Rhodium-catalyzed asymmetric synthesis of 3,3-disubstituted 1-indanones

Article abstract of DOI:10.1002/anie.200700226

(Chemical Equation Presented) Rapid access to enantioenriched indanones that are difficult to obtain by other methods is gained through the highly enantioselective addition of aryl boronates to aryl alkynyl ketones under rhodium catalysis (see scheme). Th

Full text of DOI:10.1002/anie.200700226

Angewandte
Chemie
DOI: 10.1002/anie.200700226
Asymmetric Catalysis
Rhodium-Catalyzed Asymmetric Synthesis of 3,3-Disubstituted
1-Indanones**
Ryo Shintani,* Keishi Takatsu, and Tamio Hayashi*
The enantioselective construction of 1-indanones with a
stereocenter at the 3-position is a subject of importance
because of the high utility of indan structures in organic
chemistry.[1] Several research groups have focused on the
development of a catalytic asymmetric synthesis of these
compounds, but most were successful only in the preparation
of 3-monosubstituted 1-indanones.[2] In fact, to the best of our
knowledge, only one recent report by Murakami and co-
workers describes the catalytic asymmetric construction of
3,3-disubstituted 1-indanones.[3] Herein we describe the
development of a highly enantioselective synthesis of 3,3-
disubstituted 1-indanones by the addition of aryl boronates to
aryl silylethynyl ketones under rhodium catalysis [Eq. (1)].
of 1a catalyzed by Rh/(R)-binap (5 mol%) at 508C, indanone
3aa was produced in 29% yield with 80% ee; the major
product was found to be the uncyclized hydrophenylation
product 4[6] (Table 1, entry 1). This outcome indicates that
intermediate A, generated by phenylrhodation of the alkyne,
can be protonated easily before it is engaged in the
subsequent cyclization process (Scheme 1). To suppress the
undesired formation of 4, we used aprotic phenylboronic acid
pinacol ester (PhBpin) as the nucleophile. As expected, enone
4 was not obtained under these conditions; however, unfortu-
nately the reaction became very sluggish, with 3aa isolated in
only 20% yield after 10 h and 65% recovery of the starting
alkyne 1a (Table 1, entry 2). The slowness of this reaction is
probably due to the bulkiness of the pinacol moiety, which
may retard the transmetalation of the phenyl group and thus
decrease catalytic turnover. On the basis of this hypothesis,
we tested the less bulky boronic ester 2a and found that the
reaction proceeded smoothly to give 3aa in 83% yield with
86% ee (Table 1, entry 3).[7] The use of (R)-segphos[8] as the
ligand gave 3aa in higher yield and with a higher ee value
In 2005, we reported the Rh/dppf-catalyzed addition of
aryl zinc chlorides to aryl alkynyl ketones to give 3,3-
disubstituted 1-indanones (dppf = 1,1’-bis(diphenylphospha-
nyl)ferrocene).[4] Our efforts to develop an effective asym-
metric variant of this reaction were hampered by the fact that
the indanones are only formed in high yield with the dppf
ligand on rhodium. For example, in the reaction of 1-phenyl-
3-triethylsilyl-2-propyn-1-one (1a) with phenylzinc chloride,
we found that indanone 3aa was formed with relatively high
enantioselectivity (84% ee) when (R)-binap[5] was used as the
ligand, but in very low yield (29%), with significant decom-
position of the substrate 1a [Eq. (2); DCE = 1,2-dichloro-
ethane, cod = 1,5-cyclooctadiene].
Table 1: Optimization of the rhodium-catalyzed asymmetric synthesis of
3aa.
We therefore decided to reinvestigate the reaction con-
ditions and alter them to favor formation of the indanone in
high yield in the presence of an axially chiral bisphosphine
ligand, such as (R)-binap. When phenylboronic acid
(2.0 equiv) was employed as the nucleophile in the reaction
Entry
PhB(OR)2
Ligand
Yield [%]
ee [%]
1
PhB(OH)2
PhBpin
2a
2a
2a
(R)-binap
(R)-binap
(R)-binap
(R)-segphos
(R)-segphos
29[a]
20[c]
83
87
89
80
86
86
99
98
2[b]
3
[*] Dr. R. Shintani, K. Takatsu, Prof. Dr. T. Hayashi
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-3988
4
5[d]
[a] The enone 4 was obtained in 69% yield. [b] Reaction time: 10 h.
[c] Compound 1a was recovered in 65% yield. [d] The reaction was
conducted with 1.2 equiv of 2a for 12 h.
E-mail: shintani@kuchem.kyoto-u.ac.jp
thayashi@kuchem.kyoto-u.ac.jp
[**] Financial support was provided in part by a Grant-in-Aid for
Scientific Research and the Ministry of Education, Culture, Sports,
Science, and Technology, Japan (21st Century COE, Kyoto University
Alliance for Chemistry).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 3: Scope of the rhodium-catalyzed asymmetric synthesis of 3,3-
disubstituted 1-indanones with respect to the substrate 1.
Scheme 1. A possible pathway for the formation of the undesired
enone 4.
