Reductive hydrobenzylation of terminal alkynesviaphotoredox and nickel dual catalysis

Article abstract of DOI:10.1039/d1cc03668h

A photoredox/nickel dual catalyzed reductive hydrobenzylation of alkynes and benzyl chlorides by employing alkyl amines as a stoichiometric reductant is described. This synergistic protocol proceedsviaMarkovnikov-selective migratory insertion of an alkyne into nickel hydride, followed by cross-coupling with benzyl chloride, providing facile access to important 1,1-disubstituted olefins. This reaction enables the generation of nickel hydride by utilizing readily available alkyl amines as the hydrogen source. The mild conditions are compatible with a wide range of aryl and alkyl alkynes as well as chlorides.

Full text of DOI:10.1039/d1cc03668h

ChemComm
View Article Online
View Journal
COMMUNICATION
Reductive hydrobenzylation of terminal alkynes
via photoredox and nickel dual catalysis†
Cite this: DOI: 10.1039/d1cc03668h
ab
a
Xian Zhao,a Shengqing Zhu,a Feng-Ling Qing
and Lingling Chu
*
Received 8th July 2021,
Accepted 12th August 2021
DOI: 10.1039/d1cc03668h
rsc.li/chemcomm
A photoredox/nickel dual catalyzed reductive hydrobenzylation of alkenes, which are prevalent in biologically active compounds,8 have
alkynes and benzyl chlorides by employing alkyl amines as a stoichio- been disclosed (Fig. 1).
metric reductant is described. This synergistic protocol proceeds via
In 2016, Fu and co-workers reported the first example of
Markovnikov-selective migratory insertion of an alkyne into nickel nickel-catalysed9 hydroalkylation of terminal alkynes with alkyl
hydride, followed by cross-coupling with benzyl chloride, providing iodides in the presence of silanes, affording 1,1-dialkyl alkenes
facile access to important 1,1-disubstituted olefins. This reaction enables with excellent Markovnikov selectivity.7a Migratory insertion of
the generation of nickel hydride by utilizing readily available alkyl amines Ni–H into alkynes deters the regioselectivity, while the use
as the hydrogen source. The mild conditions are compatible with a wide of highly reactive iodides is required to facilitate the subse-
range of aryl and alkyl alkynes as well as chlorides.
quent alkyl coupling. Additionally, silanes are typically
employed as the stoichiometric reductants in these metal
Alkenes are ubiquitous in chemical synthesis, not only as hydride-enabled hydroalkylation reactions.7,8 It would be inter-
important structural motifs in pharmaceuticals, agrochemicals, esting to explore simple and abundant agents as the hydrogen
and natural products,1 but also as versatile building blocks for source of metal hydride.7c,10 Following our continuous interest
numerous valuable transformations.2 Therefore, the develop- in the area of photoredox/nickel dual catalysis,11,12 we herein
ment of efficient methodologies for their synthesis has been report a photoredox/Ni-catalyzed reductive hydroalkylation of
extensively pursued. Among various synthetic strategies,3
transition-metal-catalyzed hydrofunctionalization of simple
and readily accessible alkynes represents one of the most
efficient methods to synthesize substituted alkenes.4 Impress-
ive progress has been achieved in hydroarylation of alkynes;5
nonetheless, catalytic hydroalkylation of alkynes remains
underexplored and is highly sought after.
Migratory insertion of alkynes into metal hydride bonds followed
by alkyl couplings represents an efficient approach for the catalytic
hydroalkylation of terminal alkynes.6,7 Notably, the Lalic group has
developed a series of Cu–H enabled hydroalkylations of terminal
alkynes with various alkyl electrophiles, allowing for the regio- and
stereo-selective preparation of diverse alkenes.6a,b,f,g Despite impress-
ive progress, these precedents are known to furnish 1,2-disubstituted
alkenes with anti-Markovnikov selectivity, and rare examples of
Markovnikov hydroalkylation of alkynes to forge 1,1-disubstituted
a State Key Laboratory for Modification of Chemical Fibers and Polymer Materials,
College of Chemistry, Chemical Engineering and Biotechnology, Center for
Advanced Low-Dimension Materials, Donghua University, Shanghai 201620,
China. E-mail: Lingling.chu1@dhu.edu.cn
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, Shanghai 200032, China
Fig. 1 Metal hydride-enabled reductive hydroalkylation of alkynes.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1cc03668h
This journal is © The Royal Society of Chemistry 2021
Chem. Commun.

