Formal [4+ 2] reaction between 1,3-diynes and pyrroles: Gold(I)-catalyzed indole synthesis by double hydroarylation

Article abstract of DOI:10.1002/chem.201405903

Indole synthesis by a gold(I)-catalyzed intermolecular formal [4+2] reaction between 1,3-diynes and pyrroles has been developed. This reaction involves the hydroarylation of 1,3-diynes with pyrroles followed by an intramolecular hydroarylation to give the 4,7-disubstituted indoles. This reaction can also be applied to the synthesis of carbazoles when indoles are used as the nucleophiles instead of pyrroles.

Full text of DOI:10.1002/chem.201405903

DOI: 10.1002/chem.201405903
Communication
&
Gold Catalysis
Formal [4+2] Reaction between 1,3-Diynes and Pyrroles: Gold(I)-
Catalyzed Indole Synthesis by Double Hydroarylation
Yuka Matsuda, Saori Naoe, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*[a]
Abstract: Indole synthesis by a gold(I)-catalyzed intermo-
lecular formal [4+2] reaction between 1,3-diynes and pyr-
roles has been developed. This reaction involves the hy-
droarylation of 1,3-diynes with pyrroles followed by an in-
tramolecular hydroarylation to give the 4,7-disubstituted
indoles. This reaction can also be applied to the synthesis
of carbazoles when indoles are used as the nucleophiles
instead of pyrroles.
The indole scaffold is a significant structural motif that can be
found in a large number of alkaloids, as well as several other
bioactive compounds, and a wide range of synthetic methods
have been developed for the construction of this core struc-
ture.[1,2] According to the classification system proposed by
Taber et al.,[2a] the majority of the traditional synthetic ap-
proaches to indoles are based on the construction of the pyr-
role ring on an existing benzene ring (Figure 1, Types 1–7). In
Scheme 1. Indole syntheses by an intermolecular [4+2]-type reaction.[4–6]
TFA=trifluoroacetic acid.
Compared with isolated alkynes,[7,8] the use of gold catalysis
with conjugated diynes,[9,10] especially for intermolecular reac-
tions, stands at the very beginning. We designed a new Type 8
indole synthesis based on the gold(I)-catalyzed intermolecular
formal [4+2] reaction between 1,3-diynes and pyrroles, which
could be used to provide convenient access to 4,7-disubstitut-
ed indoles. Although numerous 4,7-disubstituted indoles have
been reported to show interesting biological activities,[11] the
existing synthetic methods suffer from multistep synthesis, low
availability of the substrates, and/or limited substrate
scope.[12,13] It was envisaged that the intermolecular hydroaryl-
ation of 1,3-diyne 1 with pyrrole 2 would proceed to give
enyne-type intermediate 3,[14] which would undergo an intra-
molecular 6-endo-dig hydroarylation to afford 4,7-disubstituted
indole 4 (Scheme 2). Herein, we report a gold(I)-catalyzed inter-
molecular [4+2]-type reaction for the direct synthesis of 4,7-
disubstituted indoles by using readily available 1,3-diynes and
pyrroles. Furthermore, this reaction provided facile access to
1,4-disubstituted carbazoles when N-substituted indoles were
used as the nucleophile instead of pyrroles.
Figure 1. Classification of indole syntheses (Taber et al., 2011).[2a]
contrast, very few indole syntheses have been reported to pro-
ceed by a [4+2]-type reaction (classified as Type 8),[3] including
the hetero-Diels–Alder (DA) reaction of N-methylpyrroles
(Scheme 1a)[4] and the thermal DA reaction of N-tosylpyrroles
(Scheme 1b).[5] The application of these reactions, however,
has been limited because of their requirement for highly acti-
vated substrates, such as dicyanopyridazine, Danishefsky’s
diene, and nitrated pyrroles. A related transformation involving
the Ru-catalyzed annulation of pyrroles has been developed,
but this process requires pent-1-en-4-yn-3-ol derivatives as the
C4 synthon (Scheme 1c).[6]
The gold-catalyzed reaction of 1,3-diyne 1a with pyrrole 2a
was selected as a model reaction, and this reaction was sub-
jected to a series of screening experiments to identify the opti-
mum conditions for the transformation (Table 1). The treat-
ment of a mixture of 1a and 2a (10 equiv) with 10 mol% of
[IPrAuCl] and AgNTf2 in toluene at 808C gave the desired prod-
uct 4a in 22% yield (Table 1, entry 1). Several phosphine li-
gands were tested in the reaction (entries 2–6) and [BrettPhos-
AuCl] was identified as the optimum catalyst for the reaction,
[a] Y. Matsuda, S. Naoe, Dr. S. Oishi, Prof. Dr. N. Fujii, Prof. Dr. H. Ohno
Graduate School of Pharmaceutical Sciences, Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: nfujii@pharm.kyoto-u.ac.jp
hohno@pharm.kyoto-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405903.
