Formal [4?+?4] cycloaddition of 3-arylcyclobutanones with anthracene and their acid-promoted intramolecular cyclization with skeletal rearrangement

Article abstract of DOI:10.1016/j.tetlet.2019.07.001

A reaction of 3-arylcyclobutanones with anthracene in the presence of TiCl₄ gave 14-aryl-9,10-dihydro-9,10-butanoanthracen-12-ones as a formal [4 + 4] cycloadduct of anthracenes with a C4 unit formed by cleaving the more substituted C2–C3 bond of cyclobutanones. On the other hand, activation of 3-arylcyclobutanones with TfOH in the absence of nucleophiles gave 2-tetralones with skeletal rearrangement.

Full text of DOI:10.1016/j.tetlet.2019.07.001

Accepted Manuscript
Formal [4+4] cycloaddition of 3-arylcyclobutanones with anthracene and their
acid-promoted intramolecular cyclization with skeletal rearrangement
Mayu Kanie, Yuya Ikawa, Tomoyuki Yoshimura, Jun-ichi Matsuo
PII:
S0040-4039(19)30640-9
https://doi.org/10.1016/j.tetlet.2019.07.001
TETL 50910
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 May 2019
29 June 2019
2 July 2019
Please cite this article as: Kanie, M., Ikawa, Y., Yoshimura, T., Matsuo, J-i., Formal [4+4] cycloaddition of 3-
arylcyclobutanones with anthracene and their acid-promoted intramolecular cyclization with skeletal rearrangement,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.07.001
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Formal [4+4] cycloaddition of 3-
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arylcyclobutanones with anthracene and
their acid-promoted intramolecular
cyclization with skeletal rearrangement
Mayu Kanie, Yuya Ikawa, Tomoyuki Yoshimura, Jun-ichi Matsuo*
O
X
R1
R2
TiCl4
anthracene
R1
O
~69%
R2
R1
R2
O
TfOH
~75%
X
X

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Formal [4+4] cycloaddition of 3-arylcyclobutanones with anthracene and their acid-
promoted intramolecular cyclization with skeletal rearrangement
Mayu Kanie, Yuya Ikawa, Tomoyuki Yoshimura, and Jun-ichi Matsuo*
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A reaction of 3-arylcyclobutanones with anthracene in the presence of TiCl4 gave 14-aryl-9,10-
dihydro-9,10-butanoanthracen-12-ones as a formal [4+4] cycloadduct of anthracenes with a C4
unit formed by cleaving the more substituted C2-C3 bond of cyclobutanones. On the other
hand, activation of 3-arylcyclobutanones with TfOH in the absence of nucleophiles gave 2-
tetralones with skeletal rearrangement.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
cyclobutanone
anthracene
Lewis acid
[4+4] cycloaddition
LA
Cyclobutanones have been used as a useful building block in
organic chemistry particularly by utilizing facile ring cleavage of
their four-membered rings.1 Recently, 3-arylcyclobutanones 1
were activated with a Lewis acid to from a zwitterionic
R1
R1
O
R2
O
LA
R2
Ar
1
Ar
2
intermediate
2 by cleaving the more substituted C2-C3
cyclobutanone bond (Scheme 1).2,3 The zwitterionic intermediate
2 reacted with various arenes to give Friedel-Crafts adducts2and
reacted with nitriles to give the corresponding [4+2] adducts.3
During our investigation on the above-mentioned Friedel-Crafts
reaction, we found that Friedel-Crafts reaction of 3-
arylcyclobutanones 1 to anthracene did not occur and formal
Scheme 1. Activation of 1 to a zwitterionic intermediate 2.
O
R1
R2
R1
Ar
O
R2
LA
[4+4] cycloadducts
3
were obtained (Scheme 2).
The
+
photochemical dimerization of anthracenes4 and photochemical
cycloaddition of dienes5 have been reported as suprafacial
[4π+4π] photocycloaddition.6 Except for photochemical
cycloaddition, there have been no reports about formal [4+4]
cycloaddition to anthracenes.7
Ar
1
3
Scheme 2. Formal [4+4] cycloaddition
R1
Moreover, during the optimization of the reaction conditions
for the [4+4] cycloaddition of 1 and anthracene, activation of 3-
arylcyclobutanones 1 with TfOH was found to give 2-tetralones 4
by cycloisomerization with skeletal rearrangement (Scheme 3).
In the literature, cyclization of 2-arylcyclobutanones to 2-
tetralones and 2-naphthols was reported.8 However,
isomerization of 3-arylcyclobutanones to 2-tetralones has not
been reported. We describe here details of these two new
reactions of 3-arylcyclobutanones 1.
R1
R2
O
O
R2
H+
X
1
4
X
Scheme 3. Cycloisomerization
First, suitable reaction conditions for the formal [4+4]
cycloaddition reaction of cyclobutanone 1 and anthracene were
screened (Table 1).
A solution of cyclobutanone 1a in
dichloromethane was added to a mixture of an equimolar amount
of anthracene and 1.1 equivalent of TiCl4 at –40 °C, and then the
reaction temperature was allowed to rise to room temperature.

