Cobalt/Lewis Acid Catalysis for Hydrocarbofunctionalization of Alkynes via Cooperative C-H Activation

Article abstract of DOI:10.1021/jacs.0c06412

A catalytic system comprising a cobalt-diphosphine complex and a Lewis acid (LA) such as AlMe3 has been found to promote hydrocarbofunctionalization reactions of alkynes with Lewis basic and electron-deficient substrates such as formamides, pyridones, pyridines and related azines, imidazo[1,2-a]pyridines, and azole derivatives through site-selective C-H activation. Compared with known Ni/LA catalytic systems for analogous transformations, the present catalytic systems not only feature convenient setup using inexpensive and bench-stable precatalyst and ligand such as Co(acac)3 and 1,3-bis(diphenylphosphino)propane (dppp) but also display distinct site-selectivity toward C-H activation of pyridone and pyridine derivatives. In particular, a completely C4-selective alkenylation of pyridine has been achieved for the first time. Meanwhile, the present catalytic system proved to promote exclusively C5-selective alkenylation of imidazo[1,2-a]pyridine derivatives. Mechanistic studies including DFT calculations on the Co/Al-catalyzed addition of formamide to alkyne have suggested that the reaction involves cleavage of the carbamoyl C-H bond as the rate-limiting step, which proceeds through a ligand-to-ligand hydrogen transfer (LLHT) mechanism leading to an alkenyl(carbamoyl)cobalt intermediate.

Full text of DOI:10.1021/jacs.0c06412

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Article
Cobalt/Lewis Acid Catalysis for Hydrocarbofunctionalization
of Alkynes via Cooperative C–H Activation
Chang-Sheng Wang, Sabrina Di Monaco, Anh Ngoc Thai, Md. Shafiqur
Rahman, Benjamin Piaoxiang Pang, Chen Wang, and Naohiko Yoshikai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06412 • Publication Date (Web): 23 Jun 2020
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Cobalt/Lewis Acid Catalysis for Hydrocarbofunctionalization of Alkynes
via Cooperative C–H Activation
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Chang-Sheng Wang,† Sabrina Di Monaco,†,§ Anh Ngoc Thai,†,|| Md. Shafiqur Rahman,† Benjamin
Piaoxiang Pang,† Chen Wang,*,†,‡ and Naohiko Yoshikai*,†
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
‡Zhejiang Key Laboratory of Alternative Technologies for Fine Chemical Process, Shaoxing University, Shaoxing 312000,
P.R. China
ABSTRACT: A catalytic system comprised of a cobalt–diphosphine complex and a Lewis acid (LA) such as AlMe3 has been found
to promote hydrocarbofunctionalization reactions of alkynes with Lewis basic and electron-deficient substrates such as formamides,
pyridones, pyridines and related azines, imidazo[1,2-a]pyridines, and azole derivatives through site-selective C–H activation.
Compared with known Ni/LA catalytic systems for analogous transformations, the present catalytic systems not only feature
convenient set up using inexpensive and bench-stable precatalyst and ligand such as Co(acac)3 and 1,3-
bis(diphenylphosphino)propane (dppp), but also display distinct site-selectivity toward C–H activation of pyridone and pyridine
derivatives. In particular, a completely C4-selective alkenylation of pyridine has been achieved for the first time. Meanwhile, the
present catalytic system proved to promote exclusively C5-selective alkenylation of imidazo[1,2-a]pyridine derivatives. Mechanistic
studies including DFT calculations on the Co/Al-catalyzed addition of formamide to alkyne have suggested that the reaction involves
cleavage of the carbamoyl C–H bond as the rate-limiting step, which proceeds through a ligand-to-ligand hydrogen transfer (LLHT)
mechanism leading to an alkenyl(carbamoyl)cobalt intermediate.
this seminal report, Nakao and Hiyama have significantly
expanded the scope of Ni/LA catalysis to achieve C–H
INTRODUCTION
The transition metal-catalyzed addition of an unactivated C–
H bond across unsaturated hydrocarbons such as olefins and
alkenylation and alkylation of Lewis basic substrates such as
pyridines,5,6 imidazoles,7,8 formamides,9 pyridones,10 aryl
alkynes represents an atom-economically ideal approach to C–
carbonyl compounds,11 and aryl sulfones12 with alkynes and
C
bond formation.1 To achieve this type of
alkenes, respectively, through appropriate modification of the
supporting ligand for Ni(0) and choice of the Lewis acid
cocatalyst. The concept of the Ni/LA cooperative C–H
activation has also been adopted by other research groups to
hydrocarbofunctionalization reactions in a synthetically useful
manner, it is crucial that the catalyst can target a specific C–H
bond among others in the given substrate. In this respect,
directing groups have been extensively used to ensure high
efficiency and site-selectivity of the activation of the proximal
C–H bond through chelation assistance. Nevertheless, although
powerful and reliable, the covalently linked directing groups
inevitably limit the reaction scope to specific types of
achieve
(enantioselective)
intramolecular
hydrocarbofunctionalization
reactions
of
pyridones,13
imidazoles,14,15 and pyridines16 through development of novel
chiral phosphorus- or N-heterocyclic carbene ligands.17
Scheme 1. Ni0/Lewis Acid Cooperative C–H Activation
substrates.
Therefore
the
development
of
hydrocarbofunctionalization reactions that do not rely on
chelation assistance represents an important subject.
Besides substrates bearing directing groups, electronically
biased substrates have been successfully employed for
hydrocarbofunctionalization via site-selective C–H activation.
