Ligand-Enabled Cross-Coupling of C(sp3)-H Bonds with Arylsilanes

Article abstract of DOI:10.1021/jacs.5b00890

Pd(II)-catalyzed cross-coupling of C(sp³)-H bonds with organosilicon coupling partners has been achieved for the first time. The use of a newly developed quinoline-based ligand is essential for the cross-coupling reactions to proceed.

Full text of DOI:10.1021/jacs.5b00890

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Ligand-Enabled Cross-Coupling of C(sp3)–H Bonds with Arylsilanes
Jian He, Ryosuke Takise, Haiyan Fu, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 30 Mar 2015
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Ligand-Enabled Cross-Coupling of C(sp3)–H Bonds with Arylsilanes
Jian He, Ryosuke Takise, Haiyan Fu, Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037
H cross-coupling with arylsilanes, cross-coupling of inert C(sp3)–
ABSTRACT: Pd(II)-catalyzed cross-coupling of C(sp3)–H bonds
with organosilicon coupling partners has been achieved for the
first time. The use of a newly developed quinoline-based ligand is
essential for the cross-coupling reactions to proceed.
H bonds with organosilicon reagents remains to be reported.
Encouraged by our recent observation that pyridine- and
quinoline-based ligands promote C(sp3)–H olefination via a
Pd(II)/Pd(0) catalytic cycle,16 we launched our efforts to develop
new ligands that could promote β-C(sp3)–H cross-coupling of
carboxylic acid derivatives with organosilicon reagents.
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Inspired by the Pd(0)-catalyzed cross-coupling reactions,1 we
embarked on the development of Pd(II)-catalyzed cross-coupling
of C–H bonds with organometallic reagents. A Pd(II)/Pd(0)
catalytic cycle has been established for the cross-coupling of
C(sp2)–H bonds with organotin2 and organoboron reagents3 with
limited substrate scopes. Subsequently, C–H cross-coupling with
readily available organoboron reagents are expanded to broadly
useful substrates including benzoic acids and phenyl acetic acids.
Table 1. Screening of Ligand for C(sp3)–H Cross-Coupling
with Arylsilanesa,b
In contrast, analogous cross-coupling of C(sp3)–H bonds with
4,5
organometallic reagents has met with limited success.6 Although
pyridine-directed C(sp3)–H cross-coupling with alkyl boronic
acids is successful,3 extending this methodology to aliphatic acid
substrates affords poor yields (<30%) (Eq 1).4 The development
of an efficient N-methoxyamide directing group allowed for a rare
cross-coupling of β-C(sp3)–H bonds with boronic acids (Eq 2).7
Unfortunately, this protocol is incompatible with the substrates
containing α-hydrogen atoms. Although β-C(sp3)–H arylation
with aryl halides via Pd(II)/Pd(IV) catalysis has been developed to
accommodate a broader range of substrates,8 the C(sp3)–H cross-
coupling reaction involving a Pd(II)/Pd(0) catalytic cycle offers a
distinct platform for ligand development that will lead to
improved catalysis and selectivity. Herein, we report the first
example of β-C(sp3)–H cross-coupling of carboxylic acids with
arylsilanes using perfluorinated N-arylamide auxiliary (Eq 3).9
The discovery of a new quinoline-based ligand is crucial for the
development of this cross-coupling of C(sp3)–H bonds with
arylsilanes.
Scheme 1. Palladium-Catalyzed C(sp3)–H Activation/Cross-
Coupling Reactions of Carboxylic Acid Derivatives
a
Reaction conditions: substrate 1 (0.1 mmol), 2a (2.0 equiv.), Pd(OAc)2 (10 mol%),
ligand (20 mol%), AgF (3.0 equiv.), 1,4-dioxane (1.0 mL), 110 °C, 12 h. b The yield
was determined by 1H NMR analysis of the crude product using CH2Br2 as the
internal standard. c After 8 h, the second batch of 2a (2.0 equiv.) and AgF (3.0 equiv.)
was added, and the reaction proceeded for another 10 h.
