Cu-Catalyzed C-H Alkenylation of Benzoic Acid and Acrylic Acid Derivatives with Vinyl Boronates

Article abstract of DOI:10.1021/acs.orglett.0c01469

An efficient Cu-catalyzed C-H alkenylation with acyclic and cyclic vinyl boronates was realized for the first time under mild conditions. The scope of the vinyl borons and the compatibility with functional groups including heterocycles are superior than Pd-catalyzed C-H coupling with vinyl borons, providing a reliable access to multisubstituted alkenes and dienes. Subsequent hydrogenation of the product from the internal vinyl borons will lead to installation of secondary alkyls.

Full text of DOI:10.1021/acs.orglett.0c01469

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Letter
Cu-Catalyzed C−H Alkenylation of Benzoic Acid and Acrylic Acid
Derivatives with Vinyl Boronates
Jian-Jun Li, Cheng-Gang Wang, Jin-Feng Yu, Peng Wang,* and Jin-Quan Yu*
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ABSTRACT: An efficient Cu-catalyzed C−H alkenylation with
acyclic and cyclic vinyl boronates was realized for the first time
under mild conditions. The scope of the vinyl borons and the
compatibility with functional groups including heterocycles are
superior than Pd-catalyzed C−H coupling with vinyl borons,
providing a reliable access to multisubstituted alkenes and dienes.
Subsequent hydrogenation of the product from the internal vinyl
borons will lead to installation of secondary alkyls.
Scheme 1. Synopsis for Cu-Catalyzed C−H Alkenylation
with Vinyl Boronates
u-catalyzed or -mediated C−H functionalization has
Cattracted great attention due to the abundance, low cost,
and low toxicity of copper.1−3 Since the early finding of its
capability of functionalizing the aromatic C−H bonds,1
a
diverse range of C−H activation reactions has been
developed,2,3 thus providing a complementary approach to
construct a carbon−carbon or carbon−heteroatom bond. It is
worth noting that Cu(II) catalyst has been shown to catalyze
transformations that are not successful with Pd catalysts. The
exceptional tolerance of the heterocycle is also a practical
advantage of Cu catalysts.3a,c However, development in this
field is still at an early stage compared to the state of the art Pd-
catalyzed C−H functionalizations.4 Here we report a Cu(II)-
catalyzed alkenylation of benzoic acid and acrylic acid
derivatives with vinyl boronates for the first time. With the
aid of an oxazoline-aniline directing group, a series of
multisubstituted alkenes and dienes were constructed in high
efficiency in the presence of cyclic and acyclic alkenyl
boronates (Scheme 1B). Hydrogenation of the resulting
internal alkenes could also provide the corresponding
secondary alkylated arenes (Scheme 1C).
Substituted alkenes and dienes are ubiquitous motifs in
natural products, pharmaceuticals, and organic materials.5 In
addition, they are widely used synthons participating in many
reduction and oxidation processes.6 C−H coupling with vinyl
borons could provide an attractive route for this class of
compounds.7 Attempts to achieve this transformation using Pd
catalysts have been largely unsuccessful due to the decom-
position of vinylboronates in the presence of Pd(II) catalysts.8
Our early finding of Cu-catalyzed C−H coupling with aryl-
boronate3d prompted us to investigate the feasibility of using
Cu catalysts to effect this transformation.
Recently, Daugulis,9a Piguel,9b Charette,9c and others9d have
demonstrated the direct alkenylation of acidic C−H in the
presence of strong base with vinyl halides. Employing allylic
halides via an allylation/isomerization sequence, Li, Chen,10a
and Chang10b have achieved the C−H alkenylation of relatively
Received: April 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01469
© XXXX American Chemical Society
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more acidic aryl C−H bonds (azoles or fluorinated benzenes,
Scheme 1A). Despite this progress, Cu-catalyzed alkenylation
of inert C−H bond remains a significant challenge. We
envisioned Cu-catalyzed C−H coupling with alkenyl boronates
could be an attractive approach owing to the availability of
vinyl boronates.