2
Tetrahedron
Under these reaction conditions, cyclobutanone 1a was
less efficiently than that with 2,2-dimethylcyclobutanone 1a
probably due to their steric hindrance (entries 1 and 2).
Spirocyclobutanones 1d-f having five-, six-, and seven-
membered rings reacted with anthracene to afford the
corresponding cycloadducts 3d-f in good to moderate yields
(entries 3-5). The present cycloaddition was greatly influenced
by substitution patterns at the 2-position of cyclobutanones: 2-
monoalkyl substitution and 2-nonsubstitution resulted in low
yields of cycloadducts (entries 6-8). It was noted that trans-2-
methoxycyclobutanone 1h gave 3h in 24% yield as a single
diastereomer and the stereochemistry of 3h was determined by
completely consumed, and a formal [4+4] adduct 3a was
obtained in 69% yield by purification with silica gel preparative
TLC (entry 1). The structure of 3a was confirmed by X-ray
crystallography.9 The order of addition was important for
effective cycloaddition between 1a and anthracene: addition of
TiCl4 to a mixture of 1a and anthracene at –40 °C and then
raising the reaction temperature to rt for 1 h gave 3a in a lower
yield (35%) along with many byproducts which were difficult to
be isolated. Activation of 1a with other Lewis acids such as
AlCl3, SnCl4, SiCl4, and Me3SiOTf was found to be less effective
compared with TiCl4 (entries 2-5). Effects of Lewis acids
including BF3•OEt2 and EtAlCl2 were not studied in the reaction
of 1a with anthracene since we knew that ring cleavage of 1a
with BF3•OEt2 or EtAlCl2 did not proceed at rt.2,3 Interestingly,
a reaction of 1a with anthracene in the presence of five
equivalents of TfOH at –40 °C to rt for 1 h gave a formal [4+4]
adduct 3a in 36% yield along with 2-tetralone derivative 4a in
32% yield (entry 6). This result suggested that the carbon
skeleton of 1a rearranged during the formation of 4a from 1a.
Solvents which can be used in this reaction were limited because
Friedel-Crafts reaction of aromatics2 and formal [4+2]
cycloaddition with nitriles3 proceeded when aromatics and
nitriles were used as a solvent. Then, effects of solvents were
investigated by using CS2, nitromethane, and 1,2-dichloroethane
(DCE). It was found that these solvents were less effective
compared with dichloromethane (entries 7-9). Therefore, optimal
Lewis acid and solvent were TiCl4 and dichloromethane.
X-ray crystallography (entry 7).9
Reactions of 3-
arycyclobutanones 1j-l having methyl, methoxy, and bromo
groups on the para-position of the 3-aryl group proceeded in 30-
47% yields (entries 9-11). Apparent differences in reactivities of
these three cyclobutanones 1j-l were not observed.
Table 2 Formal [4+4] cycloaddition of 3-arylcyclobutanones 1b-
l and anthracene.a
O
X
R1
R2
R1
O
H
R2
TiCl4
+
CH2Cl2
–40 °C to rt, 1 h
3b-l
1b-l
X
entry
1
R1
R2
Et
X
3
yield (%)b
42
Et
H
3b
3c
3d
3e
3f
3g
3h
3i
2
Bn
Bn
H
26
Table 1. Effects of Lewis acids for formal [4+4] cycloaddition
of 1a and anthracene.a
3
-(CH2)4-
H
60
4
-(CH2)5-
-(CH2)6-
H
47
5
H
48
O
6
H
Me
OMe
H
H
trace
24c
7
H
H
Ph
O
O
Lewis acid
8
H
H
trace
30
+
9
Me
Me
Me
Me
Me
Me
Me
OMe
Br
3j
CH2Cl2
–40 °C to rt, 1 h
Ph
1a
3a
4a
10
11
3k
3l
47
37
aCyclobutanone 1 (1 equiv), anthracene (1 equiv), and TiCl4 (1.1 equiv) were
used. bIsolated yield.
cCompound 3h was a single diastereomer. Compound 1h was a single trans-
isomer.
entry
Lewis acid
TiCl4
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CS2
69
34
3
NRc
<2
36e
22
56
21
Besides anthracene, we tested a reaction of 1a with 9,10-
dimethylanthracene (Scheme 4). However, the desired [4+4]
product 3m was not formed but a Friedel-Crafts adduct 5 was
isolated in 12% yield.10 Steric hindrance of the methyl group of
9,10-dimethylanthracene caused Friedel-Crafts alkylation with 1a
at sterically less hindered position to give 5.
AlCl3
SnCl4
SiCl4
Me3SiOTf
TfOHd
TiCl4
TiCl4
MeNO2
DCE
TiCl4
aCyclobutanone 1a (1 equiv), anthracene (1 equiv), and Lewis acid (1.1
Scheme 4. A TiCl4-promoted reaction of 1a with 9,10-
dimethylanthracene.
equiv) were used.
bIsolated yield.
cNo reaction.
dFive equivalents of TfOH were used.
eCompound 4a was obtained in 32% yield.
The scope and limitations of the present formal [4+4]
cycloaddition
were
studied
by
using
various
3-
arylcyclobutanones 1b-l (Table 2). Cycloaddition of 2,2-diethyl-
and 2,2-dibenzylcyclobutanones 1b,c with anthracene proceeded

