Synthesis of Vinyl Carboxylic Acids using Carbon Dioxide as a Carbon Source by Iron-Catalyzed Hydromagnesiation

Article abstract of DOI:10.1002/cctc.201600279

An iron-catalyzed synthesis of α,β-unsaturated carboxylic acids from alkynes and carbon dioxide was developed. This reaction proceeds through hydromagnesiation of alkynes followed by carbon dioxide insertion under atmospheric pressure and ambient temperature in the presence of iron and a Grignard reagent as a catalyst and hydride source, respectively. Several symmetrical and unsymmetrical alkynes were transformed into the corresponding acids in good to excellent yields. The methodology provides an efficient route to the synthesis of vinyl carboxylic acids.

Full text of DOI:10.1002/cctc.201600279

DOI: 10.1002/cctc.201600279
Communications
Synthesis of Vinyl Carboxylic Acids using Carbon Dioxide
as a Carbon Source by Iron-Catalyzed Hydromagnesiation
Rajagopal Santhoshkumar+,[a] Ya-Chun Hong+,[a] Ching-Zong Luo,[a] Yun-Ching Wu,[a] Chen-
Hsun Hung,[a] Kuen-Yuan Hwang,[b] An-Pang Tu,[b] and Chien-Hong Cheng*[a]
An iron-catalyzed synthesis of a,b-unsaturated carboxylic acids
from alkynes and carbon dioxide was developed. This reaction
proceeds through hydromagnesiation of alkynes followed by
carbon dioxide insertion under atmospheric pressure and am-
bient temperature in the presence of iron and a Grignard re-
agent as a catalyst and hydride source, respectively. Several
symmetrical and unsymmetrical alkynes were transformed into
the corresponding acids in good to excellent yields. The meth-
odology provides an efficient route to the synthesis of vinyl
carboxylic acids.
These reactions are very interesting, but they require pyro-
phoric diethylzinc as a reducing reagent or N-heterocyclic car-
bene ligands. Recently, Martin et al.[5f] demonstrated the Ni-cat-
alyzed hydrocarboxylation of alkyne by using simple alcohols
as a proton source, which resulted in exceptional chemoselec-
tivity. However, the development of a method for the ligand-
free, nontoxic-metal-catalyzed hydrocarboxylation of alkynes
under mild reaction conditions is highly desirable. Our contin-
ued interest in first-row transition-metal-catalyzed reductive
coupling reactions of different p components[13] motivated us
to extend the reactions of alkynes with CO2. Herein, we wish
to report the iron-catalyzed synthesis of a,b-unsaturated car-
boxylic acids from alkyne by using CO2 as the carbon source.
Initially, diphenylacetylene (1a) was treated with ethylmag-
nesium bromide in diethyl ether as the hydride source in the
presence of 5 mol% FeCl2 by using diethyl ether as the solvent
at ambient temperature for 15 min, and this was followed by
trapping with CO2. The reaction gave desired carboxylic acid
2a in 90% yield with high (E) stereoselectivity. The effects of
different solvents were tested (see the Supporting Informa-
tion). We observed that ether solvents such as Et2O and THF
were highly effective, whereas 1,4-dioxane was less effective.
Hydride sources other than EtMgBr, such as iPrMgBr, CyMgBr
(Cy=cyclohexyl), CpMgBr (Cp=h5-cyclopentadienyl), and Et2Zn
gave lower yields or the starting material remained un-
changed. Furthermore, the addition of 5 mol% N,N,N’,N’-tetra-
methylethylenediamine, tri(n-butyl)phosphine, 2,2’:6’,2’’-terpyri-
dine, and bidentate phosphine ligands completely retarded
the catalytic reaction. A control experiment revealed that the
reaction did not proceed without FeCl2 or EtMgBr, and the use
of other transition metals in place of iron failed to provide the
desired product.
The utilization of carbon dioxide (CO2) for the synthesis of
high-value-added products and iron-catalyzed reactions have
undergone explosive growth over the last decade.[1,2] Iron and
CO2 are attractive in organic synthesis owing to their low cost,
abundance, nontoxicity, and environmentally benign nature.
However, the activation of thermodynamically and kinetically
stable raw materials is highly challenging. Thus, the efficient
transition-metal-catalyzed conversion of CO2 is highly attrac-
tive. Illustrative examples are cycloaddition[3] and the direct
carboxylation of organometallics[4] and unsaturated com-
pounds such as alkynes,[5] alkenes,[6] allenes,[7] and dienes.[8] Be-
sides these reactions, CO2 insertion into carbon–halogen,[9]
carbon–oxygen,[10] and activated CÀH bonds[11] has been stud-
ied. In a similar manner, iron-catalyzed reactions provide an
ideal economic as well as ecological alternative to typical tran-
sition metals. In 2012, Hayashi and co-workers reported the
carbometalation of alkynes with alkyl Grignard reagents.[12a]
Later, Greenhalgh and Thomas demonstrated the hydrocarbox-
ylation of styrene derivatives,[6d] and Nakamura et al. developed
the hydromagnesiation of diarylalkynes,[12b] which was pro-
posed to involve hydrometalation as the key step.
