Methylene C(sp3)-H arylation of aliphatic ketones using a transient directing group

Article abstract of DOI:10.1021/acscatal.7b02905

Palladium-catalyzed methylene β-C(sp³)-H arylation of aliphatic ketones using a transient directing group is developed. The use of α-benzyl β-alanine directing group that forms a six-membered chelation with palladium is crucial for promoting the methylene C(sp³)-H bond activation.

Full text of DOI:10.1021/acscatal.7b02905

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Letter
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Methylene C(sp)–H Arylation of Aliphatic
Ketones Using a Transient Directing Group
Kai Hong, Hojoon Park, and Jin-Quan Yu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02905 • Publication Date (Web): 13 Sep 2017
Downloaded from http://pubs.acs.org on September 14, 2017
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Methylene C(sp3)‒H Arylation of Aliphatic Ketones Using a Transient Directing Group
Kai Hong, Hojoon Park, Jin-Quan Yu*
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037
RECEIVED DATE (automatically inserted by publisher); yu200@scripps.edu
an optimal transient directing group in our prior work, -arylation
Abstract: Palladium-catalyzed methylene -C(sp3)–H arylation
of aliphatic ketones using a transient directing group is developed.
The use of -benzyl -alanine directing group that forms a
six-membered chelation with palladium is crucial for promoting
the methylene C(sp3)–H bond activation.
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of acyclic ketone (1) using this transient directing group provided
the desired product in only 24% NMR yield with severe
decomposition of the substrate (Table 1, TDG-1 with AgTFA as
the additive). In our extensive search for ligands that can
accelerate methylene C–H insertion, we have recently shown both
experimentally and computationally that six-membered chelation
with Pd(II) is significantly more effective than the five-membered
chelation.13 We therefore envisioned that TDG based on -amino
acid could form the 6-membered chelation in the precursor and
promote the formation of the desired 5,6-fused palladacycle
intermediate (Scheme 1B).
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Keywords: C−H activation, arylation, transient directing group,
-amino acid, ketone, palladium
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Ketones are abundant in natural products and drug molecules.
In addition, carbonyls serve as extremely versatile functional
group handles for a wide range of transformations. Reactions of
aliphatic ketones typically rely on the reactivity of the carbonyl
group or the acidic -carbon centers.1 Therefore, -C–H
functionalization via directed C–H activation2 would extend the
versatility of ketones by rendering the inert -carbon center
reactive.3 Directed -C–H activation of ketones via metal
insertion has been investigated using pre-installed oxime or imine
directing groups.4-6 To omit the installation and removal steps, we
have extensively exploited the transient directing group (TDG)
strategy7 to achieve -C(sp3)–H activation of ketones and
aldehydes. Our investigations regarding the utility of bidentate
monoprotected amino acid (MPAA) ligands in transition metal
catalyzed C–H functionalizations8,9 has led us to develop the
Pd-catalyzed C(sp3)−H functionalization of ketones using a
catalytic amino acid as a transient directing group (Scheme
1A).10,11 Subsequently, the Ge group reported that β-amino acids
could serve as transient directing groups that promote
palladium-catalyzed -C–H arylation of aliphatic aldehydes .12
Despite these advances, the activation of -methylene C–H bonds
of acyclic ketones or aldehydes using either pre-installed or
transient directing groups has remained an unsolved challenge.
Herein we report the development of a modified -amino acid
directing group that enables palladium catalyzed methylene
-C(sp3)−H arylation of linear aliphatic ketones (Scheme 1B).
Extensive modification of the -amino acids revealed that the
efficiency of the transient directing group in this transformation is
critically dependent on the structure of the amino acid. The
6-membered chelation of the -amino acid directing group with
the Pd(II) catalyst is crucial for this reaction.
Scheme 1. Pd(II)-Catalyzed C(sp3)–H Arylation Using a
Transient Directing Group Strategy
To test this hypothesis, -alanine (TDG-2) was first examined
under the same conditions (AgTFA as the additive). The yield was
increased to 41% with improved mass balance. To rule out the
enone as a possible intermediate, we have also treated the
corresponding enone with the standard arylation conditions and
no product was obtained. An extensive survey of palladium
sources, silver additives, and solvents was then performed (see
supporting information). The use of a 3:1 mixture of HFIP and
acetic acid as the solvent is the optimal media for this reaction.
