.
Angewandte
Communications
DOI: 10.1002/anie.201307090
CÀH Activation
À
An Efficient Palladium-Catalyzed C H Alkoxylation of Unactivated
Methylene and Methyl Groups with Cyclic Hypervalent Iodine (I )
Oxidants**
3+
Gang Shan, Xinglin Yang, Yu Zong, and Yu Rao*
[
6,7]
Over the last two decades, transition-metal-catalyzed direct
knowledge, C(sp3)ÀH alkoxylation
of unactivated meth-
functionalization of CÀH bonds has emerged as a valuable
ylene positions has not yet been achieved.
[1]
tool for organic synthesis. Compared to C(sp2)ÀH bond
Alkyl ethers serve as important structural motifs found in
[
8]
activation, however, the catalytic functionalization of C(sp3)À a diversity of pharmaceuticals and natural products. The
[
2,3]
[9]
H bonds,
especially unactivated methylene C(sp3)ÀH
classic approaches to alkyl ethers, such as Williamson and
bonds, remains an important fundamental challenge. Because
Mitsunobu reactions, suffer from shortcomings which have
limited their applications in the synthesis of complex alkyl
of steric hindrance and intrinsic inertness, methylene CÀH
[
10]
bonds are significantly more difficult to cleave than primary
ethers. Although a number of new protocols have been
developed in recent years, new methods for alkyl ether
synthesis are still in great demand. Direct transformation of
readily available alkanes into valuable complex alkyl ethers
by transition-metal-catalyzed C(sp3)ÀH functionalization of
CÀH bonds. In addition, the potential competing b-hydride
elimination from cyclometallates also complicates the pro-
cess. Therefore, only a few examples of C(sp3)ÀH bond
activations of unactivated methylenes have been reported
[
4]
thus far. Among these successful discoveries of methylene
C(sp3)ÀH bond activation, the majority of studies were
focused on CÀH arylation, acetoxylation, or amidation. In
unactivated methylenes is arguably a highly efficient and
atom-economic method toward these compounds.
Herein, we report the first example of a palladium(II)-
catalyzed C(sp3)ÀH alkoxylation of an unactivated methyl-
[4h]
a recent C(sp3)ÀH amidation study, NFSI served as both an
3
+
intriguing oxidant and nitrogen source, and further theoret-
ene with cyclic hypervalent iodine (I ) oxidants. Our
[11]
ical studies revealed a low-energy barrier for reductive CÀN
preliminary mechanistic study revealed that either DMP
5
+
bond formation from a high-oxidation-state palladium cata-
(I ) or 1-acetoxy-1,2-benziodoxole-3(1H)-one serve as intri-
+
3
lyst. More recently, an elegant example of ligand-enabled CÀ guing precursors to the oxidant I
for the C(sp3)ÀH
H arylation of methylene C(sp3)ÀH bonds was reported by
alkoxylation.
[
5]
Yu and co-workers (Scheme 1). However, to the best of our
In our continuous studies of CÀO bond formation through
[12]
palladium catalysis, we envisioned that certain oxidative
[
13]
conditions could promote palladium(II)-catalyzed C(sp3)À
H bond activation through an orthometalation process by
coordination with specific directing groups. In a subsequent
step C(sp3)ÀO bond formation by the reductive elimination
could afford the corresponding alkyl ether derivatives with
suitable oxidants and alcohol partners (Scheme 1). To test our
hypothesis, a model study was initiated with the butyramide
derivative 1, which contains an 8-aminoquinoline-derived
[14]
auxiliary (Q; Table 1). This specific auxiliary (Q) was first
reported by the group of Daugulis and has been developed as
an effective directing group for the activation of C(sp3)ÀH
Scheme 1. A new approach for unactivated methylene C(sp3)ÀH bond
alkoxylation. TFA=trifluoroacetate, Q=8-aminoquinoline-derived aux-
iliary.
bonds. At the beginning of our investigations, a variety of
oxidants, such as PhI(OAc) , PhI(TFA) , K S O , NaIO ,
2
2
2
2
8
4
NaIO , and selectfluor, were examined in the presence of
3
Pd(OAc) in a MeOH/xylene cosolvent system. Among them,
2
[
+]
[+]
[
*] G. Shan, X. Yang, Y. Zong, Prof. Dr. Y. Rao
MOE Key Laboratory of Protein Sciences, Department of Pharma-
cology and Pharmaceutical Sciences, School of Medicine and
School of Life Sciences, Tsinghua University
a small amount of the desired product 2a (12–15%) was
observed with PhI(OAc)2 and NaIO4 (entries 1 and 8).
However, further attempts failed to improve the yields, with
methoxylation of the 8-aminoquinoline auxiliary (2b) leading
to the major product. We then turned our attention to other
hypervalent iodine reagents. Delightfully the methoxylation
product 2a was observed in 31% yield in the presence of IBX
Beijing, 100084 (China)
E-mail: yrao@mail.tsinghua.edu.cn
+
[
] These authors contributed equally to this work.
[
**] This work was supported by the national “973” grant (grant no
(
entry 9). Further investigations revealed that DMP was
superior to IBX with a notably higher level of efficiency
entry 10). A control reaction showed that omission of the
Pd(OAc)2 catalyst resulted in complete inactivity of this
2
011CB965300), NSFC grant (grant no 21142008), and Tsinghua
University Initiative Scientific Research Program.
(
1
3606
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 13606 –13610