Manganese-catalyzed construction of tetrasubstituted benzenes from 1,3-dicarbonyl compounds and terminal acetylenes

Article abstract of DOI:10.1021/ol800969h

(Chemical Equation Presented) Treatment of β-keto esters with terminal acetylenes in the presence of a catalytic amount of a manganese complex, MnBr(CO)₅, and molecular sieves, gave multisubstituted aromatic compounds in good to excellent yields. This reaction employs [2 + 2 + 2] cycloaddition of β-keto esters and 2 equiv of terminal acetylenes with dehydration. In the case of a 1,3-diketone, the corresponding acetophenone derivative and its deacylated compound can be synthesized selectively.

Full text of DOI:10.1021/ol800969h

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3009-3011
Manganese-Catalyzed Construction of
Tetrasubstituted Benzenes from
1,3-Dicarbonyl Compounds and Terminal
Acetylenes
Yoichiro Kuninobu,* Mitsumi Nishi, Salprima Yudha S., 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 April 28, 2008
ABSTRACT
Treatment of ꢀ-keto esters with terminal acetylenes in the presence of a catalytic amount of a manganese complex, MnBr(CO)5, and molecular
sieves, gave multisubstituted aromatic compounds in good to excellent yields. This reaction employs [2 + 2 + 2] cycloaddition of ꢀ-keto
esters and 2 equiv of terminal acetylenes with dehydration. In the case of a 1,3-diketone, the corresponding acetophenone derivative and its
deacylated compound can be synthesized selectively.
Benzene rings are key structures in many organic molecules,
such as functional materials and bioactive compounds. There
have been many reports on the construction of aromatic rings;
in particular, transition-metal-catalyzed reactions are power-
ful and efficient.1,2 Among them, [2 + 2 + 2] cycloaddition
of three acetylenes is one of the most well-known reactions;3
however, the construction of the desired substituted benzene
rings is difficult due to the low pair selectivity and regio-
selectivity (Scheme 1, A).4 Here, we disclose a regioselective
synthesis of terphenyls from two terminal acetylenes and one
1,3-dicarbonyl compound via dehydration (Scheme 1, B).
Scheme 1
.
Formation of Benzenes by [2 + 2 + 2]
Cycloaddition
(1) (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y.
J. Am. Chem. Soc. 2002, 124, 12650–12651. (b) Shen, H.-C.; Pal, S.; Lian,
S.-S.; Liu, R.-S. J. Am. Chem. Soc. 2003, 125, 15762–15763. (c) Shibata,
T.; Fujimoto, T.; Yokota, K.; Takagi, K. J. Am. Chem. Soc. 2004, 126,
8382–8383. (d) Yoshida, K.; Imamoto, T. J. Am. Chem. Soc. 2005, 127,
10470–10471. (e) Yamamoto, Y. Synth. Org. Chem. Jpn. 2005, 63, 112–
121. (f) Tanaka, K. Synlett 2007, 1977, 1993. (g) Austin, W. F.; Zhang,
During an investigation on the catalytic activities of
rhenium complexes,5,6 we accidentally found that benzenes
Y.; Danheiser, R. L. Tetrahedron 2008, 64, 915–925
.
(2) Transition-metal-mediated reactions have also been reported. See:
(a) Iwasawa, N.; Shido, M.; Maeyama, K.; Kusama, H. J. Am. Chem. Soc.
2000, 122, 10226–10227. (b) Ohe, K.; Miki, K.; Yokoi, T.; Nishino, F.;
Uemura, S. Organometallics 2000, 19, 5525–5528. (c) Yawer, M. A.;
Hussain, I.; Reim, S.; Ahmed, Z.; Ullah, E.; Iqbal, I.; Fischer, C.; Reinke,
(4) To overcome the difficulty, several methods have been developed.
See: (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539–
556. (b) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901–2916. (c)
Mori, N.; Ikeda, S.; Odashima, K. Chem. Commun. 2001, 181–182.
