The TaCl5-Mediated Reaction of Dimethyl 2-Phenylcyclopropane-1,1-dicarboxylate with Aromatic Aldehydes as a Route to Substituted Tetrahydronaphthalenes

It is found that the reaction of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate with 2 equivalents each of aromatic aldehydes and TaCl5 in 1,2-dichloroethane at 23 °C for 24 h after hydrolysis gives substituted 4-phenyl-3,4-dihydronaphtalene-2,2(1H)-dicarboxylates in good yield. This represents a new type of reactions between 2-arylcyclopropane-1,1-dicarboxylates and aromatic aldehydes, yielding chlorinated tetrahydronaphthalenes with a cis arrangement of the aryl and chlorine substituents in the cyclohexene moiety. A plausible reaction mechanism is proposed.

In this paper, we report a new type of 2-arylcyclopropane-1,1-dicarboxylate reactivity with aromatic aldehydes to produce tetrahydronaphthalene (tetraline) derivatives.This approach is based on the use of TaCl 5 and is demonstrated in Scheme 1.The tetrahydronaphthalene moiety is a key structural motif in molecules of interest that have diverse biological properties, including anticancer, antimicrobial and antiviral activity [21,22].
tetrahydronaphthalene moiety is a key structural motif in molecules of interest that have diverse biological properties, including anticancer, antimicrobial and antiviral activity [21,22].Scheme 1. New type of DAC reactivity with aromatic aldehydes.
Scheme 1. New type of DAC reactivity with aromatic aldehydes.
The molecular structure of substituted 4-phenyl-3,4-dihydronaphtalene-2,2(1H) -dicarboxylates 2a-g was identified by one-dimensional ( 1 H, 13 C) and two-dimensional (HSQS, HMBC, COSY, NOESY) NMR spectral methods (see Supplementary Materials).The X-ray diffraction analysis performed on substituted tetrahydronaphthalene 2a allowed for the unambiguous attribution of relative stereochemistry (Figure 1).TaCl5 has proven to be a unique Lewis acid that facilitates a new mode of interactio between 2-arylcyclopropane-1,1-dicarboxylates and aromatic aldehydes.To ou knowledge, the formation of tetrahydronaphthalenes in these reactions has not been pre viously reported.All previously used Lewis acids in the reaction between 2-arylcyclopro pane-1,1-dicarboxylates and aromatic aldehydes resulted in the formation of product with different structures (see Scheme 1).
To better understand the reaction mechanism, we studied the reaction between di methyl 2-phenylcyclopropane-1,1-dicarboxylate 1 and 2 equivalents of TaCl5 in 1,2-dichlo roethane at room temperature.The reaction mixture was stirred for 18 h and quenche with water.It was found that, as a result of the reaction, all of the original DAC 1 had bee converted to dimethyl 2-(2-chloro-2-phenylethyl)malonate 3, with a yield of 81% (Schem 3).It is known that when dimethyl 2-arylcyclopropane-1,1-dicarboxylates 1 react wit TaCl 5 has proven to be a unique Lewis acid that facilitates a new mode of interaction between 2-arylcyclopropane-1,1-dicarboxylates and aromatic aldehydes.To our knowledge, the formation of tetrahydronaphthalenes in these reactions has not been previously reported.All previously used Lewis acids in the reaction between 2-arylcyclopropane-1,1dicarboxylates and aromatic aldehydes resulted in the formation of products with different structures (see Scheme 1).
To better understand the reaction mechanism, we studied the reaction between dimethyl 2-phenylcyclopropane-1,1-dicarboxylate 1 and 2 equivalents of TaCl 5 in 1,2dichloroethane at room temperature.The reaction mixture was stirred for 18 h and quenched with water.It was found that, as a result of the reaction, all of the original DAC 1 had been converted to dimethyl 2-(2-chloro-2-phenylethyl)malonate 3, with a yield of 81% (Scheme 3).TaCl5 has proven to be a unique Lewis acid that facilitates a new mode of interaction between 2-arylcyclopropane-1,1-dicarboxylates and aromatic aldehydes.To our knowledge, the formation of tetrahydronaphthalenes in these reactions has not been previously reported.All previously used Lewis acids in the reaction between 2-arylcyclopropane-1,1-dicarboxylates and aromatic aldehydes resulted in the formation of products with different structures (see Scheme 1).
