Salt-Free Strategy for the Insertion of CO2 into C?H Bonds: Catalytic Hydroxymethylation of Alkynes

Article abstract of DOI:10.1002/chem.201800526

A copper(I) catalyst enables the insertion of carbon dioxide into alkyne C?H bonds by using a suitable organic base with which hydrogenation of the resulting carboxylate salt with regeneration of the base becomes thermodynamically feasible. In the presence of catalytic copper(I) chloride/4,7-diphenyl-1,10-phenanthroline, polymer-bound triphenylphosphine, and 2,2,6,6-tetramethylpiperidine as the base, terminal alkynes undergo carboxylation at 15 bar CO₂ and room temperature. After filtration, the ammonium alkynecarboxylate can be hydrogenated to the primary alcohol and water at a rhodium/molybdenum catalyst, regenerating the amine base. This demonstrates the feasibility of a salt-free overall process, in which carbon dioxide serves as a C1 building block in a C?H functionalization.

Full text of DOI:10.1002/chem.201800526

A Journal of
Accepted Article
Title: Salt-Free Strategy for the Insertion of CO2 into C-H Bonds:
Catalytic Hydroxymethylation of Alkynes
Authors: Timo Wendling, Eugen Risto, Thilo Krause, and Lukas J
Goossen
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To be cited as: Chem. Eur. J. 10.1002/chem.201800526
Link to VoR: http://dx.doi.org/10.1002/chem.201800526
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Chemistry - A European Journal
10.1002/chem.201800526
COMMUNICATION
Salt-Free Strategy for the Insertion of CO
Catalytic Hydroxymethylation of Alkynes
2
into C–H Bonds:
[
a]
[b]
[a]
[a]
Timo Wendling, Eugen Risto, Thilo Krause and Lukas J. Gooßen*
Abstract: A copper(I) catalyst enables the insertion of carbon dioxide
into alkyne C–H bonds using a suitable organic base with which
hydrogenation of the resulting carboxylate salt with regeneration of
the base becomes thermodynamically feasible. In the presence of
2
Sustainable C–C bond formation starting from CO and non-
activated substrates would logically be initiated by catalytic C–H
carboxylation leading to carboxylic acids (Scheme 1B).
Unfortunately, the insertion of CO
2
into C–H bonds is
θ
catalytic copper(I) chloride
polymer-bound triphenylphosphine, and 2,2,6,6-tetramethylpiperidine
as the base, terminal alkynes undergo carboxylation at 15 bar CO
/
4,7-diphenyl-1,10-phenanthroline,
thermodynamically unfavorable (for terminal alkynes: G = 19.1
−
1 [9]
kcal mol ). Sufficient driving force for the carboxylation process
2
is gained only by adding a base and stabilizing the product as the
θ
−1 [9]
and room temperature. After filtration, the ammonium
alkynecarboxylate can be hydrogenated to the primary alcohol and
water at a rhodium / molybdenum catalyst, regenerating the amine
base. This demonstrates the feasibility of a salt-free overall process
in which carbon dioxide serves as a C1 building block in a C–H
functionalization.
carboxylate salt (for terminal alkynes: G = -10.1 kcal mol ).
However, known follow-up steps, for example neutralization of the
carboxylate salt or esterification via nucleophilic substitution,
would again inevitably lead to the formation of salt waste. Salt-
free processes, such as a C–H carboxylation with subsequent
hydrogenation to the alcohol appeared to be out of reach: The
addition of base that enables the C–H carboxylation precludes the
subsequent hydrogenation, since only the hydrogenation of
carboxylic acids but not of metal carboxylates is
Carbon dioxide is an abundant carbon source. The Earth
atmosphere contains an estimated 3,080 gigatonnes of carbon
dioxide,[1] and anthropogenic emissions add an average of 33 Gt
of this greenhouse gas each year,[2] exacerbating global warming.
Methods for the chemical use of CO have thus be highly sought-
2
after. Present-day industrial processes include the synthesis of
urea, the Kolbe-Schmitt synthesis of salicylic acid, and
θ
−1
thermodynamically feasible (for acetic acid: G = -5.3 kcal mol ;
θ
−1 [10]
for sodium acetate: G = 12.6 kcal mol ).
A) Contemporary carboxylation strategies: Salt w aste
CO2
HX
(
poly)carbonate production from epoxides. Together, they
consume only about 200 MtCO
/a.[ 3 , 4 ] Research focus
increasingly turns to the hydrogenation of carbon dioxide,
M, CO2
2
B) Dream reaction: Salt-free CH carboxylation
replacing syngas by CO
creation.[
2 2
/H -based methods in chemical value-
CO2
4,5]
H2
Existing strategies for C–C bond-forming reactions with carbon
dioxide as C1 building block require prefunctionalized
compounds and/or inevitably lead to salt waste (Scheme 1A).
One of the few sustainable methods is the catalytic double-bond
Gθ
ca. 19 kcal mol1
G
θ
ca. 5 kcal mol1

