First synthesis of 1-(indol-2-yl)azulenes by the Vilsmeier-Haack type arylation with triflic anhydride as an activating reagent

Article abstract of DOI:10.1016/j.tetlet.2012.01.044

Azulene derivatives reacted with 2-indolinones in the presence of triflic anhydride (Tf₂O) to afford 1-(indol-2-yl)azulenes in good yields. In the cases of the reaction of 6-tert-butyl-1-(methylthio)azulene (11) and 1-(1,4-dihydropyridin-4-yl)a

Full text of DOI:10.1016/j.tetlet.2012.01.044

Tetrahedron Letters 53 (2012) 1493–1496
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First synthesis of 1-(indol-2-yl)azulenes by the Vilsmeier–Haack type
arylation with triflic anhydride as an activating reagent
Taku Shoji a, , Yuta Inoue a, Shunji Ito b
⇑
a Department of Chemistry, Faculty School of Science, Shinshu University, Matsumoto 390-8621, Japan
b Graduate School of Science and Technology, Hirosaki University, Hirosaki 036-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Azulene derivatives reacted with 2-indolinones in the presence of triflic anhydride (Tf2O) to afford
1-(indol-2-yl)azulenes in good yields. In the cases of the reaction of 6-tert-butyl-1-(methylthio)azulene
(11) and 1-(1,4-dihydropyridin-4-yl)azulene 14, 1,10-biazulene derivative 24 and 1-(indol-2-yl)azulene
(2) were obtained under the similar reaction conditions, respectively, instead of the presumed electro-
philic substitution products.
Received 12 December 2011
Revised 9 January 2012
Accepted 10 January 2012
Available online 20 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Azulene
Indole
Coupling reaction
Electrophilic substitution
Indole derivatives are found in numerous natural products and
a number of biologically active pharmaceuticals. Therefore, it is
important to develop general methods to synthesize or modify
such compounds.1 Transition metal-catalyzed cross-coupling reac-
tion is frequently utilized for the synthesis of arylindole deriva-
tives. However, the methods for the preparation of these
substances using more readily available reagents are more advan-
tageous. Recently, Shibata et al. have reported electrophilic homo-
coupling reaction of indole derivatives with the triflic anhydride
(Tf2O) and 2,4,6-tri-tert-butylpyridine as activating reagents.2
From a view point of electrophilic cross-coupling reaction, Black
and Rezaie have reported the Tf2O-activated Vilsmeier–Haack
(V–H) type arylation of 2-indolinones with 4,6-dimethoxybenzofu-
ran to give 2-indolylbenzofurans in good yields.3 The electrophilic
cross-coupling reactions should have a great potential to provide a
facile and an efficient synthetic route for the functionalization of
indole derivatives because the reactions do not require any expen-
sive transition metal catalyst, aryl halide and a metallic coupling
reagents such as boranes and stannanes.
N-containing heterocycles.6 Although many aryl- and heteroaryl-
azulenes have been synthesized as described in the literatures,
the carbon–carbon bond formation between azulene and indole
derivatives has never been reported so far.7 If the Tf2O-activated
V–H type arylation of 2-indolinones proceeds with azulene deriva-
tives at the 1-position, a new and facile synthetic route to 1-(indol-
2-yl)azulene derivatives will be established. Moreover, success of
the one-step synthesis of 1-(indol-2-yl)azulenes would provide a
novel possibility for the directive heteroarylation methodology of
azulene derivatives using the electrophilic substitution reaction.
We report herein the first synthesis of 1-(indol-2-yl)azulenes by
the Tf2O-activated V–H type arylation of 2-indolinones with azu-
lene derivatives.