Among notable strategies to achieve such transformations is the
cooperation of electron-rich nickel(0) and Lewis acidic main
group metals (e.g., Zn, Al, and B) for the C–H activation of
innately Lewis basic and electron-deficient substrates (Scheme
1).2 In 2008, Nakao and Hiyama first demonstrated the concept
of Ni/LA cooperative C–H activation by the C2-selective
alkenylation of pyridines with alkynes.3,4 Thus, coordination of
the pyridine nitrogen to Lewis acidic ZnPh2 makes the pyridine
core more electron-deficient, thereby enhancing its reactivity
toward an electron-rich Ni(0)–trialkylphosphine catalyst. Since
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Ni(cod)2 (3 mol %)
P(iPr)3 (12 mol %)
ZnPh2 (6 mol %)
Mechanistic studies have suggested that the Co/Al-catalyzed
R2
Ni0Ln
H
1
2
3
addition of a formamide to an alkyne involves a rate-limiting
bimetallic C–H bond cleavage process that occurs through a
ligand-to-ligand hydrogen transfer (LLHT) mechanism.25
R2
R1
+
N
N+
toluene, 80 °C
N
–
R1
ZnPh2
H
4
5
6
7
8
9
Scheme 2. Parallelism between Ni and Co Catalysis and
This Work
H
–
H
LA
Ni0Ln
H
O
Ni0
Ln
+
NR
–
(a)
+
N
LA
Ni(cod)2 (10 mol %)
PCyp3 (10 mol %)
N+
LA
H
R2N
Ni0Ln
–
H
N
toluene, 35 °C
H
pyridine
imidazole
ref 7, 8
formamide
ref 9
Pr
N
10
11
12
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O
ref 3, 5, 6
H
CoBr2 (10 mol %)
DPEphos (10 mol %)
Me3SiCH2MgCl (50 mol %)
–
+
O
Pr
–
LA
O+
LA
O
O
S+
Pr
Pr
Ni0
H
Ln
–
Ni0
Ln
R
Ni0
Ln
THF, 20 °C
R
+
LA
O
N
H
H
R
(b)
pyridone
ref 10
aryl carbonyls
ref 11
aryl sulfones
ref 12
–
cat. Co– dppp
cat. AlMe3
R1
N
R2
R4
O
O
Al
R1
CoLn
H
O
H
+
N
R2
H
L = PR3 or NHC; LA = AlIII, ZnII, BIII Lewis acids
+
heptane, 60 °C
R2N
R3
R4
R3
■ Other combination of transition metals and Lewis acids?
■ Possibility for unique reactivity or site-selectivity?
Al –
H
H
Co
Ln
H
N
X
CoLn
H
R
–
Given the broad scope and the high tunability of Ni/LA
bimetallic catalytic systems, we became interested in the
“generality” of the transition metal/Lewis acid cooperative C–
H activation. Thus, we wondered if analogous mode of C–H
activation is viable with different combinations of low-valent
transition metals and Lewis acids. In this respect, our attention
was attracted to the parallelism between low-valent nickel and
cobalt in the C–H activation of azole derivatives (Scheme 2a).
Nakao and Hiyama reported alkenylation of relatively acidic
heteroarenes, including benzoxazole, with alkynes promoted by
a Ni(0)–trialkylphosphine catalyst.18,19 Later, we demonstrated
alkenylation of (benz)oxazole and (benzo)thiazole derivatives
using low-valent Co–diphosphine catalyst generated by
reduction of a Co(II) salt with a Grignard reagent,20,21 which
appeared to share a similar mechanistic pathway with the Ni(0)
catalysis. Meanwhile, our exploration of low-valent Co–
diphosphine catalysts generated from Co(II) and metallic
reductant for alkyne transformations22 led us to come across a
notable side reaction, that is, the addition of DMF (used as
solvent) to an internal alkyne through carbamoyl C–H bond
cleavage.23 This observation, together with the apparent
parallelism between Ni and Co for the benzoxazole C–H
activation, inspired us to explore Co/LA catalysis for
cooperative C–H activation.24
N+
+
Al
N+
H
O
N
Co
Ln
–
H
R
H
Al
pyridine, pyrimidine
pyridone
imidazo[1,2-a]pyridine
–
–
Al
N+
H
Ti
N+
■ Bench-stable Co precatalysts
■ Inexpensive and stable ligand
(dppp) across diverse substrates
H
S
O
■ Opportunity for unique site selectivity
(pyridones, pyridines)
Co
Co
Ln
Ln
thiazole, oxazole
RESULTS AND DISCUSSION
Discovery
of
Co/Al
Cooperatively
Catalyzed
Hydrocarbamoylation of Alkynes. We have demonstrated
that low-valent cobalt catalysts generated from cobalt salts,
supporting ligands, and Grignard reagents promote
hydroarylation reactions of alkynes and alkenes via chelation-
assisted C–H activation.21a,26 While a catalyst generated by the
same reduction method is used, the C2-alkenylation of azole
derivatives (Scheme 2a) is distinct from these chelation-assisted
hydroarylations. However, the parallelism between this C2-
alkenylation and the analogous Ni(0)-catalyzed reaction has
long escaped our attention. In the meantime, we have explored
another type of low-valent cobalt catalysts, generated from
cobalt(II) salt, diphosphine ligand, and metallic reductant (e.g.
Zn), for hydroacylation,27 cycloaddition,22a,b and homoenolate
transformation.22d On studying alkyne cycloaddition using this
type of cobalt–diphosphine catalyst,28,29 we have observed the
addition of DMF (solvent) to an internal alkyne to afford an α,β-
Herein, we report that the combination of cobalt–diphosphine
and Lewis acid catalysts is highly effective for
hydrocarbofunctionalization of alkynes with Lewis basic and
electron-deficient substrates, including formamides, pyridones,
pyridines and related azines, imidazo[1,2-a]pyridines, and
azole derivatives, via site-selective C–H activation (Scheme
2b). Compared with typical Ni/LA catalytic systems comprised
of air-sensitive Ni(cod)2 and electron-rich trialkylphosphine or
N-heterocyclic carbene, the present systems are easy to set up
using air- and moisture-stable precatalyst (Co(acac)3) and
diphosphine ligand (dppp), the latter serving as a common
inexpensive ligand encompassing diverse classes of substrates.
Furthermore, the Co/LA systems have proven to show distinct
site selectivity compared with the known Ni/LA systems in the
C–H activation of pyridone and pyridine derivatives.
unsaturated amide as
a
byproduct. This alkyne
hydrocarbamoylation reaction is reminiscent of the one
catalyzed by Ni/Al catalyst,9a,30 and has triggered our interest in
the feasibility of C–H activation by Co/LA cooperative
catalysis.
