Utilizing Carbonyl Coordination of Native Amides for Palladium-Catalyzed C(sp3)?H Olefination

Article abstract of DOI:10.1002/anie.201906075

Pd^II-catalyzed C(sp³)?H olefination of weakly coordinating native amides is reported. Three major drawbacks of previous C(sp³)?H olefination protocols, 1) in situ cyclization of products, 2) incompatibility with α-H-containing substrates, and 3) installation of exogenous directing groups, are addressed by harnessing the carbonyl coordination ability of amides to direct C(sp³)?H activation. The method enables direct C(sp³)?H functionalization of a wide range of native amide substrates, including secondary, tertiary, and cyclic amides, for the first time. The utility of this process is demonstrated by diverse transformations of the olefination products.

Full text of DOI:10.1002/anie.201906075

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Accepted Article
Title: Utilizing Carbonyl-Coordination of Native Amides for Pd–
catalyzed C(sp³)–H Olefination
Authors: Hojoon Park, Yang Li, and Jin-Quan Yu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906075
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Utilizing Carbonyl-Coordination of Native Amides for Pd–
catalyzed C(sp3)–H Olefination
Hojoon Park,[a] Yang Li,[a] and Jin-Quan Yu*[a]
Abstract: Pd(II)–catalyzed C(sp3)–H olefination of weakly-
coordinating native amides is reported. Three major drawbacks of
previous C(sp3)–H olefination protocols – 1) in situ cyclization of
products, 2) incompatibility with -H-containing substrates, and 3)
installation of exogenous directing groups – are addressed via
harnessing the carbonyl-coordination of amides to direct C(sp3)–H
activation. The method enables direct C(sp3)–H functionalization of a
wide range of native amide substrates, including secondary, tertiary,
and cyclic amides, for the first time. The utility of this process is
demonstrated by diverse transformations of the olefination products.
The Mizoroki-Heck reaction[1] has proven to be a powerful
technology for C–C bond formation.[2] While progress has been
made for the alkyl-variant of the Mizoroki-Heck reaction,[3] the
well-known challenges of this process[4] – undesired -hydride
elimination[4a] and slow oxidative addition[4b] – still limit its
development and application. Recently, alkyl-Mizoroki-Heck
reaction operating via alkyl hybrid organometallic-radical
intermediates has been shown as a promising strategy.[5] As an
alternative approach, our group developed the Pd–catalyzed
directed C(sp3)–H olefination (Scheme 1A).[6a] Presumably, the
intramolecular coordination of the directing group with the alkyl-
Pd intermediate prevents premature -hydride elimination. Since
then, several reports on Pd-catalyzed C(sp3)–H olefination have
been disclosed.[6] However, the resulting olefination products
often undergo subsequent cyclization.[6a,6c-e,6h] For example, using
the acidic amide directing group gives lactam products which
require strongly basic conditions to restore the desired alkenyl
moiety.[6a] Even with a weakly-nucleophilic carboxylic acid, the
product undergoes a facile cyclization to form a lactone.[6h] While
reversibly-cyclizing[6b] and non-cyclizing[6f,6g] C(sp3)–H olefination
reactions have been reported, the directing groups that are used
therein are either synthetically limited heterocycles or exogenous
auxiliaries, and the substrate scopes are mostly limited to - or -
quaternary substrates. Overall, C(sp3)–H olefination still remains
largely underdeveloped compared to other extensively studied
reactions such as C(sp3)–H arylation.
Scheme 1. Pd-catalyzed C(sp3)–H Olefination.
ree of Lewis-basicity,[7] which inevitably causes subsequent
cyclization via addition to the double bond (Scheme 1A).
However, utilizing a neutral, oxygen-based functional group that
would not cyclize, such as a carbonyl, as a directing group for
C(sp3)–H activation is substantially less effective due to the
weakly-coordinating nature.[8]
Recently, we reported the C(sp3)–H arylation of Weinreb
amides enabled by a pyridine-3-sulfonic acid ligand.[9] Both
experimental and computational studies indicated that the non-
coordinating anionic sulfonate group of the ligand is crucial in
promoting the reaction via preserving the cationic character of the
Pd center. While the scope of this method was limited to -
quaternary substrates, we reasoned that this is due to the
unfavorable Pd(II)/Pd(IV) catalysis with weak-coordination. On
the other hand, C(sp3)–H olefination involving Pd(II)/Pd(0)
catalysis would benefit from weak-coordination and extend the
scope to a broader range of native amides through carbonyl
coordination (Scheme 1B). Amides are undoubtedly one of the
most ubiquitous functional groups in organic chemistry,[10] and
thus the direct coupling of native amides with olefins through
C(sp3)–H activation would be highly desirable. In terms of C–C
bond disconnection strategy, such transformation extends the
classical Michael addition disconnection from the -position of a
carbonyl to the -position. Herein, we report the development of
C(sp3)–H olefination of native amides enabled by 5-
(trifluoromethyl)-pyridine-3-sulfonic acid ligand. Another unique
advantage of utilizing the carbonyl-coordination, besides the non-
cyclizing aspect, is that structurally diverse amides, including non-
acidic secondary, tertiary, and cyclic amides, becomes available
in the substrate scope (Scheme 1C).