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with the desired product 4a being formed in 56% yield
(entry 6). Various silver salts were tested in the reactions (en-
tries 6–10), and AgSbF6 afforded the best results in terms of
the reaction time and yield (entry 10). To simplify the protocol
and avoid any issues associated with the use of a hygroscopic
silver salt, we used the gold complex [BrettPhosAu-
(MeCN)SbF6],[15] which was prepared in advance. A series of dif-
ferent solvents were then screened in the reaction with
5 mol% loading of the catalyst, and the use of 1,2-dichloro-
ethane (DCE) led to an increase in the yield of 4a to 66%
(entry 14). Finally, we examined the effect of the reactant stoi-
chiometry. As the number of equivalents of the pyrrole de-
creased (e.g., 10, 5, and 1.1 equiv), so too did the yield of 4a
(entries 14–16). This reduction in the yield was attributed in
part to a competition between pyrrole 2a and indole 4a in
terms of their ability to behave as nucleophiles towards 1a. It
is noteworthy that a small amount of carbazole 5a was pro-
duced as an over-reaction product from the nucleophilic addi-
tion of 4a to 1a (entry 16).
Scheme 2. Our concept: Gold(I)-catalyzed [4+2]-type indole synthesis by
double hydroarylation.
Table 1. Optimization of the reaction conditions.[a]
We proceeded to investigate the scope of this indole syn-
thesis under the optimized conditions (Table 1, entry 14) using
a variety of symmetrical 1,3-diynes 1b–l (Table 2). The diaryl-
Table 2. Reaction of various symmetrical 1,3-diynes.
Entry
Cat. [mol%]
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
[IPrAuCl]/AgNTf2 [10]
[Ph3PAuCl]/AgNTf2 [10]
[JohnPhosAuCl]/AgNTf2 [10]
[XPhosAuCl]/AgNTf2 [10]
[L1AuCl]/AgNTf2 [10]
[BrettPhosAuCl]/AgNTf2 [10]
[BrettPhosAuCl]/AgOTf [10]
[BrettPhosAuCl]/AgBF4 [10]
[BrettPhosAuCl]/AgPF6 [10]
[BrettPhosAuCl]/AgSbF6 [10]
[BrettPhosAu(MeCN)SbF6][d] [5]
[BrettPhosAu(MeCN)SbF6][d] [5]
[BrettPhosAu(MeCN)SbF6][d] [5]
[BrettPhosAu(MeCN)SbF6][d] [5]
[BrettPhosAu(MeCN)SbF6][d] [5]
[BrettPhosAu(MeCN)SbF6][d] [5]
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
24
24
24
24
24
24
24
24
24
7.5
12
15
15
12
12
15
22[c]
trace
26[c]
32[c]
41
56
32
37
trace
57
50
41
51
66
59
43[g]
Entry
Substrate
R
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
12
4
18
24
24
7
66
85
57
<18[c]
<26[c]
71
63
80
56
35
C6H4(4-OMe)
C6H4(4-Cl)
C6H4(4-CN)
C6H4(4-CO2Me)
C6H4(4-Me)
C6H4(3-Me)
C6H4(2-Me)
nBu
9
10
11
12
13
14
15[e]
16[f]
EtOH
DCE
DCE
DCE
9
12
24
24
3
9
10d
11
12
1j
1k
1l
Cy
2-thienyl
3-thienyl
62
77
[a] Unless otherwise noted, the reactions were conducted using 10 equiv
of 2a at 808C. [b] Isolated yields. [c] Containing small amounts of impuri-
ties. [d] Prepared by mixing [BrettPhosAuCl] and AgSbF6 in MeCN and
CH2Cl2 followed by filtration. [e] Using 5 equiv of 2a. [f] Using 1.1 equiv
of 2a. [g] Carbazole 5a was produced in 5% yield.
5
[a] Prepared by mixing [BrettPhosAuCl] and AgSbF6 in MeCN and CH2Cl2
followed by filtration. [b] Isolated yields. [c] Containing small amounts of
impurities. [d] Using 10 mol% of the catalyst.
substituted 1,3-diyne 1b bearing an electron-donating me-
thoxy group reacted smoothly to afford the corresponding
product 4b in 85% yield (entry 2). Although the chlorinated
derivative 1c showed sufficient reactivity (57%, entry 3), 1,3-
diynes bearing a cyano- or methoxycarbonyl-substituted diaryl
group (i.e., 1d and 1e) gave complex mixtures including low
yields of 4d and 4e, respectively (<18–26%, entries 4 and 5).
