3,4,5-Trimethylphenol and Lewis Acid Dual-Catalyzed Cascade Ring-Opening/Cyclization: Direct Synthesis of Naphthalenes

Article abstract of DOI:10.1021/acs.orglett.7b03392

A 3,4,5-trimethylphenol and Lewis acid dual-catalyzed cascade reaction of donor-acceptor (D-A) cyclopropanes via ring-opening and cyclization is developed. In this reaction, a phenolic compound was used as a covalent catalyst for the first time. Additiona

Full text of DOI:10.1021/acs.orglett.7b03392

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
3,4,5-Trimethylphenol and Lewis Acid Dual-Catalyzed Cascade Ring-
Opening/Cyclization: Direct Synthesis of Naphthalenes
He Ma, Xiu-Qin Hu,* Yong-Chun Luo, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, P. R. China
S
* Supporting Information
ABSTRACT: A 3,4,5-trimethylphenol and Lewis acid dual-
catalyzed cascade reaction of donor−acceptor (D−A) cyclo-
propanes via ring-opening and cyclization is developed. In this
reaction, a phenolic compound was used as a covalent catalyst
for the first time. Additionally, control experiments proved that
3,4,5-trimethylphenol completed the catalytic cycle by
accomplishing the C−C bond cleavage. Using this strategy, a
wide variety of substituted naphthalenes has been synthesized
from D−A cyclopropanes in moderate to high yields under
mild conditions.
Scheme 1. Reactions of D−A Cyclopropanes with Phenolic
onor−acceptor (D−A) cyclopropanes have become an
Compounds
D
important class of building blocks for the construction of
cyclic and noncyclic compounds.1 Because of their special
reactivities, ring-opening,2 cycloaddition,3 and rearrangement
reactions4 have been developed. Among them, the ring-opening
reactions of D−A cyclopropanes with carbon nucleophilies are
very useful in the development of cascade reactions for the
construction of carbocyclic skeletons. For example, the cascade
annulation reactions of D−A cyclopropanes with indoles5 and
silyl enol ethers6 were all developed on the basis of the
corresponding ring-opening reactions. In order to develop the
annulation reactions between D−A cyclopropanes and phenol
derivatives, we focused our attention on the Friedel−Crafts
reactions of D−A cyclopropanes with phenols first. In 2016,
Biju and co-workers reported a Lewis acid-catalyzed Friedel−
Crafts reaction of naphthol with D−A cycloprapanes which
furnished chain products with excellent yields (Scheme 1).7 In
2017, our group developed the [4 + 2]-annulation reaction of
D−A cyclopropanes with electron-rich phenols for the
preparation of dihydronaphthols and dihydronaphthalenes.8
Recently, we also discovered that 3,4,5-trimethylphenol could
act as a novel organocatalyst9 and form a cooperative catalytic
system to catalyze the rearrangement of D−A cyclopropanes.10
This cooperative catalytic system had two attractive features:
(a) 3,4,5-trimethylphenol completed the catalytic cycle by
accomplishing the C−C bond cleavage, and (b) a phenolic
compound was used as an organocatalyst for the first time.
The ring-opening intermediate A was common in most
research reports (Scheme 2),11 and the nucleophilic reagents
stay on the product molecules through the whole reaction
processes except the iodide. In a previous report, MgI2 acted as
a bifunctional catalyst in which the nucleophilic iodide formed a
C−I bond and was then released via an SN2 reaction (Scheme
2, i).12 In this work, we hypothesized that, after control
experiments, 3,4,5-trimethylphenol would fall off from the
intermediates through an elimination reaction and at the same
time accomplish the catalytic cycle (Scheme 2, ii).
The initial study began with the reaction of D−A
cyclopropane (1a) catalyzed by 3,4,5-trimethylphenol (2a)
and Sc(OTf)3 (1 mol %) in 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) at 0 °C, and the expected product 3a was successfully
produced in 85% yield (Table 1, entry 1). After the substituted
phenolic compounds were screened, 3,4,5-trimethylphenol 2a
was identified as the optimal organocatalyst for the reaction
(Table 1, entries 1−3). In the absence of 2a, 4,5-dihydrofuran13
4 isomer was produced, and no product 3a was generated from
the D−A cyclopropane (Table 1, entry 4). Several Lewis acids
Received: October 31, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Nucleophilic Reagents’ Catalytic Cycle
Scheme 3. Scope of the Synthesis of Naphthalenes
a
Table 1. Optimization of the Reaction Conditions
a
Unless otherwise noted, the reaction was conducted with 1 (0.2
mmol), 2a (0.04 mmol), and Hf(OTf)4 (0.5 mol %) in HFIP (2.0 mL)
in an ice−water bath, and the temperature of the system was then
b
allowed to rise spontaneously to room temperature. 60 mol % of 2a
was used. The reaction was conducted at 40 °C.
