TFA-Catalyzed [3+2] Spiroannulation of Cyclobutanols: A Route to Spiro[cyclobuta[a]indene-7,1′-cyclobutane] Skeletons

Article abstract of DOI:10.1002/asia.202001048

A straightforward method for the synthesis of spiro[cyclobuta[a]indene-7,1′-cyclobutane] derivatives from cyclobutanols has been developed via one-pot [3+2] spiroannulation. A series of new spiro[cyclobuta[a]indene-7,1′-cyclobutane] derivatives are facile

Full text of DOI:10.1002/asia.202001048

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: TFA-Catalyzed [3 + 2] Spiroannulation of Cyclobutanols: a Route
to Spiro[cyclobuta[a]indene-7,1'-cyclobutane] Skeletons
Authors: Zhenyu An, Yafeng Liu, Yanwei Sun, and RuLong Yan
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Chemistry - An Asian Journal
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TFA-Catalyzed [3 + 2] Spiroannulation of Cyclobutanols: a Route
to Spiro[cyclobuta[a]indene-7,1'-cyclobutane] Skeletons
Zhenyu An,[a] Yafeng Liu,[b] Yanwei Sun,[c] and Rulong Yan[a]*
Dedication
[a]
Z. An, and Prof. Dr. R. Yan
State Key Laboratory of Applied Organic Chemistry, Key laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, College
of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China. E-mail: yanrl@lzu.edu.cn
[b]
[c]
Y. Liu
Chemical Science and Engineering College, North Minzu University, Yinchuan 750000, China.
Y. Sun
Research Institute of Exploration & Development, Tuha Oilfield Company, Xinjiang 830000, China.
Supporting information for this article is given via a link at the end of the document.
Abstract:
spiro[cyclobuta[a]indene-7,1'-cyclobutane]
cyclobutanols has been developed via one-pot [3
spiroannulation. series of new spiro[cyclobuta[a]indene-7,1'-
A
straightforward method for the synthesis of
derivatives from
2]
+
A
cyclobutane] derivatives are facilely synthesized in good yields
under mild reaction conditions.
Spirocyclic skeletons are treated as a topic of interest for
synthetic chemists because of their widespread occurrence in
natural products and pharmacologically active molecules.1
Especially, all-carbon spirocyclic compounds involving
spiroindene scaffolds serve as very useful building blocks in
organic syntheses,2 which exhibit broad biological activities such
as inhibitory activity of UPP synthase3 and calf DNA
polymerase.4 High synthetic value of spiroindene scaffolds
prompts chemists to develop more efficient and simple synthetic
methods to broaden the synthetic scope and scalability.5 In 2015,
Sasai accomplished the synthesis of spirocyclic ketones through
the Pd-catalyzed intramolecular α-arylation of α-substituted
cyclic ketones.6 Subsequently, Luan described intermolecular
sprioannulation reactions to synthesize spiro[cyclohexane-1,1’-
Scheme 1. Reactions of cyclobutanols.
functionalization, and there is very less research on cyclobutanol
to construct spirocyclic scaffold. Herein, we disclosed a method
to
synthesize
spiro[cyclobuta[a]indene-7,1'-cyclobutane]
derivatives from cyclobutanols through intermolecular Friedel-
Crafts reaction under mild conditions.13
indene]-2,5-dien-4-ones
polycyclic molecules containing spiroindene skeletons.7 Recently,
Yao established novel three-component spiroannulation
and
spiro[4,5]decane-embedded
HFIP is a kind of unique solvent owing to its high ionization
power, strong hydrogen bond ability, low nucleophilicity and mild
acidic character.14 So we started our investigation from the
reaction of 1-phenylcyclobutanol (1a) using HFIP as solvent in
the presence of TFA at 60 °C under argon atmosphere. To our
delight, the desired product 2a was obtained in 90% yield (Table
1, entry 1). Then, several Lewis acids and Brønsted acids, such
as BF3·OEt2, FeCl3, (CF3CO)2O, AcOH, and TfOH, were tested
and TFA (10 mol %) showed higher catalytic efficiency for this
process (Table 1, entries 2-6). Further screening on solvents
indicated that HFIP was the most effective (Table 1, entries
7−11). When the reaction was carried out at room temperature,
the yield of 2a was improved to 95% with excellent
diastereoselectivity (dr > 20:1), favouring the cis diastereomer
(Table 1, entry 12). However, increasing the reaction
temperature to 100 ˚C resulted in a lower yield (Table 1, entry
13). Furthermore, it was found that lower yield was obtained
under air conditions (Table 1, entry 14). Finally, strong acid HCl
and H2SO4 were also examined as catalyst, affording 2a in 30%
and 40% yields, respectively (Table 1, entries 15-16). So the
optimized reaction system was established as Table 1, entry 12.
