Regioselective solvent-dependent benzannulation of conjugated enynes

Article abstract of DOI:10.1039/c2cc30777d

The transformation of enynes under cobalt-catalysis leads to symmetrical benzannulation products in dichloromethane. In tetrahydrofuran the cobalt-catalysed reactions afforded the unprecedented unsymmetrical benzannulation products in moderate to good yields and good regioselectivities. In addition, cyclotrimerisation of the alkyne subunit can be realised when electron-deficient enynes are applied in the cobalt-catalysed transformations to generate 1,2,4-trivinylbenzene derivatives using tetrahydrofuran as solvent.

Full text of DOI:10.1039/c2cc30777d

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COMMUNICATION
Regioselective solvent-dependent benzannulation of conjugated enynesw
Florian Punner and Gerhard Hilt*
¨
Received 3rd February 2012, Accepted 20th February 2012
DOI: 10.1039/c2cc30777d
The transformation of enynes under cobalt-catalysis leads to
symmetrical benzannulation products in dichloromethane. In
tetrahydrofuran the cobalt-catalysed reactions afforded the
unprecedented unsymmetrical benzannulation products in
moderate to good yields and good regioselectivities. In addition,
cyclotrimerisation of the alkyne subunit can be realised when
electron-deficient enynes are applied in the cobalt-catalysed
transformations to generate 1,2,4-trivinylbenzene derivatives
using tetrahydrofuran as solvent.
Scheme 2 Solvent-dependent cobalt-catalysed benzannulation reaction.
solvents of choice for regioselective reactions. In the presence
of the cobalt catalyst system in dichloromethane, the starting
material 4 is converted into the styrene derivatives 5 and 6 as
well as an unidentified side-product (B13%) which were
isolated in a combined yield of 90%. The regioisomers 5 and
6 were generated in an acceptable regioselectivity (5 : 6 =
78 : 22; see Scheme 2).
The benzannulation of conjugated enynes such as 1 is a
powerful method for the direct synthesis of arene derivatives
from acyclic starting materials in a single cycloaddition reaction.1
The benzannulation reaction is formally a transformation which
involves a [4 + 2] cycloaddition followed by a 1,3-hydrogen shift
to generate the two different regioisomers 2 and 3 (Scheme 1).
For the benzannulation of enynes and cross-coupling of enynes
with alkynes described by Gevorgyan and Yamamoto palladium-
catalysts proved to be highly effective.2 For intramolecular reac-
tions also high temperature or Brønsted/Lewis acid catalysts lead
to the formation of aromatic systems as reported by Danheiser
et al.3 When palladium-catalysts are applied, it is proposed that
the benzannulation reaction mechanism proceeds via palladacycle
intermediates in a stepwise fashion.4 The symmetrical products of
type 2 are obtained exclusively in good to excellent yields in the
palladium-catalysed benzannulation process.
On the other hand, changing the solvent to tetrahydrofuran
inverted the ratios of 5 : 6 (7 : 93). The mixture of the isomers
was isolated in 85% yield and after single recrystallization
pure 6 was obtained in 60% yield.
Noteworthily, in this case, the cyclotrimerisation product 7
was generated only in trace amounts. The formation of
products of type 7 can be enforced when the cobalt catalyst
is used with tetrahydrofuran as solvent and electron-deficient
enynes as substrates (see below). Most importantly, the reaction
of 4 performed in tetrahydrofuran is the first example of
a regioselective benzannulation in which the unsymmetrical
2,3-diphenyl-styrene derivative 6 is formed predominantly.
Herein, we focussed our attention not only upon enyne 4
but also to the use of enynes with aliphatic substituents. The
results of the cobalt-catalysed benzannulation reactions in
dichloromethane for the formation of the symmetrical products
of type 2 are summarised in Table 1.
Based on our success in cobalt-catalysed cycloaddition
reactions5 we continued our study on the conversion of
conjugated enynes such as but-3-en-1-ynylbenzene (4) in the
presence of Co(dppp)Br2 (10 mol%), zinc powder (20 mol%),
and zinc iodide (20 mol%) at ambient temperatures. In a
survey applying 4 as a test substrate we investigated the
solvent dependency of the benzannulation reaction and we
identified dichloromethane as well as tetrahydrofuran as
The present reaction tolerated simple alkyl-substituted
enynes (entries 1 and 2) affording the corresponding symmetrical
products 2a and 2b in good yields. However, the sensitivity of
the catalyst toward steric change became apparent when the
alkyl group of the enyne was replaced by a trimethylsilyl group
(entry 3) or a cyclohexenyl group (entry 4). Thus, such non-
aryl-substituted but more hindered enynes exhibited only
modest reactivity and after prolonged reaction times moderate
yields were obtained. However, the application of enynes in
the cobalt-catalysed benzannulation reaction did not reach the
level of regioselectivity for the symmetrical products of type 2
as in the corresponding palladium-catalysed reactions and
therefore was not investigated in more detail.