Palladium precursors other than Pd(OAc)2 gave similar results.
When only AgTFA was used as the additive, a large amount of
homocoupling product (Ar−Ar) was generated along with the
rapid deactivation of the catalyst. Notably, the use of binary silver
salts (a 1:2 mixture of AgTFA and AgOAc) as the additives
suppressed the formation of the homocoupling product, allowing
formation of the desired product in 57% yield. Significantly lower
conversion and yields were observed when AgOAc or another
silver salt was used alone. Next, derivatives of -alanine, such as
ester and amides, were synthesized and evaluated (TDG-3 to 5).
Loss of reactivity with these TDGs suggests the 6-membered
imino-carboxyl chelation is crucial for the methylene C–H
insertion. To further improve the reactivity, we investigated the
influence of the substituents on -alanine. We found that
-C(sp3)−H activation of ketones and aldehydes using either
pre-installed or transient directing groups is largely limited to
primary C−H bonds (Scheme 1A).10-12 For example, palladium
catalyzed C−H arylation of the β-methylene C−H bonds on an
acyclic aldehyde has been reported to provide only 25% yield
when employing a transient directing group strategy.12 This is
unsurprising as methylene C−H bonds are significantly more
resistant to palladium insertion than primary C−H bonds due to
the steric hindrance. Indeed, while glycine was demonstrated to be
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substituents at the -position significantly reduce the reactivity
synthetic elaborations via cross-coupling reactions (2i and 2j).
(TDG-6 and 7), presumably due to slowing the imine formation.
While the presence of an -methyl group has negligible effect,
moderate-sized -substitution generally enhanced the yield
(TDG-9 to 12), and TDG-11 with a benzyl substituent was
optimal. As a comparison, the analogous L-phenylalanine gave
only 8% yield under the same conditions. The bulky tert-butyl and
1-adamantyl group, as well as aryl groups, affect the reaction
adversely (TDG-13 to 16). Further increasing temperature lead to
poor material balance. Finally, 84% NMR yield was obtained
when the reaction was extended to 72 hours with 10 mol% of
Pd(OAc)2, 30 mol% of TDG-11, 2.0 equiv. of methyl
4-iodobenzoate, 1.0 equiv. of AgTFA and 2.0 equiv. of AgOAc in
HFIP/AcOH at 120 oC.
Electron-neutral iodides, such as iodobenzene and iodotoluenes,
were equally effective coupling reagents (2k−2m). However, the
reaction with 4-iodobiphenyl gave lower yield of the desired
product (48%). Electron-rich aryl iodides are weaker oxidants to
convert the alkyl Pd(II) species into the corresponding Pd(IV)
complex. As a consequence, a reduced yield was obtained with
3-iodoanisole (2o). While both meta- and para-substituted aryl
iodides were suitable coupling partners, ortho-substituted aryl
iodides are less effective due to the steric hindrance (2p and 2q).
Lastly, a heteroaryl iodide was examined under the standard
conditions. The reaction efficiency was considerably influenced
Table 2. Scope of Aryl Iodides in Methylene C−H Arylationa,b
Table 1. Screening of the Transient Directing Groupa,b
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a Standard conditions: 0.2 mmol of 1, 2.0 equiv. of methyl 4-iodobenzoate, 10 mol%
of Pd(OAc)2, 30 mol% of TDG, 1.0 equiv. of AgTFA, 2.0 equiv. of AgOAc, 1.5 mL
b
of HFIP, 0.5 mL of acetic acid, 120 oC, under air, 48 h. The yield was determined
by 1H NMR analysis of the crude product using CH2Br2 as the internal standard. c 3.0
equiv. of AgTFA was employed as the additive. d ArF = 4-(CF3)C6F4. e Reaction was
conducted for 72 h.
a Conditions: 0.2 mmol of 1, 2.0 equiv. of aryl iodide, 10 mol% of Pd(OAc)2, 30 mol%
of TDG-11, 1.0 equiv. of AgTFA, 2.0 equiv. of AgOAc, 1.5 mL of HFIP, 0.5 mL of
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acetic acid, 120 oC, under air, 72 h.
Isolated yields.
1.0 equiv.
