Synthesis of 3,3-disubstituted α-tetralones by rhodium-catalysed reaction of 1-(2-haloaryl)cyclobutanols

Article abstract of DOI:10.1039/c2cc16907j

The rhodium-catalysed reaction of 1-(2-haloaryl)cyclobutanols afforded 3,3-disubstituted α-tetralones. The reaction was applied to the asymmetric synthesis of α-tetralones bearing a chiral quaternary carbon centre at the 3-position, which was otherwise di

Full text of DOI:10.1039/c2cc16907j

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COMMUNICATION
Synthesis of 3,3-disubstituted a-tetralones by rhodium-catalysed reaction
of 1-(2-haloaryl)cyclobutanolsw
Naoki Ishida, Shota Sawano and Masahiro Murakami*
Received 8th November 2011, Accepted 6th December 2011
DOI: 10.1039/c2cc16907j
The rhodium-catalysed reaction of 1-(2-haloaryl)cyclobutanols
afforded 3,3-disubstituted a-tetralones. The reaction was applied
to the asymmetric synthesis of a-tetralones bearing a chiral
quaternary carbon centre at the 3-position, which was otherwise
difficult to execute.
(1.1 equiv.) for 15 h, a-tetralone 2a was obtained in 96%
isolated yieldz (eqn (1)).6 No formation of acyclic ketone 3a
and indanol 4a was detected by GC-MS analysis of the
reaction mixture, being suggestive that the intermediacy of
the ring-opened (d-ketoalkyl)rhodium species was unlikely.3
Transition metal-catalysed reactions involving an elementary
step to cleave a carbon–carbon single bond render it possible
to reconstruct a main framework of organic molecules,
providing unique synthetic transformations.1 We and others
have developed palladium-2 and rhodium-catalysed3 reactions
of cyclobutanols,4,5 in which intermediary metal cyclobutano-
lates produce a variety of compounds depending upon the
transition metals and the substituents. For example, rhodium
cyclobutanolates undergo ring opening by b-carbon elimina-
tion to generate (d-ketoalkyl)rhodium(I) species, with which
three pathways are known to ensue. When a 3,3-dialkyl-
substituted cyclobutanol is employed as the starting substrate,
ð1Þ
the resulting alkylrhodium(I) intermediate undergoes
a
1,3-rhodium shift to form a rhodium enolate, protonation of
which furnishes an acyclic ketone.3d On the other hand, in the
case that an aryl group is attached to the 3-position, a
1,4-rhodium shift occurs with the ring-opened (d-ketoalkyl)-
rhodium(I) species to furnish an arylrhodium(I) intermediate,
which intramolecularly adds to the carbonyl group to afford
indanols.3b,c When a cyclobutanol has an alkene or allene
substituent at the 1-position, the alkylrhodium(I) intermediate
undergoes 1,2-addition across the carbon–carbon double
bond, leading to the formation of cyclohexanones or cyclo-
hexenones.3e Herein is disclosed a rhodium-catalysed reaction
of cyclobutanols bearing an o-bromoaryl moiety at the 1-position,
which furnishes 3,3-disubstituted a-tetralones. Unlike the previous
examples, the reaction mechanism involves a rhodium(I)/(III)
oxidation/reduction process.
The following experiments were carried out in order to
provide information for mechanistic interpretation of the reac-
tion pathway (eqn (2)). When the same reaction conditions were
applied to cyclobutanol 1b lacking a bromo group on the
phenyl ring, indanol 4b was the sole product obtained (84%
yield).3b,c The reaction of 1b in the presence of bromobenzene
also yielded indanol 4b in 83% yield without participation of
bromobenzene. This result stands in marked contrast to that
obtained with a palladium(0) catalyst; bromobenzene partici-
pates in the palladium-catalysed reaction of cyclobutanol 1b to
form a d-arylated ketone.2d The contrasting results indicate that
rhodium(I) is far less reactive towards bromobenzene than
palladium(0).7 Overall, the presence of the bromo group within
the cyclobutanol skeleton dictated the reaction pathway to a
new direction, i.e., to the formation of a-tetralones.
When a dioxane solution of 1-(2-bromophenyl)-3,3-diphenyl-
cyclobutanol (1a) was heated at 120 1C in the presence
of [Rh(OH)cod]2 (5 mol%), DPPB (11 mol%) and K3PO4
Department of Synthetic Chemistry and Biological Chemistry,
Kyoto University, Katsura, Kyoto 615-8510, Japan.
E-mail: murakami@sbchem.kyoto-u.ac.jp; Fax: +81 75 383 2748;
Tel: +81 75 383 2747
ð2Þ
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data for new compounds. See DOI:
10.1039/c2cc16907j
c
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Chem. Commun., 2012, 48, 1973–1975 1973

