Rhenium-catalyzed synthesis of indenones by novel dehydrative trimerization of aryl aldehydes via C-H bond activation

Article abstract of DOI:10.1021/ol100947p

By heating aryl aldehydes with catalytic amounts of a rhenium complex, ReBr(CO)₅, and N-phenylacetamide in toluene, indenone derivatives are obtained in good to excellent yields. This reaction proceeds via (1) the formation of an isobenzofuran derivative by the insertion of an aldehyde into the C-H bond of another aldehyde (C-H bond activation) and successive intramolecular nucleophilic cyclization, (2) nucleophilic addition of the formed isobenzofuran derivative to the third aldehyde, (3) isomerization, and (4) intramolecular aldol condensation.

Full text of DOI:10.1021/ol100947p

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2948-2950
Rhenium-Catalyzed Synthesis of
Indenones by Novel Dehydrative
Trimerization of Aryl Aldehydes via
C-H Bond Activation
Yoichiro Kuninobu,* Takashi Matsuki, and Kazuhiko Takai*
DiVision of Chemistry and Biochemistry, Graduate School of Natural Science and
Technology, Okayama UniVersity, Tsushima, Kita-ku, Okayama 700-8530, Japan
kuninobu@cc.okayama-u.ac.jp; ktakai@cc.okayama-u.ac.jp
Received April 26, 2010
ABSTRACT
By heating aryl aldehydes with catalytic amounts of a rhenium complex, ReBr(CO)5, and N-phenylacetamide in toluene, indenone derivatives
are obtained in good to excellent yields. This reaction proceeds via (1) the formation of an isobenzofuran derivative by the insertion of an
aldehyde into the C-H bond of another aldehyde (C-H bond activation) and successive intramolecular nucleophilic cyclization, (2) nucleophilic
addition of the formed isobenzofuran derivative to the third aldehyde, (3) isomerization, and (4) intramolecular aldol condensation.
Cyclic compounds are useful and indispensable entries in
organic chemistry. Transformation via C-H bond activation
is one of the most efficient and powerful methods to construct
cyclic skeletons, and the skeletons have been constructed
by intramolecular cyclization1,2 and annulation reactions. We
previously reported the rhenium-catalyzed synthesis of cyclic
compounds via C-H bond activation (two-component an-
nulation).3 These annulation reactions proceed via intermo-
lecular insertion of an unsaturated molecule into a C-H
bond, followed by intramolecular nucleophilic cyclization.3
Three-component cycloadditions via C-H bond activation
have also been reported (three-component annulation);
however, these examples are rare.3d,4 We report herein a
rhenium-catalyzed three-component cycloaddition via C-H
bond activation to produce indenone derivatives.5-7
(4) (a) Tasukawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2002, 124, 12680. (b) Kuninobu, Y.; Nishina, Y.; Takai, K. Tetrahedron
2007, 63, 8463. (c) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew.
Chem., Int. Ed. 2008, 47, 4019
.
(5) There have been several reports on transition-metal-catalyzed
syntheses of indenone derivatives. See: (a) Larock, R. C.; Doty, M. J. J.
Org. Chem. 1993, 58, 4579. (b) Miura, T.; Murakami, M. Org. Lett. 2005,
7, 3339. (c) Wender, P. A.; Paxton, T. J.; Williams, T. J. J. Am. Chem.
Soc. 2006, 128, 14814. (d) Harada, Y.; Nakanishi, J.; Fujihara, H.; Tobisu,
M.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2007, 129, 5766. (e)
(1) (a) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2001, 123, 9692. (b) Youn, S. W.; Pastine, S. J.; Sames,
D. Org. Lett. 2004, 6, 581
.
(2) Yang, S.; Li, Z.; Jian, X.; He, C. Angew. Chem., Int. Ed. 2009, 48,
3999
.
Liu, C.-C.; Korivi, R. P.; Cheng, C.-H. Chem.sEur. J. 2008, 14, 9503.
(3) (a) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2005,
127, 13498. (b) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J. Am.
Chem. Soc. 2006, 128, 202. (c) Kuninobu, Y.; Nishina, Y.; Shouho, M.;
Takai, K. Angew. Chem., Int. Ed. 2006, 45, 2766. (d) Kuninobu, Y.; Nishina,
Y.; Nakagawa, C.; Takai, K. J. Am. Chem. Soc. 2006, 128, 12376. (e)
Kuninobu, Y.; Nishina, Y.; Matsuki, T.; Takai, K. J. Am. Chem. Soc. 2008,
130, 14062.
(6) Indenones are used as starting materials for synthesizing indenes
and indenyl-transition-metal complexes. See: (a) Anstead, G. M.; Ensign,
J. L.; Peterson, C. S.; Katzenellenbogen, J. A. J. Org. Chem. 1989, 54,
1485. (b) Xi, Q.; Zhang, W.; Zhang, X. Synlett 2006, 945
(7) Indenones are key intermediates for the synthesis of bioactive
products. See: Walspurger, S.; Vasilyev, A. V.; Sommer, J.; Pale, P.
.
Tetrahedron 2005, 61, 3559
.
10.1021/ol100947p  2010 American Chemical Society
Published on Web 06/07/2010

