Lewis Acid-Catalyzed Annulation of Propargylic Alcohols with (Z)-2-Styryl-1H-Indoles

Article abstract of DOI:10.1002/adsc.201800907

A novel copper(II) trifluoromethanesulfonate-catalyzed intermolecular cascade annulation strategy for the construction of a great variety of pentacyclic compounds possessing valuable carbazole fragments was developed employing propargylic alcohols and (Z)-2-styryl-1H-indoles as the initial substrates. This protocol, which entails a sequential Meyer-Schuster rearrangement/isomerization/-cyclization cascade, enables facile and atom-economical access to various pentacyclic compounds with broad functional-group tolerance in good yields under mild conditions. The conversion could be efficiently scaled up to gram quantities, accentuating a potential application of this work. (Figure presented.).

Full text of DOI:10.1002/adsc.201800907

Title: Lewis Acid-Catalyzed Annulation of Propargylic Alcohols with
(Z)-2-styryl-1H-indoles
Authors: Xue-Song Li, Ya-Ping Han, Xin-Yu Zhu, Yu Xia, Wan-Xu Wei,
Ming Li, and Yong-Min Liang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800907
Link to VoR: http://dx.doi.org/10.1002/adsc.201800907

10.1002/adsc.201800907
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201
Lewis Acid-Catalyzed Annulation of Propargylic Alcohols with
(Z)-2-Styryl-1H-indoles
Xue-Song Li,a Ya-Ping Han,a Xin-Yu Zhu,a Yu Xia,a Wan-Xu Wei,a Ming Li,a Yong-
Min Liang*a
a Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province and State Key Laboratory
of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000,
People’s Republic of China
Fax: +86-931-8912582; e-mail: liangym@lzu.edu.cn
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
potent inhibitory effect of Epstein-Barr virus and
Abstract. A novel copper(II) trifluoromethanesulfonate-
catalyzed intermolecular cascade annulation strategy for the shows the potential ability to inhibit 12-O-
tetradecanoylphorbol-13-acetate.[11] Furanoclausamine
construction of a great variety of pentacyclic compounds
possessing valuable carbazole fragments was developed
employing propargylic alcohols and (Z)-2-styryl-1H-
indoles as the initial substrates. This protocol, which entails
a sequential Meyer–Schuster rearrangement/isomerization/-
cyclization cascade, enables facile and atom-economical
access to various pentacyclic compounds with broad
functional-group tolerance in good yields under mild
conditions. The conversion could be efficiently scaled up to
gram quantities, accentuating a potential application of this
work.
A and B, which were isolated from the stems of
Clausena anisata, are identified as having the ability
to display cytotoxicity against various tumor cell lines
and the human leukemia cell line HL-60.[12]
Carbazole alkaloid oridamycin A isolated by the
Imamura group from the fermentation broth of
Streptomyces sp. KS84 are believed to hold anti-
Saprolegnia parasitica activity.[13] Owing to the
significant pharmaceutical and biological activities of
such compounds, as well as their wide applications in
synthetic chemistry, a versatile, efficient, and atom-
economical method for constructing carbazole
derivatives is highly desirable.[14] General strategies
to access this key motif rely on the use of transition
metal catalysts such as Pd, Rh, Mn or Ru via a
Keywords: copper(II) trifluoromethanesulfonate-catalyzed;
propargylic alcohols; 2-alkenylindoles; cascade annulation;
carbazole derivatives
cascade annulation pathway.
A
series of
preeminent and attractive works have been reported
by the Cho, Witulski, Buchwald group among
others.[15] In 2002, Witulski et al. reported novel Rh-
catalyzed inter- and intramolecular alkyne
cyclotrimerization syntheses of substituted carbazoles
During the past decade, Lewis acid-catalyzed tandem
annulation for the benign construction of carbocycles,
heterocycles, and bridged rings of great complexity
has been the focus of an increasingly large number of
organic research initiatives due to its high bond-
forming efficiency and fundamental scientific
appeal.[1] In particular, the annulation of propargylic
alcohols with a wide array of nucleophiles or
electrophiles has provided a powerful method for the
efficient generation of quinolines,[2] pyrroles,[3]
furans,[4] azepines,[5] pyridines,[6] azoles,[7] and
thiazoles.[8]
