Cobalt-Catalyzed Markovnikov-Type Selective Hydroboration of Terminal Alkynes

Article abstract of DOI:10.1002/anie.202012164

A cobalt-catalyzed Markovnikov-type hydroboration of terminal alkynes with HBpin to access α-alkenyl boronates with good regioselectivity and atom economy is reported. A new ligand has been developed for the cobalt hydride catalyst that has been used for a unique Markovnikov selective insertion of terminal alkynes into metal hydride bond. This operationally simple protocol exhibits excellent functional group tolerance to deliver valuable alkene derivatives.

Full text of DOI:10.1002/anie.202012164

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Cobalt-Catalyzed Markovnikov-Type Selective Hydroboration of
Terminal Alkynes
Authors: Jieping Chen, Xuzhong Shen, and Zhan Lu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012164
Link to VoR: https://doi.org/10.1002/anie.202012164

10.1002/anie.202012164
Angewandte Chemie International Edition
COMMUNICATION
Cobalt-Catalyzed Markovnikov-Type Selective Hydroboration of
Terminal Alkynes
Jieping Chen+, Xuzhong Shen+, and Zhan Lu*
Department of Chemistry, Zhejiang University, Hangzhou 310058, China
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
Abstract: Here, we reported a cobalt-catalyzed Markovnikov-type
hydroboration of terminal alkynes with HBpin to access α-alkenyl
boronates with good regioselectivity and atom economy. A new ligand
has been developed for cobalt hydride catalyst which has been used
for a unique Markovnikov selective insertion of terminal alkynes into
metal hydride bond. This operationally simple protocol exhibits
excellent functional group tolerance to deliver valuable alkene
derivatives.
Compared to the protonboration, metal-catalyzed selective
hydroboration of alkynes using hydroboranes offers an atom-
economic way to access α-alkenyl boronates. Nevertheless,
Markovnikov-type selective hydroboration of terminal alkynes with
HBpin via a metal hydride strategy has not been explored due to
several challenges in this system: (1) The insertion of terminal
alkyne into metal hydride species usually delivers the
intermediate bearing the metal at terminal carbon due to the steric
and electronic effect;[11] (2) The intrinsic background reactions
affording anti-Markovnikov selective hydroboration products may
lower the regioselectivity;[4] (3) In the presence of metal hydride
species, the side-reactions including alkyne hydrogenation,
double hydroboration, and isomerization may become
dominant.[12]
Alkenyl boronates are widely used as important synthons, for
instance, in Suzuki–Miyaura coupling, Petasis reaction,
conjugative addition, and so on.[1] Traditionally, the borylation of
alkenyl metallic reagents has been widely used for the selective
preparation of these useful compounds.[2] Avoiding the use of the
stoichiometric amount of alkenyl metallic reagents, hydroboration
of alkynes has been regarded as a step-economic and atom-
economic synthetic pathway to access alkenyl boronates from
readily available starting materials.[3] Commonly, the anti-
Markovnikov products with β(E)-selectivity are usually obtained in
noncatalytic hydroboration of terminal alkynes.[4] Various metal
catalysts have been discovered for selective hydroboration of
terminal alkynes to efficiently produce β(E)- and β(Z)-alkenyl
boronates, respectively.[5,6] However, hydroboration of terminal
alkynes to access α-alkenyl boronates is still challenging and less
explored. In 2011, Hoveyda and coworkers reported a catalytic
strategy for α-selective protonboration of terminal alkynes with
B2pin2 by using a NHC-Cu catalyst with moderate to excellent
regioselectivity.[7] Subsequently, Yoshida and coworkers used
1,8-diaminonaphthalene (dan) as a protecting group for boron to
achieve the same transformation with a better regioselectivity.[8]
Later, the palladium catalyst has been found by Prabhu and co-
workers to promote protonboration of terminal alkynes with a
moderate to excellent Markovnikov-type regioselectivity.[9]
Although these reactions involving boryl-metal intermediates
could deliver α-alkenyl boronates via copper- or palladium-
catalyzed protonboration pathways, the use of diboron reagents
would cause the stoichiometric extra amount of undesired
byproduct, reducing the atomic economy of the reaction.[10]
Scheme 1. Metal-Catalyzed Selective Hydroboration of Terminal Alkynes
[*]
Jieping Chen+, Xuzhong Shen+, and Zhan Lu*
Department of Chemistry, Zhejiang University
Hangzhou 310058 (China)
In recent years, cobalt-hydride catalysis, which emerged as an
economical and ecologically tool for sustainable synthesis, has
shown its unique reactivity and selectivity on various organic
E-mail: luzhan@zju.edu.cn
Homepage: http://mypage.zju.edu.cn/lu
These authors contributed equally to this work.