As a preliminary experiment for the synthesis of 1-(indol-2-
yl)azulenes, the Tf2O-activated V–H type arylation of 2-indolinone
with azulene (1) was examined in five different organic solvents
(Scheme 1). As summarized in Table 1, yields of the product were
significantly dependent on the solvent employed. The reaction of 1
with 2-indolinone in dichloromethane in the presence of Tf2O gave
Azulene (C10H8) has attracted the interest of many research
groups owing to its unusual properties as well as its beautiful blue
color.4 We have recently reported the synthesis of several arylazu-
lene derivatives by the transition-metal catalyzed cross-coupling
reactions.5 More recently, we have also demonstrated a new and
two-step strategy for the heteroarylation of azulenes at the
1-, 1,3-, 5-, and 5,7-positions by the reaction with the triflate of
H
N
O
H
N
1) Tf2O, Solvent
2) aq. K2CO3
1
2
⇑
Corresponding author. Tel./fax: +81 263 34 2476.
E-mail address: tshoji@shinshu-u.ac.jp (T. Shoji).
Scheme 1. Reaction of azulene (1) with 2-indolinone.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.044

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T. Shoji et al. / Tetrahedron Letters 53 (2012) 1493–1496
Table 1
R3
N
1) Indolinone
Tf2O, CH2Cl2
2) aq. K2CO3
R2
R1
Synthesis of 1-(indol-2-yl)azulene (2)
3: R1=Cl, R2=H, R3=H
4: R1=H, R2=Cl, R3=H
5: R1=H, R2=H, R3=Ph
1
Entry
Solvent
Yield of 2 (%)
1
2
3
4
5
Dichloromethane
1,2-Dichroloethane
Toluene
Acetonitrile
Chloroform
89
76
75
59
Scheme 3. Reaction of azulene (1) with 2-indolinone derivatives.
33
Table 2
Synthesis of 1-(indol-2-yl)azulene derivatives
the desired 1-(indol-2-yl)azulene (2) in an 89% yield (entry 1).8
When 1,2-dichroloethane and toluene were used as a solvent, com-
pound 2 was obtained in 76% and 75% yields, respectively (entries
2 and 3). Despite the fact that the highly polar solvent, acetonitrile,
was a successful solvent in the Tf2O-activated Reissert–Henze type
electrophilic heteroarylation of azulenes,9 the yield of the reaction
to give 2 was moderate with acetonitrile as the solvent (59%, entry
4). The reaction in chloroform was also revealed to be insufficient
due to the low product yield (33%, entry 5), because of the signif-
icant decomposition of the product under the reaction conditions.
Among the solvents tested, dichloromethane was found to be the
best with respect to the yield of the product (89%).
Presumed reaction mechanism of this reaction is illustrated in
Scheme 2. Namely, the reaction of Tf2O with 2-indolinone forms
a Vilsmeier salt analogue, which is attacked by 1 at the most reac-
tive site 1-position, to give 1-(indol-2-yl)azulene (2).
To examine the generality of the reaction of 2-indolinones, we
investigated the reaction of 1 with three commercially available
indolinone derivatives under the optimized reaction conditions
(Scheme 3 and Table 2). 5-Chloro-2-indolinone and 6-chloro-2-
indolinone were reacted with 1 in the presence of Tf2O to give
the corresponding 1-(5- and 6-chloroindol-2-yl)azulenes (3 and
4) in 91% and 89% yields, respectively (entries 1 and 2). The reac-
tion of 1 with 1-phenyl-2-indolinone gave the presumed substi-
Entry
Indolinone
Reaction time (h)
Product, yield (%)
H
N
1
3
3, 91
O
O
Cl
Cl
H
N
2
3
2.5
17
4, 89
5, 27
Ph
N
O
H
N
O
H
N
1) Tf2O, CH2Cl2
2) aq. K2CO3
Azulene
Azulene
Scheme 4. Reaction of azulene derivatives (6ꢀ14) with 2-indolinone.
