Regio- and chemoselective n-1 acylation of indoles: Pd-catalyzed domino cyclization to afford 1,2-fused tricyclic indole scaffolds

Article abstract of DOI:10.1002/chem.201406617

A concise method for the synthesis of 1,2-fused tricyclic indole scaffolds by domino cyclization involving a Pd-catalyzed Sonogashira coupling, indole cyclization, regio- and chemoselective N-1 acylation, and 1,4-Michael addition is reported. This method

Full text of DOI:10.1002/chem.201406617

DOI: 10.1002/chem.201406617
Communication
&
Synthetic Methods
Regio- and Chemoselective N-1 Acylation of Indoles: Pd-Catalyzed
Domino Cyclization to Afford 1,2-Fused Tricyclic Indole Scaffolds
Yongxian Liu, Yuanqiong Huang, Hongjian Song,* Yuxiu Liu, and Qingmin Wang*[a]
synthesis, and these one-pot processes can be used to con-
Abstract: A concise method for the synthesis of 1,2-fused
struct polycyclic compounds rapidly. Recently, Fan et al. report-
tricyclic indole scaffolds by domino cyclization involving
ed the use of a Pd-catalyzed domino reaction to construct 3,4-
a Pd-catalyzed Sonogashira coupling, indole cyclization,
fused tricyclic azepino[5,4,3cd]indoles;[13] Lu et al. used a one-
regio- and chemoselective N-1 acylation, and 1,4-Michael
pot PdII-catalyzed reaction to construct cycloalkane-fused in-
addition is reported. This method provides straightforward
doles (Scheme 1a,b).[14] However, no Pd-catalyzed domino
access to tetrahydro[1,4]diazepino[1,2-a]indole and hexa-
hydro[1,5]diazocino[1,2-a]indole scaffolds.
Fused polycyclic indole scaffolds[1–4] (Figure 1) are found in nu-
merous natural products and synthetic drug molecules. Impor-
tant examples include streptocarbazoles and evodiagenine
(Figure 1), which have a tetrahydro[1,4]diazepino[1,2-a]indole
core structure. These compounds have attracted the attention
Scheme 1. Pd-catalyzed domino cyclization to form fused indoles.
method for the synthesis of 1,2-fused tricyclic indoles has been
Figure 1. Natural products with fused polycyclic indole scaffolds.
reported. As part of our ongoing work on the use of domino
cyclization reactions to prepare bioactive molecules, we have
of pharmacologists and organic chemists owing to their re-
markable medicinal properties and their synthetically challeng-
ing heptacyclic structure. They have been examined as poten-
tial kinase inhibitors,[5] antiviral and antiallergic agents,[6–7] in-
hibitors of hepatitis C virus replication,[8–10] and antitumor
agents;[11] however, only a few methods for their synthesis
have been reported.[12] Therefore, a convenient strategy for ef-
ficiently constructing tetrahydro[1,4]diazepino[1,2-a]indole
scaffolds is desirable.
developed a method for the Pd-catalyzed domino synthesis of
1,2-fused tricyclic indoles from substituted 2,2,2-trifluoro-N-(2-
iodophenyl)acetamides and N-protected (prop-2-yn-1-yl)acry-
lamides (Scheme 1c). This method provides straightforward
access to 1,2-fused tricyclic indoles.
To optimize the domino cyclization, we used 2,2,2-trifluoro-
N-(2-iodophenyl)acetamide (1a) and N-(prop-2-yn-1-yl)-N-
tosylacrylamide (2a) as model substrates (Table 1). Under the
initial conditions, the target product 3aa was obtained in 67%
yield (entry 1) and its structure was confirmed by X-ray diffrac-
tion.[15] The effect of the solvent was then investigated, and
1,4-dioxane was found to give the best yield of 3aa (82%,
entry 3). When acetonitrile was used, the yield decreased to
38% (entry 2); most of 1a did not participate in the predomi-
nant reaction, which resulted in a complex mixture of side
products. Increasing the temperature had a negative effect;
the yield was only 25% when the reaction was conducted at
908C (entry 4). When lowering the temperature to 70 or 608C,
the yield was only 72 and 50%, respectively (entries 5 and 6).