c
entry
Lewis acid
2
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
Sc(OTf)3 (1 mol %)
Sc(OTf)3 (1 mol %)
Sc(OTf)3 (1 mol %)
Sc(OTf)3 (1 mol %)
Sn(OTf)2 (1 mol %)
Hf(OTf)4 (1 mol %)
none
2a
2b
2c
8
48
48
48
8.5
10
48
7
85
complex
complex
0
noticeable influences on the reaction. In general, substrates
with an electron-donating methyl group gave good yields (3b−
d) (Scheme 3), and the substrate with a fused ring also worked
well (3e) (Scheme 3). However, the reaction did not occur for
the D−A cyclopropane with an electron-withdrawing sub-
stituent probably due to the lower nucleophilicity of the
substrate (3f) (Scheme 3). Methoxy group substituted D−A
cyclopropane gave the product only in 41% yield even when 60
mol % of the 3,4,5-trimethylphenol 2a was used, probably
because the high nucleophilicity of the substrate led to a more
complex reaction (3g) (Scheme 3). The reaction proceeded
smoothly to afford the product when substituent R2 was the
other alkyl group (3h) (Scheme 3). In addition, when R3 was
changed to long aliphatic chain, the desired product was also
obtained with satisfying yield (3i) (Scheme 3). Furthermore,
because of the steric and electronic influence of the phenyl
group, 1-phenylnaphthalene was not obtained (3j) (Scheme 3).
To gain more insight into the applicability of this reaction,
further investigation on the scope of benzylic substrates was
conducted, and it was found that the reaction temperature
needed to be raised to 40 °C to obtain good results. As
depicted in Scheme 3, reactions of different D−A cyclo-
propanes with the electron-withdrawing groups on the benzyl
group proceeded smoothly to furnish the products in 76−84%
yields (3l−n and 3r,s) (Scheme 3). However, lower yields were
obtained when the substituents of the benzyl group were
replaced with the electron-donating groups (3o−q,t,u)
(Scheme 3). In view of above situations from 3k to 3u, the
electron-rich effect of substituents on the benzyl group might
weaken the activity of the carbonyl and then reduce the rate of
the nucleophilic attack.
2a
2a
2a
2a
2a
2a
2a
2a
2a
81
87
NR
79
Hf(OTf)4 (2.5 mol %)
Hf(OTf)4 (0.5 mol %)
Hf(OTf)4 (0.5 mol %)
Hf(OTf)4 (0.5 mol %)
Hf(OTf)4 (0.5 mol %)
Hf(OTf)4 (0.5 mol %)
15
48
48
26
9
98
b
10
41
c
11
69
d
12
92
e
13
84
a
Unless otherwise noted, the reaction was conducted with 1a (0.2
mmol), 2 (0.04 mmol), and the Lewis acid in HFIP (2.0 mL) in an
ice−water bath, and the temperature of the system was then allowed to
rise spontaneously to room temperature. 10 mol % of 2a was used.
1.0 mL of HFIP was used. 4.0 mL of HFIP was used. The reaction
was conducted at room temperature.
b
c
d
e
were tested in the reaction, and Hf(OTf)4 was proved to be the
best cocatalyst with the product yield of 87% (Table 1, entries
5−6). In particular, the presence of a Lewis acid was also
proved to be necessary to activate the D−A cyclopropane
(Table 1, entry 7). Subsequently, adjusting the loading of
Hf(OTf)4 to 0.5 mol % gave the desired product 3a in 98%
yield, and the 3,4,5-trimethylphenol 2a could be completely
recycled (Table 1, entry 9). However, reducing the dosage of
3,4,5-trimethylphenol to 10 mol % had a negative impact on the
cascade reaction with a product yield of 41% (Table 1, entry
10). Further screening of the reaction temperature and the
reactant concentration (Table 1, entries 11−13) demonstrated
that reaction conditions of entry 9 were optimal.
