Cu-catalyzed selective cascade sp3 C-H bond oxidative functionalization towards isoxazoline derivatives

Article abstract of DOI:10.1039/c5cc01004g

The first Cu-catalyzed cascade sp³ C-H bond oxidative functionalization of the 2-ethylazaarenes has been developed. The two different sp³ C-H bonds in 2-ethylazaarenes are selectively oxidized and four new types of bonds (CO, CN, C-C, C-O) are constructed in one operation. Starting from the simple substrates and cheap nitro source, this reaction provides an efficient approach to produce new kinds of isoxazolines.

Full text of DOI:10.1039/c5cc01004g

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Cu-Catalyzed Selective Cascade sp3 C-H Bonds
Oxidative Functionalization towards Isoxazoline
Derivatives
Cite this: DOI: 10.1039/x0xx00000x
Gang-Wei Wang,a Ming-Xing Cheng,a Ran-Song Ma a and Shang-Dong Yang*a.b
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org
The first Cu-catalyzed cascade sp3 C–H bonds oxidative 1,3-dicarbonyl compounds) with hydroxylamine, and
functionalization of the 2-ethylazaarenes has been developed. condensation of oxime dianions are also common approaches to
The two different sp3 C–H bonds in 2-ethylazaarenes are isoxazolines derivatives.9 Recently, several new strategies have
selectively oxidized and four new types of bonds (C=O, C=N, been developed10 such as, palladium-catalyzed cyclization of β,
C–C, C–O) are constructed in one operation. Starting from γ-unsaturated oximes,10e-10i gold-catalyzed cyclization and
the simple substrates and cheap nitro source, this reaction rearrangement of alkynyl oxime,10d and base-mediated
provides an efficient approach to new kinds of isoxazolines.
rearrangement of oxetanes10f as well as by using acetone (or
acetophenone) as solvent to access isoxazolines derivatives
under iron salts or ammonium cerium nitrate (CAN),10a-10c these
achievements represent important advances in this field.
However, the direct production of new isoxazoline derivatives
from brief steps, simple substrates and cheap reagents is highly
attractive alternative. Recently, transition-metal-catalyzed
benzylic sp3 C–H bond oxidative functionlization of
alkylazaarenes has been a hot topic.11 We speculate that, the
application of transition-metal-catalyzed sp3 C–H bonds
oxidation in a cascade manner will provide not only a cutting-
edge method for C–H bond functionalizations, but also a more
straightforward and simple access to isoxazoline derivatives.
Under our persistent endeavors, we have developed the first
Cu-catalyzed selective cascade sp3 C–H bonds oxidative
functionalization reaction of the alkylazaarenes to produce a
series of new kinds of isoxazoline derivatives which may be
Transition-metal-catalyzed sp3 C–H bond functionalization
has unimpeachably emerged as an atom- and step-economical
synthetic method for the construction of new C–X bonds (X=C,
N, O, etc).1 In particular, multiple C–H bonds
functionalizations which involve cascade reaction procedures to
achieve complex structures with non-prefunctionalized
substrates in a single operation represents an advanced
methodology in organic synthesis,2 because potentially difficult
work-up and isolation steps can be avoided and the generation
of chemical waste is minimized. Although some
groundbreaking results have been made,3 the reaction types of
transition-metal-catalyzed cascade C–H functionalization are
still very limited, especially in the field of sp3 C–H bonds.
