Direct ortho -C-H functionalization of aromatic alcohols masked by acetone oxime ether via exo -palladacycle

Article abstract of DOI:10.1021/acs.orglett.5b00594

A simple and practical exo-oxime ether auxilixary for ortho-C-H functionalization of aromatic alcohols has been developed. Selective olefination of aromatic alcohols were first achieved via a six- or seven-membered exo-acetone oxime ether palladacycle with broad substrate scope. In addition, the crystal of the exo-palladacycle intermediate was obtained for the first time, and the application of this method in total synthesis of 3-deoxyisoochracinic acid was accomplished via a novel retro-synthetic disconnection approach, thus demonstrating the utility of this transformation.

Full text of DOI:10.1021/acs.orglett.5b00594

Letter
pubs.acs.org/OrgLett
Direct ortho-C−H Functionalization of Aromatic Alcohols Masked by
Acetone Oxime Ether via exo-Palladacycle
Kun Guo, Xiaolan Chen, Mingyu Guan, and Yingsheng Zhao*
Key Laboratory of Organic Synthesis of Jiangsu Province College of Chemistry, Chemical Engineering and Materials Science
Soochow University, Suzhou 215123, PR China
S
* Supporting Information
ABSTRACT: A simple and practical exo-oxime ether
auxilixary for ortho-C−H functionalization of aromatic alcohols
has been developed. Selective olefination of aromatic alcohols
were first achieved via a six- or seven-membered exo-acetone
oxime ether palladacycle with broad substrate scope. In
addition, the crystal of the exo-palladacycle intermediate was
obtained for the first time, and the application of this method in total synthesis of 3-deoxyisoochracinic acid was accomplished via
a novel retro-synthetic disconnection approach, thus demonstrating the utility of this transformation.
catalyst.6 However, this reaction was limited in intramolecular
ransition-metal-catalyzed selective functionalization of C−
TH bonds has become a powerful strategy in the synthesis of C−H transformation (Scheme 1B).
natural products and pharmaceuticals.1 So far, the primary
Benzyl alcohols are important versatile synthetic precursors in
synthetic chemistry and usually are the omnipresent component
strategy to achieve high site-selective C−H transformation is the
of many natural products and drug molecules.7 Herein, we used a
employment of directing groups,2 apart from the electronically
simple and potential exo-oxime ether directing group for direct
activated substrates.3 However, there are still a few examples of
C−H functionalization of benzyl alcohols at ortho-positions.
extensive applicable directing groups for functionalization of
Phenethyl alcohols were also effective despite their relatively
widely used alcohols.4 In 2010, Yu5 reported hydroxy-directed
remote coordination8 (Scheme 1C). Moreover, a crystal of six-
ortho-C−H olefination of tertiary phenethyl alcohols in the
membered exo-palladacycle intermediate was successfully
presence of palladium catalyst promoted by monoprotected
prepared. Finally, we demonstrated the utility of ortho-C−H
amino acid ligands (Scheme 1A). Due to competitive
decomposition, primary and secondary alcohol substrates gave
lower yield. Meanwhile, Hartwig developed a practical hydroxyl-
directed ortho-silylation of benzyl alcohols by employing Ir
olefination by total synthesis of a rare fungal metabolite, 3-
deoxyisoochracinic acid, from commercially available 2-benzy-
loxybenzyl alcohol.
Oxime ethers which were first disclosed by Sanford9a present
an excellent directing ability for carbonyl compounds and have
been employed in C−O, C−N, C−X, and C−C bond formation
via a five-membered endo-palladacycle intermediate (Scheme
2A). However, Dong9b made a brilliant modification of oxime
ethers and achieved an opposite selective C−H transformation of
aliphatic alcohols at β position affording the chemically
differentiated 1,2-diols. The catalytic cycle might go through a
five-membered exo-palladacycle, and the site selectivity in this
protocol was achieved by blocking the potential reactive position
of aldehyde (Scheme 2B).
