Cu-catalyzed formal methylative and hydrogenative carboxylation of alkynes with carbon dioxide: Efficient synthesis of α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1002/chem.201301456

The sequential hydroalumination or methylalumination of various alkynes catalyzed by different catalyst systems, such those based on Sc, Zr, and Ni complexes, and the subsequent carboxylation of the resulting alkenylaluminum species with CO₂ catalyzed by an N-heterocyclic carbene (NHC)-copper catalyst have been examined in detail. The regio- and stereoselectivity of the overall reaction relied largely on the hydroalumination or methylalumination reactions, which significantly depended on the catalyst and alkyne substrates. The subsequent Cu-catalyzed carboxylation proceeded with retention of the stereoconfiguration of the alkenylaluminum species. All the reactions could be carried out in one-pot to afford efficiently a variety of α,β- unsaturated carboxylic acids with well-controlled configurations, which are difficult to construct by previously reported methods. This protocol could be practically useful and attractive because of its high regio- and stereoselectivity, simple one-pot reaction operation, and the use of CO ₂ as a starting material. Copyright

Full text of DOI:10.1002/chem.201301456

FULL PAPER
Synthesis
M. Takimoto, Z. Hou* ...... &&&& — &&&&
Cu-Catalyzed Formal Methylative and
Hydrogenative Carboxylation of
Alkynes with Carbon Dioxide: Effi-
cient Synthesis of a,b-Unsaturated
Carboxylic Acids
Aluminate your chemistry! Methyla-
tive and hydrogenative carboxylation
of alkynes has been developed by a
combination of their regio- and stereo-
selective methyl- and hydroalumina-
tion catalyzed by Sc, Zr, or Ni catalysts
and the N-heterocyclic carbene–Cu-
catalyzed carboxylation of the result-
ing alkenylaluminum species with CO2
to afford a,b-unsaturated carboxylic
acids (see scheme; IPr=1,3-bis(2,6-di-
AHCTUNGTRENNiGUN sopropenyl)imidazol-2-ylidene).
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DOI: 10.1002/chem.201301456
Cu-Catalyzed Formal Methylative and Hydrogenative Carboxylation of
Alkynes with Carbon Dioxide: Efficient Synthesis of a,b-Unsaturated
Carboxylic Acids
Masanori Takimoto[a, b] and Zhaomin Hou*[a, b]
Abstract: The sequential hydroalumi-
nation or methylalumination of various
alkynes catalyzed by different catalyst
systems, such those based on Sc, Zr,
and Ni complexes, and the subsequent
carboxylation of the resulting alkenyla-
luminum species with CO2 catalyzed by
an N-heterocyclic carbene (NHC)–
copper catalyst have been examined in
detail. The regio- and stereoselectivity
of the overall reaction relied largely on
the hydroalumination or methylalumi-
nation reactions, which significantly de-
pended on the catalyst and alkyne sub-
strates. The subsequent Cu-catalyzed
carboxylation proceeded with retention
of the stereoconfiguration of the alke-
nylaluminum species. All the reactions
could be carried out in one-pot to
afford efficiently a variety of a,b-unsa-
turated carboxylic acids with well-con-
trolled configurations, which are diffi-
cult to construct by previously reported
methods. This protocol could be practi-
cally useful and attractive because of
its high regio- and stereoselectivity,
simple one-pot reaction operation, and
the use of CO2 as a starting material.
Keywords: alkynes
· aluminum ·
carbon dioxide · carboxylation ·
copper
Introduction
organic synthesis.[2] The a,b-unsaturated carboxyl units are
usually constructed by using the Wittig reaction or the
Horner–Wadsworth–Emmons reaction (HWE reaction)
through condensation of aldehydes or ketones with stabi-
lized phosphonium ylides or phosphoryl carbanions bearing
a CO2R substituent.[2] However, these reactions, though con-
venient, always yield a stoichiometric amount of unwanted
byproducts with relatively large molecular weights, such as
phosphine oxides and phosphate salts, thus limiting their
synthetic utility especially in large-scale preparations.
a,b-Unsaturated carboxylic acids and derivatives, especially
those with branching b-methyl groups, are important sub-
structure motifs widely existing in biologically active natural
products and medicines (Figure 1).[1] Moreover, a,b-unsatu-
rated carboxylic acids can serve as useful building blocks in
Carbon dioxide (CO2) is a readily available, nontoxic, and
inherently renewable chemical feedstock. The use of CO2 as
a building block in organic synthesis has received much cur-
rent interest.[3] In principle, the hydrogenative or alkylative
addition of CO2 to alkynes could serve as an efficient syn-
thetic route to a,b-unsaturated carboxylic acids. However,
only limited success has been achieved to date in the catalyt-
ic transformation of alkynes and CO2 into a,b-unsaturated
carboxylic acids,[4–9] despite recent advances in this area.
