Dimerization of terminal arylalkynes in aqueous medium by ruthenium and acid promoted (RAP) catalysis: Acetate-assisted (sp)C-(sp2)C bond formation

Article abstract of DOI:10.1002/adsc.201100600

The hexamethylbenzene ruthenium(II) dimer [{RuCl(m-Cl)(h₆-C ₆Me₆)}]₂ (5 mol%), tested among a series of ruthenium(II) and ruthenium(IV) complexes, represents an efficient precatalyst source for the dimerization of terminal arylalkynes ArCΞ CH [Ar=C ₆H5, 3,4,5-(OMe)₃C₆H₂, 4-MeOC ₆H₆, 2-MeOC₆H₆, 4-MeC ₆H₆, 2,4,5-Me3C₆H₂, 4-BrC ₆H₆, 4-ClC₆H₆, 4-FC ₆H₆, 4-HC(=O)C₆H₆, 4-CH ₂=CHC₆H₆, 3-NCC₆H₆, 4-O2NC₆H₆, 4-EtO2C-(CH₂)3OC₆H ₆, 4-HO(CH₂CH₂O)₃C₆H ₆, 3-HO(CH₂CH₂O)₃-C ₆H₆] in acetic acid/water mixture (1:1, v/v). The reactions proceed for 24 h at room temperature under heterogeneous conditions and afford the dimeric enyne derivatives (E)-Ar-CH=CH-C-C-Ar in high yields and stereoselectivity. The preformed acetato complex [RuCl(h₆-C ₆Me₆)(k2-OAc)] catalyzes the dimerization of phenylacetylene under analogous conditions, with rapid substrate conversion. The presence of cosolvents of acetic acid different from water reduces dramatically the efficiency and selectivity of the reaction. The aqueous medium facilitates the activation stage of the precatalyst by assisting the splitting of the ruthenium dimer. The addition or generation in situ of acetate salts results in shorter reactions times (0.5-3 h) and excellent yields, due to the rapid formation of active acetato complexes. Circumstantial evidence indicates that the p-bound alkyne molecule is activated by intramolecular proton abstraction. This is currently the most efficient, E-selective and wide-scope catalytic system for the alkyne dimerization reaction in protic aqueous media.

Full text of DOI:10.1002/adsc.201100600

FULL PAPERS
DOI: 10.1002/adsc.201100600
Dimerization of Terminal Arylalkynes in Aqueous Medium by
Ruthenium and Acid Promoted (RAP) Catalysis: Acetate-
2
À
Assisted (sp)C
N
Alessandra Coniglio,a Mauro Bassetti,a,* Sergio E. Garcꢀa-Garrido,b,*
and Josꢁ Gimenob
a
Istituto CNR di Metodologie Chimiche, Sezione Meccanismi di Reazione, and Dipartimento di Chimica, Universitꢂ “La
Sapienza”, P. le Aldo Moro 5, I-00185 Roma, Italy
Fax : (+39)-06-490-421; phone: (+39)-06-499-13769; e-mail: mauro.bassetti@uniroma1.it
Departamento de Quꢀmica Orgꢃnica e Inorgꢃnica, Instituto de Quꢀmica Organometꢃlica “Enrique Moles” (Unidad
b
Asociada al C.S.I.C.), Universidad de Oviedo, C/Julꢀan Claverꢀa 8, E-33071 Oviedo, Principado de Asturias, Spain
Fax : (+34)-985-103-446; phone: (+34)-985-103-461; e-mail: garciagsergio@uniovi.es
Received: July 29, 2011; Revised: September 27, 2011; Published online: January 12, 2012
Dedicated to Dr. Christian Bruneau, on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100600.
Abstract: The hexamethylbenzene ruthenium(II) of cosolvents of acetic acid different from water re-
(h6-C6Me6)}]2 (5 mol%), tested duces dramatically the efficiency and selectivity of
dimer [{RuClACHTUNGTRENNUNG(m-Cl)ACHUTNGTRENNUGN
among a series of ruthenium(II) and ruthenium(IV) the reaction. The aqueous medium facilitates the ac-
complexes, represents an efficient precatalyst source tivation stage of the precatalyst by assisting the split-
ꢀ
for the dimerization of terminal arylalkynes ArC
ting of the ruthenium dimer. The addition or genera-
CH [Ar=C6H5, 3,4,5-(OMe)3C6H2, 4-MeOC6H4, 2- tion in situ of acetate salts results in shorter reactions
MeOC6H4, 4-MeC6H4, 2,4,5-Me3C6H2, 4-BrC6H4, 4- times (0.5–3 h) and excellent yields, due to the rapid
ClC6H4, 4-FC6H4, 4-HC(=O)C6H4, 4-CH2=CHC6H4, formation of active acetato complexes. Circumstan-
3-NCC6H4, 4-O2NC6H4, 4-EtO2C-(CH2)3OC6H4, 4- tial evidence indicates that the p-bound alkyne mole-
HOACHTUNGTRENNUNG(CH2CH2O)3C6H4, 3-HOCAHUTNGTERNN(GUN CH2CH2O)3-C6H4] in cule is activated by intramolecular proton abstrac-
acetic acid/water mixture (1:1, v/v). The reactions tion. This is currently the most efficient, E-selective
proceed for 24 h at room temperature under hetero- and wide-scope catalytic system for the alkyne dime-
geneous conditions and afford the dimeric enyne de- rization reaction in protic aqueous media.
