Distal γ-C(sp3)?H Olefination of Ketone Derivatives and Free Carboxylic Acids

Article abstract of DOI:10.1002/anie.202003271

Reported herein is the distal γ-C(sp³)?H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino-acid directing group and using the ligand combination of a mono-N-protected amino acid (MPAA) and an electron-deficient 2-pyridone were critical for the γ-C(sp³)?H olefination of ketone substrates. In addition, MPAAs enabled the γ-C(sp³)?H olefination of free carboxylic acids to form diverse six-membered lactones. Besides alkyl carboxylic acids, benzylic C(sp³)?H bonds also could be functionalized to form 3,4-dihydroisocoumarin structures in a single step from 2-methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ-C(sp³)?H olefinated products.

Full text of DOI:10.1002/anie.202003271

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Accepted Article
Title: Distal γ-C(sp3)−H Olefination of Ketone Derivatives and Free
Carboxylic Acids
Authors: Han Seul Park, Zhoulong Fan, Ru-Yi Zhu, and Jin-Quan Yu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003271
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10.1002/anie.202003271
Angewandte Chemie International Edition
RESEARCH ARTICLE
Distal γ-C(sp3)−H Olefination of Ketone Derivatives and Free
Carboxylic Acids
Han Seul Park, Zhoulong Fan, Ru-Yi Zhu, and Jin-Quan Yu*
Abstract: We herein report the distal -C(sp3)–H olefination of
ketone derivatives and free carboxylic acids. Fine tuning of our
previously reported imino-acid directing group and use of the ligand
combination of mono-N-protected amino acid (MPAA) ligands and
electron-deficient 2-pyridone ligands were critical for the -C(sp3)–H
olefination of ketone substrates. In addition, MPAA ligands were
found to enable the -C(sp3)–H olefination of free carboxylic acids to
form diverse 6-membered lactones. Besides alkyl carboxylic acids,
benzylic C(sp3)–H also could be functionalized to form 3,4-
dihydroisocoumarin structures in a single step from 2-methyl benzoic
acid derivatives. The utility of these protocols was demonstrated in
large scale reactions and diversifications of the -C(sp3)–H olefinated
products.
ketones has thus far been limited to Pd(II)/Pd(IV) catalytic cycles.
To expand the scope of transformations, it is necessary to
unlock the reactivity of Pd(II)/Pd(0) catalysis for ketones.
Especially, C(sp3)–H olefination[6b,6e,7]
, a formal alkyl-Heck
reaction, poses its unique importance as Heck type reactions of
alkyl halides are usually suffered by premature -H elimination
and slow oxidative addition.[8] However, we also anticipated that
the imino-acid bidentate directing group might prove challenging
for the desired -C(sp3)-H olefination reaction, since the high
stability of the resultant bicyclic palladation intermediate might
hinder the necessary olefin migratory insertion step.
Herein we report the palladium catalyzed olefination of
unactivated -C(sp3)–H bonds of ketone substrates through
oxime-based directing group modification and use of a mono-N-
protected amino acid (MPAA) and electron-deficient 2-pyridone
ligand combination. Building on the observed ligand effect in -
C(sp3)–H olefination of ketone derivatives, we also developed -
C(sp3)–H olefination reaction of free carboxylic acids using
MPAA ligands. Without installation of exogenous directing
groups, both aliphatic carboxylic acids and 2-methyl benzoic
acid derivatives were olefinated (Scheme 1C-D).
Introduction
Carbonyl groups are common functional motifs in
agrochemicals, pharmaceuticals and natural products. In recent
years, palladium catalyzed C–H activation reactions directed by
binding motifs have been proven to be useful synthetic
strategies. Although ligand development has enabled carbonyl
directed Pd-catalyzed C(sp2)–H activation reactions,[1] the
corresponding palladation of C(sp3)–H bonds remains
challenging due to the weakly coordinating nature of the
carbonyl oxygen to palladium (Scheme 1A). Thus, the
development of synthetically useful directing groups (DGs) has
been a major focus for the palladium catalyzed C(sp3)–H
activation of ketones. The stoichiometric palladation of oximes[2]
was successfully exploited in pioneering studies towards
developing catalytic reactions,[3] albeit with limited substrate
scope and transformations (Scheme 1B).
