Gold-catalyzed intramolecular alkyne cycloisomerization cascade: Direct synthesis of aryl-annulated[a]carbazoles from aniline-substituted diethynylarenes

Article abstract of DOI:10.1002/adsc.200900880

Aniline-substituted diethynylarenes, which are readily synthesized through Sonogashira coupling reactions from commercially available 1,2-dihaloarenes, directly produce aryl- and heteroaryl-annulated [a]carbazoles by the gold-catalyzed intramolecular casc

Full text of DOI:10.1002/adsc.200900880

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DOI: 10.1002/adsc.200900880
Gold-Catalyzed Intramolecular Alkyne Cycloisomerization
Cascade: Direct Synthesis of Aryl-Annulated[a]carbazoles from
Aniline-Substituted Diethynylarenes
Kimio Hirano,a Yusuke Inaba,a Toshiaki Watanabe,a Shinya Oishi,a
Nobutaka Fujii,a,* and Hiroaki Ohnoa,*
a
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
Fax : (+81)-75-753-4570; e-mail: hohno@pharm.kyoto-u.ac.jpnfujii@pharm.kyoto-u.ac.jp
Received: December 18, 2009; Published online: February 9, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900880.
Abstract:
Aniline-substituted
diethynylarenes,
structure optimization and their application. There-
fore, development of a concise and reliable methodol-
ogy to obtain substituted aryl- and heteroaryl-annu-
which are readily synthesized through Sonogashira
coupling reactions from commercially available 1,2-
dihaloarenes, directly produce aryl- and heteroaryl-
annulated[a]carbazoles by the gold-catalyzed intra-
molecular cascade hydroamination/cycloisomeriza-
tion without producing theoretical by-products. This
new atom-economical route is easily applicable to
various aryl-annulated[a]carbazoles containing an
alkyl, aryl or ester substituent.
AHCTUNGTRENNUNG
struction of heterocyclic frameworks by multi-bond
forming processes.[8] As part of this, we designed a
cascade reaction strategy for the assembly of a ben-
zo[a]carbazole scaffold based on gold-catalyzed 5-
endo-dig hydroamination[9] followed by 6-endo-dig cy-
cloisomerization[10] of aniline-substituted diethynyl-
Keywords: alkynes; carbazoles; cascade reactions;
ACHTUNGTRENNUNG
gold catalysis; heterocycle synthesis
a
catalytic cycloisomerization cascade of diyne deriva-
tives directly giving aryl-annulated[a]carbazoles with-
out producing theoretical by-products, is unprecedent-
Catalytic cascade reactions are becoming increasingly ed.[12] Herein we present a concise synthesis of aryl-
important for the direct construction of target mole- and heteroaryl-annulated[a]carbazoles by a gold-cata-
cules and for reducing waste product formation.[1] lyzed intramolecular hydroamination-cycloisomeriza-
Among them, the catalytic cycloisomerization cascade tion cascade of aniline-substituted diethynylarene de-
would have undeniable benefits from both atom-eco- rivatives.
nomical and environmental points of view. In recent
The substrates 1 required for the designed cascade
years, gold catalysts have emerged as effective tools reaction were readily prepared starting from commer-
for various transformations. Based on the versatile re- cially available 1,2-dihaloarenes. The representative
activity of gold catalysts, several gold-catalyzed cas-
cade transformations were recently reported.[2]
Currently, aryl-annulated carbazoles with diverse
biological activity have attracted considerable atten-
tion in organic chemistry.[3] In particular, aryl- and
heteroaryl-annulated[a]carbazoles exhibit
a broad
range of biological activities such as antitumor[4] and
antimicrobial,[5] and are also utilized in the field of
materials chemistry as light-emitting diodes[6] and
fluorescence reagents.[7] However, most of the report-
ed synthetic methods for this class of compounds re-
quire multistep conversions,[3] which restricts efficient Scheme 1. Hydroamination-cycloisomerization cascade.
368
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Adv. Synth. Catal. 2010, 352, 368 – 372