Entry
Substrate
Product
Yield [%]
ee [%]
1
2
3
4
1b: R1 =SiEt3, R2 =2-Me
1c: R1 =SiEt3, R2 =3-Me
1d: R1 =SiEt3, R2 =4-Me
1e: R1 =SiEt3, R2 =4-MeO
1 f: R1 =SiEt3, R2 =4-F
1g: R1 =SiMe2Et, R2 =H
1h: R1 =SiMe2tBu, R2 =H
1i: R1 =GeEt3, R2 =H
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
86
84[a]
83
82
79
90
75
88
94
98
98
98
99
94
98
97
(Table 1, entry 4; 87% yield, 99% ee). A similar result was
obtained with (R)-segphos even with 1.2equivalents of 2a
(Table 1, entry 5; 89% yield, 98% ee).
Under these conditions, a variety of aryl boronates can be
used with substrate 1a to give 3,3-disubstituted 1-indanones in
high yield with excellent enantioselectivity (Table 2,
entries 1–7). A methyl group can also be installed with
moderate efficiency (Table 2, entry 8; 51% yield, 87% ee).
With regard to the variability of the substrate, substituents on
5[b]
6
7[c]
8[b]
[a] The cyclization occurred exclusively at the less hindered site on the
aromatic ring. [b] The reaction was conducted with 8 mol% of the
catalyst. [c] The reaction was conducted with 8 mol% of the catalyst and
1.5 equiv of 2a for 24 h.
Table 2: Scope of the rhodium-catalyzed asymmetric synthesis of 3,3-
disubstituted 1-indanones with respect to the nucleophile.
Entry
R
P
Product
Yield [%]
ee [%]
1
2a)
h (
3aa
3ab
3ac
3ad
3ae
3af
89
71
83
88
89
91
91
51
98
98
99
98
98
96
98
87
2[a]
3
4-MeOC6H4 (2b)
4-MeC6H4 (2c)
4-BrC6H4 (2d)
4-CF3C6H4 (2e)
3-ClC6H4 (2 f)
2-naphthyl (2g)
Me (2h)
4[b]
5
6
7
3ag
3ah
8[c]
[a] The reaction was conducted with 8 mol% of the catalyst and 1.5 equiv
of 2b for 24 h. [b] The reaction was conducted with 8 mol% of the
catalyst. [c] The reaction was conducted with 8 mol% of the catalyst and
3 equiv of 2h for 24 h.
Figure 1. X-ray structure of 3jg with thermal ellipsoids drawn at the
50% probability level (Flack parameter=0.01(3); hydrogen atoms are
omitted for clarity).
the benzene ring can be varied both sterically and electroni-
cally with maintenance of the high yield and ee value of the
product (Table 3, entries 1–5). Other silyl groups or a germyl
group can also be used as a substituent on the alkyne (Table 3,
entries 6–8).[9]
Indanone 3jg, which was obtained from the reaction of 1-
(3-chlorophenyl)-3-triethylsilyl-2-propyn-1-one (1j) with the
2-naphthylboronate 2g [Eq. (3)], furnished single crystals
suitable for X-ray analysis. Its absolute configuration was
determined to be R (Figure 1).[10]
By analogy with the rhodium-catalyzed formation of 3,3-
disubstituted 1-indanones by using aryl zinc chlorides,[4]
a
proposed reaction pathway to indanone 3aa under the
present conditions is illustrated in Scheme 2. Thus, insertion
of the alkyne of 1a into the phenyl–rhodium bond generates
the alkenyl rhodium species A, which undergoes a 1,4-
rhodium migration to produce the aryl rhodium intermediate
B.[6,11] Intramolecular 1,4-addition of B leads to the oxa-p-
allyl rhodium species C, and transmetalation of the phenyl
group from boron to rhodium releases the product as the
Scheme 2. Proposed catalytic cycle of the rhodium-catalyzed addition
of the phenylboronate 2a to the aryl alkynyl ketone 1a.
boron enolate D along with a phenyl rhodium species for the
next cycle. The formation of the boron enolate D was
1
confirmed by H NMR spectroscopy before the reaction was
quenched with water (1H NMR (CDCl3): d = 6.38 (s, 1H at
3736
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Chemie
the 2-position of the indanone enolate), 3.74 (s, 4H on the two
methylene carbon atoms of the boronate), and 1.02ppm
(s, 6H of the two methyl groups of the boronate)).
The stereodetermining step of the catalytic cycle is that
from B to C (Scheme 2), and the observed stereochemical
outcome can be rationalized as shown in Figure 2. Thus, the
riched indanones that are difficult to obtain by other methods.
Future studies will focus on the improvement of the catalyst
system to overcome the current limitation in terms of
applicable substrates and nucleophiles.
alkene binds to rhodium from its 2Re face to avoid steric Experimental Section
General procedure (Tables 2and 3): A solution of [{Rh(OH)(cod)} 2]
(2.3 mg, 10 mmol Rh) and (R)-segphos (6.2mg, 10 mmol) in 1,4-
dioxane (0.5 mL) was stirred for 5 min at room temperature. The aryl
repulsion between the Ar group at the 3-position and the
phenyl group on the phosphorus atom of (R)-segphos. This
facial selectivity leads to the formation of R indanones.
