Dihydrobiphenylenes through ruthenium-catalyzed [2+2+2] cycloadditions of ortho-alkenylarylacetylenes with alkynes

Article abstract of DOI:10.1002/anie.201309496

A new synthetic route to dihydrobiphenylenes has been developed. The process involves a mild Ru^II-catalyzed [2+2+2] dimerization of ortho-alkenylarylacetylenes or its more versatile variant, the Ru-catalyzed [2+2+2] cycloaddition of ortho-ethynylstyrenes with alkynes. Mechanistic aspects of this [2+2+2] cycloaddition are discussed. A new synthetic route to dihydrobiphenylenes involves a mild Ru^II-catalyzed [2+2+2] dimerization of ortho-alkenylarylacetylenes or its more versatile variant, the Ru-catalyzed [2+2+2] cycloaddition of ortho-ethynylstyrenes with alkynes. The mechanistic aspects of this [2+2+2] cycloaddition are also discussed. Copyright

Full text of DOI:10.1002/anie.201309496

Angewandte
Chemie
DOI: 10.1002/anie.201309496
Biphenylenes
Dihydrobiphenylenes through Ruthenium-Catalyzed [2+2+2]
Cycloadditions of ortho-Alkenylarylacetylenes with Alkynes**
Silvia Garcꢀa-Rubꢀn, Carlos Gonzꢁlez-Rodrꢀguez, Cristina Garcꢀa-Yebra, Jesffls A. Varela,
Miguel A. Esteruelas,* and Carlos Saꢁ*
Abstract: A new synthetic route to dihydrobiphenylenes has
been developed. The process involves a mild RuII-catalyzed
[2+2+2] dimerization of ortho-alkenylarylacetylenes or its
more versatile variant, the Ru-catalyzed [2+2+2] cycloaddi-
tion of ortho-ethynylstyrenes with alkynes. Mechanistic aspects
of this [2+2+2] cycloaddition are discussed.
C
yclobutane and benzannulated cyclobut(adi)ene deriva-
tives, including biphenylene, are attractive molecules that can
be used as starting materials for chemical synthesis and as
spacers and building blocks for functionalized organic mate-
rials.[1] In the case of biphenylenes, synthetic methods that
rely on ring-closure reactions, in which the cyclobutadiene
ring is formed either by dimerization of benzynes[2] or by
coupling reactions,[3] have been mainly exploited. However,
Vollhardtꢀs studies on the simultaneous formation of two
rings by cobalt-catalyzed [2+2+2] cycloaddition of ortho-
diethynylarenes with alkynes[4] has dominated this field
because of the enormous synthetic potential towards [N]phe-
nylenes,[5] molecules that contain biphenylene units with
unique combinations of aromatic and antiaromatic proper-
ties.[6] Typically, most [(Cp)CoI]-catalyzed cocyclizations of
ortho-diethynylarenes require irradiation and/or heating at
relatively elevated temperatures.[7]
Scheme 1. Ru-catalyzed [2+2+2] dimerization of ortho-ethynylstyrene
(1a) to dihydrobiphenylene 2a. Tp=tris(pyrazolyl)borate.
During our synthetic work towards the formation of 1,4-
diaryldienes, required for the investigation of “formal”
ruthenium-catalyzed [4+2+2] cycloadditions,[8] we discovered
a new route to dihydrobiphenylene 2a [Scheme 1, Eq. (1)].