The carbazole derivatives represent an important
class of N-containing compounds because they are
ubiquitous core structures in biologically active
natural products, pharmaceuticals, agricultural
chemicals, and materials science.[9] It has been shown
that carbazole alkaloids exhibit potential biological
activities, especially with antioxidative activity,
hypotensive activity, platelet aggregation inhibition,
antimicrobial and antiinflammatory activities, and
inhibition of protein kinase C.[10] For example,
clausamine isolated from Clausena anisata exhibits a
Figure 1. Representative carbazole-containing compounds
1
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10.1002/adsc.201800907
Advanced Synthesis & Catalysis
derivatives (Scheme 1a).[16] In 2009, an asymmetric Table 1. Optimization of the reaction conditions of 1a with
Pd-catalyzed dearomatization of
naphthalene (Z)-2-styryl-1H-indole a)
derivatives, reported by Buchwald and co-workers,
delivered benzocarbazole derivatives at high
efficiency (Scheme 1b).[17] It is noteworthy that
precious metals used as catalysts have seriously
hindered the synthetic utility of such transformations
in synthesis methodology. In terms of sustainability,
they are supposed to be replaced by widely abundant
and inexpensive catalysts. Inspired by these intriguing
investigations in the area of carbazole derivatives and
our previous work on the transformation of
propargylic alcohols, we herein present an
unprecedented Cu(II) trifluoromethanesulfonate-
catalyzed cascade annulation of propargylic alcohols
and (Z)-2-styryl-1H-indoles, leading to the facile
assembly of highly strained pentacyclic systems
possessing functionalized carbazole fragments
11,11,12-triphenyl-5,11-dihydroindeno[1,2
temp yield
(°C) (%) b)
entry catalyst (mol %)
solvent
1
2
Y(OTf)3 (20)
Yb(OTf)3 (20)
AgOTf (20)
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
THF
90
90
29
21
46
0
3
90
4
Zn(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (15)
Cu(OTf)2 (12)
Cu(OTf)2 (12)
Cu(OTf)2 (12)
Cu(OTf)2 (12)
Cu(OTf)2 (12)
90
5
90
55
19
34
15
24
47
51
70
66
64
33
64
71
70
6
90
b]carbazole in good yields under mild conditions.
7
DCE
90
8
CH3NO2
CH3CN
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
90
Scheme 1. Summary of current methods and our new
anticipated strategy for carbazole derivatives
9
90
10
11
12
13
14
15c)
16d)
17e)
18f)
70
110
120
120
120
120
120
120
120
a)
Unless otherwise noted, all reactions were performed
with 1a (0.1 mmol) and (Z)-2-styryl-1H-indole 2a (1.3
b)
equiv.) in solvent (2.0 mL) for 2 h. Yields are given for
c)
d)
isolated products. The reaction was conducted for 3 h.
e)
Initially, propargylic alcohol 1a (0.1 mmol) and
(Z)-2-styryl-1H-indole 2a (1.3 equiv.) were chosen as
the model substrates to optimize the reaction
conditions. Product 12-(4-methoxyphenyl)-11,11-
diphenyl-5,11-dihydroindeno[1,2-b]carbazole 3a was
obtained in 29% yield in the presence of a catalytic
amount of Y(OTf)3 (20 mol %) in toluene at 90 °C for
2 h under an air atmosphere (Table 1, entry 1). The
structure of product 3a was unambiguously assigned
by NMR spectroscopy and X-ray crystallography (see
the Supporting Information).[18] After careful
screening of catalysts, it was found that other Lewis
acids could also catalyze this tandem annulation
reaction, with Cu(OTf)2 furnishing the best yield of
the desired 3a (entries 2−5). Notably, various
representative solvents such as THF, DCE, CH3NO2,
and CH3CN were not effective in promoting this
The reaction was conducted for 4 h. The reaction was
conducted for 5 h. f) The reaction was conducted for 6 h.
desired product was obtained in 71% yield when the
reaction time was extended to 5 h (entries 15−18).
Ultimately, the optimal conditions for the generation
of product 3a were settled as 1a (0.1 mmol), (Z)-2-
styryl-1H-indole 2a (1.3 equiv.) in the presence of
Cu(OTf)2 (12 mol %) in toluene (2.0 mL) at 120 °C
for 5 h.
The generality of the scope of propargylic alcohols
for the annulation reaction with respect to (Z)-2-
styryl-1H-indole 2a was investigated under the above
optimized conditions. As shown in Scheme 2,
different substituents of varying electron-rich
character, such as methoxy, methyl, ethyl, and 3,5-
dimethyl (3a−3i) or electron-deficient character
including phenyl, nitryl, cyano, and ester (3j−3m) at
