Decarboxylative Synthesis of Functionalized Oxindoles via An Iron-Initiated Radical Chain Process and Application in Constructing Diverse Fused-Indoline Heterocycles

Article abstract of DOI:10.1002/adsc.201700976

Rapid construction of diverse fused-indoline?heterocycle (FIH) frameworks including high-value pyrroloindolines, furoindolines and thienoindolines in a two-step sequence has been described. The key to success hinges on the adoption of peresters as α-heteroatom alkyl radical precusors, which can smoothly react with N-arylacrylamides via a radical chain process initiated by inexpensive FeCl₂?4H₂O to afford the functionalized oxindoles, the key intermediates to FIH skeletons. The approach features operationally-simplicity, broad substrates scope and mild conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201700976

Title: Decarboxylative Synthesis of Functionalized Oxindoles via
A Iron-Initiated Radical Chain Process and Application to
Construction of Diverse Fused-Indoline Heterocycles
Authors: Zhihao Cui and Da-Ming Du
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700976
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10.1002/adsc.201700976
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Decarboxylative Synthesis of Functionalized Oxindoles via An
Iron-Initiated Radical Chain Process and Application in
Constructing Diverse Fused-Indoline Heterocycles
Zhihao Cui and Da-Ming Du*
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, People’s Republic of
China
e-mail: dudm@bit.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Rapid construction of diverse fused-
indoline−heterocycle (FIH) frameworks including high-
value pyrroloindolines, furoindolines and thienoindolines in
a two-step sequence has been described. The key to success
hinges on the adoption of peresters as α-heteroatom alkyl
radical precusors, which can smoothly react with N-
arylacrylamides via a radical chain process initiated by
inexpensive FeCl24H2O to afford the functionalized
oxindoles, the key intermediates to FIH skeletons. The
approach features operationally-simplicity, broad substrates
scope and mild conditions.
Keywords: FeCl24H2O; Peresters; Oxindoles; Fused-
indoline−heterocycle skeletons; Electron catalysis
In the total known indole alkaloids so far, those
bearing the fused-indoline−heterocycle (FIH)
skeletons, such as pyrroloindoline and furoindoline
(Figure 1), hold a large proportion. These tricyclic
Scheme 1. Synthesis of FIH Skeletons
indole
alkaloids
usually
display
various
bioactivities,[1] ranging from acetyl cholinesterase
inhibitors[2], antibacterial[3a] and anticancer activity[3b]
to potential drug candidates for Alzheimer’s disease.[4]
Due to these intriguing bioactivities, many
approaches have been developed for efficient
construction of the core FIH skeletons in the past
5]
decades,[1b,
such as 1,4-addition of Grignard
reagent,[5a]
Fisher indolization,[5b] domino
olefination/ isomerization/Claisen rearrangement
(OIC) (Scheme 1a),[5c] [4+1] cyclization,[5d] [3+2]
annulation,[5f,
annulation,[5h]
iodine(III)-mediated intramolecular
5g]
3,3-rearrangement,[5e]
Wittig
olefination–Claisen rearrangement,[5i] alkyl radical
(Scheme 1b) [5j] and carbamoyl radical[5k] (Scheme 1c)
addition/oxidative annulation. Although all roads
lead to the same destination, many drawbacks still
exist such as several steps, poor overall yields, harsh
conditions, pre-functionalized complex precursors or
excess reagents. Particularlly, most of them can
produce only one type of FIH skeleton and lack
ability to construct the diversity. Hence, a unified
Figure 1. Indole Alkaloids Bearing FIH Skeletons
1
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10.1002/adsc.201700976
Advanced Synthesis & Catalysis
Table 1. Optimization of Reaction Conditions.[a]
Table 2. Substrate Scope of N-arylacrylamides 1.[a, b]
Entry
2
Cat.
Solvent
Yield (%)[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[c]
17[c]
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
1,4-dioxane
DMF
n.r.
n.r.
70
n.r.
n.r.
