Iron-Catalyzed Synthesis of Oxindoles: Application to the Preparation of Pyrroloindolines

Article abstract of DOI:10.1021/acs.orglett.7b00078

A novel and highly efficient synthetic approach to pyrroloindolines has been developed. The process is based on tandem radical addition/cyclization with inexpensive iron catalyst. This method tolerates a wide range of N-methyl-N-arylacrylamides as well carbamoyl radicals, providing access to a variety of functionalized 3,3-disubstituted oxindoles, key intermediates for many bioactive pyrroloindolines such as (±)-esermethole, (±)-deoxyeseroline, and (±)-physovenol methyl ether.

Full text of DOI:10.1021/acs.orglett.7b00078

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Synthesis of Oxindoles: Application to the
Preparation of Pyrroloindolines
Valquírio G. Correia,† Juliana C. Abreu,† Caio A. E. Barata, and Leandro H. Andrade*
Departament of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, Av. Prof. Lineu Prestes 748, 05508-900, Sao
̃
̃
Paulo, Brazil
S
* Supporting Information
ABSTRACT: A novel and highly efficient synthetic approach to
pyrroloindolines has been developed. The process is based on tandem
radical addition/cyclization with inexpensive iron catalyst. This method
tolerates a wide range of N-methyl-N-arylacrylamides as well carbamoyl
radicals, providing access to a variety of functionalized 3,3-disubstituted
oxindoles, key intermediates for many bioactive pyrroloindolines such as
( )-esermethole, ( )-deoxyeseroline, and ( )-physovenol methyl ether.
he pyrroloindoline skeleton occurs frequently in many
alkaloids isolated from various natural sources displaying
cyanation or cross-coupling reactions,11 intramolecular aza-
Pauson−Khand-type reaction,12 [4 + 1] cyclization reaction,13
and oxidative cyclization using hypervalent iodine.6c,7j Addi-
tionally, asymmetric methods have also been developed to
obtain the pyrroloindolines. In general, the asymmetric
methods include both transition-metal-catalyzed and organo-
catalyzed reactions,3,6a,d,7k−m,14 except for three examples using
enzyme-catalyzed reactions.15 Despite the significant number of
approaches for the synthesis of the pyrroloindoline skeleton,
they employ several steps and make use of prefunctionalized
precursors. Therefore, new synthetic methods able to give
access to this ring-system in a short and straightforward fashion
using a minimally functionalized precursor would be highly
desirable. We envisioned that a method with carbamoyl radical
via an Fe-catalyzed radical addition/cyclization would fit such
requirements (Scheme 1).
T
remarkable biological properties (Figure 1).1 For instance,
Although acyl radical chemistry has been known for almost a
century,16 the related carbamoyl species were scarcely
exploited. Carbamoyl radical generation can be induced by
light,17 a redox system18 or thermally19 and has been used for
different purposes.20 Considering that α,β-unsaturated amides
Figure 1. Indole alkaloids named pyrroloindolines.1,6
(−)-phenserine (B) has been used in the treatment of
Alzheimer’s disease,2 and (−)-flustramine B (J) exhibits potent
anticancer activity.3 (−)-Physostigmine (A) shows physiolog-
ical effects such as anticholinergic and miotic activities4 and
recently has also shown activity against hepatitis B virus
transcription.5
Scheme 1. Retrosynthetic Analysis for Pyrroloindolines
The combination of structural features and biological
activities presented by natural alkaloids containing the
pyrroloindoline ring system makes them attractive targets for
development of new methods that allow their constructio-
n.1a,6a,b,d,7 The racemic routes developed so far include Cu(I)-
catalyzed vinylation−cyclization,7i Wittig olefination−Claisen
rearrangement,8 [3,3]-sigmatropic rearrangement of N-amino-
skatole derivatives,9 C-arylation of cyclic amides,10 palladium-
catalyzed intramolecular cyanoamidation, domino Heck−
Received: January 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
are reactive toward different radicals, including acyl radical,21
we proposed the exploitation of such amides with a carbamoyl
radical. In our synthetic approach for bioactive pyrroloindo-
lines, the exploitation of such amides with carbamoyl radical
would lead to the key intermediates, functionalized 3,3-
disubstituted oxindoles.
