H2O2-mediated oxidative formation of amides from aromatic amines and 1,3-diketones as acylation agents via C-C bond cleavage at room temperature in water under metal-free conditions

Article abstract of DOI:10.1039/c3gc41260a

1,3-Diketones, as novel acylation agents, reacted with aromatic amines promoted by commercially available H₂O₂ (30% aq.) as the sole oxidant at room temperature under metal-free conditions in water, leading to a novel and rapid amide bond formation strategy. The reported method is high-yielding, simple and mild, and is the first example of the use of 1,3-diketones as acylation agents via C-C bond cleavage.

Full text of DOI:10.1039/c3gc41260a

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H2O2-mediated oxidative formation of amides from aromatic amines
and 1,3-diketones as acylation agents via C−C bond cleavage at room
temperature in water under metal-free conditions
Xi Sun,a Min Wang,b Pinhua Li,b Xiuli Zhang,*a,c and Lei Wang*b,c
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
synthesis.11 It should be noted that the first example of CuIꢀ
1,3-Diketones, as novel acylation agents, reacted with
50 catalyzed arylation/C−C bond activation of 1,3ꢀdiketones with
aryl halides to αꢀarylketones was reported by Lei in 2010.7b Later
on, CuIꢀcatalyzed tandem cyclization leading to isocoumarins
from oꢀhalobenzoic acids and esters or 2ꢀhaloꢀNꢀphenyl
benzamides with 1,3ꢀdiketones was developed by Xi,12a Yao,12b
55 and Fan.12c On the other hand, Kuninobu and Takai developed
In(OTf)3ꢀcatalyzed synthesis of esters and amides by reactions of
alcohols and aliphatic amines with 1,3ꢀdiketones via C−C bond
cleavage in a retroꢀaldolꢀtype reaction, regarded as an acylation
reaction of alcohols or amines from another viewpoint.12d Most
60 recently, a TBHP/I2ꢀpromoted reaction of aliphatic secondary
amines with 1,3ꢀdiketones for the synthesis of αꢀketoamides was
also reported.12e
The importance and value of amide motifs can be shown from
their wide occurrence in natural products, pharmaceuticals,
65 polymers, and biological systems, and broad applications as
versatile building blocks in organic synthesis.13 As a result, the
synthesis of amides is a greatly valuable project and a variety of
methods are available for their preparation, such as the acylation
of amines using carboxylic acids or their derivatives;14 transitionꢀ
70 metalꢀcatalyzed amidation of aryl halides or nitriles with
nitrogenꢀcontaining reagents,15 as well as the oxidative coupling
of alcohols16 or aldehydes17 with amines; the direct carbonylation
of alkenes or alkynes;18 and Mnꢀ or Feꢀcatalyzed C−C bond
cleavage with a nitrogen source.19 Nevertheless, most of the
75 reported approaches have the drawbacks, such as the use of
transition metals, unstable starting materials, expensive reagents,
toxic solvents and/or harsh oxidants, and drastic reaction
conditions. Therefore, the more simple and green method for the
synthesis of amides would be highly desirable. Hydrogen
80 peroxide (H2O2) is a mild and comparatively inexpensive oxidant
and widely used in laboratory and industry with regard to the
formation of water as the sole byꢀproduct. In a continuation to our
interest in the synthesis of nitrogenꢀcontaining compounds,20
herein, we firstly illustrated a novel and rapid amide bond
85 formation strategy from aromatic amines and 1,3ꢀdiketones via
C−C bond cleavage promoted by H2O2 (30% aq.) as the sole
oxidant at room temperature under metalꢀfree conditions in water.
The reported method is highꢀyielding, simple and mild, and it is
the first example of 1,3ꢀdiketones as acylation agents (Scheme 1).
aromatic amines promoted by the commercial available H2O2
(30% aq.) as sole oxidant at room temperature under metal-
10 free conditions in water, leading to a novel and rapid amide
bond formation strategy. The reported method is high-
yielding, simple and mild, and it is the first example of 1,3-
diketones as acylation agents via C−C bond cleavage.
