Nickel-Catalyzed Addition-Type Alkenylation of Unactivated, Aliphatic C-H Bonds with Alkynes: A Concise Route to Polysubstituted γ-Butyrolactones

Article abstract of DOI:10.1021/acs.orglett.5b01128

(Chemical Equation Presented). Through the nickel-catalyzed chelation-assisted C-H bond activation strategy, the addition-type alkenylation of unreactive β-C(sp³)-H bonds of aliphatic amides with internal alkynes is developed for the first time to produce γ,δ-unsaturated carboxylic amide derivatives. The resulting alkenylated products can further be transformed into polysubstituted γ-butyrolactones with pyridinium chlorochromate (PCC).

Full text of DOI:10.1021/acs.orglett.5b01128

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Addition-Type Alkenylation of Unactivated,
Aliphatic C−H Bonds with Alkynes: A Concise Route to
Polysubstituted γ‑Butyrolactones
Mingliang Li, Yudong Yang, Danni Zhou, Danyang Wan, and Jingsong You*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, and State Key Laboratory of
Biotherapy, West China Medical School, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China
S
* Supporting Information
ABSTRACT: Through the nickel-catalyzed chelation-assisted
C−H bond activation strategy, the addition-type alkenylation
of unreactive β-C(sp3)−H bonds of aliphatic amides with
internal alkynes is developed for the first time to produce γ,δ-
unsaturated carboxylic amide derivatives. The resulting alkenylated products can further be transformed into polysubstituted γ-
butyrolactones with pyridinium chlorochromate (PCC).
few years, it was determined that the unactivated C(sp3)−H
ecently, transition-metal-catalyzed C−H bond activation
bonds of aliphatic amides can efficiently couple with electron-
Rhas emerged as a highly effective strategy for the
deficient alkenes through the palladium-catalyzed chelation-
assisted C−H activation, albeit the resulting β- or γ-alkenyl
carboxylic amides inevitably undergo tandem intramolecular
hetero-Michael addition to result in lactams.5 In contrast, the
addition of C(sp3)−H bonds of aliphatic acid derivatives with
alkynes is still underrepresented. This is not surprising
considering the following possible reasons. First, an alkyne
can compete with a carboxylic acid derivative for access to the
coordination sites at the metal center, which disturbs the
cleavage of an unreactive C(sp3)−H bond.6 Second, the
relatively strong π-coordination interaction of alkyne to the
metal center may result in a higher barrier to migratory
insertion of alkyne into cyclometalated species.7 Although the
addition of (hetero)aryl C(sp2)−H bonds with alkynes has
been well explored in recent years,8 expansion this chemistry to
C(sp3)−H sites is doubtless a conceptual and practical
challenging task. To the best of our knowledge, there is only
one example describing the rhodium-catalyzed alkenylation of
C(sp3)−H bonds with internal alkynes, but the transformation
is limited to the reactive benzylic α-C(sp3)−H bond of 8-
methylquinoline.9 The alkenylation of unreactive remote
C(sp3)−H bonds with alkynes still remains unsolved (Scheme
1b).
construction of synthetically enabling synthons and richly
functionalized molecules.1−3 The synthesis of γ,δ-unsaturated
aliphatic carboxylic acids has been attracting much attention
due to their versatility in organic transformations.4 Both
transition-metal-catalyzed β-C(sp3)−H addition of aliphatic
acid derivatives with alkynes and olefination with alkenes would
be ideal methods to enrich the diversity of structurally limited
β-alkenyl carboxylic acid derivatives (Scheme 1a). In addition
to step economy and simplicity, the addition-type alkenylation
is also a highly atom-economical process because every atom of
two substrates remains in the targeted molecule. Over the past
Scheme 1. Transition-Metal-Catalyzed Chelation-Assisted
C(sp3)−H Alkenylation
Nickel, an abundant and inexpensive transition metal, has
shown potential in direct C−H bond functionalization.10
Recent reports have demonstrated that nickel can efficiently
catalyze the addition reactions of C(sp2)−H bonds of electron-
deficient heteroarenes and fluoroarenes with internal alkynes
via a hydronickelation.8c,11 In 2011, Chatani reported the Ni-
catalyzed chelation-assisted oxidative cycloaddition of C(sp2)−
H bonds of aromatic amides with alkynes via the formation of a
bicyclic nickelacyle intermediate.12 Recently, the nickel-
Received: April 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01128
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Letter
catalyzed direct functionalization of unactivated C(sp3)−H
bonds has also achieved initial progress, including the
dehydrogenative [4 + 2] cyclization of formamides with
alkynes, and the arylation, alkylation, and intramolecular
amidation of aliphatic amides.13 Inspired by the above works,
we surmised that addition-type alkenylation of unactivated
C(sp3)−H bonds with internal alkynes could be feasible with
the assistance of a suitable bidentate directing group to form a
bicyclic nickelacyle species (Scheme 1c).
