Electrochemical Synthesis of 1-Naphthols by Intermolecular Annulation of Alkynes with 1,3-Dicarbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.9b04549

C-centered radical cyclization under electrochemical conditions is a feasible strategy for constructing cyclic structures. Reported herein is the electrochemical synthesis of highly functionalized 1-naphthols using alkynes and 1,3-dicarbonyl compounds by

Full text of DOI:10.1021/acs.orglett.9b04549

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Electrochemical Synthesis of 1‑Naphthols by Intermolecular
Annulation of Alkynes with 1,3-Dicarbonyl Compounds
Mu-Xue He, Zu-Yu Mo, Zi-Qiang Wang, Shi-Yan Cheng, Ren-Ren Xie, Hai-Tao Tang,*
and Ying-Ming Pan*
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical
Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China
*
S Supporting Information
ABSTRACT: C-centered radical cyclization under electro-
chemical conditions is a feasible strategy for constructing cyclic
structures. Reported herein is the electrochemical synthesis of
highly functionalized 1-naphthols using alkynes and 1,3-
dicarbonyl compounds by (4 + 2) annulation of C-centered
radical. Electrolysis was conducted with Cp Fe as redox
2
catalyst, thereby eliminating the use of oxidants and transition-
metal catalysts. The synthesized 1-naphthol compounds
showed good antitumor activity in vitro, and further studies
indicated that compound 3bl induced tumor cell apoptosis.
he development of new, efficient, and environmentally
inexpensive and environmentally friendly synthesis method is
an important endeavor.
T
friendly synthetic methods to construct polysubstituted
naphthalene compounds have been a topic of great research
interest because these backbone motifs are ubiquitous in
Carbon-centered radicals, which have numerous properties
and high reactivity, are attractive reaction intermediates in
organic synthesis. The efficient construction of C−C bond
cyclization reactions via the C-radical pathway has been
1
natural products and bioactive compounds. Highly substituted
1
-naphthols have a broad spectrum of biological activities, such
2 3 4
17
as V-ATPase inhibition and anticancer, anti-inflammatory,
studied. Electron transfer produces a C-centered radical from
5
6
7
8
antiviral, antimalarial, antiplatelet, and antibacterial proper-
ties (Figure 1). Although many methods to synthesize 1-
transition-metal catalysts, such as Pd(II) and Co(III). Addition
of stoichiometric oxidants [Ag(I), Cu(II), and X ] or
2
photocatalysts to the reaction can play a similar role (Scheme
14−16,18
1
a).
C-radical intermediates are more electrophilic than
neutral substrates. Subsequent nucleophilic attack and further
oxidation of these C-radicals lead to bioactive compounds.
Organic electrosynthesis is a convenient and environmentally
friendly synthetic tool that can employ electrons as reagents
Scheme 1. Different Methods To Generate and Cyclize C-
Radicals
Figure 1. Biological activity of 1-naphthol derivatives.
naphthol compounds have been reported, the strategies often
9
have several defects, including complex synthesis steps,
10
restricted reaction substrates, and use of transition-metal
catalysts such as Se, Pd, and Rh. Catalytic activation of
11
12
13
C−H bonds to form carbon radicals and synthesize 1-naphthol
14
15
16
compounds was developed by Yu, Narender, and Wang.
In these reports, however, the use of expensive noble metals,
stoichiometric oxidants, and transition-metal catalysts was
indicated as a common shortcoming. Therefore, developing an
Received: December 18, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
9
and generate radical intermediates. Xu’s group recently
reported the selective and efficient electrochemical intermo-
lecular C-radical reactions of 1,3-dicarbonyl compounds via a
phenothiazine-based redox catalyst using N-allyl amides as
four-atom donors reacted with dimethylmalonate to form
pyrrolidines via (4 + 1) annulation or with ketoesters to give
tetrahydropyridine derivatives via (4 + 2) annulation (Scheme
reaction time was shortened to 1 h after addition of 50 mol %
NaOEt, but more byproducts were formed and the desired
yield decreased (entry 10). The change in solvent had a
negative effect on product yield (entries 11−12). We also
tested the yield variation under different constant potential
conditions, and results showed that increases (entry 13) or
decreases (entry 14) in potential slightly reduced yield.
