Substituents Regulate the Cyclization of Conjugated Alkynes to Accurately Construct Cyclo-(E)-[3]dendralenes

Substituent-regulated cyclization of conjugated alkynes with acid catalysis was developed in this paper, and it provides a straightforward synthesis of cyclic-(E)-[3]dendralenes. Depending on the electronic effect of the aromatic ring pairing, a variety of phosphinyl quintuplet/hexa cyclo-[3]dendralenes with diverse substitution patterns are accessible, with good efficiency and high stereoselectivity. This self-cyclization process achieves the first precise construction of a phosphinylcyclo-(E)-[3]dendralene from conjugated alkynes to aromatization.


Introduction
Dendralenes, commonly known as cross-conjugated oligoalkenes, are an important class of oligo-olefinic hydrocarbon structures, exclusively comprising sp 2 -hybridized carbons [1]. Until the turn of the century, dendralenes had received little attention, most likely due to the erroneous assumption that they were too unstable to be handled in the laboratory using standard equipment and methods [2,3]. These formations were difficult to synthesize for a long time and were believed to be unstable entities from their discovery in 1955, which limited further research. A noticeable breakthrough in the practical synthesis of dendranlenes was reported by Sherburn and co-workers in 2009, finding that dendralenes are actually stable and also have surprising reactivities [4]. Subsequently, dendralenes attracted increased interest because of their unusual structure and electronic phenomenon, with widespread applications of dendralenes in polymer chemistry [5,6], theoretical chemistry [7][8][9][10], materials chemistry [11,12], electrochemistry [13], and synthetic chemistry [14][15][16][17][18][19][20][21][22][23][24][25][26], among which, cyclo- [3]dendralene, as the primary member of the family, has attracted the greatest attention owing to its wide existence in naturally occurring products and engagement in synthetic compounds [27]. For linear dendralenes, the physical and chemical properties of the annulenes are dominated by this parity-dependent behavior. Alternation of melting points in families of compounds with even-and odd-length chains has also been reported, and this is related to the property of the packing of molecules in crystal lattices. In these systems, an alternation in behavior does not extend to any other physical or chemical property [28]. Notably, when all double bonds in a dendralene molecule are in the same plane, the endo-type dendralenes will produce significant site resistance. Single bonds will then be rotated to reduce the site resistance, making the molecule resemble a "propeller" shape. However, cyclic-dendralenes limit the rotation of the single bond, which will affect the arrangement of the double bond and the chemical properties of the molecule [28]. Although cyclic-(E)- [3]dendralenes are also important skeletons in natural products, as shown in Scheme 1 [29,30], only a handful of cases have been devoted to synthesizing these stereo-structures, sometimes with unsatisfied stereoselectivity.
Initially, phosphinyl-conjugated enynes were prepared according to our previous study, and substrate 1a was selected as a model. As shown in Table 1, solvents and acids played crucial roles in producing the target phosphinyl cyclic-(E)- [3]dendralenes. Successful research indicated that using AgSbF6 directly in 1,4-dioxane, the self-cyclization Scheme 1. Naturally occurring cyclo-(E)- [3]dendralenes.
Initially, phosphinyl-conjugated enynes were prepared according to our previous study, and substrate 1a was selected as a model. As shown in Table 1, solvents and acids played crucial roles in producing the target phosphinyl cyclic-(E)- [3]dendralenes. Successful research indicated that using AgSbF 6 directly in 1,4-dioxane, the self-cyclization reaction produced phosphinyl cyclic-(E)- [3]dendralenes (2a) in a 78% yield (entry 3). Interestingly, DCM was proven to be the best choice and enhanced the isolated yield to 90% (entry 1). However, it is accompanied by a small amount of 3a production. As a comparison, other solvents, including DMF, acetonitrile, and toluene led to negative results.
Afterward, systematic screenings of the conditions were further performed using varieties of Lewis acid catalysts (entries 6-11). Although no acid was better than that of trifluoroacetic acid, it is quite clear that weak lewis acids, such as AgCl and AgOAc, rendered the decomposition of starting materials, leading to only trace amounts of the products. The target product 2a was then achieved in yields of 40% (entry 8) and 61% (entry 9) by changing the optimum conditions and the type of Lewis acid. It is worth mentioning that a small amount of six-membered ring products (3a) appeared when the type of catalyst was changed (entry 1, entry 13), indicating that regioselective cyclization reactions might be feasible. The target product can hardly be obtained after reducing the ratios of acid catalysts from 30 to 10 mol% (entry 12). Thus, by using TFA as a promoter in DCM with no additives, an efficient self-cyclization reaction of conjugated enynes was achieved to produce phosphinyl cyclic-(E)- [3]dendralenes. Moreover, the X-ray structure of 2a was obtained, and this confirmed the relative stereochemistry of products and revealed multiple double bonds in [3]dendralenes with a "fan-like" dimensional orientation. reaction produced phosphinyl cyclic-(E)- [3]dendralenes (2a) in a 78% yield (entry 3). Interestingly, DCM was proven to be the best choice and enhanced the isolated yield to 90% (entry 1). However, it is accompanied by a small amount of 3a production. As a comparison, other solvents, including DMF, acetonitrile, and toluene led to negative results. Afterward, systematic screenings of the conditions were further performed using varieties of Lewis acid catalysts (entries [6][7][8][9][10][11]. Although no acid was better than that of trifluoroacetic acid, it is quite clear that weak lewis acids, such as AgCl and AgOAc, rendered the decomposition of starting materials, leading to only trace amounts of the products. The target product 2a was then achieved in yields of 40% (entry 8) and 61% (entry 9) by changing the optimum conditions and the type of Lewis acid. It is worth mentioning that a small amount of six-membered ring products (3a) appeared when the type of catalyst was changed (entry 1, entry 13), indicating that regioselective