Synthesis of Naphthalenyl Triflates via the Cationic Annulation of Benzodiynes with Triflic Acid

Article abstract of DOI:10.1021/acs.orglett.9b01590

A highly efficient and regioselective annulation of benzodiynes promoted by triflic acid has been developed. This protocol provides a step and atom-economic access to a series of naphthalenyl triflates. Furthermore, direct synthetic applications of this r

Full text of DOI:10.1021/acs.orglett.9b01590

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Naphthalenyl Triflates via the Cationic Annulation of
Benzodiynes with Triflic Acid
Chenxin Ge,† Guohua Wang,† Panpan Wu,‡,§ and Chao Chen*,†,‡,§
†Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, China
‡School of Chemical & Environmental Engineering, Wuyi University, Jiangmen 529000, China
§International Healthcare Innovation Institute (Jiangmen), Jiangmen 529000, China
S
* Supporting Information
ABSTRACT: A highly efficient and regioselective annulation of benzodiynes promoted by triflic acid has been developed. This
protocol provides a step and atom-economic access to a series of naphthalenyl triflates. Furthermore, direct synthetic
applications of this reaction are also elaborated through cross-coupling reactions to generate synthetically useful
multisubstituted naphthalenes.
Scheme 1. Synthesis of Naphthalenes via Annulations of
Acyclic Enediynes
aphthalene, which is the simplest fused cyclic aromatic
Nhydrocarbon, is a highly attractive structural backbone
that widely exists in various biologically active natural
products.1 A few representative examples include Nafcillin,2
Cambinol,3 Naproxen,4 and Velpatasvir.5 Especially Nafcillin,
which is available in the market, has been used as antimicrobial
drugs, because of its satisfactory antimicrobial action. In
addition, naphthalene derivatives are also employed as
semiconductors for unique organic π-conjugated electronic
properties.6 Conventional synthetic approaches for the
construction of polysubstituted naphthalene backbones were
based on the intramolecular diradical cyclization (Bergman
cyclization; see Scheme 1a).7 However, these methods
required highly diluted conditions and relatively high temper-
ature. Because of their unique electron-rich properties,
enediynes have attracted much more attention for the
electrophilic cyclization reactions to deliver versatile organic
molecules. More recently, enediynes have been notably
investigated in combination with a range of transition-metal
catalysts for fruitful transformations. For instance, methods of
cyclization of enediynes catalyzed by organometallic species
such as Pd,8 Pt,9 Ru,9b,10 In,11 and Au12 were well-established
(Scheme 1b). Among them, enediynes have been extremely
successful when treated with gold catalysts, which accounts for
its coordination to high Lewis acidic Au catalysis, followed by
approaches of nucleophiles to realize intramolecular or
intermolecular cyclization. Whereas, significant drawbacks to
the cyclization reactions of the synthetically useful acyclic
polyynes were the necessary noble metal, excessive nucleo-
philic reagents, and sometimes the utility of oxidizing agents
and ligands for the reactions limiting the utility of the
transformation. Generally speaking, the naphthalene deriva-
tives prepared by these methods are not easy to be further
modified. Therefore, a more mild, green, and environmentally
friendly method to the cycloaromatization of enediynes has
attracted great interest.
In recent years, TfOH has been shown to be efficient proton
acid for activation of alcohols13 and unsaturated systems,
especially alkynes and alkenes.14 This strategy has been used in
the synthetic methods to construct carbon−carbon and
carbon−heteroatom bond. Meanwhile, our group have
Received: May 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01590
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Organic Letters
Letter
previously reported TfOH-promoted bicyclization of arylace-
tylenes to benzobicyclo[3.2.1]octanes.15 A formal Au-catalyzed
carbocyclization reaction of benzodiyne scaffolds has been
successfully developed for the direct construction of
substituted naphthalenes reported by Fujii and co-workers.12b
We envisioned that 1,5-benzodiynes designed with one
terminal alkyne underwent a similar annulation mode
promoted by TfOH in light of the mechanistic proposal for
the construction of functionalized naphthalene compounds.
And we finally found that a class of naphthalenyl triflates could
be directly assembled rather than other nucleophiles-
substituted naphthalene compounds (Scheme 1c). As a
continuation of our ongoing research studies on cascade
cyclization reactions for the selective synthesis of polysub-
stituted naphthalene compounds,16 herein, we report the
efficient synthesis of naphthalenyl triflates via the cationic
annulation of benzodiynes with triflic acid under mild
conditions, which features step economy and atom economy
and avoids the use of external nucleophiles.
Finally, it was found that excessive TfOH slightly diminished
the product yield (Table 1, entry 8 vs entry 7).