À
À ꢀ À
rivatives (E)-Ar CH=CH C C Ar in high yields
and stereoselectivity. The preformed acetato com-
plex [RuClACHTUNGTRENNUNG ACHTUGNTRENNUGN
(h6-C6Me6)(k2-OAc)] catalyzes the dimeri- Keywords: bifunctional catalysis; conjugated enynes;
zation of phenylacetylene under analogous condi- dimerization; ruthenium carboxylate catalysts; termi-
tions, with rapid substrate conversion. The presence nal alkynes
Introduction
catalysts for aqueous organic synthesis,[3] with special
emphasis on the activation of alkynes.[4]
The development of organic transformations in aque-
The catalytic dimerization of terminal alkynes is an
ous media has become a major cornerstone in atom economic process affording conjugated 1-en-3-
modern chemistry, in light of the expected environ- yne moieties, which are key structural units found in
mental, safety and cost benefits.[1] In this context, the natural and/or biologically active products[5] and in
design and application of transition metal complexes materials.[6] The reaction consisting in the formal self-
for organic synthesis in water have rendered aqueous addition of two alkyne molecules has gained increas-
organometallic catalysis a rapidly emerging field.[2] In ing interest due to the advent of selective catalytic
the past decade, we have been involved in the devel- systems able to overcome the intrinsic limits of
opment and application of ruthenium complexes as chemo-, regio- and stereo-selectivity,[7,8] which are
148
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Adv. Synth. Catal. 2012, 354, 148 – 158

Dimerization of Terminal Arylalkynes in Aqueous Medium by Ruthenium and Acid Promoted Catalysis
the reaction efficiency by using additives, in particular
acetate salts as cocatalysts.
Acetic acid and water (1:1) were introduced into a
Schlenk tube previously charged with complex I
(5 mol%). The addition of phenylacetylene upon stir-
ring caused the immediate formation of dark orange
droplets which disappeared a few minutes later in the
heterogeneous mixture. The unsoluble dimer 1,4-di-
phenyl-1-buten-3-yne was isolated from the reaction
mixture in 38% yield (E:Z stereoisomeric ratio 99:1)
by filtration followed by column chromatography.
Other experiments were then performed using
AcOH/H2O in different volume ratios in order to find
Scheme 1. Types of products of transition metal-catalyzed
C C couplings of terminal alkynes.
À
otherwise hindering any practical use of the reaction. how the composition of the medium was affecting the
In fact, several products can arise from the coupling reaction. As shown in Table 1, the two solvents in
process of alkynes, including dimeric E-, Z-, or gem-1- nearly equal volumes afforded the best combination
en-3-ynes, butatrienes, as well as cyclotrimers and of E-stereoselectivity and conversion into the 1,4-di-
linear oligomers (Scheme 1). Ideally, the catalytic phenylenyne (entry 1).
system should be applicable to various substrates and
provide one isomer in high yields. The implementa-
tion of the process in water-based media would repre- Catalyst Screening
sent a significant advancement in the field; in fact,
some articles have started to appear in the literature The influence of the precatalyst on the reaction ste-
based on catalysis by ruthenium or rhodium com- reoselectivity was studied for a wide series of rutheni-
plexes in aqueous systems.[9]
um complexes including analogous dimeric deriva-
We reported that (E)-1,4-diaryl-1-buten-3-ynes and tives [{RuX(m-X)
(h6-arene)}2] (X=Cl, arene=mesityl,
hybrid metal organic systems can be obtained in the hexamethylbenzene; X=I, arene=p-cymene), mono-
presence of the complex [{RuCl
(m-Cl)(h6-p- nuclear ruthenium(II) complexes [RuCl2(h6-p-
cymene)}2] (I) in AcOH.[10] The same catalytic system cymene)(PMe3)], [RuCl(h5-indenyl)
(PPh3)2], [RuCl2
promotes the polyaddition of aromatic diynes and af- (PPh3)3], and the dimeric ruthenium(IV) complex
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
fords conjugated homo and co-polymers featuring the [{RuClACTHNUTRGNEUNG
(m-Cl)(h3:h3-C10H6)}2] (C10H16 =2,7-dimethyloc-
repeat unit ( Ar C C CH=CH ).[11] The active cata- ta-2,6-diene-1,8-diyl), and their activity was compared
lytic species, formed in situ by interaction with the ter-
À
À ꢀ À
À
minal triple bond, is compatible with ring substituents
of different nature and with the presence of water in
Table 1. Dimerization of phenylacetylene (1) catalyzed by
the reaction mixture.[10a,12] In contrast with the majori-
ty of ruthenium catalysts which work in refluxing sol-
vents,[13] the reactions promoted by I/AcOH proceed
at room temperature and afford the enyne fragment
with an E-configuration of the double bond. In light
of the remarkable tolerance exhibited by this rutheni-
um-and-acid promoted (RAP) catalysis toward polar
components in both substrate and medium, we have
complex [{RuCl
(m-Cl)(h6-p-cymene)}2] (I) in different acetic
ACHTUNGTRENNUNG
acid/water mixtures.[a]
Entry
AcOH/H2O
1a+1b [%][b,c]
E/Z[b]
À
addressed in this work the development of the C C
coupling process in aqueous environment.
1
2
3
4
5
1:1
4:6
3:7
2:8
1:9
75
71
69
29
21
96:4
97:3
97:3
74:16
77:23
Results and Discussion
Our investigation developed along the following
lines: (i) the choice of the most appropriate reaction
conditions for the dimerization of phenylacetylene (1)
[a]
Reaction conditions: 1 (100 mL, 0.91 mmol), I (28 mg,
0.044 mmol), AcOH/H2O (10 mL), 24 h, room tempera-
ture.
catalyzed by the complex [{RuClACHTUNGTRNEUNG
(m-Cl)(h6-p-cyme-
[b]
[c]
Determined on the basis of 1H NMR analysis of the
crude extracts, by integration of the enyne signals vs. the
overall aromatic region.
ne)Cl}2] (I) in aqueous AcOH; (ii) the selection of the
most active and selective ruthenium precursor; (iii)
the application of the dimerization process to various
aromatic terminal alkynes; (iv) the improvement of
Other unidentified species were also formed; the gem-
enyne isomer was observed only in traces (<1%).