Recently, we have designed L,X-type covalent and
transient directing groups to enable a wide range of C(sp3)–H
activation reactions with both ketones and aldehydes.[4] In
particular, a new aminooxy acetic acid directing group enabled
C(sp3)–H iodination[5a] and (hetero)arylation[5b-c] of ketones with a
broad substrate scope and superior reactivity. However, most
transformations with this DG target the β-C(sp3)–H bond, with
only one example of -C(sp3)–H (hetero)arylation.[5c] Because -
functionalized carbonyls cannot be accessed through traditional
carbonyl reactivity, such as enolate chemistry or conjugate
addition, the selective functionalization of -C(sp3)–H bonds
could be extremely useful.
Scheme 1. Pd(II)-Catalyzed C(sp3)–H Activation of Ketones and Free
Carboxylic Acids
Results and Discussion
To address this synthetic need, we aimed to further
develop the -C(sp3)–H activation of ketones using our new
imino-acid directing group. The -C(sp3)–H activation[4e,6] is
relatively uncommon and Pd-catalyzed C(sp3)–H activation of
Table 1. Directing Group Evaluation for γ-C(sp3)–H Olefination of Ketone
Derivatives[a,b]
[*]
H. S. Park, Dr. Z. Fan, Dr. R.-Y. Zhu, 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.
1
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[a] Reaction conditions: 1a-x (0.05 mmol, 1.0 equiv), ethyl acrylate (2.0 equiv),
Pd(OAc)2 (10 mol%), AgOAc (2.0 equiv), HFIP (0.5 mL), 110 °C, under air, 15
h. [b] Yield determined by 1H NMR analysis of the crude mixture using CH2Br2
as the internal standard. HFIP = 1,1,1,3,3,3-Hexafluoro-2-propanol.
Based on our previous success in the -C(sp3)–H arylation
of ketone derivatives, -C(sp3)–H olefination was investigated
with 4,4-dimethyl pentanone as a model substrate. Trace
amount (less than 5%) of the desired product was observed with
the optimal directing group (DG1) for -C(sp3)–H arylation. The
yield was not further improved despite extensive screening of
conditions with DG1. Therefore, we decided to tune the
properties of the directing group. Gratifyingly, the yield increased
to 22% when the electron deficient amide was introduced
instead of the weakly coordinating carboxylic acid (DG2).
Installation of an electron rich amide to the directing group
afforded 2a-3 in 8% yield (DG3). Removal of the gem-dimethyl
groups resulted in no product formation under the same
conditions probably due to a diminished Thorpe-Ingold effect
(DG4 and DG5).
Having identified DG2 as the optimal directing group, we
turned our attention to exploring the ligand effects in -C(sp3)–H
olefination. We first tried electron-deficient 2-pyridone ligand(L1)
which was critical for the -C(sp3)–H arylation.[5c] However, a
noticeable increase in yield was not observed. The mono-N-
protected amino acid (MPAA) Ac-Phe-OH (L2) ligand led to a
dramatic increase in yield to 38%. Among various N-protecting
groups, acetyl protection gave the best yield whereas carbamate
based protecting groups resulted significant decrease in yields
(L2-L4). Next, MPAA ligands bearing different side chains were
also examined. Ac-Ala-OH (L5) provided the product in 45%
yield. Further increasing the side chain sterics was detrimental
to the reactivity (L6-L8). Ac-βAla-OH (L9) afforded a slightly
lower yield than L5. Removing the methyl from L5 suppressed
the reactivity (L10). The combination of a protected amino group
and a free carboxylic acid group was essential for the higher
reactivity for MPAAs in this reaction, since modification to either
site led to no improvement in yields (L11-L13). Further
screening of conditions revealed that the use of oxygen as a co-
oxidant in addition to silver salts aided catalytic turnovers.