This process involves the [2+2+2] dimerization of the starting
[*] Dr. S. Garcꢀa-Rubꢀn,[+] Dr. C. Gonzꢁlez-Rodrꢀguez,[+] Dr. J. A. Varela,
Prof. C. Saꢁ
ortho-ethynylstyrene (1a,
a 1,5-enyne) instead of the
expected Dixneuf product, the 1,4-diaryldiene 3a, derived
from head-to-head dimerization of arylacetylenes 1 with
trapping of MeOH [Scheme 1, Eq. (2)].[9] Even more strik-
ingly, aromatization to naphthalene (4) was not detected in
this case, despite it being the thermodynamically favored
product often observed on reacting 1,5-arenynes 1 in the
presence of other RuII catalysts [Scheme 1, Eq. (3)].[10]
Herein we present our novel and mild procedure to obtain
dihydrobiphenylenes 2 by simple Ru-catalyzed [2+2+2]
dimerization of ortho-alkenylarylacetylenes 1 (1,5-enynes)
in MeOH at room temperature [Scheme 1, Eq. (1) and
Table 2] and dihydrobiphenylenes 6 by [2+2+2] cocyclization
of 1 with different alkynes 5 (Table 3).[11]
Departamento de Quꢀmica Orgꢁnica y Centro Singular de Inves-
tigaciꢂn en Quꢀmica Biolꢂgica y Materiales Moleculares (CIQUS)
Universidad de Santiago de Compostela
15782 Santiago de Compostela (Spain)
E-mail: carlos.saa@usc.es
Homepage: http://www.usc.es/gi1603/saa
Dr. C. Garcꢀa-Yebra, Prof. M. A. Esteruelas
Departamento de Quꢀmica Inorgꢁnica
Instituto de Sꢀntesis Quꢀmica y Catꢁlisis Homogꢃnea (ISQCH)
Universidad de Zaragoza-CSIC
50009 Zaragoza (Spain)
E-mail: maester@unizar.es
[+] These authors contributed equally to this work.
[**] This work was supported by MICINN (projects CTQ2011-28258,
CTQ2011-23459, and Consolider Ingenio 2010 (CSD2007-00006)),
Xunta de Galicia, the European Regional Development Fund
(projects CN2011/054 and EM 2012/051), the DGA (E35), and the
European Social Found (FSE). S.G.-R. thanks the MEC for a FPU
fellowship, and C.G.-R. thanks the MICINN for a Juan de la Cierva
Contract (JCI-2011-09946).
The ruthenium-catalyzed dimerization of 1a was opti-
mized by systematically changing the reaction parameters
(Table 1). On changing the solvent polarity, the catalytic
activity changed dramatically (lower reaction yields, longer
reaction times, and recovery of the starting material, entries 2
and 3 vs entry 1, Table 1). Removal of MeOH as an additive
was also detrimental for the catalytic activity with either THF,
acetone, or acetic acid as solvents (entries 4–6, Table 1).[9a,b]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309496.
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Table 1: Optimization of Ru-catalyzed [2+2+2] dimerization of ortho-ethynylstyrene
(1a) to dihydrobiphenylene 2a.[a]
To our delight, not only [2+2+2] dimerizations of
ortho-alkenylarylacetylenes 1, but also [2+2+2]
cocyclizations with different terminal alkynes 5
were possible to obtain substituted dihydrobipheny-
lenes 6 in fairly good yields (Table 3). Typically,
under optimized conditions (5.0 equivalents of
alkynes 5), parent and electron-rich phenyl-, naph-
thyl-, and thiophenylacetylenes (5a–c, 5e, and 5 f,
respectively) could be cocyclized with ortho-ethynyl-
styrene (1a) to give their corresponding dihydrobi-
phenylenes (6a–c, 6e, and 6 f, respectively) in fairly
good yields (entries 1–6, Table 3). On the other hand,
electron-rich ortho-alkenylarylacetylene 1h and
naphthylenyne 1j also participated as partners in
[2+2+2] cycloadditions with 5a to afford the corre-
sponding dihydrobiphenylenes 6h and 6j, respec-
Entry
Catalyst
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
[(Cp*)RuL3]PF6
[(Cp*)RuL3]PF6
[(Cp*)RuL3]PF6
[(Cp*)RuL3]PF6
[(Cp*)RuL3]PF6
[(Cp*)RuL3]PF6
[(Cp*)RuL3]PF6
[(Cp*)RuL3]PF6
[(Cp*)RuL3]PF6
[(Cp)RuL3]PF6
THF/MeOH (3 equiv)
Acetone/MeOH (3 equiv)
DMF/MeOH (3 equiv)
THF
Acetone
AcOH
MeOH
EtOH
iPrOH
MeOH
3
48
48
48
48
48
1
12
24
48
48
48
65
36[c]
32[c]
19[c]
14[c]
18[c]
72 (63)[d]
50
9
38[c]
21[e]
50
10
11
12[f]
[(Cp*)RuCl(cod)]
[Au(PPh3)Cl]/AgSbF6
MeOH
MeOH
[g]
–
[a] Typical reaction conditions: catalyst (10 mol%), RT, [1a]=0.3m. [b] Yields of
isolated products. [c] Minor amounts of 1a were recovered. [d] Reaction was
performed with 1.2 mmol of 1a. [e] 1008C. [f] 3 mol% of catalyst was used. [g] 1-(2- tively, in quite good yields (entries 7 and 8, Table 3).