With the optimal conditions in hand, the scope of the
transformation was then examined. The diverse derivatives of
benzodiynes 1 required for the annulation were easily prepared
using the different reactivity between I and Br atoms in
Sonogashira reactions, as depicted in Scheme 2. Starting from
Scheme 2. Representative Preparation of Substrates
commercially available 1-bromo-2-iodobenzene 3, under
standard Sonogashira conditions, the aryl iodide coupled
with arylyne catalyzed by cocatalyst PdCl2(PPh3)2 and CuI at
room temperature. Subsequently, less-reactive aryl bromide
was coupled with the utilization of bulky electron-rich ligand
P(t-Bu)3 for the full conversion of starting materials. Finally,
products benzodiynes 1 were obtained using K2CO3 and
THF/MeOH to remove the protecting group TMS.
Initially, studies were started with benzodiyne 1a as a model
substrate (Table 1). To our delight, when 1a was treated with
a
Table 1. Screening of the Conditions for Annulation of 1a
As depicted in Scheme 3, various substituents R3 on the
aromatic system were evaluated. A variety of functional
aromatic rings bearing alkyl groups, such as methyl, ethyl,
and tert-butyl, were all tolerated, affording the corresponding
naphthalenyl triflates 2b−2d in moderate yields, regardless of
the steric bulkiness of the R3 group. Note that the reaction
with alkyl-substituted alkyne 1e resulted in no desired products
under the standard conditions. This observation implied that
the existence of the ortho-arylyne substituent was indispen-
sable for the current annulation. Furthermore, the reactions of
1f, 1g, and 1h bearing weak electron-withdrawing aryl groups
(R3 = F, Br, Cl) under the optimized conditions afforded the
corresponding products (2f−2h) in moderate to good yields.
The position of substituent on the aryl ring had a little effect
on the yields, with the ortho- and meta-chloro-substituted
aromatic alkyne slightly diminishing the product yields
respectively (2i−2j). The reaction of 1k, which had an
electron-withdrawing substituent (R3 = CF3) resulted in no
products under the standard conditions. When the temper-
ature was elevated to 80 °C, product 2k was obtained, with the
isolated yield of 40%. We assumed that decreased nucleophil-
icity of the internal alkyne enabled one to stabilize the
intermediate vinyl cation, thus unwanted side reactions were
formed instead. Byproduct o-acetyl internal diarylyne 2l′ (R3 =
COOMe) was indeed detected and isolated, which could be
explained by protonation of the terminal alkyne, followed by
hydrolysis for residual H2O in solution. Biphenyl alkyne 1m
was also reacted to provide the corresponding product 2m in
60% yield. Among the applied heteroaromatic ring substrate,
thiophene-substituted alkyne turned out to be a suitable
substrate (2n).
TfOH
temperature, gas chromatography (gc)
entry
[mol %]
solvent
t [°C]
yield [%]
b
1
100
100
100
100
100
100
100
200
100
100
DCE
DCE
80
80
80
80
80
80
50
50
50
50
35
45
66
2
3
4
5
6
7
8
CHCl3
toluene
DMF
CH3CN
CHCl3
CHCl3
CHCl3
CHCl3
35
n.r.
n.p.
71
53
78
c
9
d
e
10
86 (79)
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), TfOH, anhydrous
solvent (0.1 M), T: 6 h, N2. Air atmosphere. Substrate
concentration = 0.05 M. Substrate concentration = 0.02 M. Isolated
yield.
b
c
d
e
TfOH in DCE at 80 °C in air, after 6 h, a 35% yield of
disubstituted annulation product naphthalenyl triflates 2a was
obtained, accompanied by the formation of unidentified
oligomer (visible on TLC and monitored by GC-MS)
(Table 1, entry 1). This provided evidence that TfOH-
promoted 6-endo-dig annulation was viable. It was found that
the reaction afforded an improved yield when set up under N2
(Table 1, entry 2). We then investigated a range of solvents
using the benzodiyne 1a as a substrate at 80 °C. CHCl3 was
proved superior to toluene, DMF, and CH3CN (entries 3−6).
Further screening of temperature showed that 50 °C gave
better results, affording the product 2a in 71% yield (Table 1,
entry 7). Considering the tendency to polymerize at high
concentrations of benzodiynes, we speculated that the low
concentration of 1a (0.02 M) in CHCl3 was a key factor for
achieving the high yield of 2a (Table 1, entries 9 and 10).
