Gold-catalyzed benzylic azidation of phthalans and isochromans and subsequent FeCl3-catalyzed nucleophilic substitutions

Article abstract of DOI:10.1248/cpb.c15-00347

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.

Full text of DOI:10.1248/cpb.c15-00347

Vol. 63, No. 10
Chem. Pharm. Bull. 63, 757–761 (2015)
757
Communication to the Editor
es, 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 moiety30–33)
(Chart 1). Consequently, the iron-catalyzed Friedel–Crafts
arylation and allylation gave the 1-aryl/allyl phthalan and iso-
chroman 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 bisin-
dolylarylmethane derivatives (5).34–39) The obtained product (3)
could also be converted into the corresponding bisarylindolyl-
methane 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 sub-
stitutions (Chart 2) to produce the various pharmaceutically
useful compounds.
Gold-Catalyzed Benzylic Azidation
of Phthalans and Isochromans
and Subsequent FeCl3-Catalyzed
Nucleophilic Substitutions
Shota Asai,a Yuki Yabe,a Ryota Goto,a
Saori Nagata,a Yasunari Monguchi,a Yasuyuki Kita,b
,a
,a
Hironao Sajiki,* and Yoshinari Sawama*
a Gifu Pharmaceutical University; 1–25–4 Daigaku-nishi, Gifu
501–1196, Japan: and b College of Pharmaceutical Sciences,
Ritsumeikan University; 1–1–1 Nojihigashi, Kusatsu, Shiga
525–8577, Japan.
Received April 20, 2015; accepted July 7, 2015
The benzylic positions of the phthalan and isochroman de-
rivatives (1) as benzene-fused cyclic ethers effectively under-
went 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 nu-
cleophile accompanied by elimination of the azido group and
subsequent ring opening of the cyclic ether nucleus produced
the bisindolylarylmethane derivatives.
We first examined the catalyst and solvent efficiencies for
the direct benzylic azidation of phthalan (1a) using TMSN3
(4eq) 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
Key words azidation; gold catalyst; phthalan; isochroman;
iron-catalyzed nucleophilic substitution
Phthalan1–3) and isochroman4–8) derivatives are pharma- (10mol%) and AgSbF6 (10mol%) improved the reaction ef-
ceutically useful and also utilized as reaction precursors to ficiency to produce 2a in 20% yield (entry 4). The solvent
construct various frameworks.9–13) We have continuously significantly influenced the azidation, and 2a was obtained in
investigated the iron14–20)- or gold21–23)-catalyzed activation 69% yield in 1,4-dioxane in the presence of (Ph3P)AuCl and
at the benzylic position of various skeletons accompanied by AgSbF6 for 5.5h (entry 8), while CH2Cl2, (CH2Cl)2, benzene
the benzylic C–O bond cleavage. During these investigations, and toluene were less effective solvents (entries 4–7). Other
the benzylic position of phthalan (1; n=1) as a benzene fused combinations of the gold catalyst and silver salts, solvents and
cyclic ether was found to be directly azidated in the presence azido sources had no influence on the present azidation (see
of a gold catalyst and trimethylsilylazide (TMSN3) without the Supplementary Materials). Additionally, the reaction under
C–O bond cleavage to give the 1-azido phthalan (2) (Chart 1). oxygen atmosphere (entry 9) or using molecular sieves 4A
The direct azidations at the benzylic position of phthalan and (MS4A) to remove the contaminated H2O derived from the
isochroman (1; n=2) were previously accomplished using stoi- reagents (entry 10) led to lower yield.
chiometric iodine reagents9–11) in the presence of azido sourc-
The (Ph3P)AuCl-catalyzed benzylic azidation could be ap-
Chart 1. Catalytic Direct Azidation of Phthalans and Isochromans and the Subsequent Lewis Acid-Catalyzed Transformation
*To whom correspondence should be addressed. e-mail: sajiki@gifu-pu.ac.jp; sawama@gifu-pu.ac.jp
© 2015 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
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Table 1. Catalyst and Solvent Efficiencies of Direct Benzylic Azidation
plied 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-chloroiso-
of Phthalana,b)
Entry
Catalyst
Additive
Solvent
Time (h) Yield (%)
1
2
FeCl3
—
CH2Cl2
CH2Cl2
8
24
24
24
24
24
24
Trace
Trace
Trace
20
AuCl3
—
3
HAuCl4·3H2O
(Ph3P)AuCl
(Ph3P)AuCl
(Ph3P)AuCl
(Ph3P)AuCl
(Ph3P)AuCl
(Ph3P)AuCl
(Ph3P)AuCl
—
CH2Cl2
4
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
CH2Cl2
5
(CH2Cl)2
Benzene
28
6
48
7
Toluene
44
8
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
5.5
69
9c)
10d)
5.5
7
34
59
a) Conditions: catalyst (10mol%), additive (10mol%), TMSN3 (4eq), solvent
(substrate concentration; 1M), at rt under Ar. b) Optimization details using other cata-
lysts, 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.
Chart 2. Transformation of Azido Compounds as Key Reaction Inter-
mediates
Table 2. Scope and Limitation of the Substratesa)
Entry
1
Substrate
Product
Time (h)
5.5
Yield (%)
69
2
3
4
24
20
24
41
48
36
5
24
0
a) Inapplicable substrates under the present reaction conditions are described below.