Interestingly, adding the 2-pyridone ligand, which was not an
effective ligand alone, in the presence of MPAA ligand promoted
the reactivity synergistically. After screening of 2-pyridone
ligands with various electronic properties, a ligand combination
of L5 and L14 was found to be optimal for this reaction (See SI
for detailed screening information).
[a] Reaction conditions: 1a (0.05 mmol, 1.0 equiv), ethyl acrylate (2.0 equiv),
Pd(OAc)2 (10 mol%), ligand (20 mol%), AgOAc (2.0 equiv), HFIP (0.5 mL),
110 °C, under air, 15 h. [b] Combined yield of mono/di products determined by
1H NMR analysis of the crude mixture using CH2Br2 as the internal standard.
Product observed as E/Z mixture. [c] Two ligands were applied 20 mol% each,
oxygen atmosphere. [d] AgOAc (2.0 equiv) and Ag2CO3 (1.0 equiv) were used
instead of AgOAc (2.0 equiv)
The attempted β-C(sp3)–H olefination of substrate 1a’
(derived from pinacolone) under the same conditions afforded
trace amount of product determined by 1H NMR. Moreover,
when 1a and 1a’ were reacted in the same pot, only 1a was
functionalized in 70% yield whereas 1a’ provided trace amount
of product (Scheme 2). These results were interesting
considering that β-C(sp3)–H functionalization is typically favored
over the -C(sp3)–H bond.[9] This unusual preference for -
C(sp3)–H functionalization is likely the result of the greater
stability of the five-six bicyclic intermediate arising from 1a’
compared to the analogous six-six bicycle resulting from 1a; its
greater stability thus renders it more inert to migratory insertion
of the bound alkene. Similar trends favoring insertion to six-six
palladacycles were observed for alkyne[10a-b] and alkene[10c]
coupling partners when bidentate directing groups were applied.
Scheme 2. Competition Experiment, conditions: 1a (0.05 mmol), 1a’ (0.05
mmol), Pd(OAc)2 (10 mol%, 0.01 mmol), L5 (20 mol%, 0.02 mmol), L14 (20
mol%, 0.02 mmol), ethyl acrylate (3.0 equiv, 0.3 mmol), AgOAc (2.0 equiv, 0.2
mmol), Ag2CO3 (1.0 equiv, 0.1 mmol), HFIP (1 mL), 120 °C, 6 h, Combined
yield of mono/di products determined by 1H NMR analysis of the crude mixture
using CH2Br2 as the internal standard. Yields were calculated based on the
initial amount of substrates.
Table 2. Ligand Evaluation for γ-C(sp3)–H Olefination of Compound 1a[a,b]
Table 3. Scope of Ketone Derivatives [a,b,c]
2
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[a] Reaction conditions: 1 (0.1 mmol, 1.0 equiv), ethyl acrylate (3.0 equiv),
Pd(OAc)2 (10 mol%), L5 (20 mol%), L14 (20 mol%), AgOAc (2.0 equiv),
Ag2CO3 (1.0 equiv), HFIP (1.0 mL), 120 °C, oxygen atmosphere, 15 h. [b]
Isolated yields; products isolated as E/Z mixture. [c] Numbers in parentheses
indicate the ratio of mono:di. [d] L9 (20 mol%) instead of L5.
[a] Reaction conditions: 1a (0.1 mmol, 1.0 equiv), olefin (3.0 equiv), Pd(OAc)2
(10 mol%), L5 (20 mol%), L14 (20 mol%), AgOAc (2.0 equiv), Ag2CO3 (1.0
equiv), HFIP (1.0 mL), 120 °C, oxygen atmosphere, 15 h. [b] Combined
isolated yields of mono and di products; products isolated as E/Z mixture. [c]
Numbers in parentheses indicate the ratio of mono:di.