View Article Online
Communication
ChemComm
terminal alkynes and readily available benzylic chlorides with
We began our investigations by exploring the reductive
alkyl amine as the reductant, furnishing 1,1-disubstituted hydroalkylation of aryl alkyne 1 with benzylic chloride 2
alkenes with Markovnikov selectivity. This photochemical (see Tables S1–S6 in the ESI†). After careful optimizations, we
reductive protocol enables the generation of nickel hydride found that a combination of Ir[dF(CF3)(ppy)2](Phen)PF6, Ni(acac)2,
from simple alkyl amines.13 It should be noted that several 4,40-di-tert-butyl-2,20-bipyridine (dtbbpy), 1-ethylpiperidine as the
examples of photoredox/nickel catalyzed hydroalkylations of reductant, and difluoroacetic acid (HCF2CO2H) as the additive,
alkynes with alkyl carboxylic acids or oximes have been pre- with irradiation of the reaction mixture in DMAc with a 90 W Blue
viously disclosed, where migratory insertion of Ni–alkyl species LED at 35 1C provided the optimal results, leading to the formation
is proposed.7d,14
of the branched-selective product 3 in 93% isolated yield. Control
Scheme 1 Substrate scopes. Reaction conditions: Ir[dF(CF3)(ppy)2](Phen)(PF6) (1 mol%), Ni(acac)2 (10 mol%), dtbbpy (13 mol%), alkynes (0.2 mmol),
benzyl chlorides (1.3 equiv.), HCF2CO2H (2.0 equiv.), 1-ethylpiperidine (3.0 equiv.), DMAc [0.025 M], 35 1C, 24 h. 90 W blue LEDs. Isolated yields.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2021

View Article Online
ChemComm
Communication
reactions in the absence of photocatalyst, nickel catalyst, reduc- Adamantane and Borneol also proved to be suitable coupling
tant, acid, or light disclosed that all these reaction parameters were partners (40–41, 68–93%).
required for this transformation to proceed, while a low yield of
alkene 3 was still observed in the absence of ligand.
To probe the possible reaction pathway, several preliminary
mechanistic studies have been performed (Scheme 2).
The use of 1-ethylpiperidine as the stoichiometric reductant The addition of radical inhibitor TEMPO to the template
proved to be optimal, since switching to other commonly employed reaction didn’t shut down the productive reactivity; 34% of
alkyl amines (triethylamine, diisopropylethylamine, etc.) resulted in product 3 was still obtained in the presence of 3 equivalents
significant decreases in reaction efficiency. Similar to previous of TEMPO (Scheme 2A). These results, together with the for-
reports,15 we also found that an acidic additive has an intriguing mation of the cyclopropyl retained product 26 in the case of
effect on this transformation, where difluoroacetic acid gave much cyclopropyl acetylene (Scheme 1), suggested that this hydroalk-
higher yields than trifluoroacetic acid and formic acid.
ylation reaction might not involve a radical intermediate.
With the optimized reaction conditions in hand, we next turned On the other hand, control reactions without benzyl chlorides
our attention to exploring the generality of this photochemical led to the formation of styrene 42 and 1,3-diene 43 (Scheme 2B).
