Selective Formation of Internal Olefinic Trimer of α-Methylstyrenes with HI Gas and Ketones

Reaction of α-methylstyrene in the presence of HI gas and methyl p-tolyl ketone selectively resulted in an internal olefinic trimer. We revealed that the ketones with the stabilization of the protonated state were efficient to give the corresponding trimers, whereas the other ketones gave the usual indane compound. From the investigation for the mechanistic path, we found that the trimer is a kinetic product and that indane is a thermodynamic product.

We have been interested in the application of HI gas for organic synthesis, and we reported the α-alkylated ketone formation with two ketones 12 and the indane formation via styrene derivatives. 13 We attempted the reaction of the combination of ketone and styrene derivatives to find the unique selective formation of indane (1) and internal olefinic trimer (2), which was rarely obtained in the acidic conditions. Herein, we report the formation of 2 with HI under solventfree conditions. This reaction showed the complete selectivity with or without methyl p-tolyl ketone (Scheme 1). In addition, we also revealed that 2 is a kinetic product and 1 is a thermodynamic (equilibrium controlled) product.

■ RESULTS AND DISCUSSION
We examined the reaction of α-methylstyrene in the presence of 0.2 equiv molar amounts of methyl p-tolyl ketone because the reactivity of acetophenone was higher than that of αmethylstyrene based on the yield of the product (61 12 and 38%, 13 respectively). When the reaction was conducted with 1 equiv of HI gas based on α-methylstyrene at 25°C under solvent-free conditions, the indane derivative (1a) was obtained in 51% yield as a major product and the methyl ptolyl ketone was completely recovered (entry 1 in Table 1). By decreasing the amount of HI (entries 2−7), trimeric compound (2a) was obtained in combination with dimeric products (3 and 4). As a result, 2a was obtained as a major product with no formation of 1a in the case of the lower amount than 0.6 equivalent of HI. The formation of 2a was reported as one of the mixture of trimers in the reaction of αmethylstyrene with chloroacetic acid derivatives by Kimura et al. 14 Under our conditions, constitutional isomers of 2a were not found in 1 H NMR analysis. Collins et al. synthesized 2a by the elimination of the corresponding alcohol. 15 We varied the amount of ketone under 0.20 equivalent of HI. As a result, the ketone in larger quantities than 0.1 equivalent amount was efficient to form 2a (entries 8−11). No formation of the αalkylated ketone, 1,3-di(p-tolyl)butan-1-one, 12 was observed even when 1 equivalent of methyl p-tolyl ketone was used (entry 8). From those results, we found that a 1:1 ratio of HI and ketone is one of the best ratios to produce 2a, considering the efficiency with the amount of the introduced materials (entry 5). When the control experiment was conducted without methyl p-tolyl ketone, the reaction produced 1a with no formation of 2a, 3, or 4 (entry 13).
Next, we examined various ketones as an additive in this reaction (Table 2). Unique selectivity was observed by using methyl tolyl ketone isomers. When o-and p-isomers were added, 2a was obtained as a major product (entries 1 and 3). Contrarily, 1a was formed in the presence of methyl m-tolyl ketone (entry 2). The addition of acetophenone and benzophenone was ineffective in producing 2a (entries 4 and 5), but fluorenone was efficient for 2a (entry 6). When pmethoxyphenyl methyl ketone was used, a lower yield of 2a was observed with 3 as a main product (entry 7). HI was wellknown as a cleavage reagent of the methoxy group. 16 Thus, dissipation of HI occurred to interrupt the formation of a trimer. When we treated with p-chlorophenyl methyl ketone, 2a was still formed as a major product (entry 8). An aliphatic ketone such as an acetone was insufficient to result in 2a (entry 9). We found that benzamide was capable of forming 2a, but that they gave a lower yield than that of methyl p-tolyl ketone (entry 10). In the case of addition of amines, higher pK BH + of conjugated acid in dimethyl sulfoxide (9.0, 3.6, and 2.5 for trimethylamine, aniline, N,N-dimethylanilne, respectively) 17 gave a higher yield of 2a (entries 11−13). However, the formation of 1a or the recovery of α-methylstyrene were also observed. No formation of 1a and 2a was found in the case of phosphine and sulfur oxides (entries 14 and 15). An aqueous solution of HI, which means H 2 O as an additive, gave 2a in 52% yield with the concomitant with 1a (23%) (entry 16). This result was a clear contrast in the case of using gaseous HI (entry 13 in Table 1). From those results, one possibility that arose as a reason for occurring selectively was the difference of the basicity of the additive. The acidity of the conjugated acid of ketones was reviewed by Freiberg. 18 The pK BH + values for methyl p-tolyl ketone, acetophenone, benzophenone, pmethoxyphenyl methyl ketone, p-chlorophenyl methyl ketone, and acetone 19 were −4.02, −4.32, −4.95, −3.31, −4.85, and −2.85, respectively, even though pK BH + value was determined by fitting into the Bunnett−Olsen equation 20 in aqueous sulfuric acid. We could not find any relation between pK BH + value and the selectivity in our investigation. Therefore, we suspected that the stabilization of the protonated complex of the carbonyl moiety would be affected to produce 2a. Methyl  Benzamide was used as an additive. e Triethylamine was used as an additive. f Aniline was used as an additive and the recovery of αmethylstyrene (12%) was observed. g N,N-Dimethylaniline was used as an additive and the recovery of α-methylstyrene (51%) was observed. h DMSO was used as an additive and the recovery of αmethylstyrene (57%) was observed. i Triphenylphosphine oxide was used as an additive and the recovery of α-methylstyrene (66%) was observed. j 57 wt % aqueous HI (0.02 equiv) was used instead of HI gas.