ester (2) as an alkenylating reagent (Scheme 3). Normally, the
ortho-substituted substrates gave lower yields in comparison
a b
,
Scheme 3. Evaluation of Benzoic Acids
In our initial screening using a readily removable oxazoline-
aniline directing group, we found that cross-coupling of
substrate 1a with (E)-1-pentenylboronic acid pinacol ester (2)
proceeded in 7% yield of monoalkenylated product along with
11% yield of a hydroxylation byproduct under our previous
conditions (66% yield for arylation, see Supporting Informa-
tion for more information). After systematically tuning the
reaction parameters (Scheme 2), the yield of alkenylation
a b
,
Scheme 2. Effects of Reaction Parameter
a
The yield was determined by 1H NMR using dibromomethane as an
b
internal standard. Isolated yield.
products is improved to 86% as measured by NMR (77%
isolated yield) with a mono/di selectivity of 2.1/1.0. The
optimized conditions consist of copper(II) benzoate (30 mol
%), Ag2O (2.0 equiv), the potassium salt of pivalic acid
(KOPiv) (2.0 equiv), KHCO3 (2.0 equiv), and dimethyl
sulfoxide (DMSO) (2.0 mL). The reaction is run under N2
atmosphere at 45 °C. Control experiments demonstrated that
the reaction cannot proceed in the absence of copper(II)
benzoate and bases, while only trace amounts of the desired
alkenylation products were observed without the use of Ag2O
(entry 6). Both KOPiv and KHCO3 are crucial for maintaining
the high efficiency (entries 3 and 4), in which KOPiv played a
major role providing 3a in 66% yield alone. It is noteworthy
that the reaction can also be performed under air, albeit with
lower yield and 6% of hydroxylated byproduct (entry 7).
Cu(OAc)2 and Cu(OPiv)2 could also promote this C−H
alkenylation reaction with a slightly lower yield in comparison
with (PhCO2)2Cu (entries 9 and 10). Notably, the reaction
temperature is pivotal for suppressing the formation of the
hydroxylation byproduct (entries 11−13). Higher temperature
normally led to lower yield of desired alkenylation product and
higher yield of hydroxylation byproduct (see Supporting
Information for more information). Replacement of DMSO
by other solvents, like MeOH, dioxane, MeCN, toluene, and
dichloromethane, shut down the reaction, while dimethylfor-
mamide (DMF) provided the desired products in 54% yield
(entries 14−16). In addition, reducing the loading of
(PhCO2)2Cu and tuning the concentration all led to inferior
results.
a
Reaction conditions: 1 (0.1 mmol), 2 (0.3 mmol), Cu(PhCO2)2
(0.03 mmol), Ag2O (0.2 mmol), KOPiv (0.2 mmol), KHCO3 (0.2
mmol), DMSO (2.0 mL), N2, 45 °C, 12 h. Isolated yield. Single-
crystal X-ray structure of 3a (mono) with thermal ellipsoids at 30%
probability levels. Cu(OPiv)2 (0.03 mmol). 60 °C. Cu(PhCO2)2
(0.035 mmol), 50 °C. 9 h.
b
c
d
e
f
g
with meta- and para-substituted benzoic acids (3k and 3l).
Both electron-rich and electron-deficient group-substituted
benzoic acids are well-tolerated, giving the corresponding
alkenylated arenes in moderate to good yields. The para-
substituted substrates (3b−3j and 3w) provided a mono- and
diproducts mixture in high efficiency, while the monoalkeny-
lation happened with meta-substituted substrates (3m−3r) due
to the steric hindrance. This protocol features good functional
group tolerance with alkyl, aryl, vinyl, amino, chloro, methoxyl,
methylthio group, and trifluoromethyl groups, in which the
compatibility with the vinyl group highlights the impressive
mild conditions. Heterocyclic substrates (3u−3w) are also
suitable substrates for this alkenylation, albeit lower yields were
obtained. Not surprisingly, the C−H alkenylation proceeded at
the ortho-position to oxazoline-aniline directing group rather
than at the strong coordinating heterocycle site (3w).