Table 1 summarizes results of the addition of DMF (1a) to 5-
decyne (2a) under various Co and Co/LA catalytic systems (see
Tables S1–S6 for detailed optimization results). We first found
that, in DMF as solvent, a catalyst generated from CoI2 (2.5 mol
%), dppp (2.5 mol %), and Zn (25 mol %) promoted the
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11f
12f
13f,h
14
Co(acac)3
Co(acac)3
Co(acac)3
CoI2
dppb
dppbz
PCy3
dppp
dppp
dppp
AlMe3
60
60
60
60
60
60
32
76
0
hydrocarbamoylation to 2a to afford the α,β-unsaturated amide
1
2
3
4
5
6
7
8
3aa in good yield of 71% with exclusive syn-selectivity (entry
1), which was accompanied by a small amount (5%) of
hexabutylbenzene formed by cyclotrimerization of 2a. The
yield of 3aa could be improved to 99% by the addition of
DABCO (25 mol %; entry 2). However, no
hydrocarbamoylation took place when the amount of 1a was
reduced to 2 equiv and the reaction was performed with 5 mol
% each of CoI2 and dppp in toluene at 60 °C (entry 3). In stark
contrast, the addition of AlMe3 (20 mol %) to this system
dramatically promoted the hydrocarbamoylation to afford 3aa
in 99% yield (96% isolated yield; entry 4). Other cobalt
precatalysts such as CoBr2, CoCl2, and Co(acac)3 also proved
effective, with slightly deviating yields of 3aa (entries 5–7). Zn
could be omitted from the catalytic system, while in such case
the catalytic activity was largely dependent on the precatalyst.
Thus, a catalytic system comprised of Co(acac)3, dppp, and
AlMe3 efficiently promoted the hydrocarbamoylation in
heptane (entry 8), while the reaction became rather sluggish
using CoI2 or CoBr2 (Table S3). A preformed Co(I) complex
CoCl(PPh3)3 also served as a viable precatalyst in the absence
of Zn (entry 9), while no reaction was observed using Co2(CO)8
(entry 10).
AlMe3
AlMe3
AlCl3
0
15
CoI2
Zn(OTf)2
Ti(OiPr)4
25
27
16
CoI2
aUnless otherwise noted, the reaction was performed using 0.4
mmol of 1a and 0.2 mmol of 2a in toluene (0.3 mL). bdppp = 1,3-
9
bis(diphenylphosphino)propane;
bis(diphenylphosphino)ethane;
dppe
dppbz
=
=
1,2-
1,2-
10
11
12
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22
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bis(diphenylphosphino)benzene. cDetermined by GC using n-
tridecane as an internal standard. Isolated yield is shown in
parentheses. dThe reaction was performed in DMF (0.3 mL) instead
of toluene, using 2.5 mol % each of CoI2 and dppp. eDABCO (25
mol %) was added. fThe reaction was performed in heptane instead
of toluene, in the absence of Zn. g2.5 mol % of Co2(CO)8 was used.
h10 mol % of PCy3 was used.
With the effective Co/Al catalytic systems in hand, we
explored the scope of formamides and alkynes (Table 2). A
variety of acyclic and cyclic N,N-dialkylformamides
participated in the addition to 2a to afford the corresponding
α,β-unsaturated amides 3aa–3ia in good yields with exclusive
syn-selectivity, except for bulky N,N-diisopropylformamide
that reacted sluggishly (see 3fa). On the other hand, formamides
bearing N-aryl substituent failed to participate in the desired
reaction. Besides 2a, symmetrical and unsymmetrical
dialkylacetylenes underwent addition of 1a to afford the
corresponding products 3ab–3ad in good yields. The reaction
of 2,2-dimethyloct-3-yne took place with exclusive
regioselectivity, with the C–C bond formation at the less
hindered acetylenic carbon (see 3ad). Phenyl cyclohexyl
acetylene and vinyl cyclohexyl acetylene were also amenable to
the hydrocarbamoylation, again with C–C bond formation at the
less hindered acetylenic carbons (see 3ae and 3af). The
regioselectivity trend observed for such unsymmetrical alkynes
may be rationalized by the preference of the cobalt center to
avoid a steric repulsion with the bulkier alkyne substituent
during the LLHT process. The addition of 1a to
diphenylacetylene was also feasible, albeit with moderate yield
and opposite stereoselectivity (see 3ag). The reaction between
1a and 2a could be scaled up to 6 mmol scale, affording the
adduct 3aa in a preparatively useful yield (1.06 g, 84%).
Diphosphine ligands other than dppp also gave rise to active
catalysts, albeit with reduced efficiency (entries 11 and 12),
while no desired reaction took place with monophosphines such
as PCy3 (entry 13). No catalytic activity was observed using
AlCl3 in place of AlMe3, even when using the CoI2/Zn
combination to ensure the reduction of the Co precatalyst (entry
14). Meanwhile, Zn(OTf)2 and Ti(OiPr)4 promoted the
hydrocarbamoylation albeit with much reduced efficiency
(entries 15 and 16), suggesting Co/Zn and Co/Ti cooperations
in the C–H activation. While all the experiments shown in Table
1 (and hereafter) were set up in a glove box, the present catalytic
system did not actually need such a facility. Thus, the reaction
in entry 8 could be performed outside the glove box using the
standard Schlenk technique, without apparent decrease in the
efficiency (93% yield).
Table 1. Addition of DMF to 5-Decyne under Co and Co/Al
Catalysisa
Table 2. Co/Al-Catalyzed Addition of Formamides to
Alkynesa
entry CoXn
ligandb
LA
T
yield
(°C) (%)c
1d
2d,e
3
CoI2
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
none
100
100
60
60
60
60
60
60
60
60
71
CoI2
none
99
CoI2
none
0
4
CoI2
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
99 (96)
83
5
CoBr2
6
CoCl2
99
7
8f
9f
10f,g
Co(acac)3
Co(acac)3
CoCl(PPh3)3
Co2(CO)8
91
99 (96)
88
0
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4d was also amenable to C6-alkenylation to afford 5da in 68%
1
2
3
4
5
6
7
8
yield. N-Methylpyrimidin-4-one (4e) and -quinolin-4-one (4f)
also underwent site-selective C–H activation of the C2 position
to afford the alkenylated products 5ea and 5fa in good yields.
