β-Arylation of oxime ethers using diaryliodonium salts through activation of inert C(sp 3)-H bonds using a palladium catalyst

Article abstract of DOI:10.1039/c5sc03903g

An efficient method of selective β-arylation of oxime ethers was realized by using a palladium catalyst with diaryliodonium salts as the key arylation reagents. The reaction proceeded smoothly through the activation of inert C(sp³)-H bonds to give corresponding ketones and aldehydes. This convenient procedure can be successfully applied to construct new C(sp³)-C(sp²) bonds on a number of complex molecules derived from natural products and thus serves as a practical synthetic tool for direct late-stage C(sp³)-H functionalization.

Full text of DOI:10.1039/c5sc03903g

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Chemical Science
EDGE ARTICLE
β‐Arylation of Oxime Ethers Using Diaryliodonium Salts through
Activation of Inert C(sp3)‐H Bond with Palladium Catalyst
Jing Peng, Chao Chen,* Chanjuan Xi
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient method of selective β‐arylation of oxime ethers was realized by using palladium catalyst with diaryliodonium
salts as the key arylation reagents. The reaction proceeded smoothly through the activation of inert C(sp3)‐H bonds to give
corresponding ketones and aldehydes. This convenient procedure can be successfully applied to construct new C(sp3)‐
C(sp2) bonds on a number of complex molecules derived from natural products and thus serves as a practical synthetic
tool for direct late‐stage C(sp3)‐H functionalization.
DOI: 10.1039/x0xx00000x
www.rsc.org/
which could be easily converted to important β‐aryl ketones,
amines and so on.8 The reaction proceeds smoothly via C(sp3)‐
H activation with diaryliodonium salts as the key coupling
Introduction
Arylation via direct activation of inert C‐H bonds has emerged
as a fascinating field, which could provide useful aromatic
compounds with high atom‐ and step‐economy.1 In the past
decade, significant progress has been made in the
development of transition‐metal catalyzed arylation on C(sp2)‐
H which enables coupling a large range of substrates to various
aromatic reagents,2 including more challenging work on
enantioselective construction of stereo‐centers published in
most recent years.2j‐2l In comparison, arylation on inert C(sp3)‐
H bond (simple alkyl C‐H bond) is much less explored with a
scope of limited substrates reported.3 One of the most
successful strategies is transition‐metal catalyzed‐arylation of
partner reagents (Scheme 1).
HCHO
HCl
Ar
I Ar
2
O
Ar
O
O
N
H
N
Ar
R1
R1
R1
Pd(OAc)2 (5 mol%)
R2 R2
one-pot
R2 R2
R2 R2
1
4
3
L
O
N
Pd L
R1
via
Key intermediate
R2 R2
5
Scheme 1. Pd‐catalyzed β‐arylation reaction of oxime ethers via C(sp3)‐H bond
carboxylate derivatives, including carboxylic acids, esters and activation.
amides.4 Assisted by big auxiliary groups, alkyl amines could
also be selectively arylated on the chain.5
In light of these advances, we were encouraged to develop
Results and discussion
new arylation reactions through direct activation on alkyl C‐H
bonds with a wider scope of substrates which offers
unprecedented opportunities to efficiently synthesize valuable
aromatic compounds.6 As to chelation‐assisted C‐H bond
functionalization, facile introduction and removal of the
directing group could enlarge the scope of substrates from
pre‐designed molecules and consequently enable the protocol
applicable to various natural products, generating new and
attractive sources for bioactive compounds with high diversity
and functionality.7 With this ultimate goal in mind, we
successfully developed a Pd‐catalyzed β‐arylation reaction on
inert C(sp3)‐H bond of oxime ethers to give useful outcomes,
As revealed by known work, the main issues of transition‐
metal catalyzed functionalization on C(sp3)‐H bonds not only
resulted from the inertness and abundance of C(sp3)‐H bonds
in organic compounds, but more essentially, from the inherent
instability of in‐situ generated catalytic metal species, which
may easily undergo β‐hydrogen elimination or side reactions.9
To some extent, a good solution is adjusting electronic and
coordination effects of the catalytic species, but this generally
required additional modification of the substrates.10 Hence, a
more straightforward solution might be to accelerate the
transformation of the catalytic metal species by accomodating
the proper coupling reagents with an appropriate chelating
group.11 With this strategy, we successfully realized the β‐
arylation reaction on the C(sp3)‐H bond of oxime ethers with
Pd(OAc)2 as the catalyst. During the study of C‐C bond
formation on inert C‐H bonds, we intiated the investigation
with arylating 2‐methylcyclohexanone O‐methyl oxime, which
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
E‐mail:chenchao01@mails.tsinghua.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
is quantitatively synthesized from
α
‐methylcyclohexanone. To
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Journal Name
‐
begin with, when PhBr or PhI was used as the coupling reagent while 2a•BF4 failed to generate 3aa. For futher modification,
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DOI: 10.1039/C5SC03903G
under various conditions, it always failed to give the desired when the reaction was completed under the optimazed
arylation product, 3aa, and dehydrogenation side products 1a’ condition, entry 17, the mixture was treated with
and 1a’’ were observed with Pd‐black formed. This implied formaldehyde in an acidic system,14 and 2‐benzyl
that the putative Pd‐species
Pd(OAc)2, but due to the instability, PhBr or PhI could not be experimental details, see Supporting Information). In
coupled to species before it underwent β‐hydrogen‐ accordance with the intial proposal, ketoximes and ketones
5 was generated from 1a with cyclohexanone, 4aa, was isolated in 80% yield (For
5
elimination. In order to facilitate the desired arylation reaction, can be easily interconverted, making this method an efficient
Ph2I+PF6 , 2a•PF6 (1 equiv) was chosen as the coupling reagent approach to β‐aryl ketones.
