Dearomatization of 3-cyanoindoles by (3 + 2) cycloaddition: From batch to flow chemistry

Article abstract of DOI:10.1039/d0ob00582g

1,3-Dipolar dearomatizing cycloadditions between a non-stabilized azomethine ylide and 3-cyanoindoles or benzofuran afford the corresponding 3D-heterocycles bearing a quaternary carbon centre at the ring junction. While 6 equivalents of ylide precursor 1 are required for full conversion in a classical flask, working under flow conditions limits the excess (3 equiv., t^R = 1 min) and leads to a cleaner process, affording cycloadducts that are easier to isolate.

Full text of DOI:10.1039/d0ob00582g

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DOI: 10.1039/D0OB00582G
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Dearomatization of 3-Cyanoindoles by (3+2) Cycloaddition: From
Batch to Flow Chemistry
Maxime Manneveau,a Saori Tanii,b Fanny Gens,a Julien Legros,a* and Isabelle Chataignera,c*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
1,3-Dipolar dearomatizing cycloadditions between
a non- another (3+2) reaction takes place between the C≡N and the
stabilized azomethine ylide and 3-cyanoindoles or benzofuran dipole in this case (Scheme 1).9 With the less aromatic indole
afford the corresponding 3D-heterocycles bearing a quaternary ring, we show herein that 3-cyanoindoles behave again as C=C
carbon centre at the ring junction. While 6 equivalents of ylide dipolarophiles10 and undergo fast dearomatization through
precursor 1 are required for full conversion in a classical flask, 1,3-dipolar cycloaddition to afford original 3D-scaffolds within
working under flow conditions limits the excess (3 equiv., tR = 1 a single minute reaction time (Scheme 1).
min) and leads to a cleaner process, affording cycloadducts that
EWG =
N
EWG =
are easier to isolate.
EWG
N
Bn
EWG
NO2
CO2R
CN
N
Bn
R
R
R
Dearomative processes have turned into a hot topic for their
ability to metamorphose trivial aromatic compounds into
valuable functionalized polycyclic compounds in one single
operation.1 Different types of cycloadditions have shown their
efficiency in dearomatizing electron-poor arenes, in concerted
or stepwise reactions. This includes (2+1),2 (4+2),3 (3+2)4 or
combined (4+2)/(3+2) cycloadditions.5 In most of the cases
considered, the aromatic ring is substituted by a nitro group
owing to its high electron-withdrawing power. Hence,
nitroarenes, in particular 3-nitroindoles, have been recently
efficiently reacted with different 1,3-dipoles in (3+2) (formal)
cycloadditions,4b,6 or with electron-rich 1,3-dienes, enolates or
enamines in (4+2) (formal) cycloaddition processes among
other processes.3b,7 The situation becomes more complex
when the nitro substituent on the aromatic ring is replaced by
a cyano group, a motive much less attracting and possibly
sensitive to the reaction conditions. The Mayr scale indeed
shows a huge difference between the electrophilicities of
nitrostyrene (E(Ph-C=C-NO2) = −13.85) and cinnamonitrile
(E(Ph-C=C-CN) = −24.60) for instance.8 This dissimilarity
translates into a different reactivity toward nucleophiles and
we have shown that cycloadditions between electron-poor
benzonitriles and a non-stabilized azomethine ylide derails the
dearomatization process observed with nitrobenzenes, since
ref 8
ref 4a, 6
H
+
Bn
N
+
CN
CN
This work
1 min
Bn
R'
R'
N
N
R
N
R
H
Scheme
1 (3+2) (hetero)cycloadditions involving electron-poor benzenic
derivatives with a non-stabilized azomethine ylide.
Our previous works prompted us to launch this study on
cyanoindole 2a, bearing an activating/protecting tosyl group
on the nitrogen atom. Reacting 2a with a large 9 equiv excess
of hemiaminal 1 and a catalytic amount of trifluoroacetic acid
(TFA), added over 30 min at 0 °C, resulted in the conversion of
most of the starting material (84%) and formation of a single
adduct (Table 1, entry 1). The dearomatized indoline 3a was
isolated in 58% yield.11 In order to enhance the conversion, we
explored the influence of the nitrogen protecting group, as this
was shown to have a great impact on the reactivity in
cycloadditions of indolic derivatives.12 In particular, carbonyl
based protecting groups (amide, carbamate) were found to be
more reactive than their sulfonyl based counterparts, in some
cases. However, the benzoylated indole 2c did not lead to the
desired cycloadduct (entry 2) while carbamate 2d furnished 3d
in a lower yield under the same conditions (entry 3). We thus
turned our attention toward the trifluoromethylsulfonyl (Tf)
group having a stronger electron-withdrawing inductive effect.