In order to develop a broadly useful C(sp3)–H olefination
reaction, the following criteria must be met: 1) the installed alkenyl
moiety remains intact without undergoing further reactions, 2) -
H-containing substrates are compatible, and 3) ideally, native
functionalities are used as directing groups. To the best of our
knowledge, there is no protocol reported that satisfies all three
criteria above. The dilemma is that due to the inertness of C(sp3)–
H bonds, directing groups used for C(sp3)–H activation – either
nitrogen-based or anionic directing groups – require a certain deg-
[a]
H. Park, Dr. Y. Li, Prof. Dr. J.-Q. Yu, Department of Chemistry, The
Scripps Research Institute, 10550 North Torrey Pines Road, La
Jolla, CA 92037 (USA).
E-mail: yu200@scripps.edu
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Evaluation of Ligands for C(sp3)–H Olefination[a,b]
Table 2. Substrate Scope of Amides - A [a,b,c]
[a] Conditions: 1o (0.1 mmol), Pd(OAc)2 (10 mol%), Ligand (10 mol%), ethyl
acrylate (0.2 mmol), AgOAc (0.2 mmol), HFIP (0.5 mL), 70 oC, 24 h. [b] The
yield and mono:di ratio was determined by 1H NMR analysis of the crude product
using CH2Br2 as the internal standard. [c] ethyl acrylate (0.4 mmol), AgOAc (0.3
mmol), HFIP (1.0 mL), 36 h, isolated yield/mono:di ratio.
To develop the proposed olefination reaction, we first
investigated the ligand effect for the coupling of Weinreb amide
1o and ethyl acrylate (Table 1). While no product was observed
in the absence of ligand, using pyridinesulfonic acid ligands L1
and L2 enabled the reaction giving 31% and 30% yields of the
product, respectively. This is in clear contrast with the previous
arylation[9] where -H-containing substrates were incompatible,
implying that unlike Pd(II)/Pd(IV) catalysis, Pd(II)/Pd(0) catalysis
can benefit from weakly-coordinating substrates. Pyridine-2-
sulfonic acid (L3) completely inhibited the reaction, supporting our
hypothesis that the charge separation between Pd and ligand is
crucial for reactivity. The bidentate binding mode of L3 would
quench the charge separation and lead to catalyst deactivation.
Next, substitution effect on the pyridine-3-sulfonic acid ligand was
examined. While electron-donating substituents (L4, L5)
decreased the yield, electron-withdrawing substituents (L6, L7)
improved the yield. This trend led us to prepare –CF3-containing
pyridine-3-sulfonic acid ligands L8–L10. To our delight, L8 was
shown to be the superior ligand giving 65% yield, which was
further improved to 75% isolated yield with high mono-selectivity
under slightly modified reaction conditions. Interestingly, only 6%
and 38% yields were observed with L9 and L10, respectively,
implying that the pyridine-coordination needs to be finely tuned
through both sterics and electronics. An analogous carboxylic
acid ligand L11 was ineffective, showing the importance of the
non-coordinating property of the sulfonate anion. Simple pyridine
ligands (L12, L13) were ineffective in promoting the reaction. To
show that the pyridinesulfonic acid ligands are not serving as
simple sulfonic acid additives, 4-nitrobenzenesulfonic acid (L14)
was tested, and only trace amount of product was observed.
Using a combination of ligands L12 and L14 were also ineffective.
[a] Conditions: 1 (0.1–0.2 mmol), Pd(OAc)2 (10 mol%), L8 (10 mol%), ethyl
acrylate (4 equiv.), AgOAc (2–3 equiv.), HFIP (0.1–0.2 M), 70–80 oC, 24–36 h.
See Supporting Information for details. [b] Isolated yield/mono:di ratio. [c] The
isolated mono:di ratio does not necessarily reflect the mono:di selectivity of the
reaction. [d] 1.0 g (6.37 mmol) scale.
Other X-type ligands (L15–L18) did not promote the reaction as
well. Besides ligand effect, it is important to note that using HFIP
as the solvent was also crucial in observing any reactivity.
