Dimerization/Elimination of β-Styrylmalonates under Action of TiCl4

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.


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 crossdimerization in reactions of ACDCs with styrylmalonate [28,[34][35][36]). However, there is still 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]. Scheme 1. Known types of cyclodimerization of ACDC and isomeric styrylmalonates [18,[26][27][28][29][31][32][33][34][35][36]].

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. TiCl 4 in 1,2-dichloroethane under reflux conditions gives almost exclusively cyclohexadienol 2a, whereas the reaction with excess TiCl 4 (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 1 H 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). In order to study the effect of electronic and steric factors on the reactions, the d merization reaction was performed with a number of substituted β-styrylmalonates. was found that β-styrylmalonates with an acceptor substituent in the aromatic ring well as various halo-substituted derivatives readily enter the process under study o heating in dichloroethane, while the position of the halogen atoms in the aromatic moie does not significantly affect the occurring reactions. The process with these substrat occurs quite selectively without significant formation of side products. Moreover, th final compounds, i.e., the corresponding 2-hydroxycyclohexa-2,4-diene-1,1,3-t carboxylates 2a-e, do not require additional purification after extraction. The sterical hindered β-styrylmalonate and a styrylmalonate with a donor substituent in the aromat ring underwent this type of dimerization somewhat less readily (Scheme 2). The 1 H NM spectra of the reaction mixtures contained a significant number of dimers 4f,g formed b (4 + 2)-annulation, as we reported previously [18]. Moreover, the donor moiety styrylmalonate 1f partially favors yet another reaction pathway to give not only com pound 2f (Scheme 2) but also a small amount of substituted dihydro-5, 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 cyclo Scheme 2. Scope of the reaction for cyclohexadienols 2. * Compound 3f is formed additionally. 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. 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. TiCl 4 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 TiCl 4 (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. 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 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. TiCl 4 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 SiO 2 . 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)malonat curred more selectively. According to the 1 H NMR spectra of the reaction mixt homo-dimerization/elimination product 2f was detected in trace amounts, whe cross-coupling product 6f (2f/6f ratio approximately 1:16) predominated (Scheme total yield of cyclohexadienols 2f and 6f was smaller than in the case of unsub styrylmalonate 1a and was approximately the same as in the homo-di tion/elimination reaction of (4-methylstyryl)malonate 1f (see Scheme 2), which is to the fact that its dimerization to give the (4 + 2)-annulation product 4f occu readily.
Finally, we tested the variant of the asymmetric reaction of dimerization/elim of β-styrylmalonates, for which no asymmetric processes have been described in erature so far. In fact, this turned out to be not an easy task, since the standard metric catalytic approaches using chiral ligands, which were used for ACDC r [38][39][40][41], would hardly work for the processes under consideration under condi equimolar amounts of strong Lewis acids. As a result, after a series of experime focused not on the elusive development of a catalytic variant with chiral ligands the use of chiral substituents in ester groups. As such a fragment, we used an a natural (-)-menthyl substituent [42] and synthesized the corresponding styrylm 1h (according to the standard method from ACDC). Under the influence of 1.5 TiCl4 under standard conditions, the menthyl styrylmalonate 1h also enters the zation/elimination reaction with the formation of dihydromethanobenzoannu (Scheme 5), while the cyclohexadienol derivative 2h is not formed even when u equiv. TiCl4. The steric effect of the substituents in the ester groups undoubtedly the efficiency of the process, and the yield of tricycle 3h turns out to be low, only 1 "e.r." turns out to be good enough (9:1) for such a simple chirality induction The same reaction of benzylidenemalonate 5 with (4-methylstyryl)malonate 1f occurred more selectively. According to the 1 H 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. TiCl 4 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. TiCl 4 . 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.
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. Scheme 5. Development of the preliminary asymmetric version of the reaction for the dihydromethanobenzoannulene 3h.
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 Scheme 5. Development of the preliminary asymmetric version of the reaction for the dihydromethanobenzoannulene 3h.
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 TiCl 4 . 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]. 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 aro-  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 aro-Scheme 7. Probable mechanism for the formation of 2-hydroxycyclohexa-2,4-diene-1,1,3-tricarboxylates 2.
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 TiCl 4 , 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). matic ring of V occurs first, followed by cyclization with involvement of malonyl m ties to form bicyclic titanium enolate VI (Scheme 8).

Experimental Section
See Supplementary Materials.

Conclusions
Thus, we have discovered a new previously unknown variant of dimerizatio β-styrylmalonates 1 that is accompanied by elimination of an alcohol molecule and is observed in the case of isomeric ACDCs. Titanium tetrachloride acts as a catalyst. process we discovered is quite general for various substituted β-styrylmalonates and a rule, gives high yields of the corresponding 2-hydroxycyclohexa-2,4-diene-1 tricarboxylates 2, up to 93%. A variant of controlling the dimerization process to r deeper transformations by varying the amounts of TiCl4 and reaction temperature gave 9,10-dihydro-5,9-methanobenzo [8]annulenes 3 was suggested. The effect of tronic and steric factors on the observed process was noted: halo-substituted styry lonates and styrylmalonates containing an acceptor moiety in the aromatic nucleus cessfully undergo this reaction. Moreover, the principal possibility to perform sim reactions with Knoevenagel adducts 5 was shown.
Supplementary Materials: The following supporting information can be downloaded www.mdpi.com/xxx/s1, copies of NMR spectra. Experimental section. Reference [45] is citied i supplementary materials.