Rhenium- and aniline-catalyzed one-pot annulation of aromatic ketones and α,β-unsaturated esters initiated by C-H bond activation

Article abstract of DOI:10.1002/anie.200503627

(Chemical Equation Presented) Several reaction steps, including C-H activation, lead to indene derivatives in good yields in the rhenium-catalyzed reaction of aromatic ketimines and ethyl acrylate. Indene derivatives can also be obtained by the reactions

Full text of DOI:10.1002/anie.200503627

Communications
generate reactive species for the addition. If CÀH bond
activation can be used to start the sequential reaction, it is not
necessary to prepare a halogen-containing compound, and the
process does not form an inorganic by-product. Thus, the
reaction process becomes more atom-economical. Most
practical CÀH bond-activation processes use ruthenium and
[
3,4]
rhodium catalysts.
These catalysts promote CÀH bond
activation of the ortho positions of aromatic ketones and
successive insertion of nonpolar unsaturated bonds. However,
the reaction terminates by reductive elimination after the
insertion step. We recently found that a rhenium complex,
[
{ReBr(CO)3
A
H
R
U
(thf)} ], catalyzes the CÀH bond activation of
2
aromatic aldimines. Insertion of internal acetylenes or aryl
isocyanates occurs at the carbon–rhenium bond, and more
importantly, further intramolecular cyclization to the aldi-
[
5]
[6]
mine moiety proceeds to give indenes or phthalimidines.
The difference could result from the fact that the rhenium–
carbon bonds are more polar than rhodium– or ruthenium–
carbon bonds. We disclose herein that the rhenium catalyst
[
{ReBr(CO)3(thf)} ] and p-anisidine cocatalyst promoted the
A
H
R
U
G
2
one-pot annulation of aromatic ketones with a,b-unsaturated
esters to give indene derivatives. The reaction produces only
water as a side product, and hence is environmentally benign.
The reaction of aromatic ketimine 1a and ethyl acrylate
(
2a) in the presence of [{ReBr(CO)3
A
H
R
U
G
[
7,8]
Annulation Reactions
indene derivative 3a in 85% yield [Eq. (1)].
In this
reaction, the imine moiety acted as a directing group for the
DOI: 10.1002/anie.200503627
CÀH bond activation and also as an acceptor for the
[
9]
cyclization. Acetophenone, which bears a ketone group,
remained unchanged under similar reaction conditions. The
formation of 3a with the rhenium catalyst is in sharp contrast
Rhenium- and Aniline-Catalyzed One-Pot
Annulation of Aromatic Ketones and
a,b-Unsaturated Esters Initiated by
CÀH Bond Activation**
to the result with a rhodium complex, [RhCl
A
H
R
U
G
catalyzes only CÀH bond activation and insertion of an
[
10]
acrylate.
Yoichiro Kuninobu,* Yuta Nishina, Makoto Shouho,
and Kazuhiko Takai*
Although there have been many reports on the synthesis of
cyclic compounds, annulation methods from two molecules
have been shown to be particularly effective. Two typical
approaches are employed to construct cyclic frameworks by
[
1]
annulation: cycloaddition reactions and sequential addi-
In the reaction shown in Equation (1), aniline was formed
as a side product. This suggests the formation of indene
derivative 3a by the reaction of acetophenone with ethyl
acrylate (2a) in the presence of a catalytic amount of the
rhenium complex and aniline, because a ketimine is formed
in situ by the reaction of acetophenone with aniline. We
carried out the following reactions to examine this hypothesis.
The reaction of acetophenone (4a) with ethyl acrylate (2a) in
the presence of a catalytic amount of the rhenium complex
[
2]
tion–cyclization reactions. In the latter approach, a starting
point such as a carbon–halogen bond is usually required to
[
*] Dr. Y. Kuninobu, Y. Nishina, M. Shouho, Prof. Dr. K. Takai
Division of Chemistry and Biochemistry
Graduate School of Natural Science and Technology
Okayama University
Tsushima, Okayama 700-8530 (Japan)
Fax: (+81)86-251-8094
[
{ReBr(CO)3(thf)} ] and aniline in toluene at 1508C for 24 h
A
H
R
U
G
2
E-mail: kuninobu@cc.okayama-u.ac.jp
ktakai@cc.okayama-u.ac.jp
gave the corresponding indene derivative 3a in 56% yield.