The reaction of 6 that possesses an electron-withdrawing sub-
stituent at the 1-position with 2-indolinone in the presence of
Tf2O in dichloromethane at room temperature gave methyl
1-(indol-2-yl)azulene-3-carboxylate (15) in 71% yield, along with
22 in a 22% yield (entry 1). Generation of 22 should be attributed
to the condensation between the two molecules of 6 under the
acidic reaction conditions. As similar with 6, the reaction of 1-phe-
nylazulene (7) with 2-indolinone under the similar reaction condi-
tions afforded the corresponding substitution product 16 in an 88%
yield (entry 2). The substrate 8 possessing an electron-donating
tert-butyl group at the 6-position afforded the di-substituted prod-
uct, 6-tert-butyl-1,3-di(indol-2-yl)azulene (23) (13%) in addition to
the desired substitution product 17 (64%) (entry 3). Formation of
the di-substituted product 23 indicates that tert-butyl group at
the 6-position enhances the reactivity toward the V–H type reac-
tion, because generation of the di-substituted product was not ob-
served in the reaction of 1. The reaction of more electron-rich
substrates 9 and 10 resulted in decrease of the product yields
(18: 47%, 19: 45%) due to the decomposition of the products
(entries 4 and 5) during the reaction. Furthermore, products 18
and 19 were found to be unstable under ambient condition and
exhibited ready decomposition to give an unidentified complex
mixture. Instead of the formation of the presumed indole deriva-
tive, 1,10-biazulene derivative 2410 was obtained in a 43% yield
by the reaction of 11 under the similar reaction conditions (entry
6). Recently, we have reported the formation of the 3,30-methyl-
thio-1,10-biazulene derivative by the treatment of 1-methylthio-
azulene with pyridine N-oxide and Tf2O.9 Therefore, the
formation of the 1,10-biazulene derivative 24 in this reaction is
attributable to the presence of Tf2O, which should act as an oxidant
for the homo-coupling reaction of 11.
tution product
5 in 27% yield (entry 3). Low yield of the
product 5 might be ascribed to the steric effect of the phenyl
moiety on the nitrogen atom to the electrophilic reaction. These
results show the generality of the V–H type reaction of azulene
(1) with 2-indolinone derivatives, although the N-phenyl substi-
tuent of 2-indolinone was directly affected toward the product
yield.
A series of azulene derivatives were subjected to this V–H type
reaction under the optimized reaction conditions to explore the
scope of this reaction (Scheme 4). Examined compounds and yield
of the products are summarized in Table 3. The by-products of
reaction are also shown in the Figure 1.
O
H
N
F3C S OTf
O
O
H
TfO-
N+
TfO
H
N
TfO
TfO-
1
H
N+
Hydrolysis
2
TfOH
H
TfO-
The reaction of the substrates 12 and 13 having a phenyl group
at the 2-position also afforded the desired products 20 and 21,
respectively, in satisfactory yields. Substrate 12 reacted with 2-
Scheme 2. Presumed reaction mechanism.

T. Shoji et al. / Tetrahedron Letters 53 (2012) 1493–1496
1495
Table 3
Synthesis of 1-(indol-2-yl)azulene derivatives
Entry
1
Azulene
Reaction time (h)
2.5
Product
Yield (%)
CO2Me
H
N
MeO2C
71
88
6
15
Ph
H
N
Ph
2
3
3
7
16
17
H
N
t
t
-Bu
-Bu
8
2.5
64
47
45
t
-Bu
-Bu
t
-Bu
H
t
N
4
5
3
2
9
t
-Bu
18
H
N
H3CO
10
H3CO
19
SCH3
t-Bu
6
7
3
3
24
43
82
11
Ph
Ph
H
N
12
13
20
CO2Me
Ph
Ph
H
N
MeO2C
8
9
6
3
65
72
21
Tf
N
2
14
affect the electrophilic substitution reaction. On the other hand,
2-phenylazulene derivative 13 bearing a methoxycarbonyl group
at the 1-position was converted into indole derivative 21 in a
65% yield, along with decarboxylated product 1211 in a 27% yield
(entry 8).