With the optimal ligand in hand, we evaluated the substrate
scope of the olefination. First, isobutyramide substrates bearing
diverse amino-groups were tested (Table 2). Simple di-alkyl
amides with varying sterics were compatible (2a–2e). Amides
containing a wide range of cyclic amino-groups were suitable
substrates as well (2f–2k). A gram-scale reaction was conducted
to give 2j in good yield. Substrates derived from amino acids such
as proline (2l), sarcosine (2m), and isonipecotic acid (2n) also
provided the products in moderate to good yields. It is noteworthy
that previous works on peptide/amino acid-directed C–H
functionalization[11] cannot utilize these amino acids due to the
lack of nitrogen-coordinating site. As described in Table 1,
Weinreb amide 1o also gave good yield. With secondary amide
(1p), expected primary olefination products and subsequent
vinylic olefination products were obtained in 61% total yield (2p:
2p’ = 2:1). No cyclization was observed, implying that carbonyl-
coordination was utilized instead of nitrogen-coordination. With s-
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Table 3. Substrate Scope of Amides - B [a,b,c]
Table 4. Olefin Coupling Partner Scope [a,b]
[a] Conditions: 1j (0.1–0.2 mmol), Pd(OAc)2 (10 mol%), L8 (10 mol%), olefin (4
equiv.), AgOAc (2–3 equiv.), HFIP (0.1–0.2 M), 70–80 oC, 24–36 h. See
Supporting Information for details. [b] Isolated yield.
des (4k–4m) were suitable substrates as well. Cyclopropyl
substrates (4n–4q) also gave moderate to good yields of the
products. The formation of 4q with 1-aminocyclopropane-1-
carboxylic acid (ACCA) amide substrate was particularly
interesting, as 2-vinyl-ACCA is a motif that is present in numerous
drug molecules, especially for the treatment of hepatitis C virus.[13]
ACCA-containing dipeptides, however, were incompatible with
our olefination conditions. Propionamide substrate delivered 4r in
37% yield. The lower yield with 4r is presumably due to the less
rigid conformation of the substrate. Lastly, the advantage of
utilizing carbonyl-coordination was further demonstrated with the
C(sp3)–H olefination of lactam substrates (4s–4v). Both 6- (4s–
4u) and 7-membered (4v) ring-size, as well as -tertiary (4u–4v)
and -quaternary (4s–4t) structures, were tested and
successfully provided the olefination products. Unfortunately, 4-
or 5-membered lactams were not reactive, presumably due to the
unfavorable geometry between directing group, catalyst, and C–
H bond. Albeit low yield, N-alkyl pyridone also underwent the
reaction to give the product 4w in 23% yield.
Finally, the scope of the olefin coupling partner was
investigated (Table 4). Commonly used Michael acceptors,
including acrylate (5a), vinyl ketone (5b), vinyl phosphonate (5c),
vinyl sulfonate (5d–5e), and vinyl sulfate (5f) were installed
through C(sp3)–H olefination in moderate to good yields. Most
interestingly, ethenesulfonyl fluoride (ESF)[14] was also reactive
and gave 5g in good yield. ESF has been extensively utilized for
the sulfur (VI) fluoride exchange (SuFEx) click reaction.[15] To the
best of our knowledge, there is no report of ESF being directly
installed at an alkyl carbon center via either C(sp3)–H
olefination[16] or even aliphatic Mizoroki- Heck reaction.[17] We
anticipate this protocol to be applied to explore new Fsp3-rich
substrates for SuFEx chemistry. Various di-substituted Michael
acceptors were compatible with the reaction to give products 5h–
5k. It is noteworthy that fumarate and maleate were successfully
employed as coupling partner for C(sp3)–H olefination for the first
[a] Conditions: 3 (0.1–0.2 mmol), Pd(OAc)2 (10 mol%), L8 (10 mol%), ethyl
acrylate (4 equiv.), AgOAc (2–3 equiv.), HFIP (0.1–0.2 M), 70–80 oC, 24–36 h.
See Supporting Information for details. [b] Isolated yield/mono:di ratio. [c] The
isolated mono:di ratio does not necessarily reflect the mono:di selectivity of the
reaction. [d] Phenyl vinyl sulfone was used for purification purpose.
econdary pivalamides (1q–1u), the desired olefination products
were delivered in moderate to good yields (2q–2u) with trace
amounts of vinylic olefination products. Lastly, we tested whether
a coordinating group as weak as an anilide-carbonyl could also
serve as a directing group for C(sp3)–H activation. Anilides have
only been used as substrates for C(sp3)–H activation through
nitrogen-coordination via deprotonation of the acidic N–H.[6a,12]
With 1v, only C(sp2)–H olefination product 2v’ was isolated. To
our delight, with the ortho-positions of the phenyl ring blocked with
methyl groups, 1w underwent the reaction to give 2w in 54% yield,
demonstrating that Pd/L8 system can exploit extremely weak
coordination for C(sp3)–H activation.