This result shows that aniline was regenerated after the
formation of the indene derivative, and that the desired
catalytic cycle was at play. The yield of 3a increased to 86%
when the reaction was carried out at 1808C. The use of p-
anisidine as a cocatalyst instead of aniline afforded 3a in 93%
[
**] Financial support by a Grant-in-Aid for Scientific Research on
Priority Areas (No. 14078219, “Reaction Control of Dynamic
Complexes”) from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
[
8]
yield (Table 1, entry 1). In general, an effective synthesis of
2
766
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 2766 –2768

Angewandte
Chemie
[
a]
Table 1: Rhenium- and aniline-catalyzed annulation of aromatic ketones with a,b-unsaturated esters.
ketones, 2a was treated with ace-
tophenone derivatives that have
methyl groups at the ortho, meta
and/or para positions (Table 1,
entries 5–7). Only the single prod-
uct 3e was obtained in 11yield by
using an aceotophenone derivative
with a methyl group at the ortho
position; however, acetophenone
derivatives 4 f and 4g afforded
indene derivatives 3 f and 5 f
[
b,c]
Entry
Ketone
Olefin
Product
Yield [%]
1
2
1
2
3
4
4a (R =H)
2a (R =Et)
3a
3b (R =OMe; R =Et)
93 (99)
80 (82)
85 (89)
37 (53)
1
1
2
4b (R =OMe)
2a
2a
2a
1
1
2
4c (R =Me)
3c (R =Me; R =Et)
1
1
2
4d (R =CF )
3d (R =CF ; R =Et)
3
3
5
2a
11 (16)
(
77:23) and 3g and 5g (88:12) in
8% and 88% yields, respectively.
Similarly, 4h gave 3h and 5h in
good yields and selectivity
Table 1, entry 8). Indene deriva-
6
68 (69)
6
2a
(
A
H
R
U
G
tive 3i was obtained in 84% yield
by treatment of ketone 4i with 2a
(
Table 1, entry 9). Benzophenone
4j afforded indene derivative 3j in
2% yield (Table 1, entry 10). The
8
8 (93)
7
8
2a
A
H
R
U
G
7
reactions of ketone 4a and methyl
acrylate (2b) or phenyl acrylate
9
0 (93)
(
2c) led to the corresponding
indene derivatives 3k and 3l in
1% and 28% yields, respectively
2a
2a
AHCTREUNG
[80:20]
8
(
[
13]
Table 1, entries 11 and 12).
[
d]
However, a bulky tert-butyl acry-
late did not afford an indene deriv-
ative. Ethyl methacrylate and ethyl
trans-crotonate did not give the
indene derivatives either.
To investigate the compatibility
of functional groups under the
reaction conditions, we added sev-
eral substrates in the reaction of
acetophenone (4a) with ethyl ac-
rylate (2a). When 1-dodecene was
added, the indene derivative 3a
was obtained in 97% yield, and 1-
dodecene was recovered quantita-
9
84 (86)
72 (74)
1
0
2a
2
1
2
1
1
1
2
4a
4a
2b (R =Me)
3k (R =H; R =Me)
81 (90)
28 (29)
2
1
2
2c (R =Ph)
3l (R =H; R =Ph)
1
[
a] Olefin: 1.5 equiv. [b] Yields of isolated product. Yields determined by H NMR spectroscopy are
reported in parentheses. [c] The ratios of 3 and 5 are given in square brackets. [d] 48 h.
aromatic ketimines is difficult because of the slow reaction
tively. Under similar conditions, 2-dodecanone and methyl
[
11]
rates and low yields owing to a side reaction. From this
viewpoint, the yield obtained in entry 1 deserves special
mention.
laurate were recovered quantitatively, and 3a was obtained in
[
14]
77% and 84%, respectively.
