Lewis Acid-Catalyzed Formal (4+2)-Cycloaddition between Cross-Conjugated Azatrienes and Styrylmalonates: The Way to Functionalized Quinolizidine Precursors

Quinolizidine and azaphenalene alkaloids are common in nature and exhibit a pharmaceutical activity, which stirs up increased interest in expanding the range of methods for the synthesis of the corresponding derivatives. In this work, we attempted to adapt our previously presented method for the synthesis of tetrahydropyridines to the preparation of potential precursors for these heterocycles as a separate development of a necessary intermediate stage. To this end, we studied the reactions of β-styrylmalonates with N-protected cross-conjugated azatrienes in the presence of Sn(OTf)2. Moreover, the regioselectivity of the process involving unsymmetrically substituted azatrienes was estimated. The diene character of vinyltetrahydropyridines was studied in detail with the participation of PTAD. Finally, for the Ts-protected highly functionalized vinyltetrahydropyridines synthesized, a detosylation method to give new desired azadiene structures as precursors of the quinolizidine core was suggested.


Introduction
Quinolizidine motifs are widely distributed in natural products. These structures have long been of interest, primarily in the context of pharmaceuticals. Today, they continue to attract increasing attention from researchers [1][2][3][4][5][6], along with their related azaphenalene alkaloids [7][8][9]. Such acute attention prompts a search for new methods for the synthesis of compounds containing these structural cores. One of the possible strategies for synthesizing quinolizidine structures may involve the functionalization of an appropriate nitrogencontaining monocyclic precursor. We have recently presented a useful method for highly diastereoselective construction of 1,2,3,4-tetrahydropyridines from styrylmalonates [10][11][12][13][14] 1 and conformationally non-rigid 1-azadienes that undergo a formal (4+2)-cycloaddition in the presence of Lewis acids [15]. In order to expand the prospects for the synthetic application of the previously discovered reaction and to switch to quinolizidine precursors, modifying the substrate in such a way as to create the possibility of completing a second ring has been suggested.
One of the possible ways to develop this approach involves studying the reaction of cross-conjugated azatrienes 2 as initial substrates (Scheme 1). This method makes it possible to switch to the corresponding vinyltetrahydropyridines 3 containing a diene system, which opens access to further functionalization. Since we are interested in obtaining structures that contain a nodal nitrogen atom, it seems appropriate to "turn" the diene system in its direction by removing the protective group followed by migration of the double bond. It should be noted that such an unusual deprotection seems to be an interesting and promising challenge. It may result in a new class of azadienes 4 that retains the trans,trans-orientation

Results and Discussion
The implementation of the idea of synthesizing azadienes 4 is closely related to the choice of a removable protective group. In our previous work, substrates containing sulfonyl protective groups such as tosyl (Ts) and nosyl (Ns) were studied because of the availability of well-known and simple methods for the synthesis of the corresponding starting compounds, the acceptor effect that promotes the reaction, and the prominent stability of these groups. These circumstances prompted us to decide first to study the possibility of removing these protective sulfonyl groups in the corresponding substrates. Since the removal of the tosyl group usually requires rather drastic conditions, such as a strongly acidic medium (HBr/AcOH [16], TfOH [17]) or the presence of powerful reducing agents (Na/Hg [18,19], Na/NH3 [20], Na(Li)/naphthalene [21][22][23][24][25], SmI2 [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43], Mg/MeOH [15,27,[44][45][46], etc.), the nosyl group was chosen as the most preferred one. For this purpose, protected azatriene 2a was obtained and then reacted with styrylmalonate in the presence of Sn(OTf)2 as a Lewis acid (Scheme 2). As a result, vinyltetrahydropyridine 3a was synthesized in a good yield, as those obtained earlier in the reaction with azadienes. Further, a number of attempts were made to remove the nosyl group [47,48]; however, due to side processes, the desired product was not identified in the reaction mixture, as well as any other products in preparative amounts. It is most probable that the thiolate anion is capable of reacting with the azadiene fragment of newly formed denosylated sub-Scheme 1. Reactions of styrylmalonates 1 with cross-conjugated azatrienes 2 and further possible transformations of the products.