49
42
79
82
68
trace
trace
84
n.r.
n.r.
51
2a
2b
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
FeSO47H2O
FeSO47H2O
FeSO47H2O
CuCl
CuBr
FeCl3
Fe(acac)3
Cp2Fe
FeCl24H2O
FeBr2
FeCl24H2O
FeCl24H2O
FeCl24H2O
FeCl24H2O

THF
DMF
DMF
MeCN


48
[a]Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), cat.
(0.02 mmol), solvent (1.0 mL), 50 C, 12 h, Ar. [b]Isolated
yield. [c]Performed at 100 C.
method achieving types of FIH skeletons via a short
and straightforward pattern under mild conditions is
of high necessity.
[a]Reaction conditions: N-arylacrylamides 1 (0.2 mmol), 2c
(0.4 mmol), FeCl24H2O (0.02 mmol), DMF (1.0 mL), Ar,
50 C, 12 h. [b] Isolated yield.
Retrosynthetically, we envision that the reaction of
α-heteroatom
acids
and
N-methyl-N-
5k, 6, 7g]
arylacrylamides,[5j,
which are the common
radical acceptors and precursors of oxindoles, via a
radical addition/cyclization fashion may construct
the desired oxindoles, the key intermediates to FIH
skeletons (Scheme 1d).[1, 5j, 5k]
o
50 C (Table 1). Smoothly as the redox-active esters
2a and 2b run in decarboxylative functionalizations
catalyzed by iron and nickel,[9a-9d] they did not work
under our reaction conditions (Table 1, entries 1 and
2). When tert-butyl perester 2c[9i-9k] was employed,
the expected oxindole 3ac was obtained in 70% yield
(Table 1, entry 3). Then, we chose acrylamide 1a and
tert-butyl perester 2c as the model substrates to
screen the metal salts and the solvents. Results of
optimization of the initiators showed that Fe(II) salts
outperformed Fe(III) salts (Table 1, entries 6-10) and
copper salts did not initiate the reaction (Table 1,
entries 4 and 5). FeCl24H2O furnished the optimal
outcome (Table 1, entry 9). On the other hand, the
survey of solvents exhibited that DMF was superior
to other solvents and gave 3ac with a satisfactory
yield (Table 1, entries 11−14). The absence of the
initiator made this reaction completely shut down
α-heteroatom acids including amino acids, glycolic
acid and thioglycolic acid as the chemical feedstock,
are widely employed in myriad aspects of organic
chemistry. In the past decades, Ag/ persulfate system
mediating decarboxylation reactions of alkyl
carboxylic acids have become one of the main means
to access alkyl radicals. [7] However, such system is
ill-suited to α-heteroatom acids due to the ease of
overoxidation of the generated radicals.[8] Recently,
another protocol that uses the activated carboxylic
acids to achieve alkyl radicals receives widespread
attention.[9] We consider that this pre-activation
strategy might serve for our design.
We initiated our investigation by screening three
kind of activated glycine, reacting with N-methyl-N-
arylacrylamide 1a in the presence of FeSO47H2O at
2
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10.1002/adsc.201700976
Advanced Synthesis & Catalysis
Table 3. Reaction Scope of α-heteroatom acids.[a , b]
Table 4. Construction of FIH Skeletons.[a , b]
[a]Reaction conditions: N-arylacrylamides 1 (0.2 mmol), 2
(0.4 mmol), FeCl24H2O (0.02 mmol), DMF (1.0 mL), Ar,
50 C, 12 h. [b] Isolated yield.
[a]
Overall yield of two steps. [b]Reaction conditions: (a)
FeCl24H2O (0.1 equiv), DMF, 50 C, Ar, 12 h; (b)
(Table 1, entry 15). As the reaction was performed at
the elevated temperature (100 C) in DMF and
MeCN without use of initiators, the oxindole 3ac was
achieved in moderate yields (Table 1, entries 16 and
17).