Scheme 2. Nickel-Catalyzed C(sp3)−H Alkenylation of
a b c
, ,
Aliphatic Amides with Internal Alkynes
Considering that 8-aminoquinoline is a highly efficient
bidentate directing group in transition-metal-catalyzed C−H
bond activation,10b,14 our study was initiated with the reaction
of 2,2-dimethyl-3-phenyl-N-(quinolin-8-yl)propanamide 1a and
1,2-diphenylethyne 2a (eq 1). To our delight, the desired
product 3a was obtained in 28% yield (E/Z = 1/2.8) in the
presence of Ni(cod)2 and PPh3 in toluene (Table S1, entry 1).
The yield was decreased to less than 10% in the absence of
PPh3 (Table S1, entry 6). Other phosphine ligands proved to
be less efficient (Table S1, entries 10−13). The addition of i-
PrOH as cosolvent could improve the yield to 54% when
Ni(OAc)2 was used instead of Ni(cod)2 (Table S1, entry 21).15
Other nickel(II) sources such as Ni(acac)2 and Ni(OTf)2 gave
diminished yields, and no desired product was afforded when
NiCl2 and Ni(dppe)Cl2 were used (Table S1, entries 16−19).
Finally, the alkenylated product could be obtained in 78% yield
in the presence of Ni(OAc)2 (30 mol %) and PPh3 (60 mol %)
in a mixture of i-PrOH and toluene (1:5). Efforts to improve
the yield proved fruitless by using other bidentate directing
groups, such as pyridin-2-yl methanamine and 2-(methylthio)-
aniline (Table S1, entries 25−26). With the optimized
conditions in hand, we next screened the substrate scope
(Scheme 2). A range of 2,2-disubstituted propanamides bearing
linear or cyclic chains were transformed into the alkenylated
products in moderate to high yields (3a−d). It is noteworthy
that the alkenylation only occurred at the C(sp3)−H bond and
the C(sp2)−H bond functionalization was not detected when 2-
phenyl substituted amides were attempted (3e and 3f). In
addition to the methyl group adjacent to an α-quaternary
carbon center, the methyl adjacent to an α-tertiary carbon
center could also undergo the C(sp3)−H bond alkenylation
with an internal alkyne (3f). The reaction conditions exhibited
good alkyne compatibility, and an E/Z value of up to 1:20
could be obtained (3g−r). The alkynes with both electron-
donating and -withdrawing groups on the aromatic rings
worked well, giving the corresponding products in moderate to
high yields (3g−n). No obvious steric effect was found even
with 1,2-di(naphthalen-2-yl)ethyne (3o). The internal alkyne
with a heteroaromatic moiety could also furnish the
corresponding product in a high yield (3p). The reactions
with unsymmetrical alkynes delivered the desired products in
good yields (3q and 3r).
a
Reactions were carried out with Ni(OAc)2 (30 mol %), PPh3 (60 mol
%), amide 1 (0.6 mmol), and internal alkyne 2 (0.2 mmol) in a
mixture of i-PrOH (0.1 mL) and toluene (0.5 mL) at 170 °C for 24 h.
b
c
1
Isolated yields. The ratio of E/Z was determined by H NMR. Q =
8-quinolinyl.
Scheme 3. Mechanistic Experiments
CC bond was deuterated, which implied that the hydrogen
source in protonolysis might come from the generated AcOH
in the reaction system (eq 3). KIE (kinetic isotope effect)
experiments were carried out with two independent reactions.
The KIE value was found to be kH/kD = 1.0, indicating that the
cleavage of the methyl C−H bond with a nickel species was not
involved in the rate-determining step (eq 4). Based on the
above results, a tentative mechanism of alkenylation was
proposed in Scheme 4. Initially, a bidentate chelation process of
To gain insight into the reaction mechanism, H/D exchange
reactions were carried out. When the reaction was performed
with D2O instead of an alkyne, 12% of the methyl hydrogen in
1c was deuterated, thus indicating the C−H bond activation is
reversible (Scheme 3, eq 2). When [D3]-1c was subjected to
the reaction conditions, 13% of the hydrogen on the resulting
B
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Letter
a b
,
Scheme 4. Plausible Mechanism of Alkenylation
Scheme 5. Construction of γ-Butyrolactones
amide 1 with a Ni(II) species forms complex IM1. The
following C(sp3)−H nickelation delivers the cyclometallic
intermediate IM2, followed by a coordination of internal
alkyne 2 to the nickel(II) center. The resulting intermediate
IM3 undergoes a migratory insertion of the alkyne to lead to a
seven-member metallacycle IM4. The sterically congested
structure of IM3 is supposed to render the migratory insertion
at higher temperature. After a protonation with AcOH (or i-
PrOH if it exists), the product 3 is released, and the Ni(II)
species is regenerated to accomplish a catalytic cycle.
