Direct synthesis of 1,3-dicarbonyl compounds via radical coupling of aldehydes with ketones under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2015.10.006

An efficient approach for the synthesis of 1,3-diketones from aldehydes and ketones has been developed using Bu₄NI (TBAI) as the catalyst. In the presence of DTBP-TBHP/p-TsOH, aldehydes undergo radical coupling with ketones to provide the desired products in moderate to high yields at 120 °C. Although various substituents on the aromatic ring of aldehydes are well tolerable under the standard reaction conditions, the protocol is limited by the scope of ketones. The method exhibits advantages in terms of the easy access of the starting materials, operational simplicity, functional group tolerance, and the absence of metal catalyst.

Full text of DOI:10.1016/j.tetlet.2015.10.006

Accepted Manuscript
Direct Synthesis of 1,3-Dicarbonyl Compounds via Radical Coupling of Alde-
hydes with Ketones under Metal-Free Conditions
Xuqian Shen, Arun Jyoti Borah, Xihan Cao, Weixiang Pan, Guobing Yan,
Xiangmei Wu
PII:
S0040-4039(15)30203-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.006
TETL 46835
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 August 2015
28 September 2015
3 October 2015
Please cite this article as: Shen, X., Borah, A.J., Cao, X., Pan, W., Yan, G., Wu, X., Direct Synthesis of 1,3-
Dicarbonyl Compounds via Radical Coupling of Aldehydes with Ketones under Metal-Free Conditions,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.10.006
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Direct Synthesis of 1,3-Dicarbonyl Compounds via
Radical Coupling of Aldehydes with Ketones under
Metal-Free Conditions
Leave this area blank for abstract info.
Xuqian Shen,† Arun Jyoti Borah,† Xihan Cao, Weixiang Pan, Guobing Yan* and Xiangmei Wu*
Department of Chemistry, Lishui University, Lishui 323000, People’s Republic of China
E-mail: gbyan@lsu.edu.cn
20 mol% TBAI
2.0 eq. TBHP
2.0 eq. DTBP
O
O
O
CHO
+
R
R
10 mol% p-TsOH
120 oC, 24h
Yields: 42-88%

1
Tetrahedron Letters
Direct Synthesis of 1,3-Dicarbonyl Compounds via Radical Coupling of
Aldehydes with Ketones under Metal-Free Conditions
Xuqian Shen,† Arun Jyoti Borah,† Xihan Cao, Weixiang Pan, Guobing Yan* and Xiangmei Wu*
Department of Chemistry, Lishui University, Lishui, 323000,Zhejiang Province, China
ARTICLE INFO
ABSTRACT
An efficient approach for the synthesis of 1,3-diketones from aldehydes and ketones has been
developed using Bu4NI (TBAI) as the catalyst. In presence of DTBP-TBHP/p-TsOH, ,
aldehydes undergo radical coupling with ketones to provide the desired products in moderate to
high yields at 120°C. Although various substituents on the aromatic ring of aldehydes are well
tolerable under the standard reaction conditions, the protocol is limited by the scope of ketones.
The method exhibits advantages in terms of the easy access of the starting materials, operational
simplicity, functional group tolerance and the absence of metal catalyst.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Metal-free
2011 Elsevier Ltd. All rights reserved.
1,3-dicarbonyl
Rdical coupling
1,3-diketones are very important compounds in synthetic
organic chemistry. They are vital building blocks in many
pharmaceuticals as well as natural products that exhibit high
the carbonyl carbon attacks nucleophilically on electrophilic α-
haloketones to afford 1,3-diketones.10b Ryu’s protocol was based