The oxidative cycloaddition of CO2 and the C–C triple
bond of alkynes to low-valent transition-metal species, such
as Ni0 or TiII, was reported to give the corresponding metal-
lacyclic a,b-unsaturated carboxylates, which on hydrolysis
afforded a,b-unsaturated carboxylic acids.[4] However, a stoi-
chiometric amount of transition-metal reagents was usually
required in such transformations. Electrochemical reduction
of a nickel metallacycle on a Mg-anode was reported to lead
to catalytic formation of the a,b-unsaturated carboxylic acid
products, but this reaction generally suffered from poor re-
gioselectivity.[6]
Figure 1. Some examples of biologically active compounds bearing an
a,b-unsaturated carboxyl unit.
[a] Dr. M. Takimoto, Prof. Z. Hou
Organometallic Chemistry Laboratory, RIKEN
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
Fax : (+81)48-462-4665
E-mail: houz@riken.jp
[b] Dr. M. Takimoto, Prof. Z. Hou
Advanced Catalysis Research Group
RIKEN Center for Sustainable Resource Science
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
Recently, Tsuji and co-workers reported the catalytic hy-
drogenative carboxylation of alkynes with CO2 by using a
CuI salt as a catalyst and hydrosilane as a hydrogen sour-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301456.
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Efficient Synthesis of a,b-Unsaturated Carboxylic Acids
FULL PAPER
ce.[7a] Ma and co-workers found that the analogous hydroge-
native carboxylation reactions could also be realized by
using a nickel catalyst with diethylzinc as a hydride sour-
ce.[7b,c] In both cases, the substrate scope was limited to inter-
nal alkynes, while terminal alkynes are not applicable.
In contrast to hydrogenative carboxylation of alkynes,
which adds a hydrogen atom and CO2 to a C–C triple bond
to give a,b-unsaturated carboxylic acids without a substitu-
ent on the b-carbon atom, alkylative carboxylation of al-
kynes leads to simultaneous addition of both an alkyl group
and CO2 to afford tetrasubstituted olefinic units. However,
studies on the alkylative carboxylation of alkynes with CO2
were even scarcer. In 2005, Mori and co-workers achieved
the methylative caroboxylation of alkynes with CO2 by
using Me2Zn as a methyl source to react with a nickel metal-
lacycle intermediate.[9a] This reaction required a large excess
Results and Discussion
Regio- and stereospecific formal methylative carboxylation
of internal alkynes by using a Sc/Cu catalyst combination:
At first, we examined the carboxylation of the alkenylalumi-
num species 2a prepared by the scandium-catalyzed me-
thyalalumination of an internal alkyne containing a tethered
ether group (1a) (Table 1). In the presence of a catalytic
Table 1. One-pot sequential methylalumination/carboxylation of an inter-
nal alkyne.[a]
amount of 1,8-diazabicycloACTHNUTRGENUGN[5.4.0]undec-7-ene (DBU) and
usually yielded a regioisomeric mixture of the a,b-unsaturat-
ed carboxylic acid products. Very recently, Ma and co-work-
ers reported the Ni-catalyzed methylative carboxylation of
homopropargylic alcohols through a methylzincation/car-
boxylation cascade.[9b] In this reaction, a hydroxyl group in
the alkyne substrates served as a directing group to enhance
the regioselectivity and the reactivity. Similar to the hydro-
genative carboxylation mentioned above, all of these alkyla-
tive carboxylation reactions were limited to internal alkynes,
whereas terminal alkynes are not suitable.
Entry
Catalyst
none
T [8C][b]
3a [%][c]
1
2
3
4
5
6
7
70
70
RT
70
70
RT
RT
0
86
ACHUTNGREN[NUG CuClACHTUNGTRENNUNG
A
E
100
8[e]
28[e]
29
CuCl[d]
IPr[d]
[f]
[Ni
N
[g]
PdA(OAc)2/PCy3
5[e]
[a] The reaction was carried out in “one-pot” by addition of a THF solu-
tion of [CuCl(IPr)] to a toluene solution of 2a prepared by reaction of
1a with Me3Al in the presence of [Sc(Cp*)(R)2]/[Ph3C][B(C6F5)4], and
AHCTUNGTRENNUNG
N
G
ACHTUNGTRENNUNG
It is well known that the hydroalumination and methylalu-
mination of terminal and internal alkynes can be achieved
in a regio- and stereospecific fashion by choosing an appro-
priate catalyst.[10,11] Various alkenylaluminum species with
well-controlled configurations could be generated in this
way. We envisioned that if the alkenylaluminum species
could be added to CO2 in a stereospecific manner,[12–15] a,b-
unsaturated carboxylic acids with the desired structural pat-
terns would be efficiently synthesized from alkynes and
CO2. We have recently reported that N-heterocyclic carbene
(NHC)–copper complexes can serve as an excellent catalyst
for the carboxylation of various substrates with CO2.[15] In
this paper, we report the regio- and stereospecific, formal
methylative and hydrogenative carboxylation of alkynes
with CO2 by combination of the catalytic methylalumination
and hydroalumination of various alkynes with the Cu-cata-
lyzed carboxylation of the resulting alkenyl (Scheme 1). A
variety of a,b-unsaturated carboxylic acids, which were diffi-
cult to prepare previously, could be obtained efficiently by
using this protocol.
