Rhenium-catalyzed synthesis of multisubstituted aromatic compounds via C-C single-bond cleavage

Article abstract of DOI:10.1021/ol801226t

(Chemical Equation Presented) A reaction between a β-keto ester and an acetylene in the presence of a rhenium complex, [ReBr(CO)₃(thf)] ₂, as a catalyst, provided a 2-pyranone derivative in excellent yield via retro-aldol reaction (C-C single bond cleavage). By adding an acetylene-bearing ester group(s) after the formation of 2-pyranones, an aromatization reaction proceeded and multisubstituted aromatic compounds were obtained in good to excellent yields.

Full text of DOI:10.1021/ol801226t

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3133-3135
Rhenium-Catalyzed Synthesis of
Multisubstituted Aromatic Compounds
via C-C Single-Bond Cleavage
Yoichiro Kuninobu,* Hisatsugu Takata, Atsushi Kawata, and Kazuhiko Takai*
DiVision of Chemistry and Biochemistry, Graduate School of Natural Science and
Technology, Okayama UniVersity, Tsushima, Okayama 700-8530, Japan
kuninobu@cc.okayama-u.ac.jp; ktakai@cc.okayama-u.ac.jp
Received May 30, 2008
ABSTRACT
A reaction between a ꢀ-keto ester and an acetylene in the presence of a rhenium complex, [ReBr(CO)3(thf)]2, as a catalyst, provided a 2-pyranone
derivative in excellent yield via retro-aldol reaction (C-C single bond cleavage). By adding an acetylene-bearing ester group(s) after the
formation of 2-pyranones, an aromatization reaction proceeded and multisubstituted aromatic compounds were obtained in good to excellent
yields.
Aromatic skeletons are important as the fundamental structures
of natural products, functional materials, and starting substrates
of organic molecules. Thus, the development of an efficient
method for the synthesis of aromatic compounds, in particular
multisubstituted ones, is useful. Several methods for the
synthesis of multisubstituted aromatic compounds have previ-
ously been reported.1 As a new strategy for the synthesis of
multisubstituted aromatic compounds, we disclose here the
retro-synthesis of a multisubstituted aromatic compound from
a ꢀ-keto ester and two kinds of acetylenes via carbon-carbon
bond cleavage of the ꢀ-keto ester (Figure 1).
Figure 1
compounds.
. Synthetic strategy for the multisubstituted aromatic
presence of a rhenium complex, [ReBr(CO)3(thf)]2, in a
sealed tube at 180 °C for 24 h. We unexpectedly obtained
2-pyranone 3a in a quantitative yield (eq 1).2–4 The
compound is formally generated via cleavage between R-
and ꢀ-carbons of 1a, insertion of the acetylene,5 followed
by cyclization. This result encouraged us to use the 2-pyra-
none as a component of a multisubstituted aromatic com-
pound by the reaction with a second acetylene.6
As a preliminary investigation, a reaction of ꢀ-keto ester
1a with diphenylacetylene (2a) was carried out in the
(1) Trimerization of acetylenes: (a) Vollhardt, K. P. C Angew. Chem.,
Int. Ed. Engl. 1984, 23, 539. Dehydrative trimerization of ketones: (b)
Elmorsy, S. S.; Pelter, A.; Smith, K Tetrahedron Lett. 1991, 32, 4175. [3
+ 3] Cycloaddition: (c) Katritzky, A. R.; Li, J.; Xie, L Tetrahedron 1999,
55, 8263. Diels-Alder reaction: (d) Danishefsky, S.; Yan, C.-F.; Singh,
R. K.; Gammill, R. B.; McCurry, P. M., Jr.; Fritsch, N.; Clardy, J. J. Am.
Chem. Soc. 1979, 101, 7001. (e) Olsen, R. K.; Feng, X.; Campbell, M.;
Shao, R.; Math, S. K. J. Org. Chem. 1995, 60, 6025. (f) Sestelo, J. P.;
Real, M. d. M.; Mourin˜o, A.; Sarandeses, L. A. Tetrahedron Lett. 1999,
40, 985. Bergman cyclization: (g) Jones, R. R.; Bergmann, R. G J. Am.
Chem. Soc. 1972, 94, 660. Benzannulation of vinylketenes with acetylenes:
(h) Danheiser, R. L.; Gee, S. K J. Org. Chem. 1984, 49, 1672. [4 + 2]
Cycloaddition of carbonyl compounds: (i) Boger, D. L.; Mullican, M. D.
J. Org. Chem. 1980, 45, 5002. Ring-closing metathesis: (j) Yoshida, K.;
Imamoto, T J. Am. Chem. Soc. 2005, 127, 10470.
10.1021/ol801226t CCC: $40.75
Published on Web 06/19/2008
2008 American Chemical Society

