Synthesis of indolequinones via a Sonogashira coupling/cyclization cascade reaction

Article abstract of DOI:10.1016/j.tetlet.2011.07.008

A mild strategy for constructing indolequinone motifs is described on the basis of the Sonogashira reaction and a copper-catalyzed intramolecular cyclization cascade reaction. The first step involves the palladium- and copper-catalyzed reaction between ha

Full text of DOI:10.1016/j.tetlet.2011.07.008

Tetrahedron Letters 52 (2011) 4665–4670
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Synthesis of indolequinones via a Sonogashira coupling/cyclization
cascade reaction
Mitsuaki Yamashita a, , Kazunori Ueda b, Koichi Sakaguchi b, Akira Iida b,c,
⇑
⇑
a Faculty of Pharmacy, Takasaki University of Health and Welfare, Nakaorui-machi, Takasaki 370-0033, Japan
b School of Agriculture, Kinki University, Naka-machi, Nara 631-8505, Japan
c Research and Development Center for Medicinal Plants, Kadoma-machi, Kanazawa 920-1164, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild strategy for constructing indolequinone motifs is described on the basis of the Sonogashira reac-
tion and a copper-catalyzed intramolecular cyclization cascade reaction. The first step involves the pal-
ladium- and copper-catalyzed reaction between halogenated naphthoquinone and terminal acetylene
to generate a coupling product, which then reacts in a copper-catalyzed intramolecular cyclization with
the nitrogen functional group adjacent to the carbon–carbon triple bond.
Received 19 May 2011
Revised 17 June 2011
Accepted 1 July 2011
Available online 8 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indolequinones
Sonogashira coupling
Cascade reaction
Copper
Palladium
Heterocycles, particularly indoles, are interesting and valuable
because they are widely found in various biologically active natural
and artificial compounds.1 Therefore, development of efficient
methods to synthesize these compounds continues to be an active
research area. In particular, the intramolecular cyclization of o-alk-
ynylanilines, which is typically prepared from o-haloanilines via
the Sonogashira reaction, has been widely reported.2,3 Despite
the early successes using this method, there are limited applica-
tions for synthesizing indolequinones. These motifs are often found
in antitumor agents such as mitomycin C4 and EO9.5 Recently, Shv-
artsberg group reported the stepwise synthesis of indolequinones
from 3-acetylamino-2-bromo-1,4-naphthoquinone and terminal
acetylenes by the Sonogashira reaction followed by the intramolec-
ular cyclization of the isolated coupling products with K2CO3 in
MeCN at 80 °C.6 Some significant drawbacks of this method are
the limitation of substituents on naphthoquinone substrates and
the undesired elimination reactions during the cyclization step.
In addition, we found that the dehalogenated compound of starting
naphthoquinone 1a was gradually formed during the reaction with
increasing temperature. Thus, development of one-pot synthesis of
indolequinones under mild conditions is still challenging in organ-
ic synthesis (Scheme 1). Herein, we describe the development of a
cascade reaction for constructing indolequinone motifs involving
the Sonogashira reaction and intramolecular cyclization.
To screen the optimal reaction conditions, 2-bromo-3-(methyl-
amino)naphthalene-1,4-dione (1a) having an electron-donating
substituent on amino group was selected, because no coupling
reaction was observed under the reported conditions.6 The results
are shown in Table 1. According to the procedure in the Castro–Ste-
phens reaction,7 the reaction of 1a with 4a (10 equiv with respect
to 1a) in the presence of Cu2O (1 equiv with respect to 1a) and pyr-
idine (50 equiv with respect to 1a, pyridine:copper = 25:1) in DMF
at room temperature was examined. However, no conversion was
observed. Alternatively, adding of 3 mol % Pd(OAc)2 to the reaction
mixture showed a mild conversion to the coupling product 2aa and
the cyclized product 3aa in 3% and 6% yields, respectively (Table 1,
entry 2). The use of 20 equiv of pyridine (pyridine:copper = 10:1)
did not give the desired product, while 100 equiv of pyridine (pyr-
idine:copper = 50:1) gave the desired product in moderate yield
(41%) (Table 1, entry 3). Moreover, the use of 200 equiv of pyridine
(pyridine:copper = 100:1) was not effective in increasing the yield
further, which suggests that the optimum amount of pyridine is
100 equiv (pyridine:copper = 50:1). In addition, using 200 equiv
of pyridine decreased the yield because of a slower cyclization pro-
cess (Table 1, entry 4). The best result was obtained using 2.0 equiv
of acetylene 4a with respect to 1a with a reaction time of 24 h (Ta-
ble 1, entry 5). Regardless of the amount of acetylene, coupling
reactions were completed within about 4 h (TLC monitoring). We
speculate that the cyclization process starts from the ligation of
the acetylene moiety of the coupling product 2aa to the copper
⇑
Corresponding authors. Tel.: +81 27 352 1180 (M.Y.), tel./fax: +81 742 43 7274
(A.I.).