With the best conditions in hand, we next explored the
scope of ketone derivatives. Oximes derived from methyl
ketones with various alkyl chains were preferentially
functionalized at the -position (2a-g). Substrates with linear
alkyl chains afforded moderate to good yields (2a-d). Substrates
with bulky β-groups such as isobutyl (2e) or isopropyl (2f) were
also compatible. Substrates with cyclic substituents such as
cycloheptyl (2h) and cyclohexyl (2i) provided the desired
products. Functional groups such as tetrahydropyran ring (2j),
methyl ester (2k) and protected piperidine (2l) were also
tolerated. Aromatic substituents such as phenyl (2m) and 4-
methoxyphenyl (2n) were compatible with the new conditions. In
addition to methyl ketones, substrates bearing alkyl chains with
different chain lengths (2o-q) were tested and exhibited similar
yields to corresponding methyl ketone substrates (2h and 2j).
Next, we examined the scope of partner olefins. A range of
acrylates with various alkyl chains (3a-3i) and olefins with
electron withdrawing groups were compatible with the optimized
conditions. The reaction was mono selective when diethyl
phophonate was applied as the coupling partner (3j). Phenyl
vinyl sulfone also gave the olefinated product albeit in low yield
(3k). Complex acrylic acid derivatives could be used for this
reaction (3l-3n). Acrylic esters derived from (-)-menthol (3l),
tetrahydrogeraniol (3m) and cholesterol (3n) were also
successfully employed in the reaction.
C(sp3)–H activation[11] reactions of carboxylic acids
employing various nitrogen-based auxiliaries have been
extensively studied.[12] The apparent disadvantages of installing
and removing auxiliaries prompted us and others to use free
carboxylates as directing groups through ligand development. A
series of β-C(sp3)–H functionalization reactions of free carboxylic
acids have been achieved including olefination,[7f] oxidation,[13a-b]
arylation,[13c-e] and cross-coupling.[13f-g] However, it is rather
challenging to perform -C(sp3)–H activation with weakly
coordinating carboxylates because the formed 6-membered
palladacycles are highly unstable. Indeed, only -C(sp3)–H
arylations are reported for free carboxylic acids so far.[14]
Given the fact that MPAA ligands were able to promote -
C(sp3)–H olefination reactions of ketone substrates, we decided
to revisit the -C(sp3)–H olefination of free carboxylic acids which
previously required nitrogenous directing groups. With the model
substrate 4,4-dimethyl butanoic acid (4a), the ligand effect on -
C(sp3)–H olefination of free carboxylic acids was explored (Table
5). No product was observed without ligand. Gratifyingly, mono-
N-protected amino acid ligand Ac-Phe-OH (L2) provided 55%
yield of a cyclized lactone product generated via olefination
followed by intramolecular conjugate addition of the carboxylate.
Replacing the acetyl N-protecting group with different groups
such as Boc or Fmoc was detrimental to the reactivity (L2-L4).
L5, which was the best MPAA ligand for the olefination of ketone
derivatives gave a lower yield compared to L2. Changing the
side chain sterics or chain length decreased the reactivity (L7,
L9 and L10). 2-Pyridone ligand (L1) was not as effective as
Table 4. Scope of Olefin Partners[a,b,c]
3
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MPAA ligands. Acetyl-protected aminoethyl phenyl thioether
ligand (L15), the critical component for the successful β-C(sp3)–
H olefination of free carboxylic acids, provided just 20% yield in
-C(sp3)–H olefination. Other monodentate ligands previously
used to promote C(sp3)–H olefination (L16 and L17)[6b,7g]
showed poor to almost no reactivity in this case. Fine tuning of
the reaction conditions revealed that increasing the loading of
silver carbonate to 2 equiv. is beneficial to the reactivity.
Table 5. Ligand Evaluation for Free Carboxylic Acid γ-C(sp3)–H Olefination[a,b]
[a] Reaction conditions: 4a (0.10 mmol, 1.0 equiv), Benzyl acrylate (2.0 equiv),
Pd(OAc)2 (10 mol%), ligand (10 mol%), Na2HPO4•7H2O (1.0 equiv), Ag2CO3
(1.0 equiv), HFIP (1.0 mL), 120 °C, under air, 18 h. [b] Yield determined by 1
H
NMR analysis of crude mixture using CH2Br2 as internal standard. [c] 2.0 equiv
of Ag2CO3 instead of 1.0 equiv.