Treatment of benzaldehyde (1a) with catalytic amounts of a
rhenium complex, ReBr(CO)5, and N-phenylacetamide in
toluene gave indenone derivative 2a in 98% yield (eq 1).8-11
Without the rhenium catalyst or amide, the reaction did not
proceed, and starting material was recovered completely.
as a methoxycarbonyl group and bromine atom (entries 4 and
5). When 3-methylbenzaldehyde (1g) was used, indenones 2g
and 2g′ were generated in 89% and 8% yields, respectively
(entry 6). In this reaction, although there are two possible
products, 2g was formed selectively. 2-Methylbenzaldehyde
(1h), with only one ortho position available for reaction, also
provided the corresponding indenone 2h in 98% yield (entry
7). However, thiophene-2-carbaldehyde, pyridine-4-carbalde-
hyde, trans-2-decenal, and trans-cinnamaldehyde did not pro-
duce the corresponding indenone derivatives.
To elucidate the reaction mechanism, we attempted to capture
a reaction intermediate. By heating benzaldehyde (1a) in the
presence of an olefin with an electron-withdrawing group, 3a
or 3b, naphthalene derivatives 4a and 4b were obtained in 45%
and 90% yields, respectively (eq 2). This result indicates the
formation of isobenzofuran intermediates12,13 because the
naphthalene derivatives 4 must be produced by the dehydra-
tion of 5. The intermediate 5 is derived from a Diels-Alder
reaction between isobenzofuran intermediates and dieno-
philes 3 by overcoming the nucleophilic addition of the
isobenzofuran intermediate to the third aldehyde. The reac-
tions in eq 2 are also three-component cycloaddition reactions
via C-H bond activation.
To examine the scope and limitations of the substrates, several
aldehydes were investigated (Table 1). By the reaction of an
Table 1. Synthesis of Indenones from Several Aldehydesa
Next, we investigated the intermediate that formed after
the generation of the isobenzofuran intermediate. It has
already been reported that an acetal intermediate (in Scheme
1, between steps 8 and 9) was formed by the reaction
(8) Investigation of several transition-metal complexes: [ReBr(CO)3-
(thf)]2, 98%; Re2(CO)10, 80%; MnBr(CO)5, 0%; Mn2(CO)10, 0%; Ru3(CO)12,
0%; RuH2(CO)(PPh3)3, 0%; RhCl(PPh3)3, 0%; Ir4(CO)12, 0%.
(9) Investigation of several additives: aniline, 80%; 4-methoxyaniline,
75%; 4-trifluoromethylaniline, 98%; N-methylaniline, 62%; N,N-dimethy-
laniline, 0%.
(10) The present reaction requires 180 °C, whereas the reaction reported
in ref 3d proceeds at 115 °C. When the reaction was carried out at 115 °C
in the presence of catalytic amounts of ReBr(CO)5 and N-phenylacetamide,
an intermediate, isobenzofuran, was not observed, and benzaldehyde was
recovered completely. The result indicates that the formation of the
isobenzofurans from 2 equiv of aldehydes requires heating at 180 °C.
(11) In the case of known cyclotrimerizations of aldehydes, 1,3,5-
trioxane derivatives are formed. See: (a) Ishii, Y.; Nakano, T. (Daicel
Chemical Industries, Ltd.), JP P2002-145877A, 2002. (b) Griesbeck, A. G.;
a 1.0 M. b Isolated yield. c 2.0 M.
aldehyde with a methoxy group at the para position, 1b, the
corresponding indenone derivative 2b was obtained in 77%
yield (entry 1). When an aldehyde bearing a methyl group, 1c,
was used, indenone 2c was produced in almost quantitative yield
(entry 2).
The corresponding indenone 2d was generated by the reaction
of an aldehyde with an electron-withdrawing group, 1d (entry
3). These reactions were not affected by functional groups, such
El-Idreesy, T. T.; Fiege, M.; Brun, R. Org. Lett. 2002, 4, 4193
.
(12) We have already reported the rhenium-catalyzed synthesis of
isobenzofuran derivatives via the insertion of aldehydes into a C-H bond
of aromatic compounds followed by intramolecular nucleophilic cyclization
and dehydration. See ref 3d.
(13) There has been a report on the reaction between 1-phenylisoben-
zofuran and a dienophile by Diels-Alder reaction. See: Tobia, D.; Rickborn,
B. J. Org. Chem. 1986, 51, 3849
.
Org. Lett., Vol. 12, No. 13, 2010
2949