transformations.[11d] Our group reported
hydroboration/hydrogenation of internal alkynes in 2017.[13]
a
sequential
[+]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202012164
Angewandte Chemie International Edition
COMMUNICATION
However, only linear product was observed when
phenylacetylene was used as a starting material. With our
continuous interests on cobalt-catalyzed hydrofunctionalization of
alkynes,[14] here we report a mechanistically distinctive cobalt-
catalyzed α-selective hydroboration of terminal alkynes with
HBpin to access branched alkenyl boronates with good
regioselectivity and excellent functional group tolerance.
With the optimized conditions in hand, the substrate scope was
explored and shown in Table 2. A variety of alkynes could
undergo this reaction smoothly to afford various branched alkenyl
boronates in 47-85% yields. Phenyl acetylene with para-, meta-,
or ortho-methyl substituent (1c, 1j, 1p) could undergo this reaction
to deliver branched products with good regioselectivity. Among
which, the yield decreased slightly when the more steric hindered
substrate (1p) was employed, but a slightly higher regioselectivity
(b/l = 93/7) was observed. Both electron-enriched and electron-
deficient substrates could undergo this transformation smoothly.
For broader synthetic interests, various functional groups were
investigated. Protected alcohol, ether, sulfide, halide, nitrile, and
ester could be well tolerated. Notably, 1-ethynyl-4-vinylbenzene
(1g) and 1-(4-ethynylphenyl)ethan-1-one (1h), which could easily
undergo reduction of alkene or ketone in the presence of HBpin,
were transformed into the corresponding branched alkenyl
boronates (3g, 3h) successfully. It turned out that the reactions
possess good functional group tolerance. Terminal alkynes with
multi-substitution on phenyl rings (3s-3u) could deliver products
We performed the study to use 1-(tert-butyl)-4-ethynylbenzene
1a as
a
model substrate and 4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (HBpin) 2a as a boryl source (Table 1). The
reaction was carried out in the presence of 5 mol% of Co(OAc)2
and 6 mol% of L1 in a solution of tetrahydrofuran (THF) at room
temperature to afford a mixture of alkenyl boronates products in
84% yield with a ratio of 70/30 b/l selectivity (entry 1). Introducing
a gem-methyl group onto the oxazoline ring (L2) resulted in 78%
yield with 91/9 b/l selectivity. Removing the methyl group on the
pyridine moiety (L3) led to 89% yield with 85/15 b/l selectivity
(entry 3). When we changed the group on the pyridine moiety, the
regioselectivity of the product changes (entries 4 and 5). When N-
(oxazolinylphenyl)quinoline-2-carboxamide (L6, OPQC) was
used, the regioselectivity was improved to 93/7 b/l selectivity.
Unsymmetrical ligand L7 (entry 7) or symmetrical ligand L8 (entry
8) showed poor regioselectivities for this transformation. The time
course shown that the model reaction could completed in 3 h (See
supporting information). In order to make all the reactions with full
conversion, the reaction time is still extended to 24 h. The
standard conditions are identified as 0.6 mmol of alkyne, 0.72
mmol of HBpin, 5 mol% of Co(OAc)2, and 6 mol% of L6 in 2.4 mL
of THF for 24 h.
Table 2. Reaction Scope[a]
Table 1. Ligand Optimization [a]
Entry
Ligand
L1
Yield (%)[b]
b/l[b]
70:30
91:9
1
2
3
4
5
6
7
8
84
78
89
64
81
84
63
95
L2
L3
85:15
72:28
88:12
93:7
L4
L5
L6
L7
71:29
80:20
L8
[a] The reaction was conducted using 1a (0.6 mmol), 2a (0.72 mmol), Co(OAc)2
(5 mol %), and ligand (6 mol %) in a solution of THF (2.4 mL) at room
temperature for 24 h in glovebox. [b] Determined by 1H NMR using TMSPh as
an internal standard.
[a] 1 (0.6 mmol), 2 (0.72 mmol), Co(OAc)2 (5 mol%), and L6 (6 mol%) in THF
(2.4 mL) under N2 at rt for 24 h, NMR yield using TMSPh as an internal standard
(isolated yield was in the parentheses). [b] 0.2 mmol scale.