hydroalkylation protocol. As depicted in Scheme 1, a wide range of We surmised that Ni–H species could be involved,10a and the
terminal aryl alkynes bearing electron-donating, -withdrawing, and formation of 1,3-diene 43 could proceed via migratory insertion
-neutral substituents could participate well in this synergistic of alkyne into the Ni–H bond followed by dimerization of vinyl
protocol, generating the desired a-benzylic alkenes with exclusive nickel. To further unravel the hydrogen source of Ni–H species,
Markovnikov selectivity (3–16, 50–99%). The mild condition is deuteration experiments were performed. In the presence of
compatible with a series of functional groups, including esters, deuterium-labeled DCO2D, the reaction of alkyne 1 and
trifluoromethylates, boronate esters, and halides, offering useful benzylic chloride led to 10% of product 3 together with 14%
handles for further synthetic manipulations (7–10 and 12–13, of 1,3-diene 43, without the observation of the deuterium-
15–16, 50–98%). Steric hindrance of alkynes showed little impact labeled product 3-D1 (Scheme 2C). These results indicated that
on the reaction efficiency, and alkynes with ortho-substituents all alkyl amines other than acids might be the hydrogen source for
reacted smoothly with high efficiency (14–16, 62–91%). Heteroaryl Ni–H species in this photochemical reaction.
alkynes, such as thiophenyl and indolyl proved to be viable sub-
Although elucidation of a detailed mechanism requires further
strates, delivering the corresponding heteroaryl-substituted alkenes studies, we have proposed a plausible reaction pathway for this
with moderate yields (17–19, 60–73%). Besides (hetero)aryl alkynes, photoredox/nickel catalyzed hydroalkylation of alkynes based on
terminal aliphatic alkynes also were competent substrates in this these mechanistic studies. As shown in Scheme S1 in the ESI,†
reductive hydroalkylation system (20–26, 63–97%). Aliphatic alkynes upon irradiation with visible light, the photoexcited catalyst *IrIII
tethered with esters, ethers, and free alcohols were all well-tolerated, (E1/2*
III/II = +1.39 V vs. SCE)16 undergoes a single-electron transfer (SET)
further demonstrating the robust compatibility of this protocol event with alkylamine(EP/2 = +1.1 V vs. SCE)17 to form the reducing
(20–25, 63–97%). The reaction of cyclopropyl acetylene afforded photocatalyst IrII as well as amino radical cation A (see Section 6 in
the cyclopropyl retained adduct 26 in 72% yield. Furthermore, we the ESI† for fluorescence quenching studies, determination of the
found that cyclohexylene-incorporated alkyne was a viable coupling fluorescence quantum yield, and light-on/light-off experiments). The
partner, furnishing 1,3-diene product 27 with moderate efficiency. latter one A undergoes a deprotonation to give amino radical B,
It should be noted that internal arylalkynes were applicable which then is trapped by Ni(0) C to afford alkyl–NiI species D.
substrates, albeit with poor selectivity (see Scheme S2 in the ESI†), Subsequent rapid b-hydride elimination of alkyl–NiI D releases Ni–H
whilst (trimethylsilyl)acetylene was not a suitable substrate for species E. At this juncture, migratory insertion of Ni–H E into the
this reaction.
Next, we examined the scope of benzylic chlorides under the
optimal conditions (Scheme 1). A wide range of benzylic chlorides
incorporated with para- and/or meta-substituents such as alkyl,
ethers, esters, and halides, were suitable coupling partners, furnish-
ing the a-benzyl alkenes with exclusive Markovnikov selectivity and
moderate to high efficiency (28–35, 46–90%). Nonetheless, neither
secondary benzyl chlorides nor nonactivated alkyl chlorides worked
in this protocol (see Scheme S3 in the ESI†).
To further demonstrate the synthetic utility of this photoredox/
nickel reductive hydroalkylation protocol, we have examined several
complex molecules derived from biologically active drugs and
natural products. As illustrated in Scheme 1, alkyne derivatives of
estrone, ibuprofen (anti-inflammatory drug), Febuxostat (xanthine
oxidase inhibitor), and Tolmetin (anti-inflammatory drug) all under-
went selective coupling with benzylic chlorides, furnishing the
corresponding substituted alkenes with moderate to high efficiency
Scheme 2 Mechanism studies.
(36–39, 75–81%). Furthermore, benzylic chlorides derived from
This journal is © The Royal Society of Chemistry 2021
Chem. Commun.

