Gold-Catalyzed Benzylic Azidation of Phthalans and Isochromans and Subsequent FeCl₃-Catalyzed Nucleophilic Substitutions

Abstract

The benzylic positions of the phthalan and isochroman derivatives (1) as benzene-fused cyclic ethers effectively underwent gold-catalyzed direct azidation using trimethylsilylazide (TMSN₃) to give the corresponding 1-azidated products (2) possessing the N,O-acetal partial structure. The azido group of the N,O-acetal behaved as a leaving group in the presence of catalytic iron(III) chloride, and 1-aryl or allyl phthalan and isochroman derivatives were obtained by nucleophilic arylation or allylation, respectively. Meanwhile, a double nucleophilic substitution toward the 1-azidated products (2) occurred at the 1-position using indole derivatives as a nucleophile accompanied by elimination of the azido group and subsequent ring opening of the cyclic ether nucleus produced the bisindolylarylmethane derivatives.

Phthalan^1–3) and isochroman^4–8) derivatives are pharmaceutically useful and also utilized as reaction precursors to construct various frameworks.^9–13) We have continuously investigated the iron^14–20)- or gold^21–23)-catalyzed activation at the benzylic position of various skeletons accompanied by the benzylic C–O bond cleavage. During these investigations, the benzylic position of phthalan (1; n=1) as a benzene fused cyclic ether was found to be directly azidated in the presence of a gold catalyst and trimethylsilylazide (TMSN₃) without the C–O bond cleavage to give the 1-azido phthalan (2) (Chart 1). The direct azidations at the benzylic position of phthalan and isochroman (1; n=2) were previously accomplished using stoichiometric iodine reagents^9–11) in the presence of azido sources, such as TMSN₃ and NaN₃. Although gold catalysts were used for the C–C and C–N bond formation on the benzylic position via C–H bond activation,^12,13) the azidation method was never reported in the literature. Azido derivatives are easily transformed into amines²⁴⁾ and triazoles by the Huisgen cyclization with alkynes.^25,26) Furthermore, the nucleophilic substitution of an azido functionality as a leaving group was also reported in the literature.^27–29) In this report, we have applied 1-azido products (2) as key intermediates to the Lewis acid-catalyzed nucleophilic substitution to give highly functionalized phthalan and isochroman derivatives via the oxonium ion intermediate (A) generated by the chemoselective elimination of the azido group of the N,O-acetal moiety^30–33) (Chart 1). Consequently, the iron-catalyzed Friedel–Crafts arylation and allylation gave the 1-aryl/allyl phthalan and isochroman derivatives (3, 4) (Chart 2), while the use of highly nucleophilic indole derivatives effectively facilitated the double substitutions via elimination of the azido group and the subsequent ring opening of the cyclic ether to give the bisindolylarylmethane derivatives (5).^34–39) The obtained product (3) could also be converted into the corresponding bisarylindolylmethane derivatives (6) by the FeCl₃-catalyzed ring-opening indolylation.^40–42) We now report the direct gold-catalyzed azidation of phthalan and isochroman derivatives (Chart 1) and the subsequent unique FeCl₃-catalyzed nucleophilic substitutions (Chart 2) to produce the various pharmaceutically useful compounds.

Chart 1. Catalytic Direct Azidation of Phthalans and Isochromans and the Subsequent Lewis Acid-Catalyzed Transformation

Chart 2. Transformation of Azido Compounds as Key Reaction Intermediates

We first examined the catalyst and solvent efficiencies for the direct benzylic azidation of phthalan (1a) using TMSN₃ (4 eq) as an azido source at room temperature (Table 1). While the use of trivalent FeCl₃, AuCl₃ and HAuCl₄·3H₂O in CH₂Cl₂ gave only trace amounts of the desired 1-azido phthalan (2a) (entries 1–3), the combined use of monovalent (Ph₃P)AuCl (10 mol%) and AgSbF₆ (10 mol%) improved the reaction efficiency to produce 2a in 20% yield (entry 4). The solvent significantly influenced the azidation, and 2a was obtained in 69% yield in 1,4-dioxane in the presence of (Ph₃P)AuCl and AgSbF₆ for 5.5 h (entry 8), while CH₂Cl₂, (CH₂Cl)₂, benzene and toluene were less effective solvents (entries 4–7). Other combinations of the gold catalyst and silver salts, solvents and azido sources had no influence on the present azidation (see Supplementary Materials). Additionally, the reaction under oxygen atmosphere (entry 9) or using molecular sieves 4A (MS4A) to remove the contaminated H₂O derived from the reagents (entry 10) led to lower yield.

Table 1. Catalyst and Solvent Efficiencies of Direct Benzylic Azidation of Phthalan^a,b)

Entry	Catalyst	Additive	Solvent	Time (h)	Yield (%)
1	FeCl3	—	CH2Cl2	8	Trace
2	AuCl3	—	CH2Cl2	24	Trace
3	HAuCl4·3H2O	—	CH2Cl2	24	Trace
4	(Ph3P)AuCl	AgSbF6	CH2Cl2	24	20
5	(Ph3P)AuCl	AgSbF6	(CH2Cl)2	24	28
6	(Ph3P)AuCl	AgSbF6	Benzene	24	48
7	(Ph3P)AuCl	AgSbF6	Toluene	24	44
8	(Ph3P)AuCl	AgSbF6	1,4-Dioxane	5.5	69
9c)	(Ph3P)AuCl	AgSbF6	1,4-Dioxane	5.5	34
10d)	(Ph3P)AuCl	AgSbF6	1,4-Dioxane	7	59

a) Conditions: catalyst (10 mol%), additive (10 mol%), TMSN₃ (4 eq), solvent (substrate concentration; 1 M), at rt under Ar. b) Optimization details using other catalysts, solvents, solvent concentrations, reaction temperatures, etc., are described in the Supplementary Materials. c) The reaction was carried out under O₂ instead of Ar. d) The reaction was carried out with MS4A.