The N-Tf-indole 2d was found to fulfil the desired criteria of
the reaction, leading to a full conversion of the starting
material and affording the dearomatized cycloadduct 3d in an
increased 78% yield (entry 4). Further optimization of the
reaction was achieved by studying the influence of the
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reaction time and of the hemiaminal excess. The best result aromatic ring had no undesirable effect on the reaction yields
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DOI: 10.1039/D0OB00582G
was observed in the presence of a 6-fold excess of 1 (entry 5). and the desired product 3g and 3h were isolated in 93% and
With 4 equiv. of 1 only 73% conversion was observed (entry 6). 73% yield, respectively. No competition of other aromatic or
With 6 equiv, the reaction time could even be reduced (entries C≡N bonds was observed. Different 3-cyanoindoles bearing an
7 and 8) and we noticed that the conversion was nearly extra aromatic substituent in position 5 were also well-
complete just after the end of the catalyst dropwise addition tolerated, furnishing the aryl substituted cycloadducts 3i-3p in
(30 minutes), furnishing the cycloadduct in a similar 88% good yields. The aromatic can be a simple phenyl group (3i), a
isolated yield (entry 8).
phenyl bearing an electron-withdrawing (3j-3k) or an electron-
donating group (3l-3m), an electron-rich heteroaromatic (3n-
3o) or an electron-poor pyridine (3p), showing the broad
diversity of the possible aromatic substitution. The indole
derivative bearing a silylalkynyl group in position 5 could also
be used in this reaction, leading to the exclusive formation of
3q, isolated in 92% yield. No competitive cycloaddition
involving the triple bond was observed in this case, as
expected with the electron-rich azomethine ylide dipole
engaged in the reaction. The 3-cyano-2-methyl-N-
trifluoromethylsulfonylindole however proved inert in this
process, as anticipated for an aromatic tetrasusbstituted
dipolarophile. Note that different aromatic substrates can also
react efficiently, as demonstrated with 3-cyanobenzofuran
furnishing the dearomatized tetrahydrobenzofuropyrrole 3r in
a good 90% yield.
Despite, the large scope of substrates that can be used
under these conditions, the use of a large excess of the ylide
precursor (6 equiv) remains a drawback. This dipole is
generated by the slow addition of TFA on a mixture of
hemiaminal and dipolarophile in dichloromethane. The slow
addition intends to avoid the competitive self-condensation of
the reactive dipole. However, the TFA concentration increases
along the addition, which may speed up the ylide consumption
in the competitive process. In this perspective, miniaturized
reactors in continuous flow have been shown to be a
remarkable tool for organic synthesis.15 This is notably due to
precise control of reaction time in flow microreactors
(residence time tR), allowing highly reactive compounds to be
formed and trapped before further adverse transformation
can occur.15b,16 Whereas a slow addition of a reagent cannot
be achieved in an integrated flow set-up, it is worth to note
that each point of a simple tubular reactor describes a specific
state of the reaction progress without accumulation of
reagents, by contrast with the previous discontinuous batch
reactor. Hence, Ley reported the flow synthesis of 3-
nitropyrrolidines from an in situ generated ylide and
nitroalkenes as dipolarophiles (tR = 30-90 min at 60-120 °C).17
In this context, we decided to transpose our dearomative (3+2)
cycloaddition of cyanoindoles from batch to flow conditions
and implemented the new process described on Scheme 3.
Table 1.Optimization of reaction conditions.[a]
CN
CN
TFA (cat.)
added over 30 min
Bn
Bn
N
+
MeO
N
SiMe3
0 °C to RT
N
R
N
R
H
1
2a: R = Ts
3a: R = Ts
3b: R = Bz
3c: R = CO2Et
3d: R = Tf
2b: R = Bz
2c: R = CO2Et
2d: R = Tf
Equiv. of
Conv. (%) [c]
Entry
R
Time[b] (h)
1
(Yield (%))[d]
84 (58)
1
Ts
Bz
18
18
18
18
24
24
2
9
2
3
4
5
6
7
8
9
9
9
6
4
6
6
100 (0)[e]
70 (41)
100 (78)
100
CO2Et
Tf
Tf
Tf
73
Tf
100 (80)
97 (88)
Tf
0
a Reactions were carried out on 0.5 mmol of 2 and 4 to 9 equiv of 1 in DCM (2
mL). 2 mL of a 0.18M solution of TFA in DCM were added dropwise at 0°C over 30
min. The mixture was warmed up at r.t. and stirred for the requisite time.
bReaction time after the end of the dropwise TFA addition; cconversion of 2,
determined by 1H NMR on the crude mixture (considering the indole/indoline H2
shifting, from 7.92 to 5.15 ppm on the triflated compounds for instance);
disolated yield; edegradation of the product.