‐
‐
12
and 3aa was formed, albeit in 17% yield (Table 1).
The
With the optimized conditions established the scope of
addition of base slightly increased the yield of 3aa, but the diaryliodonium salts were examined for β‐arylation of 1a. As
best yield was only 27% when Ag2CO3 (2 equiv) was employed. shown in Scheme 2, diaryliodonium salts with a range of
By adding pivalic acid, the starting materials were fully substituents were efficiently coupled using these conditions.
converted to produce 3aa with 50% yield.13 In order to further Most of the products were isolated in the ketone form
4 rather
accelerate the transfer step of the phenyl group, we added the than oxime ethers 3 since ketones were considered to be more
polar solvent, hexafluoroisopropanol (HFIP) to the reaction, synthetically useful. The diaryliodonium triflates with F‐, Cl‐ and
resulting in an increase to 82% yield of 3aa. The use of 2a•OTf‐ Br‐ substituents at para position (2b‐2d) reacted smoothly with
gave an even better result (87%, entry 17
，
isolated in 83%),
1a generating corresponding products (4ab‐4ad) in good yields.
The use of methyl and butyl substituted diphenyliodonium
t
triflates (2e‐2f) and 1a provided products (4ae‐4af) in slightly
lower yields. Diaryliodonium triflates bearing strong
a
Table 1. Optimization of reacting conditions for 3aa.[a]
electron‐withdrawing group (‐CO2Me and ‐CF3) or strong
electron‐donating group (‐OMe) also yielded to desired
products (4ag‐4ai) while 3ah was obtained under a lower
temperature of 70oC. The reaction of 1a with ortho‐substituted
diaryliodonium triflates (2j‐2l) could also afford expected
products (4aj‐4al) in satisfactory yields. However, the use of
asymmetric diaryliodonium salts Ar‐I+‐MesX‐ failed to give
products. A number of selected oximes (3aa,3ad, 3ag, 3ah, 3ai,
3aj, and 3ak) were isolated to demonstrate the original
efficiency.
MeO
MeO
N
Pd(OAc)2 (5 mol %)
N
Ph2I+X-
Ph
+
H
base, additive
12 h, solvent
-
2a
85 o
C
3aa
X
1a
L
O
O
O
N
Pd L
N
N
1a'
1a''
5a
Entry
Solvent
Base (equiv)
Additive
(equiv)
Yield
MeO
O
N
[b]
MeO
Pd(OAc)2 (5 mol %)
HCHO, HCl
Ar
THF,r.t., 5 h
N
Ar2I+OTf-
+
Ar
H
PivOH (0.6 equiv)
Ag2CO3 (2 equiv)
DCE:HFIP(3:1)
85 oC, 5 h
1
2
3
4
5
6
7
8
9
DCE
DCE
CH3CN
DMSO
EtOH
DCE
DCE
DCE
DCE
None
None
None
None
None
None
None
None
None
None
None
None
None
Trace
17%
N.R.
N.R.
N.R.