Gold-Catalyzed Intramolecular Alkyne Cycloisomerization Cascade:
the desired carbazole 2a in 33% and 42% yield, re-
spectively, accompanied by formation of unidentified
high polar compounds on TLC (entries 2 and 3). The
use of the gold-oxo complex [(Ph3PAu)3O]BF4 result-
ed in a 21% yield of 2a, with 71% recovery of the
starting material 1a (entry 4). To our delight, treat-
ment of aniline 1a with NaAuCl4·2H2O afforded 2a in
good yield (64%, entry 5). Although activation of
AuCl with AgOTf gave several side products
(entry 6), a combination of Ph3PAuCl and a silver salt
generally gave better results (70–80%, entries 7–10).
Scheme 2. Representative preparation of substrates 1.
preparation of substrates 1 is shown in Scheme 2. The Of the four silver salts tested (AgBF4, AgSbF6,
iterative Sonogashira reactions of 1,2-dihalobenzenes AgNTf2, and AgOTf), AgOTf has proven to be the
3 with substituted acetylenes 4 and ethynylanilines 5 most promising additive (80%, entry 10). Next, we
(the order depending on the substrate) gave the ani- optimized the reaction conditions (reaction tempera-
line-substituted diethynylanilines 1 without producing ture, time, and solvent) using Ph3PAuCl/AgOTf. The
undesirable indoles. Other heterocyclic congeners cascade reaction at room temperature required 7 h to
were also prepared in the same manner, using 1,2-di- reach completion affording a 70% yield of 2a
haloheteroarenes.
(entry 11), which was inferior to that obtained at
Initially, screening of gold catalysts for the cascade 808C (81% within 1.5 h, entry 12). Investigation of
reaction was carried out using the aniline derivative the catalyst loading and reaction solvent (entries 13–
1a by treatment with 20 mol% gold catalyst for 16 h 16) revealed that 5 mol% Ph3PAuCl/AgOTf in MeCN
(Table 1, entries 1–10). Whereas Ph3PAuCl was inef- most effectively produced 2a in 80% yield (entry 13).
fective in producing 2a (entry 1), the reaction using
With the conditions optimized (Table 1, entries 12
AuCl and AuCl3 as a ligand-free gold catalyst gave and 13), we then investigated the cascade reaction
Table 1. Optimization of reaction conditions using 1a.
Entry
Au catalyst [mol%]
Solvent
T [8C]
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
Ph3PAuCl [20]
AuCl [20]
AuCl3 [20]
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
DCE[d]
Tol[e]
80
80
80
80
80
80
80
80
80
80
r.t.
80
80
80
80
80
16
16
16
16
16
16
16
16
16
16
7.0
1.5
1.5
1.5
3.0
8.0
n.r.[b]
33
42
A
21
NaAuCl4·2H2O [20]
AuCl/AgOTf [20]
64
n.d.[c]
73
Ph3PAuCl/AgBF4 [20]
Ph3PAuCl/AgSbF6 [20]
Ph3PAuCl/AgNTf2 [20]
Ph3PAuCl/AgOTf [20]
Ph3PAuCl/AgOTf [20]
Ph3PAuCl/AgOTf [20]
Ph3PAuCl/AgOTf [5]
Ph3PAuCl/AgOTf [5]
Ph3PAuCl/AgOTf [5]
Ph3PAuCl/AgOTf [5]
74
70
80
70
81
80
71
73
9
10
11
12
13
14
15
16
33
[a]
Yields of isolated 2a.
n.r.=no reaction.
n.d.=not detected.
DCE=1,2-dichloroethane.
Tol =toluene.
[b]
[c]
[d]
[e]
Adv. Synth. Catal. 2010, 352, 368 – 372
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369

