Nickel-Catalyzed Reductive 1,2-Dialkynylation of Alkenes Bearing an 8-Aminoquinoline Directing Group

Article abstract of DOI:10.1021/acs.orglett.9b03147

An unprecedented nickel-catalyzed reductive 1,2-dialkynylation of alkenes bearing an 8-aminoquinoline directing group has been developed. This method proceeded through a migratory insertion/reductive-coupling process under mild conditions with a wide substrate scope and good functional group tolerance, providing direct access to the synthetically flexible 1,5-diynes. Moreover, the 1,2-dialkynylation products could be further converted to borate-ester- or azide-functionalized 1,5-dienes, ditriazole, β-diyne primary amide, and trisubstituted benzene.

Full text of DOI:10.1021/acs.orglett.9b03147

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Reductive 1,2-Dialkynylation of Alkenes Bearing an
8‑Aminoquinoline Directing Group
Rui Pan, Cong Shi, Dongquan Zhang, Yang Tian, Songjin Guo, Hequan Yao,* and Aijun Lin*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: An unprecedented nickel-catalyzed reductive
1,2-dialkynylation of alkenes bearing an 8-aminoquinoline
directing group has been developed. This method proceeded
through a migratory insertion/reductive-coupling process
under mild conditions with a wide substrate scope and good
functional group tolerance, providing direct access to the
synthetically flexible 1,5-diynes. Moreover, the 1,2-dialkynyla-
tion products could be further converted to borate-ester- or
azide-functionalized 1,5-dienes, ditriazole, β-diyne primary amide, and trisubstituted benzene.
a b
,
Table 1. Effect of Reaction Parameters
lkynes are fundamental structural motifs present in
Anumerous natural products, pharmaceuticals, and func-
a
b
entry
1
2
3
4
5
6
7
8
deviation of standard conditions
yield (%)
none
93
n.d.
17
75
84
51
73
65
40
84
86
33
60
48
n.r.
c
DG B−F instead of DG A
DG G instead of DG A
NiCl2(dme) instead of NiI2
NiBr2(dme) instead of NiI2
Ni(acac)2 instead of NiI2
Ni(OAc)2·4H2O instead of NiI2
THF instead of DMF
DME instead of DMF
DMA instead of DMF
MeCN instead of DMF
DMSO instead of DMF
Zn instead of Mn
9
10
11
12
13
14
Figure 1. Nickel-catalyzed reductive dicarbofunctionalization of
alkenes.
Mg instead of Mn
No NiI2
d
15
tional materials.1 Meanwhile, they also serve as highly versatile
functional groups in synthetic transformation.2 Therefore,
tremendous contributions have been made for the incorporation
of the alkynyl group into organic molecules.3 Furthermore, the
class of diyne compounds exhibits special reactivity patterns that
are frequently employed as important synthons to construct
diverse sophisticated and valuable structures including poly-
substituted heterocyclic/aromatic rings, fused/spiro polycyclic
compounds, and macromolecular polymers.4,5 However,
compared with their broad applications in organic chemistry,
efficient synthetic methods to access diynes are relatively
circumscribed.6
a
Standard reaction conditions: NiI2 (10.0 mol %), 1 (0.2 mmol), 2
(1.0 mmol), Mn (0.6 mmol), DMF (1.0 mL), 25 °C, 72 h, under
argon. Isolated yields. n.d. = not detected. n.r. = no reaction.
b
c
d
community, as it represents a powerful tool to access
functionalized and complex structures from simple alkenes
with two C−C bonds forming in high efficiency.7 Recently, the
Over the past few decades, the transition-metal-catalyzed
dicarbofunctionalization of alkenes has flourished in the organic
Received: September 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03147
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 1. Substrate Scope
a
b
Reaction conditions: NiI2(10.0 mol %), alkene (0.2 mmol), alkyne (1.0 mmol) and Mn (3.0 equiv), DMF (1.0 mL) as solvent, 25 °C. Isolated
c
d
e
f
g
h
yields. 40 °C. NiI2 (20.0 mol %). MeCN (1.0 mL) as solvent. 100 h. THF (1.0 mL) as solvent. Zn (3.0 equiv) as reductant.