Scheme 1 Benzannulation reaction of enynes.
Fachbereich Chemie, Hans-Meerwein-Str., 35043 Marburg, Germany.
E-mail: Hilt@chemie.uni-marburg.de; Fax: +49 6421 2825677;
Tel: +49 6421 2825601
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc30777d
Furthermore, the main focus of this investigation was directed
toward the unprecedented synthesis of the unsymmetrical
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3617–3619 3617

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Table 1 Cobalt-catalysed benzannulation of conjugated enynes in CH2Cl2
Table 2 Cobalt-catalysed benzannulation of conjugated enynes in
tetrahydrofuran
Entry
Substituent R
Product
t/h
Yielda (%)
Entry Substituent R
Product
t/h
Yielda (%)
1
C6H13
24
74
1
C6H9
220 39
2
3
C5H11
40
67b
2
(3,5-tBu)2C6H3
48 86b
SiMe3
C6H9
140
48
30
4
19b
a
Reaction conditions: enyne (0.5–1.0 mmol), Co(dppp)Br2 (10 mol%),
Zn powder (20 mol%), ZnI2 (20 mol%), CH2Cl2, ambient temperature.
3
4
2-Naphthyl
26 76
b
Co(dppp)Br2 (5 mol%), Zn powder (10 mol%), ZnI2 (10 mol%).
benzannulation products of type 3. These products are of
considerable interest because the vinyl group is not flanked by
two substituents so that the products of type 3 could be accessible
for several follow-up reactions, such as polymerisations.
p-MeOC6H4
48 39
For this set of experiments the ratio of regioisomers could
not be determined accurately, because small amounts of the
side products of type 2 and 7 were formed and the signals in
the NMR spectra could not be assigned unambiguously. Also,
in many cases the products were mostly inseparable by GC or
GC-MS chromatography. Fortunately, the products of type 3
were separable by regular column chromatography and finally
after a single recrystallization the products were obtained in
pure form. The results of the cobalt-catalysed benzannulation
reaction of enynes in tetrahydrofuran are summarised in Table 2.
When the cyclohexenyl-substituted enyne was used (entry 1),
a chemoselective reaction was observed to generate 3a in
which only the terminal double bond of the enyne reacted
while the double bond of the cyclohexene subunit remained
unchanged. A number of aromatic-substituted enynes applied
in the cobalt-catalysed benzannulation process (entries 2–6)
generated the desired unsymmetrical products in good yields.
Of particular interest is the reaction of the bromo-substituted
enyne (entry 6) in which the bromo-substituent remained
unchanged in product 3f without undergoing protodebromi-
nation or formation of cross-coupling products. A comparable
reaction with the previously described palladium-based catalysts
could be challenging.2
5
6
7
p-ClC6H4
m-BrC6H4
2-C5H4N
18 66
24 65
26 40b
8
96 55c
a
Reaction conditions: enyne (0.5–1.0 mmol), Co(dppp)Br2
(10 mol%), Zn powder (20 mol%), ZnI2 (20 mol%), tetrahydrofuran,
Also, the application of the pyridine-substituted enyne
(entry 7) is remarkable leading to the bis-pyridine-type product
3g in 40%. In earlier investigations of cobalt-catalysed reactions,
the pyridine moiety decreased the reactivity of the cobalt
b
ambient temperature. Co(dppp)Br2 (15 mol%), Zn powder (30 mol%),
c
ZnI2 (30 mol%). Co(dppp)Br2 (20 mol%), Zn powder (40 mol%),
ZnI2 (40 mol%).
c
3618 Chem. Commun., 2012, 48, 3617–3619
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reactions, the cobalt-catalysed transformation broadened the
scope of this reaction. By the proper choice of solvent the
unprecedented formation of the unsymmetrical 2,3-diaryl-
substituted styrene derivatives was made possible in good yields.
Several aryl-substituted enynes could be applied in the reaction
and the high functional group tolerance of the cobalt-catalysed
transformation allowed the incorporation of halide functional-
ities into the starting materials. Finally, with acceptor-substituted
enynes a new and very interesting substance class, the 1,2,4-
triacyl-3,5,6-trivinylbenzenes 9b/9c, could be obtained.
