Bu4NI-Catalyzed α-Oxyacylation of Carbonyl Compounds with Toluene Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b00749

A TBAI (tetrabutylammonium iodide)-catalyzed direct α-oxyacylation of carbonyl compounds from readily available toluene derivatives has been developed. The distinguished features of this metal-free protocol include the employment of simple starting material, a wide carbonyl compound scope, and mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.6b00749

Letter
pubs.acs.org/OrgLett
Bu4NI-Catalyzed α‑Oxyacylation of Carbonyl Compounds with
Toluene Derivatives
Chengliang Li,†,§ Tao Jin,† Xinglu Zhang,† Chunju Li,† Xueshun Jia,*,†,§ and Jian Li*,†,‡
†Department of Chemistry, Innovative Drug Research Center, Shanghai University, 99 Shangda Road, Shanghai 200444, P. R. China
‡Shanghai Key Laboratory of High Temperature Superconductors, Shanghai University, Shanghai, 200444, P. R. China
§College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, P. R. China
S
* Supporting Information
ABSTRACT: A TBAI (tetrabutylammonium iodide)-cata-
lyzed direct α-oxyacylation of carbonyl compounds from
readily available toluene derivatives has been developed. The
distinguished features of this metal-free protocol include the
employment of simple starting material, a wide carbonyl
compound scope, and mild reaction conditions.
he selective α-oxygenation of carbonyl compounds
catalyzed benzylic Csp3−H bond activation12 of arylmethane
Tconstitutes an important reactivity mode in organic was particularly important since it provided a new opportunity
for the direct formation of a carbon−carbon and carbon−
heteroatom bond in an efficient manner.13 Additionally, the
versatile reactivity of arylmethanes also made them good
substrates in cascade processes involving benzylic Csp3−H
bond activation to construct structurally complex heterocyclic
compounds.14 Recently, reactions using toluene derivatives as
acyl precursor became another research focus and much
progress had been achieved in this area.15 Stimulated by these
fundamental works, we became interested in exploring novel
reactions using toluene derivatives as versatile building blocks.
Most recently, we have just disclosed a palladium-catalyzed
direct synthesis of isoxazoline from toluene derivatives.16 Our
literature survey showed that the reactions between carbonyl
compounds and arylmethanes remained underexploited, and
only examples on C−C bond formation were reported. Li and
co-workers explored an efficient CDC reaction between a
benzylic C−H bond and activated ketone to form a new
Csp3−Csp3 bond (Scheme 1, eq 1).17 More recently, Song
and co-workers developed an interesting Fe-catalyzed double
CDC reaction of an arylmethane and a 1,3-dicarbonyl
compound (Scheme 1, eq 2).18 As a continuation of our
previous research,19 herein we report that, in the presence of
TBAI (tetrabutylammonium iodide), the reactions between
carbonyl compounds and simple arylmethanes could furnish
the C−O bond formation using toluene derivatives as an
oxyacylative precursor (Scheme 1, eq 3).
synthesis, as the resultant α-oxygenated carbonyl moieties are
common structural motifs in many natural products and
biologically active molecules.1 As such, transformations toward
the preparation of such skeletons have been extensively
investigated in the past decades.2 Among them, the selective
α-hydroxylation of Csp3−H of ketones seems to provide a
direct and efficient approach. For instance, Ritter,3a Jiao,3b and
Schoenebeck3c reported the selective and efficient preparation
of α-hydroxycarbonyls from ketones using molecular oxygen
as the oxidant, respectively. On the other hand, α-oxyacylation
of carbonyl compounds has also received considerable
attention from the synthetic community. Traditionally, these
compounds could be prepared from α-halocarbonyl com-
pounds4 and the oxidative coupling of carbonyl compounds
with highly toxic heavy-metal oxidants.5 To overcome the
drawbacks of traditional methods, hypervalent iodines6 and
other oxidants7 were widely investigated to promote the α-
oxyacylation of ketones. More recently, reactions using other
oxyacylative reagents other than carboxylic acids have also
been disclosed.8 Compared with the popularity of ketone α-
oxyacylation, successful examples with other carbonyl
compounds are still rare. In 2009, Maruoka and co-workers
reported the α-oxybenzoylation reaction of aldehyde using
benzoyl peroxide as the reagent.9 In 2011, Ishihara and co-
workers reported another intramolecular and intermolecular
α-oxyacylation reaction of carbonyl compounds with carbox-
ylic acids.10 While impressive achievements have been made
to date, most of the reported examples suffered from harsh
conditions, a limited substrate scope, or highly toxic reagents.