Under optimal conditions (Table 1, entry 1), acetyl benzene
and alkyne substrates were expanded and explored, respec-
tively. The scope of the electrochemical synthesis of 1-
naphthols was first explored by changing the substituents of
acetyl benzene substrate (Scheme 2). In the absence of
2
0
1
b). Intermolecular cyclization of 1,3-dicarbonyl compounds
under electrochemical conditions is rarely reported. Inspired
by previous works on C-radical reactions, we report herein the
electrochemical synthesis of highly functionalized 1-naphthols
using alkynes and 1,3-dicarbonyl compounds by (4 + 2)
annulation (Scheme 1c). The proposed reaction uses
inexpensive Cp Fe as a redox catalyst to produce H as the
a
2
2
Scheme 2. Substrate Scope of Acetyl Benzene
only theoretical byproduct.
Cyclization of ethyl benzoylacetate 1a and phenylacetylene
a was used as a model reaction to optimize the electrolysis
2
conditions (Table 1 and Table S1). The results of electrolysis
a
Table 1. Optimization of Reaction Conditions
b
entry
variation from standard conditions
none
no electricity
yield (%)
1
2
3
4
5
6
74
NR
22
36
trace
40
no Cp Fe
2
no NaOEt
reaction at rt
reaction at 80 °C
constant current: 10 mA
c
7
48
8
9
NH I (30 mol %) as base
trace
trace
32
27
trace
61
4
a
Na CO (30 mol %) as base
Reaction conditions: reticulated vitreous carbon (RVC) anode (100
2
3
PPI, 1 cm × 1 cm × 1.2 cm), Pt plate cathode (1 cm × 1 cm),
undivided cell, constant potential = 1.15 V vs Ag/AgCl, 1a (0.5 mmol,
1
mol %), Et NOTs (2.0 equiv), THF/EtOH = 1:1 (10 mL), 100 °C, 2
h. Isolated yields.
1
1
1
1
1
0
1
2
3
4
NaOEt (50 mol %) as base
EtOH as solvent
.0 equiv), 2a (0.75 mmol, 1.5 equiv), Cp Fe (10 mol %), NaOEt (30
2
CH CN as solvent
3
4
constant potential: 1.2 V vs Ag/AgCl
constant potential: 1.0 V vs Ag/AgCl
55
a
Reaction conditions: reticulated vitreous carbon (RVC) anode (100
PPI, 1 cm × 1 cm × 1.2 cm), Pt plate cathode (1 cm × 1 cm),
substitution, ethyl benzoylacetate 1a reacted with phenyl-
acetylene 2a gave a yield of 74%. Electron-donating (3ba−3ca)
or electron-withdrawing (3da−3fa) substituents at the para
position of the benzene ring were studied, and all groups
provided good yields. However, in general, electron-donating
groups had higher yields than electron-withdrawing groups due
to the stronger electron-donating ability of the former.
Monosubstitution of the phenyl ring at the ortho (3ia)
position produced the desired product in moderate yields. Two
easily separated isomers could be obtained from the methoxy
groups of disubstituted phenyl rings at a 3ga-1/3ga-2 ratio of
1:5. Moreover, compounds with low steric resistance (3ga-2)
produced higher yields, thereby showing that the reaction has
good regioselectivity. The meta-substituted compound 3ha
(2.5:1) could also give two isomers. The target product of
cyclization (3ja) was obtained by connecting other hetero-
cyclic rings to the benzene ring. We applied the proposed
method to the cyclization of benzoylacetone and benzoylace-
tonitrile with phenylacetylene and obtained products with
yields of 71% (3ka) and 47% (3la), respectively.