This article is protected by copyright. All rights reserved.

10.1002/anie.202012164
Angewandte Chemie International Edition
COMMUNICATION
in moderate to good yields. Fused ring (1v) and heterocyclic ring
(1w), were converted to branched alkenyl boronates in 60%-83%
yields with good regioselectivities.
using cobalt complex L6·CoBr and NaOAc as an additive could
give 3b in 76% NMR yield with 92/8 b/l (eq 8).
Alkenyl substituted terminal alkyne (1x) could also undergo this
transformation to afford branched alkenyl boronate as major
product although with a slightly lower regioselectivity (b/l = 88/12).
Furthermore, aliphatic terminal alkynes (1y, 1z, and 1aa) could
deliver branched product as major products. Terminal alkyne
contained in bioactive moiety(1ab) could also be converted into
corresponding α-alkenyl boronates, which demonstrated that this
transformation would be suitable for late-stage functionalization of
complicated molecules.
The reaction could be carried out on gram scale at room
temperature to afford 1.98 g of 3a with 92/8 b/l selectivity (70%
yield) (eq 1). To showcase the utility of α-alkenyl boronates, 3a
could be converted into alkenyl azide[15] (eq 2) or 1,1-diaryl
olefins[1] (eq 3), respectively. Additionally, alkenyl boronate with a
bromo substituent at meta-position (3o) could undergo Suzuki-
Miyaura coupling reaction to construct cyclic trimer compound (eq
4), which could be potentially applied in materials science.[16]
Scheme 3. Deuterium Labelling
Figure 1. X-ray diffraction of L6·CoBr
Scheme 2. Gram-Scale Reaction and Synthetic Applications
Scheme 4. Reaction Conducted Using Complex L6·CoBr
To elucidate the possible reaction pathway, several control
experiments were conducted. The alkyne hydroboration could
proceed smoothly in the presence of radical scavengers, such as
BHT or 1,1-diphenylethylene, which suggest this transformation
did not undergo radical process (See supporting information). The
deuterium experiment of deuterated alkyne 8 with HBpin was
conducted under standard condition to give four alkenyl
boronates (eq 5). No phenylacetylene was observed, even when
shortening the reaction time to 20 min, which ruled out the
possible H-D exchange between alkyne and HBpin reported by
literatures[17] (eq 6). The alkenyl boronates (3b) with DBpin was
conducted to give deuterated alkenyl boronates, indicating that
the product might undergo insertion into Co-H, then β-H
elimination to give deuterated alkenyl boronates (eq 7). Although
the single crystal of L6·Co(OAc)2 was failed to obtain, we got the
X-ray diffraction of L6·CoBr, which indicated the formation of an
unsymmetrical NNN tridendate cobalt complex.[18] The reaction of
1b with HBpin using L6·CoBr did not occur. However, the reaction
On the basis of the experimental studies and previously
reported literatures,[11d,13,14g] a possible mechanism is shown in
Scheme 5. The cobalt hydride species A is obtained from the
reaction of Co(OAc)2 with L6 and HBpin. The alkyne coordination
with species A followed by the insertion of terminal alkyne into the
cobalt hydride bond delivers majorly α-selective cobalt alkenyl
species C. The following σ-bond metathesis of C with HBpin
regenerates species A and delivers the corresponding alkenyl
boronate. The cobalt-hydride species will insert into the alkenyl
boronate, then β-H elimination to give product. However, the
Crabtree-Ojima-type[19] isomerization between C and E could not
be ruled out.
This article is protected by copyright. All rights reserved.

10.1002/anie.202012164
Angewandte Chemie International Edition
COMMUNICATION
2003, 68, 6031-6034; f) P. M. Mirzayans, R. H. Pouwer, C. M. Williams,
P. V. Bernhardt, Tetrahedron 2009, 65, 8297−8305; g) A. Bismuto, S. P.
Thomas, M. J. Cowley, Angew. Chem. Int. Ed. 2016, 55, 15356–15359.
a) B. M. Trost, Z. T. Ball, Synthesis 2005, 6, 853−887; b) J. Chen, J. Guo,
Z. Lu, Chin. J. Chem. 2018, 36, 1075−1109; c) J. V. Obligacion, P. J.
Chirik, Nat. Rev. Chem. 2018, 2, 15−34; d) H. Wen, G. Liu, Z. Huang,
Coord. Chem. Rev. 2019, 386, 138−153.
