Z-Selective (Cross-)Dimerization of Terminal Alkynes Catalyzed by an Iron Complex

Article abstract of DOI:10.1002/anie.201601382

Efficient iron-catalyzed homocoupling of terminal alkynes and cross-dimerization of aryl acetylenes with trimethylsilylacetylene is reported. The complex [Fe(H)(BH₄)(iPr-PNP)] (1) catalyzed the (cross-)dimerization of alkynes at room temperatur

Full text of DOI:10.1002/anie.201601382

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201601382
German Edition: DOI: 10.1002/ange.201601382
À
C C coupling
Z-Selective (Cross-)Dimerization of Terminal Alkynes Catalyzed by an
Iron Complex
Orestes Rivada-Wheelaghan, Subrata Chakraborty, Linda J. W. Shimon, Yehoshoa Ben-David,
and David Milstein*
In memory of Alex Nerush
Abstract: Efficient iron-catalyzed homocoupling of terminal
alkynes and cross-dimerization of aryl acetylenes with trime-
thylsilylacetylene is reported. The complex [Fe(H)(BH4)(iPr-
PNP)] (1) catalyzed the (cross-)dimerization of alkynes at
room temperature, with no need for a base or other additives, to
give the corresponding dimerized products with Z selectivity in
excellent yields (79–99%).
the Fe–PNP and Fe–PNN types,[5b, 7] we describe herein the
first iron-catalyzed Z-selective homo- and cross-coupling of
terminal alkynes in the absence of additives under mild
conditions. Mechanistic insight, including isolation of the
likely actual catalyst, is provided.
When a solution of phenylacetylene and [Fe(H)(BH4)-
(iPr-PNP)] (1; 1 mol%)[7a] in THF was stirred at room
temperature for 24 h, 1,4-diphenyl-1-buten-3-yne was
formed quantitatively (94% Z and 6% E; Scheme 1). An
increase in the catalyst loading to 3 mol% resulted in
complete conversion after 15 h into the Z dimerized product
as the only product (Table 1, entry 1). Significantly, the
catalyst remained fully active after completion of the
reaction. Thus, at a catalyst loading of 3 mol%, the addition
of the same amount of phenylacetylene after the dimerization
reaction was completed yielded the homocoupling product
again with no substantial change in the catalytic activity.
C
onjugated 1,3-enynes are important building blocks in
organic synthesis for the preparation of polysubstituted
aromatic rings and natural products, and key units found in
a variety of biologically active molecules, drug intermediates,
and organic materials.[1] Several methods for their synthesis
are known, such as Sonogashira coupling between terminal
alkynes and vinyl halides, cross-coupling of terminal alkynes
with preactivated alkenes, Wittig olefination of conjugated
alkynals, and dehydration of propargylic alcohols.[2] Direct
hydroalkynylation across the carbon–carbon triple bond or
alkyne dimerization to form conjugated enynes is the most
attractive method as it is fully atom economical.[3] However,
this process has resulted in relatively few applications owing
to issues of chemo-, regio-, and stereoselectivity. The dime-
rization of terminal alkynes has been investigated with a large
number of transition-metal-based catalysts, mostly based on
precious metals.[3,4] Since iron salts are readily available,
inexpensive, and environmentally benign, the development of
iron-based catalysts for organic transformations is currently
a very active area of research.[5] We are aware of only
a marginally catalytic (maximum 3 turnovers) E-selective
alkyne dimerization involving iron to give enyne products,[6]
with FeCl3, a ligand, and KOtBu (300 mol%) at high temper-
atures.[6a] Following our studies on iron pincer complexes of
Scheme 1. Dimerization of phenylacetylene as catalyzed by complex
1 in THF or C6H6.
