Novel one-pot approach to synthesis of indanones Through Sb(V)-catalyzed reaction of phenylalkynes with aldehydes

Article abstract of DOI:10.1021/ol800539a

Catalytic SbF₅ and the use of EtOH as an additive efficiently converted a mixture of phenylalkynes and aldehydes to indanone compounds in one pot, and the reaction stereoselectively afforded the corresponding 2,3-disubstituted indanones as a single trans-isomer.

Full text of DOI:10.1021/ol800539a

ORGANIC
LETTERS
2
008
Vol. 10, No. 9
783-1785
Novel One-Pot Approach to Synthesis of
Indanones through Sb(V)-Catalyzed
Reaction of Phenylalkynes with
Aldehydes
1
Akio Saito,* Masaharu Umakoshi, Naomi Yagyu, and Yuji Hanzawa*
Laboratory of Organic Reaction Chemistry, Showa Pharmaceutical UniVersity, 3-3165
Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
akio-sai@ac.shoyaku.ac.jp; hanzaway@ac.shoyaku.ac.jp
Received March 10, 2008
ABSTRACT
5
Catalytic SbF and the use of EtOH as an additive efficiently converted a mixture of phenylalkynes and aldehydes to indanone compounds in
one pot, and the reaction stereoselectively afforded the corresponding 2,3-disubstituted indanones as a single trans-isomer.
3
1-Indanone compounds are important synthetic intermediates
synthesis of indanones via Nazarov cyclization of phenyl
for pharmaceutical agents and biologically active
alkenyl ketone intermediates have been known as convenient
methods, while the procedures often required stoichiometric
1
compounds, and there are numerous methods available for
2
4,5
6
the preparation of 1-indanones. One-pot approaches for the
amounts of promoters and organometallics. The formation
of conjugated enones from alkyne and aldehyde by formal
alkyne-carbonyl metathesis has received attention because
of the atom-economical process alternative to the Wittig
(
1) For examples: (a) Bogeso, K. P.; Christensen, A. V.; Hyttel, J.;
Liljefors, T. J. Med. Chem. 1985, 28, 1817–1828. (b) Bogeso, K. P.; Arnt,
J.; Frederiksen, K.; Hansen, H. O.; Hyttel, J.; Pedersen, H. J. Med. Chem.
1
2
995, 38, 4380–4392. (c) Sugimoto, H. Pure Appl. Chem. 1999, 71, 2031–
7,8
reaction (Scheme 1). Although alkyne-carbonyl metath-
037. (d) Guillon, J.; Dallemagne, P.; Leger, J.-M.; Sopkova, J.; Bovy,
P. R.; Jarry, C.; Rault, S. Bioorg. Med. Chem. 2002, 10, 1043–1050.
2) For a recent summary of the synthesis of 1-indanones, see: Wessig,
P.; Glombitza, C.; Muller, G.; Teubner, J. J. Org. Chem. 2004, 69, 7582–
(
7
591.
Scheme 1. Alkyne-Carbonyl Metathesis
(
(
3) For review: Pellissier, H. Tetrahedron 2005, 61, 6479–6517.
4) Examples of Knoevenagel condensation-Nazarov cyclization: (a)
Satori, G.; Bigi, F.; Maggi, R.; Bernardi, G. L. Tetrahedron Lett. 1993, 34,
7339–7342. (b) Bhattacharya, A.; Segmuller, B.; Ybarra, A. Synth. Commun.
1
996, 26, 1775–1784. (c) Lawrence, N. J.; Armitage, E. S. M.; Greedy, B.;
Cook, D.; Ducki, S.; McGown, A. T. Tetrahedron Lett. 2006, 47, 1637–
1
640. (d) Cui, H.-F.; Dong, K.-Y.; Zhang, G.-W.; Wang, L.; Ma, J.-A. Chem.
Commun. 2007, 2284–2286.
5) Examples of Friedel-Craft acylation-Nazarov cyclization: (a)
(
esis is promoted by miscellaneous Lewis acids and Brønsted
Dietrich, U.; Hackmann, M.; Rieger, B.; Klinga, M.; Leskela, M. J. Am.
Chem. Soc. 1999, 121, 4348–4355. (b) Jaroch, S.; H o¨ lscher, P.; Rehwinkel,
H.; S u¨ lzle, D.; Burton, G.; Hillmann, M.; McDonald, F. M. Bioorg. Med.
Chem. 2002, 12, 2561–2564. (c) Yin, W.; Ma, Y.; Xu, J.; Zhao, Y. J. Org.
Chem. 2006, 71, 4312–4315.
9
,10
acids,
to the best of our knowledge, a one-pot approach
to the catalytic formation of indanones by a reaction of
1
1
alkyne and aldehyde has yet to have been achieved. We
10.1021/ol800539a CCC: $40.75
Published on Web 04/09/2008
 2008 American Chemical Society