This last observation was supported by in-line infrared
analysis of the reaction mixture. 2d is characterized by
absorption bands at 1429 cm-1 and 977 cm-1, probably
corresponding to the reactive olefinic C2=C3 double bond. On
the other hand, 1 features signals at 1067 cm-1 and 1249 cm-1,
possibly corresponding to the CH3-O-CH2 and Si-CH3 fragments.
These latters disappear while adding TFA to the reaction
mixture. Alongside, bands at 1406 cm-1 and 1200 cm-1,
illustrating the formation of cycloadduct 3d, appear once the
TFA is added dropwise. The intensity of these signals is almost
at its maximum at the end of the TFA addition, suggesting that
the desired product 3d was nearly entirely formed.
The reaction was extended to other 3-cyanoindole
derivatives (Scheme 2).13 We first turned our attention to
cyanoindoles bearing a bromine atom on the aromatic 6-
membered ring. Thus the 5- and 6-bromoindole derivatives
nicely furnished the corresponding dearomatized indolines 3e
and 3f in 92 and 79 % yield, respectively, within 2h.14 Addition
of an electron-withdrawing group on positions 4 or 5 of the
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0OB00582G
CO2Me
Br
CN
CN
CN
CN
O2N
CN
Bn
Bn
Bn
Bn
N
N
N
Bn
N
N
Br
N
N
N
N
H
H
N
H
Tf
H
H
Tf
Tf
Tf
Tf
3e
3g
3f
3h
3i
Batch: 92%
Flow: 86%
Batch: 93%
Flow: 88%
Batch: 79%
Batch: 73%
Flow: 75%
Batch: 97%
Flow: 97%
O2N
NC
MeO
NC
NC
NC
NC
Bn
Bn
Bn
N
N
N
Bn
N
N
H
Tf
N
N
N
H
Tf
H
H
Tf
Tf
3l
3j
3m
3k
Batch: 91%
Flow: 86%
Batch: 95%
Flow: 86%
Batch: 93%
Flow: 81%
Batch: 94%
Flow: 92%
N
TMS
S
O
NC
NC
NC
NC
NC
Bn
N
Bn
N
Bn
Bn
Bn
N
N
N
N
N
N
N
O
H
H
H
H
H
Tf
Tf
Tf
Tf
3n
3o
3p
3q
3r
Batch: 95%
Flow: 86%
Batch: 95%
Flow: 86%
Batch: 97%
Flow: 93%
Batch: 92%
Flow: 91%
Batch: 90%
Scheme 2 Scope of the (3+2) dearomatizing cycloaddition. Comparison of batch (6 equiv of 1, 0.72 eq of TFA over 30 min then 2 h, 0 °C to RT) and flow (3 eq of 1, 0.24
eq of TFA, 1 min, 36 °C) conditions.
Table 2 Optimization of reaction conditions between 1 and 2d in flow process.[a]
The system was composed of two inlets, inlet 1 containing TFA
and inlet 2 containing a mixture of hemiaminal 1 and
cyanonidole 2d (set-up A). The influence of several parameters
was investigated (Table 2).
Flow
rate[b]
(mL/min)
2
Reactor
volume
(mL)
10
Equi
v of
1
tR
(min)
[TFA] Conv
Entry
T°C
(M)
(%)
1
2
5
1
6
20
20
20
20
20
20
20
50
36
36
36
0.18
0.18
0.18
0.18
0.18
0.12
0.08
0.08
0.06
0.06
0.06
97
98
Bn
NC
N
10
10
6
3
4
5
6
7
8
9
10
11
20
20
20
20
20
20
20
20
10
10
10
10
10
20
20
20
0.5
0.5
0.5
0.5
0.5
1
1
1
1
6
4
2
4
4
4
4
3
100
73
40
95
75
100
100
100
40
R
inlet 1
N
H
3d
Tf
in CH2Cl2
inlet 2
quench
temp.-control.
bath
20
20
2
Set-up A
[a] Reaction conditions: DCM (0.25 M), quench: Et3N (1.5 mmol). [b] Total flow rate.