To better understand the reaction mechanism, we studied the reaction between dimethyl 2-phenylcyclopropane-1,1-dicarboxylate 1 and 2 equivalents of TaCl5 in 1,2-dichloroethane at room temperature.The reaction mixture was stirred for 18 h and quenched with water.It was found that, as a result of the reaction, all of the original DAC 1 had been converted to dimethyl 2-(2-chloro-2-phenylethyl)malonate 3, with a yield of 81% (Scheme 3).It is known that when dimethyl 2-arylcyclopropane-1,1-dicarboxylates 1 react with SnCl4 or TiCl4 without aldehyde presence, a fast cyclopropane ring opening occurs, and a similar chlorinated product is formed after quenching with water or methanol [23].At the It is known that when dimethyl 2-arylcyclopropane-1,1-dicarboxylates 1 react with SnCl 4 or TiCl 4 without aldehyde presence, a fast cyclopropane ring opening occurs, and a similar chlorinated product is formed after quenching with water or methanol [23].At the same time, in the presence of GaCl 3 , the reaction yields b-styryl malonate 4 upon quenching [20].In this reaction, the behavior of TaCl 5 is similar to that of TiCl 4 and SnCl 4 .However, in the reaction of 2-arylcyclopropane-1,1-dicarboxylates 1 with aromatic aldehydes, the formation of substituted tetrahydronaphthalenes 2 was not observed under the influence of the two last Lewis acids, as it was when using TaCl 5 .This suggests that the cause of the unusual course of the reaction between 2-arylcyclopropane-1,1-dicarboxylates 1 and aromatic aldehydes in the presence of TaCl 5 may be due to the nature of the interaction between aromatic aldehydes and TaCl 5 .Indeed, TaCl 5 has a strong affinity for the oxygen atoms in carbonyl and carboxyl groups, acting as a powerful Lewis acid [24].
We hypothesized that the key factor in determining the unique course of the reaction along a route I (Scheme 4) is the formation of an intermediate B, which is an active carbocation.This intermediate is formed through the interaction between an aromatic aldehyde and TaCl 5 in ionic form.According to the proposed mechanism, the subsequent reaction of the intermediate B with complex A (complex between 2-arylcyclopropane-1,1-dicarboxylate 1 and TaCl 5 ) results in the formation of an intermediate C, in which a tantalum atom is bonded to OCHAr and carboxylate groups.The subsequent electrophilic attack by the positively charged methine carbon atom on the quaternary carbon atom in the cyclopropane ring causes its opening and the formation of the carbocationic intermediate D. Next, the reaction of electrophilic substitution into an aromatic ring with the participation of an aryl substituent derived from the aromatic aldehyde results in the sequential formation of cyclic intermediates E and F. At the final stage of the reaction, the hydroxyl group is substituted by a chlorine atom through the S N 2 mechanism, under the action of tantalum(V) chloride, to form intermediate G.The reaction of 2-arylcyclopropane-1,1-dicarboxylates 1 with aromatic aldehydes in the presence of GaCl 3 , which proceeds along a route II, has been previously described in detail [25].
The key step in the proposed mechanism is the conversion of the intermediate C to D, during which the cyclopropane ring opens.According to the results of quantum chemical modeling using the B3LYP/6-31G(d)/LanL2DZ method, the activation barrier for the reaction between formaldehyde and dimethyl 1-phenylcyclopropane-1,1-dicarboxylate in complex with TaCl 4 + was found to be 14.56 kcal/mol.The structure of the transition state is shown in Figure 2.
According to Scheme 4, the relative stereochemistry of carbon atoms in the cyclohexane ring is determined during the formation of the intermediate E. The large steric bulk of the aryl group and the tantalum-containing unit favor their trans location in the transition state.The subsequent S N 2 substitution of the oxygen atom with a chlorine atom under the action of TaCl 5 results in a reversal of the configuration of the corresponding carbon atom, forming a reaction product G with cis-oriented aryl and chlorine substituents on the cyclohexane ring.
