Efficient alkyl ether synthesis via palladium-catalyzed, picolinamide-directed alkoxylation of unactivated C(sp3)-H and C(sp2)-H bonds at remote positions

Article abstract of DOI:10.1021/ja3023972

We report the efficient synthesis of alkyl ethers by the functionalization of unactivated sp³- and sp²-hybridized C-H bonds. In the Pd(OAc)₂-catalyzed, PhI(OAc)₂-mediated reaction system, picolinamide-protected amine substrates undergo facile alkoxylation at the γ or δ positions with a range of alcohols, including t-BuOH, to give alkoxylated products. This method features a relatively broad substrate scope for amines and alcohols, inexpensive reagents, and convenient operating conditions. This method highlights the emerging value of unactivated C-H bonds, particularly the C(sp³)-H bond of methyl groups, as functional groups in organic synthesis.

Full text of DOI:10.1021/ja3023972

Communication
pubs.acs.org/JACS
Efficient Alkyl Ether Synthesis via Palladium-Catalyzed, Picolinamide-
Directed Alkoxylation of Unactivated C(sp3)−H and C(sp2)−H Bonds
at Remote Positions
Shu-Yu Zhang, Gang He, Yingsheng Zhao, Kiwan Wright, William A. Nack, and Gong Chen*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
demonstrated excellent directing abilities that enable a range
ABSTRACT: We report the efficient synthesis of alkyl
ethers by the functionalization of unactivated sp3- and sp2-
hybridized C−H bonds. In the Pd(OAc)2-catalyzed,
PhI(OAc)2-mediated reaction system, picolinamide-pro-
tected amine substrates undergo facile alkoxylation at the γ
or δ positions with a range of alcohols, including t-BuOH,
to give alkoxylated products. This method features a
relatively broad substrate scope for amines and alcohols,
inexpensive reagents, and convenient operating conditions.
This method highlights the emerging value of unactivated
C−H bonds, particularly the C(sp3)−H bond of methyl
groups, as functional groups in organic synthesis.
of transformations, including arylation, alkenylation, and
alkylation of γ-C(sp3)−H bonds. More recently, we demon-
strated the efficient synthesis of azetidine, pyrrolidine, and
indoline by intramolecular amination of remote C−H bonds
(Scheme 1).19 An illustrative example is valine substrate 1,
Scheme 1. Pd-Catalyzed, PA-Directed Functionalization of
γ-C(sp3)−H Bonds
fundamental challenge in organometallic and synthetic
A
chemistry is the development of broadly applicable
methods for the catalytic functionalization of C−H bonds,
particularly unactivated sp3-hybridized C−H bonds.1−3 Over
the last two decades, C−H functionalization methods have
been considerably advanced in the area of C−C bond
formation. In parallel, the development of C−O bond
formation reactions has greatly accelerated in recent years
following landmark reports on Pd-catalyzed C(sp3)−H
acetoxylation reactions by the Sanford4 and Yu5 laboratories
using different organic oxidants.6−9 Despite the success of C−H
oxygenation methods, C−H alkoxylation reactions remain
scarce; existing reports have been limited to the directed
ortho alkoxylation of the C(sp2)−H bonds of arenes.10
Organometallic research has yet to yield a viable method for
alkyl ether formation via the alkoxylation of truly unactivated
C(sp3)−H bonds.11
which is readily cyclized at the γ position to form the four-
membered azetidine product 2 (eq 1 in Scheme 1).
In the course of investigating this C−H amination reaction
system, we made the intriguing observation of acetoxylated side
products. Substrate 1 provides a small amount of acetoxylated
product 3 under standard amination conditions in toluene;
substrate 4 yields more acetoxylated product 6 than azetidine 5
(eq 2 in Scheme 1). When AcOH is used as the solvent,
acetoxylation becomes the major reaction pathway, with
substrate 1 yielding acetoxylated 3 as the major product and
substrate 4 yielding acetoxylated 6 as the sole product. The
mechanistic rationale for the effect of the substrate β-
substituent on product distribution is currently being
investigated.20 We also observed that the concentration of
Ether moieties are ubiquitous in natural products and
pharmaceuticals.12 Although powerful, the conventional ether
syntheses (e.g., the Williamson and Mitsunobu reactions) have
innate shortcomings, particularly in the preparation of complex
alkyl alkyl ethers.13 Thus, a number of other creative ether
synthesis methods have emerged in the past decade, and new
methods are still in great demand.14−16 Herein we describe a
highly efficient method for the synthesis of alkyl ethers via Pd-
catalyzed, picolinamide (PA)-directed alkoxylation of unac-
tivated C(sp3)−H and C(sp2)−H bonds at remote positions
using alcohols.
