Convergent integration of two self-labor domino sequences: A novel method for the synthesis of oxazole derivatives from methyl ketones and benzoins

Article abstract of DOI:10.1039/c2cc18077d

A highly efficient method for the synthesis of oxazole derivatives from methyl ketones, benzoins and ammonium acetate has been established via a novel strategy - convergent integration of two self-labor domino sequences. Owing to the simple and readily av

Full text of DOI:10.1039/c2cc18077d

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Professor Anxin Wu, Central China Normal University,
China
Convergent integration of two self-labor domino sequences:
a novel method for the synthesis of oxazole derivatives from
methyl ketones and benzoins
Based on convergent integration of two self-labor domino
sequences, a novel method for the synthesis of polysubstituted
oxazoles from methyl ketones and benzoins was obtained. It could
provide an efficient example for self-labor logical synthesis of
organic compounds and their derivatives.
See Anxin Wu et al.,
Chem. Commun., 2012, 48, 3485.
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COMMUNICATION
Convergent integration of two self-labor domino sequences: a novel
method for the synthesis of oxazole derivatives from methyl ketones
and benzoinsw
Wei-Jian Xue, Qi Li, Yan-Ping Zhu, Jun-Gang Wang and An-Xin Wu*
Received 26th December 2011, Accepted 7th January 2012
DOI: 10.1039/c2cc18077d
A highly efficient method for the synthesis of oxazole derivatives
from methyl ketones, benzoins and ammonium acetate has been
established via a novel strategy—convergent integration of two
self-labor domino sequences. Owing to the simple and readily
available starting materials, mild reaction conditions, facile
operation, and the high bioactivity of oxazole derivatives, this
reaction promises diverse applications in medical chemistry.
Additionally, this reaction could provide an efficient example
for self-labor synthesis strategy of organic compounds.
In modern synthetic chemistry, domino strategy is a useful
procedure for self-organized synthesis of organic compounds.1
From previous knowledge and extensive literature review, it
could be inferred that most domino reactions proceed along a
linear route. However, we thought that a convergent domino
reaction strategy in one pot should be more effective for the
logical synthesis of complex organic compounds from easily
available starting materials (Fig. 1). Recently, we developed a
Scheme 1 Integration of two parallel linear domino reactions.
self-sorting domino reaction2a,b and a focusing domino reaction.2c
In this communication, a novel synthetic strategy, convergent
been classified into three typical synthetic methods: cyclization of
integration of two self-labor domino sequences, will be discussed.
acyclic precursors,6 oxidation of oxazolines,7 and the coupling of
In recent years, extensive research has been carried out for the
the prefunctionalized oxazoles with other organometallic reagents.8
Herein, we developed an innovative method for the synthesis
of the oxazole derivatives via a convergent integration of two
self-labor domino sequences from two different substrates,
methyl ketones and benzoins.
synthesis of oxazole derivatives,3 since oxazoles are considered to
be significant biological products4 and important chemical blocks.5
Up to now, the synthetic methodologies of oxazole derivatives have
In our previous reports on the synthesis of 1,4-enedione
derivatives, it was concluded that acetophenone could be sequen-
tially converted to phenylglyoxal via Kornblum oxidation in the
presence of DMSO (Scheme 1a).2a According to the previous
literature,9 benzoins could be oxidized to benzils which could
further react with benzaldehyde to afford imidazoles in the presence
of benzylamine and ammonium acetate (Scheme 1b and c). We
therefore tried to design a convergent integration of two self-labor
domino sequences which could merge the previous fundamental
reactions (Scheme 1a, b and c) together (Scheme 1d). Fortunately,
oxazole derivatives were obtained in a novel manner (Scheme 1d).
Initially, our investigations were focused on the favorable
conditions of the reaction to synthesize the oxazole derivatives
in the presence of molecular iodine and various amines
(Table 1). A 48% yield of the compound 3a was obtained
when CuO was used as the oxidant. However, it was noticed
Fig. 1 Convergent domino reaction strategy.
Key Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan 430079, P. R. China.
E-mail: chwuax@mail.ccnu.edu.cn; Tel: +86 027 6786 7773
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. CCDC 848144–848146.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2cc18077d
c
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Chem. Commun., 2012, 48, 3485–3487 3485