Isoxazolines constitute an important class of heterocycles in
organic chemistry and pharmaceutical science, which are
frequently found in a wide range of natural products and
biologically active compounds as well as chiral ligands4,5
Moreover, isoxazoline derivatives as excellent precursors have
been widely used in the synthetic chemistry.6 As a consequence,
the development of synthetic methods for these compounds has
lasted for more than one hundred years.7 Among them, the most
classic and long-studied method is the 1,3-dipolar cycloaddition
of dipolarophiles with nitrile oxides which is in situ generated
from specific substrates such as hydroximinoyl chlorides,
aldoximes and primary nitro compounds.6c,8 Besides that,
oximation and cyclization of α, β-unsaturated compounds (or
Scheme 1. Cu-catalyzed selective cascade sp3 C–H bond oxidative
functionalization towards new kinds of isoxazoline derivatives
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used as ligands or biologically active molecules. Two groups of product in a trace amount (3f). Synthetically important
different sp3 C–H bonds of 2-ethylquinoline (and quinoxaline) functional group such as cyan, hydroxyl, isoindoline-1,3-dione
are selectively functionalized resulting in construction of four and phosphate were well tolerated under catalytic system (3i
,
new types of bonds (C=O, C=N, C–C, C–O) in one operation. 3k 3h 3j). Disubstituted alkene, such as cyclohexene and 1,2-
,
,
This ability to achieve the isoxazoline derivatives in one pot via diphenylethene failed to provide any desired product. Next,
sp3 C–H bonds cascade functionalizations has never been different alkylazaarenes were applied into the reaction to
demonstrated (Scheme 1).
2-Ethylquinoline 1a was initially used as the substrate to substituent groups (Me, OMe, OPh) at different positions
react with butyl acrylate 2a in order to identify the suitable exhibited moderate to good reactivity (3l 3m 3n 3o), and 2-
expand the substrate scope. 2-ethylquinoline bearing different
,
,
,
reaction conditions. After a series of screens on different ethylquinoxaline and 2-ethylbenzo[h]quinoline also could be
catalysts, oxidants, solvents, and nitro sources, we settled on successfully oxidized to afford the products in moderate yields
the following reaction conditions: 10 mol % of CuBr as
(3p, 3r). When 2-ethylpyridine used as substrate, desired
catalysts, 2.5 equiv of K2S2O8 as oxidant, 6 equiv of KNO3 as product was only obtained in a trace amount (3q). When we
nitro source, and DMF/CH3CN = 10/1 (v/v) as a solvent at 80 used alkylarylketones as substrates, ethylbenzene and 2-
oC for 24 hr in an open tube. (Details see SI). Upon ethylnaphthalene for example, no desired products were
optimization of the reaction conditions, different alkenes were detected (3s, 3t). Other 2-substituted quinolines, such as 2-
first applied to test the generality of this reaction system. By propylquinoline could not provide any oxidized product, and
using 2-ethylquinoline 1a as the standard substrate, a variety of different oxidized product was obtained when 2-
terminal alkenes were successfully converted into desired methylquinoline was used as substrate (Details see SI). Besides
products in moderate to good yields (Table 1). Aliphatic alkenes, terminal alkynes were also suitable substrates for this
alkenes were the good reaction partners under reaction reaction, alkyl-substituted acetylene converted into the desired
conditions. (3b, 3c, 3d). Allylbenzene and allylpentafluoro products in moderate yields (3v, 3x). Methyl propiolate
benzene provided products in a yield of 79% and 74%, furnished the product in a yield of 67% (3u). Unlike the styrene,
respectively (3e
,
3f). However, styrene only produced desired
ethynylbenzene reacted smoothly with 2-ethylquinoline 1a and
gave the product in 50% yield (3w).
Table 1. Reaction substrates scope.a,b
In order to expand the synthetic efficiency of this reaction, a
chiral carbohydrate-derivative 4a was applied in the reaction
system to our delight, desired product 5a which may possess
interesting biologically actives12 was obtained in a yield of 61%
with an excellent diastereoselectivity (dr > 20:1), and 0.51
mmol of 4a was recycled. Furthermore, the success of gram-
scale reaction between 1a with 2a under standard conditions
showed the robustness and potential industrial application of
our transformation (Scheme 2).
Scheme 2. Synthetic application
Next, several control experiments were carried out to probe
the mechanism of this cascade oxidation reaction (Scheme 3).