Set-up B
TFA
TFA, Cyanoindole 2d
Hemiaminal 1
Hemiaminal 1, Cyanoindole 2d
First experiments were assessed with a 10 mL-microreactor
tube, immersed in a 20 °C bath, with 6 equivalents of 1 and
[TFA] = 0.18 M (0.72 equiv), at a total flow rate of 2 mL/min
(entry 1). The result was encouraging since 97% conversion
into 3d was attained within only 5 min reaction. Whereas it is
often claimed that microflow systems provide enhanced
mixing, the T-shaped mixers and reactor sizing imposes a
Scheme 3 Flow set-up for the (3+2) dearomatization of cyanoindoles.
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J. Name., 2013, 00, 1-3 | 3
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formal laminar regime. With such features mixing is actually
increased according to some adjustments: high flow rates in
the reactor (>10 mL/min) and close media for each inlet (both
in CH2Cl2 here). Increasing the flow rate to 10 then 20 mL/min
reduced the residence time to 1 min and 30 s respectively
(entries 2 and 3). Delightfully, at both these tR, a nearly
complete conversion of the substrate into cycloadduct was
observed.
It was then assessed if the quantity of 1 could be reduced.
Unfortunately, conversion dropped significantly (entries 4 and
5). It was next noticed that the TFA loading was essential and
that decreasing its quantity increased the conversion of the
substrate (entry 6). Parameters were then tuned in order to
get the highest yield at the shortest tR with the lowest quantity
of TFA and ylide precursor 1 (entries 7-11). An optimum result
was found at a flow rate of 20 mL/min in a 20 mL-reactor
heated at 36 °C (tR = 1 min) with 3 equiv of 1 and 0.24 equiv of
TFA (C = 0.06 M; entry 10). For comparison, a reaction run in 1
minute (TFA addition) in classical batch conditions led to 44%
conversion into 3d, confirming the positive effect of the flow
conditions on this transformation.
The scope of the reaction was then evaluated with the
same flow set-up and compared to batch conditions (Scheme
2). Results were in line with the first experiment and all the
twelve substrates involved gave excellent yields (75-97%)
within only 1 min and 3 equiv of 1. It is worth noting that the
setup had to be adapted for the substrate 2j which was
insoluble in CH2Cl2. However when adding the proper amount
of TFA in the same syringe (inlet 1), the solution turned
homogeneous and the syringe pumps could be triggered to
start the reaction which took place nicely (set-up B).
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Bn
Bn
DOI: 10.1039/D0OB00582G
NC
NC
N
Suzuki
coupling
N
Br
Ph
(96%)
N
H
N
H
Tf
Tf
3e
4e
NH2
reduction
(95%)
Bn
N
Ph
N
H
H
5e
Scheme 4 Further functionalizations of product 3e. Suzuki coupling: PhB(OH)2,
XPhos-Pd-G2 (1.5 mol%), K3PO4, dioxane/H2O, Δ; Reduction: LiAlH4, THF, reflux.
In short, we have shown that 3-cyanoindoles behave as
C=C dipolarophiles when reacted with an electron-rich
azomethine ylide 1,3-dipole. The dearomatization of these
heterocycles takes place smoothly, in the absence of any metal
catalyst. The (3+2) cycloaddition affords novel and highly
functionalized tricyclic indolines bearing a quaternary centre at
the ring junction, from easily available substrates. This reaction
is very simple to set up and allows an efficient dearomatization
process to take place under classical batch conditions using a
6-fold excess of reagent, in 30 to 150 minutes. When
transposed to flow conditions, the reaction rate is accelerated
to only 1 min, with a lesser excess of reagents. These results
pave the way to fast dearomatizing processes for the access to
a large family of structurally sophisticated 3D molecules in a
very simple way.
The heterocyclic dearomatized compounds resulting from
this transformation represent interesting scaffolds that could
easily undergo further functionalization in an effort to further
increase their molecular diversity (Scheme 4). For instance, 3e
reacted nicely under classical Suzuki coupling conditions to
furnish the expected product 4e. The cyano group could then
be reduced into the corresponding amine by LiAlH4.