cyclization reactions might be feasible. The target product can hardly be obtained after reducing the ratios of acid catalysts from 30 to 10 mol% (entry 12). Thus, by using TFA as a promoter in DCM with no additives, an efficient self-cyclization reaction of conjugated enynes was achieved to produce phosphinyl cyclic-(E)- [3]dendralenes. Moreover, the X-ray structure of 2a was obtained, and this confirmed the relative stereochemistry of products and revealed multiple double bonds in [3]dendralenes with a "fan-like" dimensional orientation. Encouraged by the preliminary results, we continued to investigate the substrate scope of various phosphinyl-conjugated enynes, and the results are depicted in Schemes 3 and 4. The stereoselectivity and dimensional orientation of all functional moieties were elucidated by the X-ray structure of 2a (CCDC 2214047). It is worth mentioning that the electronic effect of the variation in the R 1 and R 2 groups would render further stereodiversity to produce cyclic- [3]dendralenes. In general, good to excellent yields of the corresponding cyclic-(E)- [3]dendralene products were obtained from para-substituted aryl alkynes containing electron-withdrawing groups, such as fluorine, chlorine, and nitro (2be). In addition, para-substituted aryl alkynes with cyano and ester groups were also tested and, to our delight, were found to be applicable to the system, with good yields ranging from 79 to 85% (2d and 2f). We investigated the substrate scope of enynes, and the results Encouraged by the preliminary results, we continued to investigate the substrate scope of various phosphinyl-conjugated enynes, and the results are depicted in Schemes 3 and 4. The stereoselectivity and dimensional orientation of all functional moieties were elucidated by the X-ray structure of 2a (CCDC 2214047). It is worth mentioning that the electronic effect of the variation in the R 1 and R 2 groups would render further stereodiversity to produce cyclic- [3]dendralenes. In general, good to excellent yields of the corresponding cyclic-(E)- [3]dendralene products were obtained from para-substituted aryl alkynes containing electron-withdrawing groups, such as fluorine, chlorine, and nitro (2b-e). In addition, para-substituted aryl alkynes with cyano and ester groups were also tested and, to our delight, were found to be applicable to the system, with good yields ranging from 79 to 85% (2d and 2f). We investigated the substrate scope of enynes, and the results are depicted in Scheme 4. Quite interestingly, phosphinyl-conjugated enynes bearing electron-donating groups, including methyl, methoxy, t-butyl, and phenyl at the para-positions; methyl at the meta-position was well-tolerated in the system, affording the six-membered ring products (3g-3l) in medium to excellent yields, among which, para-methoxyand meta-methylderivated conjugated enynes were good candidates as well, and the corresponding products 3g and 3i were obtained in 80% and 84% yields. The stereoselectivity was elucidated through the X-ray structure of 3i (CCDC 2068909). In addition, pyridine-yl and thiopheneyl enynes were also tested, although the conditions needed to be altered and, to our delight, were found to be applicable to the system, with moderate yields (3m and 3n) ranging from 60% to 65% (see Supporting Information (SI) for details).
are depicted in Scheme 4. Quite interestingly, phosphinyl-conjugated enynes bearing electron-donating groups, including methyl, methoxy, t-butyl, and phenyl at the para-positions; methyl at the meta-position was well-tolerated in the system, affording the six-membered ring products (3g-3l) in medium to excellent yields, among which, para-methoxyand meta-methyl-derivated conjugated enynes were good candidates as well, and the corresponding products 3g and 3i were obtained in 80% and 84% yields. The stereoselectivity was elucidated through the X-ray structure of 3i (CCDC 2068909). In addition, pyridineyl and thiophene-yl enynes were also tested, although the conditions needed to be altered and, to our delight, were found to be applicable to the system, with moderate yields (3m and 3n) ranging from 60% to 65% (see Supporting Information (SI) for details). Scheme 3. Substrate scope on alkynes a,b . a Phosphinyl-conjugated enynes (1a, 0.1 mmol), catalyst (30 mol%), in 3 mL refluxing solvent for 3 h. b Isolated yields. c The stereochemistry was determined using X-ray. Finally, in order to study the effect of olefins next to the diphenylphosphine oxide group in this reaction, as shown in Scheme 5, compound 1p was synthesized and reacted under template conditions. It is noteworthy that these double bonds are crucial for the modulation reaction. If the functional group attached to the phosphorus oxygen is not an Finally, in order to study the effect of olefins next to the diphenylphosphine oxide group in this reaction, as shown in Scheme 5, compound 1p was synthesized and reacted under template conditions. It is noteworthy that these double bonds are crucial for the modulation reaction. If the functional group attached to the phosphorus oxygen is not an olefin, the terminal aryl substituent of the alkyne is not affected by the regulation of this reaction. For example, a substrate of 1g does not give the six-membered ring product 2p according to the previous pattern but only the five-membered ring product 2p . This approach offers a novel complementary strategy to synthesize stereodivergent indene skeletal compounds. Scheme 4. Substrate scope on allenylphosphine oxides and the formation of (Z,Z)- [3]Dendralenes a,b . a Phosphinyl-conjugated enynes (1a, 0.1 mmol), catalyst (30 mol%), in 3 mL refluxing solvent for 3 h. b Isolated yields. c The stereochemistry of 3i was determined using X-ray.
Finally, in order to study the effect of olefins next to the diphenylphosphine oxide group in this reaction, as shown in Scheme 5, compound 1p was synthesized and reacted under template conditions. It is noteworthy that these double bonds are crucial for the modulation reaction. If the functional group attached to the phosphorus oxygen is not an olefin, the terminal aryl substituent of the alkyne is not affected by the regulation of this reaction. For example, a substrate of 1g′ does not give the six-membered ring product 2p according to the previous pattern but only the five-membered ring product 2p′. This approach offers a novel complementary strategy to synthesize stereodivergent indene skeletal compounds.

