Ligand-promoted alkylation of C(sp3)-H and C(sp2)-H bonds

Article abstract of DOI:10.1021/ja508165a

9-Methylacridine was identified as a generally effective ligand to promote a Pd(II)-catalyzed C(sp³) - H and C(sp²) - H alkylation of simple amides with various alkyl iodides. This alkylation reaction was applied to the preparation of unnatural amino acids and geometrically controlled tri- and tetrasubstituted acrylic acids.

Full text of DOI:10.1021/ja508165a

Communication
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Open Access on 09/10/2015
Ligand-Promoted Alkylation of C(sp3)−H and C(sp2)−H Bonds
Ru-Yi Zhu, Jian He, Xiao-Chen Wang, and Jin-Quan Yu*
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
conditions; (2) potential β-hydride elimination of palladium
ABSTRACT: 9-Methylacridine was identified as a gen-
erally effective ligand to promote a Pd(II)-catalyzed
C(sp3)−H and C(sp2)−H alkylation of simple amides
with various alkyl iodides. This alkylation reaction was
applied to the preparation of unnatural amino acids and
geometrically controlled tri- and tetrasubstituted acrylic
acids.
alkyl species or base-promoted eliminations of alkyl halides. We
therefore set out to identify a ligand to promote this alkylation
while preventing the β-hydride elimination. In addition, we
hoped that the ligand may allow us to perform the alkylation
under acidic or neutral conditions so that the N-alkylation of
the acidic amide can be minimized.
Our initial experimental efforts focused on the development
of conditions for C−H methylation using methyl iodide, as this
would avoid the complication of β-hydride elimination. An
extensive survey of Pd sources, silver additives, and solvents was
performed using our previously developed quinoline ligand
L1.13a We found that treatment of 1a with 2.5 equiv of MeI, 10
mol % of Pd(TFA)2, 20 mol % of L1, and 2.0 equiv of Ag2CO3
in DCE at 80 °C for 20 h gave the desired product in 17% yield
(Table 1). The replacement of Ag2CO3 by silver pivalate
(AgOPiv) dramatically improved the yield to 74%. Notably, the
absence of ligand decreased the yield to less than 5%. The
significant impact of the ligand on this methylation reaction led
us to focus on the screening of various pyridine and quinoline
ligands for the β-methylation of amide 1a (Table 1). Among
various pyridine ligands tested (L2−L5), 2,6-dimethoxypyr-
idine (L5) gave the best result. These results suggest that both
the steric bulk and electron-donating ability of the pyridine
ligands were crucial for higher reactivity. We then turned our
attention to the quinoline ligands (L6−L11). During this
screen a similar trend was observed using quinoline ligands (L1,
L6−L8) with 2-alkoxyquinoline ligands affording better yields.
Further enhancement of the electron-donating ability of the
ligand by introducing another methoxy group did not have
much impact on the yield (L9). Other structural modifications
of 2-alkoxyquinoline ligands (L10, L11) affected the methyl-
ation reaction adversely. It was noticed that quinoline ligands
were generally better than the corresponding pyridine ligands,
which led us to reason that the phenyl motif in the quinoline
ligand might play a pivotal role in this reaction. Therefore, we
started to screen acridine ligands (L12−L17). After a
systematic survey of acridine ligands, 9-methylacridine was
identified as the optimal ligand (L13). Pd(TFA)2 and AgOPiv
can be reduced to 5 mol % and 1.5 equiv respectively with L13,
albeit giving slightly lower yields (see Supporting Information).
With the optimal reaction conditions in hand, various amides
derived from corresponding carboxylic acids were methylated at
the β-position selectively in good yields (Table 2). The
unreacted starting materials were mostly recovered. For
aliphatic amides (3a−c), better yields were obtained with the
ones having bulkier α-substituents. Substrates containing
ransition metal catalyzed C−H alkylation1 represents a
T
useful alternative tool for C−C bond formation especially
when rearrangement, poor selectivity, or functional group
tolerance become problematic in traditional alkylation reac-
tions.2 While alkylation of C(sp2)−H and C(sp3)−H bonds via
cross-coupling with alkylborons has been demonstrated,3 alkyl
halides have been more widely utilized as the alkylating
reagents in Pd-,4,5 Ni-,6,7 Ru-,8 Co-,9 and Fe10-catalyzed C−H
alkylation for the past few years. By employing pyridine-based
auxiliaries, Daugulis,4c,5a,e Ackermann,6b,8 Chen,4d,5b,c and
Chatani6a have greatly improved the scope of this potentially
powerful methodology. Recently, alkylations of aromatic
C(sp2)−H bonds using Co(II) and Fe(III) catalysts have
been developed by Nakamura,9a,10a Yoshikai,9b and Cook.10b,c
Despite these achievements, the scope and efficiency of
transition metal catalyzed C−H alkylation has lagged behind
the rapid progress of the Pd(0)-catalyzed cross-coupling of
organometallic reagents with alkyl halides.12 For example, the
C(sp3)−H alkylation is limited to primary alkyl halides, and
only a few examples of using alkyl halides containing β-
hydrogen have been reported.4c,5 The stereoselective syntheses
of tri- and tetrasubstituted olefins via vinylic C(sp2)−H
alkylation is potentially attractive, and yet only a few pioneering
examples are reported using Ru,11 Ni,6a and Fe10a,c catalysts.