1,3-Dimethyluracil (4g) proved particularly reactive,
undergoing smooth C6-alkenylation at 80 °C in excellent yield
(see 5ga). 1,6-Dimethylpyridone (4b) reacted smoothly with
tBu-substituted unsymmetrical alkynes to afford the
corresponding products 5bd and 5bh with exclusive regio- and
stereoselectivity. Note that pyridone derivatives 4b, 4c, and 4f
have not been examined in the Ni/Al-catalyzed alkenylation
reaction.10a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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Scheme 2. Co/Al-Catalyzed Alkenylation of Pyridone
Derivatives with Alkynes
aUnless otherwise noted, the reaction was performed on a 0.2
mmol scale under the conditions in Table 1, entry 7. Conditions:
Co(acac)3 (5 mol %), dppp (5 mol %), AlMe3 (40 mol %), heptane,
100 °C, 72 h.
b
Scope
of
Co/LA
Cooperative
Catalysis
for
Hydrocarbofunctionalization
of Alkynes.
Having
demonstrated the Co/Al-catalyzed hydrocarbamoylation of
alkynes, we became interested in the generality of Co/LA
systems for C–H activation as well as their potential uniqueness
in comparison with the known Ni/LA catalytic systems. As
such, we set out to explore the addition of a series of Lewis basic
substrates to alkynes. First, we examined the reactivity of
pyridone derivatives in light of their structural analogy to
formamide. Coordination of the Lewis basic pyridone oxygen
to a Lewis acid would give rise to a pyridinium-type species,
which would possess intrinsically electron-deficient C4 and C6
positions (Scheme 2a). The Ni/Al catalytic system was reported
to promote highly C6-selective alkenylation of N-
methylpyridone (4a) with an alkyne, which was accompanied
by a trace amount of C4, C6-dialkenylated product (Scheme
2b).10a By contrast, the Co/Al system was found to promote the
activation of C4 and C6 positions of 4a at comparable rates.
Thus, using an excess amount (3 equiv) of 2a with increased
loadings of the cobalt catalyst (10 mol %) and AlMe3 (40 mol
%) at 100 °C, the dialkenylated product 5aa was obtained in
good yield. As expected from this observation, 6-substituted
pyridone derivatives 4b and 4c underwent smooth C4-
alkenylation with 5 mol % Co and 20 mol % Al at 100 °C to
give 5ba and 5ca in good yields, while 4-substituted pyridone
aThe reaction was performed using 0.2 mmol pyridone
derivative, 0.3 mmol alkyne, 5 mol % Co(acac)3, 5 mol % dppp,
and 20 mol % AlMe3 in heptane at 100 °C for 24 h. bE/Z = 71:29.
cThe reaction was performed at 80 °C.
We next turned our attention to the activation of pyridine
derivatives. Pyridine is an intrinsically electron-deficient
aromatic system, and its complexation with a Lewis acid is
expected to render it even more electron-deficient to enhance
its reactivity toward electron-rich low-valent transition metal
species, especially at the C2 and C4 positions (Scheme 3a). A
few Ni/LA-based catalytic systems have been reported for the
alkenylation of pyridine with alkynes (Scheme 3b). As
mentioned in Introduction, Nakao and Hiyama demonstrated
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exclusively C2-selective alkenylation of pyridine with alkynes
using Ni(0)–trialkylphosphine catalyst and ZnR2 (R = Me or
1
2
3
4
5
6
7
8
9
Ph).3 The use of AlMe3 instead of ZnR2 also resulted in site-
selective C2 activation, while affording a dienylated product
through incorporation of two alkyne molecules. Following this
report, Ong and coworkers reported C4-selective alkenylation
of pyridine using a Ni/Al catalytic system featuring a
bifunctional NHC ligand.6 Meanwhile, Nakao and Hiyama
combined a Ni(0)–bulky NHC catalyst with a bulky aluminum
Lewis acid, MAD ((2,6-tBu-4-MeC6H2O)2AlMe), to achieve
C4-selective alkylation of pyridine with alkenes, while
application of the Ni/MAD system to the alkenylation reaction
was not described.5 Instead, they briefly noted C4-selective
alkenylation using a catalytic system comprised of Ni(cod)2,
1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes), and
AlMe3. Nonetheless, these “C4-selective” alkenylation
reactions were accompanied by substantial amount of the C3-
alkenylation product.
10
11
12
13
14
15
16
17
18
19
20
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24
25
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With brief screening of reaction conditions for the cobalt-
catalyzed reaction between pyridine (6a) and 2a (see Table S7),
we have found that a catalytic system comprised of Co(acac)3
(5 mol %), dppp (5 mol %), and MAD (40 mol %) effects the
C4-alkenylation reaction in heptane at 100 °C, affording the
product 7aa in 81% yield with exclusive site selectivity
(Scheme 3c). The reaction could be performed on a 6 mmol
scale in a comparable yield (78%). Using AlMe3 (40 mol %)
instead of MAD, the reaction still displayed selectivity toward
the C4 position, affording the alkenylation products in an
overall yield of 48% with the ratio of C2:C3:C4 = 5:13:82. By
contrast, the use of ZnMe2 (40 mol %) as the Lewis acid under
otherwise identical conditions resulted in preferential C2-
alkenylation, yet producing sizable amounts of C3- and C4-
alkenylation products (overall yield 47%, C2:C3:C4 =
60:12:28). Thus, compared with Ni catalysts, the Co–dppp
catalyst appeared to have intrinsic preference toward C4-
activation, which would be reinforced by the bulky MAD that
blocks the C2 and C3 positions. For 2-substituted pyridine
derivatives, the reaction became sluggish with the Co/MAD
system, but instead the use of AlMe3 proved to efficiently
promote C4-selective alkenylation to afford the alkenylated
products 7ba–7ea in good yields. Furthermore, 3-substituted
pyridines also underwent C4-alkenylation with 2a under
Co/MAD or Co/AlMe3 system (see 7fa and 7ga). The pyridine
C4-alkenylation could also be performed using unsymmetrical
dialkylalkynes or aryl alkyl alkynes, affording the products 7ad
and 7ah in excellent yields.