a
[
6,7]
H2
base, CO2

carboxylation with CO
2
and hydrogen rather than with CO and
θ

1

H-base
θ
G ca. 13 kcal mol
1


G
c
a
.

1
0
k
c
a
l
m
o
l
water via in situ reverse water-gas shift reaction (rWGSR).[
However, most current research focuses on the carboxylation of
organometallic reagents or of carbon electrophiles with
stoichiometric-metal reducing agents. While for laboratory
applications, this approach has evident advantages over the
carbonylation of aryl halides with toxic carbon monoxide, its
sustainability and economic viability are inherently limited by the
cost of reagents and/or the formation of stoichiometric salt waste.
8 ]
2
Scheme 1. Utilization of CO as C1 building block in C–C bond formation.
Still, we saw a chance to bring these steps together by
substantially increasing catalyst performance in both steps. The
carboxylation step needs to be made to work with a base that
leads to a marginally stabilized salt in a process that is only just
thermodynamically feasible. In the ensuing hydrogenation step, a
stoichiometric amount of base is regenerated. Whereas the
reduction of a sodium carboxylate to the alcohol and NaOH is
endergonic, it might be thermodynamically feasible to
hydrogenate the carboxylates of weak bases, e.g. amines. To
achieve favorable kinetics for the hydrogenation of such salts, we
would need to develop an exceptionally active hydrogenation
[
[
a]
b]
T. Wendling, T. Krause, Prof. Dr. L. J. Gooßen
Fakultät für Chemie und Biochemie
Ruhr-Universität Bochum
Universitätsstraße 150, 44801 Bochum (Germany)
E-mail: lukas.goossen@rub.de
Dr. E. Risto
FB Chemie-Organische Chemie
Technische Universität Kaiserslautern
Erwin-Schrödinger-Str. Geb. 54, 67663 Kaiserslautern (Germany)
a
catalyst system. By systematically expanding the pK ranges of
both steps, an area of overlap might arise, even though C–H
carboxylation and hydrogenation presently appear incompatible
based on available thermodynamic data (Figure 1).
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
yield
yield
bar, 160 °C, 16 h. [d] Yields determined by GC analysis using n-hexadecane
as internal standard. [e] pK
a
values in MeCN.[
16]
The scope of this hydrogenation protocol was found to extend to
TMP salts of aliphatic and aromatic carboxylic acids (see SI,
Table S8). This proves that the hydrogenation of ammonium
carboxylates with formation of alcohols, water and amines is
thermodynamically feasible for a wide range of substrates.
hydrogenation
carboxylation
We proceeded to probe the feasibility of C–H carboxylations with
amine bases, which would afford ammonium carboxylates. C–H
carboxylations are only just starting to develop.[ 17 ] Nolan,[ 18 ]
Hou,[19] Zhang,[20] Lu,[21] and ourselves [22] disclosed effective
methods for the C–H carboxylation of certain heteroarenes and
terminal alkynes based copper, silver, or gold catalysts. All these
goal
pKa
free acid
state of the art
NR3
DBU M CO
2 3
after reaction development
protocols employ only mild bases with pK
those of the C–H groups, e.g. Cs CO or K
a
values lower than
CO . Nevertheless,
a
Figure 1. pK -Gap to be overcome for the realization of the outlined strategy.
2
3
2
3
hydrogenation of the resulting cesium or potassium carboxylates
to the corresponding alcohols would likely remain endergonic.
We decided to use phenylacetylene as a model substrate for
testing even milder bases. From past experience we knew that
decarboxylation of the product is facile, so that it would be difficult
to probe forcing conditions for carboxylate hydrogenation without
losing a large fraction of the product via protodecarboxylation.
However, the alkynyl moiety opened up an opportunity for
irreversibly blocking this unwanted reverse reaction by upfront C–
C triple bond hydrogenation of the phenylpropiolate intermediate
Probing this hypothesis, we first investigated the base tolerance
of carboxylic acid hydrogenations for the model substrate n-
nonanoic acid following literature procedures (Table 1). In the
absence of base, n-nonanol was formed in high yields with
homogeneous ruthenium / triphos,[11] cobalt / triphos, [12] and
iridium / bipyridine systems.[13] Several heterogeneous catalysts,
such as bimetallic combinations of group 8–10 with group 6 or 7
metals were also effective.[14] However, none of these state-of-
the-art hydrogenation catalysts yielded any n-nonanol in the
presence of inorganic carbonates. Strong organic bases, such as
(
Scheme 2).
[cat.]
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), also suppressed
hydrogenation. Only after hydrogenolysis of the DBU, traces of
alcohol started to form. Even amines were found to strongly retard
the hydrogenation for all catalysts except a heterogeneous Rh /
Mo system (entry 3). With 1 mol% Rh on alumina doped with 0.5