Vinylphenyl)ethanone was isolated in 70% yield. L=CH3CN. cod=1,5-cycloocta-
diene, Cp=cyclopentadienyl, Cp*=pentamethylcyclopentadienyl.
Interestingly, not only arylacetylenes act as cyclo-
addition partners; conjugated enyne 5k smoothly
gave dihydrobiphenylene 6k in an excellent yield
(entry 9, Table 3) and even cyclohexylacetylene 5l (a
Interestingly, dihydrobiphenylene 2a was obtained in a fairly
good yield (72%) in just one hour at room temperature when
MeOH was used as solvent (entry 7, Table 1).[12] Other
alcohols, such as ethanol or iso-propanol, were less effective
and required longer reaction times to give lower yields
(entries 8 and 9, Table 1). Modification of the electronic
nature of the catalyst by using the cationic ruthenium catalyst
[(Cp)Ru(CH3CN)3]PF6 (entry 10) or the neutral ruthenium
catalyst [(Cp*)RuCl(cod)] (entry 11, Table 1) was not bene-
ficial. On the other hand, the use of AuI and PtII catalysts
under the same conditions did not lead to dimerization, but to
alkyne activation of 1a (ketone, dimethylketal), with the
alkene unit remaining untouched (entry 12, Table 1).[13]
Having identified the optimized reaction conditions
(entry 7, Table 1), we proceeded to investigate the substrate
scope of the dimerization (Table 2). The (ortho-alkenyl)phe-
nylacetylenes 1b and 1c afforded the corresponding dihy-
Scheme 2. Deuterium-labeling experiments.
drobiphenylenes 2b and 2c, respectively, with moderate to
good yields (entries 1 and 2, Table 2).[14] However, internal
alkyne 1-(hex-1-yn-1-yl)-2-vinylbenzene (1d) failed to react,
and the starting material was completely recovered. The
electronic nature of the phenyl ring did not appear to have an
influence on the course of the reaction, irrespective of the
location and electron-richness of the substituents, since the
bromo-, methyl-, and methoxy-substituted derivatives 1e–1g
afforded the corresponding dihydrobiphenylenes 2e–g in
rather good yields (entries 3–5, Table 2). Fused aliphatic rings
on the ortho-ethynylstyrene, that is, 1h and 1i, or aromatic
rings, such as in naphthyl derivative 1j, also afforded the
corresponding dihydrobiphenylenes 2h–j in fairly good yields
(entries 6–8, Table 2).[15] Notably, the phenyl ring present in
1a is crucial, because the analogous cyclohexene derivative 7
gave the tetrahydronaphthalene (8) in a low yield of 30%
(entry 9, Table 2).[10c] To our surprise, ortho-allylphenylacety-
lene (9) also dimerized to give the corresponding dihydro-
fluorene 10, albeit in a lower yield despite the decrease in ring
strain caused by the formation of the five-membered ring
(entry 10, Table 2).
Scheme 3. Catalytic cycle for the Ru-catalyzed [2+2+2] dimerization/
cycloaddition of ortho-alkenylarylacetylenes with alkynes.
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Table 2: Ru-catalyzed [2+2+2] dimerization of ortho-alkenylarylacety-
lenes 1 to dihydrobiphenylenes 2.[a]
Table 3: Ru-catalyzed [2+2+2] cocyclization of ortho-alkenylarylacetylenes
1 with alkynes 5.[a]
Entry Substrate
Product
Yield
[%][b]
Entry Enyne Alkyne
Dihydrobiphenylene
Yield
[%][b,c]
1
2
3
4
1b
1c
1e
1 f
2b
2c
2e
2 f
55
63
65
70
1
2
3
4
1a
1a
1a
1a
5a R=H
6a R=H
65[d]
70[e]
88
5b R=Me
5c R=OMe
5d R=CF3
6b R=Me
6c R=OMe
6d R=CF3
26
5
1a
5e
6e
90
55
6
1a
5 f
6 f
7
1h
1j
5a
5a
5k
5l
6h
6j
57
67
85
35
5
6
7
1g
1h
1i
2g
2h
2i
64
70
68
8
9
1a
1a
6k
6l
10
8
1j
7
2j
8
82
30
33
[a] Typical reaction conditions: [(Cp*)Ru(CH3CN)3]PF6 (10 mol%), enyne
1 (0.3 mmol), alkyne 5 (1.5 mmol), MeOH (1.5 mL), RT, 1–24 h. [b] Yields of
isolated products. [c] Low amounts of the 1,4-diaryldienes 3 (<5% with
respect to 5) were also isolated in most cases (up to 20% when toluene 5b
was used). [d] The same yield was obtained using 1.2 mmol of 1a. [e] Yield
calculated with trimethoxybenzene as internal standard, 59% yield of isolated
product. Naph=6-methoxy-2-naphthyl.