Kimio Hirano et al.
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Table 2. Reaction of various aniline derivatives.[a]
Entry
1
R1
R2
t [h][c]
2
Yield [%][b,c]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
n-Pr
c-Hex
t-Bu
p-MeC6H4
p-MeOC6H4
p-F3CC6H4
p-NCC6H4
p-ClC6H4
Ph
H
H
H
H
H
H
H
H
0.75
0.75
24
3.5 (0.83)
4.0 (1.5)
0.50
1.0
0.75
2b
2c
2d
2e
2f
2g
2h
2i
87
82
19
42 (65)
29 (45)
84
78
81
9
10
11
1j
1k
1l
CO2Me
CF3
Me
2.0 (2.0)
5.5 (1.0)
2.0 (0.83)
2j
2k
2l
35 (44)
52 (88)
29 (78)
Ph
Ph
[a]
Unless otherwise stated, all the reactions were carried out with Ph3PAuCl/AgOTf [5 mol%] in MeCN at 808C.
Yields of isolated products.
Reaction times and yields in parentheses indicate those with 20 mol% of the catalyst.
[b]
[c]
using various substrates. First, substituent R1 on the para-position to the amino group (Table 2, entries 9–
alkyne terminus was evaluated (Table 2, entries 1–8). 11). With 5 mol% Ph3PAuCl/AgOTf, these anilines
Anilines 1b and 1c with an n-propyl or cyclohexyl gave moderate yields of the desired carbazoles 2j–l
group were good substrates for the gold-catalyzed cas- regardless of the electronic properties of the substitu-
cade cyclization (entries 1 and 2). However, 1d bear- ent R2 (29–52% yield, entries 9–11). Although the use
ing a tert-butyl group afforded 2d in only 19% yield of 20 mol% catalyst in the reaction of 1j only slightly
(entry 3), presumably due to steric repulsion of the increased the yield of 2j (44%, entry 9),[13] it efficient-
tert-butyl group and the gold complex on the second ly improved the reactivity of 1k and 1l to give 2k and
cyclization, as well as the formation of a sterically 2l in 88% and 78% yield, respectively (entries 10 and
congested product. Reaction of 1e or 1f, which have 11). The decreased nucleophilicity of aniline 1j bear-
electron-rich aryl groups (p-MeC6H4 or p-MeOC6H4) ing a methoxycarbonyl group would be less appropri-
as the R1 substituents, with 5 mol% of the catalyst ate for the gold-catalyzed hydroamination-cycloiso-
gave 2e and 2f in relatively low yields (42% and 29%, merization reaction.
respectively). Yields were improved to 65% and 45%,
Finally, we investigated the cascade cyclization of
respectively (entries 4 and 5), with increased loading heterocyclic congeners 6 and 8. A diethynylthiophene
of the catalyst (20 mol%). In contrast, the reactions derivative 6, which has a five-membered heterocycle
of 1g and 1h bearing an electron-deficient aryl group connecting to two alkynes, can be used for this cas-
(p-F3CC6H4 or p-NCC6H4) with 5 mol% of the cata- cade reaction to give the corresponding thienocarba-
lyst resulted in 2g or 2h in good yields (84% and zole 7 in 61% yield (Scheme 3). Unfortunately, the
78%, entries 6 and 7). The versatility of the reaction cascade cyclizaion of the aniline 8 involving a pyri-
can be seen by the cascade cyclization of aniline 1i dine moiety did not afford the desired pyridocarba-
containing a chlorophenyl group to produce the corre- zole 9 by treatment with 20 mol% Ph3PAuCl/AgOTf.
sponding 6-(p-chlorophenyl)benzo[a]carbazole 2i in However, the more electrophilic NaAuCl4·2H2O
81% yield (entry 8). From these observations, many (20 mol%) produced 9 in 40% yield (Scheme 3). In-
substituent types on the alkyne terminus are tolerated terestingly, the base-promoted reaction of the same
for the cascade cyclization, while a tert-butyl group aniline 8 dramatically changed the cyclization mode
and electron-rich aryl substituents on the alkyne ter- leading to the formation of isomeric product 10[14] in
minus decrease the reactivity of the substrates.
60% yield, through cascade 5-endo-dig/5-exo-dig cycli-
We next applied the gold-catalyzed cascade cycliza- zation. These results demonstrate that the isomeric
tion to anilines 1j–l having a substituent R2 at the annulated carbazoles can be selectively synthesized
370
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Adv. Synth. Catal. 2010, 352, 368 – 372

Gold-Catalyzed Intramolecular Alkyne Cycloisomerization Cascade:
8.0 Hz, 1H, 7-H), 7.81–7.83 (m, 1H, 4-H), 7.95 (br s, 1H,
NH); 13C NMR (125 MHz, C6D6): d=111.9, 117.9, 120.6,
121.4, 121.6, 122.0, 123.2, 125.0, 125.4, 125.8, 126.3, 128.9,
129.2 (2C), 129.8, 130.4 (2C), 133.3, 136.3, 137.8, 139.8,
142.5; HR-MS (FAB): m/z=293.1208, calcd. for C22H15N
[M+]: 293.1204.
Acknowledgements
This work was supported in part by Kaken Pharmaceutical
Co., Ltd., a Grant-in-Aid for Encouragement of Young Sci-
entists (A) from the Ministry of Education, Culture, Sports,
Science and Technology of Japan, Targeted Proteins Research
Program, and the Program for Promotion of Fundamental
Studies in Health Sciences of the National Institute of Bio-
medical Innovation (NIBIO). T.W. is grateful to Research
Fellowships of the Japan Society for the Promotion of Sci-
ence (JSPS) for Young Scientists.
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Adv. Synth. Catal. 2010, 352, 368 – 372
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371

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1
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tives, not carbazoles. For example, the reaction of 11
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Adv. Synth. Catal. 2010, 352, 368 – 372