nickel-catalyzed reductive approach has gained increasing
concern, which directly uses two organohalide electrophiles as
functionalization reagents, avoiding the additional steps in the
preparation of sensitive organometallics or organic boronic
acids. It shows unique merits in step economy and functional
group tolerance. With this strategy, Nevado,8a,d Chu,8b and
Diao8c have, respectively, described the nickel-catalyzed three-
component reductive dicarbofunctionalization of alkenes to
achieve alkene alkylarylation, alkylacylation, and diarylation
(Figure 1a, top). The nickel-catalyzed reductive alkylarylation,
dialkylation, diarylation, and arylalkenylation of tethered alkenes
incorporated in organohalides have also been independently
realized by Peng,8e−h Diao,8i Kong,8j Wang,8k,l and Shu8m
(Figure 1a, bottom). Despite these elegant works, exploring the
novel nickel-catalyzed reductive dicarbofunctionalization of
alkenes to enrich the diversification of the introduced
B
DOI: 10.1021/acs.orglett.9b03147
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Organic Letters
Letter
Scheme 2. Further Studies of the Reaction
Scheme 3. Mechanistic Studies
a
Ni(tmhd)2, EtOH, 120 °C, 48 h; then TBAF (1 M in THF), Et2O,
b
rt, 1 h. BnN3, CuSO4·5H2O, sodium L-ascorbate, DMF, rt, 48 h.
c
d
TMSN3, Ag2CO3, H2O, DMSO, 80 °C, 1 h. HBpin, AgOAc,
e
toluene, 120 °C, 48 h. IBX, HFIP/H2O, 60 °C, air atmosphere.
f
Ni(tmhd)2, MeOH, 120 °C, 48 h; then Pd/C (10 wt %), B2(OH)4,
g
H2O, CH2Cl2, rt. NaOH, EtOH, 130 °C, 24 h; then 1 M HCl.
nylsilyl (TBDPS), t-butyldimethylsilyl (TBS), triphenylsiyl, and
triethylsilyl (TES), the corresponding products 4−7 could be
isolated in 63−92% yield (Scheme 1a). To exhibit the
robustness and generality of this reaction, we explored a wide
range of aryl-substituted bromoalkynes (Scheme 1b). These
transformations proceeded smoothly when halogen and
electron-donating groups were installed on the phenyl unit
(9−13). Good tolerance of functional groups including
acylamino, nitro, cyano, methylsulfonyl, acetyl, and ester was
observed in products 13−17, 19, and 20. The alkynyl bearing
para-trifluoromethyl in the phenyl moiety produced 18 in 87%
yield, and its relative configuration was confirmed by X-ray
crystal structure analysis (see the SI for details). The aryl-
substituted bromoalkynes with ortho or meta substituents
delivered the products 21−26 in 60−73% yield. Notably,
substituents on the C−C triple bond could be other aryl groups
such as naphthyl, benzofuryl, and thienyl, and these alkynylating
reagents generated the corresponding products 27−29 in
moderate to good yield. In addition, alkyl-substituted
bromoalkynes could also be adaptable in this transformation,
as illustrated by the formation of 30 and 31 (Scheme 1b).
Subsequently, the compatibility of alkene for this reaction was
investigated (Scheme 1c). The alkenes bearing monosubstitu-
tion at the α-position and disubstitution at the β-position were
well tolerated and afforded the products 32 and 33 in 68 and
61% yield, respectively. Moreover, three other types of alkenes,
including internal alkene (34), β,γ-terminal alkene (35), and
aryl-substituted alkenes (36−40) turned out to be successful
substrates for this transformation.
functionality is still highly desirable, which could ulteriorly
enhance the applicability of this method. As our sustained focus
on the field of alkene functionalization,9 we herein describe a
nickel-catalyzed reductive 1,2-dialkynylation of alkenes bearing
an 8-aminoquinoline directing group to produce synthetically
attractive 1,5-diyne compounds with double C(sp)−C(sp3)
bond formation for the first time (Figure 1b).