3
Ph
O
along with enone 7l that was formed by skeletal rearrangement
O
in less than 25% yield (entry 7).
TiCl4
+
CH2Cl2
–40 °C to rt, 1 h
Table 4. TfOH-promoted cycloisomerization of 3-
arylcyclobutanones 1 to 4.a
Ph
1a
5
12%
R1
R1
R2
O
O
O
R2
TfOH
Ph
DCM
rt, 1 h
X
1
4
X
O
Br
O
3m (0%)
6k
7l
MeO
As described above, activation of 1a with TfOH in the
entry
R1
Et
R2
Et
X
4
yield (%)b
presence of anthracene gave 2-tetralone derivative11 4a as well as
a formal [4+4] adduct 3a (Table 1, entry 6). Reaction conditions
for isomerization of 1a to 4a were screened in the absence of
anthracene (Table 3). It was found that treatment of 1a with an
equimolar amount of TfOH in refluxing DCE gave a 2-tetralone
derivative 4a in 35% yield (entry 1).12 A stoichiometric amount
of TiCl4, a catalytic amount of Sc(OTf)3, and excess TFA were
used instead of TfOH, but these reagents did not effectively
promote the conversion of 1a to 4a (entries 2-4). Activation of
1a with a stoichiometric amount of TiCl4 did not give 4a but
afforded enone 6a in 10% yield (entry 2). The rearrangement of
1a to 4a took place at room temperature by using three
equivalents of TfOH (entry 5) and the use of five equivalents of
TfOH gave 4a in 75% yield (entry 6). The catalysis of Tf2NH
was less effective compared with TfOH (entry 7).
1
2
3
4
5
6
7
H
4b
4d
4e
4g
4j
72
-(CH2)4-
-(CH2)5-
H
45
H
57
Me
Me
Me
Me
H
H
mixture
66
0c
Me
Me
Me
Me
OMe
Br
4k
4l
51d
aTfOH (5 equiv) was used.
bIsolated yield.
cCompound 6k was obtained in 79% yield.
dCompound 7l was obtained in less than 25% yield.
To obtain mechanistic information on the present
cycloisomerization, enone 7a, a simplified structure of 7l that
was obtained as a byproduct (Table 4, entry 7), was treated with
five equivalents of TfOH at room temperature (Scheme 5).
However, it was found that cyclization of 7a to 4a did not
proceed.13 This result suggested that the present
cycloisomerization of 1a to 4a with TfOH did not procced via
enone 7a.14
Table 3. Optimization of reaction conditions for cyclization of 1a
with skeletal rearrangement to 4a.
O
O
O
acid
solvent
Ph
6a
1a
4a
entry
acid (equiv)
solvent
DCE
conditions
yield (%)a
O
O
TfOH
(5 equiv)
1
2
3
4
5
6
7
rt to reflux, 3 h
rt to reflux, 3 h
reflux, 4 h
35
0b
TfOH (1.0)
TiCl4 (1.0)
Sc(OTf)3 (0.2)
TFA (50)
DCE
CH2Cl2
rt, 1 h
DCE
trace
7
7a
4a
none
DCM
DCM
DCM
reflux, 4 h
rt, 75 min
31
75
40c
TfOH (3.0)
TfOH (5.0)
Tf2NH (5.0)
Scheme 5. Attempted cyclization of 7a to 4a with TfOH
rt, 75 min
rt, 75 min
aIsolated yield.
bCompound 6a was obtained in 10% yield.
cDetermined by 1H NMR analysis by using an internal standard.
A
proposed mechanism for the TfOH-promoted
cycloisomerization of cyclobutanones 1 to 2-tetralone 4 is shown
in Scheme 6. Cyclobutyl cation 8, which is formed by
protonation of 1, is rearranged to 10. Carbon-carbon bond
cleavage of 10 proceeds to give cyclopropylcarbinyl cation 11,
and isomerization occurs to form homoallyl cation 12.15
Cyclization of the aryl group of 12 or 13 proceeds to give 4a.16
The
generality
of
the
present
TfOH-promoted
cycloisomerization was studied by using various 3-
arylcyclobutanones 1 (Table 4). 2,2-Diethylcyclobutanone 1b
and spirocyclobutanones 1d,e were isomerized smoothly to the
corresponding 2-tetralone derivatives 4b,d,e (entries 1-3).
Treatment of 2-monomethylcyclobutanone 1g with TfOH gave a
complex mixture of products, though the disappearance of 1g
was checked by TLC analysis (entry 4). p-Methoxy substitution
on the 3-aryl group resulted in the formation of undesired enone
6k in 79% yield (entry 6). A cyclobutanone 1l bearing a p-
bromophenyl group gave the desired product 4l in 51% yield