Selective C−C bond cleavage (activation) by transition metals,
15 similar to the recent emergence of C−H bond activation, has also
attracted great attention in organic and organometallic chemistry.1
As a unique synthetic strategy, it allows chemists to approach the
desired molecules by reorganizing the existing molecular
skeletons, instead of traditional retrosynthetic disconnections.
20 However, the cleavage of C(sp3)−C(sp3) bond has emerged as a
tremendous challenge owing to its relatively high bond strength.2
To facilitate C−C bond cleavage, various processes involving the
following modes have been developed, such as the relief of ring
strain,3 chelation assistance,4 and employing functional fragment
25 as the leaving groups, including carboxylic acids,5 nitriles,6
carbonyls,7 and so on.8 Obviously, main stream development is
still restricted to the transitionꢀmetalꢀassisted approach to activate
the inert C−C bond. Consideration from the environmental and
economic point of view, the development of metalꢀfree organic
30 reactions has been paid much attention in modern organic
synthesis, especially in the pharmaceutical industry due to the
avoidance of metal contamination.9 However, there have been a
few examples for the cleavage of the C−C single bond in the
absence of transition metals.10
35
1,3ꢀDiketones, which are inexpensive and available starting
materials, have been used as the important substrates in organic
a
Department of Chemistry, Anhui Agricultural University, Hefei, Anhui
230036, P. R. China, E-mail: zhxiuli@163.com
40 b Department of Chemistry, Huaibei Normal University, Huaibei, Anhui
235000, P R China; E-mail: leiwang@chnu.edu.cn
Tel.: +86-561-380-2069; fax: +86-561-309-0518
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
45 P R China
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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40
With the optimized reaction conditions in our hand, a wide
range of anilines (2) with pentaneꢀ2,4ꢀdione (1a) were
investigated to illustrate the efficiency and scope of this novel
strategy for the synthesis of aromatic amides (Scheme 2).
Anilines bearing electronꢀrich substituents (Me, Et, iꢀPr, OMe,
Scheme 1 H2O2ꢀmediated reaction of 1,3ꢀdiketones with amines
45 OEt) on their paraꢀ, and metaꢀpositions underwent the acylation
transformation smoothly to give the desired anilides in good to
excellent yields (82−96%, Scheme 2, 3b−f, 3h, and 3i). On the
other hand, anilines with halogen groups, such as F, Cl, Br, and I
on their paraꢀ, and metaꢀpositions also gave the desired products
50 in 86−94% yields (3n−s). Disubstituted anilines, such as 2,3ꢀ
dimethylaniline, 2,4ꢀdimethylaniline, 2,5ꢀdimethylaniline, and
3,4ꢀdimethylaniline also underwent the amidation reactions with
1a and afforded the corresponding products (3j−m) in 69–83%
yields with observed steric effect. It should be noted that anilines
55 with electronꢀwithdrawing groups, such as CH3CO, CN, and NO2
on their paraꢀpositions gave the desired products in moderate
yields at a higher reaction temperature (70 °C) (3u−w). In
addition, 2ꢀnaphthaleneamine also reacted with 1a to generate the
corresponding product (3x) in 81% yield. To our great delight,
At the outset of this study, the optimization of reaction
conditions was focused on oxidant and solvent using a model
reaction of pentaneꢀ2,4ꢀdione (1a) with aniline (2a), and the
results were summarized in Table 1. Gratifyingly, when the
5
model reaction was performed in the presence of
a
commercial avalible H2O2 (30% aq.) without additional
10 solvent at room temperature, Nꢀacylation of 2a underwent
very smoothly and the product Nꢀphenylacetamide (3a) was
obtained in 88% yield (Table 1, entry 1). This reaction also
proceeded well using cumene hydroperoxide as an oxidant
and afforded 80% yield of 3a (Table 1, entry 2), whereas tertꢀ
15 butyl hydroperoxide (TBHP) and PhI(OAc)2 exhibited
relatively lower efficiency (Table 1, entries
3 and 4).