Vol. 63, No. 10 (2015)
Chem. Pharm. Bull.
759
Chart 3. Chemical Modification of the Obtained 1-Azidophthalan (2a)
chroman 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-methoxyisochro-
man (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, benzylmeth-
ylether as an acyclic substrate, phthalide derivatives a pos-
sessing 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.
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 (5mol%) (Chart
1) and the subsequent nucleophilic substitution using 1,3-di-
methoxybenzene 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 nucleo-
philic reagent gave the bisindolylmethane (5a) in 99% yield
Chart 4. Gold-Catalyzed Direct Arylation, Bisarylation and Allylation
of 1a
via the elimination of the azido group and the ring opening 1-arylphthalan derivative (3d) with 1,3-dimethoxybenzene
of the cyclic benzyl ether moiety (in other words, the elimina- and bisindolylarylmethane derivative (5c) with N-methylin-
tion of the benzyl ether substructure). Additionally, 3a was dole (entries 7, 8). Isochroman (1c) could be converted into
also smoothly reacted with N-methylindole in the presence of the corresponding 1-arylated isochroman (3e) by the use of
FeCl3 to produce the ring-opened bisarylindolylmethane prod- 1,3-dimethoxybenezene as a nucleophile in 56% yield and the
uct (6) in quantitative yield.
bisindolylarylmethane derivative (5d) was also obtained by the
We next examined the one-pot transformation of phtha- nucleophilic attack of N-methylindole in 57% yield (entries 9,
lan and isochroman derivatives (1a–d) to 3, 4 and 5 via the 10). 7-Chloroisochroman could be converted into the corre-
1-azidated phthalan and isochroman derivatives (2) as inter- sponding 3f and 5e, while the yields were not satisfied (entries
mediates (Table 3). As the result of the primary gold-catalyzed 11, 12). Although the (Ph3P)AuCl-catalyzed direct arylation
azidation of phthalan (1a) for 6h and subsequent arylation by using 1,3-dimethoxybenezene and N-methylindole, and al-
the stepwise addition of FeCl3 and 1,3-dimethoxybenzene, lylation using allylTMS of phthalan (1a) could slightly proceed
1,3,5-trimethoxybenezene or 1-methoxynaphthalene, the cor- without the azidation step and the addition of FeCl3, the reac-
responding 1-arylated phthalans (3a–c) were obtained in good tion efficiencies were not improved (Chart 4).
yields (entries 1–3). Meanwhile, the use of N-methylindole
In conclusion, we have achieved the (Ph3P)AuCl-catalyzed
and indole instead of arenes as nucleophiles gave the bisin- benzylic azidation of phthalan and isochroman derivatives
dolylarylmethane derivatives (5a, b) by the one-pot azidation, and the subsequent FeCl3-catalyzed nucleophilic substitu-
the subsequent nucleophilic substitution accompanying with tions of the azidated products. As a consequence, the 1-aryl
the elimination of the azido group and the ring opening of and allyl phthalan and isochroman, bisindolylarylmethane
the cyclic benzyl ether moiety.44) Furthermore, allylTMS was and bisarylindolylmethane derivatives possessing unique and
also a good nucleophile to form the 1-allylated phthalan (4) pharmaceutically useful skeletons could be easily constructed.
in 49% yield (entry 6). 5,6-Dichlorophthalan (1b) could also
be applied in the one-pot reaction to give the corresponding
Acknowledgments This work was supported by Grand-

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Chem. Pharm. Bull.
Vol. 63, No. 10 (2015)
Table 3. One-Pot Synthesis Using Phthalan and Isochroman Derivatives (1a–d) as Substrates
Time Yield
Time Yield
Entry SM
Nucleophile
Product
Entry SM
Nucleophile
Product
(h)
(%)
(h)
(%)
1
2
1a
1a
15
64
7a,b) 1b
1
40
15
17
73
71
8b) 1b
24
43
56
3a)
1a
1a
1a
1a
9b)
1c
3
4
24
24
15
93
87
49
10b)
1c
16
29
24
57
36
29
5
11a,b) 1d
6
12b) 1d
a) A total of 50mol% FeCl3 was used. b) The first azidation step was carried out for 24h.
in-Aid for Young Scientists (B) from the Japan Society for the
Supplementary Materials The online version of this ar-
Promotion of Science (JSPS) and Ritsumeikan Global Innova- ticle contains supplementary materials.
tion Research Organization (R-GIRO) project.
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trifluoromethanesulfonate (TMSOTf): 71% and BF
Brønsted acid [trifluoroacetic acid (TFA): trace] in the reaction of
2a using 1,3-trimethoxybenzene.
3·Et2O: 53%] and
44) The yields of 5a and b in the one-pot method were better than the
yield of 2a for the benzylic azidation (Table 2, entry 1). During
the direct azidation of the phthalan (1a, b) and isochroman (1c, d)
derivatives and their work-up process, the N,O-acetal moiety of the
azidated products, which are generally acid-labile, may be partially
decomposed.