As mentioned above, in the absence of aromatic aldehydes, dimethyl 2-phenylcyclopropane-1,1-dicarboxylate 1 reacts with 2 equivalents of TaCl 5 to form dimethyl 2-(2-chloro-2phenylethyl)malonate 3. We found that the reaction proceeds in a similar manner in the presence of p-methoxybenzaldehyde.It is possible that the presence of an electron-donating substituent in the aromatic ring decreases the electrophilicity of the intermediate B, and the pathway of the reaction proceeds along route II (Scheme 4).Probably for the same reason, aliphatic aldehydes do not exhibit activity in the reaction under study.
So, let us take a look at the pathways of the reaction we are studying (Scheme 4).The first pathway (route I in Scheme 4) is carried out using TaCl 5 as a Lewis acid, and it leads to the formation of substituted tetrahydronaphthalenes.When GaCl 3 is used as a Lewis acid, a second pathway (route II in Scheme 4) is realized.Obviously, the main difference between these Lewis acids is their acidity.The B3LYP/6-31G(d)/LanL2DZ method was used to calculate the geometric parameters of the complexes TaCl 5 , TiCl 4 , SnCl 4 , ZnCl 2 and GaCl 3 with methyl acetate (MeC(OMe)=O→MX n complex).The carbonyl bond length decreases in the order of the following complexes: Ester-GaCl 3 ( We hypothesized that the key factor in determining the unique course of the reaction along a route I (Scheme 4) is the formation of an intermediate B, which is an active carbocation.This intermediate is formed through the interaction between an aromatic aldehyde and TaCl5 in ionic form.According to the proposed mechanism, the subsequent reaction of the intermediate B with complex A (complex between 2-arylcyclopropane-1,1-dicarboxylate 1 and TaCl5) results in the formation of an intermediate C, in which a tantalum atom is bonded to OCHAr and carboxylate groups.The subsequent electrophilic attack by the positively charged methine carbon atom on the quaternary carbon atom in the cyclopropane ring causes its opening and the formation of the carbocationic intermediate D.
Next, the reaction of electrophilic substitution into an aromatic ring with the participation of an aryl substituent derived from the aromatic aldehyde results in the sequential formation of cyclic intermediates E and F. At the final stage of the reaction, the hydroxyl group is substituted by a chlorine atom through the SN2 mechanism, under the action of tantalum(V) chloride, to form intermediate G.The reaction of 2-arylcyclopropane-1,1-dicarboxylates 1 with aromatic aldehydes in the presence of GaCl3, which proceeds along a route II, has been previously described in detail [25].The main method for the synthesis of substituted 3,4-dihydronaphthalene-2,2(1H)dicarboxylates is the intramolecular Lewis acid-catalyzed cyclization of malonates substituted at the 2,2-position with arylmethyl and unsaturated (4-bromobut-2-en-yl [28], propargyl [29], homoallenyl [30] and 2-alkenyl [31,32]) substituents.InCl 3 , (NHC)GaX 3 /AgSbF 6 , Fe(III) complex, Pd(OAc) 2 and Hg(OTf) 2 have been used as Lewis acids.None of the known methods lead to the production of tetrahydronaphthalenes that are similar in structure to compounds 2. The presence of a chlorine atom on the tetrahydronaphthalene ring greatly expands the range of possible chemical transformations that can be carried out further, including dechlorination reactions.For example, these reactions can be facilitated by the use of frustrated Lewis acid-base pairs [33].A significant positive aspect of this transformation is the high level of stereoselectivity in the reaction, which leads to the production of tetrahydronaphthalenes with a cis arrangement of the aryl and chlorine substituents in the cyclohexene moiety.D, during which the cyclopropane ring opens.According to the results of quan ical modeling using the B3LYP/6-31G(d)/LanL2DZ method, the activation bar reaction between formaldehyde and dimethyl 1-phenylcyclopropane-1,1-dicar complex with TaCl4 + was found to be 14.56 kcal/mol.The structure of the tran is shown in Figure 2. According to Scheme 4, the relative stereochemistry of carbon atoms in th ane ring is determined during the formation of the intermediate E. The large of the aryl group and the tantalum-containing unit favor their trans location in tion state.The subsequent SN2 substitution of the oxygen atom with a chlorine a the action of TaCl5 results in a reversal of the configuration of the correspond atom, forming a reaction product G with cis-oriented aryl and chlorine substitu cyclohexane ring.