H-base
1
a
2a
recycling
[
cat.], H2
[cat.], H2
mol% Mo(CO)
presence of
tetramethylpiperidine (TMP) or triethylamine (NEt
0 bar H
6
, encouraging yields were obtained not only in the
triarylamines but even of 2,2,6,6-
) at 160 °C and
H-base
5a
4a
3
7
2
.
Scheme 2. Salt-free carboxylation of terminal alkynes.
Table 1. Investigation of the base-tolerance for state-of-the-art
hydrogenation methods for carboxylic acids.
Effective systems for the C–H carboxylation step were sought
starting from literature protocols based on copper or silver (Table
2).[20a, 21, 22] Several catalyst systems gave high yields in
combination with cesium carbonate (entries 1-5), and with the
strong organic base DBU, but none of them was active in
combination with tertiary amines (see also Table S1). However,
when using bulky, secondary amines, in particular TMP,
encouraging activity was detected for copper iodide (entry 8; see
also Table S3 in SI).
The presence of amine ligands, particularly of 4,7-diphenyl-1,10-
phenanthroline (BPhen), had a beneficial effect (entry 11). The
key factor in this process was the solvent system. Only a
substoichiometric amount of a polar, aprotic solvent must be
present, just sufficient to keep the reaction mixture stirrable (entry
[cat.]
H , base
2
Entry
Catalyst
system
Yield (%)[d] in presence of
-
-
NPh
3
TMP
18.6
NEt
3
DBU
24.3
2 3
Cs CO
[
e]
pK
a
1.3
18.8
8
n.a.
0
1[a]
Ru/triphos/
73
42
17
8
Sn(OTf)
2
2[b]
3[c]
Co/triphos
Rh/Mo
0 [15]
75
0
0
0
0
0
0
0
49
68
56
NPh
amine. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene. [a] Nonanoic acid (0.50
mmol), base (0.50 mmol), Ru(acac) (4 mol%), triphos (5 mol%), Sn(OTf)
10 mol%), toluene (2 mL), water (0.5 mL), 60 bar, 160 °C, 48 h. [b] Nonanoic
acid (0.50 mmol), base (0.50 mmol), Co(BF ·6 H O (5 mol%), triphos (5
mol%), THF (3 mL), 80 bar, 100 °C, 16 h. [c] Nonanoic acid (0.50 mmol),
base (0.50 mmol), Rh/Al (1 mol%), Mo(CO) (0.5 mol%), DME (1 mL), 70
3 3
=triphenylamine. TMP=2,2,6,6-tetramethylpiperidine. NEt =triethyl-
12). Further important factors to improved yields were to reduce
3
2
the temperature to 25 °C (entry 13), and to adjust the CO
pressure to between 15 and 50 bar. At higher pressures, the CO
2
(
2
)
4 2
2
neutralizes the amine base, and at lower pressures, the reaction
becomes slow. After these modifications, the best yields were
obtained with copper(I) chloride (entry 17). Since compatibility
checks had revealed that both DMSO and the Cu / amine catalyst
O
2 3
6
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COMMUNICATION
would hamper the subsequent hydrogenation steps, DMSO was
replaced by NMP (entry 18), and polymer-bound
triphenylphosphine was added to aid catalyst removal during
work-up (entry 19) (See Table S4, S5 and additional experiments
in the SI for details). Under these conditions (1.20 eq. TMP, 1
syringe filter with methanol, adding 2 mol% rhodium on alumina,