The (Ph₃P)AuCl-catalyzed benzylic azidation could be applied to various phthalan and isochroman derivatives (1a–d) possessing a cyclic benzyl ether backbone (Table 2). The non-substituted and 5,6-dichlorophthalans (1a, b) underwent the direct benzylic azidation to give the corresponding 1-azidated products (2a, b), respectively. Isochroman and 7-chloroisochroman were also reacted with TMSN₃ in the presence of (Ph₃P)AuCl and AgSbF₆ to give the corresponding 1-azidated products (entries 3, 4) respectively, while 7-methoxyisochroman (1e) possessing a relatively electron-rich aromatic nucleus was hardly transformed into the desired azidated product (2e). Furthermore, other substrates, such as indane and indene without the corresponding benzylic oxygen atom, benzylmethylether as an acyclic substrate, phthalide derivatives a possessing lactone moiety and nitrogen-containing heterocycles, were also inadequate. Namely, the specific cyclic benzyl ether structures were essential for the present direct benzylic azidation, while the reason and reaction mechanism are still unclear.

Table 2. Scope and Limitation of the Substrates^a)

Entry	Substrate	Product	Time (h)	Yield (%)
1			5.5	69
2			24	41
3			20	48
4			24	36
5			24	0

a) Inapplicable substrates under the present reaction conditions are described below.

The chemical modification of the obtained 1-azido phthalan (2a) was next investigated (Chart 3). The N,O-acetal moiety of 2a was chemoselectively activated by FeCl₃ (5 mol%) (Chart 1) and the subsequent nucleophilic substitution using 1,3-dimethoxybenzene accompanied by elimination of the azido group gave the 1-arylated phthalan (3a) in 90% yield.⁴³⁾ It is noteworthy that the use of N-methylindole as a highly nucleophilic reagent gave the bisindolylmethane (5a) in 99% yield via the elimination of the azido group and the ring opening of the cyclic benzyl ether moiety (in other words, the elimination of the benzyl ether substructure). Additionally, 3a was also smoothly reacted with N-methylindole in the presence of FeCl₃ to produce the ring-opened bisarylindolylmethane product (6) in quantitative yield.

Chart 3. Chemical Modification of the Obtained 1-Azidophthalan (2a)

We next examined the one-pot transformation of phthalan and isochroman derivatives (1a–d) to 3, 4 and 5 via the 1-azidated phthalan and isochroman derivatives (2) as intermediates (Table 3). As the result of the primary gold-catalyzed azidation of phthalan (1a) for 6 h and subsequent arylation by the stepwise addition of FeCl₃ and 1,3-dimethoxybenzene, 1,3,5-trimethoxybenezene or 1-methoxynaphthalene, the corresponding 1-arylated phthalans (3a–c) were obtained in good yields (entries 1–3). Meanwhile, the use of N-methylindole and indole instead of arenes as nucleophiles gave the bisindolylarylmethane derivatives (5a, b) by the one-pot azidation, the subsequent nucleophilic substitution accompanying with the elimination of the azido group and the ring opening of the cyclic benzyl ether moiety.⁴⁴⁾ Furthermore, allylTMS was also a good nucleophile to form the 1-allylated phthalan (4) in 49% yield (entry 6). 5,6-Dichlorophthalan (1b) could also be applied in the one-pot reaction to give the corresponding 1-arylphthalan derivative (3d) with 1,3-dimethoxybenzene and bisindolylarylmethane derivative (5c) with N-methylindole (entries 7, 8). Isochroman (1c) could be converted into the corresponding 1-arylated isochroman (3e) by the use of 1,3-dimethoxybenezene as a nucleophile in 56% yield and the bisindolylarylmethane derivative (5d) was also obtained by the nucleophilic attack of N-methylindole in 57% yield (entries 9, 10). 7-Chloroisochroman could be converted into the corresponding 3f and 5e, while the yields were not satisfied (entries 11, 12). Although the (Ph₃P)AuCl-catalyzed direct arylation using 1,3-dimethoxybenezene and N-methylindole, and allylation using allylTMS of phthalan (1a) could slightly proceed without the azidation step and the addition of FeCl₃, the reaction efficiencies were not improved (Chart 4).

Table 3. One-Pot Synthesis Using Phthalan and Isochroman Derivatives (1a–d) as Substrates

Entry	SM	Nucleophile	Product	Time (h)	Yield (%)	Entry	SM	Nucleophile	Product	Time (h)	Yield (%)
1	1a			15	64	7a,b)	1b			1	40
2	1a			15	73	8b)	1b			24	43
3a)	1a			17	71	9b)	1c			3	56
4	1a			24	93	10b)	1c			16	57
5	1a			24	87	11a,b)	1d			29	36
6	1a			15	49	12b)	1d			24	29

a) A total of 50 mol% FeCl₃ was used. b) The first azidation step was carried out for 24 h.

Chart 4. Gold-Catalyzed Direct Arylation, Bisarylation and Allylation of 1a

In conclusion, we have achieved the (Ph₃P)AuCl-catalyzed benzylic azidation of phthalan and isochroman derivatives and the subsequent FeCl₃-catalyzed nucleophilic substitutions of the azidated products. As a consequence, the 1-aryl and allyl phthalan and isochroman, bisindolylarylmethane and bisarylindolylmethane derivatives possessing unique and pharmaceutically useful skeletons could be easily constructed.

Acknowledgments

This work was supported by Grand-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS) and Ritsumeikan Global Innovation Research Organization (R-GIRO) project.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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