Nickel-Catalyzed Stereoselective Alkenylation of C(sp3)-H Bonds with Terminal Alkynes

Article abstract of DOI:10.1021/acs.orglett.6b03856

A nickel-catalyzed stereoselective alkenylation of an unactivated β-C(sp³)-H bond in aliphatic amide with terminal alkynes using 8-aminoquinoline auxiliary is reported for the first time. This reaction displays excellent functional group tolerance with respect to both aliphatic amides and terminal alkynes and features a cheap nickel catalytic system. The 8-aminoquinolyl directing group could be smoothly removed, and the resultant β-styrylcarboxylic acid derivatives could serve as versatile building blocks for further transformation.

Full text of DOI:10.1021/acs.orglett.6b03856

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Stereoselective Alkenylation of C(sp3)−H Bonds
with Terminal Alkynes
Cong Lin,† Zhengkai Chen,‡ Zhanxiang Liu,† and Yuhong Zhang*,†,§
†Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, China
§State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: A nickel-catalyzed stereoselective alkenylation of an unactivated β-C(sp3)−H bond in aliphatic amide with
terminal alkynes using 8-aminoquinoline auxiliary is reported for the first time. This reaction displays excellent functional group
tolerance with respect to both aliphatic amides and terminal alkynes and features a cheap nickel catalytic system. The 8-
aminoquinolyl directing group could be smoothly removed, and the resultant β-styrylcarboxylic acid derivatives could serve as
versatile building blocks for further transformation.
unctionalized alkene derivatives are powerful building
blocks in organic synthesis, as exemplified by their frequent
particular, the involvement of terminal alkynes into unreactive
C(sp3)−H activation reaction has been underdeveloped due to
the relatively high reactivity and the tendency of self-di- or
trimerizations of terminal alkynes.
F
application in diverse cross-coupling reactions, cycloaddition,
and metathesis reactions.1 Traditional approaches to build an
alkene moiety usually involved prefunctionalized starting
materials such as the Mizoroki−Heck, Suzuki, Negishi, and
Stille reactions, resulting in operational complexity and metal
waste.2 From the point of step- and atom-economic strategy,
transition-metal-catalyzed direct functionalization of C−H
bonds represents an ideal and appealing tool for the construction
of structurally diverse alkenes.3 Over the past few years, several
pioneering works for the efficient synthesis of alkene derivatives
though different transition-metal-catalyzed direct C(sp2)−H
bond functionalization have been demonstrated.4 However, the
synthetic protocol involving the direct cleavage of inert C(sp3)−
H bonds remains quite limited owing to the low reactivity of
C(sp3)−H bonds. For instance, in 2016, Yu and co-workers
reported the first example of palladium-catalyzed pyrazole-
directed alkenylation of C(sp3)−H bonds,5 whereas the
transformation was limited to the utilization of electron-deficient
alkenes as coupling partners and the irremovable directing group.
The alkenylation of unactivated C(sp3)−H bonds by the
employment of vinyl iodide has been developed by Chen,6
Shi,7 and Baran,8 respectively. Recently, the addition-type
alkenylation of unreactive C(sp3)−H bonds with internal alkynes
was achieved by You, Maiti, and others,9 resulting in the
formation of trisubstituted alkene products, which had relatively
narrow applications in organic synthesis. Despite these
significant advancements, the exploration and development of
efficient approach to the alkenylation of C(sp3)−H bonds with
readily accessible terminal alkynes to afford synthetically useful
disubstituted alkene derivatives remains a challenge.9d In
Nickel is an inexpensive and sustainable transition metal that
has been considerably exploited in various C−H bond
functionalizations. Much progress has been attained in terms of
nickel-catalyzed C(sp2)−H bond transformations, which was
pioneered by Chatani, Ge, and others.10 More recently, the initial
achievement related to C(sp3)−H bond cleavage, including
nickel-catalyzed arylation,11 alkylation,12 intramolecular amida-
tion,13 and C−S bond formation14 of aliphatic amides, has been
disclosed herein, further highlighting the formidable catalytic
ability of nickel catalyst. Our groups also demonstrated a nickel-
catalyzed unactivated C(sp3)−H bond functionalization of
aliphatic amides for the efficient construction of C−S bonds.14a
Inspired by the above encouraging works and our continuous
investigations on C(sp3)−H bond functionalizations,15 we
envisioned that the strategy of nickel-catalyzed alkenylation of
unactivated β-C(sp3)−H bonds of aliphatic amides and terminal
alkynes with the assistance of an 8-aminoquinolyl auxiliary was
feasible to lead to a wide range of disubstituted alkene derivatives.
We chose the amide 1b and phenylacetylene 2a as model
substrates to initiate our investigation. The reaction was
performed in the presence of 20 mol % of Ni(OAc)2 and 50
mol % of NaOAc in DMF at 160 °C under N2 atmosphere.