and hydrogenating the C–C triple bond at room temperature and
10 bar H
2
pressure (see Table S4 in SI for details). The
ammonium propanoate was thus obtained in near-quantitative
yield. This intermediate is no longer prone to decarboxylation, so
that it now became possible to probe forcing conditions for the
carboxylate hydrogenation. Intricate reaction development led to
a process in which the volatile methanol is removed upfront,
3
mol% CuCl,1 mol% BPhen, 2.5 mol% poly-PPh , 100 µL NMP,
room temperature, 15 bar CO , 12 h), the reaction gave 83 % yield
2
when trapping the product as the methyl ester.
6
followed by addition of the Mo(CO) cocatalyst in NMP, and
stirring the reaction mixture at 180 °C and 70 bar H
SI,Table S5 and S6).
2
for 14 h (see
Table 2. Optimization for the copper-catalyzed carboxylation.
The overall process afforded 3-phenylpropanol (5a) in 68% yield
based on phenylacetylene. The scope of this prototype process
was found to extend to a range of aromatic alkyne substrates
bearing hydrogenation-stable functional groups, such as methoxy,
dimethylamino or trifluoromethyl (Table 3). Expectedly, non-
overlapping limitations of the individual step add up in the overall
procedure: The carboxylation with TMP as the base gives good
yields for aryl and heteroaryl substituted acetylenes whereas 5w
and other alkyl substituted acetylenes give only low yields (see
Table S7, SI). The hydrogenation steps have a relatively broad
scope, but it does not include the heteroarene substituents that
are tolerated in the first step (see SI, Table S8). As a result, the
scope is presently limited to phenyl acetylenes. The TMP base
can be recovered in reasonable yield (40 %, see SI). This
suggests that the base does not get destroyed in the process, but
substantial reaction development is still required to bring the
1
) base, catalyst
) esterification
2
1
a
3a
Entry
Catalyst system
Solvent (mL)
p
T
(°C)
Yield
g]
(%)[
(
mol%)
(bar)
2 3
with Cs CO
1[a]
2[b]
I (1)
DMF (3)
DMF (2)
5
1
35
25
40
50
25
90
0[23]
CuCl (2)/TMEDA
CuI (1)
3[c]
4[d]
5[e]
DMSO (2)
DMSO (3)
DMF (5)
20
1
56
76
85
4
AgBF (0.25)
AgI (1)
2
with TMP
6[a]
7[b]
8[c]
9[d]
I (1)
CuCl (2)/TMEDA
CuI (1)
DMF (3)
DMF (2)
5
35
25
40
50
25
40
40
25
25
25
25
25
25
5
1
0
2
recovery of CO and base to an acceptable level.
DMSO (2)
20
1
10
0
AgBF
4
(0.25)
DMSO (3)
Table 3. Scope for the sequential synthesis of alcohols.[a]
1
0[e]
AgI (1)
DMF (5)
2
0
step 1
1[f]
1 mol% CuCl
1
1
1
1
1
1
1
1
CuI (1)/BPhen (1)
CuI (1)/BPhen (1)
CuI (1)/BPhen (1)
CuI (1)/BPhen (1)
CuI (1)/BPhen (1)
CuI (1)/BPhen (1)
CuCl (1)/BPhen (1)
CuCl (1)/BPhen (1)
CuCl (1)/BPhen (1)/
DMSO (2)
20
20
20
15
5
16
43
89
85
57
6
1
2
mol% BPhen
.5 mol% poly-PPh3
2[f]
DMSO (0.05)
DMSO (0.05)
DMSO (0.05)
DMSO (0.05)
DMSO (0.05)
DMSO (0.05)
NMP (0.05)
r.t., 15 bar CO2
2 h, NMP
+H-TMP
3[f]
4[f]
5[f]
6[f]
7[f]
8[f]
9[f]
1
1a - 1j
B1
2a- 2j
R = aryl or benzyl
step 2
1.) MeOH, filtration
