H2O2-promoted reactions of aliphatic primary amines with 1,3-diketones for the synthesis of 1 H -pyrrol-3(2 H)-ones at ambient temperature in water

Article abstract of DOI:10.1021/ol500546p

A green organic reaction of aliphatic primary amines with 1,3-diketones promoted by 30% aqueous H₂O₂ has been developed. It provides an inexpensive, regioselective, and efficient approach to 1H-pyrrol-3(2H)-ones with high yields from the simple and readily available starting materials in one pot via multicomponent tandem cyclization reactions and C-C cleavage under very mild and environmentally friendly reaction conditions.

Full text of DOI:10.1021/ol500546p

Letter
pubs.acs.org/OrgLett
H2O2‑Promoted Reactions of Aliphatic Primary Amines with 1,3-
Diketones for the Synthesis of 1H‑Pyrrol-3(2H)‑ones at Ambient
Temperature in Water
Xi Sun,† Pinhua Li,‡ Xiuli Zhang,*,†,§ and Lei Wang*,‡,§
†Department of Chemistry, Anhui Agricultural University, Hefei, Anhui 230036, P. R. China
‡Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P.R. China
S
* Supporting Information
ABSTRACT: A green organic reaction of aliphatic primary amines with 1,3-diketones promoted by 30% aqueous H2O2 has
been developed. It provides an inexpensive, regioselective, and efficient approach to 1H-pyrrol-3(2H)-ones with high yields from
the simple and readily available starting materials in one pot via multicomponent tandem cyclization reactions and C−C cleavage
under very mild and environmentally friendly reaction conditions.
he 1H-pyrrol-3(2H)-one ring system is found in many
natural products, pharmaceuticals, and biologically active
Scheme 1. H2O2-Promoted Reactions of Aliphatic Primary
Amines with 1,3-Diketones
T
compounds,1 and yet despite this, only a few established
methodologies are available for the synthesis of 1H-pyrrol-
3(2H)-ones.2 However, the restricted reaction conditions,
limited substrate scope, and complex byproducts produced by
these methods remain a disadvantage. Therefore, to develop a
rapid, mild, green, and efficient method for the direct
construction of 1H-pyrrol-3(2H)-one scaffolds with multiple
functional groups is still highly desirable. In this general
direction, an elegant synthesis of 1H-pyrrol-3(2H)-ones was
developed recently by Guan using Cu(TFA)2-catalyzed
oxidative tandem cyclization of enamino amides.3
isolated in 81% yield (Table 1, entry 1). It was characterized by
1H and 13C NMR, HRMS, and further confirmed by X-ray
diffraction analysis.6 Cumene hydroperoxide and TBHP (tert-
butyl hydroperoxide) as oxidant exhibited relatively lower
efficiency (Table 1, entries 2 and 3). Unfortunately, other
oxidants, PhI(OAc)2, DDQ (2,3-dichloro-5,6-dicyanobenzoqui-
none), BQ (1,4-benzoquinone), DTBP (di-tert-butyl peroxide),
(NH4)2S2O8, and K2S2O8 were ineffective, and no desired
product was isolated (Table 1, entries 4−9). When the reaction
was performed in toluene, dioxane, and THF, 38−52% yields of
3a were obtained. However, other organic solvents including
DMF, DMSO, CH3CN, and DME stopped the reaction
completely, and only starting materials were recovered (Table
1, entries 10−16). With respect to the oxidant loading, 2.0
equiv of 30% aqueous H2O2 was found to be optimal. The
concentration of H2O2 (aq) in the range of 20−30% led to the
most efficient reactions. Therefore, the optimized reaction
As inexpensive and available starting materials, 1,3-diketones
have been widely used as starting materials in organic
synthesis.4 In 2013, a H2O2-mediated oxidative formation of
amides was reported from aromatic amines and 1,3-diketones.5
However, the reactions of 1,3-diketones with aliphatic primary
amines could not afford the desired N-acylation products.5
Herein, we describe an efficient one-pot multicomponent
tandem cyclization reaction of aliphatic primary amines with
1,3-diketones promoted by 30% aqueous H2O2 without any
additives, which generates multifunctionalized 1H-pyrrol-
3(2H)-ones in good yields (Scheme 1).