NH2NH2 (10.0 equiv), MeOH; then LiAlH4 (8.0 equiv),
o
THF, 0 C; (c) LiAlH4 (8.0 equiv), THF, 0 C; (d) LiAlH4
(8.0 equiv), THF,  60 C.
With the optimized conditions in hand, we then
made an investigation of the scope of N-
arylacrylamides 1 (Table 2). Halogens including F, Cl,
Br anchoring on different position of N-aryl motif can
be tolerated under the reaction conditions (3bc-3dc).
With respect to variation of electron properties on
aromatic rings, neither did the electron−withdrawing
substitutes made a big difference to the reactivity
(3gc and 3hc), nor did the electron−donating (3ec,
3fc, 3ic-3kc). The existence of terminal alkyne did
not alter the reaction chemoselectivity (3kc). N-
pyridylacrylamides (1l to 1n) were also amenable to
this reaction and no alkylated pyridine products,
generated through Minisci reaction pattern,[7b-7d, 7i, 9h,
For examples, three types of frequently-used FIH
skeletons were rapidly synthesized, starting from N-
arylacrylamides 1 and tert-butyl peresters of α-
heteroatom acids (Table 4). A two-step sequence
allowed access to hexahydropyrrolo[2,3-b]indole 4ic
and 4rc, core skeletons of ()-esermethole, ()-
physostigmine and ()-flustramine B,
flustramine E, in 86% and 62% overall yields
respectively. Also, hexahydrofuro[2,3-b]indole
()-
skeletons 4ig ((±)-physovenol methyl ether) and 4rg
were obtained in satisfactory yields after reduction of
the generated oxindoles (3ig and 3rg) by LiAlH4, so
were
a
similar
two-step
sequence
for
hexahydrothieno[2,3-b]indole 4ii and 4ri. Although
thia-physostigmine exhibited stronger inhibitory
activity over acetyl cholinesterase and lower toxicity
than (-)-physostigmine, [2, 11] the synthetic difficulty of
thienoindoline skeleton limited the further
pharmacological evaluation and application. Our
approach would be an ideal alternative of the
previous synthetic route.[11]
10]
were detected. Variation of N-substituents had no
big effect on the reaction results (3oc-3qc).
Substitutes such as allylic, prenyl or even propargyl
units at the R3 site lived in perfect harmony with the
radical addition/annulation process (3rc-3tc) and no
other addition byproducts were detected.
Furthermore, the substrate scope of α-heteroatom
acids was also examined (Table 3). This reaction
proceeded well with tert-butyl peresters of L-valine
and L-phenylalanine, furnishing the corresponding
oxindoles 3ad and 3ae in satisfying yields
respectively (69% and 88%). tert-Butyl peresters of
phenoxyacetic acid and glycolic acid also reacted
well with N-methyl-N-arylacrylamide 1a, affording
oxindole 3af and 3ag in moderate yields. Notably, α-
thioglycolic acid peresters smoothly underwent the
radical addition/cyclization process, delivering the
title products 3ah and 3ai in 75% and 57% yields.
All of the synthetized oxindoles above could be
easily converted into FIH compounds after reduction.
To showcase the scalability, a gram−scale reaction
was carried out and the corresponding oxindole 3ic
was accessed in 90% yield (Scheme 2A). It is worthy
to note that evaluation of thermal stability of
peresters is also of indispensability to application
safety. Decomposition temperatures of the synthetic
peresters measured by DSC ranged from 100 C to
130 C (see Supporting Information), which
demonstrates that it is of relative safety to perform
the gram−scale reaction under our mild conditions,
but of potential danger at high temperature.
3
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10.1002/adsc.201700976
Advanced Synthesis & Catalysis
ring furnishes the radical intermediate III, which
undergoes the single electron oxidation by perester to
afford the cation intermediate IV and alkyl radical I,
which further propagates the radical chain.
Deprotonation of cation IV finally produces the
oxindole.