2.) 2 mol% Rh/Al O3
2
step 3
mol% Mo(CO)6
180 °C, 70 bar H
4 h, NMP
r.t., 10 bar H , 18 h
2
50
15
15
2
91
88
83
2
1
+H-TMP
5a - 5j
B1
4a - 4j
1
NMP (0.05)
15
25
(89)[
h]
polyPPh
3
(2.5)
See SI for details. BPhen=4,7-diphenyl-1,10-phenanthroline. TMEDA=
N,N,N’,N’-tetramethylethane-1,2-diamine. [a] 1a (1.00 mmol), base (1.20
R = CF3 5m: 69%
R = H 5a: 68%
Me 5b: 70%
F 5d: 62%
OMe 5n: 72%
NMe2 5p: 78%[b]
5i: 73%
3 2 3
mmol), I = (BPhen)Cu(4-F-PPh ) NO (1 mol%), DMF (3 mL), 5 bar, 35 °C,
16 h. [b] 1a (1.00 mmol), base (1.20 mmol), CuCl (2 mol%), TMEDA (1.5
OMe 5e: 72%
mol%), DMF (2 mL), 1 bar, r.t., 16 h. [c] 1a (1.00 mmol), base (1.20 mmol),
CuI (1 mol%), DMSO (2 mL), 20 bar, 40 °C, 16 h. [d] 1a (1.00 mmol), base
(1.20 mmol), AgBF
4
(0.25 mol%), DMSO (3 mL), 1 bar, 50 °C, 16 h. [e] 1a
(
1.00 mmol), base (1.50 mmol), AgI (1 mol%), DMF (5 mL), 2 bar, r.t., 16 h.
R = 3- or 2-thienyl: 0%
alkyl: 0%
5
t: 52%[b]
5w: 37%
[f] 1a (1.00 mmol), B1 (1.20 mmol), Cu-source (1 mol%), BPhen (1 mol%),
solvent, 12 h. [g] Yields of the corresponding methyl esters determined by
GC analysis after esterification with methyl iodide (8 eq.) and DMSO (1 mL)
using n-dodecane as internal standard. [h] Isolated without esterification as
the free phenylpropiolic acid.
[
a] Step 1: 1a-j (2.00 mmol), B1 (2.40 mmol), CuCl (1 mol%), BPhen (1
mol%), poly-PPh (2.5 mol%), NMP (100 µL), r.t., 15 bar CO , 12 h. Step 2:
MeOH (4-6 mL), filtration, Rh/Al (2 mol%), r.t., 10 bar H , 18 h. Step 3:
3
2
We next investigated a way to hydrogenate the propiolate salt with
minimal losses through protodecarboxylation. Best results were
obtained when washing the above reaction medium through a
O
2 3
2
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Chemistry - A European Journal
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COMMUNICATION
Removal of MeOH, Mo(CO)
6
(2 mol%), NMP (6 mL), 180 °C, 70 bar H
2
, 14
autoclave. It was pressurized with CO
2
(15 bar) and stirred at room
h. Isolated yields. [b] NMP (200 µL).
temperature for 12 h. The reaction mixture was dissolved in MeOH (4-6
mL) and filtered through a syringe filter (PTFE membrane, pore size 0.45
µm) into another 10 mL headspace vial with stirring bar pre-charged with
5 wt% rhodium on alumina (82.3 mg, 40 µmol). The vial was pressurized
This demonstrates the conceptual feasibility of salt-free
processes in which C–H carboxylations are performed with such
a mild base that hydrogenation of the resulting carboxylates is
possible. Its current limitations reflect those of amine base-
assisted C–H carboxylation catalysts that can be removed by
filtration. Nevertheless, this reaction represents an important
milestone in the development of salt-free C–H carboxylation
processes. It is likely that any transformation that results in the
formation of ammonium carboxylates, including (directed)
catalytic arene, alkene, and alkane C–H carboxylations, can be