(5) (a) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2005,
127, 13498–13499. (b) Kuninobu, Y.; Inoue, Y.; Takai, K. Chem. Lett. 2006,
35, 1376–1377. (c) Kuninobu, Y.; Tokunaga, Y.; Takai, K. Chem. Lett.
2007, 36, 872–873. (d) Kuninobu, Y.; Ishii, E.; Takai, K. Angew. Chem.,
Int. Ed. 2007, 46, 3296–3299. (e) Kuninobu, Y.; Yu, P.; Takai, K. Chem.
Lett. 2007, 36, 1162–1163. (f) Yudha, S. S.; Kuninobu, Y.; Takai, K. Org.
H.; Gorls, H.; Langer, P. Tetrahedron 2007, 63, 12562–12575
.
(3) (a) Grotjahn, D. B. In ComprehensiVe Organometallic Chemistry
II; Hegedus, L. S., Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Oxford, 1995; Vol. 12, pp 741-770. (b) Bonnemann, H.;
Brijoux, W. In Transition Metals for Organic Synthesis; Beller, M., Bolm,
C., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, pp 171-197.
Lett. 2007, 9, 5609–5611
.
10.1021/ol800969h CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

can be formed by reactions between ꢀ-keto esters and
acetylenes.7 Treatment of ꢀ-keto ester 1a and phenylacety-
lene (2a) with a rhenium complex, [ReBr(CO)3(thf)]2 (2.5
mol%), at 50 °C for 24 h gave ethyl 2-acetyl-3-phenyl-3-
butenoate, which is an insertion product of 2a into an R-C-H
of 1a, in 93% yield.8 When the reaction was conducted at
100 °C in the presence of molecular sieves 4A, ethyl (E)-
3-phenyl-5-oxo-2-hexenoate and ethyl (E)-3-phenyl-5-oxo-
3-hexenoate were produced in 48% and 24% yields, respec-
tively.9,10 However, when pyrrolidinone (20 mol %) was
added before the mixture was heated at 115 °C in a sealed
tube, a tetrasubstituted aromatic compound 3a was produced
in 44% yield.10 The result encouraged us to carry out further
investigations. By using a combination of ReBr(CO)5 (5.0
mol %), N,N-dimethylacetoamide (DMA), and molecular
sieves 4A as a catalyst, the yield of 3a was improved to
50% (eq 1).11
Table 1. Reactions between ꢀ-Keto Esters 1 and Acetylenes 2a
Following further investigations of catalysts, we found that
a combination of MnBr(CO)512 and molecular sieves 4A has
a higher catalytic activity and wide applicability compared
to the rhenium system. For example, treatment of ethyl
3-oxobutanoate (1a) with phenylacetylene (2a) in the pres-
ence of MnBr(CO)5 (5 mol %) and molecular sieves 4A,
without any solvents, gave ethyl benzoate (3a) in 85% yield
(Table 1, entry 1).13,14
To investigate the scope and limitations of substrates,
reactions between ꢀ-keto esters and acetylenes were carried
out (Table 1, entries 2-8). Methyl 3-oxobutanoate (1b) and
ethyl 3-oxo-3-phenylpropanoate (1c) also produced benzoates
a 1 (1.0 equiv), 2 (2.5 equiv). b Isolated yield. c The ratio between 3h
and 3h′.
3b and 3c in 65% and 88% yields, respectively (entries 2
and 3). However, by using ꢀ-keto esters with substituents at
the active methylene moiety, the multisubstituted aromatic
compounds were not formed, and carbon-chain extension
reactions and formation reactions of 2-pyranones proceeded.9
Aryl acetylenes bearing an electron-donating group at the
p- and o-positions 2b and 2c afforded aromatic compounds
3d and 3e in 77% and 74% yields, respectively (entries 4
and 5).
Benzoate 3f was obtained in 86% yield using aryl
acetylene 2d with a bromo group at the p-position (entry 6).