on formation of a metal enolate from enones via hydrometalation
strategy which can undergo subsequent cross-aldol reaction with
aldehydes and β-hydride elimination to give desired 1,3-
diketones.9a The development of more suitable protocols to
synthesize 1,3-diketones from aldehydes is highly necessary and
particularly use of easily available starting material to synthesize
such compounds will be able to draw tremendous attention to
organic chemist. Here in this paper, we have reported an efficient
protocol to synthesize 1,3-diketones via radical coupling of
aldehydes with ketones under metal-free conditions. Radical
synthesis of such compounds is sparse in the literature.7c
The most familiar and general strategy for 1,3-diketone
functionality is based on disconnection 1 (Figure 1). To the best
of our knowledge, disconnection 2, envisaging the use of the
radical synthons has never been explored.
Aldehydes are good source of acyl radicals and can be
generated by using oxidants either in presence of metal or metal
free conditions.11 Utility of ketone radical as coupling partner is
quite uncommon practices and challenging in synthetic
chemistry.12 We believe that the generation of both acyl radical
(Figure 1, X) and ketone radical (Figure 1, Y) and their
subsequent coupling would provide an alternative direct
approach to synthesize 1,3-diketones from readily available
aldehydes and ketones.
biological
activity,
including
antioxidant,
antitumor,
antimicrobial, antiviral, and antifungal activity.1 They act as
important intermediates for accessing various heterocyclic
compounds like pyrazoles, isoxazoles, triazoles, and
benzopyran-4-ones.2 1,3-diketones are also key structural units in
many chelating ligands for transition metals and lanthanide.3
They are used as important intermediates in organic synthesis,
including many venerable C-C bond forming reactions, such as
Knoevenagel condensation, Tsuji−Trost reaction and the
DeMayo reaction.4 Traditionally, these compounds can be
obtained indirectly by the aldol condensation of an enolate and a
carbonyl compound followed by oxidation of the resulting 3-
hydroxy ketones.5 Enolate chemistry remains as the common
practice for synthesis of 1,3-diketones. The classical procedure
involves acylation of a ketone by an ester in the presence of an
alkoxide base (Claisen- type condensation). Other acylating
agents like acid chlorides, acyl cyanides or 1-acylbenzotriazoles
etc. were successfully utilized in C-acylation of enolates
(including enamines and silyl enol ether) derived from ketones.6
However, the formation of lower amount of O-acylation product
is a drawback in such methods and improvement has been done
to avoid its formation.7 Another method involves C-acylation of
acetylacetone or its derivatives by acyl halides or esters followed
by base-promoted deacylation. However, this is also suffered
from the competition of O-acylation.8 Recently, transition-metal-
catalyzed hydroacylation of enones is an alternative direct
approach to achieve 1,3-diketones.9 To date, only a few methods
have been developed for the synthesis of 1,3-diketones from
aldehydes.9a,10 Yadav and co-workers developed a protocol
involving carbonyl umpolung reactivity of aldehydes, in which
O
O
O
O
O
O
1
2
R'
R'
R
R
R
R'
X
Y
Figure 1. Retrosynthesis analysis of 1,3-diketones
We have initiated our investigation by the reaction of
benzaldehyde with acetone (excess) in presence of tert-

