Rhodium-catalyzed addition of arylzinc reagents to aryl alkynyl ketones: Synthesis of β,β-disubstituted indanones

Article abstract of DOI:10.1021/ol0506819

(Chemical Equation Presented) A rhodium-catalyzed addition of arylzinc reagents to aryl alkynyl ketones for the synthesis of highly substituted indanones has been developed. The key to success has proved to be a proper choice of the reaction system, which involves the employment of dppf as a ligand and 1,2-dichloroethane as a solvent.

Full text of DOI:10.1021/ol0506819

ORGANIC
LETTERS
2005
Vol. 7, No. 10
2071-2073
Rhodium-Catalyzed Addition of Arylzinc
Reagents to Aryl Alkynyl Ketones:
Synthesis of
Indanones
â,â-Disubstituted
Ryo Shintani and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo,
Kyoto 606-8502, Japan
thayashi@kuchem.kyoto-u.ac.jp
Received March 30, 2005
ABSTRACT
A rhodium-catalyzed addition of arylzinc reagents to aryl alkynyl ketones for the synthesis of highly substituted indanones has been developed.
The key to success has proved to be a proper choice of the reaction system, which involves the employment of dppf as a ligand and
1,2-dichloroethane as a solvent.
Transition-metal-catalyzed multiple-bond-forming reactions
are powerful methods for the efficient construction of
structurally complex molecules, and rhodium-catalyzed
processes involving a 1,4-rhodium migration from an alkenyl
or alkyl carbon to an aryl carbon are becoming useful ways
of achieving such transformations in a single operation.1,2
In this context, Iwasawa1d and our group1e reported a
rhodium-catalyzed isomerization of R-arylpropargyl alcohols
to â-monosubstituted indanones and proposed the interme-
diacy of an aryl alkynyl ketone species, which undergoes a
hydrorhodation followed by a 1,4-rhodium migration. This
reaction cascade prompted us to focus on the development
of a rhodium-catalyzed addition of organometallic reagents
to aryl alkynyl ketones for the synthesis of â,â-disubstituted
indanones.3 Here we describe our significant progress toward
this goal: specifically, a Rh/dppf complex can effectively
catalyze the addition of arylzinc reagents to aryl alkynyl
ketones, furnishing highly substituted indanones in good yield
(eq 1).
Although phenylrhodation is known to occur to an internal
alkyne, generating an alkenylrhodium species,1b,c,4 one can
(1) (a) Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Am. Chem.
Soc. 2000, 122, 10464. (b) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara,
M. J. Am. Chem. Soc. 2001, 123, 9918. (c) Miura, T.; Sasaki, T.; Nakazawa,
H.; Murakami, M. J. Am. Chem. Soc. 2005, 127, 1390. (d) Yamabe, H.;
Mizuno, A.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2005, 127, 3248.
(e) Shintani, R.; Okamoto, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127,
2872.
(2) For recent examples of palladium-catalyzed transformations involving
a 1,4-palladium migration, see: (a) Campo, M. A.; Larock, R. C. J. Am.
Chem. Soc. 2002, 124, 14326. (b) Campo, M. A.; Huang, Q.; Yao, T.; Tian,
Q.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 11506. (c) Huang, Q.;
Campo, M. A.; Yao, T.; Tian, Q.; Larock, R. C. J. Org. Chem. 2004, 69,
8251. (d) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 701.
(3) For recent examples of synthetic methods for â,â-disubstituted
indanones, see: (a) Rendy, R.; Zhang, Y.; McElrea, A.; Gomez, A.; Klumpp,
D. A. J. Org. Chem. 2004, 69, 2340. (b) Prakash, G. K. S.; Yan, P.; To¨ro¨k,
B.; Olah, G. A. Catal. Lett. 2003, 87, 109. (c) Fillion, E.; Fishlock, D.
Org. Lett. 2003, 5, 4653. (d) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J.
M. J. Org. Chem. 2005, 70, 1316. (e) Lee, S. I.; Son, S. U.; Choi, M. R.;
Chung, Y. K.; Lee, S.-G. Tetrahedron Lett. 2003, 44, 4705.
(4) (a) Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi,
T. J. Am. Chem. Soc. 2005, 127, 54. (b) Miura, T.; Shimada, M.; Murakami,
M. J. Am. Chem. Soc. 2005, 127, 1094.
10.1021/ol0506819 CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/09/2005