However, other oxidants, such as 2,3ꢀdichloroꢀ5,6ꢀ
dicyanobenzoquinone (DDQ), 1,4ꢀbenzoquinone (BQ), diꢀ
tertꢀbutyl peroxide (DTBP), (NH4)2S2O8, and K2S2O8 were
20 inactive and no desired product was isolated (Table 1, entries
5–9). Subsequently, the effect of solvent on the model
reaction was investigated and a significant solvent effect was
observed (Table S1, Supporting Information). When the
model reaction was performed in toluene, only 41% yield of
25 3a was obtained. Other organic solvents, such as DMF,
DMSO, DME, CH3CN, dioxane, and THF shut down the
reaction completely. With respect to the oxidant loading, 3.0
equiv. of H2O2 was found to be optimal. When less than 2.5
equiv. of H2O2 was used, the reaction was not completed
30 (Table S1). However, no significant improvement was
observed with more than 3.0 equiv. of H2O2. It was found that
the concentration of H2O2 (aq.) affects the reaction greatly
(Table S1). H2O2 (≥25% aq.) exhibited the high efficiency to
the reaction, and lower yield of 3a was obtained when less
35 than 25% of H2O2 (aq.) was used. The optimized reaction
conditions were 30% aqueous H2O2 (3.0 equiv.) at room
temperature for 8 h.
60 Scheme 2 H2O2ꢀmediated oxidative formation of amides from
aromatic amines and pentaneꢀ2,4ꢀdione (1a)a
Table 1 Optimization of the oxidant for the model reactiona
Entry
Oxidant
H2O2
Solvent
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Yield (%)b
88
1
2
3
4
5
6
7
8
9
Cumene hydroperoxide
TBHP
80
52
PhI(OAc)2
DDQ
15
NR
BQ
NR
DTBP
NR
(NH4)2S2O8
K2S2O8
NR
NR
a Reaction conditions: 1a (0.50 mmol), 2 (0.60 mmol), H2O2 (30%
a Reaction conditions: 1a (0.50 mmol), 2a (0.60 mmol), oxidant (1.5
aq., 1.5 mmol), room temperature for 8 h. b Isolated yields. c 70 °C.
mmol), at room temperature for 8 h. b Isolated yield.
2
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The H2O2ꢀpromoted amidation of anilines with various 1,3ꢀ
diketones as different acylation agents via C−C activation was
also investigated (Table 2). When heptaneꢀ3,5ꢀdione (1b) was
20 served as acylating agent like propionyl chloride reacting with 4ꢀ
methyaniline, 4ꢀmethoxyaniline, and 4ꢀethoxyaniline, the
oxidative formation of amides through C−C activation of 1b with
amines proceeded well to generate the corresponding amides
(3ab−ad) in 85−92% yields (Table 2, entries 1−3). Intriguingly,
25 when 3ꢀmethylpentaneꢀ2,4ꢀdione (1c), instead of pentaneꢀ2,4ꢀ
dione (1a) reacted with 4ꢀbromoaniline, 67% yield of 3s was
obtained (Table 2, entry 4). However, when 2,6ꢀdimethylheptaneꢀ
3,5ꢀdione (1d) and 2,2,6,6ꢀtetramethylheptaneꢀ3,5ꢀdione (1e) was
used to react with 4ꢀbromoaniline, only a trace amount of desired
30 amides were observed owing to their steric hindrance (Table 2,
entries 5 and 6). It should be noted that when asymmetric βꢀ
diketones 1f and 1g were engaged in the reactions and the
reactions exhibited excellent selectivity, providing product 3s in
89, and 65% yields (Table 2, entries 7 and 8).21 However, when
35 1i was tested under the optimized conditions, regioisomers 3s and
3ag were generated in 74, and 20% yields (Table 2, entry 9). The
regioisomers may originate from the steric hindrance of the
carbonyl of βꢀdiketones. Similarly, only amide 3ag was isolated
in 86% yield when asymmetric βꢀdiketone 1i was employed in
40 the reaction (Table 2, entry 10). Aromatic βꢀdiketone, 1,3ꢀ
diphenylpropaneꢀ1,3ꢀdione (1j) was conducted in the reaction at
70 oC, leading to Nꢀ(pꢀtolyl)benzamide (3ah) in 42% yield (Table
2, entry 11), and 1ꢀphenylbutaneꢀ1,3ꢀdione (1k) was employed,
the unique product Nꢀ(pꢀtolyl)acetamide 3b was obtained in 84%
45 yield (Table 2, entry 12). These results indicated that the activity
of aromatic βꢀdiketones is lower than that of aliphatic ones in the
reaction.
