Multi-Metal-Catalyzed Oxidative Radical Alkynylation with Terminal Alkynes: A New Strategy for C(sp3)-C(sp) Bond Formation

Article abstract of DOI:10.1021/jacs.8b02745

A new way for C(sp³)-C(sp) cross-coupling with terminal alkynes has been developed by using a multi-metal-catalyzed reaction strategy. Alkyl radicals generated from different approaches are able to couple with terminal alkynes by judicious selection of the catalyst combination. This reaction protocol offers an efficient alternative approach for the synthesis of substituted alkynes from terminal alkynes besides traditional Sonogashira coupling. Mechanistic studies have also been carried out to clarify the role of each metal catalyst in the radical alkynylation processes. The reactions were found to go through radical reaction pathways. Synergistic cooperation of the metal catalysts is the key for controlling the reaction selectivity of alkyl radicals toward C(sp³)-C(sp) bond formation.

Full text of DOI:10.1021/jacs.8b02745

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Multimetallic-Catalyzed Oxidative Radical Alkynylation with Termi-
nal Alkynes: A New Strategy for C(sp3)-C(sp) Bond Formation
Shan Tang, Yichang Liu, Xinlong Gao, Pan Wang, Pengfei Huang, and Aiwen Lei
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Apr 2018
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Multimetallic-Catalyzed Oxidative Radical Alkynylation with Termi-
nal Alkynes: A New Strategy for C(sp3)-C(sp) Bond Formation
Shan Tang,†,§ Yichang Liu,†,§ Xinlong Gao,† Pan Wang,† Pengfei Huang,† Aiwen Lei*,†,‡
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† College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan
430072, China
‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, P. R. China
ABSTRACT: A new way for C(sp3)-C(sp) cross-coupling with terminal alkynes has been developed by using a multimetal-
lic-catalyzed reaction strategy. Alkyl radicals generated from different approaches are able to couple with terminal al-
kynes by judicious selection of catalyst combination. This reaction protocol offers an efficient alternative approach for the
synthesis of substituted alkynes from terminal alkynes besides traditional Sonogashira coupling. Mechanistic studies have
also been carried out to clarify the role of each metal catalyst in the radical alkynylation processes. The reactions were
found to go through radical reaction pathways. Synergistic cooperation of the metal catalysts is the key for controlling the
reaction selectivity of alkyl radicals toward C(sp3)-C(sp) bond formation.
a) Sonogashira-type alkynylation with alkyl halides
INTRODUCTION
[Pd] or [Ni], [Cu]
ligand, base
Alkyl
X
+
Alkyl
Alkyl
R
R
H
R
Substituted alkynes are fundamental structure motifs,
which widely exist in natural products, bioactive mole-
cules and functional materials.1 They also serve as versa-
tile synthetic intermediates in organic transformations.
Over the past decades, transition-metal-catalyzed So-
nogashira coupling has been proven to be one of the most
efficient and reliable approaches for the synthesis of sub-
stituted alkynes.2 The Sonogashira coupling of aryl elec-
trophiles has been well established for the construction of
C(sp2)-C(sp) bonds. In contrast, Sonogashira coupling of
alkyl electrophiles for C(sp3)-C(sp) bond formation still
remains challenging. Fu and co-workers were pioneers in
the Pd/Cu co-catalyzed Sonogashira coupling with unac-
tivated primary halides3 and their protocol was extended
to unactivated secondary halides by the group of Glorius.4
Similarly, Hu and co-workers developed a Ni/Cu co-
catalyzed Sonogashira-type coupling with unactivated
primary halides5 and Liu et al. modified the reaction sys-
tem to be able to deal with secondary halides.6 More re-
cently, an ultraviolet light promoted metal-free reaction
protocol was developed by Li and co-workers to achieve
the Sonogashira-type coupling with alkyl halides.7 Obvi-
ously, the developed Sonogashira-type alkynylation for
C(sp3)-C(sp) bond formation largely relies on the cross-
coupling with alkyl halides (Scheme 1a).8 It is highly ap-
pealling to develop new reaction approaches to allow
C(sp3)-C(sp) cross-coupling with more alternatives.