E-mail addresses: yamashita@takasaki-u.ac.jp (M. Yamashita), iida@nara.kin-
dai.ac.jp (A. Iida).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.008

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M. Yamashita et al. / Tetrahedron Letters 52 (2011) 4665–4670
O
O
O
O
O
R2
R2
X
Cu
R2
N
NHR1
NHR1
R1
Sonogashira
coupling
intramolecular
cyclization
O
Scheme 1. Construction of indolequinone motifs.
Table 1
Reaction of 2-bromo-3-(methylamino)naphthalene-1,4-dione with but-3-yn-2-ola
OH
4a
OH
O
O
O
O
O
pyridine
X
Pd(OAc)2, Cu2O
DMF
rt
N
NHCH3
OH
NH
CH3
2aa
CH3
3aa
O
1a: X = Br
1b: X = I
Entry
Time (h)
Alkyne 4a (equiv)
Ratio of pyridine to Cu
2aa Yield (%)b
3aa Yieldb (%)
1
2
3
4
48
48
48
48
24
48
12
12
24
24
24
24
10
10
10
10
2
2
2
2
2
10:1
25:1
50:1
100:1
50:1
500:1
25:1
50:1
50:1
50:1
50:1
50:1
trace
3
2
15
0
10
0
0
0
<13
0
0
0
6
41
28
56
0
52
51
trace
trace
47
62
5
6c
7d
8e
9f
10g
11h
12i
2
2
2
a
b
c
d
e
f
Substrate 1 (0.5 mmol), Pd(OAc)2 (3 mol %), Cu2O (0.5 mmol), acetylene, and pyridine were stirred in DMF at rt.
Isolated yield.
Cu2O (0.05 mmol) was used.
Cu2O (1.0 mmol) was used.
Pd(OAc)2 (10 mol %) was used.
CuBr was used instead of Cu2O.
CuI was used instead of Cu2O.
DMF was omitted.
g
h
i
1b was used as the substrate.
atom. Therefore, decreasing the amount of acetylene 4a probably
made the cyclization reaction faster. Decreasing the amount of
Cu2O caused no cyclized products to form after 48 h (Table 1, entry
6).8 Meanwhile, increasing the amount of Cu2O or Pd(OAc)2 did not
improve the yield either (Table 1, entries 7 and 8). The reaction
with other copper(I) salts (CuBr, CuI)9 yielded trace amounts of
the cyclized product (Table 1, entries 9 and 10). Using DMF as a sol-
vent is not essential, although the yield of 3aa slightly decreased in
the absence of DMF (Table 1, entry 11).10 Iodide 1b was also tested
as a substrate in this reaction, and a slightly better yield was ob-
tained compared to that obtained when using bromide 1a as the
substrate (Table 1, entry 12). Some palladium catalysts, such as
Pd(PPh3)2Cl2 and Pd(PPh3)4 were also used, but they gave a lower
yield of 3aa and formed byproducts such as the dehalogenated
compound of 1a.11
hindered nitrogen atom, gave no cyclized product owing to the for-
mation of unknown byproducts (Table 2, entry 1). Triethylamine
was ineffective in promoting the coupling reaction of halogenated
naphthoquinone 1a with acetylene 4a, although it is generally used
as a base in the Sonogashira reaction (Table 2, entry 4). These re-
sults suggest that pyridine acts both as a base to deprotonate acet-
ylene as well as a ligand for promoting the reaction. Similar results
were reported as amine effects.12 Coordination of pyridine to a di-
meric or polymeric copper catalyst possibly produced an active
monomeric catalyst (Scheme 2). Usually, bidentate or polydentate
ligands are known to promote copper-mediated coupling reac-
tions;2a our results showed that monodentate pyridine also pro-
moted the coupling reaction.13
In order to determine which species play an important role in
the final cyclization step, we isolated the coupling product 2aa
and tested it under various reaction conditions.14 Following the
optimized reaction conditions shown in Table 1, we obtained less
than 5% of the cyclized product 3aa (Table 3, entry 1). Meanwhile,
almost no reaction occurred in the absence of Cu2O even if 1a was
added to its reaction mixture (Table 3, entries 3 and 4). These
Further investigations were performed by varying the substitu-
ents on pyridine. The results are summarized in Table 2. Reaction
of 1a with 2,4-dimethylpyridine and 4-methylpyridine gave prod-
ucts 3aa in 33% and 55% yields, respectively (Table 2, entries 2 and
3), while reaction with 2,6-dimethylpyridine, having a sterically

M. Yamashita et al. / Tetrahedron Letters 52 (2011) 4665–4670
4667
Table 2
Effect of pyridine on the formation of coupling product 2aa and cyclized product 3aaa
OH
OH
4a
O
O
O
O
O
base
Br
Pd(OAc)2, Cu2O
N
NHCH3
1a
OH
NH
CH3
DMF
rt
2aa
CH3
O
3aa
Entry
1
Time (h)
96
Base
2aa Yieldb (%)
3aa Yieldb (%)
Recovered 1a yieldb (%)
0
0
17
43
N
2
48
0
33
N
3
4
24
48
0
55
0
5
N
Et3N
Trace
66
a
Substrate 1a (0.5 mmol), Pd(OAc)2 (3 mol %), Cu2O (0.5 mmol), acetylene (1.0 mmol), and base (50 mmol) were stirred in DMF at rt.