10%
15%
8%
23%
27%
44%
50%
57%
82%
40%
51%
87%
Trace
2 OTf-
1a
4ab-4ak
3ab-3ak
O
O
O
O
None
F
Cl
Br
K2CO3 (1)
NaHCO3(1)
Na2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
4ab: 80%
4ac: 78%
4aa: 80% (3aa: 83%)
4ad: 78% (3ad: 80%)
O
O
O
O
tBu
CO2Me
4ag: 81% (3ag: 87%)
CF3
10
11
12
13
14
15
16
17[a,d]
18[d]
DCE/t‐Butanol (4:1)
DCE
None
Me
PivOH(0.3)
PivOH(0.6)
PivOH(0.6)
PivOH(0.6)
PivOH(0.6)
PivOH(0.6)
PivOH(0.6)
None
4ae: 77%
4af: 67%
4ah: 84% (3ah: 86%)
DCE
O
O
F
O
Cl
O
Br
DCE/t‐Butanol (4:1)
DCE/HFIP(3:1)
DCE/HFIP(1:1)
DCE/HFIP(1:1)
DCE/HFIP(3:1)
DCE/HFIP(3:1)
OMe
4ai: 76% (3ai: 80%)
4aj: 74% (3aj: 78%)
4ak: 69% (3ak: 72%)
4al: 56%
Scheme 2. Scope of diaryliodonium salts to form desired β‐arylated products.
To further investigate, a series of substituted acylic oxime
substrates were examined to explore the regioselectivity of
the arylation with di(4‐bromophenyl)iodonium 2d. As shown in
Scheme 3, ketoximes 1b‐1d all reacted with 2d to give mono‐
b
a Reaction conditions: 1a (0.25 mmol), 2a•X‐ (0.25 mmol), Solvent (2 mL).
Determined by NMR using trichloroethylene as an internal. c 2a•OTf‐ was used.
d The reaction was quenched after 5 hours.
arylated products at ‐methyl group in good yield while the
2 | J. Name., 2012, 00, 1‐3
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generation of bi‐arylated compounds remained at trace reactions for reactivity, selectivity and tolerance VoiefwfAurtniccletiOonnlinael
DOI: 10.1039/C5SC03903G
amounts. The use of aldoxime 1e only produced 4ed in group (Scheme 5). Oxime 1i, derived from naturally‐occurred
moderate yield while the bulky ketoxime 1f with four ‐methyl fenchone which containes three methyl groups, and could be
groups afforded mono‐arylated product 4fd in good yield. In selectively arylated on an exo‐methyl group with 2g under
addition, we examined the effect of substituents on cyclohexyl standard condition, giving 3ig in 65% yield. Naturally abundant
oxime ethers and 4nd was isolated in 83% yield from 1n
.
in many essential oils, (+)‐carvone can be easily converted to
α,β‐unsaturated ketone oxime with α‐methyl group 1j.This can
then can be arylated with 2g to give 3jg under the synthetic
method established, albeit in 38% yield. However, with 1
equivlent of diaryliodonium salt 2g, the mono‐arylated product
of 1k derived from lanosterol was observed as two inseparable
isomers in a relevantly low yield. Alternatively, when 2
equivalents of 2g were employed in the transformation, the
bis‐arylated product 3kg was successfully obtained in 73%
isolated yield. The structure of 3kg was confirmed by XRD
analysis, shown in Figure 1 (1A). β‐Glycyrrhetinic acid is a
major metabolite of glycyrrhizin, one of the main constituents
of licorice, has been shown to exhibit anti‐ulcerative, anti‐
inflammatory, and immunomodulatory properties. Substrate
It is known that the activation of methylene C‐H bonds is
harder than methyl C‐H bonds in transition‐metal catalyzed
reactions because C‐H bonds in methylene position are more
hindered.15 As shown herein, some of the ketoximes with the
appropriate configuration, for instance 1g, could successfully
be arylated with 1d to give 4gd in 42% yield. Similarly, it also
worked with an oxime ether containing a 1‐adamantanyl group,
1h, to produce 3hg in 47%. (Scheme 4)
2g OTf-
CO2Me
MeO
N
H
O
H
Pd(OAc)2 (5 mol %)
MeO
N
MeONH2 Me
Me
Me
Me
Me
PivOH (0.6 equiv)
Ag2CO3 (2 equiv)
DCE:HFIP(3:1)
90 oC, 8 h
Me
1i
Fenchone
3ig: 65%
MeO
2g OTf-
MeO
O
N
N
Pd(OAc)2 (5 mol %)
H
H
PivOH (0.6 equiv)
Ag2CO3 (2 equiv)
DCE:HFIP (3:1)
90 oC, 8 h
CO2Me
3jg: 38%
(+)-Carvone
1j
Scheme 3. β‐Arylation of selected oxime ethers with 2d.