2
butylhydroperoxide (TBHP) and di-tert-butylhydroperoxide
(DTBP) at 120°C without any catalyst (Table1, Entries 1-2), but
no desired product was obtained. The reaction even could not
occur in presence of a metal catalyst (Table 1, Entries 3-4 ). It
excudes the possibility of formation of acyl radicals from the
aldehyde in presence of metal-oxidant system.11d-e Iodide/iodine
catalytic cycles in presence of TBHP that results in the formation
of tert-butoxyl or tert-butylperoxyl radicals have been reported
to be very effective to form acyl radicals.11b,g,i,12a Using I2 as a
catalyst, we have observed formation of both 1,2- and 1,3-
diketones with former as the major product (Table 1, Entry 5.6:1,
via 1H NMR). The 1,2-diketone may be formed via
homocoupling of acyl radical generated from the aldehyde.
Replacing iodine with Bu4NI (TBAI) under similar reaction
conditions, only 1,3-diketone was isolated in 49% yield (Table 1,
Entry 6). Another iodide equivalent, KI was found inferior
(Table 1, Entry 8). Hence, these results suggested TBAI should
be the effective catalytic system to synthesize the desired 1,3-
diketones. It has been reported that TBHP/p-TsOH system can
facilitate generation of ketone radical12b and using this system we
could isolate the desired 1,3-diketone with only 54% yield
(Table 1, Entry 9). Recently, we have reported that TBHP-DTBP
system can mediate formation of acetone radical during a α-
chalocogenation process.12e However, its application to current
investigation afforded only moderate yield of the desired 1,3-
diketone (Table 1, Entry 10). Gratifyingly, addition of catalytic
amount of acidic additive to the TBHP-DTBP system provided
high yield of the desired product (Table 1, Entries11-12). p-
TsOH was found to be superior compared to other acidic
additive. At lower temperatures, the yields of the product
gradually reduced (Table 1, Entries 13-14). Finally, we have
optimized the use of TBAI catalyst with TBHP-DTBP system in
presence of a catalytic amount of p-TsOH at 120°C to be the best
reaction conditions.
compounds in high yields (Table 2). Aldehydes bearing
electron-withdrawing substituents on the aromatic ring, except
fluoro have been found to be superior (Table 2, Entries 6-12).
Under the oxidative reaction conditions, the thio-substituents
were well tolerated and corresponding products were isolated in
high yields (Entries 4-5). Hetero aromatic aldehydes also
furnished the desired 1,3-diketones effectively (Table 2, Entries
13-16). However, 4-pyridine carboxaldehyde provided modest
yield (Entry 14, 42%).
Table 2. Scope of various aromatic aldehydes a
O
TBAI (0.2 equiv)
TBHP-DTBP (1:1)
O
O
O
+
R
H
R
p-TsOH (0.1 equiv)
120 oC, 24 h
1a-p
2a
3a-p
Product
Entry
RCHO(1a-p)
Yield (%)b
(3a-p)
R= C6H5 1a
75
70
58
77
74
83
81
62
60
55
88
81
76
42
61
70
1
2
3a
3b
3c
3d
3e
3f
R = 4-Me C6H4 1b
R =4-N,N-Me2 C6H41c
R= 2-MeS C6H41d
R = 4-PhS C6H41e
R = 4-Cl C6H4 1f
R = 4-Br C6H4 1g
R = 4-F C6H4 1h
R = 3-F C6H4 1i
3
4
5
6
7
3g
8
3h
3i
9
R = 2-F C6H4 1j
10
11
12
13
14
15
16
3j
R = 4-NO2 C6H4 1k
R = 4-CN C6H41l
R = 1-Naphthyl 1m
R = 4-Pyridinyl 1n
R = 2-Thiophyl 1o
R = 5-Me-2-Furanyl 1p
3k
3l
Table 1. Optimization of the reaction conditionsa
Catalyst
Oxidant, Additive
3m
3n
3o
3p
O
O
O
+
PhCHO
Temperature
Ph
1a
2a
3a
Catalyst
(0.2 eq.)
-
Oxidant
(2.0 eq.)
TBHP
DTBP
TBHP
TBHP
TBHP
TBHP
Additive Temp
Yield
(%)b
-
-
-
Entry
(0.1eq.)
(oC)
120
120
120
120
120
120
120
120
120
120
120
120
100
80
a Reaction conditions: 1a-p (0.3 mmol), 2a (2 mL), TBHP (2.0
eq.), DTBP (2.0 eq.), p-TsOH (0.1 equiv), 120 °C, 24h. Isolated
-
-
-
-
-
-
-
-
1
2
3
4
5
6
7
8
9
10
11
12
13
b
-
yield.
CuCl
FeCl3
I2
TBAI
TBAI
KI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
-
The scope of ketones is very limited for this protocol (Table 3).
Investigation revealed that application of an unsymmetrical
ketone, 2-butanone (2b) suffers from low regioselectivity and
produced a mixture of 1,3-diketones (Table 3, Entry 1). 3,3-
dimethylbutan-2-one (2c) provided excellent yield of the desired
1,3-diketone. Acetophenone (2d) and some symmetrical ketones
(2e-2g) were also inert under the reaction condition. The reason
is not clear at this moment. We have also carried out radical
coupling of benzaldehyde with N,N-dimethylacetamide under
the standard reaction condition (Table 3, entry 7), but the
reaction was unsuccessful.
50c
49
33
37
54
52
75
68
49
21
DTBP
TBHP
TBHP
TsOH
-
TBHP/DTBP
TBHP/DTBP
TBHP/DTBP
TBHP/DTBP
TBHP/DTBP
TsOH
AcOH
TsOH
TsOH
14
a
Reaction conditions: 1a (0.3 mmol), 2a (2 mL), TBHP (2.0 eq.),
DTBP (2.0 eq.), p-TsOH or AcOH (0.1 eq.), 120 °C , 24h. bIsolated
yield. c Yield of 1,2-diketone and 1,3-diketone mixture.
With the optimized reaction conditions in hand, we have
expanded the scope of the method to various aldehydes and
ketones. Aromatic aldehydes with various substitution pattern
were suitably transformed to the corresponding 1,3-dicarbonyl