Next, we examined the scope of the reaction under the stan-
dard reaction conditions. Various symmetrical diarylalkynes
1a–h containing electron-withdrawing groups (EWGs) and
electron-donating groups (EDGs) were successfully transformed
into the corresponding acids with high stereoselectivity
(Table 1, entries 1–8). For example, substrates 1b–d containing
a methyl substituent at the ortho, meta, and para positions of
the benzene ring afforded vinylic acids 2b–d in yields of 44,
61, and 82%, respectively. In a similar manner, electron-rich
bis(4-methoxyphenyl)acetylene (1e) also underwent the CO2
insertion reaction. Fluoro- and chloro-substituted alkynes 1 f
and 1g were tolerated under the reaction conditions and pro-
vided vinyl carboxylic acids 2 f and 2g, whereas the bromo-
and iodo-substituted alkynes gave trace amounts of the deha-
logenation products only. Thiophen-2-yl-substituted alkyne 1h
Catalytic hydrocarboxylation of alkynes by employing CO2
was developed in the presence of Cu[5d] or Ni[5e] as a catalyst.
[a] R. Santhoshkumar,+ Y.-C. Hong,+ C.-Z. Luo, Y.-C. Wu, C.-H. Hung,
Prof. Dr. C.-H. Cheng
Department of Chemistry
National Tsing Hua University
Hsinchu, 30013 (Taiwan)
Fax: (+886)3572-4698
E-mail: chcheng@mx.nthu.edu.tw
[b] K.-Y. Hwang, A.-P. Tu
Chang Chun Plastics Co., LTD
Hsinchu 30013 (Taiwan)
[+] These authors contributed equally to this work.
Supporting Information for this article can be found under http://
dx.doi.org/10.1002/cctc.201600279.
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Table 1. Iron-catalyzed hydrocarboxylation of symmetrical diarylalkynes
1a–h with CO2
Table 2. Iron-catalyzed hydrocarboxylation of unsymmetrical alkynes 1i–
p with CO2
[a]
[a]
Entry
1
2
Ratio (a/b)
Yield[b]
[%]
Entry
1
R1 =R2
2
Yield[b]
[%]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
Ph
2a
2b
2c
2d
2e
2 f
90
82
61
44
80
41
45
70
1
2
3
4
5
6
7
8
1i
2i
40:60
55:45
84:16
68:32
100:0
50:50
10:90
100:0
53
52
60
35
86
60
58
89
p-MeC6H4
m-MeC6H4
o-MeC6H4
p-MeOC6H4
p-FC6H4
1j
2j
1g
1h
p-ClC6H4
2-thienyl
2g
2h
1k
1l
2k
2l
[a] Reaction conditions: alkyne 1 (0.30 mmol), FeCl2 (5.0 mol%), EtMgBr
(0.60 mmol), Et2O (1.50 mL), RT, 15 min. [b] Yield of isolated product.
was also suitable for the hydrocarboxylation reaction, and it af-
forded product 2h in good yield.
1m
1n
1o
1p
2m
2n
2o
2p
The present catalytic reaction was successfully extended to
a variety of unsymmetrical diarylalkynes containing ortho,
meta, and para substituents on the phenyl ring; this has not
been studied in previous hydrocarboxylation protocols
(Table 2). The regioselectivity of the products imitates Alami’s
work on the ortho-directing effect for the palladium-catalyzed
hydrostannylation of internal alkynes, in which the regioselec-
tivity is controlled by the ortho substituent at the aromatic
ring, irrespective of the electronic nature of the substituent
(Scheme 1a).[14] Our results are also in accord with Helaja’s
report on electronic regioselectivity of para- and meta-substi-
tuted diarylalkynes in the cobalt-mediated Pauson–Khand reac-
tion (Scheme 1b–d).[15]
[a] Reaction conditions: alkyne 1 (0.30 mmol), FeCl2 (5.0 mol%), EtMgBr
(0.60 mmol), Et2O (1.50 mL), RT, 15 min. [b] Yield of isolated product.
gioisomer became the major species with an a/b ratio of 1:9.
Alkyne 1p containing an electron-withdrawing CF3 group at
the meta position was also a suitable candidate for the regio-
selective hydrocarboxylation reaction, and it provided only
product 2p-a in 89% yield. For 1-phenyl-1-butyne (1q), the
hydride was regioselectively added to the carbon atom near
the alkyl group to afford product 2q, albeit in low yield. The
presence of b-hydrogen atoms in 1q leading to the rearrange-
ment of the alkyne to an allene likely accounts for the low
product yield owing to the fact that under the reaction condi-
tions the allene group does not undergo hydrocarboxylation
(Scheme 2). Gratifyingly, alkyne 1r with a cyclohexyl group af-
forded corresponding acid 2r in 75% yield with a regioisomeric
ratio of 83:17.[16] Alkyne 1s containing a trimethylsilyl group
Scheme 1. Electronic nature of the unsymmetrical diarylalkynes.