Next, we studied the homodimerization of several types of
alkynes under the catalysis of 1. The complete conversion of
several para-substituted aryl acetylenes (p-CO2Me, p-Me, p-
OMe, p-tBu, p-Br, p-F, p-cyano), meta-substituted 3-ethynyl-
aniline, and 3-ethynylthiophene into their corresponding
homodimerized products was observed within 15 h at room
temperature (Table 1, entries 1–10). The observed reactivity
trend of different aryl acetylenes is related to the acidity of
[*] Dr. O. Rivada-Wheelaghan, Dr. S. Chakraborty, Y. Ben-David,
Prof. D. Milstein
Department of Organic Chemistry, Weizmann Institute of Science
76100, Rehovot (Israel)
E-mail: david.milstein@weizmann.ac.il
Dr. L. J. W. Shimon
Chemical Research Support, Weizmann Institute of Science
71600, Rehovot (Israel)
À
the C H bond of the terminal alkyne. The presence of
electron-withdrawing substituents at the para position
resulted in faster reactions than in the case of electron-
donating groups (see Table S1 in the Supporting Informa-
tion). Although complex 1 is catalytically active towards aryl
acetylenes, alkyl acetylenes do not react. Also, ortho-sub-
stituted aryl acetylenes did not undergo catalysis (see
Table S1). On the other hand, a wide range of functional
Supporting information, including a detailed description of the
synthesis and spectroscopic data of complex 2 as well as NMR
spectra of the different crude reaction mixtures and isolated
products, and the ORCID identification number(s) for the author(s)
of this article can be found under http://dx.doi.org/10.1002/anie.
201601382.
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Table 1: Dimerization of terminal alkynes as catalyzed by 1.[a]
when a solution of phenylacetylene (1 mmol), trimethylsilyl-
acetylene (3 mmol), and 1 (0.01 mmol) in THF was stirred at
room temperature, complete conversion of phenylacetylene
into a mixture of the Z and E isomeric cross-dimerized
products a,b and the phenylacetylene homodimerization
product c was observed (by GC–MS) after 17 h. This mixture
was isolated in 85% yield and showed a Z cross-selectivity of
66% (Table 2, entry 1). Higher selectivity for the Z cross-
Entry
Substrate
t
[h]
Conv.
[%][b]
Yield [%]
(a:b:c)[b]
1
2
3
15
15
15
>99
>99
>99
98:0:0
94:6:0
90:8:0
Table 2: Cross-dimerization of aryl acetylenes with trimethylsilylacetyle-
ne as catalyzed by 1.[a]
15[c]
15
>99
>99
>99
>99
>99
>99
>99
74:9:0
Entry
Aryl acetylene
Conv.
[%][b]
Yield
[%][c]
Selectivity
4
5
6
7
8
9
90:10:0
88:10:0
88:12:0
94:4:0
(a:b:c) [%][d]
1[e]
2[e]
3
>99
>99
>99
>99
>99
85
79
84
88
80
66:9:26
75:7:18
79:9:12
84:8:8
15
15
15
4[f]
5
15
98:0:0
15[c]
73:14:0
98:2:0
[a] Reaction conditions: aryl acetylene (1 mmol), trimethylsilylacetylene
(3 mmol), 1 (0.01 mmol), THF (3 mL), room temperature, 24 h.
[b] Conversion was determined by GC–MS as based on consumption of
the aryl acetylene. [c] Yield of the mixture of a, b, and c after column
chromatography (elution with hexane). [d] Selectivity was determined by
integration of the 1H NMR spectrum of the isolated mixture. [e] The
reaction was complete after 17 h. [f] The reaction was carried out with
0.5 mmol of 3-ethynylthiophene, 1.5 mmol of trimethylsilylacetylene, and
0.005 mmol of 1.
10
15[c]
>99
85:6:0
11[d]
36
15
>99
>99
0:0:80
0:0:40
12[e]
13[f]
15
12
>99
>99
94:6:0
95:5:0
[a] Reaction conditions, unless otherwise noted: substrate (0.1 mmol),
1 (3 mol%), THF (0.5 mL), room temperature. [b] The conversion and
yield are based on 1H NMR analysis with mesitylene as an internal
standard. [c] The reaction was carried out with 5 mmol of the substrate in
5 mL of THF; the yield of the isolated product is given. [d] The reactions
were carried out with 0.25 mmol of the substrate and 1 mol% of 1.