We initiated our study by identifying reliable conditions for
this nickel-catalyzed reductive alkene dialkynylation reaction.
After considerable screening of the reaction parameters (see the
Supporting Information (SI) for details), the desired product 3
was obtained in 93% yield with 10.0 mol % NiI2 as the catalyst,
DG A as the directing group, and 3.0 equiv Mn as the reducing
agent in DMF at 25 °C (Table 1, entry 1). The choice of DG A as
the directing group was essential for the dialkynylation process.
When alkenes bearing DG B−G were subjected to the optimized
conditions, only DG G could promote the transformation in
17% yield (Table 1, entries 2 and 3). Other nickel catalysts
performed this reaction with less efficiency (Table 1, entries 4−
7). Conducting the reaction in THF, DME, DMA, MeCN, and
DMSO led to 40−86% yield (Table 1, entries 8−12). When Zn
or Mg was used as the reductant, product 3 was obtained in
diminished yield (Table 1, entries 13 and 14). Without the
nickel catalyst, no reaction occurred (Table 1, entry 15).
Having optimized the reaction conditions, we then focused on
the substrate scope of this nickel-catalyzed reductive 1,2-
dialkynylation of alkenes with respect to bromoalkynes (Scheme
1a,b). We were pleased to find that by converting the TIPS
protecting group into other silyl groups, such as t-butyldiphe-
To demonstrate the synthetic utility of this reaction, a gram-
scale experiment (Scheme 2a) and further transformations of
C
DOI: 10.1021/acs.orglett.9b03147
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Organic Letters
Letter
Scheme 4. Proposed Mechanism
the dialkynylation products (Scheme 2b) were carried out.
When the reaction was tested on a 4.0 mmol scale, product 3
(2.16 g) could be obtained in 92% yield under the standard
conditions. The terminal 1,5-diyne compound 41 was achieved
in 82% yield through the sequential ethanolysis of aminoquino-
line amide and the deprotection of TIPS of product 3. Moreover,
compound 41 could be further decorated via click cycloaddition
to access ditriazole compound 42, which has a potential
application in the synthesis of metal−organic frameworks and
metal complexes.10 The silver-catalyzed hydroazidation and
hydroboration of compound 41 could afford the azide- or
borate-ester-functionalized 1,5-diene compounds 43 and 44
with good efficiency. Furthermore, the quinoline group could be
easily removed, producing β-diyne primary amide compound 45
in 86% yield by 2-iodoxybenzoic acid (IBX) oxidation. A
palladium-catalyzed hydrogenation reaction efficiently con-
verted product 8 to the corresponding alkane 46. When we
treated product 8 with NaOH in EtOH at 130 °C, a Bergman-
cyclization-type product 47 was obtained in 74% yield, which
has been confirmed by X-ray analysis (see the SI for details).
To provide insight into the mechanism of this nickel-catalyzed
reductive dialkynylation, a series of control experiments were
designed and performed. Adding 1.0 equiv of TEMPO to the
standard reaction system, the reaction was completely shut
down with 98% recovery of substrate 1 (Scheme 3a).