or Ultraviolet light
strong base
b) Sonogashira-type alkynylation with unactivated alkanes
Cu(OTf)2, Ni(acac)2
AgOAc, dppb
Alkyl
H
H
R
+
DTBP, PhCl
R
R
7a, R = Me, 73%
7k, R = Me, 76%
7c, R = Cl, 71%
7q, 66%
7b, R = OMe, 91%
7j, R = n
C5H11
,
83%
7l, R = F, 61%
7m, R = Cl, 78%
7n, R = Br, 65%
7o, R = Ac, 50%
Alkyl
S
7r, Alkyl = nC5H11, 63%
7s, Alkyl = Cy, 86%
7e, 69%
7p
, R = COOMe, 65%
n
7t, n = 1, 52%
7u, n = 3, 44%
7w 47%
7v, 49%
[C(1):C(2):C(3) = 3:6:2]
c) Sonogashira-type alkynylation with various alkyl radicals
[Cu], [M], [Ag]
Alkyl
+
Alkyl
R
H
R
[Ox]
Sources of alkyl radicals
R1 R2
N
R1 R2
[O]
-N2
R'
O
CN
R1 R2
[O]
Alkyl
R'
NC
N
O
NC
OH
O
O
O
- CO
Alkyl
Me
Scheme 1. C(sp3)-C(sp) Cross-Coupling with Terminal
Alkyl
H
Alkynes
In 2016, our group developed a multimetallic-catalyzed
oxidative radical alkynylation of unactivated alkanes with
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terminal alkynes (Scheme 1b).9 By using a catalyst combi-
Page 2 of 9
lyl acetylene could furnish the desired product with a
1
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7
8
nation of Cu(OTf)2, Ni(acac)2 and AgOAc, in situ generat-
ed cyclohexyl radical could couple with p-tolylacetylene
to afford 7a in 73% yield. Good to high yields were
observed for both aryl and aliphatic terminal alkynes (7b-
7s). Cyclic alkanes could give single products (7t-7v)
while linear alkane afforded a mixture of regioisomers
(7w). Since a lot of alkyl radicals can be easily generated
under oxidative conditions, we envisioned a general
method for C(sp3)-C(sp) cross-coupling based on this
multimetallic catalyzed oxidative radical alkynylation
strategy (Scheme 1c). By judicious selection of the catalyst
combination, tetrahydrofuran methyl radicals, α-cyano
alkyl radicals, methyl radical and unactivated alkyl radi-
cals generated under oxidative conditions were all found
to be able to couple with terminal alkynes. Synergistic
cooperation of different metal catalysts was the key for
controlling the reaction selectivity of these alkyl radicals
towards C(sp3)–C(sp) bond formation. In this article, we
aim to report the reaction development for C(sp3)–C(sp)
cross-coupling of terminal alkynes with different alkyl
radical sources. Moreover, a comprehensive mechanistic
study has been conducted to understand this novel mul-
timetallic-catalyzed radical oxidative alkynylation reac-
tion protocol.
satisfactory yield (3m).
Scheme 2. Radical C(sp3)-C(sp) Cross-Coupling be-
tween 4-Penten-1-ol and Different Terminal Alkynesa
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aStandard conditions A: 1a (5.0 equiv), 2 (0.50 mmol), Cu(OTf)2 (15
mol%), CuOAc (15 mol%), Ni(acac)2 (15 mol%), Ag2O (7.5 mol%) and
DTBP (2.0 equiv), PhCF3 (6.0 mL), 130 oC, 4 h. Isolated yields are
RESULTS AND DISCUSSION
Oxidative alkynylation of tetrahydrofuran methyl
radicals. Propargyl tetrahydrofurans can serve as useful
intermediates in the synthesis of some bioactive products
and materials.10 Chemler and co-workers reported that
tetrahydrofuran methyl radicals could be generated from
4-penten-1-ol derivatives under copper-catalyzed oxida-
tive conditions.11 We envisioned the synthesis of propar-
gylic tetrahydrofurans through a cascade oxidative cy-
clization/C(sp3)-C(sp) cross-coupling between 4-penten-1-
ol derivatives and terminal alkynes (eq. 1).
b
shown. PhCl (6.0 mL) was used instead of PhCF3 (6.0 mL), and
DTBP (4.0 equiv) was used. c The yield was determined by NMR with
CH2Br2 as the internal standard.
In the next step, different alkenols were applied as sub-
strates under the standard conditions (Scheme 3). Various
primary alcohols were suitable in this transformation,
which furnished the desired products in good to high
yields (3n-3u). It was worthy of noting that this transfor-
mation was applicable to the synthesis of spiro-bicyclic
heterocycles with high reaction efficiency. With the in-
crease of the substituted ring size, the reaction yields
grew by 80% to 94% (3q-3t). In addition, the oxidative
cyclization proceeded through a 6-exo-trig fashion to af-
ford propargyl tetrahydropyran 3u when 5-hexen-1-ol was
utilized as the substrate. Under slightly modified reaction
conditions, secondary and tertiary alkenols were also able
to furnish the desired products, accessing bridged-bicyclic
and spiro-bicyclic heterocycles (3v-3y). Internal alkenols
were not suitable substrates at this moment.