undivided cell, constant potential = 1.15 V vs Ag/AgCl, 1a (0.5 mmol,
1.0 equiv), 2a (0.75 mmol, 1.5 equiv), catalyst (10 mol %), base (30
mol %), electrolyte (2.0 equiv), THF/EtOH = 1:1 (10 mL), 100 °C,
−1
b
c
−1
2
h (5.3−1.2 F mol ). Isolated yields. 1.5 F mol . NR = no
reaction.
were optimal when the reaction was conducted in an undivided
cell in the presence of Cp Fe as a catalyst in THF/EtOH
2
mixed solvent at a constant potential of 1.15 V vs Ag/AgCl
with NaOEt (30 mol %) as a base (entry 1). Under these
conditions, the current and charge consumption decreased
−
1
from 35 to 8 mA (Figure S2) and from 5.3 to 1.2 F mol ,
respectively. A series of control experiments validated the
necessity of each reaction condition. The desired product 3aa
was not obtained without electricity (entry 2), whereas
reduced yield was obtained in the absence of Cp Fe (entry
2
3
) and NaOEt (entry 4). Reaction at rt (entry 5) or 80 °C
(
entry 6) led to a dramatic decrease in yield. When 1a and 2a
were reacted at a constant current of 10 mA (1.5 F mol ), the
−
1
yield decreased (entry 7). Other bases, such as NH I (entry 8)
In the above work, the p-methoxy-substituted ethyl
benzoylacetate reacted with an alkyne gave the best yield.
4
and Na CO (entry 9), were less effective than NaOEt. The
2
3
B
DOI: 10.1021/acs.orglett.9b04549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Therefore, this compound was reacted with various substituted
alkynes as a substrate to obtain highly substituted 1-naphthol
compounds (Scheme 3). First, para-, meta-, and ortho-
Scheme 4. Control Experiments
a
Scheme 3. Substrate Scope of Alkynes
The above experimental results indicate that radical
intermediates are involved in the electrochemical reaction
process. When Cp Fe was removed from the reaction, the
2
desired product 3aa could be obtained but with reduced yield
(
Scheme 4, eq d). In other words, direct electrolysis results in
lower yields than those produced by indirect electrolysis. Thus,
under the conditions of no catalyst, current and electrolyte, 3aa
was not detected in the reaction (Scheme 4, eq e). The above
reaction results indicate that 1,3-dicarbonyl compounds do not
undergo intermolecular cyclization with alkynes as a carbon
anion but reacts with alkynes after oxidation to form a carbon
radical intermediate.
Based on the above experiments and cyclic voltammetry
experiments (Figure S3), a possible mechanism of electro-
chemical intermolecular cyclization with 1a and 2a as
substrates is proposed (Scheme 5). Under electrochemical
conditions, ethanol undergoes a reduction reaction at the
a
Reaction conditions: reticulated vitreous carbon (RVC) anode (100
PPI, 1 cm × 1 cm × 1.2 cm), Pt plate cathode (1 cm × 1 cm),
undivided cell, constant potential = 1.15 V vs Ag/AgCl, 1a (0.5 mmol,
1
mol %), Et NOTs (2.0 equiv), THF/EtOH = 1:1 (10 mL), 100 °C, 2
h. Isolated yields.
.0 equiv), 2a (0.75 mmol, 1.5 equiv), Cp Fe (10 mol %), NaOEt (30
2
4
substitutions of phenylacetylene with electron-withdrawing
and electron-donating groups (3bb−3bh) resulted in a series
of target products with good yield (64−78%). We found that
electron-withdrawing groups were generally more productive
than electron-donating groups. 1-Acetylene naphthalene could
be used as a suitable substrate to react with 1,3-dicarbonyl
compounds to obtain moderate yields (3bi, 58%). Hetero-
cyclic substituted alkynes, such as 2-acetylene thiophene, could
also be reacted to generate the desired product (3bj).