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149

Alessandra Coniglio et al.
FULL PAPERS
Table 2. Dimerization of phenylacetylene (1) catalyzed by
tries 1–4), which increased with increasing electron-
releasing properties (alkyl substitution) and steric hin-
drance of the arene ligand. Substitution of the chlo-
ride by iodide dramatically decreased both product
stereoselectivity and conversion (entry 5 vs. 1).
various ruthenium complexes in acetic acid/water (1:1 v/v).[a]
Phosphine-containing complexes behaved as poor
catalysts (entries 7–9), and the same holds for the di-
meric (allyl)ruthenium(IV) complex [{Ru(h3:h3-C10H6)
Entry Ruthenium complex
1
Enynes [%][b,c] E:Z:gem[b]
AHCTUNGTRENN(GUN m-Cl)Cl}]2 (entry 6), which is otherwise an excellent
catalyst for the cyclotrimerization of alkynes in wa-
ter.[4d,g] Under the same reaction conditions, dimeriza-
tion products were not observed in the presence of
the mononuclear complexes [RuCl2(h3:h2:h3-C12H18)]
75
92
96:4:0
(C12H18 =dodeca-2,6,10-triene-1,12-diyl),[14]
[RuCl2
(h4-COD)}n] (COD=1,5-cy-
clooctadiene), or of the water soluble salt [RuCl2(h6-
ACHUTNGERN(NUG DMSO)4], and [{RuCl2CATHUNGTRENNNUG
2
3
84:16:0
p-cymene)ACHTUNGTRENN{GU PPh(OCH2CH2NMe3)2}]CAHTUNGTRNE[NUGN SbF6]2. Therefore,
the h6-arene ruthenium(II) dichloride systems repre-
sent structurally well defined molecular fragments
able to promote the selective dimerization of phenyl-
47
86
100:0:0
100:0:0
AHCTUNGTREGUNaNN cetylene, at room temperature in acidic aqueous
medium.
4
Scope of the Reaction
On the basis of the highest conversion and selectivity
exhibited by the hexamethylbenzene complex [{RuCl-
5
6
42
35
65:31:4
74:18:8
(h6-C6Me6)}2] (II) (Table 2, entry 4), this catalyst
ACHUTNGREN(NUG m-Cl)ACHTUTGNRENNUGN
was used for studying the scope of the dimerization
process under acidic aqueous conditions on a series of
arylacetylenes with different ring substitution. The
substrates, yields and stereoselectivity of the 1,4-
diaryl-1-buten-3-yne products are reported in Table 3.
Usually, the reactions proceeded under heterogeneous
conditions due to the limited solubility of the rutheni-
um complex and the substrates employed. Neverthe-
less the isolated yields of the dimeric products, which
in general precipitated from the reaction mixture (en-
tries 1–14), were from good to satisfactory. Since
loads of complex II lower than 5% resulted in de-
creasing yields of the enynes 3a and 7a, the reactions
were run with 20:1 molar ratio of substrate to cata-
lyst.
7
8
64
80:10:10
24
12
54:46:0
62:38:0
9
[a]
Reaction conditions: 1 (100 mL, 0.91 mmol), ruthenium
complex (5 mol%), AcOH/H2O (10 mL, 1:1, v:v), 24 h,
room temperature.
The diverse functional group compatibility, previ-
ously observed in RAP catalysis in neat acetic acid or
under the one-pot desilylation-dimerization se-
[b]
[c]
Determined on the basis of 1H NMR analysis of the
crude extracts, by integration of the enyne signals vs. the
overall aromatic protons.
AHCTUNGTRENNUNG
quence,[10a,12] is maintained in the acetic acid/water
Other unidentified species were also formed.
mixture. In particular, arylacetylenes with either elec-
tron-donating (entries 2/3, 5/6) or -withdrawing sub-
stituents (entries 7–12) afforded enynes with E-stereo-
to that of the p-cymene complex I. The reactions selectivity larger than 96% and similar yields, the
were performed using phenylacetylene as substrate compatible range of electronic effects varying from
and a 1:1 solvent mixture of AcOH/H2O. The results that of methoxy (sp =À0.28) to that of the nitro
are reported in Table 2.
group (sp =0.81). However, reduced yield and stereo-
(h6- selectivity were observed in the presence of the me-
The dimeric chloride complexes [{RuClACTHNUTRGENNUG(m-Cl)ACHTUTGNRENNUGN
arene)}2] exhibited the best stereoselectivity (en- thoxy ortho substituent (entry 4). Potentially coordi-
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Dimerization of Terminal Arylalkynes in Aqueous Medium by Ruthenium and Acid Promoted Catalysis
Table 3. Dimerization of arylacetylenes (1–16) catalyzed by
lytic system in the polar protic medium is maintained
also in the presence of increased lipophilic character
of the ring substituent, as for the ethyl-4-oxybutyrate
chain in 14 (entry 14).
