Metallic reductant-free synthesis of α-substituted propionic acid derivatives through hydrocarboxylation of alkenes with a formate salt

Article abstract of DOI:10.1039/c7cc01377a

A PGeP-pincer palladium-catalyzed hydrocarboxylation of styrenes to obtain pharmaceutically important α-arylpropionic acid derivatives was achieved using a formate salt as both a reductant and a CO₂ source. The reaction was also applicable to vinylsulfone and acrylates. Isotope labeling experiments demonstrated that a CO₂-recycling mechanism is operative through generation and reaction of a benzylpalladium complex as a carbon nucleophile. This protocol has realized a mild and atom economical CO₂-fixation reaction without the necessity of using strong metallic reductants.

Full text of DOI:10.1039/c7cc01377a

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DOI: 10.1039/C7CC01377A
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Metallic Reductant-Free Synthesis of α-Substituted Propionic Acid
Derivatives through Hydrocarboxylation of Alkenes with a
Formate Salt
Received 00th January 20xx,
Accepted 00th January 20xx
Jun Takaya, Ko Miyama, Chuan Zhu, and Nobuharu Iwasawa*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A PGeP-pincer palladium-catalyzed hydrocarboxylation of styrenes to electron deficient alkenes such as acrylates and
to give pharmaceutically important α-arylpropionic acid acrylonitriles.7 Recently, Mikami reported Rh-catalysis, which
derivatives was achieved using a formate salt as both a reductant was applicable to asymmetric hydrocarboxylation.8 These
and a CO2 source. The reaction was also applicable to vinylsulfone reactions required use of a stoichiometric amount of a metallic
and acrylates. Isotope labeling experiments demonstrated a CO2- reductant such as ZnEt2 to regenerate catalytically active low-
recycling mechanism is operative through generation and reaction valent metallic species.9,10 The necessity of such a highly
of a benzylpalladium complex as a carbon nucleophile. This reactive metallic reductant largely limits practical utility of the
protocol has realized a mild and atom economical CO2-fixation reactions due to cost, safety, and atom economy problems.
reaction without the necessity of using strong metallic reductants.
Therefore, development of an efficient hydrocarboxylation
reaction of alkenes without use of metallic reductant is highly
desirable.
Transition metal-catalyzed regioselective reductive
carboxylation of alkenes under a carbon dioxide atmosphere
(hydrocarboxylation reaction) has been attracting much
attention not only as a new CO2-fixation reaction but also as an
efficient synthetic method for saturated carboxylic acid
derivatives.1 In particular, the reaction of styrene derivatives is
highly useful to give α-arylpropionic acids, which constitute an
Herein
we
report
a
metallic
reductant-free
hydrocarboxylation of alkenes using a formate salt as both a
reductant and a CO2 source catalyzed by a PGeP-pincer
palladium complex (Figure 1, C). The reaction enables an
efficient access to α-arylpropionic acid derivatives from easily
available styrenes and a formate salt, which can be derived
from CO2 and H2, demonstrating a promising approach for CO2-
utilization as a C1 source in synthetic chemistry.
important
class
of
pharmaceuticals.2
However,
hydrocarboxylation of alkenes has remained unexplored
compared with that of other unsaturated hydrocarbons such
as alkynes and dienes.3 This is attributed to the difficulty of
efficient formation and nucleophilic addition of the
intermediate alkylmetal complexes, which are prone to
reversibly go back to alkenes and metal hydrides through β-
hydrogen elimination. From a practical viewpoint, sequential
carboxylation reactions of alkylmagnesium reagents pre-
A) Shirakawa, Hayashi, Thomas, Xi (Sequential carboxylation)
cat. Fe, Ti
1 atm CO2
MgX
COOH
R
R
R
RMgX
B) Rovis, Yamada, Mikami
R
1 atm CO2
Ni, Co, Rh catalyst
COOH
COOH
formed
by
Fe-
or
Ti-catalyzed
regioselective
ZnEt2
R
hydromagnesiation of alkenes under an inert atmosphere
were developed, giving liner or α-substituted saturated
carboxylic acids (Figure 1, A).4,5 In 2008, Rovis reported the
first example of Ni-catalyzed hydrocarboxylation of styrenes
C) This work
O
PGeP-Pd catalyst
+
R
H
O–
excess CO2 free
metallic reductant free
R
under atmospheric pressure of CO2 using ZnEt2 as
a
stoichiometric reductant to give α-arylpropionic acids (Figure 1,
B).6 Co-catalyzed reaction using ZnEt2 as a reductant was
reported by Yamada in 2014 although the reaction was limited
Fig. 1. Hydrocarboxylation of alkenes
We have recently reported novel utilization of a formate salt
as both a reductant and a CO2 source in hydrocarboxylation of
allenes to give β,γ-unsaturated carboxylic acid derivatives.11
A
palladium complex 1 bearing a PGeP-pincer type ligand
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Table 1. Evaluation of catalysts and formate salts
efficiently catalyzed the reaction through generation and
reaction of palladium hydride and σ-allylpalladium complexes,
which enabled reductive carboxylation of allenes using CO2
catalytically generated from the formate salt as a C1 source.