Notes and references
Scheme 3 Cyclotrimerisation of acceptor-substituted conjugated enynes.
1 (a) M. Rubin, A. W. Sromek and V. Gevorgyan, Synlett, 2003, 2265;
(b) S. Saito and Y. Yamamoto, Chem. Rev., 2000, 100, 2901;
(c) V. Gevorgyan and Y. Yamamoto, J. Organomet. Chem., 1999,
576, 232.
catalyst dramatically by coordination of the pyridine lone-pair to
the cobalt and for many attempted cycloaddition processes no
products could be isolated. Also, the thiophene-modified enyne led
to the bis-thiophene derivative 3h. These structures are of interest
due to potential photo-switchable properties.6 The application of
aliphatic substituted conjugated enynes in the cobalt catalysed
benzannulation gave the desired products only in low yields.
Finally, we also investigated the use of acceptor-substituted
enynes in cobalt-catalysed transformations. These reactions did
not lead to the desired benzannulation. Instead, the cyclotrimerisa-
tion of such enynes led predominantly to the unsymmetrical 1,2,4-
trivinyl-substituted regioisomer 9 in tetrahydrofuran (Scheme 3).7
The application of (E)-dimethyl hex-2-en-4-ynedioate led to
the formation of 9a in 50% yield which is a remarkable
product bearing six ester groups. The increased polarity of
product 9a made it possible to isolate also the corresponding
symmetrical regioisomer 8a (trimethyl 2,4,6-tris((E)-3-
methoxy-3-oxoprop-1-enyl)benzene-1,3,5-tricarboxylate) in 20%
yield in pure form. In a similar fashion, 1-phenylpent-4-en-2-
yn-1-one and 1-(3,4,5-trimethoxyphenyl)pent-4-en-2-yn-1-one
could be converted into 9b and 9c, respectively, in acceptable
yields after column chromatography and single recrystalliza-
tion. In these cases the corresponding regioisomers of type 8
could not be isolated. The 1,2,4-triacyl structures 9b and 9c
with three vinyl groups are of considerable interest as they
provide high functional group density building blocks.
2 (a) V. P. Ananikov and E. G. Gordeev, Chem. Sci., 2011, 2, 2332;
(b) S. Totos, M. Fild, C. Thone and I. Grosu, Tetrahedron, 2009,
¨
¨
¨
65, 6226; (c) V. Gevorgyan, N. Tsuboya and Y. Yamamoto, J. Org.
Chem., 2001, 66, 2743; (d) S. Saito, O. Ohmori and Y. Yamamoto, Org.
Lett., 2000, 2, 3853; (e) S. Saito, Y. Chounan, T. Nogami, T. Fukushi,
N. Tsuboya, Y. Yamada, H. Kitahara and Y. Yamamoto,
J. Org. Chem., 2000, 65, 5350; (f) V. Gevorgyan, L. G. Quan and
Y. Yamamoto, J. Org. Chem., 2000, 65, 568; (g) S. Saito, N. Uchiyama,
V. Gevorgyan and Y. Yamamoto, J. Org. Chem., 2000, 65, 4338;
(h) V. Gevorgyan, K. Tando, N. Uchiyama and Y. Yamamoto, J. Org.
Chem., 1998, 63, 7022; (i) V. Gevorgyan, L. G. Quan and
Y. Yamamoto, J. Org. Chem., 1998, 63, 1244; (j) D. Weibel,
V. Gevorgyan and Y. Yamamoto, J. Org. Chem., 1998, 63, 1217;
(k) V. Gevorgyan, N. Sadayori and Y. Yamamoto, Tetrahedron Lett.,
1997, 38, 8603; (l) V. Gevorgyan, A. Takeda and Y. Yamamoto, J. Am.
Chem. Soc., 1997, 119, 11313; (m) S. Saito, N. Tsuboya and
Y. Yamamoto, J. Org. Chem., 1997, 62, 5042.
3 (a) X. Y. Mak, A. L. Crombie and R. L. Danheiser, J. Org. Chem.,
2011, 76, 1852; (b) W. F. Austin, Y. Zhang and R. L. Danheiser,
Tetrahedron, 2008, 64, 915; (c) M. E. Hayes, H. Shinokubo and
R. L. Danheiser, Org. Lett., 2005, 7, 3917; (d) W. F. Austin,
Y. Zhang and R. L. Danheiser, Org. Lett., 2005, 7, 3905;
(e) J. R. Dunetz and R. L. Danheiser, J. Am. Chem. Soc., 2005,
127, 5776; (f) M. S. B. Wills and R. L. Danheiser, J. Am. Chem.
