Copper-Catalyzed Stereodefined Construction of Acrylic Acid Derivatives from Terminal Alkynes via CO2 Insertion

Article abstract of DOI:10.1021/acs.orglett.6b03860

IPrCuCl catalyzes the CO₂ insertion reaction undergone by a dialkylvinylborane intermediate derived from alkynyltrialkylborate by a 1,2-alkyl group migration to afford α-alkyl acrylic acids with excellent regio- and stereoselectivities.

Full text of DOI:10.1021/acs.orglett.6b03860

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Stereodefined Construction of Acrylic Acid
Derivatives from Terminal Alkynes via CO2 Insertion
Kenta Kuge, Ying Luo, Yuki Fujita, Yasuyuki Mori, Gen Onodera, and Masanari Kimura*
Graduate School of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
S
* Supporting Information
ABSTRACT: IPrCuCl catalyzes the CO2 insertion reaction undergone by a
dialkylvinylborane intermediate derived from alkynyltrialkylborate by a 1,2-alkyl
group migration to afford α-alkyl acrylic acids with excellent regio- and
stereoselectivities.
O2 fixation is among the most straightforward synthetic
catalyst and Et3N as a base could be applicable for the tandem
C
methodologies for the construction of carboxylic acids.1
dimerization of conjugated dienes to form 1,4,9-decatrienes.14
Based on the results of these multicomponent coupling
reactions, we envisaged the use of CO2 as an electrophilic
reagent instead of π-allylpalladium in the presence of
trialkylboranes and transition-metal catalysts. We could thus
succeed in the three-component coupling reaction of an alkyne,
a trialkylborane, and CO2 to yield α-substituted acrylic acids as
a single product. In contrast to the previously reported results
of Ni- and Cu-catalyzed coupling reactions with terminal
alkynes and organometalloids such as organoaluminum and
organozinc reagents with CO2 (Scheme 2), the present
Specifically, Cu- and Ni-catalyzed multicomponent coupling
reactions with alkynes, organoaluminum, or organozinc regents
under a CO2 atmosphere that provide β-substituted acrylic
acids are promising strategies for efficient modern organic
synthesis.2 CO2 insertion into the unsaturation in enynes,3
dienes,4 allenes,5 and allylating substrates6 is utilized for the
convenient and selective formation of unsaturated carboxylic
acids. Notably, among direct C−C bond transformations,
significant attention has been paid to the activation of sp2
carbon atoms via transition-metal-catalyzed C−H activation
and the incorporation of CO2 to form aromatic carboxylic
acids7 and unsaturated carboxylic acids in recent years.8
Alkenyl organoboranes are important and useful key
intermediates in organic synthesis, especially cross-coupling
reactions.9 In general, alkenyl organoboranes are prepared from
hydroborations of alkynes with organoboranes and bis-
(pinacolate)diborane.10 Although some examples of the
formation of alkenyl organoboranes via alkynyl ate comlexes
have been reported so far,11 synthetic utilities of alkynylborates
have so far been limited.12
Scheme 2. CO2 Insertion into Terminal Alkyne Using
Organozinc and Organoaluminum
From this point of view, we previously developed a Pd-
catalyzed regio- and stereoselective three-component coupling
reaction of a terminal alkyne, a trialkylborane, and allylic
alcohols to provide trisubstituted alkenes involving alkynyl ate
complexes (Scheme 1).13 In this case, the terminal alkyne
coupling reaction offers regioselectivity. Herein, we discuss
the scope and limitations of Cu-catalyzed highly regio- and
stereoselective formations of α-substituted acrylic acids by
coupling reactions of terminal alkynes and trialkylboranes
under CO2 at atmospheric pressure through the 1,2-alkyl
migration of alkynyltrialkylborate as a key intermediate
(Scheme 3).