These results prompted us to tackle on the alkene
hydrocarboxylation with a formate salt using PGeP-pincer
palladium complexes. We also expected that the pincer type
ligand stabilizes an alkylpalladium intermediate due to its
tridentate coordination structure.12 However, initial attempts
revealed that the PGeP-pincer palladium catalyst 1, which
worked efficiently in the reaction of allenes, was totally
ineffective for the reaction of 3-chlorostyrene 3a with cesium
formate in DMF even at 100 ˚C (Scheme 1). This result was
probably due to lower nucleophilicity of the alkylpalladium
complex compared with that of the σ-allylpalladium complex,
suggesting that a new design of the catalyst is necessary for
the hydrocarboxylation of alkenes. Therefore, we newly
synthesized a variety of PGeP-pincer palladium complexes
having alkyl substituents on phosphorous atoms based on the
expectation that the nucleophilic addition of the
alkylpalladium complex to CO2 would be enhanced by the
electron donating phosphine side arms (Figure 2).
View Article Online
DOI: 10.1039/C7CC01377A
OTf
under Ar
Y+
O
COOH
Pd
Ge
Me
2a
Et2P
PEt2
X mol% 2a
+
R
H
O–
R
DMF, 100 ˚C
3a
150 mol%
4a
(R = 3-ClC6H4)
Entry
X
Y
Time
Concentration
of [3a] / mol/L
Yielda /%
1
2
3
4
5
2.5
Cs
6
6
6
6
12
0.05
0.05
0.05
0.2
3
9
36
50
73
2.5
2.5
2.5
5.0
NMe3Bn
NnBu4
NnBu4
NnBu4
0.2
a NMR yield.
The reaction was applicable to various styrene derivatives
(Table 2). Other electron deficient styrenes such as 3-F, 3-CF3,
4-COOMe, 4-CN, and 3,5-Cl2-styrenes gave the corresponding
α-arylpropionic acids 4b-4f in moderate to good yields (Entries
1-6). In some cases (Entries 5 and 6), the PGeP-pincer
palladium catalyst 2b having dicyclohexylphosphines gave
better yields under modified reaction conditions. It should be
noted ester, nitrile, and chlorine functionalities were tolerated
under the reaction conditions. The reaction of 2- or 1-
vinylnaphthalenes also proceeded although the latter resulted
in a low yield due to the steric repulsion (Entries 7 and 8).
Regioselectivity was perfect in all cases, giving α-branched
propionic acid derivatives selectively. Furthermore, a 1,1-
disubstituted alkene, 2-(4-NCC6H4)propene, was employable to
give an α-qurternary propionic acid 4i in 56% yield,
demonstrating good substrate generality and compatibility
with functional groups.13
under Ar
OTf
150 mol% Cs-formate
COOH
2.5 mol% 1
Pd
Ge
Me
1
Ph2P
PPh2
R
R
DMF, 100 ˚C
3a
(R = 3-ClC6H4)
4a
trace
Scheme 1. Initial attempt using previous catalyst 1
New catalyst (for alkene)
Previous catalyst (for allene)
R
R
Furthermore, we investigated the reaction of acrylate
derivatives for an efficient synthesis of malonate derivatives
(Table 3). Treatment of phenylethyl acrylate and 1.5 equiv. of
cesium formate with 2.5 mol% catalyst 2b in 1,4-dioxane at 80
˚C under 1 atm CO2 afforded methylmalonate 6a in a good
yield (Entry 1). Under an argon atmosphere, the enolate
intermediate generated by hydrometallation of the acrylate
underwent 1,4-addition to the acrylate instead of CO2 as a side
reaction. Vinylsulfone was also employable under the same
reaction conditions (Entry 2). Moreover, ethyl methacrylate
and crotonate were carboxylated under an argon atmosphere
to give the corresponding malonate derivatives in moderate
yields (Entries 3 and 4). Consequently, this reaction exhibited
wide substrate generality to access a variety of α-branched
carboxylic acid derivatives from easily available alkenes and a
formate salt without use of highly reactive and expensive
metallic reductants.