Soc., 1998, 120, 9378; (g) R. L. Danheiser, A. E. Gould, R. F. de la
Pradilla and A. L. Helgason, J. Org. Chem., 1994, 59, 5514.
4 (a) V. P. Ananikov, J. Phys. Org. Chem., 2001, 14, 109;
(b) V. Gevorgyan, A. Takeda, M. Homma, N. Sadayori,
U. Radhakrishnan and Y. Yamamoto, J. Am. Chem. Soc., 1999,
121, 6391; (c) S. Saito, M. M. Salter, V. Gevorgyan, N. Tsuboya,
K. Tando and Y. Yamamoto, J. Am. Chem. Soc., 1996, 118, 3970.
5 (a) G. Hilt, A. Paul and K. Harms, J. Org. Chem., 2008, 73, 5187;
(b) G. Hilt, A. Paul and C. Hengst, Synthesis, 2009, 3305; (c) G. Hilt,
W. Hess and K. Harms, Synthesis, 2008, 75; (d) J. Treutwein and
G. Hilt, Angew. Chem., Int. Ed., 2008, 47, 6811; (e) G. Hilt and
J. Janikowski, Angew. Chem., Int. Ed., 2008, 47, 5243; (f) G. Hilt,
M. Arndt and D. F. Weske, Synthesis, 2010, 1321; (g) G. Hilt and
D. F. Weske, Chem. Soc. Rev., 2009, 38, 3082; (h) M. Danz and
G. Hilt, Adv. Synth. Catal., 2011, 353, 303; (i) A.-L. Auvinet,
J. P. A. Harrity and G. Hilt, J. Org. Chem., 2010, 75, 3893;
(j) G. Hilt and J. Janikowski, Org. Lett., 2009, 11, 773; (k) G. Hilt
and M. Danz, Synthesis, 2008, 2257; (l) G. Hilt, J. Janikowski and
W. Hess, Angew. Chem., Int. Ed., 2006, 45, 5204.
The remarkable solvent-dependency of the reaction of
enynes with low-valent cobalt catalysts has been identified in
earlier studies.7a The rationale for the different behaviour is
based on the incorporation of solvent molecules as additional
ligands in the course of the cobalt-catalysed reaction. Tetra-
hydrofuran as the stronger donating solvent could occupy a
coordination site more efficient than dichloromethane. This
could lead to alternative binding modes of the bidentate dppp
ligand or the coordinated starting material to the cobalt
centre. Accordingly, the absence or presence of a solvent
molecule in the ligand sphere could be sufficient to direct the
reaction into alternative pathways. The high flexibility of the
ligands of the low-valent cobalt catalyst species complicates
the investigation of all possible intermediates by quantum-
chemical methods dramatically. Thus far, neither spectroscopic
evidence could be obtained nor quantum-chemical calculations
have been conducted to underline the hypothesis.
6 P. Raster, S. Weiss, G. Hilt and B. Konig, Synthesis, 2011, 905.
¨
7 (a) G. Hilt, C. Hengst and W. Hess, Eur. J. Org. Chem., 2008, 2293;
(b) G. Hilt, W. Hess, T. Vogler and C. Hengst, J. Organomet.
Chem., 2005, 690, 5170; (c) G. Hilt, T. Vogler, W. Hess and
F. Galbiati, Chem. Commun., 2005, 1474. For selected review, see:
(d) D. Leboeuf, V. Gandon and M. Malacria, in Handbook of
Cyclization Reactions, ed. S. Ma, WILEY-VCH, Weinheim, 2009,
vol. 1, p. 367; (e) B. R. Galan and T. Rovis, Angew. Chem., Int. Ed.,
2009, 48, 2830; (f) I. Omae, Appl. Organomet. Chem., 2008, 22, 149;
(g) I. Omae, Appl. Organomet. Chem., 2007, 21, 318; (h) S. Kotha,
E. Brahmachary and K. Lahiri, Eur. J. Org. Chem., 2005, 4741;
(i) W. Hess, J. Treutwein and G. Hilt, Synthesis, 2008, 3537.
In conclusion, we described the first cobalt-catalysed benz-
annulation reaction leading to symmetrical 2,6-dialkyl-substituted
styrenes. In contrast to palladium-catalysed benzannulation
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3617–3619 3619