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Table 1 Optimization of the reaction conditionsa
Table 2 Reaction scope of aromatic ketones 1a
Yieldb (%)
Entry
Oxidant
Amine
Time/h
T/1C
Yieldb (%)
Entry
R
3
1
CuO
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
CH3COONH4
CH3COONH4
CH3COONH4
CH3COONH4
CH3COONH4
CH3COONH4
CH3COONH4
CH3COONH4
CH3COONH4
CH3COONH4
CH3COONH4
CH3COONH4
NH3ÁH2O
8
8
8
0.5
1
3
5
6
5
5
5
5
5
5
5
5
5
120
120
120
120
120
120
120
120
60
48
58
40
8
25
55
73
70
5
40
68
70
25
52
53
60
65
1
2
3
4
5
6
7
8
Ph (1a)
4-MeC6H4 (1b)
4-NO2C6H4 (1c)
4-FC6H4 (1d)
4-ClC6H4 (1e)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
73
74
70
75
76
80
67
85
83
50
0
64
52
52
70
74
2
3c
4
5
6
7
8
4-BrC6H4 (1f)
3,4-Cl2C6H3 (1g)
2-Furyl (1h)
2-Thienyl (1i)
2-Benzofuryl (1j)
3-Acetyl-1-methylpyrrole (1k)
2-Naphthyl (1l)
2-Fluorene (1m)
4-PhC6H4 (1n)
(E)–C6H5–CHQCH–(1o)
(E)-4-NO2C6H4–CHQCH– (1p)
9
9
10
11
12
13
14
15
16
17
80
10
11
12
13
14
15
16
100
140
120
120
120
120
120
(NH4)2CO3
(NH4)2SO4
NH4Cl
HCOONH4
a
Reaction was performed with methyl ketone
1 (1 mmol), 2
(1.1 mmol), ammonium acetate (2 mmol), and I2 (2,5 mmol) in DMSO
a
Reaction conducted with 1 mmol of acetophenone, 1.1 mmol of
benzoin, 2 mmol of amine and 2.5 mmol of I2 in 3mL DMSO.
b
(3 mL) at 120 1C for 5 h. Isolated yields.
b
c
Isolated yields. Only 2 mmol of I I2 was used.
effect on the overall efficiency of the reaction, and thus the
corresponding products were obtained in good yields (Table 2,
3o and 3p).
that this transformation occurred smoothly resulting in a yield
of 58%, even without the use of a metal catalyst. The dose of
iodine had an influence on the percentage yields of the reaction.
In entry 3, the yields changed from 58% to 40% while the mole
ratios of iodine and acetophenone were changed from 2.5 : 1 to
2 : 1. The effect of reaction time on the yields of 3a was
subsequently examined. A higher conversion rate was observed
when the reaction was carried out for 5 h (Table 1, entries 4–8).
A slightly lower yield was obtained when the reaction time was
prolonged to 6 h. Then, the reaction temperature was optimized
to increase the reaction yield; thus indicating that 120 1C was the
optimal temperature (Table 1, entries 9–12). Various amines
including inorganic and organic ammonium salts were then
screened in the presence of iodine in DMSO at 120 1C
(Table 1, entries 13–17). However, most of the ammonium salts
were inactive in this reaction. Ultimately, optimal conditions
were identified, that is, 1 equiv. of acetophenone (1a), 1.1 equiv.
of benzoin (2), 2.5 equiv. of ammonium acetate, and 2.5 equiv. of
iodine in DMSO at 120 1C (Table 1, entry 7).
However, no expected products were observed when 3-acetyl-
1-methylpyrrole (3k) was used as the substrate. This was
presumably caused by N-iodination of the pyrrole ring which
may have resulted in some side reactions such as nucleophilic
attack at C-5 of the pyrrole ring.10
In addition, the aromatic rings of methyl ketones with
electron-donating groups were employed to probe the scope
of the reaction. As shown in Table 3, the electron-rich groups
on the aromatic rings were favorable for the formation of two
types of oxazoles.11 This implied that electronic effect has
great influence on the reaction. Furthermore, the structures of
3a, 3l and 4r were also confirmed by X-ray crystallography.12
To investigate the detailed reaction process, we used
1
GC-MS and H NMR to detect the proposed intermediates for
this reaction. It was verified that the corresponding intermediates
6a, 8a and 5 were present in the reaction mixture. These
corresponding intermediates are listed in Scheme 2.13
Based on the successful synthesis of the oxazole 3a, the
optimized conditions were applied to a range of other aryl
methyl ketones, the ensuing results of which are listed in