Isolated yield.
b
R2
O
O
Cu
R3
n
= Ar
NHR1
R2
L = Py
Ar Pd
R3
O
O
R3
R2
O
O
Ln Cu
R3
Ln Cu
R3
R3
NHR1
N
R1
2
3
Ar Pd X
Pd(0)
X
Ar
Scheme 2. Proposed mechanism of copper- and/or palladium-catalyzed coupling and cyclization.
results suggest that the cyclization is not induced by Palladium
salts or Ar-Pd-Br species15 which are formed during the Sonogash-
ira coupling. It is noteworthy that the reaction of 2aa in the pres-
ence of 5 mol % or 20 mol % CuBr gave better results, and formed
the cyclized product 3aa in 9% and 45% yields, respectively (Table
3, entries 5 and 6). Furthermore, no conversion to 3aa was ob-
served and only the starting material 2aa was recovered when
the reaction of 2aa without acetylene under the conditions used
in entry 6 was tested (Table 3, entry 7). Shvartsberg also reported
that intramolecular cyclization of vic-amino(alkynyl)quinones pro-
ceeded in the presence of cuprous acetylide. Meanwhile, cuprous
halides were not effective.16 Differently from pyridine, triethyl-
amine was ineffective in promoting the cyclization reaction of
2aa (Table 3, entry 8). Thus, we suppose that CuBr promotes the
formation of cuprous acetylide and its pyridine complex plays a
crucial role in the intramolecular cyclization step.
acetylenes 4 were chosen to test the cascade reaction. The results
are summarized in Table 4. No coupling reaction occurred when
naphthoquinone was used with an unprotected NH2 group even
on increasing the reaction temperature to 70 °C (Table 4, entry
1).17 Shvartsberg reported that the coupling of halogenated naph-
thoquinone 1d with various acetylenes gave only the coupling
product.6 However, the coupling product, which initially forms
during the reaction between 1d and 4a, was converted into the cy-
clized product 3da, along with the migration of the acetyl group on
the nitrogen atom to the adjacent hydroxyl group (Table 4, entry
2). Acetylene 4b containing the tertiary alcohol moiety was also
tested. The reaction of 1a with 4b gave the cyclized product 3ab
in 63% yield after 24 h (Table 4, entry 4). Differently from this
result, the acetyl group of the cyclized product 3db was simulta-
neously eliminated to give alkene 5db in 61% yield when the reac-
tion of 1d with 4b was carried out at rt. On the other hand, the
coupling reaction was not observed at 0 °C. To obtain the desired
product 3db, reaction temperatures were carefully controlled.
Next, using the optimized reaction conditions found in Table 1
entry 5, a series of halogenated naphthoquinones 1 and terminal

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M. Yamashita et al. / Tetrahedron Letters 52 (2011) 4665–4670
Table 3
After stirring for 2 h at rt, the reaction mixture was cooled to 0 °C
and stirred for an additional 10 h. Finally, 3db was obtained in 28%
yield (Table 4, entry 3). These motifs could not be obtained by the
reported method.6 Reactions of 4c, 4d, 4e, and 4f, which bear an
aryl group on the alkynyl moiety, gave the corresponding 2-aryl
indolequinones 3ac, 3ad, 3ae, and 3af, respectively, in moderate
yields (Table 4, entries 5–8). It is noteworthy that the reaction with
1-bromo-4-ethynylbenzene (4f) afforded the desired product 3af
without loss of the halogen substituent, although the palladium
catalyst was present. Alkynes bearing an alkyl substituent reacted
smoothly with halogenated naphthoquinone 1a to give the desired
product 3ag in moderate yields (Table 4, entry 9). Finally, haloge-
nated naphthoquinone having a hydroxyl group on the aromatic
ring was tested because such a phenolic hydroxy group is com-
monly seen in naturally occurring naphthoquinones.18 A higher
reaction temperature (80 °C) was required to obtain 3ea, demon-
strating that the reactivity of bromide 1e is rather lower than that
of bromide 1a (Table 4, entry 10).19 A satisfactory result was ob-
tained when using iodide 1f as the substrate (Table 4, entry 11).