In order to understand the reaction mechanism, we carried
out several control experiments with the intermediates
separated. Intermediate 4,5-dihydrofuran 4 and ring-opening
product 5 were separated from the mixture of the control
reaction after 2.5 h (Scheme 4, a). Then the reaction of the 4,5-
With the optimized conditions established, the scope of the
reaction was then investigated by using various D−A
cyclopropanes 1 with different electronic and steric properties
(Scheme 3). The electronic properties of substrates had
B
DOI: 10.1021/acs.orglett.7b03392
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Organic Letters
Letter
Scheme 4. Understanding the Reaction Course
dihydrofuran 4 catalyzed by 20 mol % of catalyst 2a and 1 mol
% of Sc(OTf)3 gave the final product 3a in an excellent yield of
99% after 6 h (Scheme 4, b). It was demonstrated that 4,5-
dihydrofuran 4 was not only the product of the intramolecular
cyclization of D−A cyclopropane 1a, but also a significant
intermediate to participate in the Friedel−Crafts alkylation.
Additionally, another ring-opening intermediate product 5 also
was obtained, and its structure was confirmed by X-ray
crystallography (Supporting Information). With Sc(OTf)3 as
the catalyst in HFIP, the intermediate 5 could provide
naphthalene 3a in a yield of 86% with recovery of 2a in a
yield of 71% after 3 h (Scheme 4, c). The experimental results
confirmed that 3,4,5-trimethylphenol 2a served as an organo-
catalyst in this cascade reaction. The final elimination step
involving C−C bond cleavage required the protonation of the
phenol ring to make it a leaving group by the strong acid HOTf
generated in situ. The control experiment in the presence of
2,6-ditertbutylpyridine could not produce any corresponding
cyclization product (Scheme 4, d), which proved the existence
and importance of HOTf. No reaction occurred even after 48 h
when dihydronaphthalene obtained in our previous work8 was
tested under the new conditions, which illustrated that 3,4,5-
trimethylphenol must act as the carbon nucleophile in the
beginning of the ring-opening reactions to realize catalysis.
On the basis of the experimental results, a plausible
mechanism for the dual-catalyzed reaction was proposed
(Figure 1). There are two pathways from D−A cyclopropane
1a to intermediate 5. In the first pathway, the Lewis acid in
HFIP induces the ring-opening reaction the cyclopropane,
affording zwitterionic intermediate I. The intramolecular
cyclization of intermediate I occurs to form 4,5-dihydrofuran
4. The intermolecular Friedel−Crafts reaction between 4,5-
dihydrofuran 4 or intermediate II with catalyst 2a yields the
ring-opening product 5. In the second pathway, the ring-
opening product 5 is directly synthesized by the Friedel−Crafts
reaction between D−A cyclopropanes 1a and catalyst 2a. Next,
elimination of one molecule of water after intramolecular
Friedel−Crafts reaction of the ring-opening product 5 gives the
dihydrogen naphthol 8.8 It should be noted that the high
acidity/strong hydrogen-bond-donating property of HFIP also
plays an important role in this process.14,15 Finally, the
elimination process with aromatization as one of the main
Figure 1. Plausible mechanism for the dual-catalyzed reaction.
driving forces affords the substituted naphthalene and 3,4,5-
trimethylphenol 2a to accomplish the catalytic cycle.
In conclusion, we developed a mild and efficient method to
synthesize substituted naphthalenes from D−A cyclopropanes
in moderate to high yields by using commercially available
3,4,5-trimethylphenol and a Lewis acid as dual cocatalysts.
Additionally, we proved that 3,4,5-trimethylphenol acted as a
covalent catalyst and could be recycled in the cascade reaction
through control experiments. Currently, applying the phenolic
organocatalyst to other synthetic systems is underway in our
laboratory.
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.7b03392.
Detailed experimental procedures, full spectroscopic data
for all new compounds, and X-ray data for 5 (PDF)
Accession Codes
CCDC 1547394 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: huxiuqin@lzu.edu.cn.
*E-mail: xupf@lzu.edu.cn.
ORCID
Yong-Chun Luo: 0000-0002-9567-7297
Peng-Fei Xu: 0000-0002-5746-758X
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b03392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
We are grateful to the NSFC (21632003, 21372105, and
21572087) and the “111” program from the MOE of P. R.
China for financial support.
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