Next, we investigated the effect of different bases. Both Cs2CO3
and Na2CO3 showed a lower reactivity than K2CO3 (entries 7
Domino cyclization reactions triggered by transition-metal
catalysis have been the subject of intense research in organic
[a] Y. Liu, Y. Huang, H. Song, Y. Liu, Prof. Q. Wang
State Key Laboratory of Elemento-Organic Chemistry
Research Institute of Elemento-Organic Chemistry
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071 (China)
Fax: (+86)22-23503952
E-mail: wang98h@263.net
wangqm@nankai.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406617.
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tively). When we changed the benzenesulfonyl pro-
Table 1. Optimization of reaction conditions.[a]
tecting group to thiophen-2-ylsulfonyl, 3aj was ob-
tained in
a moderate yield; compounds with
a methyl and cyclopropyl sulfonyl protecting group
gave the expected products 3ak and 3al in 44 and
51% yield. The reaction was strongly influenced by
the steric effects of 2; 3am was obtained in only
14% yield when a methyl group was introduced to
the terminal alkenyl of 2m. Additionally, the octacy-
clic compound 3an was obtained in 61% isolated
yield. However, when a methylene group was added,
the nonacyclic compound was not obtained.
Entry
Pd(OAc)2
[mol%]
PPh3
[mol%]
Base
Solvent
T
[8C]
Yield
[%][b]
1
2
3
4
5
6
7
8
9
20
20
20
20
20
20
20
20
20
20
10
5
80
80
80
80
80
80
80
80
80
80
40
20
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
DBU
DMF
CH3CN
80
80
80
90
70
60
70
70
70
70
80
80
67
38
82
25
72
50
52
trace
38
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
A proposed mechanism for this domino cyclization
reaction is depicted in Scheme 4. The initial step in-
volves a Pd-catalyzed Sonogashira coupling of 1a
and 2a to form 4.[17] Domino indole cyclization fol-
lowed by an intramolecular transamidation reaction
10[c]
11
12
K2CO3
K2CO3
K2CO3
trace
81
32
affords key intermediate
C
via
5
(path 1,
[a] Reaction conditions: 1a (0.73 mmol), 2a (1.1 equiv), base (2 equiv), TBAB (2 equiv)
in solvent (25 mL) and H2O (1 mL), unless otherwise noted. [b] Isolated yields. [c] TBAB
was not added.
route (1))[18–20] and subsequent Michael addition gives
3aa. There is another possible pathway to 3aa: 4
can be converted to 6 through an intermolecular
and 8). When the organic base 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) was used, a portion of both substrates 1a and 2a
remained, even after a prolonged reaction time (entry 9). Little
or no reaction occurred in the absence of tetra-n-butylammo-
nium bromide (TBAB; entry 10), which revealed the importance
of the phase-transfer catalyst in the reaction.[16] Further optimi-
zation studies focused on the effect of the amounts of
Pd(OAc)2 and PPh3. When the amounts of Pd(OAc)2 and PPh3
were decreased to 10 and 40 mol%, respectively (entry 11), the
yield remained the same as compared to entry 3. However,
when the amounts were further reduced, the yield decreased
substantially (entry 12).
After having established the optimized conditions (Table 1,
entry 11), the substrate scope was investigated. First, we evalu-
ated substrates with various substituents on the benzene ring
(1a–1j, Scheme 2) and found that electronic effects strongly
influenced the reaction. Specifically, substrates with electron-
donating groups, such as methyl and methoxyl, gave lower
yields of the corresponding products (3ba and 3ia); substrates
with electron-withdrawing groups, such as fluoro (3ea), chloro
(3ca, 3ha), bromo (3da), and cyano (3 fa), gave moderate to
excellent yields. The yields decreased significantly when
strongly electron-withdrawing groups, such as trifluoromethyl
and carbonyl (3ga and 3ja), were introduced. It is worth
noting that the cyano and bromo functional groups on the
benzene ring can be used to carry out further transformations.