Table 1. Synthesis of Aromatic Compounds from ꢀ-Keto Esters and Two Acetylenesa
entry
R1
Me
Ph
Me
R2
Me
Me
H
R3
1a Ph
1b
1c
R4
Ph
R5
R6
yieldb/%
1
2
3
4
5
6
7
8
9
10
2a
CO2Et
CO2Et 4a 5a, 83 (88)
5b, 64 (67)
2a
2a
4a
4a
5c, 84 (89)
5d, 91 (92)
5e, 87 (93)
5f, 72 (77)
1a
1a
1a
Me
H
H
Ph
Ph
2b
4a
2cc
4ad
4ad
4a
nC10H21 2de
Me
nC5H11
nC5H11 1d nC6H13
Me
Ph
2e
5g + 5h, 85 (89) [5g:5h ) 96:4]f
1e
2e
2a
2a
4a
5g + 5h, 83 (89) [5g:5h ) 6:94]f
1a
1b
CO2Et
H
4b 5i, 86 (89)
5j + 5k, 77 (81) [5j:5k ) 39:61]g
4b
b
a 1 (1.0 equiv); 2 (1.2 equiv); 4 (2.0 equiv). Isolated yield. Yield determined by H NMR is reported in parentheses. c 80 °C, 8 h; 180 °C, 16 h. d 4a
1
(1.0 equiv, 8 h) was added three times. e 48 h. f The ratio of 5g and 5h is given in square brackets. g The ratio of 5j and 5k is given in square brackets.
Treatment of 1a with 2a in the presence of a catalytic
amount of [ReBr(CO)3(thf)]2 and molecular sieves at 180
°C for 24 h, followed by the addition of acetylene dicar-
boxylic acid ethyl ester (4a) and heating at 150 °C for 24 h,
gave hexasubstituted benzene derivative 5a in 83% yield
(Table 1, entry 1).7,8 Stepwise syntheses of hexasubstituted
benzenes were examined (Table 1). ꢀ-Keto esters bearing a
phenyl group at the R1 position, 1b, and without any
substituents at the R2 position, 1c, also afforded the corre-
sponding aromatic compounds 5b and 5c in 64% and 84%
yields, respectively (Table 1, entries 2 and 3). 1-Phenyl-1-
propyne (2b) inserted into a carbon-carbon single bond of
the ꢀ-keto ester regioselectively and provided the hexasub-
stituted aromatic compound 5d in 91% yield (Table 1, entry
4). Next, terminal acetylenes were investigated. It was found
that insertion of terminal acetylenes into a carbon-carbon
bond of ꢀ-keto esters occurred regioselectively, and penta-
substituted benzene derivatives 5e and 5f were obtained as
single products (Table 1, entries 5 and 6).9 Because the
introduction of the substituents into ꢀ-keto esters (R1 and
R2 positions) and acetylenes (R3 and R4 positions) is easy,
multisubstituted aromatic compounds can be synthesized
regioselectively. For example, treatment of ethyl 2-acetyl-
heptanoate (1d) with 1-phenyl-1-octyne (2e) followed by the
reaction with 4a produced hexasubstituted aromatic com-
pounds 5g and 5h (96:4) in 85% yield (Table 1, entry 7).
Also, a reaction between ethyl 2-methyl-3-oxooctanoate (1e),
2e, and 4a gave 5g and 5h (6:94) in 83% yield (Table 1,
entry 8).
By the reaction of ꢀ-keto ester 1a with diphenylacetylene
(2a) at 180 °C for 24 h, followed by the addition of ethyl
propiolate (4b) and heating at 150 °C for 24 h, multisub-
stituted benzene 5i was produced regioselectively in 86%
yield (Table 1, entry 9). However, as with the acetylene
component 4, diphenylacetylene and 6-dodecyne did not
produce the corresponding multisubstituted aromatic com-
pounds. By using dissymmetric acetylene 4b, the reaction
proceeded with moderate regioselectivity, and the mixture
of pentasubstituted aromatic compounds, 5j and 5k (39:61),
was provided in 77% yield (Table 1, entry 10).
(2) 2-Pyranones are useful as building blocks in organic synthesis and
partial structures of bioactive compounds. See: (a) Ichihara, A.; Murakami,
K.; Sakamura, S Tetrahedron 1987, 43, 5245. (b) Shi, X.; Leal, W. S.;
Schrader, E.; Meinwald, J. Tetrahedron Lett. 1995, 36, 71. (c) Kamano,
Y.; Nogawa, T.; Yamashita, A.; Hayashi, M.; Inoue, M.; Drasar, P.; Pettit,
G. R. J. Nat. Prod. 2002, 65, 1001.
(3) For some representative examples of 2-pyranone synthesis, see: (a)
Cho, S. H.; Liebeskind, L. S. J. Org. Chem. 1987, 52, 2631. (b) Tsuda, T.;
Morikawa, S.; Sumiya, R.; Saegusa, T. J. Org. Chem. 1988, 53, 3140. (c)
Larock, R. C.; Han, X.; Doty, M. J. Tetrahedron Lett. 1998, 39, 5713. (d)
Fukuyama, T.; Higashibeppu, Y.; Yamaura, R.; Ryu, I. Org. Lett. 2007, 9,
587.
(4) In our previous report (ref 5), an isocyanide ligand is efficient for
the expansion of ring skeletons. However, the addition of isocyanide was
not effective for this reaction.
(5) For a ring-expansion reaction via insertion of an acetylene into a
carbon-carbon single bond of ꢀ-keto esters, see: (a) Kuninobu, Y.; Kawata,
A.; Takai, K. J. Am. Chem. Soc. 2006, 128, 11368
.
(6) For the formation of aromatic compounds from 2-pyranones and
acetylenes, see: (a) Tam, T. F.; Coles, P. Synthesis 1988, 383. (b) Afarinkia,
K.; Vinader, V.; Nelson, T. D.; Posner, G. H. Tetrahedron 1992, 48, 9111
.
(9) When propargyl alcohol, ether, and amine were employed as
terminal acetylene 2 in the equation of Table 1, neither multisubstituted
aromatic compound 5 nor 2-pyranone 3 was produced. Instead, an
enamine of the keto moiety of ꢀ-keto ester 1 was generated in the case
of propargylamine. Both reactions using propargyl alcohol and ether
gave complex mixtures.
(7) The addition of molecular sieves is important to promote the reaction
efficiently. In the absence of molecular sieves, aromatic compound 5a was
obtained in only 49% yield
(8) Aromatic compound 5a was not formed because polymerization of
acetylene 4a occurred when 4a was added at the beginning
.
.
3134
Org. Lett., Vol. 10, No. 14, 2008