Scheme 1. Hydroxyl-Assisted C−H Transformation
Inspired by these oxime ether directed reactions, we
speculated that if the competitive C−H transformation of endo
pathway could be avoided by employing a concise acetone oxime
ether which lacks β-C−H bonds at the ketone side then the
unanswered challenge of six-membered exo-cyclopalladation10
should be overcome (Scheme 2C). Based on our development of
new directing groups for amine compounds,11 we might get a
Received: February 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00594
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Pd-Catalyzed Oxime Ether Directed C−H
Transformation
Table 1. Optimization of Reaction Conditions
b
entry
ligand
oxidant
AgOAc
yield (%) (mono/di)
1
2
3
4
5
6
7
8
8 (8/0)
Ac-Gly-OH
Ac-Ala-OH
Ac-Val-OH
Ac-Leu-OH
PivOH
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Cu(OAc)2
O2 (1 atm)
O2/Cu(OAc)2
open air
BQ
41 (36/5)
58 (51/7)
92 (62/30)
67 (56/11)
trace
HO2P(OBn)2
1,10-phenanthroline
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
11(11/0)
trace
c
9
15 (15/0)
7 (7/0)
10
d
11
11 (11/0)
5 (5/0)
12
13
14
0
K2S2O8
AgOAc
AgOAc
AgOAc
AgOAc
37 (31/6)
79 (63/16)
85 (67/18)
93 (73/20)
0
e
15
f
16
g
17
h
simple and powerful directing group for site selective
functionalization of alcohol substrates.
18
a
Conditions: 1a (0.2 mmol), 2a (0.3 mmol), Pd(OAc)2 (5 mol %),
Initially, we treated oxime 1a with ethyl acrylate 2a by
employing Pd(OAc)2 (5 mol %) as catalyst and AgOAc as
oxidant in 1,4-dioxane at 90 °C under an atmosphere of air in a
sealed tube to develop an easily accessible olefination protocol
for benzyl alcohols. However, in the first run of the experiment,
only less than 10% mono-olefinated product 3a was detected by
GC (Table 1, entry 1). To our delight, the mono-N-protected
amino acid ligand,12a which had been proven to have the ability
to enhance many C−H activations, turned out to have better
reactivity than PivOH12b and HO2P(OBn)212c (Table 1, entries
2−8). Under the optimized reaction conditions, the satisfactory
yield of olefinated products was in total 92% (mono/di = 2.1/1)
with N-acetyl-L-valine as ligand (entry 4). AgOAc was shown to
be the best oxidant in this Pd-catalyzed direct olefination (entries
9−14). Further optimization was also carried out to reduce the
diolefinated products (entries 15−17). Slightly higher mono-
selectivity could be achieved by reducing the reaction time to 12
h (entry 17).
ligand (10 mol %), oxidant (0.5 mmol), 1,4-dioxane (1 mL), 90 °C, 20
b
h. GC yield determined using tridecane as internal standard.
c
d
e
f
g
Cu(OAc)2 (0.4 mmol). Cu(OAc)2 (0.04 mmol). 4 h. 8 h. 12 h.
h
Without Pd(OAc)2. Ac = acetyl, Gly = glycine, Ala = L-alanine, Val =
L-valine, Leu = L-leucine, BQ = 1,4-benzoquinone.
alcohol (1v−x) were also transformed into the corresponding
olefinated products (3v−x) in good yields, which might be
further applied in construction of bioactive molecules. Generally,
the olefination tended to happen at less hindered positions and
afforded the mono-olefinated products in moderate to good
yields (3t−u).
Under the optimized reaction conditions, diverse olefins were
tested, and the representative data are listed in Scheme 4. A
variety of electron-deficient olefins were compatible in this
acetone oxime ether directed C−H transformation. Notably, the
olefin of 2g−i selectively gave the mono-olefinated products 4g−
i in moderate to good yields, implicating the potential application
in construction of complex molecules. Acetone oxime ether
protected phenethyl alcohols were also tested under the
optimized reaction conditions. Gratifyingly, moderate to good
yield of ortho-olefinated products were achieved, even though
those substrates maybe undergo a seven-membered palladacycle
intermediate (Scheme 5).
The ideal directing group should have sufficient ability to
tolerate C−H activation/functionalization conditions and be
easily removed from the substrate or directly converted into
diverse functional groups. Indeed, acetone oxime ether fulfilled
all of these requirements10,13 (see the Supporting Information).
First, gram-scale reactions were easily achieved in good yields
(Scheme 6). Second, selective cleavage of the N−O bond in the
products could be accomplished by Mo(CO)614a (Scheme 7A).
Alternatively, cleavage of the N−O bond by Raney Ni14b afforded
the fascinating alkylated benzyl alcohol products (Scheme 7B).