the para, ortho, or meta position on the phenyl ring
(R3), were well-tolerated and gave the desired
products in yields ranging from 37% to 76% (3a−3m).
It is noteworthy that alkynol substrates bearing
versatile halogen substituents such as F, Cl, and Br on
transformation (entries 6−9).
A
subsequent
investigation of the reaction temperature revealed that
120 °C was optimal for this cascade annulation and
gave a 70% yield of the expected product (entries
10−12). By decreasing the loading catalyst Cu(OTf)2
to 12 mol %, the yield of the product slightly reduced
to 64% (entries 13−14). The
2
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10.1002/adsc.201800907
Advanced Synthesis & Catalysis
a,
Scheme 2. Scope with respect to propargylic alcohols a, b)
Scheme 3. Scope with respect to (Z)-2-styryl-1H-indoles
b)
a)
Unless otherwise noted, all reactions were performed
with 1a (0.1 mmol) and 2 (1.3 equiv.) in the presence of
Cu(OTf)2 (12 mol %) in toluene (2.0 mL) at 120 °C for 5 h.
b) Yields are given for isolated products.
heterocyclic or alkyl substituents, for example, thienyl,
propyl, and cyclopropyl groups on the alkynol
substrates afforded the corresponding products
3aa−3ad in moderate yields.
To extend the applicability of this protocol, the
scope with respect to the (Z)-2-styryl-1H-indole 2 was
then evaluated (Scheme 3). A variety of substituents
attached to substituted (Z)-2-styryl-1H-indoles 2 were
amenable to the process including methoxy, methyl, F,
Cl, Br, and phenyl yielding corresponding carbazole
derivatives 4a−4g in 39−68% yields.
An advantage of our developed cascade annulation
is easy to scale-up to grams quantities. A gram-scale
reaction of 1.0 grams of 1a was performed under the
optimal conditions for 10 h, thus delivering 0.77
grams of the expected 3a in 47% yield, which
provides an efficient and straightforward approach for
a)
Unless otherwise noted, all of the reactions were the construction of 11-(4-methoxyphenyl)-11,12-
performed with 1 (0.1 mmol) and 2a (1.3 equiv.) in the diphenyl-5,11-dihydroindeno[1,2-b]carbazole.
presence of Cu(OTf)2 (12 mol %) in toluene (2.0 mL) at
120 °C for 5 h. b) Yields are given for isolated products.
Scheme 4. Scaled-up experiment
the aromatic ring (R3) were also amenable to cascade
annulation and furnished the corresponding products
3n−3p in good yields, which might have the potential
ability for downstream chemical modifications.
Symmetrical
propargylic
alcohol
substrates
On the basis of previously reported work[19] and
containing either electron-donating (Me, 3q) or experimental observations, a plausible mechanism to
withdrawing (F, Cl, 3r−3t) groups on the phenyl rings rationalize the formation of the desired products 3 is
(R1, R2) could undergo this transformation and were depicted in Scheme 5. The reaction begins with the
transformed into the expected products in good yields coordination of propargyl alcohol 1 to a Lewis acid
(3q−3t). Moreover, different combinations of catalyst, generating active propargyl cation species A
electron-rich and/or electron-deficient groups on the via a Meyer–Schuster rearrangement. The attack of
aromatic rings (R1, R2) of the unsymmetrical (Z)-2-styryl-1H-indole 2a onto the active C−C triple
propargylic alcohols were well tolerated, leading to bond of intermediate A gives intermediate B, which
the efficient construction of anticipated products could resonate with resonance-stabilized intermediate
3u−3z in moderate to good yields. The presence of
C. Subsequently, intermediate C undergoes an
3
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10.1002/adsc.201800907
Advanced Synthesis & Catalysis
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10:1) to afford 36.4 mg of 3a.
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Acknowledgements
We thank the National Science Foundation (NSF 21472073,
21772075 and 21532001).
4
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10.1002/adsc.201800907
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800907
Advanced Synthesis & Catalysis
UPDATE
Lewis Acid-Catalyzed Annulation of Propargylic
Alcohols with (Z)-2-styryl-1H-indoles
Adv. Synth. Catal. Year, Volume, Page – Page
Xue-Song Li,a Ya-Ping Han,a Xin-Yu Zhu,a Yu
Xia,a Wan-Xu Wei,a Ming Li,a Yong-Min Liang*a
6
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