Hydrogenolysis of 1-alkoxybenzocyclobutenes with site-selective cleavage of the sterically hindered C(sp2)-C(sp3) bond

Article abstract of DOI:10.1246/cl.150719

1-Alkoxybenzocyclobutenes undergo ring-opening hydrogenolysis with site-selective cleavage of the sterically hindered C(sp²)-C(sp³) bond on Pd/C.

Full text of DOI:10.1246/cl.150719

Received: July 30, 2015 | Accepted: August 17, 2015 | Web Released: August 21, 2015
CL-150719
Hydrogenolysis of 1-Alkoxybenzocyclobutenes with Site-selective Cleavage
of the Sterically Hindered C(sp2)-C(sp3) Bond
Shota Sawano, Naoki Ishida, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510
(E-mail: murakami@sbchem.kyoto-u.ac.jp)
1-Alkoxybenzocyclobutenes undergo ring-opening hydro-
genolysis with site-selective cleavage of the sterically hindered
C(sp2)-C(sp3) bond on Pd/C.
The selective hydrogenolysis of the C(sp2)-C(sp3) bond of
1-alkoxybenzocyclobutenes was effected when methoxybenzo-
cyclobutene 1a was treated with an atmospheric pressure of
dihydrogen gas in the presence of a catalytic amount of Pd/C
(10 wt %, 5 mol % Pd)12,13 and molecular sieves (MS) 4A14 in
dichloromethane at room temperature (eq 1). The sterically
congested bond between the benzene carbon and the tertiary
carbon was cleaved and hydrogenated to give the ring-opening
product 2a in 82% yield. There was no product derived from
hydrogenolysis of the benzylic C-O bond, the thermally labile
C(sp3)-C(sp3) bond, or the sterically more accessible C(sp2)-
C(sp3) bond. Only a small amount (<5%) of benzene-hydrogen-
ated product 3a was detected as the minor product.15
A wide variety of functional groups are hydrogenated with
the aid of homogeneous and heterogeneous transition-metal
catalysts.1 For example, π-bonds like alkenes, alkynes, and even
arenes undergo a hydrogenation reaction to afford the corre-
sponding reduced compounds. Polar σ-bonds like C-Cl and
benzylic C-O bonds undergo hydrogenolysis. In addition to
these typical reactions of π-bonds and polar σ-bonds with
dihydrogen, hydrogenolysis of nonpolar C-C σ-bonds has also
been reported. Not only strained C-C bonds2 like cyclopropanes,
but also non-strained ones3 undergo hydrogenolysis when
subjected to the appropriate reaction conditions.
OMe
Pd/C (5 mol %)
H2
n-Bu
+
(1 atm)
DCM, MS 4A
rt, 5 h
On the other hand, benzocyclobutenes exhibit unique
reactivities to open the four-membered ring.4 For example, a
thermal ring-opening reaction takes place when simply heated.
The C(sp3)-C(sp3) bond is cleaved to generate an o-quinodi-
methane intermediate.5 Cleavage of C-C bonds6 of benzo-
cyclobutenes is also promoted by metals. Action of a homo-
