Synthesis of seven-membered-ring ketones by arylative ring expansion of alkyne-substituted cyclobutanones

Article abstract of DOI:10.1002/anie.200500799

(Chemical Equation Presented) Ever-increasing circles: Seven-membered-ring ketones are constructed by a rhodium(I)-catalyzed arylative ring-expansion reaction of alkyne-substituted aryl cyclobutanones, in which two C-C bond-forming and one C-C bond-cleavi

Full text of DOI:10.1002/anie.200500799

Communications
Organic Synthesis
Synthesis of Seven-Membered-Ring Ketones by
Arylative Ring Expansion of Alkyne-Substituted
Cyclobutanones**
Takanori Matsuda, Masaomi Makino, and
Masahiro Murakami*
Medium-sized carbocyclic ring systems are often present as
the structural core in natural products of interesting biological
activities. Thus, the development of new synthetic methods
for medium-sized carbocyclic rings has been one of the prime
targets in organic synthesis.[1] Fragmentation of an easily
accessible bicyclic system circumvents unfavorable enthalpic
and entropic factors associated with direct formation of the
medium-sized ring by annulation or cyclization.[2] A number
[*] Dr. T. Matsuda, M. Makino, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University
Katsura, Kyoto 615–8510 (Japan)
Fax: (+81)75-383-2748
E-mail: murakami@sbchem.kyoto-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Young Scientists
(B; No. 15750085) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500799
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of ring-expansion reactions, which are promoted by acids,
radicals, and transition metals, as well as heat, have been
developed. Most of them are aided by the release of ring
strain as the driving force.
Recently, we found that an arylrhodium adds to a
cyclobutanone intermolecularly to afford a ring-opened
ketone through b-carbon elimination from the resulting
rhodium cyclobutanolate.[3] We then envisaged that intra-
molecular addition of an organorhodium group to cyclo-
butanone[4] followed by b-carbon elimination would provide a
ring-expansion process [Eq. (1)]. Herein, we describe a new
method for construction of seven-membered ring skeletons.
To establish a route to an organorhodium species neces-
sary for such intramolecular additions, cyclobutanones 1 that
bear an alkyne moiety were designed (Scheme 1). 2-(2-But-1-
ynylphenyl)cyclobutanone (1a) was synthesized in three steps
Scheme 2. Proposed mechanism for the formation of 3 from 1.
Arylrhodium species A, generated from hydroxorhodium F
and arylboronic acid, adds regioselectively across the carbon–
carbon triple bond[4b–d,6b,7] of 1 in preference to the carbonyl
group to afford vinylrhodium species B. Then, 1,2-addition to
the adjacent carbonyl group of the cyclobutanone[4] forms
rhodium cyclobutanolate C. b-Carbon elimination occurs
regioselectively with the benzylic carbon atom,[8] and thus the
bicyclic [3.2.0] skeleton of C is expanded with release of the
ring strain to give alkylrhodium D. Successive b-hydride
elimination/readdition processes take place, leading to the
formation of h3-oxaallylrhodium E.[9] Finally, protonolysis of
E yields 3 and regenerates F.
Scheme 1. Rhodium-catalyzed reaction of alkyne-substituted
cyclobutanone 1a with triphenylboroxin (2a). [a] Estimated from
1H NMR spectroscopy of the crude reaction mixture.
starting from commercially available 2-bromobenzalde-
hyde.[5] As a rhodium catalyst, we initially employed hydroxo-
(diolefin)rhodium(i) complexes, which have recently been
used successfully in the rhodium-catalyzed reactions of
arylboronic acids.[4b,d] Thus, a mixture of 1a, triphenylboroxin
(2a, 1.0 equiv), and water (3.0 equiv)[6] was heated in the
presence of [Rh(OH)(cod)]2 (10 mol% Rh; cod = cyclo-1,5-
octadiene) in 1,4-dioxane at 1008C. After heating for 6 h,
seven-membered-ring ketone 3aa was isolated in 54% yield
along with small amounts of 1,2-adduct 4aa and cyclobutanol
5aa. The use of P(tBu)3 as the additional ligand improved the
yield of 3aa to 73% without the formation of 4aa and 5aa.
The reaction in the presence of D2O gave [D]3aa with
deuterium incorporated exclusively at the a position of the
carbonyl group, suggesting the formation of h3-oxaallylrho-
dium prior to protonolysis, as previously reported [Eq. (2)].[3]
We propose the following mechanism for the transforma-
Compound 4aa is produced when the vinylrhodium
species B is protonated through a 1,4-shift of rhodium.
Protonolysis of the cyclobutanolate C affords 5aa.
To examine the effect of coordination of the carbonyl
group of 1, a control experiment was carried out using 2-
isopropyl-1-(pent-1-ynyl)benzene (6), whose alkyne structure