the resulting mixture was then stirred under CO2 (1 atm) for 24 h, unless
otherwise noted. [b] Temperature for the carboxylation reaction. [c] Iso-
lated yield based on 1a. [d] 5 mol%. [e] Isolated yield of the methyl ester
product prepared by reaction of 3a with CH2N2. [f] 10 mol% of [Ni-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
amount of [Sc(CH2C6H4NMe2-o)2ACHTNUGRTEN(NGUN Cp*)]/ACHTUNEGTR[NGNNU Ph3C][BACHTUNGTRENNUNG(C6F5)4]
(Cp*=pentamethylcyclopentadienyl), the reaction of 1a
with Me3Al afforded the trisubstituted alkenylalmuminum
2a regio- and stereoselectively, as reported previously.[11e]
The alkenylaluminum 2a alone did not react with CO2
(1 atm), even at 708C (Table 1, entry 1). To our delight, in
the presence of a catalytic amount of the copper complex
[CuClACTHUNRTGNEUNG(IPr)] (5 mol%) (IPr=1,3-bis(2,6-diisopropenyl)imi-
dazol-2-ylidene), the carboxylation of 2a with CO2 proceed-
ed smoothly to give the carboxylic acid product 3a after hy-
drolysis workup. A quantitative formation of 3a from 2a
and CO2 was achieved at room temperature in 24 h
(Table 1, entry 3). It is also noteworthy that the carboxyla-
tion of 2a did not require an additional base, in contrast
with the carboxylation of organoboron compounds reported
previously.[13a,e–f,15a,b] CuCl or IPr alone gave a much lower
yield under similar conditions (Table 1, entries 4 and 5).
Nickel- and palladium-based catalysts previously used in the
carboxylation of organozinc species[8a,13d] did not work well
in the present carboxylation of 2a (Table 1, entries 6 and 7).
An NOE analysis of compound 4, which was obtained by
methylation of 3a with CH2N2 followed by reduction of the
Scheme 1. Formal carboxylation of alkynes by a carboalumination (or hy-
droalumination)/carboxylation cascade.
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Z. Hou and M. Takimoto
nation: The Sc-catalyzed methylalumination of trimethylsil-
yl-substituted alkynes (TMS-alkynes) containing a tethered
ether group,[11e] such as 4, could give the corresponding alke-
nylaluminum species in an anti configuration (Scheme 3).[17]
We then decided to see if the TMS-containing anti-alkenyla-
Scheme 2. Transformation of the carboxyl group in 3a to a hydroxymeth-
yl unit for stereochemistry confirmation.
resulting ester with iBu2AlH (Scheme 2), indicated that the
methyl group and the carboxyl group in 3a should be on the
same side of the C=C double bond (cis configuration).
These results suggest that the carboxylation of the alkenyla-
luminum 2a with CO2 occurred in a stereospecific manner
with retention of the stereoconfiguration.
The sequential methylalumination/carboxylation of other
internal alkynes containing an ether tether group, such as
1b–d, could also be achieved by using the combination of
the scandium and copper catalysts to give the corresponding
b-methyl-a,b-unsaturated carboxylic acids 3b–d containing a
configurationally well-defined tetrasubstituted olefin moiety
in high yields (Table 2). Both siloxy and alkoxy groups could
Scheme 3. Formal anti-methylative carboxylation of TMS-substituted al-
kynes by using a Sc/Cu catalyst combination.
luminum species (anti-5) could be carboxylated with CO2 in
the presence of the [CuClACTHUNTGRNEUNG(IPr)] catalyst.