geneous transition-metal catalyst upon hydroxy-substituted
benzocyclobutenes (benzocyclobutenols) causes cleavage of
the C(sp2)-C(sp3) bond.7-9 It is assumed that the metal
benzocyclobutenolate intermediate is initially generated and
undergoes selective β-carbon elimination. Treatment of oxo-
substituted benzocyclobutenes (benzocyclobutenones) with a
transition-metal complex induces cleavage of the C(arene sp2)-
C(carbonyl sp2) bond or the C(sp3)-C(carbonyl sp2) bond.
Oxidative addition of the C-C bond onto the metal center10 or
β-carbon elimination from the resulting oxametallacycle inter-
mediate11 is operative for the C-C bond cleavage. Herein, we
report an interesting example of hydrogenolysis reaction of
benzocyclobutenes lacking a free hydroxy or a carbonyl group
under heterogeneous conditions (Scheme 1). Of particular note
is the chemoselectivity; the hydrogenolysis of the C(sp2)-C(sp3)
bond (a) precedes to that of other seemingly more reactive σ-
bonds, i.e., the reducible benzylic C-O bond (b), the thermally
labile C(sp3)-C(sp3) bond (c), and sterically more accessible
C(sp2)-C(sp3) bond (d).
1a
ð1Þ
OMe
n-Bu
OMe
n-Bu
+
2a
82%
3a
<5%
To obtain mechanistic insight into the facile and selective
hydrogenolysis of the C-C σ-bond under heterogeneous con-
ditions, the following control experiments were carried out.
When methoxycyclobutane lacking the fused benzene ring 1b
was subjected to the hydrogenolysis reaction conditions, the
cyclobutane ring remained intact and instead the benzylic C-O
bond was cleaved to afford cyclobutane 4 in 21% yield (eq 2).
This result suggests that the fused benzene ring facilitates the
ring-opening hydrogenolysis of the four-membered ring. The
acetoxy-substituted benzocyclobutene 1c underwent exclusive
hydrogenation of the benzene ring (eq 3). This result indicates
the electron-donating nature of the alkoxy group may assist the
C-C bond cleavage and that of the acetoxy group is not strong
enough. Hydrogenolysis of the single diastereomer of methoxy-
benzocyclobutene 1d produced a diastereomeric mixture of the
ring-opening product 2d (eq 4). This stereochemical scrambling
is suggestive that an α-alkoxyradical- or an oxocarbenium-type
intermediate may be involved in the reaction pathway.
OMe
Ph
Pd/C (5 mol %)
Ph
H2
+
1b
+
(1 atm)
DCM, MS 4A
rt, 24 h
52% recovery
a
ð2Þ
ð3Þ
R1
b
c
R1
OR2
R3
4
1b
21%
Pd/C cat.
H
H2
(1 atm)
H
+
OAc
OAc
Pd/C (5 mol %)
H2
OR2
+
n-Bu
n-Bu
R3
(1 atm)
DCM, MS 4A
rt, 24 h
d
3c
1c
81%, dr = 91:9
Scheme 1. Hydrogenolysis of 1-alkoxybenzocyclobutenes.
Chem. Lett. 2015, 44, 1521–1523 | doi:10.1246/cl.150719
© 2015 The Chemical Society of Japan | 1521