In this case, carbon-bromine bond remained intact during
the reaction. 2-Ethynyl-6-methoxynaphthalene (2e) also
provided tetrasubstituted benzene 3g in 71% yield (entry 7).
When 4-phenyl-1-butyne (2f) was used as an acetylene
component, two regioisomeric benzenes 3h and 3h′ were
obtained in 88% yield in a ratio of 2.7:1 (entry 8). Internal
acetylenes, however, did not react under the conditions.
Next, the effects of replacing ꢀ-keto esters with 1,3-
diketones were investigated. Treatment of 2,4-pentanedione
(6) (a) Ku¨hn, F. E.; Scherbaum, A.; Herrmann, W. A. J. Organomet.
Chem. 2004, 689, 4149–4164. (b) Luzung, M. R.; Toste, F. D. J. Am. Chem.
Soc. 2003, 125, 15760–15761. (c) Nolin, K. A.; Ahn, R. W.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 12462–12463. (d) Kusama, H.; Yamabe, H.;
Onizawa, Y.; Hoshino, T.; Iwasawa, N. Angew. Chem., Int. Ed. 2005, 44,
468–470. (e) Ouh, L. L.; Mu¨ller, T. E.; Yan, Y. K. J. Organomet. Chem.
2005, 690, 3774–3782
.
(7) During the preparation of this manuscript, we learned that Prof. Eiichi
Nakamura and Prof. Hayato Tsuji at the University of Tokyo also discovered
a similar manganese-catalyzed reaction. We thank Profs. Nakamura and
Tsuji for exchanging valuable information prior to publication: Tsuji, H.;
Yamagata, K.; Fujimoto, T.; Nakamura, E. J. Am. Chem. Soc. 2008, 130,
in press
(8) For rhenium-catalyzed insertion of terminal acetylenes into a C-H
bond of the active methylene moieties of 1,3-dicarbonyl compounds, see:
(a) Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett. 2005, 7, 4823–4825.
(9) Insertion of acetylenes into a C-C bond of 1,3-dicarbonyl com-
pounds occurs with a rhenium or manganese catalyst. See: Kuninobu, Y.;
Kawata, A.; Takai, K. J. Am. Chem. Soc. 2006, 128, 11368–11369.
(10) The reactivity is in sharp contrast to that of indium-catalyzed
reaction between 1a and 2a, where only an alkenylated product at the
R-position of the ꢀ-keto ester is formed quantitatively. (a) Nakamura, M.;
Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 13002–13003. (b)
Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am. Chem.
Soc. 2007, 129, 5264–5271.
(13) There have been a few reports on the synthesis of aromatic
compounds from 1,3-dicarbonyl compounds and acetylenes. However, in
each case, terminal acetylenes having an ester moiety (or moieties) are
necessary to promote the reaction. See: (a) Nair, V.; Vidya, N.; Biju, A. T.;
Deepthi, A.; Abhilash, K. G.; Suresh, E. Tetrahedron 2006, 62, 10136–
10140. (b) Zhou, Q.-F.; Yang, F.; Guo, O.-X.; Xue, S. Synlett 2007, 2073–
2076.
(11) Acetoamide, 20%; N-methylacetoamide, 22%; N-methylpyrrolidi-
none, 68%.
(12) For MnBr(CO)5-catalyzed transformation, see: (a) Kuninobu, Y.;
Nishina, Y.; Takeuchi, T.; Takai, K. Angew. Chem., Int. Ed. 2007, 46, 6518–
6520.
(14) When a gram scale reaction was carried out (1a: 1.04 g, 8.00 mmol),
aromatic compound 3a was obtained in 73% yield.
3010
Org. Lett., Vol. 10, No. 14, 2008

Table 2. Reactions between 1,3-Diketone 4 and Acetylene 2a
Scheme 2. Formation of Tetrasubstituted Aromatic Compounds
3 via a Manganacyclopentadiene Intermediate
bonyl compound and an acetylene (Scheme 3). The inter-
mediate is thought to be a manganese- and rhenium-catalyzed
carbon-chain extension reaction.8a The mechanism for the
formation of tetrasubstituted aromatic compounds, however,
is still not clear.