a
reaction to construct spiro[4.5]deca-6,9-dien-8-ones under mild
reaction conditions.8 Although several synthetic methodologies
have been developed to access these all-carbon spirocyclic
compounds, new methods for the efficient construction of such
types of skeletons are still desirable.
Cycloalkanols are important and versatile compounds, which
have been found widespread applications in organic synthesis.9
Recently, cyclobutanols are frequently employed as privileged
building blocks for the construction of carbonyl compounds.10
Particularly, Zhu and co-workers reported
a
variety of
approaches to synthesize functionalized ketones through ring-
opening/cross-coupling reactions in recent years, which open up
a new vista for the synthesis of distally functionalized ketones
(Scheme 1A).11 What’s more, Zhu’s group also reported a silver-
catalyzed ring-opening reaction for the synthesis of 1-tetralones
(Scheme 1B).12 To the best of our knowledge, most of reports
about cyclobutanols are focused on ring-opening
1
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10.1002/asia.202001048
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Table 2. Scope of substituted 1-phenylcyclobutanols. [a]
[a]
Table 1. Optimization of the reaction conditions.
Temp.
(°C)
[b]
Entry
Catalyst
Solvent
Yield (%)
1
2
TFA
FeCl3
BF3·OEt2
(CF3CO)2O
CH3COOH
TfOH
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
CH3CN
THF
60
60
60
60
60
60
60
60
60
60
60
rt
90
75
55
49
41
71
0
3
4
5
6
7
TFA
8
TFA
0
9
TFA
DMSO
CH3NO2
TFE
0
10
11
12
13
TFA
34
65
95
70
89
30
40
TFA
TFA
HFIP
HFIP
HFIP
HFIP
HFIP
TFA
100
rt
[c]
14
TFA
15
16
HCl
rt
H2SO4
rt
[a] Reaction conditions: 1a (0.30 mmol), catalyst (10 mol %), solvent (2
mL) for 8 h. [b] Yields of isolated products. [c] under air condition. TFA =
trifluoroacetic acid. HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol, TfOH =
trifluoromethanesulfonic acid, TFE = 2,2,2-trifluoroethanol. Entry in bold
highlights optimized reaction conditions, and the reaction time was
monitored by TLC.
With the optimized reaction conditions in hand, we first
examined the scope of 1-phenylcyclobutanols and the results
are summarized in Table 2. A number of substrates 1 bearing
different groups underwent the transformation to afford
corresponding cyclization products
2 in good yields with
excellent diastereoselectivity (dr > 20:1). Substrates 1 with
electron-donating groups such as methyl, ethyl, tert-butyl, n-
pentyl, methoxy, and ethoxy at the para-position of phenyl ring
smoothly proceeded to give the expected products 2b, 2f-2j in
excellent yields. Substrates 1c and 1d with ortho-methyl group
were also investigated, and products 2c and 2d were furnished
in 45% and 68% yields, respectively. These results suggested
that the steric hindrance played obvious effect on this reaction.
[a] Reaction conditions: 1 (0.30 mmol), TFA (10 mol %) in HFIP (2 mL)
1
at rt under Ar for 8 h. Value of d.r. was determined by H NMR of crude
reaction mixtures.