Based on the multimetallic catalyzed oxidative radical
alkynylation strategy, we found that 4-penten-1-ol with p-
tolylacetylene could furnish propargylic tetrahydrofuran
3a in 70% isolated yield by using Cu(OTf)2, CuOAc,
Ni(acac)2 and Ag2O as combined catalysts (Effect of reac-
tion parameters was shown in Table S1, Supporting In-
formation). The scope of terminal alkynes was then stud-
ied (Scheme 2). Phenylacetylenes bearing electron-
donating, electron-withdrawing and halide substituents
were all suitable (3b-3f). Due to the fast homo-coupling of
Scheme 3. Radical C(sp3)-C(sp) Cross-Coupling be-
tween Different Alkenols and p-Tolylacetylenea
the
methoxyphenylacetylene only gave a 54% isolated yield
(3c). Other aromatic alkynes such as 2–
alkyne
substrate,
electron-rich
4-
ethynylnaphthalene and 2–ethynylthiophene were also
able to furnish the desired products with decreased reac-
tion yields (3g and 3h). Aliphatic alkynes also showed
good reactivity in the synthesis of propargylic tetrahydro-
furans (3i-3l). It was worthy of noting that triisopropylsi-
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a Standard conditions A: 1 (5.0 equiv), 2a (0.50 mmol), Cu(OTf)2 (15
mol%), CuOAc (15 mol%), Ni(acac)2 (15 mol%), Ag2O (7.5 mol%) and
DTBP (2.0 equiv), PhCF3 (6.0 mL), 130 oC, 4 h. Isolated yields are
aStandard conditions B: AIBN (1.2 equiv), 2 (0.50 mmol), Cu(OTf)2
(7.5 mol%), CuI (7.5 mol%), Fe(acac)2 (7.5 mol%), AgF (10 mol%),
DTBP (5.0 equiv), DCE (1.0 mL), PhCF3 (1.0 mL), 80 oC, 12 h. Isolated
yields are shown. b DCE (2.5 mL) and PhCl (2.5 mL) were used.
b
shown. AgOAc (15 mol%) was used instead of Ag2O, DTBP (3.0
c
equiv) and PhCF3 (2.5 mL) were used. DTBP (6.0 equiv) and PhCF3
(2.5 mL) were used.
Oxidative alkynylation of methyl radical. Methyla-
tion is a fundamental transformation in organic chemistry.
Recently, peroxides have been recognized as efficient
methylation reagents since they can generate methyl rad-
ical during decomposition process.13 Thus, peroxides
might be used to achieve the direct methylation of termi-
nal alkynes through our multimetallic catalyzed radical
alkynylation protocol (eq. 3).
Oxidative alkynylation of α-cyano alkyl radicals.
2,2-Azobisisobutyronitrile (AIBN) is one of the most
widely used and commercially available radical initiators
in organic synthetic chemistry and polymer chemistry.
AIBN and its analogues are known to generate α-cyano
alkyl radicals under mild conditions.12 We herein illus-
trate a novel way for the synthesis of propargylic nitriles
from the direct coupling between AIBN and terminal al-
kynes (eq. 2).
-methyl
cleavage
H
R
Me
Me
R
(3)
O
O
After certain degree of optimization, we found that a
catalyst combination of Cu(OTf)2, CuI, Fe(acac)2 and AgF
could efficiently facilitate the C(sp3)-C(sp) cross-coupling
between isobutyronitrile radical and terminal alkynes
(Scheme 4). Effect of the reaction parameters was studied
to understand the role of the four different transition
metal catalysts (See Table S2, Supporting Information for
details). Phenylacetylenes bearing electron-neutral sub-
stituents such as methyl group, chloride and phenyl
groups gave the desired products in similar yields (4a-4d).