CO2CH3
NH
HN
O
Contrary to our expectations, the reaction of 14 afforded indole
derivative 2 in a 72% yield, whose formation could be ascribed by
the ipso-substitution reaction of azulene ring at the 1-position
(entry 9). This represents the first example of dihydropyridine moi-
ety acting as a leaving group during the electrophilic substitution
reaction in the field of azulene chemistry. Previously, Hafner
et al.12 and our group13 reported that 1,3-di-(isopropyl and tert-
butyl)azulenes undergo facile electrophilic ipso-substitution reac-
tions such as Friedel–Crafts acylation and Vilsmeier formylation
at their 1- and/or 3-positions in good yields. Thus, the 1,4-dihydro-
pyridyl group on 14 can be regarded as a good leaving group
toward the electrophilic ipso-substitution reaction, likewise the
isopropyl and tert-butyl groups.
23
22
t-Bu
t-Bu
SCH3
t-Bu
H3CS
Figure 1. By-products of the Tf2O-activated V–H type reaction.
24
indolinone to give 1-(indol-2-yl)-2-phenylazulene (20) in an 82%
yield as a sole product (entry 7). From the aspect of the product
yield, relatively bulky 2-phenyl substituent did not significantly
In conclusion, the Tf2O-activated V–H type reaction of azulene
(1) with 2-indolinone has been disclosed. This methodology al-
lowed us to the first synthesis of 1-(indol-2-yl)azulene (2).

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T. Shoji et al. / Tetrahedron Letters 53 (2012) 1493–1496
A. J. Org. Chem. 2005, 70, 3939–3949; (h) Shoji, T.; Ito, S.; Toyota, K.; Iwamoto,
The 1-(indol-2-yl)azulene derivatives were available by the
T.; Yasunami, M.; Morita, N. Eur. J. Org. Chem. 2009, 4307–4315; (i) Nakagawa,
K.; Yokoyama, T.; Toyota, K.; Morita, N.; Ito, S.; Tahata, S.; Ueda, M.; Kawakami,
J.; Yokoyama, M.; Kanai, Y.; Ohta, K. Tetrahedron 2010, 66, 8304–8312; (j) Ito,
S.; Shoji, T.; Morita, N. Synlett 2011, 2279–2298.
reaction of the corresponding azulene derivatives with 2-indoli-
nones in the presence of Tf2O, following the hydrolysis with aq.
K2CO3. Under the reaction conditions, we found 6-tert-butyl-1-
(methylthio)azulene (11) was converted into 1,10-biazulene deriv-
ative 24. By the Tf2O-activated V–H type reaction of 14, novel ipso-
substitution was clarified to give 2 in good yield. These results sug-
gest dihydropyridine moiety at the 1-position behaves as a good
leaving group, as well as isopropyl and tert-butyl groups. These re-
sults would warrant the development of new synthetic methodol-
ogy for azulene derivatives.
6. (a) Shoji, T.; Yokoyama, R.; Ito, S.; Watanabe, M.; Toyota, K.; Yasunami, M.;
Morita, N. Tetrahedron Lett. 2007, 48, 1099–1103; (b) Shoji, T.; Ito, S.;
Watanabe, M.; Toyota, K.; Yasunami, M.; Morita, N. Tetrahedron Lett. 2007,
48, 3009–3012; (c) Shoji, T.; Ito, S.; Toyota, K.; Yasunami, M.; Morita, N.
Tetrahedron Lett. 2007, 48, 4999–5002; (d) Higashi, J.; Shoji, T.; Ito, S.; Toyota,
K.; Yasunami, M.; Morita, N. Eur. J. Org. Chem. 2008, 5823–5831; (e) Shoji, T.;
Ito, S.; Toyota, K.; Morita, N. Eur. J. Org. Chem. 2010, 1059–1069; (f) Shoji, T.; Ito,
S.; Higashi, J.; Morita, N. Eur. J. Org. Chem. 2011, 5311–5322; (g) Shoji, T.; Inoue,
Y.; Ito, S.; Okujima, T.; Morira, N. Heterocycles 2012, 85, 35–41.