We initiated our investigation with the model substrates of
pentane-2,4-dione (1a) and benzylamine (2a) in the presence
of an oxidant, and the results are summarized in Table 1. To
our great delight, the model reaction carried out in the presence
of neat 30% aqueous H2O2 at room temperature proceeded
smoothly and only the tandem reaction product, 4-acetyl-1-
benzyl-2-hydroxy-2,5-dimethyl-1H-pyrrol-3(2H)-one (3a), was
Received: February 19, 2014
Published: April 4, 2014
© 2014 American Chemical Society
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Letter
a
Table 1. Optimization of the Oxidant and Solvent
Scheme 2. Reactions of Pentane-2,4-dione (1a) with Various
Primary Aliphatic Amines
a
b
entry
oxidant
solvent
yield (%)
1
H2O2 (30% aq)
cumene hydroperoxide
TBHP
81
2
35
3
41
4
PhI(OAc)2
NR
trace
trace
NR
NR
trace
52
5
DDQ
6
BQ
7
DTBP
8
(NH4)2S2O8
K2S2O8
9
10
11
12
13
14
15
16
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
toluene
dioxane
THF
40
38
DMF
NR
NR
NR
NR
DMSO
CH3CN
DME
a
Reaction conditions: pentane-2,4-dione (1a, 1.20 mmol), benzyl-
amine (2a, 0.50 mmol), oxidant (1.0 mmol), solvent (2.0 mL) if
b
needed, rt, air, 8 h. Isolated yield.
conditions used 30% aqueous H2O2 (2.0 equiv) at room
temperature under air for 8 h.
a
Reaction conditions: pentane-2,4-dione (1a, 1.20 mmol), primary
To evaluate the scope of this novel strategy for the synthesis
of 1H-pyrrol-3(2H)-ones, various aliphatic primary amines
were reacted with pentane-2,4-dione (1a) under the optimized
reaction conditions, as shown in Scheme 2. The expected
products were obtained in good yield. Notably, electron-
donating and electron-withdrawing groups (Me, F, Cl, and Br)
on the para-, meta-, and ortho-positions of the benzene rings in
benzylamines underwent the tandem multicomponent reac-
tions smoothly and generated the desired products (3b−g) in
74−86% yield. A slight ortho-position effect was found (3b vs
3c vs 3d). Other aliphatic straight-chain primary amines, such
as 2-phenylethanamine, n-propylamine, 3-phenylpropan-1-
amine, n-butylamine, and n-octylamine, reacted with 1a, and
3h−l were obtained in 71−85% yield. It should be noted that i-
PrNH2 and cyclopentylamine also reacted with 1a well and
afforded the corresponding products 3m and 3n in 70% and
65% yield, respectively. It was found that prop-2-yn-1-amine
reacted with 1a to provide the desired product 3o in 72% yield.
Subsequently, we attempted to investigate the scope with
various 1,3-diketones, and the results are listed in Scheme 3.
When 1-phenylbutane-1,3-dione (1b), 1-(4-chlorophenyl)-
butane-1,3-dione (1c), and 1-(4-methoxyphenylbutane-1,3-
dione (1d) were reacted with benzylamine, 3-phenylpropan-
1-amine, 2-phenylethanamine, n-PrNH2, n-octylamine, n-decyl-
amine, and allylamine under the present reaction conditions,
the corresponding products 3p−x were obtained in 51−75%
yield with high regioselectivity.
aliphatic amine (2, 0.50 mmol), H2O2 (30% aq, 1.0 mmol), rt, air, 8 h.
Isolated yield.
b
diketones, such as 1,3-diphenylpropane-1,3-dione, heptane-3,5-
dione, 2,6-dimethylheptane-3,5-dione, and 2,2,6,6-tetramethyl-
heptane-3,5-dione were used to react with benzylamine, no
desired product was observed owing to steric hindrance.