View Article Online
Communication
ChemComm
alkyne via Markovnikov selectivity gives branched vinyl–NiI species F,
which undergoes oxidative addition with benzyl chloride to form
(vinyl)(benzyl)NiIII species G. Subsequent reductive elimination of G
would produce the alkene product as well as NiI species H. Another
SET event between the reducing IrII {E1/2III/II = ꢀ1.25 V vs. SCE }16 and
NiI H {E1/2[NiII/Ni0 = ꢀ1.2 V vs. SCE]}18 regenerates the ground state
photocatalyst IrIII and Ni(0) to close the two catalytic cycles. Never-
theless, another potential reaction pathway, which proceeds via
selective insertion of benzyl–nickel species19 into alkynes followed
by protometallation, could not be ruled out. Compared with Jami-
son’s protocol which utilizes the electron-rich phosphine ligand to
facilitate the oxidative addition of benzylic chloride with Ni(0),19 the
generation of nickel hydride from alkyl amines seems to be favored
over that of nickel–benzyl in our dual photoredox/nickel reaction.
In summary, we have reported a dual photoredox and nickel
catalyzed Markovnikov selective hydrobenzylation of terminal
alkynes with benzyl chlorides, furnishing a wide array of
1,1-disubstituted alkenes with high efficiency and excellent
selectivity. Mechanistic studies suggest that the generation of
nickel hydride with alkyl amine as the hydrogen source could
be involved in this photochemical synergistic protocol.
G. Lalic, J. Am. Chem. Soc., 2017, 139, 6969–6977; (c) G. Xu,
H. Zhao, B. Fu, A. Cang, G. Zhang, Q. Zhang, T. Xiong and
Q. Zhang, Angew. Chem., Int. Ed., 2017, 56, 13130–13134;
(d) K. Nakamura and T. Nishikata, ACS Catal., 2017, 7,
1049–1052; (e) L.-J. Cheng, S. M. Islam and N. P. Mankad, J. Am.
Chem. Soc., 2018, 140, 1159–1164; ( f ) A. Hazra, J. Chen and
G. Lalic, J. Am. Chem. Soc., 2019, 141, 12464–12469; (g) A. Hazra,
J. A. Kephart, A. Velian and G. Lalic, J. Am. Chem. Soc., 2021, 143,
7903–7908.
7 (a) X.-Y. Lu, J.-H. Liu, X. Lu, Z.-Q. Zhang, T.-J. Gong, B. Xiao and
Y. Fu, Chem. Commun., 2016, 52, 5324–5327; (b) S. Yu, C. Wu and
S. Ge, J. Am. Chem. Soc., 2017, 139, 6526–6529; (c) H.-P. Deng,
X.-Z. Fan, Z.-H. Chen, Q.-H. Xu and J. Wu, J. Am. Chem. Soc., 2017,
139, 13579–13584; (d) S. Y. Go, G. S. Lee and S. H. Hong, Org.
´
Lett., 2018, 20, 4691–4694; (e) N. Cabrera-Lobera, P. Rodrıguez-
˜
´
Salamanca, J. C. Nieto-Carmona, E. Bunuel and D. J. Cardenas,
Chem. – Eur. J., 2018, 24, 784–788; ( f ) X.-Y. Lu, M.-L. Hong,
H.-P. Zhou, Y. Wang, J.-Y. Wang and X.-T. Ge, Chem. Commun.,
2018, 54, 4417–4420; (g) L. Yu, L. Lv, Z. Qiu, Z. Chen, Z. Tan,
Y.-F. Liang and C.-J. Li, Angew. Chem., Int. Ed., 2020, 59,
14009–14013; (h) X.-Y. Lu, C.-C. Liu, R.-C. Jiang, L.-Y. Yan,
Q.-L. Liu, Q.-Q. Wang and J.-M. Li, Chem. Commun., 2020, 56,
14191–14194.
8 (a) J. A. Miller and E.-i. Negishi, Tetrahedron Lett., 1984, 25,
5863–5866; (b) A. Sabarre and J. Love, Org. Lett., 2008, 10, 3941–3944.
9 For selected reviews on nickel catalysis, see: (a) J. Montgomery,
Angew. Chem., Int. Ed., 2004, 43, 3890–3908; (b) S. Z. Tasker,
E. A. Standley and T. F. Jamison, Nature, 2014, 509, 299–309;
(c) V. P. Ananikov, ACS Catal., 2015, 5, 1964–1971; (d) J. Choi and
G. C. Fu, Science, 2017, 356, eaaf7230; (e) L. Cheng and Q. Zhou, Acta
Chim. Sin., 2020, 78, 1017–1029.
