts of strong Lewis acids. As a result, after a series of experiments, we focused not on the elusive development of a catalytic variant with chiral ligands, but on the use of chiral substituents in ester groups. As such a fragment, we used an available natural (–)-menthyl substituent [42] and synthesized the corresponding styrylmalonate 1h (according to the standard method from ACDC). Under the influence of 1.5 equiv. TiCl4 under standard conditions, the menthyl styrylmalonate 1h also enters the dimerization/elimination reaction with the formation of dihydromethanobenzoannulene 3h (Scheme 5), while the cyclohexadienol derivative 2h is not formed even when using 0.5 equiv. TiCl4. The steric effect of the substituents in the ester groups undoubtedly affects the efficiency of the process, and the yield of tricycle 3h turns out to be low, only 18%, but “e.r.” turns out to be good enough (9:1) for such a simple chirality induction, which demonstrates the fundamental efficiency of this approach.
Taking these results into consideration, the following mechanism of formation of cyclohexadienols 2 may be assumed. At the first stage, β-styrylmalonate 1 is activated with titanium tetrachloride and two different intermediates I and II are generated (Scheme 6), which seems to be especially favored by the use of 0.5 equivalents of TiCl4. Subsequently, ionic (4 + 2)-cycloaddition of these intermediates occurs to give a polyfunctionally substituted cyclohexene III, which is converted to titanium enolate IV due to elimination of a methanol molecule. The ability to react with Knoevenagel adducts of type 5 (intermediate I) is an additional evidence that the reaction occurs as formal (4 + 2)-cycloaddition (Scheme 7). At the final stage of the process, hydrolysis results in the final cyclohexadienols 2. It should be noted that we did not observe the aromatization of compounds 2. At the same time, in the case of self-condensation of other 1,3-dicarbonyl compounds, in particular enaminodiones or diethyl 2-ethoxymethylenemalonates, the formation of substituted benzene compounds is observed [43,44].
The mechanism of formation of benzobicyclo[3.3.1]octenes 3, which, strangely enough, are formed at a lower temperature but with an excess of TiCl4, appears to be more complex. Control experiments with compounds 2a and 4a showed that the presence of 1.5 equivalents of titanium(IV) tetrachloride in boiling dichloromethane did not result in the formation of any amounts of compound 3a. The NMR spectra of the reaction mixtures after acid treatment contained only signals of the initial compounds, and thus we can assume that the pathway leading to compound 3a is established already at the first stages of the process. In this case, titanium tetrachloride is apparently coordinated to the malonyl moieties of both intermediates I and II. As a result, annulation to the aromatic ring of V occurs first, followed by cyclization with involvement of malonyl moieties to form bicyclic titanium enolate VI (Scheme 8).

3. Experimental Section

See Supplementary Materials.

4. Conclusions

Thus, we have discovered a new previously unknown variant of dimerization of β-styrylmalonates 1 that is accompanied by elimination of an alcohol molecule and is not observed in the case of isomeric ACDCs. Titanium tetrachloride acts as a catalyst. The process we discovered is quite general for various substituted β-styrylmalonates and, as a rule, gives high yields of the corresponding 2-hydroxycyclohexa-2,4-diene-1,1,3-tricarboxylates 2, up to 93%. A variant of controlling the dimerization process to reach deeper transformations by varying the amounts of TiCl4 and reaction temperature that gave 9,10-dihydro-5,9-methanobenzo[8]annulenes 3 was suggested. The effect of electronic and steric factors on the observed process was noted: halo-substituted styrylmalonates and styrylmalonates containing an acceptor moiety in the aromatic nucleus successfully undergo this reaction. Moreover, the principal possibility to perform similar reactions with Knoevenagel adducts 5 was shown.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28010270/s1, copies of NMR spectra. Experimental section. Reference [45] is citied in the supplementary materials.

Author Contributions

Conceptualization, D.D.B.; methodology, D.D.B. and K.V.P.; investigation, D.D.B. and G.R.C.; writing—original draft preparation, D.D.B.; writing—review and editing, R.A.N. and Y.V.T.; supervision, R.A.N. and Y.V.T.; project administration, R.A.N. and Y.V.T.; funding acquisition, R.A.N. and Y.V.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by a grant from the Russian Science Foundation (RSF grant No. 22-13-00418).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Acknowledgments