However, chain and cyclic alkane-substituted alkynes gave
low yields (3bk, 3bl). Phenylpropionic acid and 1, 3-
dicarbonyl compound generated lactone compound (3bm)
under electrochemical conditions, and the yield of compound
cathode to produce an ethoxylated anion and H . Although the
2
oxidation potential between Cp Fe and substrate 1a shows a
2
Scheme 5. Proposed Mechanism
21
3
bm dropped sharply to 27%. Moreover, symmetrical ester-
substituted alkynes did not produce naphthol compound, but
21
an uncyclized dimer was synthesized (3bn).
Having established the scope of the method, control
experiments were performed to study the reaction mechanism
(
Scheme 4). Adding 2 equiv of TEMPO or BHT to the
optimal reaction system resulted in nondetection of 1-naphthol
compound 3aa (Scheme 4, eqs a and c), but products 4 and 5
were detected under TEMPO by using HRMS (Scheme 4, eq
a). Addition of 2 equiv of styrene allowed the synthesis of small
amounts of 3aa as well as products 6 and 7 (Scheme 4, eq b).
C
DOI: 10.1021/acs.orglett.9b04549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
wide gap and the reagents are difficult to react (Ep/2 = 1.27 and
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
0
.64 V vs Ag/AgCl for 1a and Cp Fe, respectively), the
oxidation potential of the conjugate base A of substrate 1a is
slightly lower than that of Cp Fe (E = 0.59 V vs Ag/AgCl for
2
2
p/2
A). Therefore, Cp Fe could oxidize intermediate A to conduct
a single-electron transfer (SET). In other words, the
ethoxylated anion reacts with the 1,3-dicarbonyl compound
2
AUTHOR INFORMATION
Corresponding Authors
■
*
*
1
a to form the carbanion intermediate A. Note that the
Email: httang@gxnu.edu.cn.
Email: panym@mailbox.gxnu.edu.cn.
ethoxylated anion in this reaction is derived from the cathodic
reduction of ethanol and addition of NaOEt to the system.
Meanwhile, at the anode, Cp Fe is oxidized to Cp Fe , which
+
ORCID
2
2
can be oxidized to intermediate A, generating a C-radical
intermediate B. Radical intermediate B reacts with alkyne 2a to
give intermediate C, which then undergoes intermolecular
cyclization to give intermediate D. According to the control
experiment results, the adducts of radical intermediates B (or
C) and TEMPO could be detected by HRMS, which proves
that intermediates B and C are produced in the reaction
process. Finally, intermediate E is obtained by oxidation, and
Hai-Tao Tang: 0000-0001-7531-0458
Ying-Ming Pan: 0000-0002-3625-7647
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
21861006), Guangxi Natural Science Foundation of China
2016GXNSFEA380001, 2018GXNSFBA281151), Guangxi
■
(
(
1
-naphthol compound 3aa is obtained by removal of the
proton. The removed proton can combine with the ethoxylated
anion to complete the reaction cycle.
Key R&D Program (No. AB18221005), Science and
Technology Major Project of Guangxi (AA17204058-21),
Guangxi science and technology base and special talents (guike
AD19110027), College Students Innovation and Entrepre-
neurship Training Program (201910602131), and State Key
Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources (CMEMR2019-A03) for financial sup-
port.
As described above, 1-naphthol compounds have antiviral,
antibacterial, antitumor, and other biological activities. Here,
the in vitro cytotoxicities of compounds 3aa-3la and 3bb-3bn
against four cancer cell lines, namely Hela, T-24, HepG-2, and
MGC-803, and one human normal cell line, namely WI-38,
were screened by using MTT assay with 5-FU as the positive
control. As shown in Table S8, compound 3bl shows a
favorable antitumor activity against the T-24 cell line with an
IC value of 9 ± 1 μM. Moreover, the IC value of compound
5
0
50
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(
E
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Org. Lett. XXXX, XXX, XXX−XXX