Azine heterocycles other than pyridine, such as pyrimidine
and pyrazine derivatives, also underwent the addition to 5-
decyne under the Co/MAD system to afford the alkenylation
products 7ha–7ja in moderate to good yields, while pyridazine
failed to participate in the reaction. Particularly noteworthy is
the exclusive C4 selectivity observed for parent pyrimidine (see
7ha). Meanwhile, given the C4 selectivity for pyridines, it was
curious that the reaction of quinoline with 2a took place
exclusively at the C2 position even by using MAD as the Lewis
acid, affording 7ka in 66% yield.3,6
aThe reaction was performed using 0.2 mmol pyridine
derivative, 0.3 mmol alkyne, 5 mol % Co(acac)3, 5 mol % dppp,
and 40 mol % AlMe3 in heptane at 100 °C for 24 h. bMAD (40 mol
%) was used instead of AlMe3.
With successful engagement of pyridine derivatives as
substrates, we became interested in the reactivity of
imidazo[1,2-a]pyridine, which is among important heterocyclic
motifs in pharmaceuitcals,31 under the Co/Al catalysis. We
hypothesized that coordination of the nitrogen (position 1) to
AlMe3 would particularly reduce the electron density at the C3,
C5, and C7 positions and thus enhance their reactivity toward
C–H activation (Scheme 4 box). While the reaction of parent
imidazo[1,2-a]pyridine with 5-decyne afforded an intractable
Scheme 3. Co/Al-Catalyzed Alkenylation of Pyridine
Derivatives with Alkynes
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mixture of alkenylation products, 2-aryl- and alkyl-substituted
supported by a control experiment using Zn instead of AlMe3,
which did not produce the desired alkenylation product.
Scheme 5. Co/Al-Catalyzed Alkenylation
(Benzo)thiazoles
1
2
3
4
5
6
7
8
imidazo[1,2-a]pyridines underwent exclusive C–H activation at
the C5 position to afford the desired products 9aa–9ca in good
yields (Scheme 4). Unsymmetrical alkynes also participated in
the reaction with 2-phenylimidazo[1,2-a]pyridine to afford the
C5-alkenylation products 9ad, 9af, and 9ah in moderate to
good yields. While the preference for the C5 position to the C3
and C7 positions remains unclear, the present alkenylation
represents a rare example of C5-selective functionalization of
imidazo[1,2-a]pyridines.31,32
of
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Scheme 4. Co/Al-Catalyzed Alkenylation of Imidazo[1,2-
a]pyridine Derivatives
Co(acac)3 (5 mol %)
dppp (5 mol %)
AlMe3 (40 mol %)
N
R1
R3
N
N
R1
+
N
heptane, 100 °C
– AlMe3
R3
R2
R2
8
2
9
H
7
N
1.5 equiv
R1
N+
3
5
H
H
N
N
N
Ph
Cl
Me
N
N
N
Bu
Bu
Bu
Bu
Bu
Bu
9aa, 93%
9ba, 71%
9ca, 84%
aThe reaction was performed using 0.2 mmol (benzo)thiazole
derivative, 0.3 mmol alkyne, 5 mol % Co(acac)3, 5 mol % dppp,
and 20 mol % AlMe3 in heptane at 100 °C for 24 h. The E/Z ratio
was determined by GC analysis.
N
N
N
N
N
N
Ph
Ph
Ph
Bu
Ph
Unexpectedly,
analogous
C2-alkenylation
of
5-
tBu
Cy
tBu
methylbenzoxazole (12a) with 4-octyne (2i) proceeded rather
sluggishly using the above standard catalytic system. Upon re-
optimization of reaction conditions (Table S8), a Co/Ti
combination proved effective (Scheme 6). Thus, a catalytic
system comprised of CoI2 (5 mol %), dppp (5 mol %), Zn (25
mol %), and Ti(OiPr)4 (20 mol %) promoted the desired C2-
alkenylation between 12a and 2i in DME at 100 °C, affording
the product 13ai in good yield. Zn and Ti(OiPr)4 would serve as
reductant and Lewis acid, respectively, as no reaction was
observed in the absence of either. The generality of the Co/Ti
system was briefly demonstrated using a few different
benzoxazole derivatives and alkynes, affording the desired
products in moderate to high yields with syn-selectivity
(Scheme 6).33
9ad, 87%
9af, 67%
9ah, 62%
aThe reaction was performed using 0.2 mmol imidazo[1,2-
a]pyridine derivative, 0.3 mmol alkyne, 5 mol % Co(acac)3, 5
mol % dppp, and 40 mol % AlMe3 in heptane at 100 °C for 24
h.
On extending the substrate scope of the Co/Al catalytic
systems, our attention came back to the C2-alkenylation of
oxazole and thiazole derivatives. While such transformation
was achieved using Ni(0)–trialkylphosphine catalysts18 as well
as Co–diphosphine catalysts combined with Grignard reductant
(Scheme 2a),20 we were interested in the feasibility of the
Co/LA cooperative C–H activation of this class of substrates.
The present standard catalytic system (Co(acac)3/dppp/AlMe3)
proved effective for the C2-alkenylation of (benzo)thiazole
derivatives (Scheme 5). Thus, benzothiazole (10a) underwent
syn-selective addition to a series of internal alkynes to afford
the corresponding adducts 11af, 11ag, 11ai, and 11aj in high
yields. The reaction of 10a with an unsymmetrical diaryl alkyne
bearing methoxy and ethoxycarbonyl groups at the para-
positions gave a mixture of regioisomers 11ak and 11ak’ in
82% overall yield with a ratio of ca. 3:1, with preferential C–C
bond formation at the acetylenic carbon proximal to the
electron-deficient aryl group. Parent and methyl-substituted
thiazoles were also amenable to C2-alkenylation with
diphenylacetylene, affording the products 11bg–11dg in good
yields with high E/Z ratios. The role of AlMe3 as Lewis acid to
activate the thiazole nitrogen (as well as reductant) was
Scheme 6. Co/Ti-Catalyzed Alkenylation of Benzoxazoles
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aThe reaction was performed using 0.2 mmol benzoxazole
derivative, 0.3 mmol alkyne, 5 mol % CoI2, 5 mol % dppp, 25 mol
% Zn, and 20 mol % Ti(OiPr)4 in DME at 100 °C for 24 h. The E/Z
ratio was determined by GC analysis.