Results and Discussion
The implementation of the idea of synthesizing azadienes 4 is closely related to the choice of a removable protective group. In our previous work, substrates containing sulfonyl protective groups such as tosyl (Ts) and nosyl (Ns) were studied because of the availability of well-known and simple methods for the synthesis of the corresponding starting compounds, the acceptor effect that promotes the reaction, and the prominent stability of these groups. These circumstances prompted us to decide first to study the possibility of removing these protective sulfonyl groups in the corresponding substrates. Since the removal of the tosyl group usually requires rather drastic conditions, such as a strongly acidic medium (HBr/AcOH [16], TfOH [17]) or the presence of powerful reducing agents (Na/Hg [18,19], Na/NH 3 [20], Na(Li)/naphthalene [21][22][23][24][25], SmI 2 [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43], Mg/MeOH [15,27,[44][45][46], etc.), the nosyl group was chosen as the most preferred one. For this purpose, protected azatriene 2a was obtained and then reacted with styrylmalonate in the presence of Sn(OTf) 2 as a Lewis acid (Scheme 2). As a result, vinyltetrahydropyridine 3a was synthesized in a good yield, as those obtained earlier in the reaction with azadienes. Further, a number of attempts were made to remove the nosyl group [47,48]; however, due to side processes, the desired product was not identified in the reaction mixture, as well as any other products in preparative amounts. It is most probable that the thiolate anion is capable of reacting with the azadiene fragment of newly formed denosylated substrate 4 with the occurrence of further side processes. Thus, it was shown that nosyl protection was not an optimal choice for the chosen strategy, so we switched to the synthesis of tosyl derivatives. strate 4 with the occurrence of further side processes. Thus, it was shown that nosyl protection was not an optimal choice for the chosen strategy, so we switched to the synthesis of tosyl derivatives. Scheme 2. Preparation of vinyltetrahydropyridine 3a and attempts to remove the nosyl protection.
To study the scope of the reaction with the participation of sulfonyl-protected azatrienes 2a-c, we tested a number of starting styrylmalonates 1 (Scheme 3). All the corresponding vinyltetrahydropyridines 3 were obtained as single trans,trans-diastereomers. As in the case of azadienes studied in our previous work, the highest yields were achieved for para-methyl, -methoxy, and halo substituents in the aryl moiety of styrylmalonates. A noticeable decrease in yields was demonstrated for electron-withdrawing para-NO2C6H4and 1-naphtyl-substituted styrylmalonates. Our attempt to involve an analogous bis(4-MeOC6H4)-substituted azatriene (see Supplementary Materials) in the reaction failed due to side reactions of the donor substrate in the presence of Sn(OTf)2, which was confirmed by mixing these substances in the absence of styrylmalonate; only traces of the desired product were detected in the 1 H NMR spectrum. It is interesting that compound 3i showed a partial broadening of a set of signals in the NMR spectra; the same behavior was shown and studied in detail earlier in our previous work for a similar product of the reaction between the same ortho-ClC6H4-styrylmalonate and azadiene bearing a Ph group at the C=N double bond (see [15], Supplementary Materials). As in the case described in the previous work, the signals of some aliphatic (e.g., H(2), H(3), H(4) in the tetrahydropyridine ring) and aromatic protons that are spatially proximate to the ortho-ClC6H4 moiety are broadened, and apparently, those closest to the chlorine atom (especially H(2) and H(4)) undergo a downfield shift by up to 0.8 ppm that is quite noticeable in comparison with the chemical shifts of the corresponding signals of the other obtained tetrahydropyridines. Presumably, this effect can be explained by the proximity and direct influence of the chlorine atom. To study the scope of the reaction with the participation of sulfonyl-protected azatrienes 2a-c, we tested a number of starting styrylmalonates 1 (Scheme 3). All the corresponding vinyltetrahydropyridines 3 were obtained as single trans,trans-diastereomers. As in the case of azadienes studied in our previous work, the highest yields were achieved for para-methyl, -methoxy, and halo substituents in the aryl moiety of styrylmalonates. A noticeable decrease in yields was demonstrated for electron-withdrawing para-NO 2 C 6 H 4and 1-naphtyl-substituted styrylmalonates. Our attempt to involve an analogous bis(4-MeOC 6 H 4 )-substituted azatriene (see Supplementary Materials) in the reaction failed due to side reactions of the donor substrate in the presence of Sn(OTf) 2 , which was confirmed by mixing these substances in the absence of styrylmalonate; only traces of the desired product were detected in the 1 H NMR spectrum. It is interesting that compound 3i showed a partial broadening of a set of signals in the NMR spectra; the same behavior was shown and studied in detail earlier in our previous work for a similar product of the reaction between the same ortho-ClC 6 H 4 -styrylmalonate and azadiene bearing a Ph group at the C=N double bond (see [15], Supplementary Materials). As in the case described in the previous work, the signals of some aliphatic (e.g., H(2), H(3), H(4) in the tetrahydropyridine ring) and aromatic protons that are spatially proximate to the ortho-ClC 6 H 4 moiety are broadened, and apparently, those closest to the chlorine atom (especially H(2) and H(4)) undergo a downfield shift by up to 0.8 ppm that is quite noticeable in comparison with the chemical shifts of the corresponding signals of the other obtained tetrahydropyridines. Presumably, this effect can be explained by the proximity and direct influence of the chlorine atom.