7. The C–N bond formation between 2-bromoazulene and indole under the
palladium-catalyzed Hartwig–Buchwald’s condition was reported by our group
Yokoyama, R.; Ito, S.; Okujima, T.; Kubo, T.; Yasunami, M.; Tajiri, A.; Morita, N.
Tetrahedron 2003, 59, 8191–8198.
Acknowledgment
8. A typical procedure: Tf2O (203 mg, 0.72 mmol) in CH2Cl2 (5 mL) were added at
room temperature to a solution of azulene (1) (67 mg, 0.52 mmol) and 2-
indolinone (101 mg, 0.76 mmol) in CH2Cl2 (15 mL). The resulting solution was
stirred at the same temperature for 2.5 hours. The reaction mixture was poured
into a 2 M K2CO3 solution, extracted with AcOEt, washed with brine and dried
over Na2SO4. The solvent was removed under reduced pressure and the residue
was purified by column chromatography on silica gel with hexane/AcOEt
(10:1) as an eluent to give 1-(indol-2-yl)azulene (2) (113 mg, 89%) as green
crystals. 1H NMR (500 MHz, CDCl3): ppm; dH = 8.80 (d, 1H, J = 9.5 Hz, 8-H), 8.33
(d, 1H, J = 9.5 Hz, 4-H), 8.25 (br s, 1H, NH of indole), 8.06 (d, 1H, J = 4.0 Hz, 2-H),
7.66 (d, 1H, J = 7.5 Hz, 40-H of indole), 7.61 (t, 1H, J = 9.5 Hz, 6-H), 7.43 (d, 1H,
J = 4.0 Hz, 3-H), 7.41 (d, 1H, J = 7.5 Hz, 80-H of indole), 7.22–7.13 (m, 4H, 5,7-H,
5,6-H of indole), 6.79 (s, 1H, 30-H of indole) ppm; 13C NMR (125 MHz):
dC = 142.19 (C-8a), 138.78 (C-6), 137.63 (C-4), 136.55 (C-8a0 of indole), 136.01
(C-8), 135.62 (C-3a), 135.48 (C-2), 134.76 (C-1), 129.54 (C-3a0 of indole),
123.93, 123.81, 121.73 (C-7), 120.21, 120.09 (C-40 of indole), 117.93 (C-3),
110.61 (C-80 of indole), 101.20 (C-30 of indole) ppm.
9. Shoji, T.; Okada, K.; Ito, S.; Toyota, K.; Morita, N. Tetrahedron Lett. 2010, 51,
5127–5130.
10. Shoji, T.; Higashi, H.; Ito, S.; Toyota, K.; Asao, T.; Fujimori, K.; Yasunami, M.;
Morita, N. Eur. J. Org. Chem. 2008, 45, 1242–1252.
11. The ester function of 2-arylazulenes at the 1-position exhibit decarboxylation
under the acidic conditions (a) Morita, T.; Takase, K. Bull. Chem. Soc. Jpn. 1982,
55, 1144–1152; (b) Morita, T.; Abe, N.; Takase, K. J. Chem. Soc., Perkin Trans. 1
2000, 3063–3070.
12. Hafner, K.; Moritz, K. L. Justus Liebigs Ann. Chem. 1962, 656, 40–53.
13. Shoji, T.; Ito, S.; Okujima, T.; Higashi, J.; Yokoyama, R.; Toyota, K.; Yasunami,
M.; Morita, N. Eur. J. Org. Chem. 2009, 1554–1563.
This work was supported by a Grant-in-Aid for Research Activ-
ity Start-up (Grant 22850007 to T.S.) from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan.
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