The methylalumination of 4a with Me3Al was carried out
in the presence of a catalytic amount of [Sc(CH2C6H4NMe2-
Table 2. One-pot formal methylative carboxylation of internal alkynes
containing an ether tether group.[a]
o)
alkenylaluminum species was allowed to react with CO2
(1 atm) at room temperature in the presence of [CuCl(IPr)]
2CAHTUNGTREN(GNUN Cp*)]/AHCTNURTGE[GUNNN Ph3C][BACHTNGURTNE(NUGN C6F5)4] and, subsequently, the resulting
ACHTUNGTRENNUNG
(5 mol%). The (E)-a-silyl-b-methyl-a,b-unsaturated carbox-
ylic acid 6a was obtained in 74% yield after hydrolysis
(Table 3, entry 1). The carboxylation (or alumination) took
Table 3. One-pot anti-methylative carboxylation of TMS-substituted in-
ternal alkynes.[a]
Entry
1
Alkyne
Product
Yield [%][b]
92[c]
Yield [%][b]
74
2
3
86
92
Entry
1
Alkyne
Product
2
3
4b (n=2)
4c (n=1)
(E)-4b (n=2)
(E)-4b (n=1)
94
97
[a] The reaction was carried out in “one-pot” by addition of a THF solu-
tion of [CuCl(IPr)] to a toluene solution of 2 pre-prepared by reaction of
1 with Me3Al in the presence of [Sc(Cp*)(R)2]/[Ph3C][B(C6F5)4], and the
ACHTUNGTRENNUNG
4
100
G
N
ACHTUNGTRENNUNG
resulting mixture was then stirred under CO2 (1 atm) for 24 h, unless oth-
erwise noted. [b] Isolated yield based on 1. [c] Carboxylation was carried
[a] The reaction was carried out in “one-pot” by addition of a THF solu-
tion of [CuCl(IPr)] to a toluene solution of 5 pre-prepared by reaction of
4 with Me3Al in the presence of [Sc(Cp*)(R)2]/[Ph3C][B(C6F5)4], and the
À
out for 12 h. [d] TBDPS=tBu(Ph)2Si . [e] Methylalumination was car-
AHCTUNGTRENNUNG
ried out at 408C.
G
N
ACHTUNGTRENNUNG
resulting mixture was then stirred under CO2 (1 atm) for 24 h, unless oth-
erwise noted. [b] Isolated yield based on 4.
serve as a directing group to lead the carboxylation (or alu-
mination) taking place at the proximal position and the
methylation at the distal position in a regio- and stereospe-
À
cific (cis) fashion. The aromatic C Br bond is compatible
place at the distal position from the ether group, and the
methyl group was introduced to the proximal position in a
regioselective manner.[18] An NOE analysis of compound 7,
which was prepared by methylation of 6a followed by re-
duction (Scheme 4), indicated that the methyl group and the
with the catalytic reaction conditions.[16]
Anti-selective formal methylative carboxylation of SiMe3-
substituted internal alkynes by using a Sc/Cu catalyst combi-
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Efficient Synthesis of a,b-Unsaturated Carboxylic Acids
FULL PAPER
sequently, the carboxylation reaction with CO2 (1 atm) was
conducted in the presence of [CuClACTHNUTRGNEUNG(IPr)] (5 mol%). The
overall one-pot reaction afforded the (E)-b-methyl-a,b-un-
saturated carboxylic acid 10a, quantitatively, after hydrolysis
(Table 4, entry 1). In the same manner, the methylative car-
boxylation of 1-octyne 8b and terminal alkynes containing a
siloxy group, such as 8c–e, could also be achieved to give
the corresponding (E)-b-methyl-a,b-unsaturated carboxylic
acids 10b–e in high yields (Table 4, entry 2–5).[16] In all of
these reactions, the carboxyl group was introduced to the
less hindered C1-position and the methyl group was bonded
to the C2-carbon atom. The addition of these two groups
was completely controlled in a syn fashion, reflecting the
high stereoselectivity both in the Zr-catalyzed methyl-alumi-
nation reaction and in the Cu-catalyzed carboxylation reac-
tion.
The above Zr/Cu-catalyzed transformations represent the
first example of methylative carboxylation of terminal al-
kynes. Moreover, the high E selectivity of this protocol
could make it highly attractive in organic synthesis.[20] For
example, the carboxylic acid 10c (Table 4, entry 3) was pre-
viously reported as a synthetic precursor of a trans-fusari-
ninne derivative, which is a side chain commonly found in
fungal siderophores.[21] The previously reported synthesis of
10c required four-step reactions from the alkyne 8c, and the
separation of the E/Z isomers was also necessary. In con-
trast, our present method afforded 10c with complete E se-
lectivity in 88% yield in one-pot from the same starting ma-
terial 8c.
Scheme 4. Transformation of the carboxyl group in 6a to a hydroxymeth-
yl unit for stereochemistry confirmation.
carboxyl group in 6a should be on the anti side of the C=C
double bond. The regio- and stereoselective methylative car-
boxylation of TMS alkynes containing an ether group with
different tether lengths, such as 4b and 4c, could also be
achieved similarly (Table 3, entries 2 and 3). An alkyne with
a secondary tert-butyldiphenylsilyl ether (4d) is also suitable
for this reaction (Table 3, entry 4).[16] As far as we are
aware, this is the first example of anti-selective methylative
carboxylation of alkynes.