complex [{RuCl
(h6-C6Me6)}2] (II), in acetic acid/water
ACHTUNGTRENNUNG(m-Cl)ACHTUGNTRENNUGN
(1:1, v/v).[a]
Unexpectedly, the substrates bearing the hydrophil-
À
ic ACTHUNTGRNENUG(OCH2CH2)3OH oxaethylene chain in either meta
or para positions gave the corresponding E-enyne in
appreciably lower yields (entries 15, 16). In these
cases, the reactions proceeded under homogeneous
conditions due to the increased solubility of both sub-
strate and product in the reaction mixture. Although
we have not explored further the reasons of this yield
depression, it is possible that the enyne in solution
acts as inhibitor of the catalytic system by competitive
coordination of the enyne fragment to the ruthenium
center.[16]
Entry
Alkyne Yield
[%][b]
E:Z:gem[c]
1
2
1
2
64
93
100:0:0
98:2:0
The results reported in Table 3 represent the largest
data set of terminal alkynes amenable to catalytic di-
merization in an aqueous medium. The compatibility
of the procedure involves apolar, polar, or protic ring
substituents, as well lipophilic or hydrophilic alkyl
chains. Moreover, shorter reaction times and in-
creased yields and stereoselectivity are exhibited in
the presence of the hexamethylbenzene complex II in
the aqueous environment with respect to the catalytic
3
4
3
4
95
37
100:0:0
90:8:2
5
5
65
99:1:0
system based on [{RuClACTHNUTRGNEUNG
(m-Cl)(h6-p-cymene)}2] in neat
6
7
8
9
6
7
8
9
70
74
62
72
100:0:0
100:0:0
100:0:0
99:1:0
acetic acid.[10a] For instance, the yields of (E)-RC6H4
CH=CH C C C6H4R changed from 43% (R=p-
À
À ꢀ À
OMe, 48 h), 44% (R=p-Cl, 44 h) or 58% (R=p-NO2,
48 h) with I/AcOH to 95, 62 or 68%, respectively,
with II/AcOH-H2O (24 h). This catalytic system ex-
hibits a remarkable chemoselectivity, since products
deriving from the hydration of the triple bond were
not isolated or detected under the conditions of this
work.
10
11
10
11
85
38
98:2:0
100:0:0
12
13
14
15
12
13
14
15
68
60
69
42
96:4:0
100:0:0
98:2:0
87:13:0
Medium and Additive Effects
Once established in our previous studies and in this
work that acetic acid is an essential component in its
dual role of cocatalyst and cosolvent,[17,18] some ex-
periments were performed in order to test the influ-
ence of water in comparison with acetic acid and
other solvents. The results obtained for the dimeriza-
tion of 4-ethynylanisole (3) under different conditions
are reported in Table 4. GC-MS analyses were per-
formed after 3 h of reaction rather than at longer
times, in order to appreciate differences in the extent
of substrate conversions. Efficiency and stereoselec-
tivity depended significantly on the nature of the co-
solvent. It is remarkable that modest conversion and
poor selectivity were observed from the reaction in
16
16
30
98:2:0
[a]
Reaction conditions: alkyne (0.9 mmol), II (30 mg,
0.045 mmol, 5 mol%), AcOH/H2O (10 mL, 1:1, v:v),
24 h, room temperature.
[b]
[c]
Isolated yields.
1
Determined by H NMR analysis.
À
À
À ꢀ
nating moieties, such as CHO, CH=CH2 or C N, neat acetic acid at room temperature (entry 1), thus
did not inhibit the dimerization process, although the highlighting the effect arising from the presence of
yield of the cyano derivative appeared significantly water (entry 2). At this stage it can be suggested that
lower (entries 10, 11, 13).[15] The efficiency of the cata- the dissociation equilibrium of acetic acid in water
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151

Alessandra Coniglio et al.
Table 4. Dimerization of 4-ethynylanysole (3) catalyzed by complex [{RuClACUTHGNTRE(NNNUG m-Cl)ACTHUNGTRENNUNG
(h6-C6Me6)}2] (II) in acetic acid/cosolvent
FULL PAPERS
(S).[a]
Entry
Solvent mixture
Residual 3 [%][b]
E-(3a) [%][b]
Z-(3b) [%][b]
1
2
3
4
5
6
AcOH
60
10
64
37
59
26
23
89
31
47
9
14
1
1
1
28
28
AcOH/H2O
AcOH/D2O
AcOH/MeOH
AcOH/Me2CO
AcOH/CH2Cl2
41
[a]
Reaction conditions: 3 (0.9 mmol), II (30 mg, 0.045 mmol, 5 mol%), AcOH/cosolvent (10 mL, 1:1, v/v), room tempera-
ture.
[b]
Relative GC percentages at 3 h reaction time.
generates acetate ions, which attack as nucleophilic (entries 6, 7). These experiments indicate that the cat-
species the ruthenium dimer and promote the forma- alytic system is sensitive to changes in the coordina-
tion of more soluble mononuclear species.[19] Water tive environment of the metal center and in particular
itself can act as oxygen donor for the splitting of the that the presence of basic anions, most so of acetate,
À
dimer II. Changing H2O with D2O, which implies the enhances the efficiency of the C C coupling process.
formation of AcOD as well as of 4-MeOC6H4 C CD,
markedly reduced the efficiency of the dimerization
À ꢀ
Table 5. Dimerization of 4-ethynylanysole (3) catalyzed by
(entry 3). In analogy with the low activity exhibited
by the p-cymene complex I in AcOD in the dimeriza-
tion of phenylacetylene,10a this indicates the existence
of rate limiting proton transfer steps during the cata-
lytic propagation stage.
complex II in AcOH/H2O (1:1, v/v), in the presence of addi-
tives.[a]
With respect to the AcOH:H2O mixture (entry 2),
limited conversions were found with methanol, di-
chloromethane or acetone (entries 4–6), along with
lack and even inversion of stereoselectivity in the
latter case. This observation suggests that coordina-
tive interactions of water molecules with metal inter-
mediates take place in the course of the catalytic
cycle.