herein report the stereoselective synthesis of 2,3-disubstituted
indanones through the SbF -catalyzed reaction of phenyla-
5
lkyne derivatives with aldehydes.
At the outset, we focused our efforts on the screening of
catalysts (10-20 mol %) for the formation of indanone 2a
in the reaction of phenylalkyne 1 with benzaldehyde (1.2
equiv) in 1,2-dichloroethane (DCE, Table 1). Although
Table 1. Screening of Catalyst Systems for the Formation of
a
2
a
Figure 1
in the SbF
.
Effect of protic or aprotic polar additive (1 equiv to 1)
(10 mol %)-catalyzed reaction of 1 benzaldehyde (1.2
5
equiv) at 90 °C for 2 h in DCE. (Yields of 2a and 3a were
1
determined by H NMR.) TFE, 2,2,2-trifluoroethanol; HFIP,
1
,1,1,3,3,3-hexafluoro-2-propanol.
1
4
8
, however, did not yield indanone but enone 9. It should
2
be mentioned that the use of PhCH(OEt) instead of
MeOH (none)
MeOH (1 equiv to 1)
benzaldehyde showed a rather lower yield of 2a, regardless
of the presence of EtOH (Table 2). Although propiophenone
(10), propiophenone diethylacetal (11), or R-ethoxy-ꢀ-meth-
ylstyrene (12) would be expected as an intermediate from
alkyne 1 and EtOH, the use of the compounds instead of 1
brought about inferior results (see Supporting Information).
The reaction of phenylalkyne 1 with benzaldehyde at a
lower temperature (60 °C, 1 h) by the present catalytic system
afforded the enone 3a in 92% yield (Scheme 2). 3a could
be converted into the corresponding indanone 2a under
similar conditions at 90 °C within 2 h in good yield with
excellent selectivity (Scheme 2). Therefore, we believe that
the one-pot formation of 2a from 1 and aldehyde would
b
b
yield (%)
yield (%)
Catalyst (mol % to 1a) 2a 3a
1
2a
3a
1
AgSbF6 (10)
BF3·OEt2 (20)
TfOH (20)
In (OTf)3 (10)
Sc (OTf)3 (10)
Yb (OTf)3 (10)
Cu (OTf)2 (10)
SbF5 (10)
20
21
39
–
21
–
4
26
6
20
41
–
–
7
–
–
6
–
–
–
46
27
53
61
35
4
–
44
–
–
40
–
39
–
72
–
20
–
–
–
48
–
–
8
8
–
37
31
19
13
61
2
c
c
SbCl5 (10)
55
8
a
Reaction conditions: 90 °C, 18-22 h. Determined by 1H NMR
analysis using toluene as an internal standard. 90 °C, 4 h.
b
c
previously reported catalysts have brought about good results
Table 2. Formation of Indanones by SbF
5
a-EtOH-Catalyzed
Reaction of Phenylalkynes with Aldehyde
7–10
for the formation of conjugated enones,
in low yields even at 90 °C for 18-22 h (left column, Table
). On the other hand, an addition of alcohol (1 equiv to 1)
exerted a remarkable effect on the formation of 2a (right
column, Table 1). In particular, by the use of SbF in the
2a was obtained
1
5
presence of MeOH, the desired reaction stereoselectively
proceeded at 90 °C within 4 h to give 2a as a single trans-
1
2
isomer in 61% yield.
We next investigated the additive effect of alcohol (1 equiv
to 1) in the reaction of 1 with benzaldehyde (1.2 equiv) in
alkyne/R1
2
b
R CHO
time (h) product/%
1
/Me
PhCHO
2
7
8
2a
2a
2b
2c
2d
5a
5b
5c
5d
7a
7b
9
78
55 (54 )
89
75
72
78
82
66
38 (63 )
the presence of SbF
5
(10 mol %) at 90 °C for 2 h in DCE
c
PhCH(OEt)2
tBuCHO
EtCHO
CyCHO
PhCHO
tBuCHO
Ph (CH)2CHO
iPrCHO
PhCHO
MeCHO
(Figure 1). Compared with the fluorinated alcohol or aprotic
polar additive, EtOH turns out to be an efficient additive.
Thus, in the presence of EtOH, 1 was consumed at 90 °C
within 2 h to give 3a in 76% yield with complete trans-
22
72
4
10
22
96
22
48
48
4/nBu
1
3
selectivity.
Under the optimized conditions, the present catalytic
system could be applied to the reaction of substituted alkyne
compounds 1, 4, and 6 with various aldehydes (Table 2).
Thus, many aldehydes successfully reacted with alkyne 1,
d
6
/Ph
/H
59
45
60
e
8
PhCHO
4
, and 6 to give the corresponding indanone products in
a
b
c
CyCHO: cyclohexanecarboaldehyde. Isolated yield. EtOH was
d
e
moderate to high yields. In all cases, complete trans-
absent.
SbF5: 20 mol %. 3 equiv.
selectivities were observed. The reaction of terminal alkyne
1784
Org. Lett., Vol. 10, No. 9, 2008