[3]
[4]
[5]
a) H. C. Brown, S. K. Gupta, J. Am. Chem. Soc. 1972, 94, 4370−4371;
b) C. E. Tucker, J. Davidson, P. Knochel, J. Org. Chem. 1992, 57,
3482−3485; c) J. Altarejos, D. Sucunza, J. J. Vaquero, J. Carreras, Eur.
J. Org. Chem. 2020, 2020, 3024−3029.
For selected recent publications on metal-catalyzed anti-Markovnikov
hydroboration of terminal alkyne, see: a) S. Pereira, M. Srebnik,
Tetrahedron Lett. 1996, 37, 3283−3286; b) Y. D. Wang, G. Kimball, A. S.
Prashad, Y. Wang, Tetrahedron Lett. 2005, 46, 8777−8780; c) W. J. Jang,
W. L. Lee, J. H. Moon, J. Y. Lee, J. Yun, Org. Lett. 2016, 18, 1390−1393;
d) H. Ben-Daat, C. L. Rock, M. Flores, T. L. Groy, A. C. Bowman, R. J.
Trovitch, Chem. Commun. 2017, 53, 7333−7336; e) G. Zhang, S. Li, J.
Wu, H. Zeng, Z. Mo, K. Davis, S. Zheng, Org. Chem. Front. 2019, 6,
3228−3233; f) Y. Wang, R. Guan, R. Sivaguru, X. Cong, X. Bi, Org. Lett.
2019, 21, 4035−4038.
Scheme 5. Proposed Mechanism
[6]
For selected recent publications on metal-catalyzed Z–selective
hydroboration of terminal alkynes, see: a) T. Ohmura, Y. Yamamoto, N.
Miyaura, J. Am. Chem. Soc. 2000, 122, 4990−4991; b) C. Gunanathan,
M. Hꢀlscher, F. Pan, W. Leitner, J. Am. Chem. Soc. 2012, 134,
14349−14352; c) J. V. Obligacion, J. M. Neely, A. N. Yazdani, I. Pappas,
P. J. Chirik, J. Am. Chem. Soc. 2015, 137, 5855−5858. d) N. Gorgas, L.
G. Alves, B. Stꢀger, A. M. Martins, L. F. Veiros, K. Kirchner, J. Am. Chem.
In summary, we reported a mechanistically distinctive cobalt-
catalyzed Markovnikov-type hydroboration of terminal alkynes
with HBpin to access branched alkenyl boronates with good atom
economy and functional group tolerance. The unsymmetrical
NNN-tridentate ligand OPQC was found to efficiently promote a
unique Markovnikov-type terminal alkynes insertion via metal
hydride intermediate. The reaction could be carried out on a gram
scale, and α-alkenyl boronates could easily be transferred to
potentially useful alkene derivatives. The development of various
metal-catalyzed regioselective hydrofunctionalization of alkynes
via metal hydride species is currently ongoing in our laboratory.
Soc. 2017, 139, 8130−8133.
H. Jang, A. R. Zhugralin, Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2011,
133, 7859–7871.
H. Yoshida, Y. Takemoto, K. Takaki, Chem. Commun. 2014, 50, 8299–
8302.
D. P. Ojha, K. R. Prabhu, Org. Lett. 2016, 18, 432−435.
[7]
[8]
[9]
[10] a) A. L. Moure, P. Mauleón, R. G. Arrayás, J. C. Carretero, Org. Lett.
2013, 15, 2054−2057; b) L. Mao, R. Bertermann, K. Emmert, K. J. Szabꢁ,
T. B. Marder, Org. Lett. 2017, 19, 6586−6589;
[11] a) Y. Tsuji, T. Fujihara, Chem. Rec. 2016, 16, 2294–2313; b) A. M. Suess,
G. Lalic, Synlett. 2016, 27, 1165−1174; b) D. Wei, C. Darcel, Chem. Rev.
2019, 119, 2550−2610; d) W. Ai, R. Zhong, X. Liu, Q. Liu, Chem. Rev.
2019, 119, 2876−2953; e) C. Nájera, I. P. Beletskaya, M. Yus, Chem.
Soc. Rev. 2019, 48, 4515−4618.
Acknowledgements
Financial support was provided by NSFC (21922107 and
21772171), Zhejiang Provincial Natural Science Foundation of
[12] a) Z. Zuo, Z. Huang, Org. Chem. Front. 2016, 3, 434−438; b) S. Fu, N.-
Y. Chen, X. Liu, Z. Shao, S.-P Luo, Q. Liu, J. Am. Chem. Soc. 2016, 138,
8588−8594.