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Article group on o-and p-position stabilized the positive charge on carbon at the carbonyl group by an inductive effect and hyperconjugation. Chlorine atoms also stabilized its positive charge by a mesomeric effect.
Furthermore, we examined the reaction with or without methyl p-tolyl ketone in the presence of various acids (Table  3). There was no reaction in the case of a solution of HCl (entries 1 and 2). In addition, 3 was found in the reaction with a solution of HBr (entries 3 and 4). It is a clear contrast against the reaction with a solution of HI (entry 16 in Table 2). Moreover, it would be caused by the strong acidity of HI. In addition, the formation of 2a was observed in the case of a solution of HClO 4 with and without methyl p-tolyl ketone, H 2 SO 4 , and methanesulfonic acid with methyl p-tolyl ketone. We could not give the clear explanation of the decrease of the yield of 2a in the case of HClO 4 with p-tolyl ketone. One possible explanation is that the influence of water would be affected in the role of ketone. As the result, the yield of 2a could not be exceeded in the combination of HI gas and methyl p-tolyl ketone.
To gain more information for the mechanistic aspect, we examined further reactions. When 2a was treated with HI gas in the absence of ketone, 1a was formed in 84% yield based on α-methylstyrene unit (eq 1). This fact suggested that the reaction to form 2a was reversible. Moreover, no reaction of 1a in the presence of methyl p-tolyl ketone occurred (eq 2). Thus, we revealed that the formation of 1a was irreversible, and we think that 1a would be a product under thermodynamiccontrolled conditions. To reveal a kinetic product in the reaction of α-methylstyrene with HI, we stopped the reaction of α-methylstyrene and HI within 1 min. 2a was obtained in 37% yield as a main product accompanied by 3 and 4, and there was no formation of 1a. Therefore, we concluded that 2a is the kinetic product in this reaction, and that methyl p-tolyl ketone acts as an inhibitor to achieve equilibrium conditions. From those investigations, we proposed the reaction mechanism depicted as Scheme 2. At first, the protonation to α-methylstyrene occurs to produce benzyl cation A. Moreover, the addition of another α-methylstyrene forms a dimer cation B. In the case of an internal nucleophilic attack by benzene ring, 1a is obtained through intermediate C (path a). When the counter anion I − acts as a base, dimer olefins 3 and 4 are formed (path b and c). Hofmann elimination proceeds to give less-substituted olefin 3 because of the bulkiness of a base (path c). 14 Cation A can be reacted toward less hindered olefin 3 to give the trimer cation D. After deprotonation with I − , 2a is obtained. When methyl p-tolyl ketone exists in this system, the protonation with HI would be competitive with 2a and ketone. As a result, the reaction conditions with ketone situate under kinetic control to produce 2a as a major product. In the absence of methyl p-tolyl ketone, the equilibrium condition is achieved to result in the thermodynamic product 1a as major product. Complex formation with methyl p-tolyl ketone and HI would be also affected for the formation of A. However, the protonation to bulkier olefin in 2a is more difficult than in αmethylstyrene. The kinetic and thermodynamic products were supported by density functional theory (DFT) calculations (see Supporting Information). The preference of the protonation between 2a and methyl p-tolyl ketone was also