To show the potential applications of our synthetic method, we carried out the reaction between styrylmalonate 1a and azatriene 2b on a gram scale under standard reaction conditions (Scheme 4). As shown by TLC, in this case, the reaction takes longer to achieve full conversion. Fortunately, the formation of the desired vinyltetrahydropyridine 3b occurred with only a slightly lower yield in comparison with the milligram-scale synthesis.
A study of the regioselectivity of the reaction in the presence of unsymmetrically substituted azatrienes is an obvious development of this research. To identify the potential effect of electronic and sterical factors, the corresponding azatrienes 2c,d were synthesized and used in the reaction with styrylmalonate 1d as the model substrate (Table 1). It was shown that the effect of strong electron-donating and electron-withdrawing groups is not sufficient to make the process regioselective (compounds 3k and 3k ), but the situation was slightly better in the case of the sterical impact of the 2,6-Cl 2 C 6 H 3 moiety. This observation prompted us to increase steric hindrance by using a bulkier ortho-ClC 6 H 4 substituent in the starting styrylmalonate 1g, which resulted in increasing the ratio of regioisomers 3m and 3m up to 4/1 at low temperature (entry 6).
The resulting vinyltetrahydropyridines 3 contain a diene moiety that can be involved in [4+2]-cycloaddition reactions and thereby provide access to the implementation of the diene-transmissive hetero Diels-Alder reaction strategy (DTHDA) [49]. To illustrate this approach, reactions of compounds 3a,b with a commonly used dienophile PTAD were carried out (Scheme 5). The process occurs very quickly with almost quantitative yields to give classical adducts 5a,b. Purification of the latter using column chromatography was found to be difficult due to the occurrence of side reactions on silica gel, the products of which were adsorbed and partially decomposed. However, the purity and yield of the compounds obtained make it possible to do without additional purification. Nevertheless, for one of the adducts, 5a, we attempted to isolate the most stable product of transformation by carrying out the reactions with SiO 2 as an acidic reagent (Scheme 5, Table 2), and heterocycle 6 was isolated as the only product of double bond migration. Despite the low yield of this compound, it is of interest because a new asymmetric center is induced at a noticeable distance from the initial ones. In view of this, we tried to optimize the conditions for double bond migration, including the replacement of silica gel with neutral Al 2 O 3 , but we failed to achieve an improvement here ( Table 2). To show the potential applications of our synthetic method, we carried out t tion between styrylmalonate 1a and azatriene 2b on a gram scale under standard conditions (Scheme 4). As shown by TLC, in this case, the reaction takes longer to full conversion. Fortunately, the formation of the desired vinyltetrahydropyridin curred with only a slightly lower yield in comparison with the milligram-scale sy A study of the regioselectivity of the reaction in the presence of unsymm To show the potential applications of our synthetic method, we carried out t tion between styrylmalonate 1a and azatriene 2b on a gram scale under standard r conditions (Scheme 4). As shown by TLC, in this case, the reaction takes longer to full conversion. Fortunately, the formation of the desired vinyltetrahydropyridin curred with only a slightly lower yield in comparison with the milligram-scale sy A study of the regioselectivity of the reaction in the presence of unsymme substituted azatrienes is an obvious development of this research. To identify the p effect of electronic and sterical factors, the corresponding azatrienes 2c,d were synt and used in the reaction with styrylmalonate 1d as the model substrate (Table 1) shown that the effect of strong electron-donating and electron-withdrawing group sufficient to make the process regioselective (compounds 3k and 3k′), but the s was slightly better in the case of the sterical impact of the 2,6-Cl2C6H3 moiety. Thi   The resulting vinyltetrahydropyridines 3 contain a diene moiety that can be involved in [4+2]-cycloaddition reactions and thereby provide access to the implementation of the diene-transmissive hetero Diels-Alder reaction strategy (DTHDA) [49]. To illustrate this approach, reactions of compounds 3a,b with a commonly used dienophile PTAD were carried out (Scheme 5). The process occurs very quickly with almost quantitative yields to give classical adducts 5a,b. Purification of the latter using column chromatography was found to be difficult due to the occurrence of side reactions on silica gel, the products of which were adsorbed and partially decomposed. However, the purity and yield of the compounds obtained make it possible to do without additional purification. Nevertheless, for one of the adducts, 5a, we attempted to isolate the most