China (LR19B020001), ZJU-NHU United Research
&
[13] J. Guo, B. Cheng, X. Shen, Z. Lu, J. Am. Chem. Soc. 2017, 139,
15316−15319.
Development Centre, and the Fundamental Research Funds for
the Central Universities (2019QNA3008). We thank Mr. Yufeng
Sun, Mr. Zhaoyang Cheng, Mr. Yihui Mao, and Mr. Jun Guo in
this research group for helpful discussion.
[14] a) J. Guo, Z. Lu, Angew. Chem. Int. Ed. 2016, 55, 10835−10838; b) T.
Xi, Z. Lu, J. Org. Chem. 2016, 81, 8858–8866; c) T. Xi, Z. Lu, ACS Catal.
2017, 7, 1181−1185; d) J. Guo, X. Shen, Z. Lu, Angew. Chem. Int. Ed.
2017, 56, 615−618; e) J. Guo, H. Wang, S. Xing, X. Hong, Z. Lu, Chem
2019, 5, 881−895; f) Z. Cheng, S. Xing, J. Guo, B. Cheng, L.-F. Hu, X.-
H. Zhang, Z. Lu, Chin. J. Chem. 2019, 37, 457−461; g) J. Chen, X. Shen,
Z. Lu, J. Am. Chem. Soc. 2020, 142, 14455−14460.
Keywords: cobalt catalysis • hydroboration • terminal alkyne •
metal hydride species • branched alkenyl boronates
[15] V. Jayaram, T. Sridhar, G. V. M. Sharma, F. Berrꢂe, B. Carboni, J. Org.
Chem. 2018, 83, 843−853.
[1]
[2]
a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457−2483; b) S. Kotha,
K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633−9695; c) J. Yun,
Asian J. Org. Chem. 2013, 2, 1016–1025; d) R. Barbeyron, E. Benedetti,
J. Cossy, J.-J. Vasseur, S. Arseniyadis, M. Smietana, Tetrahedron 2014,
70, 8431−8452; e) H. Yoshida, ACS Catal. 2016, 6, 1799−1811; f) J.
Carreras, A. Caballero, P. J. Pérez, Chem. Asian J. 2019, 14, 329−343.
For selected transformations where alkenyl metallic reagents are used in
synthesis of α-alkenyl boronates, see: a) C. Morrill, T. W. Funk, R. H.
Grubbs, Tetrahedron Lett. 2004, 45, 7733−7736; b) W. J. Moran, J. P.
Morken, Org. Lett. 2006, 8, 2413−2415; c) F. Gao, A. H. Hoveyda, J. Am.
Chem. Soc. 2010, 132, 10961−10963; For selected transformations
where alkenyl metallic reagents are used in synthesis of β-alkenyl
boronates, see: d) Boronic Acids: Preparation and Applications in
Organic Synthesis Medicine and Materials, 2nd ed. (Ed.: D. G. Hall),
Wiley-VCH, 2011, pp. 45–60; e) C. Morrill, R. H. Grubbs, J. Org. Chem.
[16] T.-H. Shi, S. Tong, M.-X. Wang, Angew. Chem. Int. Ed. 2020, 59, 7700
−7705.
[17] a) R. P. Yu, D. Hesk, N. Rivera, I. Pelczer, P. J. Chirik, Nature 2016, 529,
195−199; b) J.-F. Chen, C. Li, ACS Catal. 2020, 10, 3881−3889.
[18] CCDC number of L6: 2026860; CCDC number of L6.CoBr: 2026489.
[19] a) C. H. Jun, R. H. Crabtree, J. Organomet. Chem. 1993, 447, 177−187;
b) I. Ojima, N. Clos, R. J. Donovan, P. Ingallina, Organometallics 1990,
9, 3127−3133.
This article is protected by copyright. All rights reserved.

10.1002/anie.202012164
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Jieping Chen+, Xuzhong Shen+, and
Zhan Lu*
Page No. – Page No.
Cobalt-Catalyzed
Markovnikov-
type Selective Hydroboration of
Terminal Alkynes
A cobalt-hydride catalyst has been developed to promote Markovnikov-type selective insertion of the terminal alkyne to access
branched alkenyl boronates. This method exhibits high atom economy and broad substrate scope with excellent functional group
tolerance.
This article is protected by copyright. All rights reserved.