To investigate the reaction mechanism, the control
experiments were performed and the results were presented in
50 Scheme 3. The condensation of 1ꢀphenylbutaneꢀ1,3ꢀdione (1k)
with aniline (2a) generated the corresponding product 4k in 90%
yield at room temperature for 6 h (Scheme 3, eq. 1). When the
prepared 4k was performed in H2O2 (30% aq., 3.0 eq.), Nꢀ
phenylacetamide (3a) was generated in 94% yield, along with
55 benzoic acid in 90% isolated yield (Scheme 3, eq. 2). Meanwhile,
when prepared 4a from the reaction of pentaneꢀ2,4ꢀdione (1a)
and aniline (2a) was carried out in H2O2 (30% aq., 3.0 eq.), 3a
was isolated in 99% yield (Scheme 3, eq. 3). What’s more, when
a radical scavenger, 2,2,6,6ꢀtetramethylpiperidylꢀ1ꢀoxyl (TEMPO)
60 was added up to equivalent of oxidant, the reaction was
completely shut down, suggesting that this reaction may involve a
radical process. Though the exact mechanism is still not clear at
present, a possible reaction mechanism was shown in Scheme 4.
Initially, an intermediate 4k was formed via the condensation of
65 aniline (2a) with 1ꢀphenylbutaneꢀ1,3ꢀdione (1k). The obtained 4k
then reacted with hydroperoxyl radical, which was generated in
situ by the reaction of hydrogen peroxide, providing an
intermediate I, followed by its reaction with hydroxyl radical,
leading to II. In the following procedure, an intramolecular C–C
70 bond cleavage of II underwent to afford III and IV, which
generated 3a via tautomerism. Finally, formic acid and benzoic
acid were formed through the αꢀcarbon cleavage of III by H2O2.
Moreover, the silver mirror was detected after the reaction mixed
when 4ꢀaminophenol, 4ꢀaminoꢀ3ꢀfluorophenol, and 2ꢀ
aminophenol (2y−aa), which are oxidized readily in the
presence of oxygen and moisture, reacted smoothly with 1a to
give the Nꢀacylated products (3y−aa) in 70–97% yields in the
presence of H2O2 (30% aq.) under air. It is obvious that ortho-
position effect was observed in the reactions of 2ꢀsubstituted
anilines (2g, 2k−m, 2t and 2aa) with 1a. It is important to
note that when the reaction scale was increased up to 10
10 mmol, 91% isolated yield of 3p was isolated from the reaction
of 1a with 4ꢀbromoaniline (2p). However, the reactions of 1a
with aliphatic primary and secondary amines (such as nꢀ
decylamine and diꢀnꢀbuthylamine), and aromatic secondary
amine (N,Nꢀdimethylaniline) could not afford the desired Nꢀ
15 acylation products under the optimized reaction conditions.
5
Table 2 Reactions of various 1,3ꢀdiketones with anilinesa
Amine
(R3 =)
Yield
(%)b
Entry
1
1,3ꢀDiketone
Product
90
4ꢀMe
4ꢀMeO
4ꢀEtO
4ꢀBr
92
2
3
4
5
85
67
trace
4ꢀBr
trace
6
4ꢀBr
89
65
7
8
4ꢀBr
4ꢀBr
74
20
9
4ꢀBr
86
10
11
12
4ꢀBr
4ꢀMe
4ꢀMe
0
42 c
84
a Reaction conditions: 1 (0.50 mmol), 2 (0.60 mmol), H2O2 (30% aq.,
1.5 mmol), at room temperature for 8 h. b Isolated yield. c 70 °C.
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purification.
with Tollens’ reagent. To further confirm the proposed
mechanism, the BayerꢀVilligerꢀtype oxidation of 1ꢀphenylbutaneꢀ
1,3ꢀdione (1k) and followed by the amideꢀester exchange should
be excluded. The results indicated that no corresponding ester
was formed when the BayerꢀVilligerꢀtype oxidation of 1ꢀ
phenylbutaneꢀ1,3ꢀdione (1k) with 30% aqueous H2O2 (3.0 equiv.)
at room temperature for 8 h (Scheme 3, eq. 4).