Pd
(alkyl)2P
P(alkyl)2
Pd
Ge
Me
Ph2P
PPh2
Ge
Me
• Alkylpalladium
• High nucleophilicity by P(alkyl)2
• !-Allylpalladium
• Relatively easy addition to CO2
Fig. 2. New design of catalysts toward hydrocarboxylation of alkenes
After screening of catalysts and reaction conditions, we
found the palladium complex 2a having diethylphosphine side
arms showed the best catalytic activity (see the Supporting
Information for details of screening). The α-arylpropionic acid
4a was obtained selectively in 73% yield by the reaction of 3a
and 1.5 equiv. tetrabutylammonium formate in DMF at 100 ˚C
under an argon atmosphere using 5.0 mol% catalyst 2a (Entry
5). The tetrabutylammonium formate was the best formate
salt among investigated (Entries 1-3). This is the first example
of hydrocarboxylation reaction of alkenes with a formate salt
as both a reductant and a CO2 source, avoiding use of a
metallic reductant and excess CO2.
2 | J. Name., 2012, 00, 1-3
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product and regenerates the palladium formate A. Several 13C-
Table 2. Hydrocarboxylation of styrene derivatives
View Article Online
labeling experiments using H13COONMe3DBOnI: 710.p10ro39v/iCd7eCdCu01s3e7f7uAl
insights into the reaction mechanism. The reaction of 4-
MeOOC-styrene 3e with 7 under the standard reaction
conditions (an argon atmosphere) afforded the carboxylation
product 4e in 82% yield with >98% incorporation of 13C at the
carboxy group, demonstrating the carboxy moiety is originated
from the formate salt via C–C bond formation (Entry 1, Table
4). On the other hand, the same reaction but under a 12CO2
atmosphere caused significant decrease of the 13C content
(%13C = 12%, Entry 2). This result clearly supports generation of
gaseous 13CO2 from the formate salt in the reaction vessel,
which reacts with the alkylpalladium complex C competing
with a large excess amount of non-labeled 12CO2, resulting in a
dramatic decrease of 13C incorporation. Lower product yield
(65%) also suggests reversibility of the decarboxylation step (A
to B), in which the equilibrium shifted to the left (A) under a
CO2 atmosphere.16 Moreover, the reaction of 2-
vinylnaphthalene 3g with deuterated formate 8 afforded the
carboxylation product 4g and recovered alkene 3g, both of
which involved deuterium at β-position in almost the same
percentage (ca. 30% D, Scheme 2). These results clearly
demonstrated that the hydrometallation step is also reversible
(B to C), and the β-hydrogen elimination of the alkylpalladium
complex is faster than the rate-determining nucleophilic
addition to CO2.
under Ar
150 mol% HCOONnBu4
OTf
R2
R2 COOMe
R1
5 mol% 2a or 2b
Pd
Ge
Me
R2P
PR2
R1
DMF, 100 ˚C, 12 h
then TMSCHN2
3
4
R = Et 2a
Cy 2b
Entry
R1
R2
H
H
H
Cat.
2a
Yielda /%
4a 71
4b 56
4c 60
1
2
3
3-ClC6H4
3-FC6H4
3-CF3C6H4
2a
2a
4
5
6
7
8
9
3,5-Cl2C6H3
4-MeOOCC6H4
4-NCC6H4
2-naphthyl
1-naphyhyl
4-NCC6H4
H
H
H
H
H
2a
2bb
2bb
2a
2a
2a
4d 64
4e 75
4f 48
4g 41
4h 24
4i 56
CH3
aIsolated yield. b2.5 mol% 2b, 150 mol% HCOOCs, [3] = 0.05 M, at 80 ˚C for 6 h.