3
Table 3. Scope of various ketonesa
O
O
Ph
3a(trace)
O
O
O
O
TBAI (0.2 equiv)
TBHP-DTBP (1:1)
p-TsOH (0.1 equiv)
TEMPO (1 equiv)
120 oC
TBAI (0.2 equiv)
O
O
H
+
TBHP-DTBP (1:1)
p-TsOH (0.1 equiv)
120 oC, 24 h
PhCHO
+
Ph O N
1a
2a
4
1a
Entry
1
2
Ketone
Product
Yieldb
70
5a, 76%
Scheme 2. Mechanism studies of 1,3-dikeone formation.
O
O
O
2b
4a
O
O
On the basis of the above experimental results and literature
data,12b,e we have proposed a plausible mechanism for this
reaction (Figure 2). As previous reported TBHP undergoes better
homolytic cleavage in presence of DTBP to furnish the hydroxyl
radical.12e The tert-butylperoxy radical (A) would be generated
via the iodide/iodine catalytic redox process. This active radical
species would abstract a hydrogen atom from the aldehyde
leading to acyl radical B. Tert-butylperoxyl radicals (also tert-
butoxyl) generated from TBHP by iodide/iodine catalytic cycle
(4a/4a'= 1:1)
4a'
4c
O
O
O
2
3
91
2c
O
-
-
-
Ph
2d
O
4
5
are proposed as active species to trap H of aldehyde to form acyl
2e
11b,g,i
radical.
The ketone radical C is formed via a alkenyl
O
-
peroxide in presence of TBHP and p-TsOH.12b Finally, the
coupling of both acyl radical and ketone radical would afford the
desired 1,3-diketones.
2f
6
7
-
-
-
-
O
O
2g
O
t-BuOOBu-t
OH-
t-BuOOH
OH-
1/2 I2
N
2h
a Reaction conditions: 1a (0.3 mmol), 2b-2c, 2e-2h (2 mL), 2d
(1.5 eq.), TBHP (2.0 eq.), DTBP (2.0 eq.), p-TsOH (0.1 eq.), 120
°C, 24h. b Isolated yield. c MeCN as solvent.
H2O
t-BuOO
A
t-BuOOH
tBuOOBu-t
I-
O
.
O
t-BuOOH, [H+]
O
O
A
Ar
.
Ar
H
Additionally, the reactions of benzaldehyde with a mixture of
two different ketones have been investigated (Scheme 1), but
only acetone can react with benzaldehyde, whereas other ketone
remains unreacted.
C
.
B
t-BuOOH
t-BuO
O
O
Ar
O
O
O
Figure 2. Possible mechanism.
O
O
TBAI (0.2 equiv)
TBHP-DTBP (1:1)
H
+
+
+
+
Ph
p-TsOH (0.1 equiv)
In summary, we have reported an effcetive radical coupling of
aldehydes and ketones using TBAI as the suitable catalyst in
presence of TBHP-DTBP/p-TsOH system. This protocol opens a
new direct approach for the synthesis of 1,3-diketone by using
readily available starting materials. Various substitution pattern
on the aromatic ring of aldehydes are well tolerable under the
reaction conditions, providing the desired 1,3-diketone in high
yields. However, the scope of ketones is very limited. In
addition, the present protocol suffers from poor regioselectivity.
Investigations are going on to get a detailed insight into the
reaction mechanism and to expand the scope of the radical
coupling of aldehydes with various ketones.
120 oC, 24h
3a, 63%
O
O
O
O
TBAI (0.2 equiv)
TBHP-DTBP (1:1)
O
H
p-TsOH (0.1 equiv)
120 oC, 24h
3a, 45%
Scheme 1
To investigate the reaction mechanism, we have performed the
radical-trap experiment. When stoichiometric amount of the
radical
scavenger
2,2,6,6-tetramethylpiperidine-N-oxide
(TEMPO) was added to the reaction mixture under the same
reaction conditions, only trace amount of product 3a was
detected. The adduct, 5a was isolated in 76% yield (Scheme 2).
These results suggested that the reaction may indeed undergo a
free-radical process.
Experimental Section
Typical procedure for radical coupling of aldehydes with
ketones:
Under air atmosphere, aldehydes (0.3 mmol), TBAI (0.2 eq.),
TBHP (2.0 eq.), DTBP (2.0 eq.), p-TsOH (0.1 eq.) and acetone
or other ketones (2 mL) were added to a screw-capped vial. The

4
7. (a) Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E.
reaction vial was placed in a temperature-controlled aluminum-
heating block set at 120 oC. The reaction progress was monitored
by TLC. After the completion of the reaction, the vial was
removed from the heating block and was left to cool to the
ambient temperature. The solution was filtered though a short
column of silica gel and washed with EtOAc. The filtrate was
concentrated under reduced pressure to leave a crude product,
which was purified by flash column chromatography on silica
gel with Petroleum ether/EtOAc as an eluent to give the desired
product.
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Acknowledgments
We thank the Natural Science Foundation of Zhejiang
Province (No. LY12B02006 , LY13B020005)and the National
Students’ Innovation and Entrepreneurship Training Program
(No. 201410352004) for financial support.
10. (a) Padwa, A.; Hornbuckle, S. F.; Zhang, Z.; Zhi, L. J. Org. Chem.
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.xxx.
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