One-pot metal-free synthesis of highly substituted pyrroles from 2-acetyl-3-methylene-1,4-dicarbonyl compounds and primary amines via TBHP and activated carbon oxidative aromatization of dihydropyrrole

Article abstract of DOI:10.1039/c3ra47782g

A metal-free one-pot cascade process for the synthesis of 1,2,3,4-tetrasubstituted pyrroles via a tandem enamine, aza-Michael addition and TBHP, activated carbon oxidative aromatization is reported. This strategy features the formation of two C-N bonds in moderate to excellent yields and a broad substrate tolerance. the Partner Organisations 2014.

Full text of DOI:10.1039/c3ra47782g

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One-pot metal-free synthesis of highly substituted
pyrroles from 2-acetyl-3-methylene-1,4-
dicarbonyl compounds and primary amines via
TBHP and activated carbon oxidative aromatization
of dihydropyrrole†
Cite this: RSC Adv., 2014, 4, 15007
Received 19th December 2013
Accepted 10th March 2014
DOI: 10.1039/c3ra47782g
*
Wei Yang, Yu Zhou, Haifeng Sun, Lei Zhang, Fei Zhao and Hong Liu
www.rsc.org/advances
A metal-free one-pot cascade process for the synthesis of 1,2,3,4- mild conditions is highly attractive. Toward this end, we
tetrasubstituted pyrroles via a tandem enamine, aza-Michael addition developed a metal-free and highly efficient strategy to synthesis
and TBHP, activated carbon oxidative aromatization is reported. This of 1,2,3,4-tetrasubstituted pyrroles using tert-butyl hydroper-
strategy features the formation of two C–N bonds in moderate to oxide and activated carbon as oxidative system via a tandem
excellent yields and a broad substrate tolerance.
enamine, aza-Michael addition and oxidative aromatization at
ambient conditions. The protocol provides a potential route for
the synthesis of tetrasubstituted pyrroles in moderate to excel-
lent yields.
Polysubstituted pyrroles are an important class of nitrogen-
containing heterocyclic compounds exhibiting a broad spec-
trum of biological properties such as antitumor,1 anti-inam-
matory2 and antibacterial3 in numerous bioactive natural
products4 and pharmaceuticals.5 Therefore, considerable efforts
have focused on the development of synthetic methods to
obtain these valuable compounds. Generally, the classical
methods include the Knorr,6 Paal-knorr7 and Hantzsch8 reac-
tions in a multistep process from preformed intermediates.
Recently, many novel synthetic approaches catalyzed by tran-
sition-metal have been reported.9 For example, we have reported
Pd(OCOCF3)2 catalyzed-cascade reaction of 2-alkenal-1,3-dicar-
bonyl compounds with primary amines to synthesize 1,2,3,5-
tetrasubstituted pyrroles in moderate to excellent yields
(Scheme 1).9a Beller's group has disclosed ruthenium catalyzed
ketones, amines and vicinal diols into pyrroles in high
temperature using borrowing hydrogen method.9b However,
metal-free mediated approaches may be less explored compared
to transition-metal catalyzed systems in recent years.10 As the
majority of transition-metal-catalyzed methods suffered from
the employment of precious, toxic transition-metal catalysts,
harsh reaction conditions and even in some cases the N-con-
taining components must be preactivated,9f–h thus, developing a
new synthetic approach obviating employment of transition-
metal catalysts from commercially accessible amines under
Initially, 3-acetyl-4-methylenehexane-2,5-dione 1a and
aniline 2a were selected as the model substrates to explore the
optimal reaction conditions for the synthesis of highly
substituted pyrrole 3a. As shown in Table 1, a variety of different
solvents were screened for their effect on the production of
compound 3a. We observed that the reaction was stirred in
toluene for 18 h at room temperature in the presence of TBHP to
afford the targeting product 3a with 78% yield whereas other
solvents such as DMF, CHCl3, THF gave the desired product in
45–62% yields (entries 1–4). Some other oxidants were probed
instead of TBHP for further improving the reaction yield. The
results showed that only 62% and 35% yields of the desired
product 3a was obtained when K2S2O8 and MCPBA were used as
oxidants respectively (entries 5 and 6). While, no targeted
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
E-mail: hliu@mail.shcnc.ac.cn
† Electronic supplementary information (ESI) available: Experimental procedures,
compound characterizations, and 1H and 13C NMR spectra. See DOI:
10.1039/c3ra47782g
Scheme
synthesis of pyrroles.