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Table 1 Scope of the rhodium-catalysed reaction of 1-(2-bromoaryl)-
cyclobutanolsa
Entry
1
2b
1c,d
2c
Scheme 1 A possible mechanism.
On the basis of these results, we propose a possible mecha-
nism for the formation of 2a from 1a as depicted in Scheme 1.
Cyclobutanol 1a initially reacts with a rhodium(I) complex in
the presence of a base to generate rhodium(I) cyclobutanolate A.
The rhodium(I) centre is geometrically constrained in
proximity to the bromoaryl group, and thus, an oxidative
addition process is facilitated to give five-membered
rhodacycle(III) B.8 Then, the four-membered carbocycle is
opened by b-carbon elimination to afford seven-membered
rhodacycle(III) C.9 Finally, reductive elimination provides
a-tetralone 2a with regeneration of the rhodium(I) catalyst.
Other cyclobutanols bearing an o-haloaryl group at the
1-position were subjected to the rhodium-catalysed reaction
conditions (Table 1). Cyclobutanols having alkyl and aryl
substituents at the 3-position participated in the reaction to
give a-tetralones in good yields (entries 1–3). On the other
hand, cyclobutanols with the 3-position being unsubstituted
provided a complex mixture, probably due to the concurrence
of b-hydride elimination with intermediate C. The azetidin-3-ol
could be employed instead of cyclobutanols to furnish
isoquinolinone 2f in 69% yield (entry 4). Both electron-
donating and -withdrawing groups were admitted on the aryl
ring (entries 5–7). An iodo counterpart of 1c underwent the
reaction at 100 1C to form 2c in 72% yield, indicating that aryl
iodides were more reactive than aryl bromides. In contrast, the
reaction of the chloro analogue of 1a was much slower. The
product 2a was obtained in 42% yield with the unreacted
starting compound remaining even after 48 h. The reaction of
the cyclobutanol bearing an o-bromobenzyl group gave a
complex mixture. These results revealed the importance of
the geometrical constraint as well as the reactivity toward
oxidative addition of the haloaryl moiety.
3c
4d
5e
6d
7f,g
Next, we examined the asymmetric induction by using
various chiral ligands to find that tol-BINAP exhibited a fairly
good enantioselectivity. When cis-1d was treated with a
Rh(I)/(R)-tol-BINAP catalyst in dioxane, (+)-2d was obtained
in 72% yield with 87% ee (eqn (3)). On the other hand, the
other diastereomer trans-1d afforded the opposite enantiomer
(ꢀ)-2d in 69% yield with 81% ee (eqn (4)). Both enantiomers
were derivatised to the corresponding tetralins and their
absolute configurations were determined by the measurement
a
Reaction conditions: 1.0 equiv. cyclobutanol 1,
[Rh(OH)cod]2, 11 mol% DPPB, 1.1 equiv. K3PO4, dioxane (0.2 M),
5
mol%
b
c
120 1C, 24 h unless otherwise noted. Isolated yields. A diastereo-
mer mixture of 1 was used. 11 mol% of BINAP was employed
e
instead of DPPB. DMSO was employed instead of dioxane. The
d
f
g
reaction was conducted at 0.1 M, 150 1C. Heated for 63 h.
c
1974 Chem. Commun., 2012, 48, 1973–1975
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of their optical rotations.10 The absolute stereochemistry
established that the (R)-tol-BINAP ligand favoured the
cleavage of the bond a located on the right in the drawings
of eqn (3) and (4), irrespective of the stereochemical arrange-
ment at the 3-position.
Notes and references
z General procedure: A mixture containing [Rh(OH)(cod)]2 (2.3 mg,
5.0 mmol, 5.0 mol%), DPPB (4.7 mg, 11 mmol, 11 mol%), K3PO4
(23.3 mg, 0.11 mmol) and 1a (37.9 mg, 0.10 mmol) in 1,4-dioxane
(0.50 ml) was stirred at 120 1C for 15 h. After being cooled to room
temperature, the reaction mixture was diluted with H2O and extracted
with AcOEt (three times). The combined organic phase was washed