Electron-rich 4-methoxyphenylacetylene also showed
similar reactivity with electron-neutral alkynes (4e). 1-
Ethynylnaphthalene afforded the corresponding propar-
gylic nitriles in 62% yield (4f). Analogues of AIBN were
also tested. 2,2-Azodi(2-methylbutyronitrile) showed sim-
By utilizing tert-butyl peroxybenzoate (TBPB) as the
methyl radical source, we found that the combination of
Cu(OTf)2, Ni(acac)2 and AgOAc as catalysts could give
good results for the methylation of terminal alkynes
(Scheme 5). 78% yield could be obtained in the case of p-
tolylacetylene (5a). The effect of each catalyst on the reac-
tion yield was demonstrated in Table S3, Supporting In-
formation. Substituted phenylacetylenes bearing halide,
electron-donating and electron-withdrawing groups were
all able to furnish the desired methylation products in
good yields (5b-5f). 1-Ethynylnaphthalene was also suita-
ble in this transformation with moderate reaction yields
(5g). Notably, aliphatic alkynes such as but-3-yn-1-yl ben-
zoate and but-3-yn-1-ylbenzene could undergo methyla-
tion with good reaction efficiency (5h and 5i). Besides
methylation, our method was also applicable to the ethyl-
ation and propylation of terminal alkynes with corre-
sponding alkyl peroxybenzoates but with decreased reac-
tion yields (5j and 5k).
ilar
reactivity
with
AIBN
(4h)
while
1,1'-
azobis(cyanocyclohexane) demonstrated decreased reac-
tion efficiency (4i).
Scheme 4. Radical C(sp3)-C(sp) Cross-Coupling be-
tween AIBN and Different Terminal Alkynesa
Scheme 5. Radical C(sp3)-C(sp) Cross-Coupling be-
tween Alkyl Peroxybenzoates and Different Terminal
Alkynesa
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increased reaction efficiency (7f). Acyclic aliphatic alde-
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1
2
3
hydes were also tested. Notably, site-specific substituted
alkynes could be obtained although with low reaction
yields (7g-7i).
4
5
6
Scheme 6. Radical C(sp3)-C(sp) Cross-Coupling be-
tween Aliphatic Aldehydes and Terminal Alkynesa
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aStandard conditions C: TBPB (2.0 equiv), 2 (0.50 mmol), Cu(OTf)2
(5.0 mol%), Ni(acac)2 (5.0 mol%), AgOAc (10 mol%), DBU (10 mol%),
o
b
PhCl (7.0 mL), 100 C, 3 h. Isolated yields are shown. Yields were
determined by 1H NMR with CH2Br2 as the internal standard.
aStandard conditions D: 6 (6.0 equiv), 2 (0.50 mmol), Cu(OTf)2 (5.0
mol%), Fe(acac)2 (5.0 mol%), AgOAc (10 mol%), dppb (5.0 mol%),
DTBP (.0 equiv), PhCl (6.0 mL), 130 oC, 3 h. Isolated yields are
shown. bPhCF3 (6.0 mL) was used instead of PhCl (6.0 mL).
Oxidative alkynylation of alkyl radicals generated
from aliphatic aldehydes. Aldehydes are readily availa-
ble and inexpensive bulk chemicals, which have been uti-
lized as a source of acyl radicals. It is known that aliphatic
acyl radicals can undergo fast decarbonylation to deliver
alkyl radicals. As shown in Scheme 1b, we achieved the
direct oxidative C(sp3)-H alkynylation of unactivated al-
kanes with terminal alkynes.9 However, the alkyl radicals
generated from hydrogen abstraction of acyclic alkanes
usually have poor regioselectivity. Thus, mixtures of regi-
oisomers were obtained for acyclic alkanes. In compari-
son, aliphatic aldehydes could furnish site-specific alkyl
radicals under oxidative conditions.14 Herein, we describe
a decarbonylative C(sp3)-C(sp) cross-coupling between
aliphatic aldehydes and terminal alkynes (eq. 4).
Mechanistic Insights. In all the above mentioned
transformations, using suitable catalyst combination was
the key for achieving the C(sp3)-C(sp) cross-coupling.
Thus, a series of experiments were carried out to under-
stand the role of each catalyst. The oxidative C(sp3)-H
alkynylation of cyclohexane (8a) with p-tolylacetylene (2a)
was selected as a model reaction for investigation.9 The
effect of each catalyst on the reaction yield was first
demonstrated
in
Table
1.
By
using
Cu(OTf)2/Ni(acac)2/AgOAc as the catalysts and dppb as
the ligand, the C(sp3)-C(sp) bond formation product 7a
could be obtained in 75% yield (Table 1, entry 1). No de-
sired product could be observed in the absence of
Cu(OTf)2 while 6% of 7a was formed in the absence of
Ni(acac)2 (Table 1, entries 2 and 3). Moreover, CuOTf
failed to give the desired product, which demonstrated
the crucial role of Cu(OTf)2 in this transformation (Table 1,
entry 4). Silver catalyst had a minor effect on the reaction
yield. Acceptable yield could still be obtained in the
absence of AgOAc (Table 1, entry 5).