Under the optimal conditions, we next evaluated the scope
of the benzoic acids using (E)-1-pentenylboronic acid pinacol
Next, the generality of alkenyl boronates was evaluated using
1o as model substrate. As depicted in Scheme 4, both cis- and
B
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a b
,
were synthesized under our mild conditions (Scheme 5), given
a variety types of dienes in 30−78% yields employing
Scheme 4. Scope of Vinyl Boronates
a b
,
Scheme 5. Alkene−Alkene Coupling
a
Reaction conditions: 1o (0.1 mmol), 4 (0.3 mmol), Cu(OPiv)2
(0.03 mmol), Ag2O (0.2 mmol), KOPiv (0.2 mmol), KHCO3 (0.2
b
c
mmol), DMSO (2.0 mL), N2, 45 °C, 12 h. Isolated yield. 50 °C.
a
Reaction conditions: 6 (0.1 mmol), 2 or 4 (0.3 mmol), Cu(OPiv)2
(0.03 mmol), Ag2O (0.2 mmol), KOPiv (0.2 mmol), KHCO3 (0.2
mmol), DMSO (2.0 mL), N2, 45 °C, and see Supporting Information
trans-vinyl boronates are compatible with this protocol, giving
corresponding cis or trans alkenes in high yields (5a and 5b).
Alkyl vinyl boronates reacted with 1o providing the desired
products in 51−82% yields (5a−5f). Notably, the compati-
bility with the cyclopropanyl group indicated this C−H
vinylation reaction through a cyclocupration intermediate
rather than a radical process. Styrene- and heterostyrene-
derived coupling partners are also tolerated under the mild
conditions albeit with moderate yields (5g and 5h). The mild
reaction conditions also allowed the coupling with base- or
acid-sensitive alkenylating reagents, like tetramethylsilane
(TMS)-vinyl, vinyl ether, and diene, etc. (5i−5k). Isoprope-
nylboronic acid pinacol ester gave the desired product in 55%
yield (5l). In addition, disubstituted (4m−4o), trisubstituted
(4p), and cyclic vinyl boronates (4q−4t) are all suitable
coupling partners for this reaction. It is worth noting that a
broad range of heterocyclic alkenyl boronates are compatible
with this reaction, providing a diverse range of novel
heteroalkenylated arenes (5u−5z).
b
for detailed reaction time. Isolated yield.
Cu(OPiv)2 as the most efficient catalyst (7a−7k). Moreover,
heterocyclic alkene substrates are also compatible providing a
direct method for synthesis of alkenylated heterocycles in high
yields (7e−7i). Notably, the incredible heteroatom tolerance
allows the direct coupling of heterocyclic substrates with
heterocylic alkenyl boronates (7l−7t) in high efficiency. The
direct coupling of 6i with an estratrien-derived vinyl boronate
demonstrated the versatility of this process for late-stage
functionalization of complex bioactive molecules (7u).
The scalability of this process was examined by the direct
coupling of 1o (1.0 g, 3.4 mmol) with (E)-1-pentenylboronic
acid pinacol ester (2), providing the desired alkenylated
product 3o in 77% yield (Scheme 6a). The directing group (9)
could be readily removed in the presence of KOH, and it was
recovered in 70% yield. The resulting alkenylated benzoic acid
(8) is a significant intermediate in organic synthesis, which
could be easily transformed to alkylated benzoic acid (10),
lactone (11), and aldehyde (12) (Scheme 6b). It is noteworthy
that hydrogenation of the heterocyclic alkene derivatives gave
alkylated tetrahydropyran (13) and piperidine (14) in 81%
and 95% yields, respectively (Scheme 6c). Because of the
Given the importance of dienes in organic synthesis and
their population in bioactive molecules, we turned to
investigate the direct coupling of a vinyl C−H bond with
vinyl boronates. Because of the instability of dienes under
oxidative conditions, the direct synthesis of dienes via C−H
activation remains challenging. To our delight, various dienes
C
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Jin-Quan Yu − The Scripps Research Institute, La Jolla 92037,
California, United States; orcid.org/0000-0003-3560-
5774; Email: yu200@scripps.edu
Scheme 6. Gram-Scale Reaction and Applications
Authors
Jian-Jun Li − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, Shanghai 200032,
China
Cheng-Gang Wang − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, Shanghai 200032,
China
Jin-Feng Yu − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, Shanghai 200032,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01469
Notes
The authors declare no competing financial interest.
CCDC 1976936 corresponds to [3a (mono)] as described in
this manuscript.