As mentioned above, in the absence of aromatic aldehydes, dimethyl 2-p propane-1,1-dicarboxylate 1 reacts with 2 equivalents of TaCl5 to form dim chloro-2-phenylethyl)malonate 3. We found that the reaction proceeds in a sim in the presence of p-methoxybenzaldehyde.It is possible that the presence of a donating substituent in the aromatic ring decreases the electrophilicity of the in B, and the pathway of the reaction proceeds along route II (Scheme 4).Proba same reason, aliphatic aldehydes do not exhibit activity in the reaction under So, let us take a look at the pathways of the reaction we are studying (Sch first pathway (route I in Scheme 4) is carried out using TaCl5 as a Lewis acid, a to the formation of substituted tetrahydronaphthalenes.When GaCl3 is used acid, a second pathway (route II in Scheme 4) is realized.Obviously, the main between these Lewis acids is their acidity.The B3LYP/6-31G(d)/LanL2DZ m used to calculate the geometric parameters of the complexes TaCl5, TiCl4, SnCl4 GaCl3 with methyl acetate (MeC(OMe)═O→MXn complex).The carbonyl bond creases in the order of the following complexes: Ester-GaCl3

Conclusions
In conclusion, we have developed a new reaction of arylcyclopropanedicarboxylates with aromatic aldehydes in the presence of TaCl 5 as a route to substituted tetrahydronaphthalenes.The presence of a chlorine atom in the tetrahydronaphthalene ring significantly expands the range of potential chemical reactions to modify the obtained compounds.One major advantage of this reaction is its strong preference for a specific stereochemistry, which results in the formation of tetrahydronaphthalenes containing aryl and chlorine substituents in a cis configuration at the cyclohexene ring.
1.246 Å) > Ester-TaCl 5 (1.244 Å) > Ester-ZnCl 2 (1.239 Å) > Ester-SnCl 4 (1.238Å) > Ester-TiCl 4 (1.236Å), which indicates the decreasing strength of the Lewis acid towards the carboxyl group in the sequence GaCl 3 -TaCl 5 -ZnCl 2 -SnCl 4 -TiCl 4 .We recently demonstrated the effectiveness of TaCl 5 in activating carboxylic acid esters for the amidation reaction with amines [26,27].Thus, if the Lewis acid is sufficiently strong, it promotes the rapid rearrangement of DAC 1 to intermediate H (route II).If the strength of the Lewis acid is not sufficient for this rearrangement, then the intermediate A acts as a nucleophile and undergoes electrophilic attack by the aldehyde complex containing the Lewis acid (route I).If the latter complex is not sufficiently electrophilic to react with DAC 1, the formation of substituted tetrahydrofurans may occur.
(1.246 Å) > Ester-T Å) > Ester-ZnCl2 (1.239 Å) > Ester-SnCl4 (1.238 Å) > Ester-TiCl4 (1.236 Å), whic the decreasing strength of the Lewis acid towards the carboxyl group in th GaCl3-TaCl5-ZnCl2-SnCl4-TiCl4.We recently demonstrated the effectiveness activating carboxylic acid esters for the amidation reaction with amines [26,2 the Lewis acid is sufficiently strong, it promotes the rapid rearrangement o intermediate H (route II).If the strength of the Lewis acid is not sufficient fo rangement, then the intermediate A acts as a nucleophile and undergoes elect tack by the aldehyde complex containing the Lewis acid (route I).If the latter

Figure 3 .
Figure 3.The numbering of atoms in the 13 С and 1 H NMR spectra of the compounds 2a-g, 3.

Figure 3 .
Figure 3.The numbering of atoms in the 13 C and 1 H NMR spectra of the compounds 2a-g, 3.