Scheme 1. Pd-Catalyzed Stereoselective Allylation of
Terminal Alkyne To Form 1,4-Pentadiene
The reaction was carried out in the presence of 0.05 mmol of
a CuCl catalyst with various carbene ligands, 2.0 mmol of base,
Scheme 3. Cu-Catalyzed CO2 Insertion into Terminal
Alkyne Using Organoboranes
reacted with the trialkylborane to give the alkynyltrialkylborate,
which was followed by the 1,2-alkyl migration process; then the
transmetalation of alkenylborane with π-allylpalladium species
provided the stereodefined trisubstituted alkenes. Furthermore,
similar multicomponent coupling reactions involving con-
jugated dienes with terminal alkynes in the presence of a Pd
Received: December 27, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b03860
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Letter
and 1.0 mmol of Et3B at room temperature under CO2
atmosphere for 24 h. The crude mixture was subjected to
silica gel column chromatography to obtain the corresponding
acrylic acid as a single product. The results summarized in
Table 1 indicate that the choice of base dramatically affected
Table 2. Cu-Catalyzed CO2 Insertion into Terminal
Acetylene
a
a
Table 1. Cu-Catalyzed CO2 Insertion into Phenylacetylene
entry
alkyne R
R′3B
yield of 1 (%)
1
Ph
Et3B
Et3B
Et3B
Et3B
Et3B
Et3B
Et3B
Et3B
Et3B
1a (78)
1b (62)
1c (73)
1d (56)
1e (68)
1f (59)
1g (83)
1h (53)
1i (24)
1j (43)
1k (23)
2
p-OMePh
o-OMePh
p-C5H11Ph
p-ClPh
3
4
5
entry
catalyst
base
solvent
yield (%)
6
o-ClPh
1
2
3
4
5
IPrCuCl
IPrCuCl
IPrCuCl
IPrCuCl
IPrCuCl
IPrCuCl
IPrCuCl
IPrCuCl
IPrCuCl
IPrCuCl
ClIPrCuCl
MeIPrCuCl
IPr*CuCl
IMesCuCl
t-BuOK
t-BuONa
t-BuOLi
EtOK
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
38 (E only)
NR
7
2,4,5-MePh
2-thiophene-yl
CH2OBn
Ph
8
NR
9
50 (E only)
61 (E only)
78 (E only)
61 (E only)
NR
10
11
n-Bu3B
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
Ph
(t-BuC2H4)3B
b
6
a
Conditions: alkyne (0.5 mmol), MeOK (2.0 mmol), and organo-
b
7
borane (3.0 mmol) in the presence of IPrCuCl (0.05 mmol) in 1,4-
dioxane (3 mL) at rt for 24 h under CO2 (1 atm).
b
8
DMA
b
9
toluene
hexane
dioxane
dioxane
dioxane
dioxane
57 (E only)
66 (E only)
70 (E only)
73 (E only)
trace
b
10
reaction proceeded with high E-stereoselectivity (entries 2 and
3, Table 2). Halogenated aromatic compounds could
participate in the reaction to form the desired products 1e
and 1f as (E)-isomers (entry 5 and 6, Table 2). Although
heteroaromatic substitutents took part in the coupling reactions
as well as phenyl groups, alkylated substitutents were not
suitable for the reactions.16
As in the case of tri-n-butylborane, a similar coupling reaction
proceeded to form product 1j as a single isomer as well as
triethylborane (entry 10, Table 2). Tris(3,3-dimethylbutyl)-
borane, which was prepared via the hydroboration of 3,3-
dimethyl-1-butene, could take part in the coupling reaction to
afford the desired product 1k (entry 11, Table 2). Therefore,
the three-component coupling reaction with terminal alkynes
under CO2 could be achieved not only with commercially
available trialkylboranes but also with organoboranes prepared
from hydroboration of alkenes for the synthesis of stereo-
defined α,β-substituted acrylic acid derivatives.17
b
11
b
12
b
13
b
14
NR
a
Entries 1−5: phenylacetylene (0.5 mmol), base (2.0 mmol), and Et3B
(1.0 mmol) in the presence of CuCl catalyst (0.05 mmol) in dioxane
b
(3 mL) at rt for 24 h under CO2 (1 atm). Entries 6−14:
phenylacetylene (0.5 mmol), base (2.0 mmol), and Et3B (3.0 mmol)
in the presence of CuCl catalyst (0.05 mmol) in solvent (3 mL) at rt
for 24 h under CO2 (1 atm).
the product yields. t-BuOK provided the desired product 1a in
38% yield (entry 1, Table 1). In contrast, similar sodium and
lithium tert-butoxide bases were ineffective for the coupling
reactions, and the expected product was not obtained at all
(entries 2 and 3, Table 1). Low product yields were observed
according to the low conversion of terminal alkynes, and (Z)-1-
phenyl-1-butene was generated as a byproduct. The use of
EtOK as a base provided the desired product in 50% yield
(entry 4). Further inspection of the bases revealed that MeOK
was the most efficient base for the three-component coupling
reactions. In particular, in the presence of 3.0 mmol of Et3B and
2.0 mmol of MeOK, the reaction mixture resulted in the
formation of product 1a in the highest yield in 1,4-dioxane.