10 (a) X. Wang, M. Nakajima, E. Serrano and R. Martin, J. Am. Chem.
Soc., 2016, 138, 15531–15534; (b) L.-J. Xiao, L. Cheng, W.-M. Feng,
M.-L. Li, J.-H. Xie and Q.-L. Zhou, Angew. Chem., Int. Ed., 2018, 57,
461–464; (c) Y. Zhang, X. Xu and S. Zhu, Nat. Commun., 2019,
10, 1752; (d) Y. He, C. Liu, L. Yu and S. Zhu, Angew. Chem., Int.
Ed., 2020, 59, 9186–9191.
We thank the National Natural Science Foundation of China
(21971036 and 21901036), the Shanghai Rising-Star Program
(20QA1400200), and the Fundamental Research Funds (CUSF-DH-
D-2019069) for the Central Universities for financial support.
Conflicts of interest
11 (a) Y.-Y. Gui, L. Sun, Z.-P. Lu and D.-G. Yu, Org. Chem. Front., 2016, 3,
522–526; (b) J. Twilton, C. Le, P. Zhang, M. H. Shaw, R. W. Evans and
D. W. C. MacMillan, Nat. Rev. Chem., 2017, 1, 0052; (c) J. A. Milligan,
J. P. Phelan, S. O. Badir and G. A. Molander, Angew. Chem., Int. Ed.,
2019, 58, 6152–6163; (d) C. Zhu, H. Yue, L. Chu and M. Rueping,
Chem. Sci., 2020, 11, 4051–4064.
12 (a) L. Guo, F. Song, S. Zhu, H. Li and L. Chu, Nat. Commun., 2018,
9, 4543; (b) L. Guo, H.-Y. Tu, S. Zhu and L. Chu, Org. Lett., 2019, 21,
4771–4776; (c) H. Li, L. Guo, X. Feng, L. Huo, S. Zhu and L. Chu,
Chem. Sci., 2020, 11, 4904–4910; (d) L. Guo, M. Yuan, Y. Zhang,
F. Wang, S. Zhu, O. Gutierrez and L. Chu, J. Am. Chem. Soc., 2020,
142, 20390–20399; (e) L. Xu, S. Q. Zhu, L. P. Huo, F. Chen, W. Yu and
L. L. Chu, Org. Chem. Front., 2021, 8, 2924–2931.
There are no conflicts to declare.
Notes and references
1 C. Oger, L. Balas, T. Durand and J.-M. Galano, Chem. Rev., 2013, 113,
1313–1350.
2 K. N. Campbell and L. T. Eby, J. Am. Chem. Soc., 1941, 63, 216–219.
3 (a) B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863–927;
(b) I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100,
3009–3066; (c) E.-i. Negishi, Z. Huang, G. Wang, S. Mohan, C. Wang
and H. Hattori, Acc. Chem. Res., 2008, 41, 1474–1485.
4 For selected reviews, see: (a) T. Kitamura, Eur. J. Org. Chem., 2009,
1111–1125; (b) Y. Yamamoto, Chem. Soc. Rev., 2014, 43, 1575–1600; 13 (a) Z. Duan, W. Li and A. Lei, Org. Lett., 2016, 18, 4012–4015;