ACKNOWLEDGMENTS
■
difficulties in installing secondary alkyls via Pd-catalyzed C−H
alkylation, this method provides a solution to this persistent
problem. In addition, the direct synthesis of substituted
piperidine or tetrahydropyran derivatives, highly valuable
motifs in medicinal chemistry, is noteworthy.
In summary, a series of alkenes and dienes was synthesized
via Cu-catalyzed C−H alkenylation with cyclic and acyclic
vinyl boronates for the first time. The procedure features mild
conditions, broad functional group, and heterocycle tolerance,
filling a significant gap in directed C−H activation reaction
development.
We gratefully acknowledge Shanghai Institute of Organic
Chemistry, State Key Laboratory of Organometallic Chemistry,
National Natural Science Foundation of China (21821002),
the Key Research Program of Frontier Science (QYZDJSS-
WSLH055) of the Chinese Academy of Sciences, and the NSF
under the CCI Center for Selective C−H Functionalization
(CCHE-1700982) for financial support.
REFERENCES
■
(1) (a) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790−6791. (b) Uemura, T.; Imoto, S.; Chatani, N.
Chem. Lett. 2006, 35, 842−843.
ASSOCIATED CONTENT
* Supporting Information
■
sı
(2) For selected reviews on Cu-catalyzed or -mediated C−H
functionalization: (a) Rao, W.-H.; Shi, B.-F. Org. Chem. Front. 2016,
3, 1028−1047. (b) Guo, X.-X.; Gu, D.-W.; Wu, Z.-X.; Zhang, W.-B.
Chem. Rev. 2015, 115, 1622−1651. (c) Hirano, K.; Miura, M. Chem.
Commun. 2012, 48, 10704−10714. (d) Wendlandt, A. E.; Suess, A.
M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062−11087.
(e) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42,
1074−1086.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01469.
Experimental procedures, complete characterization
1
data, copies of H and 13C NMR spectra, and X-ray
crystallographic data (PDF)
Accession Codes
(3) For selected examples on Cu-catalyzed or -mediated C−H
functionalization: (a) Yu, J.-F.; Li, J.-J.; Wang, P.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2019, 58, 18141−18145. (b) Kim, H.; Heo, J.; Kim, J.-
H.; Baik, M.-H.; Chang, S. J. Am. Chem. Soc. 2018, 140, 14350−
14356. (c) Shang, M.; Wang, M.-M.; Saint-Denis, T.-G.; Li, M.-H.;
Dai, H.-X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2017, 56, 5317−5321.
(d) Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. Org. Lett. 2014, 16,
5666−5669. (e) Li, Q.; Zhang, S.-Y.; He, G.; Ai, Z.-Y.; Nack, W.-A.;
Chen, G. Org. Lett. 2014, 16, 1764−1767. (f) Wang, Z.; Ni, J.-Z.;
Kuninobu, Y.; Kanai, M. Angew. Chem., Int. Ed. 2014, 53, 3496−3499.
(g) Wu, X.-S.; Zhao, Y.; Zhang, G.-W.; Ge, H.-B. Angew. Chem., Int.
Ed. 2014, 53, 3706−3710. (h) Shang, M.; Sun, S.-Z.; Wang, H.-L.;
Laforteza, B. N.; Dai, H.-X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2014, 53,
10439−10442. (i) Phipps, R. J.; Gaunt, M. J. Science 2009, 323,
1593−1597. (j) Ban, I.; Sudo, T.; Taniguchi, T.; Itami, K. Org. Lett.
2008, 10, 3607−3069. (k) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc.
2007, 129, 12404−12405. (l) Gui, Q.-W.; Chen, X.; Hu, L.; Wang,
D.-D.; Liu, J.-D.; Tan, Z. Adv. Synth. Catal. 2016, 358, 509−514.
CCDC 1976936 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Peng Wang − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis and
CAS Key Laboratory of Energy Regulation Materials, Shanghai
Institute of Organic Chemistry, Shanghai 200032, China;
orcid.org/0000-0002-6442-3008; Email: pengwang@
sioc.ac.cn
D
https://dx.doi.org/10.1021/acs.orglett.0c01469
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(4) For selected reviews on Pd-catalyzed C−H functionalization:
(a) He, G.; Wang, B.; Nack, W. A.; Chen, G. Acc. Chem. Res. 2016, 49,
635−645. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147−1169. (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2009, 48, 5094−5115.