A satisfactory reaction efficiency could be achieved by
using Cu(OTf)2, Fe(acac)2 and AgOAc as combined cata-
lysts and DTBP as the oxidant (Effect of reaction parame-
ters was shown in Table S4, Supporting Information). As
shown in Scheme 6, 50% isolated yield of 7a could be ob-
tained from the reaction between cyclohexanecarboxal-
Table 1. Effect of Catalysts on the Yields of C(sp3)-
C(sp) Cross-Coupling a
dehyde
and
p-tolylacetylene.
Electron-rich
4-
methoxyphenylacetylene furnished the desired product in
an increased yield (7b). Phenylacetylene bearing an ortho
chloride gave the C(sp3)-C(sp) cross-coupling product in
44% yield (7c). Other aromatic alkynes including 1-
ethynylnaphthalene and 2-ethynylthiophene did afford
the desired products but in decreased reaction yields (7d
and 7e). Notably, but-3-yn-1-yl, an aliphatic alkyne, could
produce the decarbonylative cross-coupling product with
entry
Variation from the standard conditions
yield (%)
75
1
none
2
without Cu(OTf)2
n.d.
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4
5
without Ni(acac)2
CuOTf instead of Cu(OTf)2
without AgOAc
6
1
2
3
4
5
6
7
n.d.
63
a Standard conditions E: 8a (4.0 mL), 2a (0.50 mmol), Cu(OTf)2 (7.5
mol%), Ni(acac)2 (7.5 mol%), dppb (7.5 mol%), AgOAc (10 mol%)
and DTBP (1.5 mmol), PhCl (3.0 mL), 130 oC, 3 h. Yields were
determined by GC analysis with biphenyl as the internal standard,
n.d. = not detected.
Standard condtions
Cu(OTf)
2
Cu(OTf)
2
+ dppb
8
Though silver catalyst was not indispensable in the al-
kynylation reaction, the addition of silver catalyst was
important for ensuring a good reaction efficiency with
both electron-deficient and electron-rich alkynes. The
effect of silver on the reaction yields of terminal alkynes
with different electron density was shown in Table 2. Sil-
ver catalyst was essential for achieving a good reaction
efficiency, especially for the reaction with electron-
deficient phenylacetylenes (Table 2, entries 1-3).
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2500
3000
3500
4000
Field (G)
Figure 1. The electron paramagnetic resonance (EPR) spectra (X
band, 9.4 Hz, 190K). (a) Standard conditions: cyclohexane (4.0 mL),
p–tolylacetylene (0.50 mmol), Cu(OTf)2 (0.038 mmol), Ni(acac)2
(0.038 mmol), dppb (0.038 mmol), AgOAc (0.050 mmol) and DTBP
(1.5 mmol) in PhCl (3.0 mL) at 130 oC for 1 h. (b) Cu(OTf)2 in PhCl. (c)
Cu(OTf)2 and dppb in PhCl.
Table 2. Effect of AgOAc on the Reaction Yields with
Different Terminal Alkynesa
Table 3. Reaction Results by Adding Different Silver
Salts in the Absence of Coppera
entry
R
Ac
yield without AgOAc
yield with AgOAc
1
14%
63%
76%
50%
73%
91%
2
3
Me
OMe
aStandard conditions E: 8a (4.0 mL), 2 (0.50 mmol), Cu(OTf)2 (7.5
mol%), Ni(acac)2 (7.5 mol%), dppb (7.5 mol%) and DTBP (1.5 mmol)
in PhCl (3.0 mL) at 130 oC for 3 h. Isolated yields are shown.
entry
[Ag]
yield of 7a
n.d.
yield of 9a
14%
1
10 mol% AgOAc
5 mol% Ag2O
5 mol% Ag2CO3
2
3
n.d.
12%
In order to get some insights into the active metal spe-
cies during the reaction, EPR detection of the reaction
system was performed (Figure 1). Obvious Cu(II) signals
were observed under the standard reaction conditions.
Moreover, the Cu(II) signal during the reaction was dif-
ferent from the signal of Cu(OTf)2 without ligand and
Cu(OTf)2 with dppb, which indicated the generation of
new Cu(II) species in the reaction process. It has been
reported that Ag(I) itself can activate C(sp)-H bonds to
form alkynyl Ag(I) species.15 However, no desired C(sp3)-
C(sp) bond formation product could be observed by
adding different Ag(I) salts in the absence of Cu(OTf)2.