Diminishing the amount of base was ineffective, and other
solvents such as THF, DMA, toluene, and hexane were not
beneficial (entries 7−10, Table 1). Although various kinds of
carbene ligands besides IPr were investigated, such as ClIPr,
MeIPr, IPr*, and IMes (entries 11−14, Table 1), the reaction
with a combination of the IPr ligand and MeOK in dioxane
provided the best results. Product 1a was obtained as a single
isomer with almost complete regio- and stereoselectivities.15
Next, we investigated the reactions of various kinds of
terminal alkynes and organoboranes (Table 2). Irrespective of
the kinds of substituents on the aromatic terminal alkynes, a
similar coupling reaction proceeded in moderate to good yields
under optimized conditions, as elucidated in Table 1. p-
Methoxy- and o-methoxyphenyl-substituted alkynes resulted in
the formation of α-ethyl-β-aryl acrylic acids 1b and 1c as a
single isomer in moderate to good yields, and the CO2 insertion
To investigate the mechanistic aspects of the catalytic
process, a deuterium-labeling experiment was performed. 1-
Deuteriophenylacetylene (95% D) underwent the coupling
reaction via treatment with MeOK and Et3B in the presence of
IPrCuCl as the catalyst in 1,4-dioxane under CO2 atmosphere
(Scheme 4). The product incorporated a deuterium atom at the
Scheme 4. Deuterium-Labeling Experiment for Cu-Catalyzed
CO2 Insertion of Phenylacetylene-d
vinylic position, affording (75% D) in a reasonable yield.
Although the reason for the incomplete incorporation of
deuterium is currently unclear, this result suggests that the
origin of the proton source at the vinylic position might be
attributed to the acetylenic terminal proton atom, giving rise to
the trisubstituted alkenes with high regio- and stereo-
selectivities.18
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Although it is premature to speculate on the reaction
mechanism based on the deuterium-labeling experiment, a
plausible reaction mechanism with terminal alkyne, Et3B, and
CO2 might be proposed, as illustrated in Scheme 5. At first, the
REFERENCES
■
(1) (a) Liu, Q.; Wu, L.; Jackstell, R.; Beller, M. Nat. Commun. 2015,
6, 5933. (b) Tlili, A.; Blondiaux, E.; Frogneux, X.; Cantat, T. Green
Chem. 2015, 17, 157−168. (c) Periana, R. A.; Mironov, O.; Taube, D.;
Bhalla, G.; Jones, C. J. Science 2003, 301, 814−818.
(2) (a) Schreiner, E.; Wilcke, T.; Muller, T. J. J. Synlett 2016, 27,
Scheme 5. Plausible Reaction Mechanism for Cu-Catalyzed
CO2 Insertion into Terminal Alkynes
̈
379−382. (b) Takimoto, M.; Gholap, S.; Hou, Z. Chem. - Eur. J. 2015,
21, 15218−15223. (c) Takimoto, M.; Hou, Z. Chem. - Eur. J. 2013, 19,
11439−11445. (d) Shimizu, K.; Takimoto, M.; Mori, M. Org. Lett.
2003, 5, 2323−2325. (e) Takimoto, M.; Shimizu, K.; Mori, M. Org.
Lett. 2001, 3, 3345−3347.
(3) (a) Mori, Y.; Kawabata, T.; Onodera, G.; Kimura, M. Synthesis
2016, 48, 2385−2395. (b) Kimura, M.; Ohira, Y.; Mori, T.; Hayashi,
M.; Onodera, G. Heterocycles 2015, 90, 832−841. (c) Mori, Y.;
Onodera, G.; Kimura, M. Chem. Lett. 2014, 43, 97−99.
(4) (a) Mori, Y.; Mori, T.; Onodera, G.; Kimura, M. Synthesis 2014,
46, 2287−2292. (b) Takimoto, M.; Mizuno, T.; Mori, M.; Sato, Y.