Our experiments commenced by investigating the coupling of
an alanine-derived amide 1 with various organosilicon reagents
(see supporting information). We examined various oxidants and
solvents, as well as those additives previously proven to be
beneficial to the Hiyama cross-coupling. We found the reaction of
amide 1 with 2 equiv. of triethoxyphenylsilane (2a) in the
presence of 10 mol% of Pd(OAc)2, 20 mol% of 2-picoline (L1),
and 3 equiv. of AgF in 1,4-dioxane at 110 °C afforded the desired
product 3a in 40% yield. AgF proves to be the only effective
additive which has dual functions in this transformation: 1) silver
salts are one of the most efficient and commonly used oxidants to
reoxidize Pd(0) to Pd(II) in Pd(II)/Pd(0) catalytic cycles;17 2)
A wide range of organosilicon reagents have been successfully
used as coupling partners in the Hiyama cross-coupling reactions
of aryl halides.1f,10 Important advances have also been made in the
cross-coupling of alkyl halides with arylsilanes.11 Despite
significant progress of Pd-,12,13 Rh-,14 and Ni-catalyzed15 C(sp2)–
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fluoride sources are known to activate organosilicon coupling
steric and electronic properties, we introduced 5-, 6-, and 7-
partners, promoting transmetallation of aryl groups to Pd(II).18
Analysis of the reaction mixture showed that a substantial amount
of organosilicon reagents were homo-coupled to give the biaryl
side product. In the absence of ligands, the desired coupling
reaction did not proceed, indicating a significant ligand effect. We
therefore began to examine a variety of substituted pyridine
ligands that could potentially accelerate the C(sp3)–H cross-
coupling further in order to outcompete the homo-coupling
process (Table 1). 2,6-Lutidine (L2) and 2,6-dimethoxypyridine
(L3) gave the desired product in lower yields (28% and 13%
respectively), demonstrating that the increase of steric bulk and
electron-donating ability of pyridine-based ligands has negative
impact on the reaction. However, replacement of 2-picoline (L1)
with electron-deficient 2-trifluoromethylpyridine (L4) resulted in
a complete loss of reactivity.
membered rings to the ligands (L16–L18), and found L18
provided the highest yield of 70%. The yield was further
increased to 93% when a second batch of 2a and AgF was added
after 8 hours.
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Cross-coupling reactions of alanine-derived amide 1 with a
broad
range
of
electron-rich
and
electron-poor
triethoxyarylsilanes were carried out under the standard
conditions (Table 2). Triethoxyarylsilanes containing methyl and
methoxy groups on the aryl ring afforded desired products in
excellent yields (3b, 3c). para-Fluoro, chloro, bromo, and
trifluoromethyl groups are well tolerated, furnishing
phenylalanine derivatives in yields from 75% to 82% (3d–3g).
This reaction is also compatible with meta- and ortho-substituted
triethoxyarylsilanes (3h, 3i). Furthermore, the cyclobutyl C(sp3)–
H bond in amide substrate 4 derived from 1-aminocyclobutane-1-
carboxylic acid was successfully functionalized to afford the
corresponding β-alkyl-β-aryl-α-amino acid derivatives in 72%
yield with high levels of diastereoselectivity (Scheme 2). The
cross-coupling reaction was also carried out on a gram scale
without a noticeable decrease in yield (3e). Importantly, in the
absence of external inorganic bases, complete retention of α-
chirality (3b) was observed in the β-C(sp3)–H cross-coupling
using amide 1 (99% ee) as the substrate.