Simultaneously, this led to the deprotection of the triflyl
group, affording 5e in 95% yield. Noteworthy, 5e bears three
differently substituted amino functional groups. These
transformations illustrate the vast potential of these
dearomatized cycloadducts, that can easily be derivatized into
differently substituted polyamino-indolines, structures of
interest as bioactive molecules, organocatalysts or
coordinating ligands for instance.18 Efforts directed toward
further derivatizations of these tricyclic indolines are currently
under way.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors gratefully acknowledge the European France-
(Manche)-England
cross-border
cooperation
program
INTERREG IV A “AI-CHEM CHANNEL” and INTERREG V A
“LABFACT”, co-financed by ERDF, and the Tohoku University
Center for Gender Equality Promotion (TUMUG) for financial
support. Labex SynOrg (ANR-11-LABX-0029), Rouen University,
CNRS and INSA Rouen are kindly thanked for financial support.
Notes and references
1 For reviews, see for instance: (a) F. López Ortiz, M. J. Iglesias, I.
Fernández, C. M. Andújar Sánchez and G. Ruiz Gómez, Chem.
Rev., 2007, 107, 1580–1691. (b) S. P. Roche and J. A. Porco,
Angew. Chem. Int. Ed., 2011, 50, 4068–4093. (c) E. Manoni, A.
De Nisi and M. Bandini, Pure Appl. Chem., 2016, 88, 207–214.
(d) J. Preindl, S. Chakrabarty and J. Waser, Chem. Sci., 2017, 8,
4 | J. Name., 2012, 00, 1-3
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7112–7118. (e) G. Huang and B. Yin, Adv. Synth. Catal., 2019,
361, 405–425.
M. Sanselme, M. Sebban, S. Lakhdar, M. DurandVeietwti,ArJt.iclLeeOgnrliones
and I. Chataigner, Chem. Commun., 201
D
9
O
, 5I:
5
1
,
0
7
.1
4
03
9
9
4
/
–
D
7
0
4
O
9
B00582G
7
.
2 D. Antoniak and M. Barbasiewicz, Org. Lett., 2019, 21, 9320– 8 (a) I. Zenz and H. Mayr, J. Org. Chem., 2011, 76, 9370–9378. (b)
9325.
D. S. Allgäuer, H. Jangra, H. Asahara, Z. Li, Q. Chen, H. Zipse, A.
R. Ofial and H. Mayr, J. Am. Chem. Soc., 2017, 139, 13318–
13329.
3 See for instance: (a) E. Wenkert, P. D. R. Moeller and S. R.
Piettre, J. Am. Chem. Soc., 1988, 110, 7188–7194. (b) B.
Biolatto, M. Kneeteman, E. Paredes and P. M. E. Mancini, J. 9 M. Beuvin, M. Manneveau, S. Diab, B. Picard, M. Sanselme, S.
Org. Chem., 2001, 66, 3906–3912. (c) I. Chataigner, E. Hess, L.
Toupet and S. R. Piettre, Org. Lett., 2001, 3, 515–518. (d) A.
R. Piettre, J. Legros and I. Chataigner, Tetrahedron Lett., 2018,
59, 4487–4491.
Chrétien, I. Chataigner and S. R. Piettre, Chem Commun, 2005, 10 The chemoselectivity of the cycloaddition can be
1351–1353. (e) J. Boonsombat, H. Zhang, M. J. Chughtai, J.
Hartung and A. Padwa, J. Org. Chem., 2008, 73, 3539–3550. (f)
N. Chopin, H. Gérard, I. Chataigner and S. R. Piettre, J. Org.
Chem., 2009, 74, 1237–1246. (g) S. Lakhdar, F. Terrier, D.
Vichard, G. Berionni, N. El Guesmi, R. Goumont and T.
Boubaker, Chem. – Eur. J., 2010, 16, 5681–5690. (h) A. S.
Kil’met’ev, E. E. Shul’ts, M. M. Shakirov, T. V. Rybalova and G.
A. Tolstikov, Russ. J. Org. Chem., 2013, 49, 872–885.
4 See for instance: (a) S. Lee, I. Chataigner and S. R. Piettre,
Angew. Chem. Int. Ed., 2011, 50, 472–476. (b) B. M. Trost, V.
Ehmke, B. M. O’Keefe and D. A. Bringley, J. Am. Chem. Soc.,
2014, 136, 8213–8216.
questionned since the reactivity of 3-carbonylated
indoles/pyrroles in (4+2) reactions involving electron-rich 1,3-
dienes depends on the nature of both the electron-
withdrawing group borne by the arene and the diene. Hence,
in the presence of polarized dienes such as Danishefsky diene,
an heterocycloaddition is observed on the C=O bond of the
activating group, being formyl, ketoester or even secondary
ketoamide. See: (a) A. Chrétien, I. Chataigner, N. L’Hélia and S.