To investigate the reaction mechanism, the control experi-
ments were performed and the results are presented in Scheme
5. The condensation of pentane-2,4-dione (1a) with benzyl-
amine (2a) generated product 4a with 85% yield in water at
room temperature.7 When 4a reacted with 1a in 1:1 molar ratio
in the presence of H2O2 (30% aq), 3a was obtained in 86%
yield. On the other hand, when the reaction of 4a was mediated
by 30% aqueous H2O2 in the absence of 1a, no product was
observed, and 4a was recovered in 95% yield. No reaction also
occurred when 1a, 2a and 30% aqueous H2O2 were kept in
darkness or in the presence of TFA (2.0 equiv) without
H2O2.2c,3 Moreover, the addition of a radical scavenger (2,2,6,6-
tetramethylpiperidin-1-yl)oxidanyl (TEMPO) suppressed the
reaction significantly, further indicating that the radical process
is most likely in this reaction.
Though the exact reaction mechanism is still not clear, a
tentative mechanism is proposed in Scheme 6 on the basis of
the literature and our observations. First, a free-radical
oxidation of pentane-2,4-dione (1a) to generate the alkyl
radical I, and an oxidation of 4 with hydroxyl radical to amino
radical II, is believed to occur.5,8 Then, radical cross-coupling of
I and II leads to intermediate III, which undergoes an
intramolecular cyclization to intermediate IV followed by
tautomerization and oxidation to intermediate V. In the
following process, a 1,3-methyl migration of V produces a
It is important to note that hexane-2,4-dione (1e) and 6-
methylheptane-2,4-dione (1f) reacted with n-PrNH2 under the
present reaction conditions to generate the product 3y in 85%
yield and 3z in 81% yield (Scheme 4). The reactions show high
regiocontrol, which originates from steric hindrance around the
carbonyl group in these β-diketones. However, when other 1,3-
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Scheme 3. Reactions of 1-Arylbutane-1,3-diones with
Primary Aliphatic Amines
Scheme 6. Proposed Reaction Mechanism
a
afford VIII and peroxyacetic acid. Finally, the desired product 3
is formed through the reaction of VIII with peroxyacetic acid,
along with the formation of acetic acid. To confirm the
proposed reaction mechanism, an important intermediate VI
was prepared according to literature.10 When the reaction of
obtained VI was carried out under the aforementioned
conditions in the presence of trace amount of HOAc, 1H-
pyrrol-3(2H)-one 3a was obtained in almost quantitatively
yield. However, the reaction of VI in the presence of 30%
aqueous H2O2 and Et3N, no product 3a was detected (Scheme
7).
a
Reaction conditions: 1-arylbutane-1,3-dione (1, 1.20 mmol), primary
aliphatic amine (2, 0.50 mmol), H2O2 (30% aq, 1.0 mmol), rt, air, 8 h.
b
Isolated yield.
Scheme 4. Tandem Reactions of 1e and 1f with n-
Propylamine
Scheme 7. Transformation of VI to 3a
Scheme 5. Control Experiments
In conclusion, we have developed a novel one-pot procedure
for the synthesis of multifunctionalized 1H-pyrrol-3(2H)-ones
through a H2O2-promoted tandem cyclization reaction of
aliphatic primary amines with 1,3-diketones under metal-free
and additive-free conditions at ambient temperature in water.11
The reaction is highly efficient and cost-effective and has a
broad substrate scope while operating under mild and
environmentally friendly conditions.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details and characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
key intermediate VI,2c,3,9 followed by its reaction with H2O2 to
generate intermediate VII. The intermediate VII proceeds to
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Letter
Z.-H.; Li, J.; Guan, Z.-H. Org. Lett. 2012, 14, 3506. (e) Witkop, B.;
Patrick, J. B. J. Am. Chem. Soc. 1951, 73, 2188.
(10) Adembri, G.; Celli, A. M.; Lampariello, L. R.; Scotton, M.; Sega,
AUTHOR INFORMATION
■
Corresponding Authors
A. Tetrahedron Lett. 1994, 35, 4023.
*E-mail: zhxiuli@163.com.
(11) The reaction solution was analyzed by ICP-MS, and the
determination data indicated that Cu, Fe, Pd, Ni, Co, Ru, and Rh are
less than 0.2 ppm (under detection limit).
*E-mail: leiwang@chnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is financially supported by the National Science
Foundation of China (Nos. 21372095, 21172092, and
20972057).
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