Instead, direct reductive addition product 9a was
obtained in 12-16% yield (Table 3, entries 1-3). According
to these experimental results, alkynyl Cu(II) species were
more likely to be formed instead of alkynyl Ag(I) species
during the C(sp3)-C(sp) cross-coupling process.
n.d.
16%
a
Reaction conditions: 8a (4.0 mL), 2a (0.50 mmol), Cu(OTf)2 (7.5
mol%), Ni(acac)2 (7.5 mol%), silver, dppb (7.5 mol%) and DTBP (1.5
mmol) in PhCl (3.0 mL) at 130 oC for 3 h. Isolated yields are shown.
Besides
the
combination
of
Cu(II)/Ag(I),
Cu(II)/Cu(I)/Ag(I) was also used as the catalyst combina-
tion for the oxidative alkynylation with some radical
sources (Schemes 3-5). In our previous study, we have
demonstrated that C(sp)-H bond cleavage was the rate-
determine step in copper-promoted homo-coupling of
terminal alkyne.16 Thus, the homo-coupling of terminal
alkyne was chosen as the model reaction to compare the
different reaction rates of C(sp)-H bond cleavage by uti-
lizing different transition metal catalysts and their com-
binations. In the presence of 7.5 mol% Cu(OTf)2, 12%
yield of homo-coupling product 10a was obtained (Table
4, entry 1). 7.5 mol% of CuOAc led to the formation of 9%
of 10a (Table 4, entry 2). Ni(acac)2 was unable to furnish
10a under similar conditions (Table 4, entry 3). Moreover,
the homo-coupling product was observed in 2% yield
when 10 mol% AgOAc was added (Table 1, entry 4). Then,
the reactions utilizing two catalysts were conducted. The
combination of Cu(OTf)2 and CuOAc gave the highest
yield of 10a (Table 4, entry 5). The combination of
Cu(OTf)2 and Ni(acacc)2 gave a similar result with
Cu(OTf)2 solely (Table 4, entry 6) while the combination
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of Cu(OTf)2 and AgOAc gave a higher yield of 10a than
Page 6 of 9
alkyne. According to these results, the generation rate of
the alkynyl metal species could be tuned by utilizing dif-
ferent catalyst combinations. The choice of copper and
silver catalyst combinations was important for achieving a
good reaction efficiency since the generation rate of the
alkynyl metal species need to match with the different
generation rates of the alkyl radicals.
that of only with Cu(OTf)2 (Table 4, entry 7). Ag(I)15 and
Cu(I)16 have both been reported to promote the C(sp)-H
bond cleavage of terminal alkynes by forming π-
complexes with the triple bond of the alkyne. It explained
why both Ag(I) and Cu(I) can promote the homo-
coupling of terminal alkyne in the presence of Cu(OTf)2.
1
2
3
4
5
6
7
8
9
Further efforts were taken to get some insights into the
role of nickel catalyst in this transformation. To simplify
the reaction system, the reactions between 8a and 2a
were carried out in the absence of ligands. In the absence
of nickel catalysts, the combination of Cu(OTf)2/AgOAc
only afforded 6% of the C(sp3)-C(sp) bond formation
product 7a along with 2% of the terminal alkyne homo-
coupling product 10a (Table 5, entry 1). Afterwards, dif-
ferent nickel catalysts were added into the reaction sys-
tem. Only Ni(acac)2 showed a high reactivity in promot-
ing the C(sp3)-H alkynylation reaction while other nickel
catalysts did not exert positive effects on the C(sp3)-C(sp)
bond formation (Table 5, entries 2-6). Other transition
metal acetylacetonate salts were then tested. Fe(acac)2
and Fe(acac)3 demonstrated similar reactivities with
Ni(acac)2 in this C(sp3)-C(sp) cross-coupling reaction (Ta-
ble 5, entries 7 and 8). Co(acac)2 and Co(acac)3 also en-
hanced this reaction but with lower reaction efficiency
(Table 5, entries 9 and 10). Interestingly, even Cu(acac)2
could enhance this alkynylation reaction (Table 5, entry
11). A control experiment regarding the role of acety-
lacetonate ion was also conducted (Table 5, entry 12).