With the optimized conditions in hand, a series of free
carboxylic acid substrates were tested for newly discovered
reactivity (Table 6). Substrates bearing various alkyl chains were
functionalized in moderate to good yields (5a-5d). A -dialkyl
substituted carboxylic acid was also compatible with this
conditions (5e). Substrates containing methoxy or phenoxy
group provided the desired products albeit in moderate yields (5f
and 5g). Substrates with phenyl and 4-methoxyphenyl groups
were also compatible substrates (5h and 5i).
To further demonstrate the generality of this free carboxylic
acid directed olefination reaction, we tried a different class of
substrate. To our delight, not only open chain aliphatic
carboxylic acids, but also 2-methyl benzoic acid derivatives with
benzylic -C(sp3)–H bonds could be functionalized under the
conditions. Benzylic -C(sp3)–H substrates afforded cyclized 3,4-
dihydroisocoumarin structures, which are commonly found in
key intermediates for the synthesis of bioactive molecules.[15]
Further optimization revealed that simply changing the base to
potassium acetate (KOAc) could increase the yield to 72% for
2,6-dimethyl benzoic acid substrate (5j). These new conditions
for benzylic -C(sp3)–H were then applied to various 2-
methylbenzoic acid derivatives. With the methyl group at the
meta position, a lower yield of 58% was obtained (5k).
Substrates containing electron-withdrawing groups (nitro, fluoro
and trifluoromethyl) afforded the products in good to excellent
yields (5l-5n). An electron-donating ortho-methoxy substituent
was also tolerated (5o). 2,6-Dimethyl benzoic acids with different
substituents were successfully converted into the corresponding
3,4-dihydroisocoumarin derivatives (5p and 5q). 2-Methyl-1-
naphthoic acid underwent olefination in 40% yield (5r).
[a] Reaction conditions: 4 (0.10 mmol, 1.0 equiv), benzyl acrylate (2.0 equiv),
Pd(OAc)2 (10 mol%), L2 (10 mol%), Na2HPO4•7H2O (1.0 equiv), Ag2CO3 (2.0
equiv), HFIP (1.0 mL), 120 °C, under air, 18 h. [b] Isolated yields. [c] Ethyl
acrylate (2.0 equiv) was used instead of benzyl acrylate. [d] KOAc (1.0 equiv)
was used instead of Na2HPO4•7H2O (1.0 equiv).
A range of olefins were shown to be compatible with the
new conditions (Table 7). Various acrylate derivatives afforded
the desired -lactone products in good yields (6a-6c). Other ,-
unsaturated activated olefins including Weinreb amide derived
acrylamide, methyl vinyl ketone and phenyl vinyl sulfone gave
the desired product in moderate to good yields (6d-6f). Notably,
five-membered lactone product was isolated as the major
product when pentafluorostyrene was applied (6g). This product
is probably generated through sequential -C(sp3)–H olefination
followed by allylic C–H functionalization.
Table 7. Scope of Olefin Partners for Free Carboxylic Acid[a,b]
Interestingly,
a 5-bromo substituted substrate delivered a
mixture of mono- and di- olefinated product (5s and 5s’).
Table 6. Scope of Free Carboxylic Acids[a,b]
4
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10.1002/anie.202003271
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Conclusion
[a] Reaction conditions: 4a (0.10 mmol, 1.0 equiv), olefin (2.0 equiv), Pd(OAc)2
(10 mol%), L2 (10 mol%), Na2HPO4•7H2O (1.0 equiv), Ag2CO3 (2.0 equiv),
In summary, the distal -C(sp3)–H olefination reactions of
ketone derivatives and free carboxylic acids were developed.
For ketone substrates, using modified imino-amide L,X-type
directing group and applying both MPAA ligand and 2-pyridone
ligand were critical to achieve a high reactivity. MPAA ligands
were found to be efficient ligands for promoting the free
carboxylic acid directed -C(sp3)–H olefination reactions. Under
similar conditions, both open chain alkyl carboxylic acids and 2-
methyl benzoic acid derivatives were functionalized in good
yields. Considering the difficulties inherent in the alkyl variant of
Heck reaction, these methods provide new synthetic
disconnections. Gram-scale reactions and derivatizations of the
olefinated products show the potential applicability of these
reactions.