(Table 1, entry 11), but no product was observed, except traces
of aniline.
The reaction scope was examined with different N-
arylacrylamides under the optimized conditions (Figure 2).
Initially, we decided to generate the carbamoyl radical using a
redox system catalyzed by iron in the presence of sulfuric acid
and hydrogen peroxide. Reaction between N-methyl-N-
arylacrylamide 1a and the carbamoyl radical precursor
(formamide or N-methylformamide) was chosen as a model
to optimize the reaction conditions. The results are summarized
in Table 1.
Table 1. Optimization of the Reaction of Carbamoyl
a
Radicals with N-Methyl-N-arylacrylamide
b
entry
R
Fe2+ (mol %)
yield (%)
1
2
3
4
5
H
20
10
5
70 (2)
H
73 (2)
71 (2)
55 (2)
96 (2)
75 (2)
97 (3)
93 (3)
92 (3)
70 (3)
<10 (4)
<10 (4)
H
H
3
H
1
c
6
H
1
7
8
9
Me
Me
Me
Me
n-Bu
n-Bu
Ph
20
10
5
c
10
5
c
11
5
c,d
12
13
5
Figure 2. Substrate scope for formamide. (a) Isolated yields. (b) The
e
5
1
regioisomeric ratio was determined by H NMR.
a
Reaction conditions: 1a (1 mmol), H2SO4 (1 mmol), H2O2 (2
b
mmol), formamides (5 mL) at 65 °C for 4 h. Conversions were based
N-Methyl- and N-benzyl-N-phenylacrylamides gave the
desired oxindoles 2 and 14 in 92 and 95% yields, respectively.
Reactions of N-methyl-N-arylacrylamides containing electron-
withdrawing or electron-donating groups at the para-position of
the aromatic ring afforded oxindoles 6−10 in good to excellent
yields, 72−91%. meta-Substituted N-methyl-N-arylacrylamide
(m-chloro) produced a mixture of regioisomers with selectivity
of 10:1 (12:12′) and 64% yield. When ortho-substituted N-
methyl-N-arylacrylamides were evaluated, good yields were
obtained, even for phenyl or chloro substituents 11 and 13,
respectively (85 and 73% yield). The presence of a free N−H
group at the N-arylacrylamide resulted in no reaction, and the
desired product 17 was not observed.
In sequence, we drove our attention to the reactivity of
carbamoyl radical generated from N-methylformamide and
N,N-dimethylformamides toward N-alkyl-N-arylacrylamides
(Figure 3).
All N-phenylacrylamides containing methyl, benzyl, or
phenyl groups at the nitrogen were able to be transformed
into the corresponding oxindoles with excellent results (i.e., 3,
26, and 27). N-Methyl-N-arylacrylamides containing electron-
withdrawing and electron-donating groups at the para-position
of the aromatic ring also gave oxindoles 18−22 in excellent
yields, 88−95%. When ortho-substituted N-methyl-N-arylacry-
lamides were evaluated, good yields were obtained (23 = 81%
and 25 = 65% yield). The use of chlorine meta-substituted N-
c
d
on GC−MS analysis. 2.5 mL of formamides. 3 mL of t-butyl alcohol.
e
2.5 g of formamide.
The lowest amount of FeSO4 as catalyst (1 mol %) yielded
96% of 2 (Table 1, entry 5). On the other hand, when larger
amounts of catalyst were employed, formation of byproducts
and decreased formation of desired oxindole 2 were observed
(Table 1, entries 1−4). When N-methylformamide was used as
a carbamoyl radical precursor, higher amounts of catalyst
(FeSO4) showed the best yields for 3, 92−97% (Table 1,
entries 7−9). In addition, an attempt to decrease the volume of
N-methylformamide considerably decreased the conversion to
3 (Table 1, entry 10). Regarding the considerations about
catalyst loading versus yield, 5% catalyst (Table 1, entry 9) was
selected for further studies. N-Butylformamide was also used,
and the desired product was observed in low concentration
(Table 1, entry 11). We assumed that the heterogeneous
system due to the presence of an aqueous solution could be the
reason for the low product formation. We then decided to
employ t-ButOH as cosolvent, a well-known solvent for radical
generation. However, once again, the product was observed in
very low concentration (Table 1, entry 12), showing that the
chemicals solubility is not the main reason for such results. We
also applied this system for aromatic formamide, N-phenyl-
formamide, which was treated with iron catalyst and H2O2
B
DOI: 10.1021/acs.orglett.7b00078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Formal Synthesis of Some Natural Products
a
Reaction conditions: (a) SOCl2, MeOH (70% yield).