Regio- and stereospecific methylative carboxylation of ter-
minal alkynes by using a Zr/Cu catalyst combination: In
contrast to internal alkynes, the methylative carboxylation
of terminal alkynes has not been reported previously. It was
well known that the methylalumination of terminal alkynes
could be achieved in a regiospecific fashion by the use of a
Zr catalyst.[11a–d]
The carboxylation of the resulting alkenylaluminum spe-
cies with CO2 was then examined in the presence of the Cu
catalyst. As shown in Table 4, the methylalumination of 4-
phenylbutyne 8a with Me3Al was first carried out in the
presence of [ZrCl2(Cp)2] (10 mol%) and methylaluminox-
ane (MAO) (10 mol%) in toluene at room temperature to
give the alkenylaluminum species 9 (R=C2H4Ph).[11d,19] Sub-
Regio- and stereospecific formal hydrogenative carboxyla-
tion of termninal alkynes by using a Ni/Cu catalyst combina-
tion: The Ni-catalyzed hydroalumination of terminal alkynes
with iBu2AlH reported recently by Hoveyda and co-work-
ers[10c] could also be efficiently combined with the Cu-cata-
lyzed carboxylation reaction. As shown in Table 5, the hy-
droalumination of 1-octyne 8b with iBu2AlH catalyzed by
Table 4. One-pot formal methylative carboxylation of terminal alkynes.[a]
[NiCl
(PPh3)2] (5 mol%) and the subsequent carboxylation
(IPr)] (5 mol%)
with CO2 (1 atm) in the presence of [CuClACHTUNGTRENNNUG
at room temperature afforded (E)-a,b-unsaturated carboxyl-
ic acid 12b in 78% yield after hydrolysis workup (Table 5,
entry 1).[19] Similarly, the formal hydrogenative C1-carboxy-
lation of alkynes 8d and 8e could also be performed effi-
ciently (Table 5, entries 2 and 3).[16] In all the cases, the car-
boxylation took place at the C1-position and the hydride
was added to the C2-position in a regio- and stereospecific
(cis) fashion. These reactions represent the first example of
(formal) catalytic hydrocarboxylation of terminal alkynes
with CO2.
Entry
1
Alkyne
Product
Yield [%][b]
100
2
3
85
88
4
5
8d (n=3)
10d (n=3)
87
When [NiCl
(dppp)] (dppp=1,3-bis(diphenylphosphino)-
2A(PPh3)2] was used as a catalyst for
78[c]
propane) instead of [NiCl CHTUGNTRENNUNG
the hydroalunination reaction,[10c] the C2 (rather than C1)
carboxylation of terminal alkynes could be achieved selec-
tively in a similar manner. As shown in Table 6, the combi-
nation of the hydroalumination of 8b with iBuAlH by
[a] The reaction was carried out in “one-pot” by addition of a THF solu-
tion of [CuCl(IPr)] to a toluene solution of 9 pre-prepared by reaction of
8 with Me3Al in the presence of [ZrCl2(Cp)2] (10 mol%) and MAO
(10 mol%), and the resulting mixture was then stirred under CO2 (1 atm)
for 24 h, unless otherwise noted. [b] Isolated yield based on 8. [c] Carbox-
ylation was performed at 508C.
ACHTUNGTRENNUNG
[NiCl
2ACHTUNGTREN(NUNG dppp)] and the subsequent carboxylation of the re-
sulting alkenylaluminum species with CO2 (1 atm) in the
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Z. Hou and M. Takimoto
Table 5. One-pot formal hydrogenative C1-carboxylation of terminal al-
kynes.[a]
Reaction mechanism: A possible reaction mechanism of the
present catalytic carboxylation of alkenylaluminum species
with CO2 is illustrated in Scheme 5. The transmetalation re-
action between [CuClACTHNUGRTENUNG(IPr)] and an alkenylaluminum spe-
cies, such as 2, would give the copper alkenyl species A,
Entry
1
Alkyne
Product
Yield [%][b]
78
2
3
79
72
[a] The reaction was carried out in “one-pot” by addition of a THF solu-
tion of [CuCl(IPr)] to a THF solution of 11 prepared by reaction of 8
with iBu2AlH in the presence of [NiCl2A(PPh3)2], and the resulting mixture
ACHTUNGTRENNUNG
Scheme 5. A possible catalytic carboxylation pathway.
CTHUNGTRENNUNG
was then stirred under CO2 (1 atm) for 24 h, unless otherwise noted.
[b] Isolated yield based on 8.
which on reaction with CO2, should afford the copper car-
boxylate B.[15a] The transmetalation between B and the alke-
nylaluminum species 2 could release the aluminum carboxy-
late C and regenerate the copper alkenyl species A, thus
completing the catalytic cycle.