(c) M. D. Greenhalgh, A. S. Jones and S. P. Thomas, ChemCatChem,
2015, 7, 190–222; (d) A. M. Suess and G. Lalic, Synlett, 2016,
1165–1174; (e) S. W. M. Crossley, C. Obradors, R. M. Martinez and
R. A. Shenvi, Chem. Rev., 2016, 116, 8912–9000; ( f ) G. Li, X. Huo,
X. Jiang and W. Zhang, Chem. Soc. Rev., 2020, 49, 2060–2118.
5 (a) C. Jia, D. Piao, J. Oyamada, W. Lu, T. Kitamura and Y. Fujiwara,
Science, 2000, 287, 1992–1995; (b) K. Gao, P.-S. Lee, T. Fujita and
N. Yoshikai, J. Am. Chem. Soc., 2010, 132, 12249–12251;
(c) D. J. Schipper, M. Hutchinson and K. Fagnou, J. Am. Chem. Soc.,
(b) A. Paul, M. D. Smith and A. K. Vannucci, J. Org. Chem., 2017,
82, 1996–2003; (c) L. Peng, Z. Li and G. Yin, Org. Lett., 2018, 20,
1880–1883; (d) J. Yi, S. O. Badir, L. M. Kammer, M. Ribagorda and
G. A. Molander, Org. Lett., 2019, 21, 3346–3351; (e) A. Dewanji,
R. F. Bu¨low and M. Rueping, Org. Lett., 2020, 22, 1611–1617;
( f ) H. Guan, Q. Zhang, P. J. Walsh and J. Mao, Angew. Chem., Int.
Ed., 2020, 59, 5172–5177; (g) Y.-L. Li, W.-D. Li, Z.-Y. Gu, J. Chen and
J.-B. Xia, ACS Catal., 2020, 10, 1528–1534; (h) W. Xu, P. Zheng and
T. Xu, Org. Lett., 2020, 22, 8643–8647.
2010, 132, 6910–6911; (d) Y. Hashimoto, K. Hirano, T. Satoh, F. Kakiuchi 14 (a) N. A. Till, R. T. Smith and D. W. C. MacMillan, J. Am. Chem. Soc.,
and M. Miura, Org. Lett., 2012, 14, 2058–2061; (e) B. Zhou, H. Chen and
C. Wang, J. Am. Chem. Soc., 2013, 135, 1264–1267; ( f ) X. Zhou, Y. Luo,
2018, 140, 5701–5705; (b) E. M. Dauncey, S. U. Dighe, J. J. Douglas
and D. Leonori, Chem. Sci., 2019, 10, 7728–7733.
L. Kong, Y. Xu, G. Zheng, Y. Lan and X. Li, ACS Catal., 2017, 7, 7296–7304; 15 (a) J. M. R. Narayanam, J. W. Tucker and C. R. J. Stephenson, J. Am.
(g) G. D. Kortman and K. L. Hull, ACS Catal., 2017, 7, 6220–6224;
(h) C. Blons, S. Mallet-Ladeira, A. Amgoune and D. Bourissou, Angew.
Chem. Soc., 2009, 131, 8756–8757; (b) J. Du, L. R. Espelt, I. A. Guzei
and T. P. Yoon, Chem. Sci., 2011, 2, 2115–2119.
Chem., Int. Ed., 2018, 57, 11732–11736; (i) M. K. Armstrong, 16 A. Singh, K. Teegardin, M. Kelly, K. S. Prasad, S. Krishnan and
M. B. Goodstein and G. Lalic, J. Am. Chem. Soc., 2018, 140, J. D. Weaver, J. Organomet. Chem., 2015, 776, 51–59.
10233–10241; ( j) H. J. Xu, Y. S. Kang, H. Shi, P. Zhang, Y. K. Chen, 17 Z. Luo, K. Imamura, Y. Shiota, K. Yoshizawa, Y. Hisaeda and
B. Zhang, Z. Q. Liu, J. Zhao, W. Y. Sun, J. Q. Yu and Y. Lu, J. Am. Chem. H. Shimakoshi, J. Org. Chem., 2021, 86, 5983–5990.
Soc., 2019, 141, 76–79; (k) D. Wang, B. Dong, Y. Wang, J. Qian, J. Zhu, 18 M. Durandetti, M. Devaud and J. Perichon, New J. Chem., 1996, 20,
Y. Zhao and Z. Shi, Nat. Commun., 2019, 10, 3539. 659–667.
6 (a) M. R. Uehling, A. M. Suess and G. Lalic, J. Am. Chem. Soc., 2015, 19 E. A. Standley and T. F. Jamison, J. Am. Chem. Soc., 2013, 135,
137, 1424–1427; (b) M. Mailig, A. Hazra, M. K. Armstrong and
1585–1592.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2021