Scheme 3. Proposed Reaction Mechanism
Figure 3. Substrate scope for N-methylformamide. (a) Isolated yields.
(b) The regioisomeric ratio was determined by 1H NMR. (c)
Dimethylformamide was used as starting material.
methyl-N-arylacrylamide as a substrate gave a mixture of
regioisomers with selectivity 24:24′ = 10:1 and 73% yield.
Once again, the N-arylacrylamide with a free NH group did not
provide the desired product, 29. Dimethylformamide (DMF)
was also used, and the carbamoyl radical was able to produce
the oxindole 30 in 43% yield.
To demonstrate the strength of our method and how this
approach can be very useful as a general method for preparing
pyrroloindoles, we selected some natural products to show their
formal synthesis (Scheme 2).
The oxindoles 3 and 20, which were obtained from reactions
between N-methyl-N-arylacrylamides and the appropriate
carbamoyl radical precursors (Figure 3), could be a synthetic
intermediate to ( )-esermethole,22 ( )-deoxyeseroline,23
( )-eseroline,24 and ( )-physostigmine.25 Another application
of our strategy involved the esterification of oxindole 8 with
thionyl chloride and methanol to afford the methyl ester 31
(70% yield).26 This compound could be transformed in a few
steps, into indole alkaloid ( )-physovenol methyl ether.27 In
this case, a system called furoindoline would be prepared using
our approach.6b Physovenol methyl ether could also be an
intermediate to the natural product ( )-physovenine.28
A plausible mechanism for the tandem radical addition/
cyclization reaction between carbamoyl radical and N-alkyl-N-
arylacrylamide is depicted (Scheme 3).18
formamide, generating the carbamoyl radical. Then, the
carbamoyl radical adds to the double bond of the α,β-
unsaturated system 1, yielding a tertiary carbon-centered radical
species I, which undergoes an intramolecular cyclization with
the aromatic ring, generating the cyclic radical II. The
rearomatization of the cyclic radical II involves the reduction
of iron(III) to iron(II) and concomitant loss of a proton,
regenerating the aromaticity of the benzene ring to produce the
corresponding oxindoles.21
In conclusion, we have developed a tandem radical addition/
cyclization method with inexpensive iron catalysts, which
provides an easy access to a variety of functionalized 3,3-
disubstituted oxindoles. This method tolerates a wide range of
N-alkyl-N-arylacrylamides as well carbamoyl radicals generated
from formamide and N-methylformamide. The functionalized
3,3-disubstituted oxindoles are key intermediates for the direct
synthesis of bioactive pyrroloindolines using only a reductive
cyclization protocol. In fact, our synthetic approach is the
shortest route described so far for the preparation of
pyrroloindolines, from the easily accessible N-aryl-N-acryl-
amides, obtained from the commercial available anilines.
In a Fenton-type reaction, hydrogen peroxide reacts with
iron(II), under heating in acidic medium, to produce iron(III),
hydroxyl radical, and water. The hydroxyl radical formed, which
has a high oxidation potential, abstracts a hydrogen from the
C
DOI: 10.1021/acs.orglett.7b00078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00078.
■
S
1
Experimental procedure, characterization data, and H
and 13C NMR spectra (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: leandroh@iq.usp.br.
ORCID
Leandro H. Andrade: 0000-0001-5975-4980
Author Contributions
†V.G.C. and J.C.A. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Prof. Timothy F. Jamison (MIT), Prof. Diogo S.
Ludtke (UFRGS), and Prof. Massuo Jorge Kato (USP) for
helpful discussions. We also appreciate FAPESP and CNPq for
financial support (FAPESP: 2016/05633-0, 2014/22457-5,
2013/04540-0; CNPq: 307543/2014-5, 141672/2015-3).
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