As a result, there is still a continuing demand to develop
novel and environmentally benign methods with a broad
scope as well as simple and readily available starting materials.
As simple and highly valuable starting materials in nature,
toluene and its derivatives have found wide application in
organic synthesis.11 Among these transformations, metal-
We began our reaction optimization using toluene 1a and
propiophenone 2a as model substrates. As shown in Table 1,
no reaction occurred when copper iodide was used as the
catalyst (Table 1, entry 1). To our delight, in the presence of
a catalytic amount of TBAI, heating the mixture of 1a and 2a
afforded α-oxybenzolated compound 3a in 64% yield (Table
Received: March 15, 2016
© XXXX American Chemical Society
A
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3a−3o. In particular, a wide range of substituents including
halide, alkyl, nitro, and cyano groups at the para-, meta-, and
ortho-position were well tolerated, and the representative
results were summarized in Scheme 2. The experimental
Scheme 1. Representative Transformation of Arylmethane
with Ketone
Scheme 2. Scope of the Reaction with Respect to the
a b
,
Arylmethane Substrate 1
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
solvent
EtOAc
oxidant
yield (%)
1
CuI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
0
0
2
NIS
EtOAc
3
KI
EtOAc
<5
0
4
I2
EtOAc
5
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
−
EtOAc
64
65
51
<5
<10
<5
75
0
6
MeCN
PhCN
7
8
PhCl
9
DCE
10
11
12
13
14
15
THF
MeCN/DMSO
MeCN
MeCN
MeCN
MeCN/DMSO
a
Reaction conditions: arylmethane 1 (3 mmol), propiophenone 2a (1
K2S2O8
DTBP
TBHP
0
mmol), TBAI (20 mol %), TBHP (6.0 equiv), MeCN/DMSO (v/v =
<5
0
b
5:1, 3 mL), 90 °C in sealed tube. Yields of product after silica gel
chromatography.
a
Until otherwise noted, all reactions were carried out with toluene 1a
(3 mmol), propiophenone 2a (1 mmol), catalyst (20 mol %), oxidant
b
(6.0 equiv), solvent (3 mL), 90 °C in sealed tube. Yields of product
after silica gel chromatography.
results also showed that strong electron-withdrawing groups
on the aromatic ring seemed to decrease the reaction
reactivity slightly (3j, 3k, 3m), whereas halide substituents
(3b−3f) favored the formation of products 3. Notably, the
present reaction was not limited to simple benzene-based
substrates; arylmethanes containing pyridyl and naphthyl
groups were also proven to be compatible in the present
transformation (3p−3r).
After having demonstrated a broad scope for substituted
arylmethane, a series of structurally diverse ketones 2 were
next examined to react with toluene 1a under the optimized
conditions. As shown in Scheme 3, all reactions proceeded
smoothly to afford the desired products 4a−4i. Upon
treatment of ketone 2 bearing diphenyl and naphthyl groups
other than the phenyl group, the corresponding α-oxy-
benzolated compounds (4e, 4f) were also isolated in
satisfactory yields. Furthermore, aliphatic ketone was also
found to be a good partner in this transformation. The
reaction using cyclohexanone furnished compound 4i in 45%
yield. More importantly, 1,3-dicarbonyl compounds including
1,3-diketones, dimethylmalonate, and ketoester, underwent
1, entry 5). Encouraged by this experimental result, we then
turned our attention to the solvent screening to improve the
reaction performance. The experimental outcome showed that
mixed solvent MeCN/DMSO (v/v = 5:1) was found to be
particularly effective to increase the yield of 3a from 64% to
75% (Table 1, entry 11). It was also worthy to note that the
oxidant also played a key role in the present reaction, and
some representative results are summarized in Table 1. For
instance, no reaction took place when H2O2 and K2S2O8 were
used (Table 1, entries 12, 13). The employment of DTBP as
the oxidant only led to a very poor yield (Table 1, entry 14).
Having the optimized conditions in hand, we turned our
attention to the scope and limitations of the present reaction.