stable product of transformation by carrying out the reactions with SiO2 as an acidic reagent (Scheme 5, Table 2), and heterocycle 6 was isolated as the only product of double bond migration. Despite the low yield of this compound, it is of interest because a new asymmetric center is induced at a noticeable distance from the initial ones. In view of this, we tried to optimize the conditions for double bond migration, including the replacement of silica gel with neutral Al2O3, but we failed to achieve an improvement here ( Table 2). Scheme 5. The reaction of vinyltetrahydropyridines 3a,b with PTAD to form adducts 5a,b and subsequent formation of isomer 6. The resulting vinyltetrahydropyridines 3 contain a diene moiety that can be involved in [4+2]-cycloaddition reactions and thereby provide access to the implementation of the diene-transmissive hetero Diels-Alder reaction strategy (DTHDA) [49]. To illustrate this approach, reactions of compounds 3a,b with a commonly used dienophile PTAD were carried out (Scheme 5). The process occurs very quickly with almost quantitative yields to give classical adducts 5a,b. Purification of the latter using column chromatography was found to be difficult due to the occurrence of side reactions on silica gel, the products of which were adsorbed and partially decomposed. However, the purity and yield of the compounds obtained make it possible to do without additional purification. Nevertheless, for one of the adducts, 5a, we attempted to isolate the most stable product of transformation by carrying out the reactions with SiO2 as an acidic reagent (Scheme 5, Table 2), and heterocycle 6 was isolated as the only product of double bond migration. Despite the low yield of this compound, it is of interest because a new asymmetric center is induced at a noticeable distance from the initial ones. In view of this, we tried to optimize the conditions for double bond migration, including the replacement of silica gel with neutral Al2O3, but we failed to achieve an improvement here ( Table 2).  The next stage of the work was the selection of the method for the removal of tosyl protection. Vinyltetrahydropyridine 3b was chosen as a model substrate. It should be noted that the removal of tosyl protection is still an urgent problem of modern organic chemistry. Despite the existence of a set of deprotection methods discussed above, the type of substrate has a very strong influence, which requires careful selection and optimization of conditions in each specific case. We tested a variety of detosylation conditions described in the literature (Table 3). It was shown that the use of SmI 2 in combination with miscellaneous additives was not effective (entries 1-4). In the case of using the Mg/MeOH system, it was not possible to stop the reduction at the stage of azadiene 4; the formation of traces of further reduction products were found (entries 5-7). An attempt at detosylation in the presence of TfOH or HBr/AcOH resulted in the formation of a complex mixture of products (entries 8-10). Finally, the formation of the desired azadiene 4 in an acceptable amount was achieved only if sodium naphthalenide was used (entries [11][12][13]. Apparently, the rather low yields of compound 4 are due to the occurrence of side reactions under harsh reducing conditions, which indicates the need for further research to develop a milder approach to the preparation of such compounds. Nevertheless, this result shows that the formation of such complexly functionalized azadienes is possible. This fact opens up the possibility of further study of such substances in reactions with various ene compounds for the formation of the desired quinolizidines. Table 3. The optimization of reaction conditions for detosylation of vinyltetrahydropyridine 3b. system, it was not possible to stop the reduction at the stage of azadiene 4; the formation of traces of further reduction products were found (entries 5-7). An attempt at detosylation in the presence of TfOH or HBr/AcOH resulted in the formation of a complex mixture of products (entries 8-10). Finally, the formation of the desired azadiene 4 in an acceptable amount was achieved only if sodium naphthalenide was used (entries [11][12][13]. Apparently, the rather low yields of compound 4 are due to the occurrence of side reactions under harsh reducing conditions, which indicates the need for further research to develop a milder approach to the preparation of such compounds. Nevertheless, this result shows that the formation of such complexly functionalized azadienes is possible. This fact opens up the possibility of further study of such substances in reactions with various ene compounds for the formation of the desired quinolizidines. Mg (40 eq), ))) MeOH 20 1 further reduction (traces) 6 Mg (10 eq), ))) MeOH 20 0. 25 7 Mg (3 eq Na-naphthalenide (6 eq) THF -78 0.25 40 13 Na-naphthalenide(6 eq) DME -60 0. 25 29 * Incomplete conversion (<10% traces of 3b were found). ** 1,2-dichloroethane.