The position of the substituent in the reactions involving the
tolyl derivatives 1 f–h had a moderate impact on the yield of
the indole products (63–80%, entries 6–8). Although the di-
butyl derivative 1i as an aliphatic 1,3-diyne was well tolerated
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under the optimized conditions (56%, entry 9), the more bulky
dicyclohexyl derivative 1j gave a much lower yield (35%,
entry 10), even when the catalyst loading was increased to
10 mol%. Pleasingly, the dithienyl derivatives 1k and 1l react-
ed smoothly to give the corresponding indoles 4k and 4l in
good yields (entries 11 and 12). These observations imply that
the electron-rich diaryldiynes have higher reactivity than elec-
tron-deficient and sterically congested ones toward the indole
formation.
Table 3. Reaction of 1a with substituted pyrroles.
Entry
Pyrrole [equiv]
R
T [8C]
t [h]
Product
Yield [%][b]
(recovery)
1
2
3
4
5
6
2a [10]
2b [10]
2c [5]
2c [5]
2d [5]
2d [5]
H
80
80
80
12
24
24
0.5
24
0.5
4a
4o
4p
4p
4q
4q
66
33
41 (25)
31 (21)
11 (77)
25 (50)
We then applied the reaction to unsymmetrical 1,3-diynes
(Scheme 3). The reaction of diaryldiyne 1m gave indole 4m
and its regioisomer 4m’ in 52 and 24% yields, respectively. A
similar result was also obtained using diyne 1n bearing phenyl
and n-butyl groups, which gave 4n and the corresponding re-
gioisomer 4n’ in 37 and 15% yields. The major products 4m
and 4n were most likely formed as a consequence of the first
1-Me
2-Me
2-Me
3-Me
3-Me
130[c]
80
130[c]
[a] Prepared by mixing [BrettPhosAuCl] and AgSbF6 in MeCN and CH2Cl2
followed by filtration. [b] Isolated yields. [c] Microwave irradiation was
used.
Scheme 3. Reaction of unsymmetrical 1,3-diynes. Reaction conditions:
1 (1 equiv), 2a (10 equiv), and [BrettPhosAu(MeCN)SbF6] (5 mol%), DCE,
808C, 8 h (for 1m) or 21 h (for 1n). [a] Determined from the combined iso-
Scheme 4. Isolation and cyclization of intermediate 3a. Reaction conditions:
[BrettPhosAu(MeCN)SbF6] (5 mol%), DCE, 808C.
1
lated yields by H NMR spectroscopy. [b] Isolated yields.
intermolecular hydroarylation occurring at the more electron-
rich triple bond of the diyne, which was directly attached to an
anisyl or phenyl group. It was assumed that the difficulty asso-
ciated with controlling the regioselectivity of the first hydro-
arylation with pyrrole resulted from the conjugated diyne
system, with the electronic effects of the terminal substitu-
ent(s) extending beyond the proximal alkyne to the distal posi-
tion.
1a (55%), enyne-substituted pyrrole 3a (20%) and the indole
4a (12%) were isolated from the reaction mixture. As expect-
ed, exposure of 3a to the optimum reaction conditions for
1.5 h led to its complete conversion to the corresponding
indole 4a in 71% yield. This result strongly supported the oc-
currence of a stepwise double hydroarylation pathway, in
which the first intermolecular hydroarylation of the 1,3-diyne
occurred at the 2-position of the pyrrole (Scheme 2).
We conducted further substrate scope on this reaction using
methyl-substituted pyrroles 2b–d as shown in Table 3. N-meth-
ylpyrrole 2b gave the desired product 4o in 33% yield along
with other unidentified byproducts (Table 3, entry 2). Under
the above-optimized conditions, methyl-substituted pyrroles
2c and 2d were converted to the corresponding indoles 4p
and 4q in low yields (41 and 11%, respectively) with a recovery
of the starting material 1a (entries 3 and 5). Microwave irradia-
tion slightly contributed to improving the yield of 4q (entry 6).
From these investigations, this reaction has a limitation in the
synthesis of 4,7-disubstituted indoles bearing pyrrole ring sub-
stitution(s). However, this will be able to be overcome by suffi-
cient reactivity of indoles at the pyrrole ring moiety.