As the second acetylene component, benzyne generated
in situ from 2-trimethylsilylphenyl triflate and cesium fluoride
could be employed; naphthalene derivatives 6a and 6b were
obtained in 92% and 96% yields, respectively (eq 2).
Scheme 1. Proposed Mechanism for the Formation of
Multisubstituted Aromatic Compounds
The first step of this substituted benzene synthesis could
be applied to an intramolecular reaction (eq 3). By heating
ꢀ-keto ester 7 in toluene at 150 °C for 24 h in the presence
of a catalytic amount of the rhenium complex and a
stoichiometric amount of molecular sieves, followed by the
addition of an acetylene 4c and heating at 150 °C for 24 h,
tetrahydronaphthalene derivative 8 was obtained in 84% yield
(eq 3).
uents regioselectively. From this viewpoint, the method is
advantageous because substituents can easily be introduced
into acetylenes and the R- and γ-positions of ꢀ-keto esters,
and the reaction proceeds regioselectively. We hope that this
reaction will give useful insights into synthetic organic
chemistry based on carbon-carbon bond cleavage under
transition metal catalysis.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research (No. 18037049) from
the Ministry of Education, Science, Sports and Culture of
Japan, and for Young Scientists (B) (No. 18750088) from
JSPS. Y.K. also gratefully acknowledges financial support
from the Sumitomo Foundation, Meiji Seika Co., and
Okayama Foundation for Science and Technology.
The proposed reaction mechanism is as follows (Scheme
1): (1) A rhenacyclopentene intermediate is formed by the
reaction between a rhenium catalyst, ꢀ-keto ester, and
acetylene. In this step, the ꢀ-keto ester and acetylene orient
regioselectively. After the formation of the rhenacyclopentene
intermediate, δ-keto ester is generated via (2-a and 3-a)
carbon-carbon bond cleavage via retro-aldol reaction,10,11
followed by reductive elimination or (2-b and 3-b), a pathway
that has a different timing for the reductive elimination.8,9
(4) Isomerization of the olefinic moiety of the δ-keto ester
and cyclization leads to 2-pyranone.12 (5) Diels-Alder
reaction occurs between 2-pyranone and the second acety-
lene. (6) Decarboxylation occurs.5
Supporting Information Available: General experimental
procedure and characterization data for multisubstituted
aromatic compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL801226T
(10) There have been some examples on chemical transformations via
carbon-carbon bond cleavage. See: (a) Murakami, M.; Ito, Y.; Murai, S.
Top. Organomet. Chem. 1999, 3, 97. (b) Jun, C.-H. Chem. Soc. ReV. 2004,
33, 610.
(11) (a) Kochetkov, N. K.; Kudryashov, L. J.; Gottich, B. P. Tetrahedron
1961, 12, 63. (b) Crombie, L.; James, A. W. G. Chem. Commun. 1966,
357.
In the case of synthesizing multisubstituted aromatic
compounds, it is important to introduce the desired substit-
(12) (a) Fried, J.; Elderfield, R. C. J. Org. Chem. 1941, 6, 566. (b) Wiley,
R. H.; Jarboe, C. H.; Hayes, F. N. J. Am. Chem. Soc. 1957, 79, 2602.
Org. Lett., Vol. 10, No. 14, 2008
3135