The reaction of 4-ethynylanisole (3) catalyzed by II
in AcOH/H2O at room temperature was investigated
upon addition of different salts and analyzed by GC-
MS (Table 5). While the alkyne was still present in
the absence of additives (27%, 30 min, entry 1), it was
all consumed at the same reaction time in the pres-
ence of sodium acetate, equimolar with the substrate
and in ten fold excess of ruthenium (entry 2). Howev-
er, no increase of conversion was observed with only
0.5 equivalent of acetate. The addition of metal (K,
Cs) carbonates or sodium sulfate also increased the
conversion of 3, which was otherwise depressed, with
loss of stereoselectivity, in the presence of PF6 salts
Entry Additive Residual 3
E-(3a)
Z-(3b)
[%][b]
[%][b]
[%][b]
1
2
3
4
5
6
7
None
27
–
15
17
11
71
91
65
78
81
26
6
–
2
16
2
2
NaOAc
Na2SO4
K2CO3
Cs2CO3
[NBu4]PF6 55
NaPF6
15
10
82
[a]
Reaction conditions: 3 (0.9 mmol), additive (0.9 mmol), II
(30 mg, 0.045 mmol, 5 mol%), AcOH/H2O (10 mL, 1:1,
v:v), room temperature.
Relative GC percentages, determined by GC-MS analysis
after 0.5 h reaction time.
[b]
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Dimerization of Terminal Arylalkynes in Aqueous Medium by Ruthenium and Acid Promoted Catalysis
ꢀ
Table 6. Dimerization of 4-R-C6H4-C CH catalyzed by com-
plex II in AcOH/H2O (1:1, v/v), in the presence of
NaOAc.[a]
Entry
R
Time [h]
Yield [%][b]
E:Z[c]
Scheme 2. Suggested pathways for initiation of II in AcOH/
H2O.
1
2
CHO (10)
NO2 (12)
1
3
66
88
96:4
94:6
[a]
Reaction conditions: alkyne (1.0 mmol), II (30 mg,
0.045 mmol, 5 mol%), NaOAc (0.9 mmol), AcOH/H2O
(10 mL, 1:1, v:v), room temperature.
[b]
[c]
Isolated yields.
1
Determined by H NMR analysis.
On the basis of these observations, the reactions of
the p-formyl- and p-nitrophenylacetylenes were re-
peated in the presence of equimolar sodium acetate.
The work-up was performed when TLC indicated the
consumption of the starting material and the products
were isolated by column chromatography (Table 6).
The results indicate that the enyne products were ob-
tained in considerably shorter reaction times than in
the absence of the salt, and in similar yields and E-
stereoselectivity (see Table 3 vs. Table 6).
The Catalytic Process
The reaction performed by complex II in AcOH/H2O
can be discussed in terms of activation stage and sub-
sequent dimerization catalytic cycle, which we pro-
pose as represented in Scheme 2 and Scheme 3, re-
spectively. Due to the dissociation equilibrium of
acetic acid in water, it is likely that the splitting of the
dimer II occurs by nucleophilic attack of the resulting
acetate ions, with formation of mononuclear spe-
Scheme 3. Proposed catalytic cycle for the dimerization of
arylalkynes in the presence of II in AcOH/H2O (L=Cl or
k1-AcO, n=0; L=H2O, n=1+).
Indeed, mixed chloro aqua complexes are formed
cies.[20] In fact, carboxylate ruthenium(II) derivatives from dimeric arene ruthenium(II) precursors under
are known to form from dinuclear h6-arene complexes acidic conditions in water.[22] It is also known that the
upon heating with a mixture of carboxylic acid and substitution of chloride by water occurs rapidly in
acetic anydride or upon reaction at room temperature half-sandwich ruthenium(II) complexes,[23] a process
with metal carboxylates.[19,21] In particular, the com- especially fast for hexamethylbenzene derivatives,[23c]
plex [RuClACHTUNGTRENNUNG
(k2-OAc)(h6-p-cymene)] was structurally and that cationic species can form from neutral chlo-
characterized.[21a,b] Under the conditions of this work, ride precursors.[23b,d,24] The aqua complexes can equili-
the presence of aqua complexes should also be taken brate by ligand exchange with corresponding adducts
into account, and we tentatively suggest the formation of acetic acid,[25] then affording acetato complexes
(2Àx)+
of species of type [RuCl
G
(H2O)3Àx
]
.
(h6-C6Me6)L]n+ (A) upon release of HCl or
[RuACTHNGUTRENNU(G OAc)ACHTGNUTRENNUNG
Adv. Synth. Catal. 2012, 354, 148 – 158
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
153

Alessandra Coniglio et al.
FULL PAPERS
H3O+. The equilibration of the acetato ligand be- ancillary ligands and of the alkyne substituents.[8n] Re-
tween bidentate and monodentate modes allows for a garding the lower activity exhibited by the iodide di-
free coordination site in a k1-16e species and there- meric complex vs. the chloride complex II (42 vs. 75%
fore for binding of the alkyne molecule. In agreement of conversion into 1a+1b, Table 1), this may depend
with these considerations, we found that phenylacety- on the lower solubility of the former in the reaction
lene in AcOH:H2O (1:1, v:v) was dimerized to the medium, other than to specific effects operating along
enyne 1a (isolated yield: 73%, E:Z:gem=100:0:0) in the catalytic cycle. Moreover, while the evident lack
the presence of the mononuclear complex [RuCl
(k2- of stereoselectivity induced by the iodide complex
ACHTUNGTRENNUNG
OAc)
ACHTUNGTRENNUNG
pared from complex II and sodium acetate in acetone. tion effects difficult to disentagle, it points out to the
When the reaction was repeated with 5 mol% of III influence imposed by a different X group in the pre-
and followed by GC-MS, conversion of the substrate cursor complex, thus implying that halide ions are af-
in about 90% was observed within 3 h, which indi- fecting the catalytic process.
cates the high activity of this monoacetato chloride
complex.