with H2O and brine, dried over MgSO4 and evaporated. The residue
was purified by preparative thin-layer chromatography on silica gel
(hexane : AcOEt = 10 : 1) to afford 2a (28.7 mg, 0.096 mmol, 96%).
1 (a) M. E. Van Der Boom and D. Milstein, Chem. Rev., 2003,
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ð3Þ
3 (a) T. Matsuda, M. Makino and M. Murakami, Org. Lett., 2004,
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and N. Cramer, Chem.–Eur. J., 2010, 16, 3383.
4 For reviews on reactions of cyclobutanes, see: (a) E. Lee-Ruff and
G. Mladenova, Chem. Rev., 2003, 103, 1449; (b) J. C. Namyslo and
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5 For other rhodium-catalysed reactions involving activation of a
carbon–carbon bond, see: (a) C.-H. Jun and H. Lee, J. Am. Chem.
Soc., 1999, 121, 880; (b) M. Murakami, T. Itahashi and Y. Ito,
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C. J. Douglas, J. Am. Chem. Soc., 2009, 131, 412.
6 The results with other ligands at 100 1C for 13 h: PPh3 (o10%),
P(t-Bu)3 (o10%), IPr (0%), DPPP (23%), BINAP (30%), DPPB
(53%).
ð4Þ
In conclusion, we have developed a rhodium-catalysed
reaction of 3,3-disubstituted 1-(2-haloaryl)cyclobutanols,
which provides 3,3-disubstituted a-tetralones having
a
quaternary carbon centre in an enantiomerically enriched
form. We failed to find such chiral a-tetralones by structural
search on electronic databases, which was probably owing to
the paucity of an appropriate synthetic method. Asymmetric
conjugate addition of carbon nucleophiles to a,b-unsaturated
carbonyl compounds is an authentic method for introducing a
chiral centre at the position b to a carbonyl group. However,
a-tetralones bearing a chiral quaternary carbon at the
3-position are inaccessible via conjugate addition to dehydro-
tetralone because 1-naphthol is the more stable tautomer of
dehydrotetralone and unreactive as the conjugate acceptor.
Therefore, the rhodium-catalysed reaction we have developed
would serve as a useful synthetic method for such chiral
a-tetralone derivatives.
7 Although the use of palladium complexes was also examined in the
reaction of 1a under various reaction conditions, tetralone 2a was
produced in less than 30% yield together with unidentified byproducts.
8 For rhodium-catalysed cross-coupling reactions which would
involve a Rh(I)–Rh(III) redox process, see: (a) R. C. Larock,
K. Narayanan and S. S. Hershberger, J. Org. Chem., 1983,
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2005, 7, 2229; (d) H. Yasui, K. Mizutani, H. Yorimitsu and
K. Oshima, Tetrahedron, 2006, 62, 1410; (e) M. L. Kantam,
S. Roy, M. Roy, B. Sreedhar, B. M. Choudary and R. L. De,
J. Mol. Catal. A: Chem., 2007, 273, 26; (f) L. Zhang and J. Wu,
Adv. Synth. Catal., 2008, 350, 2409; (g) J.-Y. Yu and R. Kuwano,
Angew. Chem., Int. Ed., 2009, 48, 7217.
9 For examples of b-carbon elimination of organorhodium(III)
species, see: (a) M. A. Huffman and L. S. Liebeskind, J. Am.
Chem. Soc., 1993, 115, 4895; (b) M. Murakami, K. Takahashi,
H. Amii and Y. Ito, J. Am. Chem. Soc., 1997, 119, 9307;
(c) P. A. Wender, A. G. Correa, Y. Sato and R. Sun, J. Am. Chem.
Soc., 2000, 122, 7815; (d) T. Matsuda, T. Tsuboi and M. Murakami,
This work was supported in part by The Asahi Glass
Foundation and a Grant-in-Aid for Scientific Research on
Innovative Areas ‘‘Molecular Activation Directed toward
Straightforward Synthesis’’ from The Ministry of Education,
Culture, Sports, Science and Technology, Japan.
J. Am. Chem. Soc., 2007, 129, 12596; (e) D. Cre
C. Aıssa, Angew. Chem., Int. Ed., 2010, 49, 620.
´
pin, J. Dawick and
¨
10 T. Fujita, K. Obata, S. Kuwahara, A. Nakahashi, K. Monde,
J. Decatur and N. Harada, Eur. J. Org. Chem., 2010, 6372.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1973–1975 1975