Table 1. Hydrogenolysis of 1-alkoxybenzocyclobutenes 1a
n-Bu
OMe
H
n-Bu
OMe
n-Bu
R1
R1
OMe
OR2
R3
H
H
H
Pd/C (5 mol %)
H2
(1 atm)
OR2
R3
H
H
+
DCM, MS 4A
rt, 24 h
1
C
A
B
2
Entry
1c
Benzocyclobutene 1
Product 2b
Scheme 2. Proposed mechanism.
On-Hex
On-Hex
H
H
OMe
Et
Et
Pd/C (5 mol %)
2e 65%
1e
H2
+
(1 atm)
OMe
DCM, MS 4A
rt, 24 h
ð4Þ
OMe
2
Me
OMe
i-Pr
Me
2d
i-Pr
1d
75%, dr = 68:32
2f 77%
Oi-Pr
n-Bu
1f
When a reaction occurs on a surface of a heterogeneous
catalyst, mechanistic interpretation tends to be speculative.
However, we tentatively propose the mechanistic scenario
shown in Scheme 2 for the production of 2a from 1a on the
basis of the experimental results mentioned above. Initially,
dihydrogen is split into two hydrogens on the surface of Pd/C
(Scheme 2). The benzene ring of 1a is then adsorbed on Pd/C to
locate the C(sp2)-C(sp3) bond in proximity to the split hydrogen,
which induces the homolytic cleavage of the C(sp2)-C(sp3) bond
with the assistance of the electron-donation from oxygen.16
Transfer of the split hydrogen onto the benzene ring generates
the α-alkoxyradical intermediate B, and subsequently, the
hydrogen remaining on the surface migrates onto the radical
carbon to produce the hydrogenolysis product C.
Various 1-alkoxybenzocyclobutenes underwent hydrogenol-
ysis of the C-C bond by means of Pd/C (Table 1). The
secondary benzocyclobutenyl ether 1e gave the ring-opening
product 2e (65% yield) together with the arene-hydrogenated
product 3e (<17%). The sterically bulkier benzocyclobutenes 1f
and 1g predominantly underwent hydrogenolysis of the C-C
σ-bond. The 6-methoxy-substituted benzocyclobutene 1h was
more reactive than 1a presumably because the electron-rich
aromatic ring facilitated adsorption on the surface of Pd/C. The
ring-opening mainly took place to furnish 2h (69%) as the
major product and hydrogenation of the benzene ring accom-
panied as the minor pathway (19%). On the other hand, the
reaction of the 6-trifluoromethyl-substituted 1i was slower than
that of 1a, so that 10 mol % Pd/C was used. The ring-opening
product 2i was obtained in 87% yield and the arene-hydro-
genation barely occurred, although it was unclear why the
selectivity was slightly altered. The benzocyclobutene bearing
an ordinary benzyl ether moiety 1j preferentially produced the
ring-opening product 2j prior to removal of the benzyl group.
Even the ester-substituted benzocyclobutene 1k, which would
undergo thermal ring opening more facilely than simple
benzocyclobutenes due to the acceleration effect of both
electron-donating methoxy and -withdrawing ester groups at
the 1-position,17 underwent selective hydrogenolysis of the
C(sp2)-C(sp3) bond.
Oi-Pr
n-Bu
3
2g 94%
OMe
1g
OMe
OMe
4d
OMe
n-Bu
n-Bu
1h
2h 69%
CF3
5e
6f
7g
CF3
OMe
OMe
n-Bu
n-Bu
1i
2i 87%
OBn
OBn
OMe
OMe
n-Bu
n-Bu
1j
2j 69%
OMe
OMe
CO2Me
CO2Me
2k 68%
1k
aReaction conditions: 1-alkoxybenzocyclobutene 1 (0.20 mmol),
Pd/C (5 mol % Pd), MS 4A (20.0 mg), dichloromethane (3.0 mL),
rt, 24 h unless otherwise noted. bIsolated yields. cThe arene-
hydrogenated product 3e was formed in <17%. dThe arene-
hydrogenated product 3h was formed in 19% yield. e10 mol %
f
g
Pd/C was used. Reaction time: 3 h. 22% 1k remained.
opening is complementary to that of thermal ring opening,
showing the new reactivity of benzocyclobutene derivatives.
This work was supported in part by a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” (No. 22105005), a
Grant-in-Aid for Scientific Research (S) (No. 15H05756) from
MEXT, the ACT-C program of the JST, Yazaki Memorial
Foundation for Science and Technology.
In conclusion, we found a new catalytic C-C bond cleaving
reaction of a benzocyclobutene ring under heterogeneous
conditions; 1-alkoxybenzocyclobutenes undergo ring-opening
hydrogenolysis with site-selective cleavage of the alkoxy-
substituted C(sp3)-C(sp2) bond by a catalytic action of Pd/C.
The unique site-selectivity observed in the present catalytic ring
Supporting Information is available electronically on J-STAGE.
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14 Addition of molecular sieves suppressed the formation of
the ring-opening ketone 5, which would be formed through
hydrolysis of 1a to benzocyclobutenol followed by ring
opening.
O
n-Bu
5
15 For hydrogenation of the benzene ring fused with cyclo-
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Tetrahedron Lett. 1994, 35, 2021.
16 Although the oxocarbenium-type intermediate is also con-
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the hydrogenolysis reaction of 1a; the ring-opening product
2a was obtained only in 10% yield in the presence of
TEMPO (1.0 equiv) under the reaction conditions otherwise
identical to eq 1.
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Chem. Lett. 2015, 44, 1521–1523 | doi:10.1246/cl.150719
© 2015 The Chemical Society of Japan | 1523