is sterically similar to that of 1, which comprises a cyclo-
butanone moiety (Scheme 3). The reaction of 6 with 2a was
sluggish at room temperature to give 1,2-adduct 7 in 14%
yield after 6 h. In contrast, the analogous alkyne 1b with a
cyclobutanone substituent furnished 80% of cyclobutanol
5ba as well as 8% of 4ba. These contrasting results obtained
with 6 and 1b clearly indicate that the carbonyl group of 1b
facilitates the initial arylrhodation of the carbon–carbon
triple bond by coordination. It also proved that the arylrho-
dation of 1b and the following intramolecular carbonyl
addition take place at room temperature and that the only
ring-opening step by b-carbon elimination requires an
À
tion, which consists of a consecutive array of two C C bond-
À
forming and one C C bond-cleaving steps (Scheme 2).
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Communications
Table 1: Rhodium-catalyzed arylative ring expansion of 1 with 2.[a]
Entry
1
R
2
Ar
3
[%][b]
1
2
3
4
5
6
1a
1a
1a
1b
1c
1d
Et
Et
Et
Pr
2b
2c
2d
2a
2a
2a
4-MeC6H4
4-MeOC6H4
4-FC6H4
Ph
Ph
Ph
3ab
3ac
3ad
3ba
3ca
3da
71
70
63
74
76
50
Scheme 3. Effect of coordination of the carbonyl group of 1.
iBu
(CH2)2OTBS[c]
elevated temperature. It is conceivable that the coordination
of the carbonyl group retards the 1,4-shift of rhodium[4c,6b,10]
which possibly occurs with the intermediate B to produce 4.
Arylboroxins 2b–2d were subjected to the arylative ring-
expansion reaction with cyclobutanone 1a to give 3ab–3ad in
63–71% yields (Table 1, entries 1–3).[11] Next, substituents at
the alkyne termini of 1 were examined. Cyclobutanones 1b–
1d, which have other alkyl substituents (R), reacted with 2a
to afford the corresponding seven-membered-ring ketones
3ba–3da (Table 1, entries 4–6).
[a] All reactions were carried out using 1 (0.20 mmol), 2 (0.20 mmol),
H2O (0.60 mmol), [Rh(OH)(cod)]2 (0.010 mmol, 10 mol% Rh), and
P(tBu)3 (0.04 mmol, 20 mol%) in 1,4-dioxane (1.0 mL) at 1008C for 6 h.
[b] Isolated yield. [c] TBS=tert-butyldimethylsilyl.
In the reaction of 1e, which contains a methyl ether
linkage, 1,2-adduct 8ea arising from arylrhodation with the
opposite regiochemistry was formed as
a byproduct
(Scheme 4). Coordination of the ether oxygen center at the
propargylic position might cause the regioisomeric 1,2-
addition to produce 8ea. With phenyl-substituted substrate
1 f, a mixture of 3 and 8 in a ratio of
Scheme 4. Rhodium-catalyzed arylative ring expansion of 1e and 1 f.
[a] Estimated by 1H NMR spectroscopy of the crude reaction mixture.
Table 2: Scope and limitation of the Rh-catalyzed arylative ring-expansion reaction.[a]
almost 1:1 was formed as a result of
the barely biased alkyne structure.
Further studies on the scope
Entry
Cyclobutanone 1
Product 3 or 5
Yield [%][b]
R1 =R2 =OMe
and limitation of the arylative ring-
expansion reaction (Table 2) were
carried out. Both fluoro and
methoxy substituents at the aryl
ring of 1 were tolerated (Table 2,
entries 1 and 2). Even a thiophene-
derived substrate afforded the cor-
responding ketone 3ia in 72%
yield (Table 2, entry 3). We failed
to obtain the seven-membered-ring
ketones from cyclobutanone 1j,
which has an additional methyl
substituent at the 2-position;
instead, the corresponding cyclo-
butanol 5ja was isolated (Table 2,
entry 4). It is likely that migration
of the rhodium from the oxygen
atom to the tertiary carbon atom is
difficult for steric reasons.[12] The
reaction of 1k, which contains a
tether that is longer by one carbon
atom, worked far less efficiently to
1
2
3ga
3ha
67
58
1g
R1 =F, R2 =H
1h
3
4
5
1i
1j
1k
3ia
5ja
3ka
72
63
17
[a] All reactions were carried out using 1 (0.20 mmol), 2 (0.20 mmol), H2O (0.60 mmol), [Rh(OH)(cod)]2
(0.010 mmol, 10 mol% Rh), and P(tBu)3 (0.06 mmol, 20 mol%) in 1,4-dioxane (1.0 mL) at 1008C for
6 h. [b] Isolated yield.
result in the formation of the eight-membered-ring ketone
3ka in only 17% yield (Table 2, entry 5).
nones 1 and arylboroxins 2 through ring opening by b-carbon
elimination.
In summary, a new rhodium-catalyzed ring-expansion
reaction was developed in which seven-membered-ring
ketones 3 were produced from alkyne-substituted cyclobuta-
Received: March 4, 2005
Published online: June 28, 2005
4610
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Keywords:
.
rhodium · boron · elimination · ketones · ring expansion
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[11] The reaction with o-tolylboroxin resulted in the formation of a
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[12] Ring expansion by b-carbon elimination failed to occur even
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