1 Transition-metal-catalyzed and metal-free mediated
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Table 1 Optimization of the reaction conditionsa
Table 2 The scope of TBHP and activate carbon oxidative aromati-
zation synthesis of pyrroles 3a
Entry
Solvent
Oxidant
Yieldb (%)
Entry
R1, R2, R3, R4, 3
Yieldb (%)
1
DMF
TBHP
45
2
3
4
5
6
7
8
9
CHCl3
THF
TBHP
TBHP
TBHP
K2S2O8
MCPBA
PhI(OAc)2
DDQ
H2O2
62
51
78
62
1
2
3
CH3, CH3, CH3, Ph, 3a
93
80
80
85
80
78
75
85
93
52
80
76
80
50
70
56
62
0
40
46
32
35
25
18
10
82
80
76
80
30
CH3, CH3, CH3, 3-EtPh, 3b
CH3, CH3, CH3, 4-MePh, 3c
CH3, CH3, CH3, 2-MePh, 3d
CH3, CH3, CH3,4-MeOPh, 3e
CH3, CH3, CH3, 2-naphthyl, 3f
CH3, CH3, CH3, 3,4-Me2Ph, 3g
CH3, CH3, CH3, 2,4-Me2Ph, 3h
CH3, CH3, CH3, 2-Me-4-FPh, 3i
CH3, CH3, CH3, 3,4-OCH2OPh, 3j
CH3, CH3, CH3, 4-BrPh, 3k
CH3, CH3, CH3, 3-ethynylPh, 3l
CH3, CH3, CH3, 3-ClPh, 3m
CH3, CH3, CH3, 4-COOCH2CH3Ph, 3n
CH3, CH3, CH3, 4-NHCOCH3Ph, 3o
CH3, CH3, CH3, 4-NH2Ph, 3p
CH3, CH3, CH3, 3,4-ClPh, 3q
CH3, CH3, CH3, 4-NO2Ph, 3r
CH3, CH3, CH3, isopentyl, 3s
CH3, CH3, CH3, Bn, 3t
CH3, CH3, CH3, n-Bu, 3u
CH3, CH3, CH3, allyl, 3v
CH3, CH3, CH3, 3-methoxy-propyl, 3w
CH3, CH3, CH3, isopropyl, 3x
CH3, CH3, CH3, t-Bu, 3y
Et, Et, CH3, Ph, 3z
CH3, Ph, CH3, Ph, 3aa
CH3, OEt, CH3, Ph, 3 ab
CH3, CH3, Ph, Ph, 3ac
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
4
35
5c
6
NPd
NPd
NPd
65
7
8
9
10
11c
12c
Air
Activated carbon
TBHP + activated carbon
76
93
10c
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
a
A mixture of 1a (0.25 mmol), 2a (0.5 mmol) and oxidant (150 mL of 5.5
M TBHP in decane solution or 0.75 mmol for the other ones) in solvent
(1 mL) was stirred at room temperature for 18 h. b Isolated yield. c 36 mg
d
activated carbon was added to the reaction. NP indicated that no
desired product 3a was obtained.
products were obtained by employing PhI(OAc)2, DDQ and H2O2
as oxidants respectively (entries 7–9). Treatment of 1a and 2a in
toluene under air atmosphere as the sole oxidant gave the
product 3a in good yield (65%, entry 10) which facilitated the
reaction operation without degas procedure. When activated
carbon was involved as the oxidant instead of TBHP, the
product 3a was formed in 76% yield (entry 11) indicating
the activated carbon is a highly effective oxidant for this trans-
formation.11 Therefore, we further explored the combined
oxidative system of activated carbon and TBHP, the reaction
yield dramatically increased to 93%. In this way, the optimal
reaction condition was identied using activated carbon and
TBHP as the oxidant system in toluene at room temperature
for 18 h.