Unfortunately, the desired product 3b was not observed (Table
1, entry 1). When HOAc was used as an additive to add to the
Received: December 26, 2016
© XXXX American Chemical Society
A
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a
a,b
Table 1. Optimization of Reaction Conditions
Scheme 1. Substrate Scope of Aliphatic Amides
b
entry
catalyst
ligand
additive
HOAc
yield (%)
1
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OTf)2
NiBr2
0
35
2
3
CF3COOH
PhCOOH
HOAc
trace
25
4
5
Ph3P
40
6
Cy3P
HOAc
trace
75
65
7
MePh2P
PrPh2P
MePh2P
MePh2P
MePh2P
MePh2P
MePh2P
MePh2P
MePh2P
HOAc
HOAc
8
9
HOAc
68
10
11
12
13
14
15
HOAc
50
NiCl2
HOAc
51
NiI2
HOAc
48
(Cy3P)2NiCl2
(Ph3P)2NiCl2
HOAc
15
HOAc
15
HOAc
0
a
Reaction conditions: 1b (0.1 mmol), 2a (0.4 mmol), Ni catalyst (20
mol %), ligand (40 mol %), NaOAc (0.05 mmol), additive (0.2
mmol), DMF (0.5 mL), under N2, 160 °C, 24 h. Q = 8-quinolinyl.
b
Isolated yield by flash column chromatography.
a
reaction, the alkenylated product 3b was isolated in 35% yield
(Table 1, entry 2). Other acidic additives, such as CF3COOH
and PhCOOH, were tested, and the results were inferior to that
of HOAc (Table 1, entries 3 and 4). We also examined the ligand
effect of the transformation, and various phosphine ligands were
employed in the reaction. Noteworthy was that MePh2P was
identified as the optimal candidate to deliver the target product
3b in 75% yield (Table 1, entries 5−8). The replacement of
Ni(OAc)2 with other nickel catalysts, including Ni(OTf)2, NiBr2,
NiCl2, NiI2, (Cy3P)2NiCl2, and (Ph3P)2NiCl2, led to the obvious
decrease in the reactivity (Table 1, entries 9−14). No reaction
occurred in the absence of nickel catalyst (Table 1, entry 15).
Among other basic additives, NaOAc turned out to be the most
efficient in the formation of desired product 3b (see the
Supporting Information). Further optimization toward the
solvents revealed that DMF was superior to other solvents (see
the Supporting Information).
Having established the optimized reaction conditions, the
generality and limitation of this new alkenylation protocol with
regard to the aliphatic amides were examined (Scheme 1).
Gratifyingly, the diverse aliphatic amides bearing β-methyl group
smoothly participated in the alkenylation reaction to provide the
corresponding products with E-configuration selectivity in
moderate to good yields (3b−j). The different kinds of
substituents located at the α-carbon of the aliphatic amides,
such as long-chain alkyl, benzyl, and even phenyl, all could be
tolerated in the transformation. Noteworthy was that a 5:1 ratio
of E/Z-configuration was observed with regard to the product 3a,
presumably due to the minor steric hindrance of α-carbon of the
pivalamide 1a. It was worth mentioning that the site of C(sp3)−
H alkenylation exclusively occurred at the β-methyl group
instead of the β-methylene or γ-methyl groups of the amides,
exhibiting the high regioselectivity of the protocol. The inertness
of the CH2 group might be attributed to the steric hindrance of
methylene C(sp3)−H bonds. Some α-cyclic amides were also
Reaction conditions: 1 (0.1 mmol), 2a (0.4 mmol), Ni(OAc)2 (20
mol %), MePh2P (40 mol %), NaOAc (0.05 mmol), HOAc (0.2
mmol), DMF (0.5 mL), under N2, 160 °C, 24 h. Q = 8-quinolinyl.
b
c
Isolated yield by flash column chromatography. The ratio of E/Z in
d
1
parentheses was determined by H NMR. 1 mmol scale
compatible with the reaction system with moderate efficiency to
lead to structurally interesting α-cyclic substituted amide
derivatives (3k−m).
After examining the compatibility of the alkenylation reaction
with a variety of the amide substrates, our attention was turned
toward the reactivity of terminal alkynes (Scheme 2). It was
observed that a wide range of terminal alkynes could be well
tolerated in the reaction (4a−o). The aryl acetylenes bearing
electron-withdrawing substituents gave the only E-configuration
alkenylated products (4a−c) in moderate yields, whereas the
electron-rich aryl acetylenes could give rise to a mixture of E- and
Z-configuration alkenylated products with E-isomer as major
products (4f−j), which possibly depends on the thermodynamic
stability of E-isomer. The ortho- and meta-substituted phenyl-
acetylenes showed comparative reactivity compared with para-
substituted phenylacetylene, revealing that the orientation of the
substituents attached in the aromatic ring had a negligible
influence on the reaction (4h−j). Several heterocyclic alkynes,
including thiophene-yl group, could serve as viable substrates in
the reaction for the successful production of the corresponding
alkenylated products (4k,l). We tested the reactivity of other
heteroaryl acetylenes such as 3-ethynylpyridine and 2-
ethynylpyridine, but no products were observed. More
significantly, the aliphatic alkynes were also applicable under
the current reaction conditions, affording the desired products in
acceptable yields (4m−o, 44−64%). As for product 4o, the
shifting of the double bond occurred during the reaction.