Next, variations of the aromatic backbone of the benzodiyne
moiety induced by TfOH were evaluated. Under the standard
conditions, these benzodiynes were found to give the desired
naphthalenyl triflates products in moderate yields. All of the
tested substrates underwent selective annulation to afford the
single isomer, regardless of whether electron-withdrawing (2o,
2p, 2q) or electron-donating substituents (2r, 2s) were
present. Note that the electron-deficient group para to the
B
DOI: 10.1021/acs.orglett.9b01590
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Letter
with various classes of nucleophiles could be effected to yield a
variety of 1,3-disubstituted naphthalenes in excellent yields.
For example, 2a underwent well-established Kumada, Suzuki,
Stille, and Sonogashira cross-coupling reactions with nucleo-
philes such as CH3MgBr, 2-naphthaleneboronic acid, PhSn(n-
Bu)3, and 4-ethynyltoluene, providing the corresponding cross-
coupling products 4, 5, 6, and 7, respectively. The structure of
the product was assigned unambiguously by the authentic
compound 4 reported previously, which was prepared by
Kumada coupling of the resulting 2a with CH3MgBr.
Scheme 3. Scope of Compounds 1 for the TfOH-Mediated
Cyclization
a
Considering a palladium catalyst that was used for the
formation of the benzodiyne substrates might affect this
annulation reaction, the amount of palladium was performed
on the reaction furnished (by ICP-OES-based methods). The
results showed that the palladium content was <10−6 M.
Furthermore, when naphthalenyl triflates (1a, 1 equiv) was
treated with Pd(OAc)2 in CHCl3, the substrates were
remained after 12 h, and target annulation products were
only formed upon the addition of TfOH under the standard
conditions (Scheme 5, eq 1). The above results further
Scheme 5. Control Experiments
a
Reaction conditions (unless otherwise noted): 1 (0.2 mmol, 1.0
equiv), TfOH (0.2 mmol, 1.0 equiv), CHCl3 (10.0 mL). All reported
yields are isolated yields. Data have been taken from ref 17. bAt 80 °C.
internal alkyne gave a small amount of 1-Cl-3-aryl-naphthalene
byproduct (2p′).
Notably, this reaction was run on a gram scale; thus, 10
mmol of substrate 1a was treated with an equivalent amount of
TfOH in 60 mL of CHCl3, producing 1.96 g of 2a in 56%
yield. Subsequently, the obtained naphthalenyl triflate 2a was
selected as a model for synthetic application studies (Scheme
4). We gladly found that traditional cross-coupling reactions
suggested that the formation of naphthalenyl triflates was not
catalyzed by palladium. The following experiment results gave
tips for the mechanism.
When substrate 1t (1 equiv) was treated with TfOH (1
equiv) under the standard conditions, only trace product 2t
was obtained detected by GC-MASS, and the major product
was 2t′ instead (Scheme 5, eq 2). Moreover, CHCl3 was
replaced with benzene, which favored the formation of product
2a′ mainly (Scheme 5, eq 3). The above results could be
attributed to the nucleophilicity between the OTf anion and
solvent to match the electrophilicity of the generated
naphthalene cation.
Scheme 4. Late-Stage Diversification of Substrates 2a
On the basis of previous literature reports18 and our results,
a mechanism for the annulation of benzodiynes was proposed
in Scheme 6. First, the electron-rich triple bond of internal
alkyne 1 was activated with the electrophilic TfOH by
protonation to generate intermediate vinyl cation intermediate
I14b,19 and OTf anion, and the subsequent 6-endo-dig alkene-
alkyne intramolecular annulation of the proximate terminal
alkyne was initiated to provide the naphthalene cation
intermediate II, Finally, irreversible intermolecular nucleophilic
approaches of the generated OTf anion or solvent gave the
a
For reaction conditions, see the Supporting Information (Figure
S24).
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01590.
Experimental procedures, compound characterization
1
data, and the copies of H, 13C, and 19F NMR spectra
Chang, H.-K.; Lush, S.-F.; Liu, R.-S. J. Org. Chem. 2005, 70, 10482.
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(PDF)
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(e) Storch, J.; Bernard, M.; Sykora, J.; Karban, J.; Cermak, J. Eur. J.
Org. Chem. 2013, 2013, 260. (f) Taduri, B. P.; Ran, Y. F.; Huang, C.
W.; Liu, R. S. Org. Lett. 2006, 8, 883.
AUTHOR INFORMATION
■
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́ ́
̃
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Corresponding Author
*E-mail: chenchao01@mails.tsinghua.edu.cn.
ORCID
Chao Chen: 0000-0002-7644-0884
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by The National Key Research and
Development Program of China (No. 2016YFB0401400),
National Natural Science Foundation of China (Nos.
21871158 and 21672120), the Fok Ying Tong Education
Foundation of China (Grant No. 151014) and Department of
Education of Guangdong Province (No. 2016KCXTD005),
and Youth Foundation of Wuyi University (No. 2017td01).
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