Table 2. Generally, high yield was obtained using an aromatic
ring with an electron-withdrawing substituent (Table 2, 3c).
The corresponding products were also obtained in good yields
with heterocyclic methyl ketones as the substrates (Table 2, 3h,
3i and 3j). When 2-acetonaphthone was employed as the
substrate, the corresponding product was isolated in moderate
yield (Table 2, 3l), which indicated that steric effect influenced
the reaction. Encouraged by the results obtained with aryl
methyl ketones, we further focused our attention on unsaturated
methyl ketones such as benzalacetone and 4-nitrobenzalacetone.
It was deduced that the presence of the unsaturated bond has no
Based on the above-mentioned experiments, it can be supposed
that this reaction would be a novel strategy—convergent integration
of two self-labor domino sequences from two different substrates.
In addition, the possible mechanism for this reaction is illustrated
with the example of acetophenone (1a), benzoin (2) and ammonium
acetate (as shown in Scheme 3). Since benzoin 2 is more reactive
than 1a toward oxidation under the reaction conditions, compound
5 is preferentially generated by oxidation of compound 2. Then,
phenylglyoxal 8a is generated by iodination and oxidation of 1a.
Subsequently, 7 is formed as a product after the addition of
ammonium acetate to 5.14 Then 9a or its enolizational isomer
10a is obtained from 7 and 8a. When 10a undergoes intramolecular
nucleophilic reaction, 11a is obtained. Consequently, 11a undergoes
dehydration reaction to afford the final product 3a. In order to
c
3486 Chem. Commun., 2012, 48, 3485–3487
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Table 3 Reaction scope of aromatic ketones 1a
Further studies on the applications of this reaction will be
reported in due course.
We acknowledge and appreciate the support of the National
Natural Science Foundation of China (Grants 20872042, and
201032001) and PCSIRT (No. IRT0953).
Notes and references
Product Yield
ratio (3 : 4) (3 + 4) (%)
Entry
17
3
4
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M. Gao, A.-X. Wu and Y.-J. Pan, J. Org. Chem., 2008, 73, 3377;
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18
58 : 42
55 : 45
95
91
19
a
Reaction was performed with methyl ketone 1 (1 mmol), benzoin 2
(1.1 mmol), ammonium acetate (2 mmol), and I2 (2,5 mmol) in DMSO
(3 mL) at 120 1C for 5 h.
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Scheme 3 The plausible mechanism of the present reaction.
verify the possible reaction mechanism, the reactions of 1a with 5,
6a and 5, 6a with 2, 8a with 2 and 8a with 7 are used to synthesize
3a. Fortunately, 3a is obtained from the above reactions.15
In conclusion, in this study, we have developed a novel
method for the synthesis of polysubstituted oxazoles from
methyl ketones and benzoins based on convergent integration
of two self-labor domino sequences. Owing to mild reaction
conditions, simple operation and without involving metal
catalysts, this reaction should be of great utility in medical
chemistry. To the best of our knowledge, this transformation
should be the first self-sequenced multipath integration reaction,
which could provide an efficient example for self-labor logical
synthesis of organic compounds and their derivatives in the research
of domino reactions, cascade reactions and tandem reactions.1,16
11 Fig. S4 (See ESIw).
12 The details of the crystal data have been deposited with Cambridge
Crystallographic Data Centre as Supplementary Publication,
CCDC 848144–848146.
13 All of benzoin was oxidized to benzil detected by GC-MS.
14 W. B. Wheatley, W. E. Fitzgibbon and L. C. Chexey, J. Org.
Chem., 1953, 18, 1564.
15 Fig. S5 (See ESIw).
16 J. Zhu and H. Bienayme
Weinheim, 2005, and references therein.
´
, Multicomponent Reactions, Wiley-VCH,
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3485–3487 3487