Adding Kacac into the reaction suppressed the C(sp3)-
C(sp) cross-coupling process. In our previous study, we
illustrated that cyclohexyl radical could be stabilized by
forming a Ni(III) complex.17 Later on, Lan and co-works
also demonstrated that Cu(acac)2 could easily react with
cyclohexyl radical to generate Cu(III) complex.18 Based on
these results, we thought that co-catalysts such as
Ni(acac)2 and Fe(acac)2 were more favorable than
Cu(OTf)2 to mediate the reactions with alkyls radicals by
forming Ni(III) or Fe(III) species. Thus, metal acety-
lacetonate salts were likely to be the key catalysts for
promoting the radical cross-coupling between alkyl radi-
cals and alkynyl metal species.
Table 4. Homo-Coupling of Terminal Alkyne by Uti-
lizing Different Catalystsa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
Cu(OTf)2
CuOAc
Ni(acac)2
AgOAc
yield (%)
1
7.5 mol%
0
0
0
0
0
12
9
2
3
4
0
0
0
7.5 mol%
0
7.5 mol%
0
0
0
n.d.
2
10
mol%
5
6
7
7.5 mol%
7.5 mol%
7.5 mol%
7.5 mol%
0
7.5 mol%
0
0
0
40
13
0
0
10
27
mol%
a
Reaction conditions: 2a (0.50 mmol), catalysts and DTBP (1.5
mmol) in PhCl (3.0 mL) at 130 oC for 3 h. Yield was determined by GC
analysis with biphenyl as the internal standard.
Figure 2. Kinetic profile of the homo-coupling reaction of 2a by
using stoichiometric amount of metal salts. Black line, Cu(OTf)2 (1.0
Table 5. Reaction Results with Co-catalystsa
o
mmol), CuOAc (1.0 mmol), 2a (0.50 mmol) in PhCl (3.0 mL), 80 C;
red line, Cu(OTf)2 (1.0 mmol), CuOAc (1.0 mmol), AgOAc (1.0
o
mmol), 2a (0.50 mmol) in PhCl (3.0 mL), 80 C; blue line, Cu(OTf)2
(1.0 mmol), AgOAc (1.0 mmol), 2a (0.50 mmol) in PhCl (3.0 mL), 130
oC.
To compare the differences between Ag(I) and Cu(I),
the homo-coupling reaction rates of 2a with stoichio-
metric amount of Cu(II)/Cu(I), Cu(II)/Ag(I) and
Cu(II)/Cu(I)/Ag(I) were determined. The homo-coupling
reaction rate by using Cu(II)/Cu(I) together was much
faster even at lower temperature than that by using
Cu(II)/Ag(I) together (Figure 2, comparing the black line
with the blue line). However, adding Ag(I) salt into the
Cu(II)/Cu(I) system could suppress the homo-coupling
entry
[M]
none
yield of 3aa
6%
1
2
3
4
5
6
7
8
Ni(OAc)2•4H2O
Ni(OTf)2
NiCl2
4%
6%
4%
Ni(COD)2
Ni(acac)2
Fe(acac)2
Fe(acac)3
n.d.
53%
o
48%
59%
reaction under 80 C (Figure 2, comparing the red line
with the black line). This might be due to the competition
between Cu(I) and Ag(I) in coordinating with terminal
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Journal of the American Chemical Society
9
10
11
Co(acac)2
Co(acac)3
Cu(acac)2
Kacacb
36%
After understanding the role of each catalyst in the rad-
1
2
3
4
5
6
7
8
ical alkynylation reaction, efforts were paid to explore the
radical generation processes in all the transformations.
Radical trapping experiments were carried out by adding 1
equiv of 1,1-diphenylethylene under the standard condi-
20%
38%
n.d.
12
aReaction conditions: 8a (4.0 mL), 2a (0.50 mmol), Cu(OTf)2 (7.5
mol%), [M] (7.5 mol%), AgOAc (10 mol%) and DTBP (1.5 mmol) in
PhCl (3.0 mL) at 130 oC for 3 h. b 15 mol% was added.
tions.
The
alkenylation
products
with
1,1-
diphenylethylene could all be observed though in differ-
ent yields (Scheme 7, 9b-9e). The GC-MS analysis of the
trapped radicals was shown in supporting information,
Figure S1-S4. These results testified the assumption that
the transformations reported in this article all proceeded
through radical alkynylation processes.