Thus, alkyne 1i containing a para-methyl group on one of
the phenyl rings gave a mixture of substituted vinylic acids
2i-a and 2i-b in 53% combined yield with the latter as the
major product. In contrast, for ortho-methyl- and meta-methyl-
substituted alkynes 1j–l, the corresponding a-regioisomers
with the carboxylic group near the methyl-substituted phenyl
ring were observed in moderate yields. Complete regioselectiv-
ity for the hydrocarboxylation of 2-methoxy-substituted alkyne
1m gave a-regioisomer 2m in 86% yield. In a similar manner,
3- and 4-methoxyphenylalkynes 1n and 1o underwent the
CO2 insertion reaction to afford a mixture of regioisomeric
products 2n and 2o in good yields. For substrate 1n, the a-
and b-regioisomers were equally formed, but for 1o, the b-re-
Scheme 2. Hydrocarboxylation of unsymmetrical alkynes. For product 2r,
the ratio of regioisomers was 83:17. For product 2s, E/Z=68:32.
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was also suitable for the reaction, and it gave vinylic acid 2s in
83% yield with an E/Z ratio of 68:32.
fined acids that could be further converted into benzofura-
none.
Furthermore, the a,b-unsaturated carboxylic acids were
easily transformed into the corresponding benzofuran-2-one
skeletons, which are present in various natural products and
bioactive molecules (Scheme 3).[17] Notably, crude product 2m
was directly converted into 3m in 83% yield with the aid of
BBr3.
Experimental Section
Synthesis of vinyl carboxylic acid 2a
A sealed tube containing FeCl2 (1.9 mg, 0.015 mmol, 5 mol%) and
diphenylacetylene (1a; 53.5 mg, 0.30 mmol) was evacuated and
purged with nitrogen gas (3ꢁ). Then, freshly distilled diethyl ether
(1.50 mL) and a solution of ethylmagnesium bromide in diethyl
ether (0.2 mL, 3 M in Et2O, 0.6 mmol) were added to the mixture
by syringe under a nitrogen atmosphere. The mixture was stirred
at ambient temperature for 15 min and then carbon dioxide was
bubbled through the mixture for 15 min. The reaction was
quenched with 1n HCl solution (2.0 mL), and the aqueous layer
was extracted with dichloromethane (2ꢁ5 mL). The combined or-
ganic phase was concentrated under vacuum, and the residue was
purified by chromatography (silica gel, n-hexane/isopropyl alcohol)
to afford desired product 2a (61 mg, 90%).
Scheme 3. Synthesis of fused lactone 3m. Reagents and conditions:
a) acid 2m (0.20 mmol), BBr3 (0.30 mmol), CH2Cl2, 08C to RT, 12 h.
On the basis of literature reports,[6d,12a] a plausible mecha-
nism is proposed, as shown in Scheme 4. The reaction is initiat-
ed by alkylation of the iron catalyst with ethylmagnesium bro-
mide, which is followed by b-hydrogen elimination to afford
hydride intermediate I. Coordination of alkyne 1a to I gives
iron alkyne hydride species II. Hydrometalation of the alkyne
gives intermediate III, which then undergoes transmetalation
with the Grignard reagent to afford vinylmagnesium bromide
IV with regeneration of the ironalkyl species for the next cycle.
Finally, insertion of CO2 with IV takes place to provide desired
product 2a.
Acknowledgements
We thank the Ministry of Science and Technology of the Republic
of China (MOST-103–2622-E-007—025) for support of this re-
search.
Keywords: carbon dioxide fixation · carboxylic acids · Grignard
reagents · hydrocarboxylation · iron
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Received: March 12, 2016
Revised: April 15, 2016
Published online on && &&, 0000
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Iron fist: The ever-growing demand for
energy has led to a concomitant in-
crease in the concentration of CO2 in
the atmosphere, and this has become
a key global environmental threat.
Hence, the utilization of CO2 to synthe-
size useful products is an excellent way
to scavenge it. Herein, the most abun-
dant transition metal, iron, is used as
a catalyst for the hydrocarboxylation of
alkynes by CO2.
R. Santhoshkumar, Y.-C. Hong, C.-Z. Luo,
Y.-C. Wu, C.-H. Hung, K.-Y. Hwang,
A.-P. Tu, C.-H. Cheng*
&& – &&
Synthesis of Vinyl Carboxylic Acids
using Carbon Dioxide as a Carbon
Source by Iron-Catalyzed
Hydromagnesiation
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