To establish the feasibility of substituted substrate 1, toluene
derivatives 1 bearing different substitution patterns were
subsequently used to react with propiophenone 2a under
optimal conditions. Pleasingly, reactions with arylmethanes 1
having electron-withdrawing and -donating groups on the
aromatic rings all worked well to give the desired products
B
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Scheme 3. Scope of the Reaction with Respect to the
Carbonyl Substrate 2
Scheme 5. Preliminary Mechanistic Study
a b
,
2a under optimal conditions essentially afforded 91% 3a in
the absence of TBHP, which indicated that perester possibly
was the reaction intermediate (Scheme 5, eq 7).
On the basis of previous reports and our experimental
observations, a possible reaction mechanism is depicted in
Scheme 6 to explain the formation of products 3−5. Initially,
a
Reaction conditions: toluene 1a (3 mmol), carbonyl compound 2 (1
Scheme 6. Proposed Mechanism
mmol), TBAI (20 mol %), TBHP (6.0 equiv), MeCN/DMSO (v/v =
5:1, 3 mL), 90 °C in sealed tube. Yields of product after silica gel
chromatography.
b
the present oxidative coupling to yield the desired products
4j−4l with good performance.
To further explore the versatility of the present reaction, we
also briefly tested the possibility of aldehydes. As shown in
Scheme 4, butyraldehyde 2a′ and 3-phenylpropanal 2b′
reacted smoothly to give α-oxybenzolated aldehyde 5a and
5b, thereby greatly expanding the carbonyl substrate scope.
Scheme 4. Scope of the Reaction with Respect to the
Aldehyde
the propiophenone was oxidized to α-carbonyl radical A,22
which involved an in situ generated oxidant through the
oxidation of TBAI by TBHP.23 On the other hand, toluene 1a
was oxidized by TBHP to perester 7 via intermediate B.24
Coupling of radical A and perester 7 essentially led to the
formation of product 3a. Another possibility involved the
formation of reactive cation intermediate C8b from A. In this
case, reactions between carboxylic anion D and cation C took
place to yield the final product 3a, which contributed to
another alternative route.
In conclusion, we have described a TBAI-catalyzed direct α-
oxyacylation of carbonyl compounds using simple toluene
derivatives as significant building blocks. The present strategy
offers several distinguishing features: (1) metal-free oxidation;
(2) simplest toluene derivatives as an oxyacylative reagent; (3)
a wide carbonyl compound scope, i.e. ketone, aldehyde, and
1,3-dicarbonyl compounds; and (4) mild reaction conditions.
Owing to these advantages, the present strategy has the
potential to be further applied in organic synthesis.
To gain further insight into the aforementioned mechanism,
several mechanistic experiments were subsequently performed.
First, TEMPO was added as a radical scavenger to the
reaction mixture of 1a and 2a under optimal conditions
(Scheme 5, eq 4). In such case, the desired α-oxyacylative
reaction was completely inhibited and no product 3a was
observed.20 To determine the real reaction intermediate,
reactions of 1a with 2-iodo-1-phenylpropan-1-one 6 and 2-
hydroxy-1-phenylpropan-1-one 6′ were also carried out,
respectively, which both failed to give the expected product
3a (Scheme 5, eqs 5 and 6). Thus, the possibility of 2-iodo-1-
phenylpropan-1-one 6 or 2-hydroxy-1-phenylpropan-1-one 6′
as the reaction intermediate could be ruled out.21 Remarkably,
the reaction between tert-butyl perester 7 and propiophenone
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00749.
■
S
Int. Ed. 2009, 48, 7094. (e) Wurtele, C.; Sander, O.; Lutz, V.; Waitz,
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Experimental procedures and full characterization of all
compounds, spectral data, and 1H and 13C NMR
spectra for all products (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xsjia@mail.shu.edu.cn.
*E-mail: lijian@shu.edu.cn.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21272148, 21472121, 21272147) and the State Key
Laboratory of Applied Organic Chemistry, Lanzhou University
for financial support. We thank Dr. H. Deng and M. Shao
(Laboratory for Microstructures, Shanghai University) for
NMR spectroscopy and X-ray measurements. This work is
also partly supported by the Shanghai Key Laboratory of High
Temperature Superconductors (No. 14DZ2260700).
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