Substrates 2b–2l (Scheme 3) were synthesized to investi-
gate the influence of the protecting group on the domino cyc-
lization reaction. All compounds with a substituted benzene-
sulfonyl protecting group gave the expected products 3ab--
3ai. Compounds with an electron-donating group gave better
yields than those with an electron-withdrawing group: the
yields of 3aa, 3ac, 3ae, and 3af (81, 67, 75, and 73%, respec-
tively) were much higher than the yields of 3ad (9%) and
3ag–3ai containing a halogen atom (35, 26, and 43%, respec-
Scheme 2. Synthesis of tetrahydro[1,4]diazepino[1,2-a]indoles. Reaction con-
ditions: 1 (0.73 mmol), 2 (0.77 mmol), TBAB (1.46 mmol), K2CO3 (1.46 mmol),
Pd(OAc)2 (10 mol%), PPh3 (40 mol%), and H2O (1 mL) in 1,4-dioxane (25 mL)
at 77–808C for 4–10 h. Isolated yields are reported.
transamidation reaction, which occurs prior to the indole cycli-
zation, and then C is formed via indole cyclization of inter-
mediate 6 (path 2).
To determine whether path 1 or path 2 is more likely, we
conducted several control experiments. First, we prepared the
proposed intermediate 5 by using reported methods[21–23] and
subjected it to alkaline conditions in the absence of a Pd cata-
lyst (Scheme 5a). To our delight, the expected cyclization pro-
ceeded smoothly to give 3aa in 92% yield, which proved that
5 is an intermediate in the domino reaction. It is worth noting
that 3aa’ was not obtained either from 5 or from 1a, which
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Scheme 5. Control experiments.
to the domino cyclization conditions (Scheme 5c), 3aa was ob-
tained in 9% yield; this suggests that path 2 cannot be ruled
out.
In summary, we developed a Pd-catalyzed domino route for
the synthesis of tetrahydro[1,4]diazepino[1,2-a]indoles by using
simple substituted 2,2,2-trifluoro-N-(2-iodophenyl)acetamides
and N-protected (prop-2-yn-1-yl)acrylamides as starting materi-
als. This method provides straightforward access to 1,2-fused
tricyclic indoles. On the basis of corresponding experiments
and X-ray crystal structures of products 3, we propose a mecha-
nism involving a Pd-catalyzed Sonogashira coupling, indole
cyclization, regio- and chemose-
Scheme 3. Synthesis of tetrahydro[1,4]diazepino[1,2-a]indoles and hexahy-
dro[1,5]diazocino[1,2-a]indoles. Isolated yields are reported.
lective N-1 acylation, and 1,4-Mi-
chael addition. Further studies
on the application of this
domino route are in progress in
our laboratory.
Experimental Section
Experimental details and additional
data can be found in the Support-
ing Information.
Acknowledgements
We are grateful to the National
Natural Science Foundation of
China (21132003, 21421062,
21372131) and the Specialized
Scheme 4. Proposed mechanism.
Research Fund for the Doctoral
Program of Higher Education
suggests that
a 1,4-Michael addition (Scheme 4, path 1,
(20130031110017) for generous financial support of our re-
search programs.
route (2)) does not occur under our reaction conditions; in ad-
dition, the C-3 acylation product 3aa“ (path 1, route (3)) was
not obtained. These results indicate that the acylation reaction
of 5 to afford C exhibits excellent chemo- and regioselectivity.
Additionally, 3ao, 3ap, and 3aq (Scheme 5b) were separated
from product mixtures that were obtained from the domino
reaction of 1a with 2. The above results indicate that path 1 is
the proposed pathway. However, when substrate 1k and 4-
methyl-N-(prop-2-yn-1-yl)benzenesulfonamide were subjected
Keywords: chemoselectivity · cyclization · domino reactions ·
indoles · palladium · regioselectivity
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Received: December 23, 2014
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COMMUNICATION
&
Synthetic Methods
Y. Liu, Y. Huang, H. Song,* Y. Liu,
Q. Wang*
&& – &&
Regio- and Chemoselective N-
1 Acylation of Indoles: Pd-Catalyzed
Domino Cyclization to Afford 1,2-
Fused Tricyclic Indole Scaffolds
Domino route: A concise method for
the synthesis of 1,2-fused tricyclic indole
scaffolds by domino cyclization is re-
ported. This method provides straight-
forward access to tetrahydro[1,4]diaze-
pino[1,2-a]indole and hexahydro[1,5]dia-
zocino[1,2-a]indole scaffolds (see figure).
Chem. Eur. J. 2015, 21, 1 – 5
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