[e] The reaction was carried out with 2 (3 mol%) and 0.13 mmol of the
substrate. [f] The reaction was carried out with 2 (5 mol%) and
0.13 mmol of the substrate in C6D6 (0.5 mL), without an internal
standard.
coupling products a was observed with 4-fluorophenylacety-
lene (75%), 4-tolylacetylene (79%), and 3-thienylacetylene
(84%; Table 2, entries 2–4). However, when 4-ethynylanisole
was used, the cross-dimerization products were obtained with
98% Z and 2% E selectivity (Table 2, entry 5), although
a small amount of the homodimerized product c of 4-
ethynylanisole was observed by GC–MS. In all cases, a 1:3
aryl acetylene/silylacetylene molar ratio was used. These
good to excellent yields show the high Z selectivity of
complex 1 in the cross-dimerization reaction. Thus, complex
1 is the first effective iron catalyst reported to date for the
cross-dimerization of terminal alkynes. The regio- and
stereoselectivity of the reaction, together with its high activity,
make complex 1 comparable to catalysts based on precious-
metal complexes.[4a–c,8] As compared to the procedure
reported by Ozawa and co-workers for the cross-dimerization
catalyzed by ruthenium,[4d] a lower catalyst loading (1 vs.
5 mol%) and a lower excess of ethynyltrimethylsilane were
required, under neutral conditions (a base is needed in the
case of Ru), for similar catalytic results. Significantly, these
reactions are performed at room temperature under base-free
conditions and with no extra additives, with earth-abundant
groups are tolerated, including amines, esters, nitriles, and
even aryl halides, which are known to readily oxidize FeII
complexes to FeIII.[5e] The catalytic reaction of ethynyltrime-
thylsilane led to a different result as compared with aryl-
substituted alkynes. The use of 1 mol% of 1 resulted in the
geminal product in 80% yield; neither the Z nor the E
coupling product was observed. An increase in the catalyst
loading to 3 mol% resulted in a lower yield of the geminal
coupling product (Table 1, entry 11).
In a pioneering study, Ozawa and co-workers observed
the Z-selective cross-dimerization of aryl acetylenes with
excess silylacetylenes in the presence of a ruthenium–vinyl-
idene complex and a base.[4d] It was of interest to us to study
this cross-dimerization with the Fe catalyst 1. Interestingly,
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iron and commercially available substrates, with no need for
further purification.
the absence of an alkyne substrate it underwent complete
decomposition within 18 h in solution at room temperature.
Since pincer complexes are capable of metal–ligand
cooperation (MLC) by aromatization–dearomatization of
the N-heterocyclic ring,[11] we explored this possibility by
Aiming to gain mechanistic insight regarding the homo-
coupling of terminal alkynes, we monitored the reaction of
complex 1 with phenylacetylene (20 equiv) in C6D6 in a sealed
NMR tube by NMR spectroscopy. At the beginning of the
reaction, the formation of H2 was observed by 1H NMR
spectroscopy (singlet at 4.5 ppm) while complex 1 was being
À
treating deuterated phenylacetylene (PhCC D) with 1. No D
incorporation at the benzylic position was observed, thus
suggesting that MLC does not take place in this case. A signal
2
À
À
consumed. Focusing on the catalyst, the reaction with PhCC
corresponding to H D at 4.5 ppm with JH–D = 43 Hz, indicat-
H yielded the novel alkynyl complex [Fe(PhCC)(BH4)(iPr-
PNP)] (2) as the major complex, which was formed before all
the substrate was consumed (Scheme 2). In contrast to 1,
complex 2 did not exhibit the triplet hydride signal at
ing HD formation, was detected at the beginning of the
reaction, while 1 was consumed to give 2. Furthermore, the
integration of the BH4 ligand signals remained unchanged
after the conversion was complete, thus indicating its
spectator behavior during the reaction.
1
À18.18 ppm in the H NMR spectrum, and the two broad
À
hydride signals at À9.63 and À28.67 ppm arising from BH4
To explore whether insertion of the alkyne triple bond
into the iron–alkynyl fragment takes place, we carried out
reactions of phenylacetylene with internal alkynes (1:1) in the
presence of 1 (1 mol%). With 2-butyne or diphenylacetylene
as the internal alkyne, only 1,4-diphenyl-1-buten-3-yne was
were shifted to À14.28 and À27.26 ppm, thus indicating
a change in the s donation of the ligand bound trans to
a hydride of BH4.
1
observed by H NMR spectroscopy. In the case of 2-butyne,
traces of other products were observed by GC–MS (see the
Supporting Information). The treatment of 2 with the same
internal alkynes gave no product of alkyne insertion, nor
a possible intermediate that could arise from alkyne insertion.