The γ-butyrolactone framework is prevalent in naturally
occurring products that often exhibit a diverse array of
biological activities.16 Despite significant progress made in the
synthesis of such structures,17 exploring an effective and concise
synthetic alternative to construct polysubstituted γ-butyrolac-
tones from the abundant, yet less functionalized molecules is
still very attractive and desirable. Based on the alkenylation of
the C(sp3)−H bond of aliphatic amides, our effort was next
devoted to the synthesis of polysubstituted γ-butyrolactones. A
logical synthetic route to γ-butyrolactones should involve
removal of the 8-aminoquinoline directing group/intramolec-
ular annulation sequence. This tedious route prompted us to
explore a more efficient and concise method. Inspired by PCC-
promoted intramolecular alkoxyhydroxylation of alkenes to
form cyclic ethers,18 we deemed that a similar oxidative
cyclization could occur with imidic acids, which are
tautomerized from the corresponding amides, to furnish the
lactone structure. Gratifyingly, when amide 3b reacted with
PCC in CH2Cl2 at 100 °C, γ-butyrolactone 4 was obtained in
78% yield in concomitance with the removal of the 8-
aminoquinoline moiety (eq 5). No desired product was
a
Reactions conditions: (1) Ni(OAc)2 (30 mol %), PPh3 (60 mol %),
amide 1 (0.6 mmol, 1 M), internal alkyne 2 (0.2 mmol), i-PrOH/
toluene (1:5), 170 °C, 24 h. (2) PCC (5.0 equiv), CH2Cl2, 100 °C, 48
b
h. Two-step overall yields. The dr value was determined by 1H NMR.
c
48 h were required in the alkenylation.
provide the desired products in satisfactory yields (5a−o). The
structure of 5o was confirmed by single crystal X-ray analysis. It
is noteworthy that an array of functional groups including
OCH3, Ac, and CO2Me were compatible with the reaction
conditions, which could offer the opportunity for further
transformations. The spiro γ-butyrolactone 5n, a feature which
often occurs in biologically active molecules, could also be
formed in a moderate yield. Unsymmetrical alkynes were also
investigated, and the corresponding products 5p and 5q were
obtained in synthetically useful yields.19
Furthermore, γ,δ-unsaturated carboxylic amides have proven
to be versatile synthons for organic transformations. Besides γ-
butyrolactones, the alkenylated products 3b could also be
converted into γ-carbonyl ester 6 and γ-lactam 7. Meanwhile,
the γ-butyrolactones 4 could also be obtained via the hydrolysis
and subsequent oxidation of γ,δ-unsaturated ester 3b-1
(Scheme 6).
In conclusion, we have developed for the first time the
nickel-catalyzed addition of unactivated C(sp3)−H bonds with
both symmetrical and unsymmetrical alkynes. A broad set of
aliphatic amides can be readily alkenylated in moderate to good
yields. A sequential C(sp3)−H alkenylation/lactonization
procedure has been developed to afford a complementary
method to construct polysubstituted γ-butyrolactones from the
less functionalized aliphatic carboxylic acid derivatives. For the
first time, PCC has proven to be an efficient reagent in the
formation of γ-butyrolactones from β-alkenylated amides.
Removal of the 8-aminoquinoline directing group is not
indispensable for lactonization. In addition, the alkenylated
afforded when other oxidants, including ceric ammonium
nitrate (CAN), 1,2-dichloro-4,5-dicyanobenzoquinone (DDQ),
phenyliodine diacetate (PIDA), and Dess-Martin periodinane,
were employed (Table S2, entries 1−4).
After the feasibility of the synthetic approach to γ-
butyrolactones was evaluated, we investigated the substrate
scope in the sequential C(sp3)−H alkenylation/lactonization
reactions (Scheme 5). It was found that electron-rich, -neutral,
and -poor symmetrical diarylacetylenes all proceeded well to
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, X-ray crystallo-
graphic data, copy of 1H−1H NOESY spectra of 3b, and copies
of 1H, 13C NMR spectra for all new compounds. The
Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01128.
(11) (a) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed.
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AUTHOR INFORMATION
Corresponding Author
■
(13) (a) Nakao, Y.; Morita, E.; Idei, H.; Hiyama, T. J. Am. Chem. Soc.
2011, 133, 3264. (b) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2014,
136, 898. (c) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014, 136,
1789. (d) Li, M.; Dong, J.; Huang, X.; Li, K.; Wu, Q.; Song, F.; You, J.
Chem. Commun. 2014, 50, 3944. (e) Wu, X.; Zhao, Y.; Ge, H. Chem.
Eur. J. 2014, 20, 9530.
*E-mail: jsyou@scu.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by grants from 973 Program
(2011CB808601) and the National NSF of China (Nos.
21432005, 21272160, and 21321061).
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