Table 6. One-pot formal hydrogenative C2-carboxylation of terminal al-
kynes.[a]
Conclusion
We have demonstrated that the combination of the hydroa-
lumination or methylalumination of various alkynes with
the carboxylation of the resulting alkenylaluminum species
with CO2 can serve as a useful protocol for the synthesis of
a variety of a,b-unsaturated carboxylic acids with well-con-
trolled regio- and stereoselectivity. The NHC–copper com-
Entry
1
Alkyne
Product
Yield [%][b]
75
2
3
85
78
plex [CuClACTHNGUTRENNU(G IPr)], acting as an excellent catalyst for the car-
boxylation reactions, matches well with various catalyst sys-
tems for the hydroalumination or methylalumination reac-
tions. In all the cases, the carboxylation proceeds in a stereo-
specific manner with retention of the stereoconfiguration of
the alkenylaluminum species and, therefore, the regio- and
stereoselectivity of the overall reaction is determined solely
by the methylalumination or hydroalumination process. In
view of the high regio- and stereoselectivity, simple one-pot
reaction operation, and the use of CO2 as a starting materi-
al, this protocol should be a practically useful and attractive
method for the synthesis of various a,b-unsaturated carbox-
ylic acids with desired configurations.
[a] The reaction was carried out in “one-pot” by addition of a THF solu-
tion of [CuCl(IPr)] to a THF solution of 13 pre-prepared by reaction of 8
with iBu2AlH in the presence of [NiCl2A(dppp)], and the resulting mixture
was then stirred under CO2 (1 atm) for 24 h, unless otherwise noted.
[b] Isolated yields based on 8.
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
presence of [CuClACHTUNGTRENNUNG(IPr)] afforded the branched carboxyla-
tion product 14b in 75% yield (Table 6, entry 1).[19] Similar-
ly, the siloxy-substituted terminal alkynes, such as 8d and
8e, could also undergo the hydrocarboxylation with the
same regioselectivity to give the corresponding a-methylene
carboxylic acids 14d and 14e (Table 6, entries 2 and 3).[16] In
all of these reactions, the carboxyl group was selectively in-
troduced to the internal carbon (C2) and the hydrogen atom
was added to the terminal carbon of the alkynes, in contrast
Experimental Section
General information: Unless otherwise noted, all manipulations were
performed under a dry nitrogen atmosphere by using standard Schlenk-
type glasswares on a dual-manifold vacuum/nitrogen line. The scandium
complex [Sc(CH2C6H4NMe2-o)
[CuCl
(IPr)][23] were prepared according to literature methods. All other
chemicals commercially available were purchased and purified when nec-
(Cp*)][22] and the copper–NHC complex
2ACHTUNGTRENNUNG
to what was observed in the [NiCl
lyst combination (see Table 5).
2ACHTUNGTREN(NUNG PPh3)2]/ACHTUNRTEGNGN[UN CuClACHTNUGRTEN(NUGN IPr)] cata-
AHCTUNGTRENNUNG
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Efficient Synthesis of a,b-Unsaturated Carboxylic Acids
FULL PAPER
essary by using standard procedures. Silica gel column chromatography
was performed with Merck Silica Gel 60 (0.040–0.063 mm). NMR spec-
troscopic data were recorded on a JEOL AL-400 or JEOL ECS-400
spectrometer.
33.8, 19.2 ppm; IR (neat): n˜ =2400–3400 (br), 3085, 3063, 3024, 2944,
2884, 2559, 2583, 1948, 1869, 1805, 1686, 1638 cmÀ1; HRMS (EI): m/z:
calcd for C12H14O2: 190.0993 [M+]; found: 190.1033.
Typical procedure for formal hydrogenative C1-carboxylation of terminal
alkyne 8b (Table 5, entry 1: synthesis of 12b): In a glovebox, a Schlenk
flask (20 mL) with a PTFE J. Young valve was charged with [NiCl2-
Typical procedure for formal syn-methylative carboxylation of internal
alkyne 1a (Table 1, entry 3; synthesis of 3a): In a glovebox, a Schlenk
AHCTUNGTREN(GNUN PPh3)2] (4.5 mg, 0.01 mmol) and THF (0.5 mL). iBu2AlH (1.0m in tol-
uene, 680 mL, 0.68 mmol) was slowly added to this mixture and after
1 min, alkyne 8b (50 mg, 0.45 mmol) in THF (1.5 mmol) was added.
(20 mL) flask with
[Sc(CH2C6H4NMe2-o)2ACHTUNGTRENNUNG
A solution of [Ph3C][BACHTUNGTRENNUNG
a
PTFE J. Young valve was charged with
(Cp*)] (4.5 mg, 0.01 mmol) and toluene (0.5 mL).
