Regioselective construction of indene skeletons by palladium-catalyzed annulation of alkynylborates with o-iodophenyl ketones

Article abstract of DOI:10.1002/ejoc.201201510

A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones to form indenes is described. Highly substituted indene skeletons are efficiently constructed with site-specific installation of the substituents. Alkynylborates react w

Full text of DOI:10.1002/ejoc.201201510

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201510
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto,[a] Hanako Sunaba,[a] Naoki Ishida,[a] and Masahiro Murakami*[a]
Dedicated to the Centenary of the Portuguese Society of Chemistry on the occasion of the 6th Spanish
Portuguese Japanese Organic Chemistry Symposium
Keywords: Synthetic methods / Carbocycles / Annulation / Regioselectivity / Boron / Palladium
A palladium-catalyzed annulation reaction of alkynylborates
with o-iodophenyl ketones to form indenes is described.
Highly substituted indene skeletons are efficiently con-
structed with site-specific installation of the substituents.
Introduction
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were
prepared from the corresponding B-aryl-9-borabicy-
clo[3.3.1]nonane (Ar-9-BBN) and terminal alkyne accord-
ing to the reported method.[6c] The borate 1a (1.0 equiv.)
was treated with o-iodoacetophenone (2a; 1.05 equiv.) in
the presence of [(dpephos)Pd(π-allyl)Cl] (1 mol-%) at 50 °C
for 1 h (Scheme 1). The reaction mixture was then treated
with hydrogen peroxide to oxidize the organoboron residue.
Purification by column chromatography on silica gel af-
forded 2,3-diarylindenol 3a in 85% yield. In contrast, the
reaction of the borate 1b with 2a selectively provided the
regioisomeric indenol 3b in 88% yield. Thus, this palla-
dium-catalyzed reaction makes possible the selective pro-
duction of both regioisomers of 2,3-diarylindenols, which
is difficult to achieve by using the conventional annulation
reaction of o-halophenyl ketones with 1,2-diarylalkynes.[4h]
The selective formation of 3a from 1a and 2a can be ex-
plained by the mechanism shown in Scheme 2, which is
based on the mechanism proposed for the palladium-cata-
lyzed reaction of alkynylborates with simple aryl halides.[6c]
Oxidative addition of 2a to palladium(0) leads to arylpalla-
dium A. Regioselective cis-carbopalladation across the car-
bon–carbon triple bond of 1a gives alkenylpalladium B.
The phenyl group on the anionic boron migrates onto the
α carbon atom and the carbon–palladium bond is substi-
tuted with inversion of the stereochemistry to afford alken-
ylborane C.[7] The ketone moiety remains intact during the
course of the palladium-catalyzed reaction; the generated
B-alkenyl-9-BBN moiety undergoes intramolecular ad-
dition at the carbonyl group[8] to form the boron indenolate
D. Upon oxidative work-up with NaOH/H2O2, D is hy-
drolyzed to the indenol 3a.
Indenes are important structural motifs found in a
number of biologically active compounds.[1] For example,
an indene framework with an exo-alkylidene moiety is im-
bedded in sulindac, which is a nonsteroidal antiinflamma-
tory drug,[1a] and dimethindene, an oral antihistamine
agent, has an indene core tethered to an amine moiety.[1b]
In addition to these commercial medicines, indene deriva-
tives have also been exploited as materials for optoelectron-
ics[2] and as ligands for transition-metal complexes.[3] Con-
sequently, the development of a new method for con-
structing indene skeletons is an attractive subject in organic
synthesis.[4]
Alkynylboron compounds have been utilized as useful in-
termediates in organic synthesis.[5] We have previously de-
veloped the palladium-catalyzed reaction of alkynylborates
with aryl halides;[6] (trisubstituted alkenyl)boranes, which
are otherwise difficult to synthesize, can be readily obtained
in a regio- and stereoselective fashion by this method. In
this work, we extended the scope of this palladium-cata-
lyzed reaction to the construction of indene skeletons. Alk-
ynylborates react with o-iodophenyl ketones to afford 2,3-
disubstituted indenols with specific installation of substitu-
ents at the 2- and 3-positions.
[a] 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
Homepage: http://www.sbchem.kyoto-u.ac.jp/murakami-lab/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201510.
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Y. Shimamoto, H. Sunaba, N. Ishida, M. Murakami