Scheme 5. Control experiments.
Based on the acid-catalyzed conjugated alkyne chemistry, self-cyclization process, and previous reports [38], a plausible mechanism is proposed in Scheme 6. Initially, the protonation of alkyne leads to the formation of an alkenyl carbocation species 1 and 1′.

Scheme 5. Control experiments.
Based on the acid-catalyzed conjugated alkyne chemistry, self-cyclization process, and previous reports [38], a plausible mechanism is proposed in Scheme 6. Initially, the protonation of alkyne leads to the formation of an alkenyl carbocation species 1 and 1 . Further dearomatization of electrophilic addition intermediates 2 and 2 gives the target products 2a and 3a , respectively.

Experimental Section
General Procedures for Substrate I Preparation [35]. Diphenylphosphine chloride (40 mmol) in CH2Cl2 (50 mL) was added dropwise to a stirred and cooled (0 °C) solution of acetylenic alcohol (40 mmol) in anhydrous ether (50 mL) and pyridine (3.88 mL, 48 mmol) under nitrogen. The stirring was maintained 1 h at 0 °C and at room temperature overnight. The solution was then quenched with cold water and extracted with CH2Cl2, and the organic layer was dried with Na2SO4. Concentration in vacuo gave the crude product that was subjected to flash chromatography on silica gel eluting with ethyl acetate and petroleum ether.
Note: The acetylenic alcohols were synthesized from terminal alkynes with corresponding ketones mediated by n-BuLi [36].
General Procedures for Substrate II Preparation [36]. To a 25 mL vial, allenylphosphine oxides (1 mmol), alkynes (2 mmol), potassium carbonate (K2CO3) (2 mmol), DMSO (10 mL), and Pd-NPS (1 mol%, 16 mg) were added. The reaction was then allowed to react at 100 °C for a certain time until the complete consumption of starting materials monitored via TLC. The reaction mixture was extracted with EtOAc (10 mL × 3). The combined organic extract was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified using column chromatography on silica gel using petroleum Scheme 6. Proposed mechanism.

Experimental Section
General Procedures for Substrate I Preparation [35]. Diphenylphosphine chloride (40 mmol) in CH 2 Cl 2 (50 mL) was added dropwise to a stirred and cooled (0 • C) solution of acetylenic alcohol (40 mmol) in anhydrous ether (50 mL) and pyridine (3.88 mL, 48 mmol) under nitrogen. The stirring was maintained 1 h at 0 • C and at room temperature overnight. The solution was then quenched with cold water and extracted with CH 2 Cl 2 , and the organic layer was dried with Na 2 SO 4 . Concentration in vacuo gave the crude product that was subjected to flash chromatography on silica gel eluting with ethyl acetate and petroleum ether.
Note: The acetylenic alcohols were synthesized from terminal alkynes with corresponding ketones mediated by n-BuLi [36].
General Procedures for Substrate II Preparation [36]. To a 25 mL vial, allenylphosphine oxides (1 mmol), alkynes (2 mmol), potassium carbonate (K 2 CO 3 ) (2 mmol), DMSO (10 mL), and Pd-NPS (1 mol%, 16 mg) were added. The reaction was then allowed to react at 100 • C for a certain time until the complete consumption of starting materials monitored via TLC. The reaction mixture was extracted with EtOAc (10 mL × 3). The combined organic extract was washed with brine and dried over anhydrous Na 2 SO 4 . The solvent was evaporated under reduced pressure, and the residue was purified using column chromatography on silica gel using petroleum ether/ethylacetate (1.5/1) as the eluent to afford the enynes. After this was finished, the compound was determined through NMR. Further, 1a-1n are known compounds; please refer to [37]. General