Over the past three years, our laboratory has been engaged in
developing synthetically useful methods based on Pd-catalyzed
C−H functionalization reactions.17 The PA group, first
introduced by the Daugulis laboratory in 2005,18 has
Received: March 11, 2012
Published: April 9, 2012
© 2012 American Chemical Society
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OAc ligands in solution affects the reaction pathway and thus
the product distribution. When considered with our working
mechanistic model,19 this suggests that the OAc ligand can
dissociate from the speculated PdIV intermediate following the
PhI(OAc)2 oxidation of the PdII palladacycle.21−23 This
speculation led us to investigate whether other nucleophilic
reagents such as alcohols or amine compounds could be used to
replace the coordinated OAc ligand; presumably, the
subsequent reductive elimination (RE) of C−OR and C−NR
could afford intermolecularly alkoxylated or aminated products.
To evaluate the viability of this approach, we carried out the
C−H functionalization reaction of 4 in MeOH solvent but
under otherwise standard conditions (5 mol % Pd(OAc)2, 2.5
equiv of PhI(OAc)2, 110 °C, Ar atmosphere). We were
delighted to observe the formation of the desired methoxylated
product 7 as the major product, albeit in low yield. Encouraged
by this initial finding, we commenced a systematic screening of
alkoxylation conditions for substrate 8 and ethanol (Table 1).23
proportion of xylene in the mixture to 4:1 improved the yield of
9 to 63% (entry 19). Finally, we were pleased to obtain 9 in
excellent yield (92%) by conducting the reaction under an Ar
atmosphere (entry 21). Interestingly, O2 seemed to inhibit the
desired C−H alkoxylation reaction, resulting in a significantly
diminished yield (entry 20); this contrasts with our C−H
alkylation reaction, in which O2 has a promoting effect.17c We
suspect that O2 binds to the palladacycle intermediate,
hampering the subsequent PdII/IV oxidation by PhI(OAc)2.24
Using the optimized reaction conditions (Table 1, entry 21),
we then explored the alcohol substrate scope of this C−H
alkoxylation reaction (Table 2). Subject to variance in
Table 2. Substrate Scope of Alcohols
Table 1. Pd-Catalyzed, PA-Directed Ethoxylations of γ-
a
C(sp3)−H Bonds
a
Standard reaction conditions for C−H alkoxylation (4 h). Isolated
b
c
yields are shown. 2 h. 12 h.
molecular weight, 20−50 equiv of alcohol was typically applied.
Unsubstituted 1° alcohols, including MeOH, n-PrOH, and even
the alcohol precursor to 15 bearing a long alkyl chain, provided
good to excellent yields. BnOH and CF3CH2OH also gave the
corresponding BnO and CF3CH2O ethers 16 and 18 in good
yields. The reaction tolerates a range of functional groups,
including halogens, cyclopropanes, esters, and alkenes (20−
23). Alkoxylation using 2° alcohols proceeds well with
additional reaction time (12 h) (24−26). Even t-BuOH
provided a moderate yield of tert-butyl ether product 27.
Interestingly, no cyclization or alkoxylation reaction occurred
when t-BuOH alone was used as the solvent.25
The reaction system tolerates a variety of picolinamide
substrates (Table 3). In general, substrates bearing 1° γ-
C(sp3)−H groups (with or without α-substitutents) were
readily methoxylated (28−30). A bismethoxylated product was
obtained in excellent yield when two γ-methyl groups were
present (32). Products 28, 31, and 35 demonstrate a high
regiopreference for 1° over 2° γ-C(sp3)−H bonds. No δ-
alkoxylated products were observed. Notably, under our
optimized C−H alkoxylation conditions, the C−H amination
reaction pathway is greatly suppressed and little amination
product is generated. Excellent yields of 31 and 32 were
obtained despite the particularly facile cyclization of the
corresponding picolinamides under amination conditions.
Encouraged by the successful alkoxylation of γ-C(sp3)−H
bonds, we then investigated whether this C−H alkoxylation
reaction can be used to functionalize C(sp2)−H bonds of
a
The screening reactions were carried out in a 10 mL glass vial with a
PTFE-lined cap on a 0.2 mmol scale ([8] ≈ 0.1 M). The reaction vial
b
was purged with gas (1 atm) and then sealed. 1H NMR yields (see
c
the Supporting Information). 1-Fluoro-2,4,6-trimethylpyridinium
triflate. Isolated yield. 5 mol % Pd(OAc)2 was used.
d
e
In EtOH solvent, PhI(OAc)2 proved to be the only effective
oxidant, yielding the alkoxylated product 9 in 6% yield along
with >80% unreacted 8 (entry 6). Use of a larger excess (5
equiv) of PhI(OAc)2 resulted in little improvement (entry 7).