Next, the scope of the carboxyl component of amides was
evaluated (Table 3). Various alkyl substituents (4a–4d),
heteroatom-containing functional groups (4e–4h), and aromatic
groups (4i–4j) on the substrate were tolerated. -Quaternary ami-
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reaction, supporting our hypothesis on the role of the non-
coordinating sulfonate group in generating a highly electrophilic
catalyst. Using our method, structurally diverse amide substrates,
including secondary, tertiary, and cyclic amides, were shown to
undergo C(sp3)–H olefination without the undesired in situ
cyclization. Finally, olefination products were further diversified
using both alkene transformation reactions and SuFEx chemistry.
Combining the versatile reactivity of olefins with the combinatorial
nature of amides (amine + carboxylic acid) would allow one to
rapidly access diverse target compounds.
Acknowledgements
We gratefully acknowledge The Scripps Research Institute and
the NIH (NIGMS, 2R01GM084019) for financial support. We
thank Dr. Milan Gembicky (UCSD) for X-ray crystallographic
analysis, and Dr. Jason Chen and Brittany Sanchez (Scripps
Automated Synthesis Facility) for assistance with HRMS. H.P.
thanks the Korea Foundation for Advanced Studies for a
predoctoral fellowship. Y.L. thanks the National Natural Science
Foundation of China (21602167), the China Scholarship Council
(CSC) fellowship program, and Xi’an Jiaotong University for
financial support..
Scheme 2. Diversification of Olefination Products. (a) 2j (0.1 mmol), dimethyl
malonate (2 equiv.), Cs2CO3 (1 equiv.), CH3CN (0.1 M), 70 oC, 32 h. (b) 2j (0.1
mmol), DBU (1.5 equiv.), CH3NO2 (0.5 M), 0 oC, 3 h. (c) 2j (0.1 mmol), PhSH (2
equiv.), K2CO3 (2.2 equiv.), THF (0.1 M), 70 oC, 32 h. (d) 2j (0.96 mmol), 10%
Pd/C (0.07 mmol), EtOAc (0.1 M), H2 balloon (1 atm), r.t., 24 h. (e) 5g (0.38
mmol), 10% Pd/C (0.03 mmol), EtOAc (0.1 M), H2 balloon (1 atm), r.t., 48 h. (f)
5g (0.1 mmol), n-amylamine (4 equiv.), CH3CN (0.1 M), r.t., 30 min. (g) 2u (0.49
mmol), DBU (1 equiv.), EtOH (0.25 M), reflux, 1 h. (h) 6d (0.053 mmol), Ar–
OTBS (1.05 equiv.), DBU (10 mol%), CH3CN (0.1 M), r.t., 16 h.
time (5j, 5k). The formation of these tri-substituted olefins with
carboxylate groups in either E- or Z-configuration could greatly
facilitate complex olefin synthesis. Unfortunately, styrenes and
aliphatic alkenes were generally not reactive under our reaction
conditions. Only pentafluorostyrene successfully delivered the
olefinated product 5l in 54% yield.
Keywords: C–H activation • Palladium catalysis • Ligand design
• Amide • Mizoroki-Heck reaction
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olefination products using the alkenyl group as the functional
group handle (Scheme 2). Michael addition products were
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heteroatom-based (6c) nucleophiles. Hydrogenation of 2j and 5g
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diazabicyclo[5.4.0]undec-7-ene (DBU) to form the lactam product
6f in 89% yield. It is important to note that while previously
reported C(sp3)–H olefination/in situ cyclization reactions produce
auxiliary-embedded lactams,[6a,6c,6d] our two-step protocol
(olefination/DBU-mediated cyclization) can be used to prepare
general N-alkyl lactams.
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acid ligand L8 was designed. Among the known classes of ligands,
only pyridinesulfonic acid ligands were effective in promoting the
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Pd(II)–catalyzed C(sp3)–H olefination
of native amide substrates was
developed. To utilize the extremely
weak-coordinating carbonyl-
coordination of amides, an electron-
deficient pyridinesulfonic acid ligand
was designed. Structurally diverse
amide substrates, including lactams,
underwent olefination without the
undesired cyclization. Olefination
products were further diversified
through synthetic transformations on
the alkenyl moiety.
Hojoon Park, Yang Li, and Jin-Quan Yu*
Page No. – Page No.
Utilizing Carbonyl-Coordination of
Native Amides for Pd–catalyzed
C(sp3)–H Olefination
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