The proposed mechanism for the formation of indene
[
15]
After testing several solvents, we found that toluene gave
derivatives is shown in Scheme 1. A ketimine is formed by
the reaction of acetophenone with aniline through dehydra-
tion. CÀH bond activation is accelerated by the coordination
[
12]
the best result (Table 1, entry 1). The concentration of the
reaction mixture proved to affect the yield of 3a markedly. In
low concentrations (0.5 and 1.0m) in toluene, the yields were
low (29% and 60%, respectively). The yield improved to
of a nitrogen atom of the ketimine derivative to a rhenium
center. After CÀH bond activation, an a,b-unsaturated
9
3% at a higher concentration (2.5m) in toluene, although the
compound inserts into the rhenium–carbon bond of an aryl–
rhenium intermediate. The intramolecular nucleophilic cyc-
lization by attack of an alkyl rhenium moiety at the imine
group followed by reductive elimination and the elimination
of aniline affords an indene derivative. The elimination of
aniline is important to promote the reaction catalytically.
In summary, we have developed a rhenium-catalyzed
conjugate addition and cyclization through CÀH bond
yield decreased to 82% in the solvent-free reaction.
The reactions of 2a and acetophenone derivatives 4b,c,
which bear an electron-donating group at the para position,
gave the corresponding indene derivatives 3b,c in 80% and
8
5% yields, respectively (Table 1, entries 2 and 3). However,
the yield decreased in the reaction of an acetophenone
derivative bearing an electron-withdrawing group (Table 1,
entry 4). To investigate the selectivity of nonsymmetric
activation in the reaction of an aromatic ketimine with an
Angew. Chem. Int. Ed. 2006, 45, 2766 –2768
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2767

Communications
in Organic Synthesis (Eds.: S. Kobayashi, K. A. Jørgensen),
Wiley-VCH, Weinheim, 2002.
[
[
[
2] a) D. P. Curran, Comprehensive Organic Synthesis, Vol. 4 , Per-
gamon, Oxford, 1991, pp. 779 – 831; b) P. Knochel, Comprehen-
sive Organic Synthesis, Vol. 4 , Pergamon, Oxford, 1991, pp. 865 –
911.
3] a) F. Kakiuchi, S. Murai, Top. Organomet. Chem. 1999, 3, 47 – 79;
b) Y. Guari, S. Sabo-Etienne, B. Chaudret, Eur. J. Inorg. Chem.
1999, 1047 – 1055; c) G. Dyker, Angew. Chem. 1999, 111, 1808 –
1822; Angew. Chem. Int. Ed. 1999, 38, 1698 – 1712.
4] For the synthesis of cyclic compounds through CÀH bond
activation, see: a) K. L. Tan, R. G. Bergman, J. A. Ellman, J. Am.
Chem. Soc. 2001, 123, 2685 – 2686; b) R. K. Thalji, K. A.
Ahrendt, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
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man, J. A. Ellman, A. J. Souers, Org. Lett. 2003, 5, 2131 – 2134;
d) R. K. Thalji, J. A. Ellman, R. G. Bergman, J. Am. Chem. Soc.
2
004, 126, 7192 – 7193.
5] Y. Kuninobu, A. Kawata, K. Takai, J. Am. Chem. Soc. 2005, 127,
3498 – 13499.
[
[
[
1
6] Y. Kuninobu, Y. Tokunaga, A. Kawata, K. Takai, J. Am. Chem.
Soc. 2006, 128, 202 – 209.
1
7] The yield determined by H NMR spectroscopy with 1,1,2,2-
tetrachloroethane as an internal standard is reported in paren-
thesis.
Scheme 1. Proposed mechanism for the formation of indene deriva-
tives.