built into a salt-free hydroxymethylation process. In an industrial
collaboration, the applicability of this process to the synthesis of
butanediol from acetylene and carbon dioxide is presently under
with H
2
(10 bar) in an autoclave, and stirred at r.t. for 18 h. After releasing
(10.6 mg, 40
the pressure, MeOH was removed in vacuo, and Mo(CO)
6
µmol) and NMP (6 mL) were added. The hydrogen pressure was set to 70
bar, and the mixture was stirred at 180 °C for 14 h (resulting in a pressure
of 100 bar). After cooling and depressurizing, the resulting mixture was
separated by distillation. For product purification and characterization on
small scale, the mixture was diluted with ethyl acetate (20 mL) and washed
with water (20 mL). The aqueous phase was extracted with ethyl acetate
(2 x 15 mL), the combined organic layers were washed with 1N HCl (15
mL) (except for basic substrates) and 10% LiCl-solution (15 mL), dried
over MgSO
4
and the solvent was removed in vacuo. The crude products
).
were purified by flash column chromatography (SiO
2
2
investigation. Conceivably, CO insertion leading to ammonium
carboxylates may also be followed up by other reaction steps that
would be endergonic for metal carboxylates, e.g. Acknowledgements
heterocyclization, esterification, or amidation.
We thank P. Weber, D. Eppel and N. Wittmack for technical
assistance and the DFG (EXC 1069 RESOLV), FCI (fellowship
to T. W.), DBU (fellowship to E. R.) and the Car Zeiss foundation
Experimental Section
(
RCR) for financial support.
Under strict exclusion of air and moisture, a 10 mL headspace vial with
stirring bar was charged with CuCl (1.98 mg, 20 µmol), 4,7-diphenyl-1,10-
Keywords: alkynes • carbon dioxide fixation • copper •
hydrogenation • rhodium
3
phenanthroline (6.72 mg, 20 µmol), PPh -polymer-bound (16.7 mg, 50
µmol) NMP (100 µL), terminal alkyne (2.00 mmol), and 2,2,6,6-
tetramethylpiperidine (339 mg, 405 µl, 2.4 mmol) and placed in an
[
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[10] The Gibbs free energies for the hydrogenation were calculated from the
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Chemistry - A European Journal
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Entry for the Table of Contents
COMMUNICATION
Timo Wendling, Eugen Risto, Thilo
Krause and Lukas J. Gooßen*
Cu/BPhen
Rh,H2
Rh/Mo,H2
Page No. – Page No.
Salt-Free Strategy for the Insertion of
2
CO into C–H Bonds: Catalytic
Hydroxymethylation of Alkynes
A catalytic system consisting of Cu(I)/BPhen allows the carboxylation of terminal
alkynes with CO with such a mild amine base that it becomes thermodynamically
2
feasible to hydrogenate the resulting ammonium carboxylates to the corresponding
alcohols under regeneration of the amine base. This provides proof of concept for
salt-free processes utilizing CO
2
as a C1 building block in C-C bond formation.
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