Table 1. Rhodium-Catalyzed Synthesis of â,â-Disubstituted
Indanones: Impact of Reaction Parameters
entry
ligand
solvent
yield of 2a (%)a
yield of 3a (%)a
1
2
3
4
5
6
7
dppf
dppf
dppf
dppp
dppb
2 PPh3
cod
DCE
THF
81 (80)b
8
6
<2
<2
31
<2
6
24
51
50
59
51
70
toluene
DCE
DCE
DCE
DCE
Figure 1. Possible pathways (desired and undesired) for the
formation of â,â-disubstituted indanones by phenylrhodation of aryl
alkynyl ketones.
a Determined by 1H NMR against an internal standard (MeNO2).
b Isolated yield in parentheses.
imagine several pathways it could take when an aryl alkynyl
ketone is used as the alkyne component (Figure 1). One
possibility is the formation of a rhodium enolate (or an oxa-
π-allylrhodium) through path a,5 whose fate would be an
undesired R,â-enone product. Alternatively, the alkenyl-
rhodium species could undergo a 1,4-rhodium migration via
path b,1b,c which would also end up with the R,â-enone
product. The third and only desirable possibility is the
formation of the other arylrhodium species by a 1,4-shift
through path c.1d,e This intermediate could cyclize by an
intramolecular 1,4-addition to form the targeted indanone,
although it could also be led to the uncyclized R,â-enone
product.
Despite the above-mentioned potential difficulties in
achieving the desired transformation, we have successfully
found a set of conditions that uniquely provide the indanones
in high yield (Table 1). Thus, substrate 1a preferentially gives
the corresponding indanone 2a by the use of PhZnCl in the
presence of a catalytic amount of Rh/dppf (dppf ) 1,1′-bis-
(diphenylphosphino)ferrocene)6 in 1,2-dichloroethane at 25
°C (80% isolated yield; entry 1).7 The choices of solvent
and ligand are critical for the realization of this selective
formation of indanone 2a. For example, in other solvents
such as THF or toluene, the yield of 2a becomes much lower
(6-8% yield) and a significant amount of undesired enone
3a is formed (entries 2 and 3).8 The use of bisphosphine
ligands other than dppf produces only a negligible amount
of indanone 2a, and the major product is undesired enone
3a (entries 4 and 5). PPh3 is somewhat effective for
generating indanone 2a, but it has much lower efficiency
(31% yield; entry 6) than dppf. The use of diene ligands
such as cod instead of phosphine ligands preferentially
produces enone 3a as well (entry 7).
Under these optimized conditions with Rh/dppf in 1,2-
dichloroethane, the scope of aryl alkynyl ketones is shown
in Table 2. Thus, several substrates bearing an alkyl group
on the alkyne undergo this addition/cyclization process to
furnish the desired â,â-disubstituted indanones in good yield
(75-84% yield; entries 1-3),9 and various substitution
patterns can be tolerated on the aromatic portion of the
substrate as well to afford the desired products in relatively
high yield (63-77% yield; entries 4-7). With regard to the
nucleophilic component, the scope of substituents on the aryl
group is fairly broad, furnishing the corresponding indanones
in high yield (72-81% yield; Table 3, entries 2-5), although
the yield becomes somewhat modest when the relatively
bulky o-tolyl group is used (53% yield; entry 6).
Table 2. Rhodium-Catalyzed Synthesis of â,â-Disubstituted
Indanones: Scope of the Aryl Alkynyl Ketone
entry
substrate
R1 ) n-Bu
yield (%)a
1
2
3
4
5
6
7
R ) H
R ) H
R ) H
R ) 4-Me
R ) 4-MeO
R ) 4-F
R ) 2-Me
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
80
84
75
74
63
68
77
R1 ) n-Hex
R1 ) i-Bu
R1 ) n-Bu
R1 ) n-Bu
R1 ) n-Bu
R1 ) n-Bu
(5) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579. (c) Hayashi, T.; Takahashi, M.; Takaya,
Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052.
(1g)
(6) Gan, K.-S.; Hor, T. S. A. In Ferrocenes; Togni, A., Hayashi, T.,
Eds.; VCH: Weinheim, 1995; Chapter 1.
a Isolated yield.
(7) For an example of the use of arylzinc reagents in the rhodium-
catalyzed conjugate addition reactions, see: Shintani, R.; Tokunaga, N.;
Doi, H.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240.
(8) 1,2-Dichloroethane is uniquely effective compared to other chlorinated
solvents as well (e.g., dichloromethane or chloroform).
By analogy with the mechanism of the rhodium-catalyzed
isomerization of R-arylpropargyl alcohols to indanones,1d,e
2072
Org. Lett., Vol. 7, No. 10, 2005

