Iron-catalyzed aerobic C-H functionalization of pyrrolones

Article abstract of DOI:10.1039/c5cc01425e

The aerobic oxidation of pyrrolones catalyzed by Fe(OTf)₃ to form reactive N-acyliminium ion intermediates that undergo nucleophilic additions with alcohols to give the corresponding products in moderate to good yields is described.

Full text of DOI:10.1039/c5cc01425e

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DOI: 10.1039/C5CC01425E
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Iron−Catalyzed Aerobic C−H Functionalization of
Pyrrolones
Cite this: DOI: 10.1039/x0xx00000x
Li-wei Liu, a Zhen-zhen Wang, a Hui-hui Zhang, a Wan-shu Wang, a Ji-zong Zhang a
and Yu Tang *a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
We commenced our investigations with the Fe-catalyzed reactions
of N-(p-methoxyphenyl)-4-phenylpyrrolone (1b) using O2 as oxidant
(Table 1). We screened several readily available iron catalysts (10.0
mol %) such as FeSO4·7H2O, FeCl3, Fe2(SO4)3, Fe(NO3)3·9H2O,
Fe(OTf)2, Fe(acac)3 and Fe(OTf)3 (Table 1, entries 1-7). We were
pleased to observe formation of 5-methoxy-N-(p-methoxyphenyl)-4-
phenylpyrrolone 3a with all catalysts except Fe(acac)3, and the
Fe(OTf)3/O2 combination afforded the desired product 3a in 89%
yield (Table 1, entry 7). When FeSO4·7H2O and Fe(OTf)2 were used in
place of Fe (III) under the same conditions, the oxidative coupling
product 3a were formed in low yields (Table 1, entries 1 and 5),
When the reaction was performed in the absence of catalyst, the
reaction didn’t occur (Table 1, entry 8). Subsequently, our solvent
study showed that CH3CN was superior to the other solvents
including EtOAc, CH2Cl2, MeOH, THF and DMF (Table 1, entries
9-14). Also the use of air as the oxidant furnished 3a in only 53%
yield compared to 89% yield with oxygen (Table 1, entry 15).
Table 1 Optimization and control experimenta
The aerobic oxidation of pyrrolones catalyzed by Fe(OTf)3 to
form reactive
N-acyliminium ion intermediates that
undergoes nucleophilic additions with alcohols to give the
corresponding products in moderate to good yields is
described.
The functionalization of C-H bonds by oxidative Mannich
reaction methods is powerful for the synthesis of nitrogen-containing
natural products and active pharmaceutical ingredients.1 An iminium
ion, generated through oxidation of the α C-H bond adjacent to the
nitrogen atom of an amine, which can be quenched with various
nucleophilic reagents to form the new C-X bonds.2 Generally, these
reactions are accomplished by a variety of conditions using
transition metal catalysts including Cu,3 Fe,4 Pd,5 Ru,6 Rh,7 Mo,8 Zr,9
and VO10 complexes. Recent advances in the oxidative C-H
functionalization of amines or amides rely on strong oxidants, such
as TBHP,11 DTBP,12 DDQ,13 PIDA14 or (NH4)2S2O8.15 Although
these methods are efficient for C-H functionalization, a practical and
efficient method for such a transformation is still a challenge in
synthetic chemistry.
Entry
1
2
3
4
5
6
7
8
Catalyst
FeSO4·7H2O
FeCl3
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOAc
CH2Cl2
MeOH
THF
T (oC)
70
70
70
70
70
70
70
70
25
25
25
25
25
25
70
Time(h)
24
24
24
24
24
12
8
12
48
48
48
48
48
48
24
Yieldb (%)
15
73
73
62
46
NR
89
NR
62
56
33
27
18
NR
53
Fe2(SO4)3
Fe(NO3)3·9H2O
Fe(OTf)2
Fe(acac)3
Fe(OTf)3
-
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Scheme 1 Examples of Pyrrolone-containing Natural Products
9
Pyrrolone systems16 exhibit
a wide range of interesting
10
11
12
13
14
pharmacological properties and can easily be transformed into highly
reactive N-acyliminium ions (Scheme 1). These ions have
historically been generated in situ by Lewis acid or Brønsted acid
promoted elimination.17 They are also suitable precursors for the
preparation of alkaloid natural products.18 With our continious
interest in developing novel methodology for the functionalization of
pyrrolones,19 we focused on exploring a mild, selective, and efficient
oxidative Mannich reaction that utilized inexpensive catalysts and
more atom economical oxidants, such as O2.
DMF
CH3CN
15c
a
Reaction conditions: Catalyst (10.0 mol %), MeOH (10.0 equiv) and
substrate 1b (0.2 mmol) in solvent (1.0 mL) under an atmosphere of oxygen.
b Isolated yield. cThe reaction was performed under an atmosphere of air. NR:
no reaction.
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aThe reaction was carried out under an oxygen atmosphere using pyrrolone
With the optimal reaction conditions in hands, the scope and
generality of this new one-pot protocol was investigated, the results
of which are summarized in Table 2. By reacting pyrrolone 1 with
benzyl alcohol, the desired products 2a-l were conveniently
generated in satisfactory to excellent yields (Table 2, entries 1-12) in
each case. It was found that the reaction was tolerant to a variety of
R substituents including electron-rich and electron-withdrawing
groups. For instance, substrates containing electron-rich substituent
such as methyl- and methoxy- groups on the benzene ring could be
converted to the corresponding products in acceptable to good yields
(Table 2, entries 1-3, 5-6). As for substrates with an electron-
withdrawing group (R = Cl) on the benzene ring, the oxidation