% yielda
T (°C)
additive
MS4A
(115 wt % Mn)
none
solvent
toluene
5
6
7
50
69 (71) 5 (7) 7 (10)
80
80
toluene/H2O 20 (24) 66 (68) - (trace)
(1:1)
Sc(OTf)3
toluene/H2O 16 (20) 68 (70) 4 (6)
(5.0 mol %)
(1:1)
Scheme 3
.
Formation of Tetrasubstituted Aromatic Compounds
3 via a Manganacyclopentene Intermediate
a Isolated yield. Yield determined by 1H NMR is reported in parentheses.
(4) with phenylacetylene (2a) in the presence of a manganese
complex, MnBr(CO)5, as a catalyst at 80 °C for 24 h gave
tetrasubstituted benzene 5 in 19% yield. Unexpectedly, the
deacylated aromatic compound 6 was also obtained in 40%
yield.15,16 By using toluene as a solvent and molecular sieves
as an additive, the ratio of 5 was increased, and 5, 6, and 7
were provided in 69%, 5%, and 7% yields, respectively
(Table 2). Similar to the case of ꢀ-keto esters, 1,3-diketones
with a substituent at the active methylene moiety did not
afford tetrasubstituted aromatic compounds.
We next focused our attention on the synthesis of
deacylated compound 6. When a mixture of toluene and
water (1:1) was used as a solvent, the ratio of 6 increased,
and deacylated aromatic compound 6 and acetophenone
derivative 5 were produced in 66% and 20% yields,
respectively (Table 2). The ratio was slightly improved by
addition of Sc(OTf)3 as an additive.
In summary, we have succeeded in the regioselective
synthesis of terphenyls by the [2 + 2 + 2] cycloaddition
reactions of ꢀ-keto esters or 1,3-diketones with 2 equiv of
terminal acetylenes in good to excellent yields. It is worth
noting because pair-selective and regioselective preparation
of only 2:1 adducts from two kinds of terminal acetylenes
using [2 + 2 + 2] cycloadditions in one operation is rather
difficult. Because of the versatility to introduce a substituent
at the γ-position of ꢀ-keto esters, we hope that the trans-
formations will become efficient methods to synthesize
terphenyls.
Acknowledgment. Financial support from the Ministry
of Education, Culture, Sports, Science, and Technology of
Japan is gratefully acknowledged. We also appreciate the
Sumitomo Foundation, Meiji Seika Co., and Okayama
Foundation for Science and Technology for financial support.
We thank Professor Isao Kadota (Department of Chemistry,
Okayama University, Japan) for aquiring the HR-MS spectra.
To elucidate the reaction mechanism, we carried out the
following experiment. When the alkenylated product 7 was
treated with phenylacetylene (2a), aromatic compounds 5
and 6 were not formed (eq 3). This result suggests that the
formation reactions of aromatic compounds 5 and 6 do not
proceed via 7 as an intermediate.
Supporting Information Available: General experimental
13
1
procedures, characterization data, and H and C NMR
spectra for aromatic compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL800969H
The para selectivity of two substituents derived from an
acetylene suggests the formation of a manganacyclopenta-
diene intermediate, where both substituents are located at
the 2- and 5-positions (Scheme 2). Another possibility is that
the reaction proceeds via the formation of a metalacyclo-
pentene intermediate by the reaction between a 1,3-dicar-
(15) In this reaction, alkenylated product 7 was formed in 41% yield as
a side product.
(16) For metal-catalyzed carbon-carbon single bond cleavage via retro-
aldol reaction by the reactions of 1,3-dicarbonyl compounds with water,
see: (a) Kawata, A.; Takata, K.; Kuninobu, Y.; Takai, K. Angew. Chem.,
Int. Ed. 2007, 46, 7793–7795.
Org. Lett., Vol. 10, No. 14, 2008
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