To provide an overview, the effect of ligands was also
explored (Table 6). Similar with siver catalyst, ligand was
also not indispensable for the C(sp3)-C(sp) bond
formation. A moderate yield could be obtained in the
absence of ligand (Table 6, entry 1). The best result was
obtained by using equal amount of dppb with the copper
and nickel catalyst (Table 6, entries 2-4). Excess amount
of ligand would suppress the alkynylation reaction (Table
6, entry 5). PPh3 was less effective than dppb in this
transformation (Table 6, entry 6). Addition of bipyridine
did not increase the reaction yield (Table 6, entry 7). It
has been reported that phosphine ligands can coordinate
with Ni(acac)2 to form six coordinated nickel complexes.19
Phosphine ligand was likely to play a role in stabilizing
the nickel complexes during the reaction.
9
10
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12
13
14
15
16
17
18
19
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21
22
23
24
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27
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29
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33
34
35
36
37
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41
42
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60
A proposed mechanism for the oxidative radical al-
kynylation of cyclohexane (8a) with p-tolylacetylene (2a)
is presented in Scheme 8. Initially, an alkynyl Cu(II) com-
plex B is generated from the Cu(OTf)2/AgOAc co-
catalyzed C(sp)-H activation of 2a. Afterwards,
transmetalation takes place between Ni(acac)2 and B to
afford a Ni(II) complex (A). At the same time, cyclohexyl
radical is generated through hydrogen abstraction by the
in situ generated tert-butoxyl radical. Then, the generated
cyclohexyl radical reacts with A to give the alkynyaltion
product 7a and Ni(acac).20 Finally, Ni(acac)2 is oxidized by
DTBP to regenerate Ni(acac)2. By using the optimized
catalytic system, C(sp3)-H bond cleavage of 8a and C(sp)-
H bond cleavage of 2a are at considerable reaction rates.
The dppb ligand is supposed to play a role in stabilizing
the nickel complexes during the reaction process. Similar
reaction mechanisms are expected for the alkyl radicals
generated from other radical sources. Besides the differ-
ences in the radical generation processes, the speeds of
C(sp)-H bond cleavage are also different by using differ-
ent copper and silver catalyst combinations.
Table 6. Effect of Ligandsa
entry
ligand
yield (%)
1
0
53
70
79
70
5
2
3
4
5
6
7
5 mol% dppb
7.5 mol% dppb
10 mol% dppb
15 mol% dppb
15 mol% PPh3
15 mol% Bipy
Scheme 8. Proposed Catalytic Cycles for the Oxida-
tive Radical Alkynylation between Cyclohexane and
p-Tolylacetylene
64
51
aReaction conditions: 8a (4.0 mL), 2a (0.50 mmol), Cu(OTf)2 (7.5
mol%), Ni(acac)2 (7.5 mol%), ligand, AgOAc (10 mol%) and DTBP
(1.5 mmol), PhCl (3.0 mL), 130 oC, 3 h. Yields were determined by GC
analysis with biphenyl as the internal standard.
Scheme 7. Radical Trapping Experiments
CONCLUSION
In summary, we have developed a versatile method for
the direct C(sp3)-C(sp) cross-coupling with terminal al-
kynes. Alkyl radicals generated from different approaches
are all able to couple with terminal alkynes by judicious
selection of the catalyst combination. The reaction proto-
col is complementary to the traditional Sonogashira cou-
pling for the synthesis of substituted alkynes. The reac-
tions are found to go through radical reaction pathways
and synergistic cooperation of the metal catalysts is the
key for controlling the reaction selectivity of alkyl radicals
toward C(sp3)-C(sp) bond formation. Cu(OTf)2 is the cru-
cial catalyst in the C(sp)-H bond activation. Ag(I) and
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Page 8 of 9
Li, S.-H.; Wang, M.-W.; Luo, X.-L.; Ding, G.-L.; Sheng, R.-L.; Fu,
Cu(I) catalysts can tune the reaction rate of C(sp)-H bond
cleavage through coordination with the carbon-carbon
triple bond. Metal acetylacetonate salts such as Ni(acac)2
and Fe(acac)2 are important for promoting the radical
cross-coupling reaction of alkynyl metal species with alkyl
radicals. Overall, the appropriate combination of these
transition metal salts is crucial for achieving a good reac-
tion efficiency.
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ASSOCIATED CONTENT
9
Supporting Information. Experiment details and spectral
data for all compounds are provided. This material is availa-
ble free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Email: aiwenlei@whu.edu.cn
Author Contributions
§Shan Tang and Yichang Liu contributed equally
.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003) and the Hubei
Province Natural Science Foundation of China (2017CFA010).
The Program of Introducing Talents of Discipline to Univer-
sities of China (111 Program) is also appreciated.
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Cu
Ag
1
2
3
Alkyl
+
Alkyl
R
H
R
Ni
or Fe
4
5
[Ox]
6
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