HFIP (1.0 mL), 120 °C, under air, 18 h. [b] Isolated yields. [c] KOAc (1.0 equiv)
instead of Na2HPO4•7H2O (1.0 equiv). [d] KHCO3 (1.0 equiv) was used instead
of Na2HPO4•7H2O (1.0 equiv).
To showcase the synthetic utility of these reactions, the
olefinations of the ketone substrate 1a and carboxylic acid
substrate 4a were conducted on larger scales (2.0 mmol) and
afforded 73% and 79% of isolated yields respectively confirming
the robustness of these conditions. These olefinated products
were successfully derivatized. The ketone auxiliary was easily
removed by acidic hydrolysis followed by esterification.[16]
Hydrogenation of 7 using Pd/C catalyst enabled the reduction of
the double bond (8a) in 98% yield. Moreover, the ketone
carbonyl group was selectively reduced to secondary alcohol
without affecting other functional groups of the molecule (e.g.
ester, 8b). Treatment with 1 equiv. of LiHMDS base at -78oC
selectively deprotonated the α-C–H of the methyl group and
provided the cyclized product through an intramolecular Michael
addition. (8c) The uncyclized product of the free carboxylic acid
could be obtained when 5a was treated with 1.2 equiv. of
LiHMDS (9a). Global reduction of 5a with LiAlH4 afforded the
1,3,7-triol (9b). Selective hydrolysis of the benzyl ester was
accomplished under acidic conditions and afforded δ-lactone
with a carboxylic acid group which could be used as a handle for
further functionalization of the product (9c) (Scheme 3).
Acknowledgements
We gratefully acknowledge The Scripps Research Institute
(TSRI), the NIH (NIGMS, 2R01GM084019) for financial support.
We gratefully acknowledge Dr. Jason Chen, Brittany Sanchez,
and Emily Sturgell (Scripps Automated Synthesis Facility) for
HRMS analysis. H.S.P. thanks the Korea Foundation for
Advanced Studies (KFAS) for a predoctoral fellowship. We thank
Dr. Kevin Wu, Alastair N. Herron and Hojoon Park for
proofreading and helpful discussions.
Conflict of interest
The authors declare no conflict of interest.
Keywords: C(sp3)–H activation • distal C–H bond • MPAA •
olefination•pyridone
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Scheme 3. Synthetic Applications: a) 1a (2.0 mmol, 1.0 equiv), ethyl acrylate
(3.0 equiv), Pd(OAc)2 (10 mol%), L5 (20 mol%), L14 (20 mol%), AgOAc (2.0
equiv), Ag2CO3 (1.0 equiv), HFIP (20.0 mL), 120 °C, oxygen atmosphere, 40 h.
b) 4a (2.0 mmol, 1.0 equiv), benzyl acrylate (2.0 equiv), Pd(OAc)2 (10 mol%),
L2 (10 mol%), Na2HPO4•7H2O (1.0 equiv), Ag2CO3 (2.0 equiv), HFIP (20.0
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mL), 120 °C, under air, 24 h. c) H2, Pd/C, MeOH, RT, 15 h. d) NaBH4 (1.0
equiv), THF, 0 oC, 4 h. e) LiHMDS (1.0 equiv), THF, -78 °C, 3 h, f) LiHMDS
(1.2 equiv), THF, -78 °C, 3 h. g) LiAlH4 (4.0 equiv), THF, 0 oC to RT, 10 h. h) 6
M HCl (aq.), 80 °C, 12 h.
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5
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RESEARCH ARTICLE
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10.1002/anie.202003271
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
Distal -C(sp3)–H olefination reactions of ketone derivatives and free carboxylic acids were realized. For ketone substrates, fine
tuning of the directing group and applying a mono-N-protected amino acid (MPAA) and 2-pyridone ligand combination were critical to
achieve high reactivity. MPAA ligands also enabled free carboxylic acid directed -C(sp3)–H olefination.
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