reaction also occurred smoothly in moderate yields (Table 2, entries
4 and 7). When there was a H or a methyl substituent at the N atom,
the desired product was obtained in a low yield (Table 2, entries 8
and 9). Substrates with aromatic rings gave better yields probably
due to resonance stabilization on the proposed N-acyliminium
intermediate (Scheme 4). Further studies revealed that the aromatic
ring could also be replaced with aliphatic groups or H at the C=C
(Table 2, entries 10-13). 5-Phenyl pyrrolone was also a suitable
substrate for the reaction, and the corresponding product was
obtained in good yield (Table 2, entry 14). In summary, electron-
donating group substituents on the N-aryl ring of 1 give the better
results than electron-donating group substituents on the N-aryl ring
and N-methyl, or H substituted pyrrolones.
1b (1.0 equiv), alcohol (10.0 equiv), Fe(OTf)3 (0.1 equiv) in CH3CN (1.0
mL). b Isolated yield.
View Article Online
DOI: 10.1039/C5CC01425E
This transformation is amenable to a number of variations, both in
the structure of the starting amides and in the nature of the
nucleophile, as indicated by the examples compiled in Table 3.
Primary and allylic alcohols were good nucleofiles for this reaction
(Table 3, entries 1, 4, 5). Isopropanol and trifluoroethanol afforded
the products in relatively lower yields (Table 3, entries 2 and 6), no
t
product being isolated when BuOH was used as nucleophile
(Table 3, entry 3)
.
The Friedel−Crafts alkylation is one of the most versatile methods
used for introduction of C (sp3) substituents onto aromatic rings.20
For this reason, we explored the use of electron-rich aromatics as
nucleophiles to form C-C bonds via the Friedel−Crafts reaction. At
the onset, 1,3,5-trimethoxybenzene was chosen as the nucleophilic
o
reagent. After 24 hours at 70 C, we obtained three products:
monosubstituted 5, and disubstituted 6 and 7 (Scheme 2). The yields
of 5 and 6 decreased and the yield of 7 increased when the reaction
time was prolonged. Also, pure
5 could be transformed into 6
and , and pure could be converted to 7 under the same
7
6
conditions leading insight into the mechanism of the transformation.
Table 2 Oxidative coupling of various amides with benzyl alcohola
Entry
1
2
3
4
5
6
7
8
R1
Ph
R2
Ph
Ph
Ph
R3
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
R4
Yieldb
58
83
62
77
77
81
74
26
34
65
35
53
81
82
H (2a)
H (2b)
H (2c)
H (2d)
H (2e)
H (2f)
H (2g)
H (2h)
H (2i)
H (2j)
H(2k)
H(2l)
p-MeOC6H4
p-MeC6H4
p-ClC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
H
Ph
p-MeOC6H4
p-MeC6H4
p-ClC6H4
Ph
Ph
Me
H
H
Ph
Ph
Scheme 2 Oxidative coupling of 1b and its derivatives with 1,3,5-
trimethoxybenzene
9
Me
10
11
12
13
14
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
H(2m)
Ph(2n)
aThe reaction was carried out under an oxygen atmosphere using pyrrolone 1
(1.0 equiv), benzyl alcohol (5.0 equiv), Fe(OTf)3 (0.1 equiv) in CH3CN (1.0
mL). b Isolated yield.
Table 3 Oxidative coupling of various alcohols with 1ba
Scheme 3 Oxidative coupling of 1o-p with benzyl alcohol and synthesis the
precursor of Jatropham
Entry
Alcohol
Time (h)
Yield (%)b
1
2
3
4
5
6
MeOH(3a)
2
2
7
2
5
12
89
55
With 1o and 1p as starting materials, eliminated products were
obtained instead of the desired substituted products through the
formation of N-acyliminium intermediate. To further demonstrate
the potential applications of this novel method, we directed our
efforts toward the synthesis of the naturally occurring Jatropham
(Scheme 3). The required substrate 1l reacted with ethanol under the
iPrOH(3b)
tBuOH(3c)
BnOH (2b)
CH2CHCH2OH(3d)
CF3CH2OH(3e)
decomposed
83
82
15
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general procedure to give 8, then clevage of 4-methoxyphenyl group
afforded 9 quantitatively, and 9 could easily be transformed to
Jatropham under the conditions given in the literature21.
Provincial Top Key Discipline of Biology and the National
Basic Research Project (2014CB932201) for financial support.
View Article Online
DOI: 10.1039/C5CC01425E
Notes and references
School of Pharmaceutical Science and Technology, Key Laboratory for
A plausible reaction mechanism is proposed based on previously
reported results4d,12c as well as those form this study, shown in
Scheme 4. The initiation step is proposed to be electron transfer
between iron (III) and the amide to produce cation 10，iron (II) and
hydrogen radical. Next, nucleophilic addition generates the cation 11.
Iron (II) and hydrogen radical are oxidized by oxygen to give the
peroxo species and regenerate iron (III). Hydrogen atom abstraction
from the cation 11 produces the desired monosubstituted coupling
product 3 or 5 and hydrogen peroxide. In the case of using 1,3,5-
trimethoxybenzene as the nucleophile, a second oxidation occurs to
give 12, which may be trapped to afford β, γ-unsaturated amide 13
through 1,4-addition, which is believed to undergo isomerization to
release the 3-phenyl substituted amide 6. Disubstituted coupling
a
Modern Drug Delivery & High-Efficiency, Tianjin University, Tianjin,
300072 P. R. China E-mail:yutang@tju.edu.cn
1
Electronic Supplementary Information (ESI) available: copies of H and
13C NMR spectra for all products. See DOI: 10.1039/c000000x/
1
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