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Mechanistic Studies. To gain insight into the working mode
of the Co/LA catalytic systems, we performed mechanistic
experiments and DFT calculations on the hydrocarbamoylation
of alkyne. The reaction of deuterated DMF (1a-d7) with 2a
under the standard conditions afforded the product 3aa-d7 in
79% yield, with clean transfer of the carbamoyl deuterium of
1a-d7 to the vinylic position (Scheme 7a). A crossover
experiment using a mixture of 1a-d7 and nondeuterated
formamide 1d afforded 3aa-d7 and 3da without any H/D
crossover, demonstrating that the carbamoyl group and the
hydrogen (or deuterium) atom of the product originate from the
same formamide molecule (Scheme 7b). The comparison of
initial rates of individual reactions of 1a and 1a-d7 gave H/D
kinetic isotope effect (KIE) of 2.5 (average of two sets of
experiments), indicating that C–H bond cleavage would be
involved in the rate-limiting step of the reaction (Scheme 7c).
Furthermore, an intermolecular competition reaction using a
mixture of 1a and 1a-d7 gave KIE of similar magnitude (3.0;
average of two runs), which would have also reflected the C–H
cleavage as the step of first irreversible conversion of
formamide (Scheme 7d).
We next explored possible reaction pathways of the Co/Al-
catalyzed hydrocarbamoylation by DFT calculations using
simple model systems, assuming that Co(II) or Co(III)
precatalyst, in the presence of diphosphine ligand, is reduced by
AlMe3 to generate a cationic (diphosphine)Co(I) species. Note
that such species have been often proposed to be generated in
catalytic systems comprised of Co(II)–diphosphine complexes
and alkylaluminum reagents (e.g., AlMe3, Et2AlCl, MAO) for
C–C bond forming reactions such as cycloaddition and
hydrovinylation, where the alkylaluminum would act as a
reductant as well as an anion abstractor,34 while species of
different oxidation state, such as (diphosphine)Co(0), may not
be excluded depending on the reducing agent and the reaction
conditions.35 Thus, the reaction of DMF and 2-butyne with
[(dppp)Co]+ was probed in the absence or presence of AlMe3.36
Reaction pathways and energy diagrams for the model Co-
and Co/Al-catalyzed hydrocarbamoylation are summarized in
Figure 1a and 1b, respectively. Note that the suffixes s and t on
the structure numberings refer to the singlet and triplet states,
respectively. First, reaction pathways in the absence of AlMe3
were probed (Figure 1a). The cationic [(dppp)Co]+ prefers to
bind one molecule of DMF and one molecule of alkyne to form
the complex CP1_t. A bis-alkyne complex CP2_t and a bis-
DMF complex CP3_t were calculated to be less stable by 6.6
and 0.9 kcal mol–1, respectively (Figure S6). Furthermore, their
singlet counterparts CP1_s, CP2_s, and CP3_s were calculated
to be even less stable (ΔG = 12.1, 16.4, and 23.9 kcal mol–1,
respectively). CP1_t may be connected to CP1_s by minimum
energy crossing point (MECP) with ΔG of 12.0 kcal/mol
(MECP1). The following C–H bond cleavage was found to take
place through a ligand-to-ligand hydrogen transfer (LLHT)
transition state,11,25,37 where the Co–carbamoyl bond, the Co–
alkenyl bond, and the vinylic C–H bond form in a concerted
fashion. Here, the singlet TS (TS1_s, ΔG = 36.0 kcal/mol) was
found to be lower in energy than the triplet TS (TS1_t, ΔG =
38.1 kcal/mol). The resulting diorganocobalt intermediates
INT1_s and INT1_t are less stable (ΔG = 16.8 and 16.6 kcal
mol–1, respectively) than the starting complexes, and are
connected by MECP2 with ΔG of 26.0 kcal mol–1. The
Scheme 7. Deuterium-Labeling and KIE Experiments
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following reductive elimination preferentially occurs in the the quintet surface, but they were significantly higher in energy
triplet state (TS2_t, ΔG = 20.3 kcal mol–1) than in the singlet
state (TS2_s, ΔG = 31.7 kcal mol–1), forming the product
complex INT2_t (ΔG = –13.7 kcal mol–1). INT2_t may
undergo ligand exchange with DMF and 2-butyne to liberate the
α,β-unsaturated amide product and regenerate the starting
complex CP1_t. Overall, LLHT (TS1_t) was found to be the
step of the highest activation barrier (ΔG‡ = 36.0 kcal mol–1).
Although energetically uphill, LLHT might be practically
irreversible as the following process (from INT1_s to TS2_t)
might be faster than reverse-LLHT.
than their singlet counterparts.
1
2
3
4
5
6
7
8
Next, we introduced AlMe3 to the system to probe its
influence on the energy landscape. AlMe3 coordinates to the
oxygen atom of CP1_t to form the bimetallic complex CP1a_t,
with stabilization by 0.8 kcal mol–1. While the corresponding
singlet complex CP1a_s is not particularly stabilized, the
LLHT TS, TS1a_s, is highly stabilized by AlMe3 coordination
(ΔG = 28.7 kcal mol–1). The following diorganocobalt species
INT1a_s and INT1a_t are also much stabilized by AlMe3
coordination, compared with their Al-free counterparts
(INT1_s and INT1_t). The triplet reductive elimination TS
(TS2a_t) is also greatly stabilized (ΔG = 12.8 kcal mol–1),
leading to the Co/Al-bound product INT2a_t. Again, the LLHT
step was found to require the highest activation energy (ΔG‡ =
29.5 kcal mol–1), which was much lower (by 6.5 kcal mol–1) than
the barrier for the Al-free pathway. We also located C–H
oxidative addition TS involving AlMe3, which was less stable
than TS1a_s by 7.3 kcal mol–1 (Figure S7b). This significant
energy gap suggests that the present Co/Al catalysis is likely to
operate by LLHT mechanism rather than the stepwise oxidative
addition–migratory insertion mechanism.