Our previous observation of pronounced solvent effects in the
C−H amination reaction system motivated us to examine the
solvent dependence of the reaction using various solvents
mixed 1:1 with EtOH. Strongly coordinating solvents such as
DMF, dioxane, and CH3CN did not promote the desired
alkoxylation reaction, while noncoordinating solvents provided
markedly higher yields. Xylene/EtOH mixtures stood out as the
best-performing solvents (entries 15 and 16). Increasing the
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Communication
a
Table 3. Substrate Scope of Picolinamides and Alcohols
Scheme 3. Plausible Mechanism
Scheme 4. Facile Removal of the PA Auxiliary
a
The standard reaction conditions were used. Isolated yields are
b
c
shown. MeOH/toluene (1:1) was used as the solvent. MeOH/
AcOH (1:1) was used as the solvent. 4 equiv of PhI(OAc)2 was used.
d
a
Scheme 2. Alkoxylation of o-C(sp2)−H Bonds of Arenes
could be displaced to form PdIV intermediate 52, which could
undergo C−OR RE to give alkoxylated products.26,27
Formation of alkoxylated products could also be explained by
an alternative SN2 pathway, but this is likely inoperative since
the use of non-nucleophilic t-BuOH also affords the alkoxylated
product.28 The role of xylene solvent in promoting the
alkoxylation reaction pathway is still under investigation.29
To enhance the synthetic utility of Pd-catalyzed, PA-directed
C−H functionalization chemistry, we previously introduced a
modified PA auxiliary 54, which can be cleaved under relatively
mild conditions (Scheme 4).17b,c This auxiliary can be readily
employed in the C−H alkoxylation reaction system. For
example, amino acid substrate 53 was equipped with the
auxiliary using a standard amide coupling. The resulting
substrate 55 was then alkoxylated by our method with
(−)-Roche ester 56 (∼18 equiv). The PAr group of 57 was
then cleanly removed in aqueous HCl/MeOH solution to give
the complex amine product 58 in good yield.
a
The standard reaction conditions with 2.5 equiv of PhI(OAc)2 were
used for all of the bisalkoxylation reactions, and 1.5 equiv of
PhI(OAc)2 was used for all of the monoalkoxylation reactions.
In summary, we have developed a highly efficient method for
the synthesis of alkyl ethers via Pd-catalyzed intermolecular
alkoxylation of truly unactivated γ-C(sp3)−H and o-C(sp2)−H
bonds at the γ and δ positions of picolinamide substrates using
a wide range of alcohols. With a simple change of reaction
solvent, the previously established intramolecular C−H
amination reaction pathway is cleanly diverted to intermolec-
ular C−H alkoxylation, forming alkyl ether products. This
reaction features a broad substrate scope, inexpensive reagents,
and convenient operating conditions. We are currently engaged
in more detailed mechanistic studies, the application of this
methodology to the synthesis of complex molecules, and the
pursuit of intermolecular C−H amination reactions.
arenes. As shown in Scheme 2A, the γ-o-C−H bonds of
benzylpicolinamides can be readily replaced with a variety of
alkoxyl groups. Both electron-rich and electron-deficient
substrates provide good to excellent yields of aryl ether
products. Only 1.5 equiv of PhI(OAc)2 is required for
monoalkoxylation, compared with 2.5 equiv under the standard
C(sp3)−H alkoxylation conditions. Substrates with two o-C−H
bonds yield bismethoxy products with 2.5 equiv of PhI(OAc)2
(e.g., 45 and 46). This reactivity is also observed in
benzylamine substrates bearing α-benzylic substituents, dem-
onstrating a regiopreference for C(sp2)−H over C(sp3)−H
(44). Additionally, β-arylethylamine substrates can be alkoxy-
lated at the δ-o-C−H position under the standard reaction
conditions (Scheme 2B). For instance, a protected phenyl-
alanine substrate was bismethoxylated in high yield (49).
Cyclization products were not observed, again indicating that
the previously dominant intramolecular C−H amination
pathway in toluene solvent is completely diverted toward
alkoxylation under the new reaction conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The detailed mechanism for this Pd-catalyzed, PhI(OAc)2-
mediated C−H alkoxylation reaction has not been firmly
established. We speculate that palladacycle 50 is first generated
and then oxidized to form PdIV intermediate 51, which can
undergo RE to form either C−N or C−OAc products (Scheme
3). In the presence of alcohol cosolvent, the OAc ligands of 51
AUTHOR INFORMATION
Corresponding Author
Guc11@psu.edu
■
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support by The
Pennsylvania State University and NSF (CAREER CHE-
1055795).
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