Due to the remarkable catalytic activity displayed
in the presence of the acetate ion, we believe that
The catalytic cycle itself (Scheme 2) is here pro- step B to C represents the key innovative event in
posed on the basis of the large body of experimental ruthenium-catalyzed alkyne dimerization. An analo-
information and accepted views for the dimerization gous step has been proposed and described in the sto-
of terminal alkynes promoted by ruthenium com- ichiometric reaction of the bis-acetato complex
ꢀ
plexes, which in general start from or involve the for- [RuACHTUNGTRENNUG 2ACHTUNTGERN(NUGN PPh3)2] with PhC CH affording the vi-
(k2-OAc)
(k1-OAc)(k2-OAc)
mation of ruthenium acetylide and/or vinylidene spe- nylidene containing species [RuACHTUNGTRENUNGN ACHTUNTGRNNEUG ACHTUNGTRENNUNG
cies.[7,8,13b,26] We have adopted the available informa- C=CHPh)
ACHTUNGTRENNUNG
tion to the present case, however by taking into spe- has shown that the lowest energy pathway involves
cific account the nature of the precursor ruthenium the intramolecular deprotonation of the p-alkyne
complex, the presence of acetic acid and that of complex by bound acetate to form a transient acety-
water, and the rate effects of the acetate, and so spe- lide, which is then reprotonated to give the isolable
cific aspects related to this catalytic system.
vinylidene complex.[30a] Other cases of stoichiometric
The link between the activation stage and the cata- and catalytic reactions have been demonstrated in
lytic cycle is the acetato complex A which forms which the alkyne to vinylidene or acetylide transfor-
adduct B with the alkyne. This same species accounts mations are assisted by intramolecular proton transfer
2
for the rapid reactions observed in the presence of to a basic ligand.[23d,31] Moreover, the (sp )-C H func-
À
the preformed chloride complex III or upon addition tionalization of (hetero)arenes assisted by a coordi-
of acetate salts to dimer II, which increases its con- nated base, in particular by carboxylates, has become
À
centration (Scheme 2). Next, the acetylide intermedi- largely recognized as a viable synthetic tool for C C
ate C becomes easily accessible if intramolecular bond formation with organic halides.[32] In analogy to
proton transfer occurs between the h2-alkyne and the the present work, ruthenium(II) acetate or carbonate
acetato ligand. Under the conditions of excess acetate complexes generated in situ from the dimer I dramati-
À
salts, pathways involving intermolecular activation of cally promote the C C coupling of 2-pyridylbenzene
the p-bound alkyne upon proton abstraction by sol- with unactivated aryl chlorides,[32d] and display higher
vated acetate ions cannot be excluded. The subse- activity in water than in the organic NMP solvent.[33]
quent and more recognized steps involve the coordi- When well defined ruthenium p-cymene carboxylate
nation of the second alkyne molecule and tautomeri- complexes are synthesized, these show a remarkable
zation to the vinylidene E,[27] alkynyl-vinylidene cou- broad scope in the direct arylations of arenes.[21c,33]
A
À
pling with formation of a ruthenium enynyl inter- kinetic study has shown recently that this C H activa-
mediate F,[28] then release of the organic enyne by tion involves autocatalysis by the generated carboxyl-
inter or intramolecular proton transfer from acid[18] or ic acids and intermolecular deprotonation.[34]
from the terminal alkyne itself.[29] In Scheme 2 and
Scheme 3, the catalytic ruthenium species have been
depicted with coordination of the arene ligand since Conclusions
removal of the C6Me6 fragment is unlikely under
these mild reaction conditions. Moreover, the changes The dimeric ruthenium complex [{RuClACTHNUTRGENNGU(m-Cl)ACHTUNGTRENNUNG
(h6-
in the stereoselectivity observed from different arene C6Me6)}2] catalyzes at room temperature the dimeri-
precursors (Table 2) can be explained in terms of the zation of terminal arylalkynes in acetic acid/water
steric effects imposed by the 6-membered ring in the mixture and affords linear 1,4-disubstituted E-enynes
course of the stereo-controlling step E to F. In fact, with satisfactory yields and wide functional group
the regio- and stereochemistry of the enyne product compatibility. In the aqueous medium, the hexame-
are known to be markedly affected by the size of the thylbenzene catalyst displays better efficiency and se-
154
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ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 148 – 158

Dimerization of Terminal Arylalkynes in Aqueous Medium by Ruthenium and Acid Promoted Catalysis
phase was washed with aqueous NaHCO3, with water, then
lectivity than analogous arene complexes. The pres-
ence of water favours the solvolysis of the starting
dimer complex and the formation of active acetato
species. The efficiency of the reaction is enhanced
dramatically in the presence of acetate, which assists
the deprotonation of the alkyne. Thus, this dimeriza-
tion process represents a new example of carboxylate
ligands playing a key cooperative effect in bifunction-
al catalysts involved in H transfer reactions. The com-
dried over MgSO4. After removal of the solvent under
vacuum, the crude product was purified by column chroma-
tography on silica gel using different mixtures of hexane/di-
chloromethane as eluent.
1,1’-(E)-1-Buten-3-yne-1,4-diylbis(3,4,5-trimethoxyben-
zene) (2a): From 3,4,5-trimethoxyphenylethyne (2, 173 mg,
0.9 mmol) and complex II (30 mg, 0.045 mmol, 5 mol%) as a
white solid; yield: 161 mg (93%). 1H NMR (300 MHz,
CDCl3): d=6.95 (d, J=16.3 Hz, 1H), 6.70 (s, 2H), 6.63 (s,
2H), 6.27 (d, J=16.0 Hz, 1H), 3.87 and 3.86 (two s, OMe,
18H); 13C NMR (300 MHz, CDCl3): d=153.3, 153.0, 141.0
(Ar-C=C-), 138.8, 131.9, 118.3, 108.6, 107.3 (-C=C-Ar),
bination
(h6-C6Me6)}2]/AcOH/H2O/
[{RuClACTHNGUTREN(UNG m-Cl)ACTHUNGTRENNNUG
NaOAc represents the most efficient and E-selective
catalytic system for dimerization of arylalkynes under
mild conditions in protic media.