Notably, Pd-catalyzed vinyl C−H alkylation has not been
reported to date. Considering the significant role played by
ligands in the Pd(0)-catalyzed cross-coupling of organometallic
reagents with alkyl halides,12 we initiated our effort to develop
ligands that can promote C−H alkylation reactions.
We have systematically developed the approach of using a
weakly coordinating substrate and a ligand to accelerate C−H
activation reactions. In this endeavor, the combination of a
weakly coordinating amide directing group (CONHAr) and
pyridine- or quinoline-based ligands has been shown to be
effective for developing a myriad of Pd-catalyzed C(sp3)−H
functionalization transformations including arylation, carbon-
ylation, and olefination.13 However, we have been unable to
achieve the C−H alkylation with alkyl halides using this simple
amide directing group due to (1) N-alkylation of the acidic
amide is a predominant reaction pathway, especially under basic
Received: August 8, 2014
© XXXX American Chemical Society
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a b
,
ab
,
Table 1. Ligand Screening
Table 2. C(sp3)−H Methylation
a
Conditions: 0.1 mmol of 1, 2.5 equiv of MeI, 10 mol % of Pd(TFA)2,
20 mol % of L13, 3.0 equiv of AgOPiv, 0.5 mL of DCE, 80 °C, under
b
air, 20 h. Isolated yields.
a b
,
Table 3. C(sp3)−H Alkylation
a
Conditions: 0.1 mmol of 1a, 2.5 equiv of MeI, 10 mol % of
Pd(TFA)2, 20 mol % of ligand, 3.0 equiv of AgOPiv, 0.5 mL of DCE,
b
80 °C, under air, 20 h. The yield was determined by 1H NMR
analysis of the crude product using CH2Br2 as an internal standard.
c
2.0 equiv of Ag2CO3 instead of AgOPiv were used.
tetrahydro-2H-pyran, trifluoromethyl, aryl, and ether groups
were well tolerated (3d−h). If the phenyl ring is located at the
β-position, two ortho positions need to be substituted in order
to avoid the remote ortho-alkylation (3g). Importantly, the
alanine-derived amide 1i could be successfully methylated to
form the unnatural amino acid derivative (3i). The higher
reactivity of the methylene C−H bonds in 3imono, presumably
due to the Thorpe−Ingold effect, led to the formation of the
dimethylated product in 20% yield. Considering the synthetic
utility of unnatural amino acids, alanine substrate 1i was
subjected to the alkylation conditions with various alkyl iodides
(Table 3). Ethylation of 1i gave 3j in 75% yield with complete
retention of chirality. The use of sterically hindered isobutyl
iodide resulted in a decrease in yield (3k). Alkyl iodides
containing aryl, chloro, benzyl protected hydroxyl, acetal, ester,
and trifluoromethyl functionalities were suitable coupling
partners, allowing the introduction of a wide range of functional
groups into amino acids (3l−q). An alkyl iodide containing a
double bond was also used to alkylate 1i to give 3r in 43% yield.
Notably, the double bond in the alkyl iodide was not preserved
in the recently reported Fe-catalyzed C−H alkylation due to a
a
Conditions: 0.1 mmol of 1i, 2.5 equiv of 2, 10 mol % of Pd(TFA)2,
20 mol % of L13, 3.0 equiv of AgOPiv, 0.5 mL of DCE, 80 °C, under
b
c
air, 20 h. Isolated yields. The ee value was determined by HPLC
d
analysis on a chiral stationary phase (SI). Using L1 instead of L13.
e
1.0 mmol scale.
presumably radical cyclization process.10c This alkylation
reaction could be scaled up without a decrease in yield (3q).