4
Tetrahedron
12. Possibility that 4a was 3,3-dimethyl-2-tetralone was ruled out
since its spectral data were different: Henrion, G.; Chavas, T. E.
J.; Le Goff, X.; Gagosz, F. Angew. Chem., Int. Ed. 2013, 52, 6277.
13. It has been reported that cyclization of 7a with AlCl3 gave 4a in
78% yield: Colonge, J.; Chambion, J. Bull. Soc. Chim. Fr. 1947,
1002.
HO
O
HO
HO
Ar
HO
H
=
Ar
Ar
Ar
Ar
O
1
8
9
10
Ar = 4-X-C6H4
14. In addition, 2-tetralones 4 were not detected in the aforementioned
formal [4+4] cycloaddition of cyclobutanones 1 with anthracene
when TiCl4 was used as a Lewis acid (Tables 1 and 2).
15. Saunders, M.; Laidig, K. E.; Wiberg, K. B.; Schleyer, P. v. R. J.
Am. Chem. Soc. 1988, 110, 7652.
HO
Ar
HO
Ar
O
X
X
16. It was thought that compound 6k was formed via an intermediate
9 and compound 7l was formed via 12 or 13.
11
12
13
4
Scheme 6. Proposed reaction mechanism from 1 to 4
In conclusion, we have developed two reactions of 3-
arylcyclobutanones: (1) TiCl4-catalyzed formal [4+4]
cycloaddition with anthracene and (2) TfOH-promoted
cycloisomerization to 2-tetralones with skeletal rearrangement.
These two reactions will broaden the synthetic utility of 3-
arylcyclobutanones.
Supplementary Material
Supplementary data associated this article can be found in the
online version at_.
• Lewis acid-catalyzed formal [4+4] cycloaddition
of 3-arylcyclobutanones and anthracene.
• TfOH-mediated cycloisomerization of 3-
arylcyclobutanones to 2-tetralones with skeletal
rearrangement.
Acknowledgments
This work was supported by Kanazawa University
SAKIGAKE project.
• A proposed reaction mechanism for the
cycloisomerization.
References and notes
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Formal [4+3] cycloaddition was reported: Ivanova, O. A.;
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V. Eur. J. Org. Chem. 2008, 5329.
6.
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(a) Huisgen, R.; Feiler, L. A.; Otto, P. Chem. Ber. 1969, 102,
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9.
CCDC1900307 (compound 3a) and CCDC 1936724 (compound
3h) contain the supplementary crystallographic data for this paper.
The data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.uk/getstructures.
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Croisy-Delcey, M.; Jacquignon, P. Can. J. Chem. 1976, 54, 1777.
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