ꢀ
103.4, 91.8 and 87.9 (-C C-), 60.9, 56.0; IR (KBr): n=2924,
1730, 1575, 1505, 1463, 1417, 1331, 1130, 994, 807, 627 cmÀ1
;
HR-MS (ESI): m/z=385.1646, calcd. for C22H25O6 [M+H]+:
385.1573.
Experimental Section
1,1’-(E)-1-Buten-3-yne-1,4-diylbis(2,4,5-trimethylbenzene)
(5a): From 2,4,5-trimethylphenylethyne (5, 130 mg,
0.9 mmol) and complex II (30 mg, 0.045 mmol, 5 mol%) as a
General Methods
1
1H and 13C NMR spectra were recorded on Bruker AvanceII
300 and DPX-300 spectrometers. Chemical shifts are report-
ed in d values relative to tetramethylsilane, with reference
to internal solvent (1H NMR: CHCl3, 7.27 ppm; 13C NMR:
CDCl3, 77.0 ppm), and coupling constants (J) are given in
Hz. Infrared spectra were recorded on a Perkin–Elmer
1720-XFT spectrometer. GC-MS analyses were obtained on
pale yellow solid; yield: 84 mg (65%). H NMR (300 MHz,
CDCl3): d=7.31 (s, 1H), 7.25 (s, 1H), 7.22 (d, J=16.3 Hz,
1H), 7.00 (s, 1H), 6.96 (s, 1H), 6.32 (d, J=16.1 Hz, 1H),
2.43, 2.35, 2.26, 2.25, 2.23 (s, Me, 18H); 13C NMR (300 MHz,
CDCl3): d=138.1, 137.3, 137.0, 136.9, 134.2, 133.7, 133.1,
132.82, 132.77, 131.9, 130.8, 126.0, 120.4, 108.2 (-C=C-Ar),
ꢀ
92.3 and 90.3 (-C C-Ar), 20.1, 19.7, 19.4, 19.3, 19.1, 19.0; IR
(KBr): n=2965, 2179, 1448, 1262, 1096, 951, 880, 801 cmÀ1
;
a
Agilent Technologies 6890N Network GC System
HR-MS (ESI): m/z=289.1951, calcd. for C22H25 [M+H]+:
289.1878.
equipped with a 5973 Network Mass Selective Detector.
High resolution ESI-TOF mass spectra were obtained on a
Waters Micromass instrument. Analytical thin-layer chroma-
tography (TLC) was performed using silica gel 60 F254 pre-
coated glass or aluminum plates, and preparative flash chro-
matography was performed using silica gel 60 (0.040–
0.063 mm). The reactions were performed under an atmos-
phere of argon using vacuum-line and standard Schlenk
techniques. The alkynes 3,4,5-trimethoxyphenylethyne (2),[35]
4-ethynylstyrene (13),[36] 1-(ethyl-4-oxy-butyrate)-4-ethynyl-
benzene (14),[37] 2-{2-[2-(4-ethynylphenoxy)ethoxy]ethoxy}-
4,4’-(E)-1-Buten-3-yne-1,4-diylbis-styrene (13a): From 4-
ethynylstyrene (13, 230 mg, 1.8 mmol) and complex II
(60 mg, 0.09 mmol, 5 mol%) as a yellow solid; yield: 135 mg
1
(60%). H NMR (300 MHz, CDCl3): d=7.39 (m, 8H), 7.00
(d, J=16.2 Hz, 1H), 6.67 (dd, J=10.9 Hz, J=6.6 Hz, 2H),
6.36 (d, J=16.2 Hz, 1H), 5.74 (d, J=17.5 Hz, 2H), 5.25 (m,
2H); 13C NMR (300 MHz, CDCl3): d=140.8, 137.9, 137.4,
136.3, 136.2, 135.8, 131.7, 126.6, 126.5, 126.2, 122.7, 114.7,
ꢀ
114.3, 107.9 (-C=C-Ar), 92.1 and 89.8 (-C C-Ar); IR (KBr):
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
n=3083, 3002, 2185, 1918, 1825, 1700, 1624, 1594, 1504,
1402, 1285, 1114, 992, 957, 908, 844, 668, 522 cmÀ1; HR-MS
(IQ): m/z=257.1334, calcd. for C20H17 [M+H]+: 257.1252.
4-(4-{4-[4-(3-Ethoxycarbonylpropoxy)phenyl]-(E)-but-1-
en-3-ynyl}phenoxy)butyric acid ethyl ester (14a): From 1-
ture. The ruthenium complexes used as catalysts were com-
mercially available with the exception of compounds
[{RuCl
(PMe3)],[40] [RuCl2(h3:h2:h3-C12H18)],[41] [{RuCl
[RuCl2(h6-p-cymene) [SbF6]2,[3c] and
{PPh(OCH2CH2NMe3)2}]
[RuCl
(k2-OAc)(h6-C6Me6)],[19] which were prepared by fol-
ACHTUNGTRENNUNG(m-Cl)ACHTUNGTRENNUNG
(h6-C6Me6)}2] (II),[39] [RuCl2(h6-p-cymene)-
N
(COD)}n],[42]
2ACHTUNGTRENNUNG
(ethyl-4-oxy-butyrate)-4-ethynylbenzene
(14,
67 mg,
A
ACHTUNGTRENNUNG
0.3 mmol), complex II (10 mg, 0.015 mmol, 5 mol%) as an
orange solid; yield: 46 mg (69%). 1H NMR (300 MHz,
CDCl3): d=7.42–7.32 (m, 4H), 6.95 (d, J=16.2 Hz, 1H),
6.88–6.80 (m, 4H), 6.23 (d, J=16.2 Hz, 1H), 5.78 (d, J=
11.8 Hz, 0.02H, Z-isomer), 4.15 (q, J=7.1 Hz, 4H), 4.02 (t,
J=6.1 Hz, 4H), 2.52 (t, J=7.2 Hz, 4H), 2.12 (quint, J=6.9,
4H), 1.26 (t, J=7.2 Hz, 6H); 13C NMR (300 MHz, CDCl3):
d=173.1, 159.2, 158.7, 140.0, 134.0, 133.1, 132.8, 129.3, 127.7,
127.5, 125.6, 119.9, 115.7, 114.63, 114.59, 105.9 (-C=C-Ar),
A
ACHTUNGTRENNUNG
lowing the methods reported in the literature. Glacial acetic
acid (Carlo Erba, reagent grade) and all other reagents are
commercially available and were used as received.