Complex 1 does not react with internal alkynes, thus
suggesting, together with the spectroscopic results of mon-
Scheme 2. Formation of the iron–alkynyl complex 2.
À
itoring the reaction with PhCC H(D), that initially coupling
À
À
of the C H bond of the terminal alkyne with Fe H takes
place to liberate H2 and generate the actual catalyst, complex
2. Moreover the lack of insertion of the internal alkyne into
phenylacetylene, plus the minor formation of the E enyne
coupling product when terminal alkynes are used, is in line
with a predominant vinylidene-based mechanism, rather than
alkyne insertion into an iron–alkynyl bond (Scheme 3).[13]
In the first step of our proposed mechanism, the terminal
alkyne coordinates to 1 to form complex A, in which the
The 31P{1H} NMR spectrum exhibited a new singlet at d =
À
86.8 ppm, and the Fe C(sp) peak appeared in the DEPTQ
NMR spectrum as a triplet at 122.4 ppm (J = 30 Hz).[9]
Cooling of a solution of 2 in pentane resulted in the formation
of small black crystals suitable for X-ray diffraction. As
anticipated, the FeII center exhibits octahedral geometry,
which includes the iPr-PNP ligand, the BH4 ligand, and the
phenylacetylide; the Fe1–C20 bond length of 1.911(3) Š is in
agreement with previously reported values (Figure 1).[9,10]
Since 2 is the only complex observed upon the reaction of
1 with excess phenylacetylene, it is probably an actual
intermediate (or resting state). Indeed, when the isolated
complex 2 was used as the catalyst, the results were similar to
those obtained with complex 1 (Table 1, entries 12 and 13).
Complex 2 could be stored at À408C in the solid state, but in
À
acidity of the terminal alkyne C H atom is enhanced.
Subsequent reaction with the hydride of 1 liberates dihydro-
gen and yields the corresponding iron–alkynyl complex 2.
Coordination of another molecule of the alkyne gives rise to
intermediate B. It is likely that B is transformed into the
Figure 1. X-ray crystal structure of complex 2 with thermal ellipsoids
set at 50% probability. The isopropyl groups are presented in wire-
frame style for clarify. See the Supporting Information for selected
bond lengths and angles.
Scheme 3. Proposed catalytic cycle for phenylacetylene dimerization.
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vinylidene intermediate C,[13] in line with the lack of reactivity
of internal alkynes with complex 2, and as observed in alkyne
dimerization catalyzed by ruthenium.[4d,8a,12] Intramolecular
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À
C C coupling of the alkynyl fragment with the a-carbon atom
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À
considering the steric effects that the pincer ligand and BH4
impose on the organic fragments. It is likely that the
formation of B is reversible, with the equilibrium lying
towards 2, and the reaction step to generate intermediate C
might be rate-determining, hence 2 accumulates. Coordina-
tion of another terminal alkyne to form intermediate E,
followed by proton transfer from the coordinated alkyne,
leads to release of the Z enyne product and regeneration of
complex 2, thus completing the catalytic cycle. We believe
that the BH4 group behaves as a spectator ligand, stabilizing
the subsequent intermediates and forbidding the coordination
of an additional terminal alkyne, which could lead to
trimerization products.[14] At the same time, its hemilability
allows the coordination of the terminal alkyne for further
reactivity.
In conclusion, the homo- and heterocoupling of terminal
alkynes to give enynes was efficiently catalyzed by a well-
defined iron complex. This reaction exhibits high regio- and
stereoselectivity under very mild, neutral conditions at room
temperature. Our studies suggest that the reaction proceeds
via the alkynyl–iron complex 2, which was characterized by X-
ray diffraction and is likely to be the actual catalyst. Alkyne
coordination to 2 may lead to a vinylidene intermediate,
À
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À
followed by C C coupling and product release upon proto-
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This research was supported by the MINERVA Foundation,
by the Israel Science Foundation, and by the Peter Cohn
Catalysis Research Fund. D.M. holds the Israel Matz Profes-
sorial Chair of Organic Chemistry. S.C. thanks the Swiss
Friends of the Weizmann Institute of Science for a generous
postdoctoral fellowship.
À
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À
Keywords: C C coupling · homogeneous catalysis ·
hydroalkynylation · iron · pincer complexes
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Received: February 7, 2016
Published online: April 21, 2016
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