High-resolution mass spectra were recorded in the Department of Structural Studies of N. D. Zelinsky Institute of Organic Chemistry RAS, Moscow.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Molecules 28 00270 sch001 550
Scheme 1. Known types of cyclodimerization of ACDC and isomeric styrylmalonates [18,26,27,28,29,31,32,33,34,35,36].
Scheme 1. Known types of cyclodimerization of ACDC and isomeric styrylmalonates [18,26,27,28,29,31,32,33,34,35,36].
Molecules 28 00270 sch001
Molecules 28 00270 sch002 550
Scheme 2. Scope of the reaction for cyclohexadienols 2. * Compound 3f is formed additionally.
Scheme 2. Scope of the reaction for cyclohexadienols 2. * Compound 3f is formed additionally.
Molecules 28 00270 sch002
Molecules 28 00270 sch003 550
Scheme 3. Reactions dimerization/elimination for 9,10-dihydro-5,9-methanobenzo[8]annulenes 3. * Formed as a minor compound under the conditions used to synthesize cyclohexadienol 2f.
Scheme 3. Reactions dimerization/elimination for 9,10-dihydro-5,9-methanobenzo[8]annulenes 3. * Formed as a minor compound under the conditions used to synthesize cyclohexadienol 2f.
Molecules 28 00270 sch003
Molecules 28 00270 g001 550
Figure 1. Structure and stereochemistry of the 9,10-dihydro-5,9-methanobenzo[8]annulene 3a.
Figure 1. Structure and stereochemistry of the 9,10-dihydro-5,9-methanobenzo[8]annulene 3a.
Molecules 28 00270 g001
Molecules 28 00270 sch004 550
Scheme 4. Cross-reaction of β-styrylmalonates 1a,f with benzylidenemalonate 5.
Scheme 4. Cross-reaction of β-styrylmalonates 1a,f with benzylidenemalonate 5.
Molecules 28 00270 sch004
Molecules 28 00270 sch005 550
Scheme 5. Development of the preliminary asymmetric version of the reaction for the dihydromethanobenzoannulene 3h.
Scheme 5. Development of the preliminary asymmetric version of the reaction for the dihydromethanobenzoannulene 3h.
Molecules 28 00270 sch005
Molecules 28 00270 sch006a 550Molecules 28 00270 sch006b 550
Scheme 6. Experimental observation by NMR of the 1st step of the styrylmalonate activation by TiCl4.
Scheme 6. Experimental observation by NMR of the 1st step of the styrylmalonate activation by TiCl4.
Molecules 28 00270 sch006aMolecules 28 00270 sch006b
Molecules 28 00270 sch007 550
Scheme 7. Probable mechanism for the formation of 2-hydroxycyclohexa-2,4-diene-1,1,3-tricarboxylates 2.
Scheme 7. Probable mechanism for the formation of 2-hydroxycyclohexa-2,4-diene-1,1,3-tricarboxylates 2.
Molecules 28 00270 sch007
Molecules 28 00270 sch008 550
Scheme 8. Probable mechanism for the formation of 9,10-dihydro-5,9-methanobenzo[8]annulenes 3.
Scheme 8. Probable mechanism for the formation of 9,10-dihydro-5,9-methanobenzo[8]annulenes 3.
Molecules 28 00270 sch008
Table
Table 1. Optimization of the reaction conditions for dimerization/elimination of β-styrylmalonate 1a.
Table 1. Optimization of the reaction conditions for dimerization/elimination of β-styrylmalonate 1a.
Molecules 28 00270 i001
EntrySolvent [e]T, °Ct, hTiCl4 (Equiv.)NMR Yields, % [a,b]
2a3a
11,2-DCE60312726
2CH2Cl240311030
3 [c]CH2Cl2253100
4CH2Cl24030.5537
5 [c]CH2Cl24030.1traces0
6CH2Cl2401.51724
7CH2Cl24031.5traces30
8CH2Cl2403225
91,2-DCE8030.593 [d]traces
101,2-DCE801.50.5868
[a] 1,4-Dinitrobenzene was used as internal standard. [b] Other compounds in the reaction mixture are [4 + 2]-products and oligomers. [c] Only starting compound. [d] Isolated yield [e] 0.113 M solution.
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Borisov, D.D.; Chermashentsev, G.R.; Potapov, K.V.; Novikov, R.A.; Tomilov, Y.V. Dimerization/Elimination of β-Styrylmalonates under Action of TiCl4. Molecules 2023, 28, 270. https://doi.org/10.3390/molecules28010270

AMA Style

Borisov DD, Chermashentsev GR, Potapov KV, Novikov RA, Tomilov YV. Dimerization/Elimination of β-Styrylmalonates under Action of TiCl4. Molecules. 2023; 28(1):270. https://doi.org/10.3390/molecules28010270

Chicago/Turabian Style

Borisov, D. D., G. R. Chermashentsev, K. V. Potapov, R. A. Novikov, and Yu. V. Tomilov. 2023. "Dimerization/Elimination of β-Styrylmalonates under Action of TiCl4" Molecules 28, no. 1: 270. https://doi.org/10.3390/molecules28010270

APA Style

Borisov, D. D., Chermashentsev, G. R., Potapov, K. V., Novikov, R. A., & Tomilov, Y. V. (2023). Dimerization/Elimination of β-Styrylmalonates under Action of TiCl4. Molecules, 28(1), 270. https://doi.org/10.3390/molecules28010270

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