In conclusion, we have developed a cascade reaction based on
the Sonogashira reaction and the subsequent cyclization. We have
demonstrated a mild and general one-pot method for constructing
substituted indolequinones. We have also shown that Cu2O is the
best copper catalyst. In addition, we have found that pyridine,
which acts both as a base and a ligand in this cascade reaction, is
required in large equivalent excess to copper metal. The detailed
mechanistic studies, catalytic version, and future applications of
this strategy are under investigation and will be reported in due
course.
Effect of additives on the conversion of coupling product 2aa to cyclized product 3aaa
OH
4a
OH
additive
pyridine
O
O
O
O
Pd(OAc)2, Cu2O
N
CH3
OH
NHCH3
2aa
DMF
rt, 24 h
3aa
Entry
Additive
3aa Yieldb (%)
1
-
<5
2c
3d
4d
5
-
<5
-
Trace
Trace
9
45
0
1a (20 mol %)
CuBr (5 mol %)
CuBr (20 mol %)
CuBr (20 mol %)
CuBr (20 mol %)
6
7c,d,e
8f
Trace
a
Substrate 2aa (0.08 mmol), Pd(OAc)2 (3 mol %), Cu2O (0.08 mmol), acetylene 4a
(0.08 mmol), and pyridine (8.0 mmol) were stirred in DMF at rt for 24 h.
b
Isolated yield.
Without Pd(OAc)2.
Without Cu2O.
Without acetylene 4a.
c
d
e
f
Et3N was used instead of pyridine.
Table 4
Effect of varying substituents on the conversion of naphthoquinones 1 to cyclized product 3aaa
R3
4
R2
R2
O
O
O
pyridine
X
Pd(OAc)2, Cu2O
R3
N
NHR1
DMF
rt, 24 h
R1
3
1
O
Entry
1c
Substrate
R3
Product
Yieldb (%)
O
Br
CH(OH)CH3 (4a)
CH(OH)CH3 (4a)
C(OH)(CH3)2 (4b)
0
NH2
O
O
1c
O
Br
2d
48
28
17
N
OAc
OAc
NHAc
H
O
O
O
O
1d
3da
3db
Br
3e
N
H
NHAc
O
O
O
1d
N
H
O
5db

M. Yamashita et al. / Tetrahedron Letters 52 (2011) 4665–4670
4669
Table 4 (continued)
Entry
Substrate
R3
Product
Yieldb (%)
O
O
Br
4
C(OH)(CH3)2 (4b)
63
44
52
43
39
56
58
82
N
CH3
OH
NHMe
O
O
O
O
1a
1a
1a
1a
1a
1a
1e
3ab
Br
Ph
5
Ph (4c)
N
CH3
NHMe
O
O
O
O
3ac
Br
O
F
6
p-MeOC6H4 (4d)
p-FC6H4 (4e)
p-BrC6H4 (4f)
CH2CH2Ph (4g)
CH(OH)CH3 (4a)
CH(OH)CH3 (4a)
N
CH3
NHMe
O
O
O
O
3ad
Br
7
N
CH3
NHMe
O
O
O
O
3ae
Br
Br
8
N
CH3
NHMe
O
O
O
O
3af
Br
(CH2)2Ph
9
N
CH3
NHMe
O
O
O
3ag
OH
OH
O
OH
OH
Br
10f,g
N
CH3
OH
OH
NHMe
O
O
O
O
3ea
3ea
I
11f,g,h
N
CH3
NHMe
O
O
1f
a
Substrate 1a (0.5 mmol), Pd(OAc)2 (3 mol %), Cu2O (0.5 mmol), acetylene 4 (1.0 mmol), and pyridine (50 mmol) were stirred in DMF at rt.
b
c
d
e
f
Isolated yield.
At 70 °C.
Reaction time was 4 h.
At rt for 2 h, then at 0 °C for 10 h.