Table 3. Hydrocarboxylation of electron deficient alkenes
under CO2 or Ar
OTf
150 mol% HCOOCs
R2 COOR4
2.5 mol% 2a or 2b
Pd
Ge
Me
R2P
PR2
R3
alkene
R1
H
80 ˚C, 6 h
5
6
then esterification
O
Pd
Ge
O
H
R = Et 2a
Cy 2b
Pd
Ge
Et2P
PEt2
Et2P
PEt2
– CO2
+ CO2
Entry
1
Alkene
ROOC
Conditionsa
Product
Yieldb /%
Me
Me
COOMe
COOMe
COOBn
COOBn
A
B
A
6a 75
6b 59
6c 50
6d 40
R'COO–
HCOO–
–
+
(R = CH2CH2Ph)
ROOC
PhO2S
EtOOC
EtOOC
R
R
R'
A
B
B
2
3
4
PhO2S
R
O
Pd
Ge
O
Pd
Ge
Et2P
PEt2
Et2P
PEt2
+ CO2
EtOOC
R
Me
Me
R' =
C
D
EtOOC
Fig. 3. Proposed reaction mechanism
Table 4. 13C-Labeling experiment
aConditions A: 2.5 mol% 2b under CO2 (1 atm) in 1,4-dioxane. The obtained
carboxylic acid was derivatized to methyl ester by TMSCHN2. Conditions B: 2.5
mol% 2a under Ar in DMF. The obtained carboxylic acid was derivatized to benzyl
ester by BnBr. bIsolated yield.
O
+ NMe3Bn
O–
O
2.5 mol% 2a
DMF, 100 ˚C, 6 h
then TMSCHN2
R
13C
13C
+
OMe
R
A proposed reaction mechanism is depicted in Figure 3. A
palladium formate complex A, which is formed from the
catalyst 2 and the formate salt by ligand exchange, undergoes
reversible decarboxylation to produce a palladium hydride
complex B and CO2.14 Hydropalladation of an alkene with B
affords an alkylpalladium complex C, which reacts with the
released CO2 to give a palladium carboxylate D.15 Ligand
exchange with the formate salt gives the hydrocarboxylation
H
3e
7
4e
(R = 4-MeOOCC6H4)
150 mol%
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2
3
L. Zhang, W. Yu, Y. Rong, X. Guo, J. Ye, Z. Shen and S. Zeng,
Entry
Atmosphere
Yield of 4ea/ %
%13C of 4e
> 98%
View Article Online
Anal. Methods, 2014, 6, 6058-6065.
DOI: 10.1039/C7CC01377A
1
2
Ar
CO2
82
65
For examples of hydrocarboxylation of dienes and alkynes,
see; (a) T. Cao and S. Ma, Org. Lett., 2016, 18, 1510-1513. (b)
X. Wang, M. Nakajima and R. Martin, J. Am. Chem. Soc., 2015,
137, 8924-8927. (c) Y. Tani, K. Kuga, T. Fujihara, J. Terao and
Y. Tsuji, Chem. Commun., 2015, 51, 13020-13023. (d) J.
Takaya, K. Sasano and N. Iwasawa, Org. Lett., 2011, 13, 1698-
1701. (e) J. Takaya and N. Iwasawa, J. Am. Chem. Soc., 2008,
130, 15254-15255.
For examples of Fe- or Ti-catalyzed sequential
hydrocarboxylation via alkylmagnesiums, see; (a) M. D.
Greenhalgh and S. P. Thomas, J. Am. Chem. Soc., 2012, 134,
11900-11903. (b) E. Shirakawa, D. Ikeda, S. Masui, M.
Yoshida and T. Hayashi, J. Am. Chem. Soc., 2012, 134, 272-
279. (c) P. Shao, S. Wang, C. Chen and C. Xi, Org. Lett., 2016,
18, 2050-2053.
Sawamura and Hou reported Cu-catalyzed carboxylation of
alkylboronic esters with CO2, which were prepared by
hydroboration of alkenes with HBpin. See: (a) H. Ohmiya, M.
Tanabe and M. Sawamura, Org. Lett., 2011, 13, 1086-1088.
(b) T. Ohishi, L. Zhang, M. Nishiura and Z. Hou, Angew. Chem.
Int. Ed., 2011, 50, 8114-8117.
b
12%
aIsolated yield. 0.15 mmol 7 under 1 atm CO2 (ca. 1.8 mmol) in a sealed tube.
See the SI for details.
b
(6% D)
+ NMe4
under Ar
COOMe
(28% D)
!
H/D
O
C
4
5
5.0 mol% 2a
1
!
"
"
+
+
H/D
R
R
O–
R
D
DMF, 100 ˚C, 6 h
then TMSCHN2
2 H/D
H/D
"
3g
8
(26% D)
(28% D)
150 mol%
(R = 2-naphthyl)
4g 6%
3g 34%
Scheme 2. Deuterium labeling experiment
As we initially described, efficient generation and reaction of
the alkylpalladium complex intermediate is one of the most
difficult problems in hydrocarboxylation of alkenes. We
propose that the PGeP-pincer type ligand plays a key role to
stabilize the alkylpalladium intermediate and accelerate
nucleophilic addition to CO2 by the dialkylphosphine side arms,
enabling facile nucleophilic addition to the catalytically
generated CO2. Investigations on the effect of the PGeP-pincer
type ligand on the structure and reactivity of alkylpaladium
complexes are ongoing in our group, and the details will be
reported in due course.