[
8] The reactions between acetophenone and ethyl acrylate did not
proceed when using ruthenium complexes [Ru (CO) ] or
3
12
[
RuH (CO)
A
H
R
U
A
H
R
U
2
3
3
a,b-unsaturated ester. After the cyclization, the elimination
of aniline gives the corresponding indene derivatives. The
indene derivatives can also be obtained by the reaction of
acetophenone with a,b-unsaturated esters in the presence of
catalytic amounts of the rhenium complex and aniline. The
latter [3+2] annulation reaction to give indene derivatives is
efficient because the reaction proceeds with only loss of
water. Further investigations of rhenium-catalyzed chemical
transformations through CÀH bond activation are now in
catalysts.
[
9] Ketimines bearing a methoxy group on a nitrogen atom of the
imine moiety and hydrazone did not afford indene derivatives.
[10] S.-G. Lim, J.-A. Ahn, C.-H. Jun, Org. Lett. 2004, 6, 4687 – 4690.
11] a) R. W. Layer, Chem. Rev. 1963, 63, 489 – 510; b) H. Heaney,
M. T. Simcox, A. M. Z. Slawin, R. G. Giles, Synlett 1998, 640 –
[
6
42.
[
12] The yield of 3a decreased when the reaction was conducted in
octane (60%). When polar solvents 1,4-dioxane, dimethoxy-
ethane, or N,N-dimethylformamide were used, the yield of 3a
decreased to 34%, 25%, and 25%, respectively. When 1,1,2,2-
tetrachloroethane was used, the indene derivative 3a was not
obtained at all.
progress.
[
[
[
13] Ethyl methacrylate, ethyl trans-crotonate, and tert-butyl acrylate
did not afford the indene derivatives and most of the acrylates
remained. Phenyl vinyl sulfone, N,N-dimethylacrylamide, and
acrylonitrile also did not give the indene derivatives as a result of
polymerization of these electrophiles under the conditions.
14] Although the reactions were conducted in toluene (2.5m), the
amounts of the additives were similar to that of toluene; because
the yield of the reaction decreases with a decrease in the
concentration of acetophenone and ethyl acrylate, the yield of
Experimental Section
3
a (rhenium-catalyzed): A mixture of phenyl-(1-phenyl-ethylidene)-
amine (97.8 mg, 0.500 mmol), ethyl acrylate (75.1 mg, 0.750 mmol),
and [{ReBr(CO) (thf)} ] (12.7 mg, 0.0150 mmol) was dissolved in
ACHTREUNG
3
2
toluene (1.0 mL) and stirred at 1508C for 24 h. The crude product was
purified by column chromatography on silica gel to give 3a (85.9 mg,
8
5% yield) as a pale yellow solid.
a (rhenium-and aniline -c atalyzed): A mixture of acetophenone
60.1 mg, 0.500 mmol), ethyl acrylate (75.1 mg, 0.750 mmol), p-
anisidine (9.2 mg, 0.0750 mmol), and [{ReBr(CO)3(thf)} ] (12.7 mg,
.0150 mmol) was dissolved in toluene (0.2 mL) and stirred at 1808C
3
(
3
a dropped to approximately 80%.
AHCTREUNG
2
15] A referee suggested an alternative mechanism through the
Baylis–Hilman reaction: 1) a tertiary alcohol is generated by the
reaction between ethyl acrylate and acetophenone with aniline;
0
for 24 h. The crude product was purified by column chromatography
on silica gel to give 3a (96.0 mg, 95% yield) as a pale yellow solid.
2) cyclization under the reaction conditions. To examine this
possibility, we synthesized the tertiary alcohol and exposed the
alcohol to the reaction conditions. However, the alcohol did not
cyclize to the indene. Thus, we are tempted to assume that the
indene derivatives are formed via CÀH bond activation.
Received: October 13, 2005
Revised: January 27, 2006
Published online: March 23, 2006
Keywords: annulation · CÀH activation · conjugate addition ·
.
cyclization · rhenium
[
1] a) Comprehensive Organic Synthesis, Vol. 5 (Ed.: L. A.
Paquette), Pergamon, Oxford, 1991; b) Cycloaddition Reactions
2
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Angew. Chem. Int. Ed. 2006, 45, 2766 –2768