(C6F5)4] (9.2 mg, 0.01 mmol) was slowly added to
After 16 h at room temperature, a solution of [CuClACHTNUTRGNE(NUG IPr)] (8.8 mg,
this in toluene (1.0 mL). After 1 min, a mixture of alkyne 1a (50 mg,
0.20 mmol) and Me3Al (2.0m in toluene, 150 mL, 0.30 mmol) in toluene
(1.0 mL) was added. After 20 h at room temperature, a solution of [CuCl-
0.023 mmol) in THF (1.5 mL) was added to the reaction mixture and the
flask was taken out from the glovebox. The Schlenk flask was evacuated
and refilled with CO2 several times. The PTFE valve was closed, and
then the mixture was stirred at room temperature for 24 h. The reaction
mixture was hydrolyzed with a 10% aqueous solution of HCl at 08C, and
the mixture was extracted with Et2O. The organic layer was washed with
brine and dried over Na2SO4. After removal of the solvent, the residue
was purified by silica gel column chromatography (hexane/AcOEt 3:1) to
afford compound 12b (colorless viscous oil, 56 mg, 78%). 1H NMR
(400 MHz, CDCl3): d=7.08 (dt, J=15.6, 7.3 Hz, 1H), 5.82 (d, J=15.6 Hz,
1H), 2.23 (dt, J=7.3, 7.3 Hz, 2H), 1.41–1.52 (m, 2H), 1.21–1.37 (m, 6H),
0.88 ppm (t, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=172.1,
152.4, 120.5, 32.4, 31.6, 28.9, 27.9, 22.6, 14.1 ppm; IR (neat): n˜ =3500–
2400 (br), 2957, 2929, 2858, 2678, 2550, 1697, 1651 cmÀ1; HRMS (EI): m/
z: calcd for C9H16O2: 156.1150 [M+]; found: 156.1140.
ACHTUNGTRENNUNG(IPr)] (4.8 mg, 0.01 mmol) in THF (2.5 mL) was added to the resulting
reaction mixture and the flask was taken out from the glovebox. The
Schlenk flask was evacuated and refilled with CO2 several times. The
PTFE valve was closed and then the mixture was stirred at room temper-
ature for 24 h. The reaction mixture was hydrolyzed with 10% aqueous
solution of HCl at 08C, and the mixture was extracted with Et2O. The or-
ganic layer was washed with brine and dried over Na2SO4. After removal
of the solvent, the residue was purified by silica gel column chromatogra-
phy (hexane/AcOEt 2:3) to afford compound 3a (colorless viscous oil,
62 mg, 100%). 1H NMR (400 MHz, CDCl3): d=7.20–7.39 (m, 8H), 7.12
(d, J=6.9 Hz, 2H), 4.38 (s, 2H), 3.35 (t, J=6.4 Hz, 2H), 2.31 (s, 3H),
2.27 (t, J=7.3 Hz, 2H), 1.73 ppm (tt, J=7.3, 6.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=174.9, 148.8, 143.2, 138.3, 128.9, 128.4, 128.2,
127.5, 127.4, 127.1, 126.7, 72.5, 69.8, 29.1, 27.7, 23.9 ppm; IR (neat): n˜ =
3600–2400 (br), 3059, 3028, 2926, 2856, 2644, 1950, 1978, 1810, 1682,
1620, 1597 cmÀ1; HRMS (EI): m/z: calcd for C20H22O3: 310.1569 [M+];
found: 310.1570.
An example of formal hydrogenative C2-carboxylation of terminal
alkyne 8b (Table 6, entry 1: synthesis of 14b): According to the above-
mentioned typical procedure for the synthesis of 12b mentioned above,
alkyne 8b (50 mg, 0.45 mmol) was reacted with iBu2AlH (1.0m in tol-
uene, 680 mL, 0.68 mmol) in THF (2.0 mL) at room temperature for 6 h
An example of formal anti-methylative carboxylation of TMS-alkyne 4a
(Table 3, entry 1: synthesis of 6a): According to the typical procedure
mentioned above, alkyne 4a (50 mg, 0.20 mmol) was reacted with Me3Al
(2.0m in toluene, 95 mL, 0.19 mmol) in toluene (2.0 mL) at room temper-
by using [NiCl
addition of [CuClAHCTUNGTRENNUNG
(dppp)] (12.3 mg, 0.023 mmol) as the catalyst. After the
(IPr)] (8.8 mg, 0.023 mmol) in THF (1.5 mL) to the re-
sulting mixture, it was stirred at room temperature for 24 h under an at-
mosphere of CO2. A crude material, which was obtained after a similar
workup procedure, was purified by silica gel column chromatography
(hexane/AcOEt 4:1) to afford compound 14b (colorless oil, 52 mg,
75%). 1H NMR (400 MHz, CDCl3): d=7.67 (d, J=6.0 Hz, 4H), 7.35–
7.45 (m, 6H), 6.29 (s, 1H), 5.63 (s, 1H), 3.69 (t, J=6.4 Hz, 2H), 2.42 (t,
J=7.3 Hz, 2H), 1.75 (tt, J=7.3, 6.4 Hz, 2H), 1.06 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3) d=172.7, 139.7, 135.6, 133.9, 129.6, 127.6, 127.3, 63.0,
31.2, 27.9, 26.8, 19.2 ppm; IR (neat): n˜ =3400–2400 (br), 3070, 3048, 2956,
2930, 2894, 2857, 2640, 1695, 1627; HRMS (EI): m/z: calcd for C9H16O2:
156.1150 [M+]; found 156.1153.