Interestingly, the alkenylation reaction proceeded with the
replacement of nickel catalyst by cobalt catalyst, producing the
B
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a,b
was not observed (Scheme 4, eq 2). This result clearly illustrated
that the C−H cleavage step was irreversible. The deuterium-
labeled product on the alkenyl carbon was detected in the
presence of deuterated acetic acid, which was indicative of the
involvement of deuteration process during the final protonation
of C−M bond of the cyclometalation intermediate (Scheme 4, eq
3).
Scheme 2. Substrate Scope of Terminal Alkynes
The parallel intermolecular kinetic isotopic experiments were
conducted (Scheme 5), and the KIE value was determined to be
Scheme 5. Intermolecular Kinetic Isotopic Effects
a
Reaction conditions: 1a (0.1 mmol), 2 (0.4 mmol), Ni(OAc)2 (20
mol %), MePh2P (40 mol %), NaOAc (0.05 mmol), HOAc (0.2
mmol), DMF (0.5 mL), under N2, 160 °C, 24 h. Q = 8-quinolinyl.
b
c
Isolated yield by flash column chromatography. The ratio of E/Z in
1
the parentheses was determined by H NMR.
3.5 and 4.6, respectively, thus implying that C−H cleavage was
involved in the rate-determining step. Based on the preliminary
mechanistic results and previous reports,11,14,15c a plausible
reaction pathway was proposed as depicted in Scheme 6. First,
alkenylated product in 30% yield (Scheme 3). The reaction
constituted the first example of Co-catalyzed alkenylation of the
C(sp3)−H bond in aliphatic amides with terminal alkynes.
Scheme 6. Proposed Reaction Mechanism
Scheme 3. Co-Catalyzed Alkenylation of 1a with 2a
To gain insight into the mechanism, we performed radical and
deuterium-labeling experiments (Scheme 4). The addition of
Scheme 4. Radical and Deuterium-Labeling Experiments
the Ni(II) center coordinated with the nitrogen in 8-amino-
quinoline auxiliary followed by ligand exchange under basic
conditions to form the intermediate A. The cleavage of the
C(sp3)−H bond of intermediate A attaching to the Ni(II) center
generated the cyclometalated intermediate B. Subsequently, the
coordination of alkyne 2a with intermediate B formed the
complex C, followed by the migratory insertion of the alkyne to
give intermediate D. Finally, the protonation of D with AcOH
radical scavenging reagents such as 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) into the reaction had no influence
on the reaction efficiency, indicating that a radical pathway may
not be involved in the reaction process (Scheme 4, eq 1). The
reaction with the deuterium labeled compound D3-1m in the
absence of phenylacetylene under the standard reaction
conditions was performed, and the deuterium−proton exchange
C
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Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Handbook of
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could deliver the alkenylated product 3a, and the Ni(II) species
was regenerated to accomplish a catalytic cycle.
The 8-aminoquinolyl auxiliary could be readily removed in
good yield upon treatment with BF3·OEt2 and sodium hydroxide
(Scheme 7, eq 6). Notably, the resultant β-styrylcarboxylic acid 5
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Scheme 7. Removal of Directing Group and Further
Application
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can act as a versatile building block for further transformation.
The catalytic hydrogenation of product E-3a also proceeded
smoothly to give saturated compound 6 in 98% yield (Scheme 7,
eq 7).
́
́
(g) Martínez, A. M.; Echavarren, J.; Alonso, I.; Rodríguez, N.; Arrayas, R.
In conclusion, we have developed for the first time the nickel-
catalyzed direct alkenylation of unactivated C(sp3)−H bonds
with terminal alkynes by the assistance of a bidentate directing
group. The transformation features inexpensive and stable
catalyst, high efficiency, good regio- and stereoselectivity, and
broad substrate scope. The preliminary mechanistic investigation
was conducted, and a tentative reaction pathway was proposed.
The pendent 8-aminoquinoline directing group can be easily
removed, and the obtained alkenylated products can be applied
as versatile intermediates for various useful transformations.
Further studies to illuminate the reaction mechanism and extend
the application of this methodology are ongoing in our
laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03856.
General procdures and 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhzhang@zju.edu.cn.
ORCID
Yuhong Zhang: 0000-0002-1033-3429
Notes
The authors declare no competing financial interest.
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(b) Li, M.; Dong, J.; Huang, X.; Li, K.; Wu, Q.; Song, F.; You, J. Chem.
Commun. 2014, 50, 3944.
ACKNOWLEDGMENTS
■
Funding from Natural Science Foundation of China (No.
21472165, 21672186, 21602202) and the Program for Natural
Science Foundation of Zhejiang Province (LY16B020005) is
acknowledged.
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Zhang, Y. J. Am. Chem. Soc. 2015, 137, 12990. (c) Lin, C.; Zhang, J.;
Chen, Z.; Liu, Y.; Liu, Z.; Zhang, Y. Adv. Synth. Catal. 2016, 358, 1778.
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