(5) For selected examples: (a) Kaur, P.; Singh, K. J. Mater. Chem. C
2019, 7, 11361−11405. (b) Ben-Califa, N.; Bishara, A.; Neumann, D.;
Kashman, Y. Invest. New Drugs 2012, 30, 98−104. (c) Zhou, X.-H.;
Luo, J.-D.; Davies, J. A.; Huang, S.; Jen, A. K. Y. J. Mater. Chem. 2012,
22, 16390−16398. (d) Ruiz-Gaspa, S.; Nogues, X.; Enjuanes, A.;
Monllau, J. C.; Blanch, J.; Carreras, R.; Mellibovsky, L.; Grinberg, D.;
Balcells, S.; Diez-Perez, A.; Pedro-Botet, J. J. Cell. Biochem. 2007, 101,
1430−1438. (e) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995,
117, 8126−8131.
(6) (a) Patai, S. The chemistry of double bonded functional groups;
Wiley: Chichester, U.K., 1997. (b) Crisp, G. T. Chem. Soc. Rev. 1998,
27, 427−436.
(7) For recent selected examples on transition-metal-catalyzed C−H
alkenylation: (a) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4,
886−896. (b) Shang, X.-J.; Liu, Z.-Q. Chem. Soc. Rev. 2013, 42,
3253−3260. (c) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170−
1214. (d) Rossi, R.; Bellina, F.; Lessi, M. Synthesis 2010, 2010, 4131−
4153. (e) Jambu, S.l.; Tamizmani, M.; Jeganmohan, M. Org. Lett.
2018, 20, 1982−1986. (f) Wang, P.; Verma, P.; Xia, G.-Q.; Shi, J.;
Qiao, J.-X.; Tao, S.-W.; Cheng, P. T.-W.; Poss, M.-A.; Farmer, M.-E.;
Yeung, K.-S.; Yu, J.-Q. Nature 2017, 551, 489−493. (g) Shang, R.;
Ilies, L.; Asako, S.; Nakamura, E. J. Am. Chem. Soc. 2014, 136, 14349−
14352. (h) Deb, A.; Bag, S.; Kancherla, R.; Maiti, D. J. Am. Chem. Soc.
2014, 136, 13602−13605. (i) Meng, L.-K.; Kamada, Y.-K.; Muto, K.;
Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed. 2013, 52, 10048−
10051. (j) Zhao, Y.-S.; He, G.; Nack, W.-A.; Chen, G. Org. Lett. 2012,
14, 2948−2951. (k) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J.
Org. Chem. 2011, 76, 3024−3033. (l) Park, S.-H.; Kim, J.-Y.; Chang,
S. Org. Lett. 2011, 13, 2372−2375. (m) Wang, D.-H.; Engle, K. M.;
Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315−319. (n) Patureau, F. W.;
Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982−9983. (o) Xu, Y.-H.;
Lu, J.; Loh, Y.-P. J. Am. Chem. Soc. 2009, 131, 1372−1373. (p) Jia, C.
G.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 844−639.
(q) Lu, M.-Z.; Chen, X.-R.; Xu, H.; Dai, H.-X.; Yu, J.-Q. Chem. Sci.
2018, 9, 1311−1316.
(8) Wasa, M.; Chan, K. S. L.; Yu, J.-Q. Chem. Lett. 2011, 40, 1004−
1006.
(9) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128−
̀
1129. (b) Besselievre, F.; Piguel, S.; Mahuteau-Betzer, F.; Grierson,
D.-S. Org. Lett. 2008, 10, 4029−4032. (c) Mousseau, J. J.; Bull, J. A.;
Charette, A. B. Angew. Chem., Int. Ed. 2010, 49, 1115−1118.
(d) Zhang, W.; Tian, Y.; Zhao, N.; Wang, Y.; Li, J.; Wang, Z.
Tetrahedron 2014, 70, 6120−6126.
(10) (a) Li, D.; Wu, X.-X.; Gao, T.; Li, B.; Chen, S. Org. Biomol.
Chem. 2017, 15, 7282−7285. (b) Xie, W.-L.; Chang, S. Angew. Chem.,
Int. Ed. 2016, 55, 1876−1880.
E
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