While these pyridine ligands have been previously shown to
promote arylation of C(sp3)–H bonds with aryl iodides,19 the
failed attempts to improve the reaction suggest that the
transmetallation and reductive elimination at the Pd(II) centers
require a different type of ligands. The tricyclic quinoline ligands
(L5, L6) were therefore chosen because they were previously
used to promote Pd-catalyzed C(sp3)–H olefination reactions via
Pd(II)/Pd(0) catalysis.16 We found that the use of L6 increased the
yield of 3a to 48%. Based on this finding, we systematically
surveyed different types of quinoline-based ligands. Gratifyingly,
the simple quinoline (L7) further improved the reactivity, giving
3a in 56% yield. While the substituent at the 6-position of
quinoline L8 did not affect the yield, installation of a methyl
group at the 8-position (L9) drastically decreased the reaction
efficiency. Any substitution at the 2-positions of quinoline-based
ligands (L10, L11) was detrimental to the cross-coupling
reactions. These investigations showed that this Hiyama-type
cross-coupling is very sensitive to the steric effect of quinoline-
based ligands. In terms of electronic effects, electron-donating
groups at the 3- or 4-positions of quinolines (L12–L14) gave
moderate yields from 48% to 52% whereas electron-deficient 4-
chloroquinoline (L15) afforded only 34% yield. Given that
quinolines containing fused carbocylic rings could have distinct
Scheme 2. Cross-Coupling of Cyclobutyl C(sp3)–H Bonds
Table 3. β-C(sp3)–H Cross-Coupling of Carboxylic Acid
Derivatives with Arylsilanesa,b
Table 2. Synthesis of Phenylalanine Derivatives using Ligand-
Enabled C(sp3)–H Cross-Coupling with Arylsilanesa,b
a
Reaction conditions: substrate 1 (0.1 mmol), 2 (2.0 equiv.), Pd(OAc)2 (10 mol%),
L18 (20 mol%), AgF (3.0 equiv.), 1,4-dioxane (1.0 mL), 110 °C. The second batch
of 2 (2.0 equiv.) and AgF (3.0 equiv.) was added at 8 h. The reactions were run for
18 h total. b Isolated yields. c The ee value was determined by chiral HPLC. d Isolated
yield of a gram-scale reaction in the parenthesis.
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a
Reaction conditions: substrate 6 (0.1 mmol), 2 (2.0 equiv.), Pd(OAc)2 (10 mol%),
We gratefully acknowledge The Scripps Research Institute and
the NIH (NIGMS, 2R01GM084019) for financial support. H. F. is
a visiting scholar sponsored by Sichuan University. We thank
NSF under the Science Across Virtual Institutes program as part
of the CCI Center for Selective C–H Functionalization for funding
a visiting student (R. T.), CHE-1205646.
L6 (20 mol%), KHCO3 (2.0 equiv.), AgF (3.0 equiv.), 1,4-dioxane (1.0 mL), 110 °C.
The second batch of 2a (2.0 equiv.) and AgF (3.0 equiv.) was added at 8 h. The
reactions were run for 18 h total. b Isolated yields.
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To investigate the compatibility of this protocol with other
aliphatic acids, amide 6a derived from 2-methylpentanoic acid
was subjected to standard conditions to afford the arylated product
7a in 45% yield. Extensive optimization including changing
ligands and bases (see SI) improved the yield to 67% (Table 3).
Under these new conditions, a variety of amides derived from
aliphatic acids were arylated in good yields (7b–7d). The cross-
coupling of amide 6e containing a trifluoromethyl group afforded
the desired product 7e in 80% yield. A number of aryl groups on
the β- and γ-positions of amide substrates are tolerated (7e–7i).
The reaction is also tolerant of different types of ether groups
including a benzyl protected β-hydroxyl group (7j–7l). Various
triethoxyarylsilane partners containing methyl, chloro, and
trifluoromethyl groups were coupled with substrate 6l to give the
desired products in good yields (7m–7o). It should be noted that
arylation of alanine-derived amide 1 under these conditions also
proceeds, albeit leading to substantial racemization of the product.
While the β- and γ-aryls did not interfere with the β-C(sp3)–H
activation, the α-aryl group in the ibuprofen-derived substrate was
preferentially ortho-arylated under these conditions (Scheme 3).
To achieve the site-selective β-C–H arylation of 8, we turned to
our previously developed arylation protocol with aryl iodides and
successfully obtained the β-arylated product 10 in 83% yield.16
The observed opposite site selectivity with Pd(II)/Pd(IV)16 and
Pd(II)/Pd(0) catalysis speaks to the importance of developing
different catalytic cycles for C–H activation reactions. We
anticipate the ability to arylate C–H bonds at different positions
using two different protocols will be highly useful in synthesis.
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Scheme 3. C–H Functionalizations of an Ibuprofen-Derived
Amide
In conclusion, ligand-enabled cross-coupling of β-C(sp3)–H
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
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data for all new compounds
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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AURHOR INFORMATION
Corresponding Author
(19) DFT computational studies on ligand-promoted C(sp3)–H arylation, see:
Dang, Y.; Qu, S.; Nelson, J. W.; Pham, H. D.; Wang, Z.-X.; Wang, X. J.
Am. Chem. Soc. 2015, 137, 2006.
yu200@scripps.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
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