The highly enantioenriched indanone 3aa can be manip-
ulated further with high stereoselectivity. For example, the
reduction of the carbonyl group followed by dehydration led
to the synthetically useful allyl silane 4 (Scheme 3). The
reduction of 3aa with HAliBu2 gave indanol 5 with cis se-
lectivity (d.r. 93:7). The protection of 5 with MeOCH2Cl
followed by separation of the diastereomers provided com-
pound 6 as a single diastereomer with 98% ee, the triethylsilyl
group of which could be removed diastereoselectively by
treatment with TBAF to give compound 7 as the cis isomer
(d.r. 91:9).
boronate
2 (0.24 mmol) and 1 (0.20 mmol) were then added
successively with additional 1,4-dioxane (0.5 mL), and the resulting
mixture was stirred for 12h at 50 8C. The reaction was quenched with
water (60 mL), and the mixture was filtered through a pad of silica gel
with Et2O. Removal of the solvent under vacuum was followed by
chromatography of the residue on silica gel with Et2O/hexane to
afford 3.
Received: January 17, 2007
Published online: April 3, 2007
Keywords: alkynes · asymmetric catalysis · boron · indanones ·
.
rhodium
In summary, we have developed a highly enantioselective
synthesis of 3,3-disubstituted 1-indanones through the addi-
tion of aryl boronates to aryl alkynyl ketones under rhodium
catalysis. This new method allows rapid access to enantioen-
[1] For examples, see: a) C. Hedberg, P. G. Andersson, Adv. Synth.
Catal. 2005, 347, 662; b) W. M. Clark, A. M. Tickner-Eldridge,
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N. H. Baine, J. Am. Chem. Soc. 1998, 120, 4550; c) R. T. Lum,
M. G. Nelson, A. Joly, A. G. Horsma, G. Lee, S. M. Meyer, M. M.
Wick, S. R. Schow, Bioorg. Med. Chem. Lett. 1998, 8, 209.
[2] For examples, see: a) J. Yun, S. L. Buchwald, J. Org. Chem. 2000,
65, 767; b) Y. Caro, M. Torrado, C. F. Masaguer, E. Raviæa,
Tetrahedron: Asymmetry 2003, 14, 3689; c) N. Kumagai, S.
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McCullagh, A. T. Morehead, Jr., J. Am. Chem. Soc. 2005, 127,
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Shimada, T. Hayashi, J. Am. Chem. Soc. 2006, 128, 2772.
[3] T. Matsuda, M. Shigeno, M. Makino, M. Murakami, Org. Lett.
2006, 8, 3379.
[4] R. Shintani, T. Hayashi, Org. Lett. 2005, 7, 2071.
[5] H. Takaya, K. Mashima, K. Koyano, M. Yagi, H. Kumobayashi,
T. Taketomi, S. Akutagawa, R. Noyori, J. Org. Chem. 1986, 51,
629.
Figure 2. Proposed stereochemical pathway for the Rh/(R)-segphos-
catalyzed asymmetric synthesis of 3,3-disubstituted 1-indanones.
[6] T. Hayashi, K. Inoue, N. Taniguchi, M. Ogasawara, J. Am. Chem.
Soc. 2001, 123, 9918.
[7] For examples of the effect of phenylboronate substituents on
reactivity, see: a) F. Kakiuchi, Y. Matsuura, S. Kan, N. Chatani, J.
Am. Chem. Soc. 2005, 127, 5936; b) K. Ukai, M. Aoki, J. Takaya,
N. Iwasawa, J. Am. Chem. Soc. 2006, 128, 8706.
[8] T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T. Miura, H.
Kumobayashi, Adv. Synth. Catal. 2001, 343, 264.
[9] To date we have not been successful in employing alkynes with
carbon-based substituents as the substrate.
[10] CCDC-631569 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[11] a) K. Oguma, M. Miura, T. Satoh, M. Nomura, J. Am. Chem. Soc.
2000, 122, 10464; b) T. Miura, T. Sasaki, H. Nakazawa, M.
Murakami, J. Am. Chem. Soc. 2005, 127, 1390; c) R. Shintani, K.
Okamoto, T. Hayashi, J. Am. Chem. Soc. 2005, 127, 2 872 ; d) H.
Yamabe, A. Mizuno, H. Kusama, N. Iwasawa, J. Am. Chem. Soc.
2005, 127, 3248.
Scheme 3. Conversion of indanone 3aa into several indan derivatives:
a) LiAlH4, THF, RT; b) cat. TsOH, C6H6, reflux, 96% (over 2 steps);
c) HAliBu2, THF, À788C, 97% (d.r. 93:7); d) MeOCH2Cl, iPr2NEt,
CH2Cl2, RT; then separation of diastereomers, major: 90%; e) TBAF,
THF, 08C, 98% (d.r. 91:9). TBAF=tetrabutylammonium fluoride.
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