CH3, CH3, OEt, Ph, 3ad
a
A mixture of 1a (0.25 mmol), 2a (0.5 mmol), 150 mL TBHP (5.5 M in
decane solution) and 36 mg activated carbon in toluene (1 mL) was
b
c
stirred at room temperature overnight. Isolated yield. The reaction
was conducted at ꢀ20 ꢁC.
With the optimal reaction conditions in hand, we then
surveyed the scope of this approach to synthesize a wide range of
pyrroles derivatives 3 (Table 2). We rstly utilized substrate 1a by the fact that 4-acetamidoaniline 2o afforded the desired
to test the reactivity of various amines. The results showed that pyrrole in higher yield than the 1,4-diaminobenzene 2p did
this protocol was compatible with signicant structurally under the same reaction conditions. Furthermore, as compared
various amines. The substitution pattern of the methyl and ethyl to 2-toluidine 2d, the substrate 2i possessing an additional
groups on the phenyl ring has a very limited impact (3b–d, electron-withdrawing group on the phenyl ring supported this
entries 2–4). With two substituents on the phenyl rings such as explanation for providing the pyrrole 3i in 93% yield (entry 9). A
2-naphthalenamine, 3,4-dimethylaniline, 2,4-dimethylaniline, 2- diverse range of functional groups such as bromo, chloro, ester,
methyl-4-uoroaniline were suitable for this protocol as illus- ethynyl, acetyl amino, amino on the anilines proceeded
trated by providing the pyrrole products 3f–i in good to excellent smoothly to yield the corresponding pyrrole derivatives 3k–q in
yields (75–93%, entries 6–9). However, the anilines bearing 56% to 80% yields. While, 4-nitroaniline couldn't afford the
strong electron-donating groups such as methoxyl, methyl- pyrrole due to the strong electron-withdrawing group reduced
enedioxyl on the phenyl rings underwent reaction to afford the the nucelophilicity of the nitrogen of the aniline (3r, entry 18). In
targeting product 3e and 3j in good yields only when the reaction addition to aromatic amines, the reaction proceeded as expected
was performed at ꢀ20 ꢁC temperature. The probable reason was when aliphatic amines were involved in the reaction (entries 19–
attributed to the electronic effect. This explanation was proved 25). The isopentyl, Bn, n-Bu, allyl, 3-methoxypropyl amines 2s–w
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afforded the desired products in moderate yields (entries 19–23).
In conclusion, we have successfully developed an efficient
While the more steric isopropyl and t-Bu amines gave the poor metal-free mediated oxidative aromatization cascade approach
yields (entries 24–25). Futhermore, by-products were observed for the one-pot synthesis of synthetically and biologically
when aliphatic amines were involved.
meaningful pyrroles. This approach features metal-free, milder
To further expand the scope of the method, we probed reaction conditions, readily available reagents and afford the
several substrate 1 derivatives. The results implied that the desired highly substituted pyrroles in cascade fashion in
more hindered substrate 1z appeared to be a good candidate for moderate to excellent yields for a diverse range of substrates.
this cascade reaction. Moreover, the variation of R2 function-
We gratefully acknowledge nancial support from the
alities on 1 such as phenyl and ethoxyl groups could react with National Natural Science Foundation of China (Grants 91229204,
aniline 2a to afford the structurally diverse pyrroles 3aa,ab and 81025017), National S&T Major Projects (2012ZX09103101-
(entries 27 and 28). Furthermore, the substrate 1ac offered the 072 and 2012ZX09301001-005).
product 3ac in good yield (80%, entry 29), while switching to
substrate 1ad lead to dramatically decrease in reaction yield
under the same conditions. These observed results indicated
Notes and references
that the ketone functional group promoted the formation of
pyrroles more easily than ester did in this cascade reaction (3ac
vs. 3ad, entries 29 and 30).
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Scheme 3 A proposed mechanism for the cascade reaction.
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