Considering that TEMPO could serve to poison the Ni catalyst,
the inhibition of this reaction cannot necessarily be taken as
proper evidence in favor of the radical process.11 In contrast, the
reaction could go smoothly in the presence of other radical
scavengers (Scheme 3a). These results (Scheme 3a) indicated
that a radical process might not be involved. With the
employment of tetrakis(dimethylamino)ethylene (TDAE) as
an organic reductant instead of Mn, product 3 could be obtained
in 70% yield (Scheme 3b). In addition, when bromoalkyne S6
was subjected to react with equivalent Mn (Scheme 3c), 92% of
S6 was recovered, and the hydrodebrominated terminal alkyne
was not detected. Taking these results (Scheme 3b,c) into
consideration, the formation of alkynylmanganese intermediate
could be ruled out. Moreover, the addition of 1-chloro-2,4-
dinitrobenzene, a single electron transfer (SET) inhibitor,12 led
to an obvious retardation of the transformation under the
standard conditions (Scheme 3d). This result revealed a
plausible catalytic cycle involving the SET processes, capable
of reducing the oxidized Ni intermediates with Mn. Then, the
sequential stoichiometric reaction of substrates 1 and 2 with
equivalent Ni(COD)2 was performed (Scheme 3e). After
quenching the reaction with water, reductive Heck byproduct
48 and product 3 were isolated in 28 and 33% yield with 32%
recovery of 1 (Scheme 3e). Compound 48 might be produced
from the migratory insertion of alkynyl−NiII species into the γ-
position of 1 and the subsequent protonation process (Scheme
3e). Besides, even in the absence of reductants, this
stoichiometric reaction could also furnish the dialkynylation
product 3 in an appreciable yield. This result demonstrated the
existence of another plausible catalytic cycle that required Mn in
the initial step of reducing NiII to Ni0 into the catalytic chain
rather than the subsequent intermediate reduction. In the radical
clock experiment (Scheme 3f), only the 1,2-dialkynylation
product 50 was obtained, whereas the ring-opening product was
not observed. This result could exclude the existence of the C-
center radical generated by homolytic Ni−alkyl bond cleavage
after the migratory insertion process.
On the basis of the aforementioned experimental results and
previous literature,3j,u,8,13,14 two possible catalytic cycles
involved in this transformation are depicted in Scheme 4 using
alkene 1 and bromoalkyne 2 as the examples. Initially, a Ni0
species I is generated under the reductive conditions, which
undergoes oxidative addition with bromoalkyne to afford the
NiII species II. After migratory insertion, an alkyl−NiII complex
III is formed, which could generate the byproduct 48 if
protonation occurs (Scheme 3e). In plausible pathway A, the
alkyl−NiI complex IV, which is generated from the reduction of
intermediate III, would go through a second oxidative addition
of bromoalkyne 2 to achieve the NiIII complex V. The reductive
elimination of the intermediate V furnishes the NiI species VI,
which undergoes a subsequent reduction and ligand exchange to
offer product 3 and regenerate the Ni0 species I to the next
catalytic cycle. In plausible pathway B, the intermediate III
would continue the transmetalation with an alkynyl−NiII species
D
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to form NiII complex VII. After the reductive elimination and
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In conclusion, we have developed a nickel-catalyzed reductive
1,2-dialkynylation of alkenes using 8-aminoquinoline as the
directing group under mild conditions with sequential formation
of two C(sp)−C(sp3) bonds. This reaction provided an efficient
method to access diverse synthetically flexible 1,5-diynes. The
more detailed mechanistic investigations of this reaction as well
as the further expansion of the nickel-catalyzed reductive
difunctionalization of alkene with novel electrophiles are
currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03147.
Experiment procedures, detailed reaction optimization,
compound characterization, and NMR spectra (PDF)
Accession Codes
CCDC 1936009 and 1940841 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
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Tellado, F. Acc. Chem. Res. 2016, 49, 703−713. (d) Xuan, J.; Studer, A.
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■
*E-mail: hyao@cpu.edu.cn (H.Y.).
*E-mail: ajlin@cpu.edu.cn (A.L.).
ORCID
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Hequan Yao: 0000-0003-4865-820X
Aijun Lin: 0000-0001-5786-4537
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge generous financial support from the National
Natural Science Foundation of China (NSFC21572272), the
Foundation of The Open Project of State Key Laboratory of
Natural Medicines (SKLNMZZCX201818), and the Innova-
tion Team of “the Double-First Class” Disciplines
(CPU2018GY35 and CPU2018GY04).
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DOI: 10.1021/acs.orglett.9b03147
Org. Lett. XXXX, XXX, XXX−XXX