directing group);16,17 (3) insertion of another aldehyde into
the formed rhenium-carbon bond; (4) elimination of the
amide; (5) intramolecular nucleophilic cyclization; (6) reduc-
tive elimination and the elimination of H2O to give an
isobenzofuran derivative3d and regeneration of the rhenium
catalyst; (7) nucleophilic addition of the isobenzofuran
derivative to the third aldehyde;18 (8) intramolecular nu-
cleophilic attack of the alkoxide to the carbon atom of the
carbonyl group;19 (9) ring-opening reaction of the acetal
intermediate;20 (10) formation of a diketone; (11) intramo-
lecular aldol reaction and dehydration leading to an indenone
derivative with the rhenium catalyst. This reaction is interest-
ing because a single complex catalyzes the many reaction
steps.
Scheme 1. Proposed Mechanism for the Formaion of Indenones 2
In summary, we have succeeded in the rhenium- and
amide-catalyzed synthesis of indenone derivatives from 3
equiv of aldehydes. This reaction can be regarded as a new
type of dehydrative trimerization of aldehydes. The rhenium
complex functions both as a catalyst for C-H bond
transformation and a Lewis acid. We hope that this reaction
will become a useful method to synthesize indenone deriva-
tives.
Acknowledgment. This work was partially supported by
the Ministry of Education, Culture, Sports, Science, and
Technology of Japan.
Supporting Information Available: General experimental
procedure, characterization data for indenones 2 and naph-
thalenes 4, and procedure for the synthesis of diketone 5.
This material is available free of charge via the Internet at
http://pubs.acs.org.
between an isobenzofuran derivative and an aldehyde.14 After
the formation of the acetal intermediate, a diketone (in
Scheme 1, between steps 10 and 11) would be formed by
rearrangement of the acetal. By heating diketone 6 in the
presence of ReBr(CO)5, indenone 2a was obtained quanti-
tatively (eq 3). This result shows that indenones are formed
via diketone intermediates.
OL100947P
(15) Another possibility is the formation of an aldimine from hydroxy
amide intermediate A by the elimination of acetic acid from A, and the
C-H activation of the aldimine occurs.
(16) The same reaction also proceeded by adding a catalytic amount of
N-methylaniline instead of N-phenylacetamide. Therefore, we think that
the amide might also react with an aldehyde with the nitrogen atom acting
as a directing group. For examples of C-H bond transformations using a
nitrogen (sp3) atom as a directing group, see: (a) Diamond, S. E.;
Szalkiewicz, A.; Mares, F. J. Am. Chem. Soc. 1979, 101, 490. (b) Uchimaru,
Y. Chem. Commun. 1999, 1133. (c) Kakiuchi, F.; Igi, K.; Matsumoto, M.;
Hayamizu, T.; Chatani, N.; Murai, S. Chem. Lett. 2002, 396. (d) Cai, G.;
Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666.
(17) In this reaction, a nitrogen (sp3) atom [not oxygen (sp2) atom] is
effective as a directing group.
(18) There have been several reports on nucleophilic addition of
isobenzofurans to electrophiles. See: (a) Friedrichsen, W. AdV. Heterocycl.
Chem. 1980, 26, 135. (b) Brown, S. N. Inorg. Chem. 2000, 39, 378.
(19) Instead of steps 7 and 8, the following step could also occur: hetero-
Diels-Alder reaction between the formed isobenzofuran intermediate and
the third aldehyde. In fact, there has been a report on a Diels-Alder reaction
between an isobenzofuran derivative and aldehyde. See ref 13.
(20) A rhenium catalyst, ReBr(CO)5, acted as a Lewis acid even in the
presence of H2O, which is formed by dehydration as shown in Scheme 1,
steps 6 and 11.
Based on the above experimental results, the mechanism
for the formation of indenones is proposed as follows
(Scheme 1): (1) formation of an R-hydroxy amide from an
aldehyde and amide;15 (2) oxidative addition of the C-H
bond of the R-hydroxy amide to a rhenium center (C-H
bond activation, R-hydroxy amide moiety works as a
(14) Yick, C.-Y.; Chan, S.-H.; Wong, H. N. C. Tetrahedron Lett. 2000,
41, 5957.
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