General Procedure for the Catalytic Dimerization of
Terminal Arylalkynes
ꢀ
91.0 and 87.9 (-C C-Ar), 66.73, 66.71, 60.4, 30.7, 24.5, 14.2;
The ruthenium complex II (5 mol%) in a 100-mL Schlenk
tube was degassed with two argon/vacuum cycles and then
dissolved in acetic acid/water (10 mL, 1:1, v:v). After addi-
tion of the alkyne (0.9–2.5 mmol), and of the additive when
appropriate, the tube was sealed with a rubber septum and
the mixture allowed to react under stirring at room temper-
ature (1–24 h). After addition of water, the mixture was ex-
tracted with dichloromethane (3ꢅ25 mL). The organic
IR (KBr): n=3434, 2973, 2185, 1727, 1600, 1507, 1467, 1244,
1172, 1036, 945, 808 cmÀ1; HR-MS (ESI): m/z=465.2272,
calcd. for C28H33O6 [M+H]+: 465.2199.
1,1’-(E)-1-Buten-3-yne-1,4-diylbis(4-{2-[2-(2-hydroxyeth-
oxy)ethoxy]ethoxy}benzene) (15a): From 4-{2-[2-(2-hydrox-
yethoxy)ethoxy]ethoxy}phenylacetylene
(15,
300 mg,
1.2 mmol) and complex II (40 mg, 0.0 6 mmol, 5 mol%) as a
Adv. Synth. Catal. 2012, 354, 148 – 158
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
155

Alessandra Coniglio et al.
FULL PAPERS
white solid; yield: 126 mg (42%). 1H NMR (300 MHz,
CDCl3): d=7.42–7.33 (m, 4H), 6.97–6.86 (m, 5H), 6.60 (d,
J=12 Hz, 0.15H, Z-isomer), 6.23 (d, J=16.2 Hz, 1H), 5.79
(d, J=12 Hz, 0.15H, Z-isomer), 4.16 (m, 4H), 3.88 (m), 3.8–
3.7 (m), 3.63 (m), 2.3 (br s, 2H); 13C NMR (300 MHz,
CDCl3): d=140.0, 132.9, 127.5, 114.8, 114.6, 106.1, 72.4, 70.8,
70.4, 69.6, 67.4, 61.8; IR (KBr): n=3274, 2877, 2189, 1669,
1601, 1507, 1448, 1359, 1247, 1179, 1105, 1062, 1030, 951,
924, 838, 693, 541 cmÀ1; HR-MS (ESI): m/z=501.2483,
calcd. for C28H37O8 [M+H]+: 501.2410.
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1,1’-(E)-1-Buten-3-yne-1,4-diylbis(3-{2-[2-(2-hydroxyeth-
oxy)ethoxy]ethoxy}benzene) (16a): From 3-{2-[2-(2-hydrox-
yethoxy)ethoxy]ethoxy}phenyl acetylene (16, 220 mg,
0.9 mmol) and complex II (30 mg, 0.045 mmol, 5 mol%) as a
dark yellow oil; yield: 65 mg (30%). 1H NMR (300 MHz,
CDCl3): d=7.3–7.2 (m, 2H), 7.10–6.95 (m, 5H), 6.92–6.82
(m, 2H), 6.35 (d, J=16.2 Hz, 1H), 4.2–4.1 (m, 4H), 3.90–
3.82 (m, 4H), 3.8–3.6 (m, 16H); 13C NMR (300 MHz,
CDCl3): d = 159.3, 158.7, 141.6 (Ar-CH=CH-), 138.0, 130.0,
129.8, 124.7, 119.6, 117.2, 115.9, 115.2, 112.6, 108.7 (Ar-CH=
CH-), 92.1 and 89.0 (-CꢀC-Ar), 72.8, 71.1, 70.6, 70.0, 67.7,
62.0; HR-MS
ACHTUNGTRENNUNG(ESI): m/z=501.2496, calcd for C28H37O8 [M+
H]+: 501.2410.
Supporting Information
Characterization data of the (E)-enyne products, figures of
1
the H and 13C NMR spectra of enynes 2a, 5a, 13a, 14a, 15a,
16a, synthetic procedures for the preparation of the alkynes
2, 14, 15 and 16 are available in the Supporting Information.
Acknowledgements
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We are indebted to the Ministerio de Ciencia e Innovaciꢀn
(MICINN) of Spain (Projects CTQ2006-08485/BQU,
CTQ2009-08746/BQU, CTQ2010-14796/BQU) and Consol-
ider Ingenio 2010 (CSD2007-00006) for financial support.
S.E.G.-G. also thanks MICINN and the European Social
Fund for the award of a “Ramꢀn y Cajal” contract. A.C.
gratefully acknowledges the support of her Chemistry Doc-
torate by contract of Consolider Ingenio 2010 (ORFEO proj-
ect).
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