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Besides the LLHT pathway, we have also found a stepwise
reaction pathway involving carbamoyl C–H oxidative addition
and subsequent migratory insertion of the alkyne into the Co–H
bond on the singlet surface, which converges to INT1_s (Figure
S7a). However, C–H oxidative addition, the highest-energy step
in this stepwise pathway, was found to require a higher
activation energy than LLHT by 3.3 kcal mol–1. Note that our
attempts to locate a C–H oxidative addition TS on the triplet
surface failed and converged to the triplet LLHT TS.
Meanwhile, we could locate the oxidative addition product, the
migratory insertion TS, and the migratory insertion product on
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Figure 1. Gibbs free energy diagram of the addition of DMF to 2-butyne promoted by [Co(dppp)]+ in the (a) absence and (b) presence of
1
AlMe3 calculated at SMD(heptane)-M06L/6-311++G(2df,2p)-SDD(Co)//M06L/6-31G(d)-SDD(Co) level.
2
3
4
5
Figure 2 shows the 3-D structures of the precursor
complexes and LLHT TSs in the absence (CP1_s and TS1_s)
and presence (CP1a_s and TS1a_s) of AlMe3. An obvious
difference between CP1_s and CP1a_s can be found in the
C3
C3
6
7
8
9
Co–O distance (2.13 Å in CP1_s and 2.48 Å in CP1a_s). The
longer Co–O distance in the latter can be attributed to the
competition between Co and Al in the coordination to the
amide oxygen, where Al apparently serves as a stronger Lewis
acid with the Al–O distance of 2.04 Å. While directly leading
to the alkenyl(carbamoyl)cobalt intermediates (INT1_s and
INT1a_s), both the TS structures at a glance appear like C–H
oxidative addition TSs. Thus, they both feature short Co–C1
(carbonyl carbon; ca. 2.0 Å) and Co–H (ca. 1.5 Å) distances
and substantially elongated C1–H bond (1.60–1.72 Å). The
significant development of the Co–C1 bond in these TSs is
also seen from wide Co–C1–O–N dihedral angles (>170°; ca.
179° in INT1_s and INT1a_s). The acetylenic carbons C2 and
C3 have similar distances from the Co center (ca. 1.9 Å), and
the formation of the C2–H bond is rather premature (ca. 2.2
Å).
P
P
C2
Co
O
C2
P
Co
P
H1
C1
O
H1
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N
C1
N
Al
CP1_s
CP1a_s
distance
distance
Co– C2: 1.85
C2– C3: 1.31
Co– C2: 1.86
C2– C3: 1.30
Co– O: 2.48
Co– C3: 1.85
Al– O: 2.04
Co– O: 2.13
Co– C3: 1.86
ADCH charge
dppp– Co: 0.627
2-butyne: 0.071
ADCH charge
dppp– Co: 0.788
2-butyne: 0.081
DMF: 0.302
DMF: 0.370
AlMe3: -0.239
Between the Al-free and the Al-containing LLHT TSs,
TS1a_s apparently features more advanced Co–C1 bond
formation and C1–H1 bond cleavage than TS1_s, as judged
from the distinctly shorter Co–C1 distance (by 0.04 Å) and
longer C1–H1 distance (by 0.12 Å). These structural features
agree with the Mayer bond orders38,39 of the Co–C1 (0.835 in
TS1a_s vs 0.764 in TS1_s) and the C1–H1 (0.133 in TS1a_s
vs 0.178 in TS1_s) bondings. The Mayer bond orders also
demonstrate that the temporary Co–H1 bonding is stronger in
TS1a_s (0.696) than in TS1_s (0.651) and that the bonding
between C2 and H1 is barely developed (ca. 0.035 for both
TSs). These differences may be qualitatively attributed to the
role of AlMe3 to reduce the electron density of DMF and
thereby to facilitate greater charge transfer from the cobalt
catalyst. This notion is in line with atomic-dipole-moment-
corrected Hirshfeld (ADCH) atomic charges,39,40 which show
that 1) AlMe3 coordination makes the DMF segment more
positively charged, 2) the positive charge of the DMF segment
decreases toward the LLHT TS, and 3) the dppp–Co segment
has greater positive charge in TS1a_s than in TS1_s.
C3
C2
P
C3
C2
Co
P
P
H1
Co
P
H1
C1
N
O
C1
N
O
Al
TS1a_s
TS1_s
distance (Mayer bond order)
Co– C1: 2.01 (0.764)
Co– H1: 1.51 (0.651)
C1– H1: 1.60 (0.178)
C2– H1: 2.23 (0.034)
Co– C2: 1.88
distance (Mayer bond order)
Co– C1: 1.97 (0.835)
Co– H1: 1.50 (0.696)
C1– H1: 1.72 (0.133)
C2– H1: 2.23 (0.035)
Co– C2: 1.88
Co– C3: 1.91
Co– C3: 1.91
C2– C3: 1.30
C2– C3: 1.30
Al– O: 2.01
ADCH charge
dppp– Co: 0.722
2-butyne: 0.177
ADCH charge
dppp– Co: 0.810
2-butyne: 0.193
DMF: 0.101
DMF: 0.217
AlMe3: -0.220
Figure 2. Precursor complexes and transition states of the LLHT
step. The distances are in Å.