Table 1. Synthesis of indenols 3.[a]
SHORT COMMUNICATION
Scheme 1. Reactions of alkynylborates 1 and o-iodoacetophenone
(2a).
[a] Reagents and conditions: 1.0 equiv. of alkynylborate 1,
1.05 equiv. of o-iodophenyl ketone 2, 1 mol-% of [(dpephos)
PdCl(π-allyl)], toluene, 50 °C, 1 h; then aq. H2O2, aq. NaOH,
MeOH, room temp., 2 h. Isolated yields are shown.
Alkenyl-substituted 3k and alkyl-substituted 3l were also
synthesized from B-alkenyl-9-BBN 1c and B-alkyl-9-BBN
1d, respectively; see Equations (1) and (2). The formation
of 3l is noteworthy from a mechanistic point of view; the n-
butyl group on the anionic boron migrates onto the α-car-
bon atom in preference to the bridgehead sp3 carbon of the
9-BBN framework.[9] This selectivity stands in sharp con-
trast to that observed in the reaction with iodine.[10]
Scheme 2. Mechanism proposed for the formation of 3a.
A wide variety of highly-substituted indenols have been
generated by this reaction (Table 1). For example, thio-
phene-substituted 3d and alkyl-substituted 3e were ob-
tained in yields of 82 and 92%, respectively. The use of o-
(1)
It was possible to directly synthesize 2,3-dialkylindenol
iodobenzaldehyde and o-iodobenzophenone gave the corre- 3m in one-pot starting from 1-octene, 4-phenylbut-1-yne,
sponding indenols 3f and 3g. Indenols equipped with alk- and o-iodoacetophenone (2a) without isolation of the inter-
oxy, trifluoromethyl, and fluoro groups on the aromatic mediates (Scheme 3). Hydroboration of 1-octene with H-9-
ring (3h–j) were also synthesized.
BBN in THF afforded B-n-octyl-9-BBN, which was then
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Regioselective Construction of Indene Skeletons
Conclusions
We have described the palladium-catalyzed annulation
reaction of alkynylborates with o-iodophenyl ketones. A
wide variety of highly substituted indenols can be regiospe-
cifically synthesized by this method.
(2)
Experimental Section
Procedure for the Palladium-Catalyzed Reaction of Alkynylborate
1a with o-Iodoacetophenone (2a): Under argon, a toluene solution
(1.0 mL) of alkynylborate 1a (80.68 mg, 0.20 mmol), [(dpephos)-
PdCl(π-allyl)] (1.44 mg, 0.002 mmol), and o-iodoacetophenone was
stirred for 1 h at 50 °C. Aqueous H2O2 (0.5 mL, 30 wt.-%), aqueous
NaOH (0.5 mL, 20 wt.-%), and MeOH (0.5 mL) were added to the
reaction mixture at 0 °C. After stirring for 2 h at room temperature,
the resulting mixture was diluted with water and extracted with
ethyl acetate (3ϫ 15 mL). The combined organic layers were
washed with brine, dried with MgSO4, and concentrated under re-
duced pressure. The residue was purified by preparative thin-layer
chromatography on silica gel (hexane/ethyl acetate = 5:1) to afford
the indenol 3a (55.9 mg, 0.17 mmol, 85% yield).
treated with 4-phenylbut-1-ynyllithium to form the corre-
sponding lithium alkynylborate. A toluene solution con-
taining o-iodoacetophenone (2a) and [(dpephos)Pd(π-allyl)-
Cl] was then added to the reaction mixture, which was
heated at 50 °C for 1 h. Oxidative work-up and purification
by column chromatography furnished 3m in a 91% isolated
yield based on 2a.
3a: 1H NMR: δ = 1.59 (s, 3 H), 2.04 (br. s, 1 H), 3.82 (s, 3 H),
6.84–6.90 (m, 2 H), 7.21–7.30 (m, 8 H), 7.42–7.48 (m, 2 H), 7.51–
7.55 (m, 1 H) ppm. 13C NMR: δ = 23.9, 55.2, 83.2, 113.9, 120.8,
121.8, 126.5, 126.8, 127.2, 128.0, 128.4, 129.4, 130.5, 135.0, 138.2,
142.3, 146.2, 149.6, 158.9 ppm. IR (ATR): ν = 3315, 1508, 1248,
˜
752, 694 cm–1. HRMS (ESI+): calcd for C23H21O2 [M + H]+
329.1536; found 329.1556.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data of new com-
pounds, H and 13C NMR spectra of compounds 3–5.
1
Scheme 3. Synthesis of indenol 3m from 1-octene.
Acknowledgments
The palladium-catalyzed annulation of 1a with 2b gave
indenol 3n in 74% yield, which was subjected to further
derivatization (Scheme 4). Oxidation of 3n with manga-
nese(IV) oxide furnished the indenone 4. The following
Wolff–Kishner reaction reduced the carbonyl group with-
out isomerization of the double bond to give indene 5 in
59% yield.[11]
This work was supported by the Japanese Ministry of Education,
Culture, Sports, Science and Technology (MEXT). Y. S. is grateful
to the Japan Society for the Promotion of Science (JSPS) for a
Research Fellowship for Young Scientists.
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Received: November 10, 2012
Published Online: January 7, 2013
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