We have also attempted alkylation of 1i with isopropyl iodide
but without success. Interestingly, alkylation of 1i with ethyl
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Journal of the American Chemical Society
Communication
bromide gave the desired product in 36% yield (see Supporting
Information).
developed,4c,d C−H alkylation directed by weakly coordinating
functional groups has been largely unsuccessful except for a
single example using dichloroethane as the alkylating reagent.4b
Thus, we wondered whether ligand L13 could promote the
alkylation of weakly coordinating benzamides. Under the
optimized conditions, the alkylation of ortho-chlorobenzamide
in the absence of ligand gave the desired product 3ab in 57%
yield (Table 5). As we expected, the use of ligand L13
Vinyl C−H alkylation could potentially lead to a fully
stereocontrolled alkene synthesis which can be especially
difficult for acyclic tri- and tetrasubstituted alkenes. However,
Pd-catalyzed vinyl C−H alkylation has not been accomplished
to date. We were pleased to find that our ligand-promoted vinyl
C−H alkylation proceeded to afford a series of geometrically
controlled tri- and tetrasubstituted acrylic amides in good to
excellent yields (Table 4). Starting from methacrylic amide,
a b
,
Table 5. Aromatic C(sp2)−H Alkylation
a b
,
Table 4. Vinylic C(sp2)−H Alkylation
a
Condition A: 0.1 mmol of 1, 2.5 equiv of 2, 10 mol % of Pd(TFA)2,
20 mol % of L13, 2.0 equiv of AgOPiv, 0.5 mL of DCE, 80 °C, under
a
Conditions: 0.1 mmol of 1, 2.5 equiv of 2, 10 mol % of Pd(TFA)2, 20
mol % of L13, 2.5 equiv of AgOPiv, 0.5 mL of DCE, 80 °C, under air,
b
c
air, 20 h. Isolated yields. 1H NMR yield without L13 in parentheses.
d
b
c
20 h. Isolated yields. 1H NMR yield without L13 in parentheses.
Condition B: 0.1 mmol of 1, 2.5 equiv of 2, 10 mol % of Pd(OAc)2,
d
20 mol % of L11, 3.0 equiv of AgOAc, 1.5 mL of DCE, 90 °C, under
Using L1 instead of L13 and 1.0 equiv of K2HPO4.
e
f
air, 20 h. Condition A, except using L1 instead of L13. Condition A,
except using 3.0 equiv of AgOPiv.
angelic amide was formed via the methylation of the terminal
vinylic C−H bond (3s). Significantly, the expected facile
isomerization of 3s to the more stable tiglic amide. Amide was
not detected by 1H NMR analysis. Di- and trisubstituted
crotonic and tiglic amides were also successfully methylated to
give the tri- and tetrasubstituted olefins (3t−u). The retention
of stereochemistry in the methylated products 3v and 3w is also
noteworthy, as these double bonds are prone to isomerization.
For example, access to these compounds via Wittig reaction
often leads to a mixture of cis- and trans-isomers.14 The
retention of stereochemistry also allowed for the introduction
of a D-labeled methyl group to give a single stereoisomer 3x. A
cyclic substrate was also compatible with this alkylation reaction
affording the methylated product in high yield (3y).
Importantly, alkylation with β-hydrogen containing alkyl
iodides proceeded to give corresponding alkylated products
in synthetically useful yields, thus demonstrating the effective-
ness of the ligand (3z−aa). A control experiment with crotonic
amide confirmed that a pyridine type ligand initially developed
for C(sp3)−H activation was also crucial for the alkylation of
vinylic C(sp2)−H bonds (3t).
improved the yield to 80%. The use of pentafluorobenzoic acid
(PFBA) was crucial for suppressing the N-alkylation of the
benzamide. A meta-bromoarene and an ortho-methylarene were
also methylated in good yields (3ac, 3ad). The use of ligand
L11 also allowed for methylation of thiophenes (3ae, 3af). The
best results for alkylation with α-iodoacetate, ethyl iodide, and
3-chloropropyl iodide were obtained by using ligand L1 (3ag−
ai). The ethylation of ortho-chlorobenzamide in the absence of
ligand proved to be inefficient (3ah).
In summary, an acridine ligand is developed to promote
alkylation of both C(sp3)−H and C(sp2)−H bonds using a
simple and weakly coordinating amide directing group. Further
optimization of ligand structures to broaden the scope of C−H
alkylation is underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Although Pd-catalyzed alkylation of aromatic C−H bonds
using Daugulis’ bidentate directing group has been well
C
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Journal of the American Chemical Society
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J.-Q. Science 2014, 343, 1216. (c) Li, S.-H.; Chen, G.; Feng, C.-G.;
Gong, W.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 5267.
(14) Calvin, J. R.; Frederick, M. O.; Laird, D. L. T.; Remacle, J. R.;
May, S. A. Org. Lett. 2012, 14, 1038.
AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Scripps Research Institute and
the NIH (NIGMS, 2R01GM084019) for financial support.
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