To probe the origin of AlMe3 effect on the activation
barriers of the LLHT process, distortion/interaction analysis41
on the precursor complexes (CP1_s and CP1a_s) and the
LLHT TSs (TS1_s and TS1a_s) was performed by separating
these structures into Co–alkyne and DMF(–AlMe3) segments
(Scheme 8). The activation energy of 24.4 kcal mol–1 from
CP1_s to TS1_s was decomposed into interaction energy in
CP1_s (–28.6 kcal mol–1), distortion energies of the Co–
alkyne segment (9.7 kcal mol–1) and the DMF segment (54.0
kcal mol–1), and interaction energy in TS1_s (–67.9 kcal mol–
1) (Scheme 8a). The same analysis on CP1a_s and TS1a_s
revealed that the distortion energy of the Co–alkyne fragment
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is comparable, while the other three components are CP1_s and TS1_s are stabilized by coordination of AlMe3 to
1
2
3
4
5
6
7
8
substantially different (Scheme 8b). Thus, the larger distortion
energy of the DMF–AlMe3 segment (66.3 kcal mol–1) is
overwhelmed by the combination of the larger interaction
energy in TS1a_s (–81.3 kcal mol–1) and the smaller
interaction energy in CP1a_s (–20.9 kcal mol–1), resulting in
the lower overall activation energy (16.6 kcal mol–1). The
larger interaction energy in TS1a_s appears to be the
consequence of the DMF activation by AlMe3, while the
smaller interaction energy in CP1a_s can be ascribed to the
weakening of the Co–O interaction (compared to that in
CP1_s) caused by the strong Al–O coordination.
yield CP1a_s and TS1a_s, respectively (see Scheme S1). This
analysis revealed that the Co–alkyne–DMF segment in
TS1a_s is distorted from that in TS1_s by only 2.7 kcal mol–
1, which is consistent with the roughly similar core structures
of TS1_s and TS1a_s (Figure 2). By contrast, the same
segment in CP1a_s is more distorted from that in CP1_s (by
13.5 kcal mol–1), reflecting the significant elongation of the
Co–O distance. As the interaction energy between the Co–
alkyne–DMF segment and the AlMe3 segment is calculated to
be larger for CP1a_s (–32.5 kcal mol–1) than for TS1a_s (–
30.3 kcal mol–1), the difference in the distortion energies
appears to contribute significantly to the overall greater
stabilization of TS1_s toward TS1a_s (–21.6 kcal mol–1) than
that of CP1_s toward CP1a_s (–13.8 kcal mol–1).
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Scheme 8. Distortion/Interaction Analysisa
CONCLUSION
In summary, we have demonstrated that Co/LA catalytic
systems promote hydrocarbofunctionalization of alkynes with
Lewis basic and electron-deficient substrates via cooperative
C(sp2)–H activation. The combination of a cobalt–dppp
complex and an aluminum Lewis acid such as AlMe3 or MAD
proved particularly effective, promoting the reaction of
formamides, pyridones, pyridines and related azines,
imidazo[1,2-a]pyridines, and thiazole derivatives, while a
titanium Lewis acid (Ti(OiPr)4) was found to be uniquely
effective for oxazole derivatives. The Co/LA systems would
serve as alternative or complementary systems to the known
Ni/LA systems, and the present study has thus far revealed
some practically or mechanistically notable features. First, the
present systems are easy to set up using readily available,
bench-stable and inexpensive cobalt precatalysts (Co(acac)3
or CoI2) as well as common diphosphine ligand (dppp). Given
that most of the Ni/LA systems employ electron-rich, air-
sensitive, and sometimes pyrophoric monodentate ligands
such as trialkylphosphines or NHCs, the effectiveness of dppp
in the Co/LA systems not only represents a practical merit but
also provides a valuable opportunity for further improvement
and design of catalysts through exploration of the vast
chemical space of bidentate ligands. Second, the Co/Al
catalytic systems display unique site selectivity toward
substrates such as pyridone and pyridine derivatives. While
the C4 and C6 positions of pyridone have proven to be equally
reactive toward the Co/Al catalyst, completely C4-selective
alkenylation of pyridine has been achieved for the first time.
The origin of such distinct site selectivity remains to be seen.
In this context, the exclusive selectivity toward the C5
position of imidazo[1,2-a]pyridines is also intriguing. Lastly,
the mechanistic study suggested that the present C–H
activation reaction proceeds via LLHT, which represents a
commonly proposed mechanism for Ni- and Ni/LA-catalyzed
hydrocarbofunctionalization of alkenes and alkynes. This
mechanistic insight may imply that the parallelism between
low-valent Ni and Co is not superficial but is based on
fundamental common reactivity shared by these 3d transition
metals,42 which would warrant further synthetic and
mechanistic explorations.
aEnergies refer to the electronic energies (kcal mol–1)
calculated
at
SMD(heptane)-M06L/6-311++G(2df,2p)-
SDD(Co)//M06L/6-31G(d)-SDD(Co) level. ΔEdist and ΔEint refer
to distortion and interaction energies, respectively.
ASSOCIATED CONTENT
Supporting Information
We also performed distortion/interaction analysis by
different fragmentation scheme (i.e., fragmentation into Co–
alkyne–DMF segment and AlMe3 segment) to probe how
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(8) (a) Shih, W.-C.; Chen, W.-C.; Lai, Y.-C.; Yu, M.-S.; Ho, J.-J.;
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ACS Publications website.
Experimental procedures, spectral data for all new compounds
and computational details (PDF)
Crystallographic data for 11ck (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: wangchen@usx.edu.cn
*E-mail: nyoshikai@ntu.edu.sg
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Present Addresses
§Department of Chemistry, University of Warwick, CV4 7AL
Coventry, United Kingdom.
||Faculty of Chemistry, VNU University of Science, Vietnam
National University, Hanoi, Vietnam.
ACKNOWLEDGMENT
This work was supported by the Singapore Ministry of Education
Academic Research Fund Tier 2 (MOE2016-T2-2-043 to N.Y.)
and Tier 1 (RG114/18 to N.Y.), Zhejiang Provincial Natural
Science Foundation of China (Grant No. LY18B020007 to
C.W.), and Nanyang Technological University. We thank Dr.
Yongxin Li (Nanyang Technological University) for his
assistance with the X-ray crystallographic analysis.
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with the Distortion/Interaction-Activation Strain Model. Angew.
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–
cat. Co– dppp
cat. AlMe3
R1
N
R2
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R4
O
O
Al
R1
CoLn
H
O
H
+
N
R2
H
+
heptane, 60 °C
R2N
R3
R4
R3
H
Al –
LA–
N+
H
CoLn
H
N
X
CoLn
H
R
–
H
N+
+
Al
N+
H
X
O
N
CoLn
CoLn
–
H
R
H
Al
LA = Al (X = S)
Ti (X = O)
C4 & C6 activations
C4 selective
C5 selective
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