The development of a reliable synthetic methodology for
the construction of carbazoles bearing multiple functionalities
in a single step is highly desirable because carbazole-contain-
ing derivatives possess a broad range of biological properties,
including antibacterial, anti-inflammatory, and antitumor activi-
ties.[8a,16,17] Carbazoles also exhibit interesting properties as or-
ganic materials, such as hole-transporting, photoconductive,
and photorefractive effects.[16] Finally, we extended our [4+2]-
type indole formation to the synthesis of carbazoles. We antici-
pated that indoles would be less reactive as nucleophiles in
this transformation than pyrroles because only trace amounts
of the corresponding carbazoles, if any, were obtained as the
over-reaction products from the reactions of diynes 1 with pyr-
role 2a. For example, the reaction of 1a with 1.1 equivalents
of 2a gave the corresponding carbazole product in only 5%
yield (Table 1, entry 16). As anticipated, the reactions of N-un-
To develop a deeper understanding of the mechanism, the
reaction of 1a and 2a was terminated before it reached com-
pletion (Scheme 4). Along with the recovered starting material
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Table 4. Direct carbazole synthesis.
Keywords: carbazoles · cascade reaction · gold catalysis ·
hydroarylation · indoles
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Entry
Substrate
R1
R2
t [h]
Yield [%][b]
(recovery)
1
6a
6a
6b
6c
6d
6e
6 f
6g
6h
6i
H
H
H
H
Me
Me
Me
Bn
PMB
Allyl
H
H
24
24
24
24
12
10
24
21
21
24
17 (72)
50 (22)
15 (72)
23 (57)
57
2[c]
3
OMe
CO2Me
H
OMe
CO2Me
H
4
5
6
7
8
9
10
70
45
78
54
H
H
56
[a] Prepared by mixing [BrettPhosAuCl] and AgSbF6 in MeCN and CH2Cl2
followed by filtration. [b] Isolated yields. [c] Using 20 mol% of the cata-
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substituted indoles 6a–c were sluggish, with the desired prod-
ucts 7a–c being formed in only 15–23% yields (Table 4, en-
tries 1, 3, and 4). It is noteworthy that large amounts of the
starting material 1a were recovered in these cases. Increasing
the loading of catalyst to 20 mol% led to a small improvement
in the yield of 7a to 50% (entry 2). In contrast, N-methyl-
indoles 6d–f reacted efficiently in the presence of 5 mol% of
the catalyst to give 7d–f in moderate yields (entries 5–7). Simi-
larly, other N-substituted indoles 6g–i bearing a benzyl, para-
methoxybenzyl (PMB), or allyl group on their nitrogen reacted
effectively to give the corresponding N-substituted carbazoles
7g–i in acceptable yields (entries 8–10). Based on these results,
it appeared likely that the proton on the indole nitrogen atom
was having an adverse impact on the formation of carbazoles
from indoles and that a protecting group was therefore neces-
sary to allow indoles to be used as substrates in this reaction.
In summary, we have developed a new method for the syn-
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and pyrroles. The use of N-substituted indoles as the nucleo-
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to the total synthesis of biologically active indole alkaloids are
currently underway in our laboratory.
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This work was supported by a Grant-in-Aid for the Encourage-
ment of Young Scientists (A), as well as Platform for Drug
Design, Discovery, and Development from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan. S.N.
would like to express her gratitude for Research Fellowships
from the Japan Society for the Promotion of Science for Young
Scientists.
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Oishi, T. Watanabe, H. Ohno, J. Sawada, K. Matsuno, A. Asai, N. Asada, K.
Kitaura, N. Fujii, J. Med. Chem. 2011, 54, 4839–4846.
[14] We recently reported that pyrrole can be used as a nucleophile in gold-
catalyzed reaction of alkynes, see ref. [8c].
[15] For preparation of related gold complexes, see: C. Obradors, D.
Leboeuf, J. Aydin, A. M. Echavarren, Org. Lett. 2013, 15, 1576–1579.
[16] For recent reviews, see: a) A. W. Schmidt, K. R. Reddy, H.-J. Knçlker,
Chem. Rev. 2012, 112, 3193–3328; b) J. Roy, A. K. Jana, D. Mal, Tetrahe-
Received: October 31, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
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Gold Catalysis
Y. Matsuda, S. Naoe, S. Oishi, N. Fujii,*
H. Ohno*
&& – &&
Indole synthesis: Intermolecular formal
[4+2] reaction between 1,3-diynes and
pyrroles provides a convenient ap-
proach to 4,7-disubstituted indoles. A
gold(I) catalyst successfully promotes
this transformation. This reaction can
also be applied to the synthesis of car-
bazoles when indoles are used as the
nucleophiles instead of pyrroles (see
scheme).
Formal [4+2] Reaction between 1,3-
Diynes and Pyrroles: Gold(I)-Catalyzed
Indole Synthesis by Double
Hydroarylation
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Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!