MeO2C
2g OTf-
Pd(OAc)2 (10 %)
H
H
H
H
PivOH (0.6 equiv)
Ag2CO3 (2 equiv)
DCE:HFIP (3:1)
85 oC, 5 h
N
OMe
N
OMe
HO
Lanosterol
MeO2C
3kg: 73%
1k
MeO2C
OMe
OMe
N
N
H
2g OTf-
HO
H
Pd(OAc)2 (10 %)
O
PivOH (0.6 equiv)
Ag2CO3 (2 equiv)
DCE:HFIP (3:1)
85 oC, 5 h
O
O
O
H
H
H
H
H
H
MeO2C
H
O
H
O
OMe
OH
OMe
3lg: 69%
1l
Glycyrrhetic acid
Scheme 4. The activation of methylene C‐H bonds to form C‐C bond.
Since the direct modification of natural products at a
normally inert position has attracted much attention due to
the potential to access to new bioactive compounds from
“starmolecules”,1a,16 some complex substrates with natural
product backbones were examined in our new arylation
Scheme 5. Modification of complex molecules derived from natural products.(see SI
for experimental details)
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DOI: 10.1039/C5SC03903G
Scheme 6. Hydrogenation of 3aa to generation 3aa‐H
Fig. 1. 1A (left), Crystal structure of compund 3kg; 1B (right), Crystal structure of
palladation intermediate 6(see SI for detailed date of the crystals).
1l, derived from Glycyrrhetinic acid, could also be bis‐arylated
on both methyl C‐H bonds to form 3lg with 69% isolated yield.
Besides natural product‐like compounds, the synthetic reagent,
methasterone was converted to oxime 1m, which was then
successfully arylated with 2d to give 4md in high yield, with
the hydroxyl group unchanged during the reaction. In addition,
oxime ethers can be easily converted to corresponding amines
which are useful building block with a range of potential
applications (Scheme 6).17
Based on the above results and literature report, a plausible
mechanism was proposed in scheme 8. First, the reaction of
oxime ether
salts generated in situ) would produce cyclopalladation species
. And the oxidative addition of diaryliodonium salt to
would afford PdIV intermediate 7 11
The reductive elimination
of would give product
, and release the PdII species into the
catalytic cycle.
1
with PdII species (Pd(OAc)2 or other palladium
5
2
5
.
7
3
In terms of the mechanism study, we proposed that the
process was initiated by a cyclometalated complex.18 Using 1a
as the starting backbone, the isolation of palladation
intermediated always failed due to the strong tendency of β‐H
elimination of 5a. When treating 1d with Pd(OAc)2, the
existence of palladation intermediate 5d was proved. By
converting 5d to
6 6 was
(Scheme 6), 19 the crystal structure of
identified indicating that palladium was bounded with CH2 and
oxime‐nitrogen atom as a cyclometalation species (Figure 1,
1B). In order to confirm the catalytic competency, complex
6
was treated with 1 equivalent of 2d and 2 equivalents of
Ag2CO3, analogously to the standard reacting condition, and
3dd was observed in 80% yield by in‐situ NMR.
Scheme 8. A plausible mechanism.
Conclusions
In summary, we have developed a novel β‐arylation reaction
on an inert C(sp3)‐H bonds of oxime ethers. The reaction offers
new opportunities to prepare useful β‐arylated oximes
from/to ketones and aldehydes via simple transformation with
good efficiency and step‐economy. The easy manipulation and
good tolerance of functional groups enable the method to
modify many complex compounds derived from natural
backbones. Further investigations on the scope, mechanism,
and synthetic application of this new reaction are underway in
our laboratory.
Scheme 7. Preparation of the palladation intermediate and its reaction with 2d.
4 | J. Name., 2012, 00, 1‐3
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R. Jazzar, A. Comte, P. Holstein, J. ‐P. Vors, M. J. Ford and O.
Acknowledgements
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This work was supported by National Natural Science
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and The National Key Basic Research Program of China (973
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Chemical Science
Page 6 of 6
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DOI: 10.1039/C5SC03903G
Chemical Science
EDGE ARTICLE
β-Arylation of Oxime Ethers Using Diaryliodonium Salts through
Activation of Inert C(sp3)-H Bond with Palladium Catalyst
Jing Peng, Chao Chen,* Chanjuan Xi
Received 00th January 20xx,
Accepted 00th January 20xx
HCHO
HCl
Ar
I Ar
DOI: 10.1039/x0xx00000x
O
Ar
O
O
N
H
N
Ar
2
R1
www.rsc.org/
R1
R1
Pd(OAc)2 (5 mol%)
R2 R2
one-pot
R2 R2
R2 R2
1
4
3
Palladium catalyzed selective β-arylation of oxime ethers was realized using diaryliodonium salts as the key arylation
reagents.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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