Notably,
3,5-dimethyl
and
3,5-dimethoxy
substituted
phenylcyclobutanols were tolerated well, giving products 2e
(confirmed by X-ray crystallography) and 2k in excellent yields.
In addition, substrates 1l-1n were also suitable for the optimal
conditions, and corresponding products 2l-2n were obtained in
good yields. On the other hand, the reaction of substrate 1o with
3,5-difluoro groups provided product 2o in 42% yield. We also
tried substrates 1p with Cl, Br, or CF3 at para-position of the
phenyl ring and only trace amounts of desired products were
detected. These results indicate that the electronic effect of
electron-withdrawing groups is critical for this transformation.
When we switched to challenging cyclobutanols 1q and 1r, the
desried products were generated with good yields. Remarkably,
Scheme 2. Reactions of 1-(4-(tert-butyl)phenyl)cyclobutanol 1g and 1-(4-
fluorophenyl)cyclobutanol 1p.
heteroaryl cyclobutanol 1s gave the product 2s in 78% yield.
Unfortunately, the method could not be extended to thienyl and
2
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10.1002/asia.202001048
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furyl substituted cyclobutanols, and no desired products were
observed.
benzene ring to produce the intermediate 6, which releases
proton to form the product 2a at the same time.
We also turned our attention to the reaction of two different
cyclobutanols. As shown in Scheme 2, 1-(4-(tert-
Based on the structure of cyclobutane skeleton, the
compound 2a could be used as liquid rocket propellant. In order
to certify the speculation, we compared the total energies of 2a
and 1,1-dimethylhydrazine through quantum mechanical
calculations, which were performed using the Gaussian 09 suite
of programs at the M062X/6-31+g(d,p) level of theory.16 The
results in Table 3 show that the absolute value of the total
energy of 2a is even higher than 1,1-dimethylhydrazine,
indicating that compound 2a possesses potential value to be
used as liquid rocket propellant.
butyl)phenyl)cyclobutanol
1g
reacted
with
1-(4-
fluorophenyl)cyclobutanol 1p, furnishing two different products
2g and 2gp at the ratio of 1.2 : 1, which are detected by GC-MS
analysis (see the Supporting Information).
Table 3. Calculated total energies of 2a and 1,1-dimethylhydrazine.
Molecule
E (a.u.)
E (kcal/mol)
|E| (kcal/mol)
2a
-773.8398
-485592.2129
485592.2129
1,1-
-190.3982
-119476.7745
119476.7745
dimethylhydrazine
In summary, we have developed a TFA-catalyzed [3 + 2]
spiroannulation reaction of cycloalkanols for the synthesis of
spiro[cyclobuta[a]indene-7,1'-cyclobutane] derivatives through
Friedel-Crafts pathway. This transformation proceeds under mild
conditions and a series of all-carbon spirocyclic compounds are
obtained in moderate to good yields.
Scheme 3. Control experiments.
Acknowledgements
In order to obtain further insights into this reaction, several
control experiments were carried out in Scheme 3. Initially, the
reactions weren’t significantly inhibited when 2.0 equiv of
TEMPO or BHT were used, which demonstrated that this
transformation might rule out a radical pathway. In addition, the
product 3 was isolated in 25% yield under standard reaction
conditions for 1 h. Then compound 3 was subjected to the
optimized conditions for 2 h, and the desired product 2a was
afforded in 97% yield, which proved that compound 3 was the
intermediate for this transformation.
This work was supported by National Natural Science
Foundation of China (21672086).
Keywords: cyclobutanols • spiroannulation • Friedel-Crafts
reaction
• spiro[cyclobuta[a]indene-7,1'-cyclobutane] • mild
conditions
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4
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Entry for the Table of Contents
TFA-catalyzed [3 + 2] spiroannulation of cyclobutanols has been achieved through Friedel-Crafts pathway. This transformation
proceeds well under mild conditions, affording a series of spiro[cyclobuta[a]indene-7,1'-cyclobutane] derivatives in good yields.
5
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