ature for 6 h by using [Sc(CH2C6H4NMe2-o)
0.0063 mmol) and [Ph3C][B(C6F5)4] (5.8 mg, 0.0063 mmol) as the cata-
lysts. After addition of [CuCl(IPr)] (2.5 mg, 0.0063 mmol) in THF
2ACHTUNGTREN(NUNG Cp*)] (2.8 mg,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(2.0 mL) to the resulting mixture, it was stirred at room temperature for
24 h under an atmosphere of CO2. A crude material, which was obtained
after a similar workup procedure, was purified by silica gel column chro-
matography (hexane/AcOEt 5:1) to afford compound (E)-6a (colorless
oil, 42 mg, 74%). 1H NMR (400 MHz, CDCl3): d=7.63–7.67 (m, 4H),
7.32–7.43 (m, 6H), 3.64 (t, J=6.4 Hz, 2H), 2.25 (t, J=7.8 Hz, 2H), 1.82
(s, 3H), 1.71 (tt, J=7.8, 6.4 Hz, 2H), 1.03 (s, 9H), 0.18 ppm (s, 9H);
13C NMR (100 MHz, CDCl3) d=178.0, 153.5, 135.5, 133.9, 131.3, 129.5,
127.6, 63.7, 35.1, 31.2, 26.8, 21.6, 19.2, À0.3 ppm; IR (neat): n˜ =3500–2400
(br), 3070, 3049, 2956, 2931, 2896, 2858, 2617, 1958, 1888, 1824, 1677,
1613 cmÀ1
; HRMS (ESI): m/z: calcd for C26H38NaO3Si2: 477.2257
[M+Na+]; found 477.2243.
Acknowledgements
Typical procedure for formal syn-methylative carboxylation of terminal
alkyne 8a (Table 4, entry 1: synthesis of 10a): In a glovebox, a 20 mL
Schlenk flask with a PTFE J. Young valve was charged with [ZrCl2(Cp)2]
(11 mg, 0.038 mmol) and toluene (1.0 mL). Me3Al (2.0m in toluene,
288 mL, 0.57 mmol) was slowly added to this mixture and after 1 min,
MAO (1.25m in toluene, 31 mL, 0.038 mmol) was added followed by
alkyne 8a (50 mg, 0.38 mmol) in toluene (1.0 mL). After 15 h at room
This work was partly supported by a Grant-in-aid for Scientific Research
(S) (no. 21225004) from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan. We are grateful to Ms. Y. Hongo and Dr.
T. Nakamura (Molecular Characterization Team, RIKEN) for high-reso-
lution mass spectroscopic analysis.
temperature, a solution of [CuClACTHNUTRGNEUGN(IPr)] (7.4 mg, 0.019 mmol) in THF
(2.0 mL) was added to the mixture and the flask was taken out from the
glovebox. The Schlenk flask was evacuated and refilled with CO2 several
times. The PTFE valve was closed and the mixture was stirred at room
temperature for 24 h. The reaction mixture was hydrolyzed with a 10%
aqueous solution of HCl at 08C, and then the mixture was extracted with
Et2O. The organic layer was washed with brine and dried over Na2SO4.
After removal of the solvent, the residue was purified by silica gel
column chromatography (hexane/AcOEt 3:1) to afford compound 10a
(colorless viscous oil, 77 mg, 100%). 1H NMR (400 MHz, CDCl3): d=
7.26 (dd, J=6.8, 6.8 Hz, 2H), 7.11–7.22 (m, 3H), 570 (s, 1H), 2.78 (t, J=
8.2 Hz, 2H), 2.46 (t, J=8.2 Hz, 2H), 2.20 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3) d=172.4, 162.1, 140.8, 128.4, 128.2, 126.1, 115.6, 42.9,
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Chem. Eur. J. 2013, 00, 0 – 0
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Received: April 17, 2013
Published online: && &&, 0000
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!