Tetrahedron 2006, 62, 7589−7597. (c) Takimoto, M.; Nakamura, Y.;
Kimura, K.; Mori, M. J. Am. Chem. Soc. 2004, 126, 5956−5957.
(d) Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2002, 124, 10008−
10009. (e) Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2001, 123,
2895−2896.
acetylide was generated from the abstraction of the terminal
proton of alkyne by MeOK as a base to react with Et3B, thus
providing alkynyltriethylborate.19 This alkynyltriethylborate ate
complex then underwent protonation at the β-carbon position
to yield a vinylic cation intermediate, which then experienced
[1,2] an ethyl group migration reaction to the empty p orbital
of the vinylic carbocation with excellent stereoselectivity to
form the vinyldiethylborane intermediate.11 Then, trans-
metalation with a carbene−copper species affords a vinylcopper
intermediate. The nucleophilic addition of vinylcopper to CO2
might have yielded a carboxylate salt, which then reacted with
MeOK to regenerate the carbene−copper species.
In summary, a Cu-catalyzed CO2 insertion reaction involving
a dialkylvinylborane intermediate derived from alkynyltrialkyl-
borate by a 1,2-alkyl group migration was carried out to afford
α-alkylated acrylic acids with excellent regio- and stereo-
selectivities. This CO2 insertion is in contrast to the previously
developed methods utilizing Cu- and Ni-catalyzed multi-
component coupling, which prepared α-substituted acrylic
acids from the terminal alkynes.
(5) (a) Gholap, S. S.; Takimoto, M.; Hou, Z. Chem. - Eur. J. 2016, 22,
8547−8552. (b) Takimoto, M.; Kawamura, M.; Mori, M.; Sato, Y.
Synlett 2011, 2011, 1423−1426. (c) Takimoto, M.; Kawamura, M.;
Mori, M. Synthesis 2004, 2004, 791−785. (d) Takimoto, M.;
Kawamura, M.; Mori, M. Org. Lett. 2003, 5, 2599−2601.
(6) (a) Mita, T.; Higuchi, Y.; Sato, Y. Chem. - Eur. J. 2015, 21,
16391−16394. (b) Duong, H. A.; Huleatt, P. B.; Tan, Q.-W.; Shuying,
E. L. Org. Lett. 2013, 15, 4034−4037.
(7) For CO2 insertion at the arene and sp2 carbon, see: (a) Ueno, A.;
Takimoto, M.; O, W. W. N.; Nishiura, M.; Ikariya, T.; Hou, Z. Chem. -
Asian J. 2015, 10, 1010−1016. (b) Mita, T.; Suga, K.; Sato, K.; Sato, Y.
Org. Lett. 2015, 17, 5276−5279. (c) Riss, P. J.; Lu, S.; Telu, S.;
Aigbirhio, F. I.; Pike, V. W. Angew. Chem., Int. Ed. 2012, 51, 2698−
2702. (d) Correa, A.; Martin, R. J. Am. Chem. Soc. 2009, 131, 15974−
15975. (e) Ohishi, T.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed.
2008, 47, 5792−5795.
(8) For CO2 insertion at the sp3 carbon, see: (a) Mita, T.; Saito, K.;
Sugawara, M.; Sato, Y. Chem. - Asian J. 2016, 11, 1528−1531.
(b) Grigg, R. D.; Rigoli, J. W.; Van Hoveln, R.; Neale, S.; Schomaker, J.
M. Chem. - Eur. J. 2012, 18, 9391−9396. (c) Ohishi, T.; Zhang, L.;
Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2011, 50, 8114−8117.
(9) (a) Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, 2005.
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147−168. (c) Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483.
ASSOCIATED CONTENT
* Supporting Information
■
S
(10) (a) Yoshida, H. ACS Catal. 2016, 6, 1799−1811. (b) Semba, K.;
Fujihara, T.; Terao, J.; Tsuji, Y. Tetrahedron 2015, 71, 2183−2197.
(c) Fujihara, T.; Semba, K.; Terao, J.; Tsuji, Y. Catal. Sci. Technol.