General Methods
All reagents and solvents used were purchased from Aldrich (St. Louis, MI, USA) or Acros Organics (Geel, Belgium) without additional purification. THF was purified by distillation over Na/benzophenone under an argon atmosphere just prior to use. All operations were performed under an argon atmosphere. Starting styrylmalonates 1 were synthesized from the corresponding D-A cyclopropanes [50,51]. TLC analysis was performed on Silufol chromatographic plates. For preparative chromatography, silica gel 60 (0.040−0.063 mm) was used. 1 H, 13 C, and 15 N NMR spectra were recorded on a Bruker AM-300 (300.1, 75.5, and 30.4 MHz, respectively) spectrometers in CDCl 3 or CD 2 Cl 2 containing 0.05% Me 4 Si as the internal standard. Determinations of structures and stereochemistry of obtained compounds and assignments of 1 H and 13 C signals were made with the aid of 1D and 2D gradient/non-gradient DEPT-135, COSY, NOESY, HSQC, HMBC, and 1 H-15 N HMBC spectra. 19 F NMR spectra were recorded on a 300 MHz spectrometer (282.4 MHz); standard-CFCl 3 . High-resolution mass spectra were obtained using simultaneous electrospray ionization (ESI) [52]. The melting points were determined using a Kofler hot-stage microscope.

General Synthetic Procedure and Spectroscopic Data for Azatrienes 2
A mixture of corresponding substituted 1,4-pentadien-3-one (10 mmol), Et 3 N (6.13 mL, 44 mmol), and p-nitrophenylsulfonamide or p-toluenesulfonamide (4.0 or 3.4 g, 20 mmol) in CH 2 Cl 2 (50 mL) was cooled to 0 • C, and titanium tetrachloride (10 mL, 1.0 M solution in CH 2 Cl 2 , 10 mmol) was added dropwise. The reaction mixture was warmed to room temperature with stirring for 7 h, after which the reaction was quenched with saturated aqueous NaHCO 3, and the mixture was extracted with CH 2 Cl 2 (30 mL × 2). The combined extracts were washed with water and brine, dried over MgSO 4 , and concentrated in vacuo. Acetone (20 mL) was added to the residue, left for 10 min, and then the precipitate was filtered off, washed with cold acetone, and dried to afford the azatrienes 2.

Conclusions
In conclusion, the Lewis acid-catalyzed reactions of formal (4+2)-cycloaddition between styrylmalonates and N-sulfonyl-protected cross-conjugated azatrienes have been studied. The reaction occurs in good yields and makes it possible to obtain the corresponding vinyltetrahydropyridines as single trans,trans-diastereomers. The regioselectivity of the reaction was studied in the case of unsymmetrically substituted azatrienes, where the maximum ratio of regioisomers reached 4/1 at best. The resulting vinyltetrahydropyridines were tested as dienes in the Diels-Alder reaction with PTAD, which is an implementation of the DTHDA concept. Finally, the optimal detosylation conditions were found to obtain a new type of highly functionalized azadienes from the vinyltetrahydropyridines discussed above. In the future, we plan to study related new precursors in order to develop an approach to the diastereoselective synthesis of polycyclic saturated nitrogen-containing heterocycles, in particular, quinolizidines and azaphenalenes.