9
10
9
10
[a] Typical reaction conditions: [(Cp*)Ru(CH3CN)3]PF6 (10 mol%), RT,
1–2 h. MeOH. [b] Yields of the isolated products.
common cationic RuII catalyst[17] is employed in the [2+2+2]
cycloaddition between alkynes and alkenes.[18] Displacement
of the solvent molecules from the metal center of A by the
substrate should lead to the key intermediate C via B.[19]
Subsequently, complex C would evolve by intramolecular
alkyne–olefin oxidative coupling to give D (path 1) or,
alternatively, by intermolecular alkyne–alkyne oxidative
coupling to afford E (path 2).[16] Insertion of the coordinated
secondary alkyl-substituted alkyne) gave the corresponding
dihydrobiphenylene 6l in moderate yield (entry 10).
In an effort to gain further insights into the reaction
mechanism for this dimerization/cycloaddition process,
a series of deuterium-labeling experiments were conducted.
When the ruthenium-catalyzed dimerizations of deuterated
ortho-ethynylstyrenes [D1]-1a’, [D2]-1a’’, and [D1]-1a’’’ were
carried out in CD3OD, deuterium scrambling in dihydrobi-
phenylenes 2a’, 2a’’, and 2a’’’ was not observed, with all
deuterium atoms located in the same positions as in the
corresponding starting materials (Scheme 2).
ꢀ
=
À
C C bond (path 1) or C C bond (path 2) into the Ru C bond
should give complex F. Finally, reductive coupling would
release the dihydrobiphenylenes with concomitant regener-
ation of the catalytic species.[20]
According to these labeling experiments (Scheme 2),
formation of a ruthenium–hydride species followed by
sequential insertion of the triple and double bonds can be
ruled out.[16] These results can be rationalized according to the
catalytic cycle shown in Scheme 3, in which, notably, a less
In summary, we have developed a new and efficient
process to access dihydrobiphenylenes. This route involves
a mild RuII-catalyzed [2+2+2] cycloaddition of ortho-alke-
nylarylacetylenes with alkynes. Deuterium-labeling experi-
ments clearly support a catalytic cycle being involved in the
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RuII-catalyzed [2+2+2] cycloaddition of two alkynes with one
alkene. More detailed mechanistic studies and further appli-
cations are currently being explored.
P. H. Dixneuf, Angew. Chem. 2009, 121, 1709 – 1712; Angew.
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Dixneuf, Adv. Synth. Catal. 2009, 351, 1488 – 1494.
Received: October 31, 2013
Published online: January 17, 2014
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[11] For the formation of 1,3-cyclohexadienes by Ru-catalyzed
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Varela, S. G. Rubꢂn, C. Gonzꢁlez-Rodrꢂguez, L. Castedo, C. Saꢁ,
J. Am. Chem. Soc. 2006, 128, 9262 – 9263.
Keywords: [2+2+2] cycloadditions · alkynes · biphenylenes ·
ortho-alkenylarylacetylenes · ruthenium
.
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[19] Coordination of styrene and acetylene units of 1a to the
ruthenium center was confirmed by 1H NMR and HSQC
experiments in CD2Cl2 between À50 and À708C. See the
Supporting Information for details.
[20] As a tentative hypothesis, we believe that MeOH helps to
recover the active Ru cationic species by decomplexation of an
initial coordinated h4-diene of dihydrobiphenylene 2.
[9] For head-to-head dimerization of alkynes with addition of
alcohols, see: a) M. Zhang, H.-F. Jiang, H. Neumann, M. Beller,
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