would preferentially activate aldehyde rather than alkyne to
bring about the formation of 3a.
In conclusion, we developed a highly stereoselective one-
pot synthesis of trans-2,3-disubstituted indanone derivatives
from phenylalkynes with aldehydes. The use of EtOH as an
Scheme 2
5
additive was found to be essential for the SbF -catalyzed
formation of indanone derivatives. Synthetic applications and
detailed mechanistic studies of the present reaction are
underway.
Acknowledgment. This work was supported by a Grant-
in-Aid for Young Scientists (B), MEXT Japan (No. 17790021).
A generous donation of HFIP by Central Glass Co., Ltd., is
gratefully acknowledged.
consist of (i) the formal alkyne-carbonyl metathesis between
both substrates and (ii) Nazarov cyclization of phenyl alkenyl
ketone intermediates. Although the precise role of EtOH is
less clear, one of the possibilities would be the generation
Supporting Information Available: Experimental pro-
cedures and physical data for 2a-2d, 3a, 5a-5c, and 7a,b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
5
of the protic catalyst SbF ·EtOH.
5
To gain a qualitative understanding of the activation of
alkyne 1 and benzaldehyde by the present catalytic system,
OL800539A
we carried out NMR studies using SbF
5
·10EtOH (a 1:10
and EtOH). The C NMR spectrum (75
MHz) of a 1:1 mixture of 1 and benzaldehyde in the presence
of 10 equiv of EtOH in (CD Cl) at room temperature
(9) Intermolecular alkyne-aldehyde metathesis by means of stoichio-
metric Lewis acid promoters: (a) Hayashi, A.; Yamaguchi, M.; Hirama,
M. Synlett 1995, 195. and references cited therein. (b) Viswanathan, G. S.;
Li, C.-J Tetrahedron Lett. 2002, 43, 1613.
1
3
mixture of SbF
5
(
10) Intramolecular coupling reaction of ω-alkynyl-ketones: (a) Harding,
2
2
C. E.; Hanack, M. J. Org. Chem. 1989, 54, 3054. and references cited
therein. (b) Sisko, J.; Balog, A.; Curran, J. Org. Chem. 1992, 57, 4341. (c)
Wempe, M. F.; Grunwell, J. R. Tetrahedron Lett. 2000, 41, 6709.
showed that the signals of the sp-carbons (δ 81.32, 87.73)
of 1 scarcely shifted (δ 81.34, 87.69) and the carbonyl-carbon
(
11) In the GaCl3-mediated reactions of phenylalkynes with aldehydes,
(
1
δ 193.78) of benzaldehyde shifted to a lower field (δ
94.20). In the case of the mixture of 1, aldehyde, and a
stoichiometric amount of SbF ·10EtOH (1/benzaldehyde/
SbF /EtOH ) 1:1:1:10), the slight shift of sp-carbons of 1
to a higher field (δ 81.12, 87.58) and the shift of carbonyl-
3
-chloro-1,2-dialkyl-1H-indene derivatives were obtained as byproducts
(4-22%). See: Viswanathan, G. S.; Li, C.-J. Tetrahedron Lett. 2002, 43,
613–1615.
12) It is one of the possibilities that small amounts of cis-indanone
1
5
(
5
included in the initially formed diastereomer mixtures would be isomerized
to trans-isomer. See: Touron, P.; Laude, B. C. R. Acad. Sci. Ser. C 1979,
289, 53.
16
carbon to a lower field (δ 194.31) were observed. A similar
(
13) Addition of 1 equiv of EtOH to 1 ended with an optimum amount
observation has been reported in the Ag(I)-catalyzed reaction
for the formation of 2a (see Supporting Information).
8
(14) Nazarov cyclization of chalcone (9) also did not proceed under
the identical conditions. Generally, 9 required more harsh conditions than
of alkyne and aldehyde. Thus, the present catalytic system
2
-substituted enones. See: Koltunov, K. Y.; Walspurger, S.; Sommer, J.
(
6) Examples of Stille-Scott cross-copling reaction-Nazarov cycliza-
tion: (a) Kerr, D. J.; Metje, C.; Flynn, B. L. Chem. Commun. 2003, 138,
–1381. (b) Kerr, D. J.; Hamel, E.; Jung, M. K.; Flynn, B. L. Bioorg. Med.
Chem. 2007, 15, 3290–3298.
7) Catalytic intermolecular alkyne-aldehyde metathesis: Curini, M.;
Epifano, F.; Maltese, F.; Rosati, O. Synlett 2003, 552.
8) Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493.
Tetrahedron Lett. 2005, 46, 8391.
(15) Il’in, E. G.; Nazarov, A. P.; Buslaev, Y. A. Dokl. Akad. Nauk SSSR
1979, 249, 1149–1152.
0
(16) By NMR studies using various equivalents of SbF5·10EtOH (0.1,
0.3, 0.5, 1 equiv to 1), we found that the change in chemical shift of 1 and
benzaldehyde depends on an amount of SbF5·10EtOH. Thus, it is suggested
that SbF5·10EtOH would induce an activation of 1 and/or benzaldehyde.
(
(
Org. Lett., Vol. 10, No. 9, 2008
1785