In summary, we have developed an efficient
approach to construct functionalized oxindoles via
electron catalyzed radical cascade addition/annulation.
This method represents
a
new gateway to
construction of types of FIH skeletons. This method
features scalability, operationally-simplicity and high
degree of tolerance. From the perspective of step-
economy, overall yield and synthesis diversity, our
approach has strong competitive advantages over the
previous methods. In fact, it is the shortest route ever
reported and the first unified approach for synthesis
of types of FIH skeletons.5
Scheme 2. (A) Gram-Scale Reaction. (B) Preliminary
Investigation of Mechanism.
Experimental Section
To probe into the plausible mechanism, radical-
trapping experiments were done (Scheme 2B).
Whether the reaction was conducted under the
standard conditions with addition of radical
scavengers BHT (3.0 equiv) or TEMPO (3.0 equiv),
no oxindole 3ac was detected by TLC and ESI-
General
procedure
for
preparation
of
functionalized oxindoles 3
N-arylacrylamides 1 (0.2 mmol), perester 2 (0.4 mmol),
and FeCl24H2O (3.96 mg, 0.02 mmol) were added into an
oven-dried Schlenk tube with a stirring bar. The tube was
repeatedly degassed and recharged with argon for three
times. Then degassed DMF (anhydrous, 1.0 mL) was
added via syringe. The resulting mixture was stirred at 50
C for 12 h. After completion, the mixture was extracted
with EtOAc for 3 times. The separated organic layer was
dried over anhydrous Na2SO4 and concentrated under
reduced pressure to furnish the crude product 3, which was
then purified by column chromatography (PE/EtOAc as
eluant).
HRMS. Meanwhile, adducts
5
and
6
were
successfully detected by ESI-HRMS (see Supporting
Information). Based on the above experiments and
literature precedence, [7k, 7l] a putative mechanism of
alkyl radical addition/annulation by electron catalysis
is proposed (Scheme 3).[12] The radical chain process
is initiated by transferring single electron of Fe (II) to
perester to deliver a reactive radical anion, which
instantly generates the α-heteroatom alkyl radical I
after cleavage of O-O bond and decarboxylation.
Addition of radical I to N- arylacrylamide gives birth
to the tertiary carbon-centered radical II.
Intramolecular annulation of radical II with aromatic
General procedure for the synthesis of
pyrroloindoline skeletons
Into a 25 mL flask equipped with a magnetic stirring bar,
the purified oxindole 3ic (or 3rc) and MeOH was placed,
followed by the addition of NH2NH2 (10.0 equiv, 80% w/w
solution in water). After stirred at room temperature for 20
h, the resulting solution was filtrated over a plug of Celite
and the filter cake was washed with AcOEt for 3 times.
The combined filtrate was concentrated under reduced
pressure to quantitatively furnish the crude amine, which
was directly placed into an oven-dried Schlenk tube
without any further purification. Then, the newly-distilled
THF was added through a syringe under argon. The
solution was cooled to 0 C and LiAlH4 (4.0 equiv) was
added portionwise over 20 min. The suspension was stirred
at 0 C for 3 h followed by another addition of LiAlH4 (4.0
equiv). Then the suspension was stirred for 1h at 0 C and
3 h at room temperature. After complete consumption of
the starting material monitored by TLC, the reaction was
quenched by saturated NaOH (4 drops to 10 drops) at 0 C,
followed by the addition of MgSO4 and silica gel. The
resulting mixture was then purified by silica gel flash
column chromatography (EtOAc/MeOH as eluant) to
afford the hexahydropyrrolo[2,3-b]indole 4ic (or 4rc).
Scheme 3. Plausible Mechanism
4
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10.1002/adsc.201700976
Advanced Synthesis & Catalysis
Acknowledgements
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Yang, Org. Biomol. Chem. 2016, 14, 4365-4377; h) J.-
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We are grateful for financial support from National Natural
Science Foundation of China (Grant No. 21272024).
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5
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Advanced Synthesis & Catalysis
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