At 80 °C.
g
h
Reaction time was 1 h.
200 equiv of pyridine were used.
Scriven, E. F. V., Bird, C. W., Eds.; Pergamon Press: Oxford, 1996; vol. 2, p 207;
(d) Sundberg, R. J. Indoles; Academic Press: London, 1996.
Acknowledgment
2. For recent reviews, see: (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009,
48, 6954; (b) Krüger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153;
(c) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395; (d) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875; (e) Cacchi, S.; Fabrizi, G. Chem. Rev.
2005, 105, 2873.
The authors are grateful to Taheebo Japan Co., Ltd. and SANSHIN
METAL WORKING Co., Ltd. for generous financial support of this
project.
3. Selected examples on palladium- and/or copper-catalyzed synthesis of indoles
from o-haloaniline or o-alkynylaniline derivatives, see: (a) Han, X.; Lu, X. Org.
Lett. 2010, 12, 3336; (b) Shen, Z.; Lu, X. Adv. Synth. Catal. 2009, 351, 3107; (c) Ye,
S.; Ding, Q.; Wang, Z.; Zhou, H.; Wu, J. Org. Biomol. Chem. 2008, 6, 4406; (d)
Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46, 2295; (e)
Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844; (f) Ambrogio, I.; Cacchi, S.; Fabrizi, G.
Org. Lett. 2006, 8, 2083; (g) Lu, B. Z.; Zhao, W.; Wei, H.-X.; Dufour, M.; Farina, V.;
Senanayake, C. H. Org. Lett. 2006, 8, 3271; (h) Arcadi, A.; Cacchi, S.; Fabrizi, G.;
Marinelli, F.; Parisi, L. M. J. Org. Chem. 2005, 70, 6213; (i) Saejueng, P.; Bates, C.
G.; Venkataraman, D. Synthesis 2005, 1706; (j) Hiroya, K.; Itoh, S.; Sakamoto, T.
J. Org. Chem. 2004, 69, 1126; (k) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett.
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Chem., Int. Ed. 2000, 39, 2488.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.008.
References and notes
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F. V., Bird, C. W., Eds.; Pergamon Press: Oxford, 1996; vol. 2, p 119; (c) Gribble,
G. W. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Ress, C. W.,
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4670
M. Yamashita et al. / Tetrahedron Letters 52 (2011) 4665–4670
In Pelletier, S. W., Ed.; Wiley: New York, 1988; p 1; (c) Franck, R. W.; Tomasz,
11. The following conversion of 1a to 3aa was observed in DMF at room
temperature using Cu2O (100 mol %), acetylene (2 equiv), and pyridine
(pyridine:copper = 50:1), 3 mol % of palladium salt: using Pd(PPh3)2Cl2, 20%
yield of 3aa was obtained; using Pd(PPh3)4, only trace amount of 3aa was
obtained. Reaction with PdCl2 gave a comparable result to that when using
Pd(OAc)2; however, a longer reaction time was required (48 h, 52% yield).
12. (a) Gonda, Z.; Tolnai, G. L.; Novák, Z. Chem. Eur. J. 2010, 16, 11822; (b) Heinre, J.
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13. Copper-catalyzed reaction promoted by monodentate pyridine, see: Hayashi,
H.; Kawasaki, K.; Fujii, M.; Kainoh, A.; Okazaki, T. J. Catal. 1976, 41, 367.
14. The coupling product was obtained by quenching the reaction after 4 h.
Coupling product 2aa and cyclized product 3aa were obtained in 37% and 31%
yields, respectively.
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Glasgow, 1990; pp 379–393.
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8. Starting product 1a was recovered in 62% yield. Although the reaction
temperature was raised to 70 °C, only trace amount of cyclized product 3aa
was observed. Dehalogenated compound of starting naphthoquinone 1a was
gradually formed during the reaction at high temperature. Moreover, addition
of bidentate ligands such as bipyridine, phenanthroline, and
effective.
9. Reaction with copper(II) salt (CuO, CuBr2, and CuCl2) was also tested; no
cyclized product was obtained using each of the three metal salts even on
increasing the temperature to 70 °C.
L
-proline were not
15. Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
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17. Starting material 1a was recovered in 62% yield and dehalogenated compound
of 1a was obtained in 9% yield.
18. Yamashita, M.; Kaneko, M.; Tokuda, H.; Nishimura, K.; Kumeda, Y.; Iida, A.
Bioorg. Med. Chem. 2009, 17, 6286.
10. DMF was used to easily dissolve substrate 3. See Supplementary data for
detailed reaction procedure.
19. No coupling reaction was observed at room temperature.