With the optimal TDG and reaction conditions in hand, we then
surveyed the scope of aryl iodides for the methylene -C(sp3)−H
arylation using 2-decanone (1) as the model substrate. As shown
in Table 2, a wide range of aryl iodides with substituents were
employed as the coupling partners. Compared with our previous
study,10a the scope of aryl iodide for C(sp3)−H arylation of
ketones was significantly expanded. Electron-deficient aryl
iodides bearing ester, trifluoromethyl and nitro groups at the
meta- or para-positions were well tolerated under the standard
conditions, providing consistently good yields (2a−2d, 2f),
although the yield slightly dropped to 66% with para-nitro
substitution (2e). Similar results were also observed with
fluoro-substituted aryl iodides (2g and 2h). Notably, chloro- and
bromo-substituted aryl iodides afforded the corresponding
products in high yield, preserving the halogen groups for further
2-iodo-6-(trifluoromethyl)pyridine was used.
by the coordination of the pyridine nitrogen with the palladium
catalyst. Arylation with 2-trifluoromethyl-2-iodopyridine gave the
desired product in 35% yield (2r).
The optimal C−H arylation conditions were then applied to a
variety of aliphatic ketones with methyl 4-iodobenzoate as the
coupling partner (Table 3), demonstrating the feasibility of this
protocol as a solution for -C(sp3)−H arylation of ketones. In the
presence of a primary -C−H bond, 2-pentanone 3a underwent
methylene C−H arylation predominantly at the -position,
furnishing the desired product 4a in 74% isolated yield. Substrates
containing bulky groups at the -position, such as cyclohexyl and
aryl groups, provided 4b and 4c in 39% and 41% yield,
respectively.14 The steric hindrance of a cyclohexyl group at the
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Experimental procedures and spectral data for all new compounds
(PDF). This material is available free of charge via the Internet at
-position has little impact on the reaction efficiency (72%, 4d).
C−H arylation of the ketones with -aryl substitution proceeded
smoothly to afford useful 1,2-diarylated compounds15 in moderate
yields (4e−4h), and considerable amounts of the starting materials
(25-37%) were retrieved in these cases (see supporting
information). Functional groups such as ether, acetate and amide
were well tolerated under the reaction conditions and the desired
products were obtained in moderate to good yields (4j−4l).
Sterically encumbered ketones other than methyl ketones are less
effective presumably due to the sluggish formation of the
ketimines. The use of 60 mol% transient directing group restored
the reactivity of these ketones and gave synthetically useful yields
(4m and 4n). The use of symmetrical 4-heptanone bearing two
reactive C−H sites led to a mixture of mono- and di-arylated
products in 54% combined yield (4o). In the presence of two
methylene carbon centers, the less hindered methylene C–H bond
was arylated preferentially accompanied by a small amount of
di-arylation (4p). In all cases, no diastereoselectivity was
observed (4n, 4odi and 4pdi ). Lastly, -branched ketones,
especially those bearing primary -C−H bonds, led to mixtures of
multi-arylated products with low yields.
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AUTHOR INFORMATION
Corresponding Author
*yu200@scripps.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge The Scripps Research Institute and
the NIH (NIGMS, 2R01GM084019) for financial support. H.P.
thanks the Korea Foundation for Advanced Studies for a
predoctoral fellowship.
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a
Conditions: 0.2 mmol of 3, 2.0 equiv. of methyl 4-iodobenzoate, 10 mol% of
Pd(OAc)2, 30 mol% of TDG-11, 1.0 equiv. of AgTFA, 2.0 equiv. of AgOAc, 1.5 mL
of HFIP, 0.5 mL of acetic acid, 120 oC, under air, 72 h. Isolated yields. 60 mol%
b
c
of TDG-11 was employed.
In summary, the methylene -C(sp3)–H arylation of aliphatic
ketones was developed using -benzyl -alanine as a transient
directing group. -Amino acid directing groups adopting
six-membered chelation with the palladium catalyst are found to
be advantageous in promoting the methylene C(sp3)–H bond
insertion. Further efforts to render this reaction enantioselective
using chiral -amino acids and their derivatives are currently
ongoing.
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ASSOCIATED CONTENT
Supporting Information
(11) For recent examples of C−H functionalization using a transient directing
group or an in situ-formed directing group, see: (a) Ma, F.; Lei, M.; Hu, L. Org.
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