2014, 4, 1699−1709. (d) Barbeyron, R.; Benedetti, E.; Cossy, J.;
Vasseur, J.-J.; Arseniyadis, S.; Smietana, M. Tetrahedron 2014, 70,
8431−8452. (e) Trost, B. M.; Ball, Z. T. Synthesis 2005, 2005, 853−
887. (f) Negishi, E.; Yoshida, T.; Abramovitch, A.; Lew, G.; Williams,
R. M. Tetrahedron 1991, 47, 343−356. (g) Brown, H. C.; Scouten, C.
G.; Liotta, R. J. Am. Chem. Soc. 1979, 101, 96−99.
(11) For a review of the advanced Wrackmeyer reaction, see:
(a) Kehr, G.; Erker, G. Chem. Sci. 2016, 7, 56−65. 1,1-Carboboration
of alkynylborates: (b) Suzuki, A.; Miyaura, N.; Abiko, S.; Itoh, M.;
Midland, M. M.; Sinclair, J. A.; Brown, H. C. J. Org. Chem. 1986, 51,
4507−4511. (c) Brown, H. C.; Molander, G. A. J. Org. Chem. 1986, 51,
4512−4514. (d) Brown, H. C.; Wang, K. K. J. Org. Chem. 1986, 51,
4514−4517. (e) Brown, H. C.; Basavaiah, D.; Bhat, N. G. J. Org. Chem.
1986, 51, 4518−4521. (f) Sikorski, J. A.; Bhat, N. G.; Cole, T. E.;
Wang, K. K.; Brown, H. C. J. Org. Chem. 1986, 51, 4521−4525.
(12) (a) Morimoto, M.; Miura, T.; Murakami, M. Angew. Chem., Int.
Ed. 2015, 54, 12659−12663. (b) Ishida, N.; Narumi, M.; Murakami,
M. Org. Lett. 2008, 10, 1279−1281. (c) Ishida, N.; Miura, T.;
Murakami, M. Chem. Commun. 2007, 42, 4381−4383.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03860.
Experimental procedures, characterization data, NMR
spectra, an dX-ray data for 1a (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: masanari@nagasaki-u.ac.jp.
ORCID
Masanari Kimura: 0000-0003-2900-9554
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge funding from a Grant-in-Aid for
Scientific Research (B) (26288052) from the Ministry of
Education, Culture, Sports and Technology (MEXT), Japan.
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DOI: 10.1021/acs.orglett.6b03860
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Organic Letters
Letter
(13) Fukushima, M.; Takushima, D.; Satomura, H.; Onodera, G.;
Kimura, M. Chem. - Eur. J. 2012, 18, 8019−8023.
(14) Kimura, M.; Takushima, D.; Fukushima, M.; Satomura, H.;
Onodera, G. Heterocycles 2012, 86, 171−180.
(15) CCDC 1517933 contains the supplementary crystallographic
data for 1a. This data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(16) Under similar conditions, 1-octyne could not provide the
desired products at all, irrespective of the kinds of bases. Although it is
premature to rationalize the reason nonarylated terminal alkynes could
not participate in the expected reactions, the exquisite balance of the
acidity of alkynes and the basicity of bases seems to be most effective
for the protonation process and regeneration of Cu active species.
(17) n-Octyl-9-BBN and Ph-9-BBN could not work as alkylating and
arylating agents, respectively. The present reaction is limited to the use
of trialkylboranes.
(18) It has been reported the protonation of lithium or sodium
alkynyltrialkylborates provided the E/Z mixture of alkenylboranes; see:
(a) Miyaura, N.; Yoshinari, T.; Itoh, M.; Suzuki, A. Tetrahedron Lett.
1974, 15, 2961−2964. (b) Binger, P.; Koster, R. Tetrahedron Lett.
̈
1965, 6, 1901−1906. In the present case, the products were obtained
with excellent stereoselectivity. This highly selective process might be
attributed to Cu-catalyzed stereocontrolled protonation with meth-
anol.
(19) Cu catalyst might act as a promoter for the formation of
alkynyltrialkylborates from terminal alkynes and trialkylboranes;
IPrCuCl seems to serve as a Lewis acid to enhance the acidity of
terminal alkynes via the π-alkyne complex. A similar assumption of the
Cu-catalyzed enhancement of the acidity of terminal alkyne has been
reported; see: Gooßen, L. J.; Rodriguez, N.; Manjolinho, F.; Lange, P.
P. Adv. Synth. Catal. 2010, 352, 2913−2917.
D
DOI: 10.1021/acs.orglett.6b03860
Org. Lett. XXXX, XXX, XXX−XXX