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Article supported from the DFT calculation because the complex of methyl p-tolyl ketone with HI was more stable with the value of 5.030 kcal/mol than that of 2a, whose value was larger than the value in the case of α-methylstyrene (3.846 kcal/mol) ( Figure 1). Finally, we examined the scope and limitation for the formation of 2 (Table 4). p-Methyl and p-chloro-αmethylstyrene gave 2 in each 41% yield with no formation of 1 (entries 1 and 3). However, indane formation occurred when a strong electron-donating substituent was introduced at para position, as in p-methoxy-α-methylstyrene (entry 2). Indane compound (1e) was obtained in 66% by C−C bond formation at the naphthalene 3 position in the case of 2-(propen-2yl)naphthalene (entry 4). Thus, the compounds with an electron-rich aromatic ring produced indane rings. It was caused because of the electron-rich aromatics accelerating intramolecular cyclization reaction (path a) of intermediate cation B in Scheme 2 or that the reverse reaction to

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Article intermediate cation D from 2 could not be inhibited by the ketone because of the large stability of D. In the case of 1-(propen-2-yl)naphthalene, the complex mixture was obtained (entry 5). Unfortunately, the reaction of m-and o-oriented methyl-α-methylstyrenes resulted in products with the possibility of isomers of 2 about 25 wt % amount, but the mixture was too complicated to determine the products. The compound with aromatic rings containing heteroatom, such as thienyl group, gave the complex mixture (entry 6). In addition, the compound with phenyl rings on aliphatic chain of αmethylstyrene did not undergo the reaction (entry 7). The less steric hindrance around the cationic carbon would also necessitate the formation of the products.

■ CONCLUSIONS
In summary, we revealed the selective formation of internal olefinic trimer (2) from α-methylstyrene by the combination of HI gas and methyl p-tolyl ketone. The additive ketones with the stabilization of the protonated cation by the inductive, hyperconjugative, and mesomeric effects were efficient at producing 2 instead of indane (1). We also found that 2 is a kinetic product under these reaction conditions and that 1 is a thermodynamic product. From those investigations, the ketone would be affected by the inhibition to result in equilibrium conditions by the formation of the protonated ketone. This result would lead to a novel controlling method for polymeric and oligomeric compounds.

■ EXPERIMENTAL SECTION
General Information. Melting points were uncorrected. NMR spectra were recorded with 300 or 400 MHz spectrometer for 1 H NMR and with 75 or 100 MHz spectrometer for 13 C NMR. Chemical shifts (δ) of 1 H NMR were expressed in parts per million downfield from tetramethylsilane in CDCl 3 (δ = 0) as an internal standard. Multiplicities are indicated as s (singlet), d (doublet), t (triplet), quartet (q), quint (quintet), m (multiplet), and coupling constants (J) are reported in hertz units. Chemical shifts (δ) of 13 C NMR are expressed in parts per million relative to the residual solvent [CDCl 3 (δ = 77.0)]. Analytical thin-layer chromatography was performed on glass plates precoated with silica gel (0.25 mm layer thickness). Column chromatography was used on 70−230 mesh silica gel. Recycling preparative gel permeation chromatography (GPC) was performed with YMC column (O-SIL-5-06-D 5−5, SIL 60A). Anhydrous tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl immediately prior to use. Other chemical materials were used as obtained commercially.
General Procedure for the Reaction of α-Methylstyrene with HI Gas in the Presence of Methyl p-Tolyl Ketone. In a round-bottom flask fitted with a three-way cock with septum was placed α-methylstyrene (0.598 g, 5.0 mmol) and methyl p-tolyl ketone (36.8 mg to 0.667 g, 0.25−5.0 mmol, 0.05−1.0 equiv). The flask was filled with nitrogen after reducing pressure. After slight decompression to ease the gas introduction, HI gas (32.0 mg to 0.637 g, 0.25−5.0 mmol, 0.05−1.0 equiv) was brought in the vessel with a syringe through the septum (the weight of HI gas was calculated with the change of the weight of the equipment before and after the introduction of HI gas). In addition, nitrogen gas was introduced into the vessel to release deference of pressure against the atmosphere. The mixture was stirred at 25°C for 1 d under sealed conditions by using a three-way cock. After reducing the pressure to release HI gas, to the reaction mixture was added saturated Na 2 S 2 O 3 (20 mL) and brine (15 mL). After being extracted with CHCl 3 (15 mL × 3), the organic layer was dried with MgSO 4 . After the concentration, ca. 10.0 mg of the residue was combined with p-chlorobenzaldehyde (ca. 10.0 mg) as an internal standard. Moreover, the mixture was measured with 1 H NMR to determine the yield by the integration of methine protons of the product and formyl peak of p-chlorobenzaldehyde (9.98 ppm). Furthermore, the reaction mixture included in p-chlorobenzaldehyde was subject to column chromatography on SiO 2 and preparative GPC to isolate the product.

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