When the standard reaction was conducted in the presence of 1,
1-diphenylethylene (2 equiv), a radical scavenger, the desired
product was not detected at all, but (2-nitroethene-1, 1-diyl)
dibenzene AA and benzophenone AB were produced (Scheme
3a). These results indicated that this reaction might involve the
generation of nitro radical, (under the open-tube condition, AB
could be generated by the reaction of 1,1-diphenylethylene with
aReaction was carried out with CuBr (10 mol %), K2S2O8 (2.5 equiv), KNO3
(6.0 equiv), 2-ethylazaarenes (0.30 mmol), alkenes or alkynes (0.9 mmol) in
b
DMF/CH3CN = 3 mL/0.3 mL at 80 ℃ for 24 h in an open tube.; Yield of
isolated product. cMixed with trace amount of impurities.
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oxygen).13 When the standard reaction was stopped at 15 pathways to generate the intermediate AC. In path I, H2O (or
minutes, 1-(quinolin-2-yl)ethan one AC was obtained in 34% OH anion) attacked at intermediate to give AC, and in path II,
yield with trace amount of 3a, and when we used AC instead of intermediate was attacked by the NO3 anion, then after the
A
A
1a as the substrate to run this reaction, 3a was isolated in an elimination of HNO2, AC was formed.15 The experiments of
excellent yield of 89%, which implied that AC might served as H2O18 proved that the path I might only served as a minor way
the key intermediate for this reaction. Then, O18–labeled at most to produce AC. Next, AC reacted with copper catalyst
experiments were preformed to find out the oxygen source for to provide the active metal enol species
the construction of the carbonyl group. When 18O2 was applied subsequently attacked by NO2 radical and the intermediate
into the reaction under the degassed condition, 3a was obtained was achieved.13b,14b The oxidation and dehydration of
led to
which would convert into the
E, and E was
F
F
in 71% yield with a trace amount of O18–labeled product 3a’
.
the formation of nitrile oxides G
This result indicated that molecular oxygen was not the oxygen desired isoxazolines through 1, 3 -dipolar cycloaddition.8
source of the carbonyl group. Then different equivalents of
H2O18 were added to the reaction, with the increase of the
H2O18, the total yield of product (3a
+3a’) was decreased and
the percentage of 3a’
[3a’/ (3a+3a’)] was increased accordingly
(Scheme 3c). This experiment showed that H2O might only
serve as a small part of the oxygen source for the carbonyl
group at most. (We could not rule out the possibility of the
oxygen exchanging of carbonyl group under high H2O18
concentration).
Scheme 4. Proposed reaction mechanism
In conclusion, we have developed the first Cu-catalyzed
cascade sp3 C–H bonds oxidative functionalization of the
ethylazaarenes, and applied it to produce a series of new kinds
of isoxazoline derivatives. The two different sp3 C–H bonds in
ethylazaarenes are selectively oxidized and four new types of
bonds (C=O, C=N, C–C, C–O) are constructed in one operation.
Preliminary mechanistic studies show that this transformation
may go through a radical process, H2O and NO3 anion provide
the oxygen source for the carbonyl group jointly, and KNO3
served as the nitrogen source for isoxazoline unit. The
combination of simple substrates and cheap catalytic system, as
well as the potential application of the final products further
increase the practicality of this methodology.
Acknowledgement
We are grateful for the NSFC (Nos. 21272100 and 21472076) and,
FRFCU (lzujbky-2013-ct02, PCSIRT (IRT1138), and Program for
New Century Excellent Talents in University (NCET-11-0215 and
Scheme 3. Mechanism experiments
Based on the above experiments and previous literatures,13-15
a possible mechanism was proposed in Scheme 4. Initially, in
the presence of Cu(I) catalyst, KNO3 reacted with K2S2O8 to
lzujbky-2013-k07) financial support.
aState Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, P. R. China. E-mail: yangshd@lzu.edu.cn;
bState Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Lanzhou 730000, P. R. China
generate the nitro radical, sulfate anion radical and Cu(II)14a,14b
,
then intermediate
(SET) process from 1a with the assistance of sulfate anion
radical.14b,14c Subsequently,
was oxidized by Cu (II) to
A was obtained by a single electron transfer
†
Electronic supplementary information (ESI) available. See DOI:
10.1039/c3cc
A
Notes and references
produce the benzylic cation B, which might go through two
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