The known antibacterial activity compound 3-deoxyisoochra-
cinic acid15 14 was synthesized from the commercial available
compounds 12 in five steps with a total yield of 40%, which
With optimized conditions in hand, a wide range of the
acetone oxime ether masked benzyl alcohols were synthesized
and tested, and representative data are shown in Scheme 3.
t
Various functional groups, such as Me, Bu, MeS, MeO, F, Cl,
CF3, COOMe, and NO2, were all tolerated. Generally,
olefination of the para-position substituted substrates (Scheme
3, 3b−i) afforded the mono-olefinated products in good yields
(56−67%) and gave the corresponding diolefinated products in
14−32% yield that could be easily separated by silica gel
chromatography. The ortho-substituted arenes gave good yields
(3j−o). It is worth mentioning that the α-substituted alcohol
1p−r gave the mono-olefinated products in 65−86% yield, and
the further olefinated products were observed in less than 10%
1
yield as analyzed by H NMR (3p−r). It is probable that the
steric effect inhibited further olefination, which resulted in a
highly selective mono-olefination reaction. The electron-with-
drawing group substituted arene reacted smoothly and afforded
olefinated products in good yield by increasing the catalyst
loading to 10 mol % (3f−i). The substrates bearing a secondary
B
DOI: 10.1021/acs.orglett.5b00594
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of Benzyl Alcohols*
Scheme 4. Scope of Olefins*
*
Conditions: 1 (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (5 mol %), Ac-
Val-OH (10 mol %), AgOAc (0.5 mmol), 1,4-dioxane (1 mL), 90 °C,
12 h. Trace o,o′-diolefinated products were observed but not isolated.
a
2 (0.18 mmol).
a
Scheme 5. Scope of Phenethyl Alcohols
*
Conditions: 1 (0.2 mmol), 2a (0.3 mmol), Pd(OAc)2 (5 mol %), Ac-
Val-OH (10 mol %), AgOAc (0.5 mmol), 1,4-dioxane (1 mL), 90 °C,
12 h. o,o′-Diolefinated products 3p−r were observed but not isolated.
a
b
c
Pd(OAc)2 (10 mol %) and Ac-Val-OH (20 mol %) used. 20 h. 100
d
°C. 120 °C.
demonstrated the utility of the acetone oxime ether assisted C−
H olefination (Scheme 8).
a
Conditions: 5 (0.2 mmol), 2a (0.3 mmol), Pd(OAc)2 (5 mol %), Ac-
Val-OH (10 mol %), AgOAc (0.5 mmol), 1,4-dioxane (1 mL), 90 °C,
To gain a deep understanding of this exo-directing group
assisted C−H transformation, we treated acetone oxime ether
protected 1a with 1.2 equiv of Pd(OAc)2 in CHCl3 and stirred
the mixture at room temperature for 5 h, an orange red palladium
complex was obtained. Single-crystal X-ray diffraction analysis
demonstrated that the six-membered exo-palladacycle inter-
mediate was successfully synthesized, which could give a clear
insight of these exo-directing group directed C−H functionaliza-
tion reactions (Scheme 2C). Based on the preliminary
experimental data, we deduced that the acetone oxime ether
assisted C−H functionalization reaction had a tendency to move
from Pd(II) to Pd(0) in the catalytic cycle. Hence, a series of C−
H transformations could potentially be developed for acetone
oxime ether masked aromatic alcohols.
20 h. o,o′-Diolefinated products 6c were observed but not isolated.
Scheme 6. Gram-Scale Reactions
intermediate crystal, which provided a clear understanding of the
exo-directed C−H transformation. To demonstrate the utility of
this transformation, total synthesis of the antibacterial activity
compound 3-deoxyisoochracinic acid was accomplished in five
steps. More detailed mechanistic studies are underway in our
laboratory.
In conclusion, we have developed a versatile and readily
transformable directing group for aromatic alcohols. Direct
olefination of aromatic alcohols masked by acetone oxime ether
were first developed with a broad substrate scope. The
mechanism study gave the first example of an exo-palladacycle
C
DOI: 10.1021/acs.orglett.5b00594
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, X-ray crystallographic analysis, and 1H
and 13C NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yszhao@suda.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundation of
Jiangsu Province of China (BK20130294), the Young National
Natural Science Foundation of China (No. 21402133), and
PAPD for financial support.
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DOI: 10.1021/acs.orglett.5b00594
Org. Lett. XXXX, XXX, XXX−XXX