In conclusion, an efficient, regioselective synthesis of
pharmaceutically useful α-branched propionic acid derivatives
was achieved through the PGeP-pincer palladium complex-
catalyzed hydrocarboxylation of alkenes using a formate salt as
both a reductant and a CO2 source. This protocol showed high
6
7
C. M. Williams, J. B. Johnson and T. Rovis, J. Am. Chem. Soc.,
2008, 130, 14936-14937.
(a) C. Hayashi, T. Hayashi, S. Kikuchi and T. Yamada, Chem.
Lett., 2014, 43, 565-567. (b) C. Hayashi, T. Hayashi and T.
Yamada, Bull. Chem. Soc. Jpn., 2015, 88, 862-870.
S. Kawashima, K. Aikawa and K. Mikami, Eur. J. Org. Chem.,
2016, 3166-3170.
8
9
Electrochemical hydrocarboxylation reactions of alkenes
were reported. For an example, see; J. Li, S. Inagi, T.
Fuchigami, H. Hosono and S. Ito, Electrochem. Commun.,
2014, 44, 45-48.
10 Quite recently, we reported
a photoredox-catalyzed
hydrocarboxylation reaction of electron-deficient styrenes
using catalytic amounts of a Ru photoredox catalyst and a Rh
hydrocarboxylation catalyst. Chem. Commun. DOI:
10.1039/C7CC00678K.
11 C. Zhu, J. Takaya and N. Iwasawa, Org. Lett., 2015, 17, 1814-
1817.
practical utility as
a
safe, atom economical, and
12 (a) C. M. Fafard and O. V. Ozerov, Inorg. Chim. Acta, 2007,
360, 286-292. (b) M.-H. Huang and L.-C. Liang,
Organometallics, 2004, 23, 2813-2816. (c) V. Pandarus and D.
Zargarian, Organometallics, 2007, 26, 4321-4334.
13 No carboxylation product was obtained with styrene, 4-
MeO-styrene, and 4-phenylbutene.
environmentally benign carboxylation of alkenes. The newly
developed PGeP-pincer palladium complex bearing
dialkylphosphine side arms plays a key role in realizing the
carboxylation reaction of alkenes. The reaction mechanism
was well clarified by the 13C- and D-labeling experiments. The
formate/PGeP-pincer palladium catalysis will open up new
possibilities of CO2-fixation in practical synthetic chemistry,
and further investigation on substrate scope and catalyst
modification is in progress.
14 (a) S. J. Mitton and L. Turculet, Chem. Eur. J., 2012, 18,
15258-15262. (b) H.-W. Suh, T. J. Schmeier, N. Hazari, R. A.
Kemp and M. K. Takase, Organometallics, 2012, 31, 8225-
8236.
15 Hydrometallation by an η2-(Ge–H)Pd(0) complex, which
could be generated by reductive elimination of a Ge–H bond
from B, should be considered as another possible pathway.
See: J. Takaya and N. Iwasawa, Chem. Eur. J., 2014, 20,
11812-11819.
This research was supported by an ACT-C program from JST
and JSPS KAKENHI Grant Number JP24245019, JP24685006,
JP25109519, JP15H00926, and JP15H05800.
16 The reversibility of the decarboxylation step (A to B) was also
confirmed by the reaction of 7 with 2a under a 12CO2
atmosphere. The 13C content of 7 decreased to 63% after 2 h
even at rt, suggesting generation of 13CO2 from formate and
incorporation of 13/12CO2 into the palladium hydride complex.
See the SI for details.
Notes and references
1
For selected reviews of CO2-fixation reactions including
hydrocarboxylation, see; (a) E. Kirillov, J.-F. Carpentier and E.
Bunel, Dalton Trans., 2015, 44, 16212-16223. (b) D. Yu, S. P.
Teong and Y. Zhang, Coord. Chem. Rev., 2015, 293-294, 279-
291. (c) Q. Liu, L. Wu, R. Jackstell and M. Beller, Nat.
Commun, 2015, 6, 5933. (d) Y. Tsuji and T. Fujihara, Chem.
Commun., 2012, 48, 9956-9964.
4 | J. Name., 2012, 00, 1-3
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