and quaternary stereocenters in a single addition/cyclization-
alkylation sequence (eq 3). In addition, a preliminary result
shows that the use of planar-chiral ferrocene-based bisphos-
phine ligand 711 leads to the formation of indanone 2a in
54% ee (eq 4).
Table 3. Rhodium-Catalyzed Synthesis of â,â-Disubstituted
Indanones: Scope of the Arylzinc Reagent
entry
Ar
product
yield (%)a
1
2
3
4
5
6
Ph
2a
2h
2i
2j
2k
2l
80
81
72
74
77
53
4-MeOC6H4
4-FC6H4
3,5-Me2C6H4
2-naphthyl
2-MeC6H4
a Isolated yield.
coupled with the mechanistic studies on the rhodium-
catalyzed 1,4-addition of organometallic reagents to R,â-
enones in aprotic media,10 a proposed reaction pathway of
the present transformation is illustrated in Figure 2. Thus,
insertion of an alkyne into the aryl-rhodium bond generates
alkenylrhodium intermediate A, which undergoes a 1,4-
hydrogen shift to produce arylrhodium species B. Intramo-
lecular 1,4-addition of B leads to oxa-π-allylrhodium C, and
transmetalation of an aryl group from zinc to C releases the
product as a zinc enolate along with an arylrhodium species
for the next cycle. Consistent with this mechanism, the
employment of deuterated substrate 4 led to a quantitative
migration of deuterium from the ortho-position to the
R-position (eq 2). Furthermore, to utilize the formation of a
zinc enolate, we decided to functionalize it by the addition
of electrophiles. For example, the addition of allyl bromide
provides R-allylated indanone 6 in 60% yield, generating
three carbon-carbon bonds, a new ring, and adjacent tertiary
In summary, we have developed a rhodium-catalyzed
addition of arylzinc reagents to aryl alkynyl ketones for the
synthesis of highly substituted indanones. The key to success
has proved to be a proper choice of the reaction system,
which involves the employment of dppf as a ligand and 1,2-
dichloroethane as a solvent. Future studies will focus on the
development of an effective asymmetric variant of this
process.
Acknowledgment. Support has been provided in part by
a Grant-in-Aid for Scientific Research, the Ministry of
Education, Culture, Sports, Science and Technology, Japan
(21 COE on Kyoto University Alliance for Chemistry).
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0506819
(9) Aryl groups, as well as sterically demanding alkyl or silyl groups,
are not very good substituents on the alkyne under the same conditions,
leading to <40% of the desired indanones.
(10) (a) Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2003,
68, 1901. (b) Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han, J. W. J. Am.
Chem. Soc. 2002, 124, 12102.
(11) Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem.
1988, 53, 113.
Figure 2. Proposed catalytic cycle of the rhodium-catalyzed
addition of arylzinc reagents to aryl alkynyl ketones.
Org. Lett., Vol. 7, No. 10, 2005
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