30 General procedure for H2O2-mediated oxidative formation of
amides from aromatic amines and 1,3-diketones
A 10 mL of reaction tube was charged with aniline (0.50 mmol),
1,3ꢀdiketone (0.60 mmol) and H2O2 (30%, aq., 1.5 mmol). After
the reaction was carried out at room temperature (about 25 °C)
35 for 8 h, it was extracted twice with EtOAc. The organic layers
were combined, dried over Na2SO4, and concentrated to yield the
crude product, which was further purified by flash
chromatography on silica gel to give the pure product.
5
Acknowledgements
40 This work was financially supported by the National Science
Foundation of China (Nos. 21172092 and 20102039).
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2 M. Murakami and Y. Ito, Cleavage of Carbon-Carbon Single Bonds by
Transition Metals. In Activation of Unreactive Bonds and Organic
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Scheme 3 The control experiments
50
10
O
O
PhNH2
2a
H
3
For selected examples, see: (a) P. A. Wender, A. G. Correa, Y. Sato and
R. Sun, J. Am. Chem. Soc., 2000, 122, 7815; (b) S. C. Bart and P. J.
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T. Seiser, O. A. Roth and N. Cramer, Angew. Chem. Int. Ed., 2009, 48,
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(f) M. Lin, F. Li, L. Jiao and Z.ꢀX. Yu, J. Am. Chem. Soc., 2011, 133,
1690; For selected reviews, see: (g) A. de Meijere, Chem. Rev., 2003,
103, 931; (h) M. Rubin, M. Rubina and V. Gevorgyan, Chem. Rev.,
2007, 107, 3117.
N
N
Ph
Ph
Ph
3a
1k
OH
O
IV
55
60
65
70
75
80
85
Ph
Ph
O
N
O
HN
O
4k
Ph
Ph
H
III
Ph
O
II
O
H
O
Ph
O
O
N
H
PhCO2H
+
HCO2H
+
H
HOO
Ph
4
5
(a) C. H. Jun, D. Y. Lee, H. Lee and J. B. Hong, Angew. Chem. Int.
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I
OH
OH + HO
H O
3
OH +
2
2
2
H2O
Scheme 4 The possible reaction mechanism
In summary, we have developed a novel and rapid amide bond
15 formation strategy from aromatic primary amines and 1,3ꢀ
diketones promoted by the commercial available H2O2 (30% aq.)
as sole oxidant at room temperature under metalꢀfree conditions
in water.22 The reported method is highꢀyielding, simple and mild,
and it is the first example of 1,3ꢀdiketones as acylation agents via
20 C−C bond cleavage. The detailed mechanistic study and further
investigation on metalꢀfree reactions are currently underway.
6
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All the direct oxidative coupling reactions of acetophenones with
and amines were carried out under an air atmosphere. 1H and 13C
25 NMR spectra were measured on a Bruker Avance 400 MHz NMR
spectrometer with CDCl3 as solvent and recorded in ppm relative
to internal tetramethylsilane standard. General chemicals were
purchased from commercial suppliers and used without further
4
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Green Chemistry
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DOI: 10.1039/C3GC41260A
Green Chemistry
Graphical Abstract
H2O2-mediated oxidative formation of amides from aromatic amines
and 1,3-diketones as acylation agents via C−C bond cleavage at room
temperature in water under metal-free conditions
Xi Sun,a Min Wang,b Pinhua Li,b Xiuli Zhang,*a,c and Lei Wang*b,c
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Metal-free H2O2-mediated formation of amides from anilines
and 1,3-diketones via C−C bond cleavage at room
10 temperature in water was developed.
15
20
a
25 Department of Chemistry, Anhui Agricultural University, Hefei, Anhui
230036, P. R. China, E-mail: zhxiuli@163.com
b Department of Chemistry, Huaibei Normal University, Huaibei, Anhui
235000, P R China; E-mail: leiwang@chnu.edu.cn
Tel.: +86-561-380-2069; fax: +86-561-309-0518
30 c State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
P R China
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1