R. Piettre, J. Org. Chem., 2003, 68, 7990–8002. (b) A. Chrétien,
I. Chataigner and S. R. Piettre, Tetrahedron, 2005, 61, 7907–
7915. In contrast, the reaction preferably involves the
aromatic C=C bond when the electron-withdrawing group is a
nitro, a tertiary ketoamide or an ester for instance. See ref. 3
and 7
5 See for instance: (a) D. Giomi, S. Turchi, A. Danesi and C. Faggi,
Tetrahedron, 2001, 57, 4237–4242. (b) I. Chataigner and S. R.
Piettre, Org. Lett., 2007, 9, 4159–4162. c) H. Gérard and I. 11 The discrepancy between the conversion rate and the
Chataigner, J. Org. Chem., 2013, 78, 9233–9242.
isolated yield may be attributed to the large amount of
aminated dimer/oligomers/polymers resulting from the self-
condensation of the in-situ generated azomethine ylide,
present in a large excess, rendering difficult the isolation of the
cycloadduct. No presence of deprotected indole substrate nor
cycloadduct was detected in the crude 1H NMR mixture.
6 See for instance : (a) S. Roy, T. L. S. Kishbaugh, J. P. Jasinski and
G. W. Gribble, Tetrahedron Lett., 2007, 48, 1313–1316. (b) S.
Lee, S. Diab, P. Queval, M. Sebban, I. Chataigner and S. R.
Piettre, Chem. - Eur. J., 2013, 19, 7181–7192. (c) A. Awata and
T. Arai, Angew. Chem. Int. Ed., 2014, 53, 10462–10465. (d) A. L.
Gerten and L. M. Stanley, Org. Chem. Front., 2016, 3, 339–343. 12 I. Chataigner, C. Panel, H. Gérard and S. R. Piettre, Chem.
(e) M. Laugeois, J. Ling, C. Férard, V. Michelet, V. Commun., 2007, 3288-3290.
Ratovelomanana-Vidal and M. R. Vitale, Org. Lett., 2017, 19, 13 3-Cyanoindoles substituted by an aromatic group were
2266–2269. (f) H. Wang, J. Zhang, Y. Tu and J. Zhang, Angew.
Chem. Int. Ed., 2019, 58, 5422–5426. (g) K. Li, T. P. Gonçalves,
K.-W. Huang and Y. Lu, Angew. Chem. Int. Ed., 2019, 58, 5427–
5431. (h) A. Cerveri, O. N. Faza, C. S. López, S. Grilli, M. Monari
prepared from non-protected 5-bromo-3-cyano-1H-indoles,
through Suzuki-Miyaura cross coupling reactions. See M. A.
Düfert, K. L. Billingsley and S. L. Buchwald, J. Am. Chem. Soc.
2013, 135, 12877–12885 and ESI.
and M. Bandini, J. Org. Chem., 2019, 84, 6347–6355. (i) L. 14 A reaction time of 2h was selected to ensure full conversion
Birbaum, L. Gillard, H. Gérard, H. Oulyadi, G. Vincent, X. for all substrates.
Moreau, M. De Paolis and I. Chataigner, Chem. – Eur. J., 2019, 15 (a) D. Webb and T. F. Jamison, Chem Sci 2010, 1, 675–680;
25, 13688–13693. (j) J. Ling, D. Mara, B. Roure, M. Laugeois
and M. R. Vitale, J. Org. Chem., 2020, 85, 3838-3848.
(b) J. Yoshida, H. Kim and A. Nagaki, ChemSusChem 2011, 4,
331–340; (c) L. Malet-Sanz and F. Susanne, J. Med. Chem.
2012, 55, 4062–4098; (d) J. C. Pastre, D. L. Browne and S. V.
Ley, Chem. Soc. Rev. 2013, 42, 8849–8869; (e) S. V. Ley, D. E.
Fitzpatrick, R. M. Myers, C. Battilocchio and R. J. Ingham,
Angew. Chem. Int. Ed. 2015, 54, 10122–10136; (f) M. B.
Plutschack, B. Pieber, K. Gilmore, P. H. Seeberger, Chem. Rev.
2017, 117, 11796–11893; (g) R. Gérardy, N. Emmanuel, T.
Toupy, V.-E. Kassin, N. N. Tshibalonza, M. Schmitz and J.-C. M.
Monbaliu, Eur. J. Org. Chem. 2018, 2301–2351.
7 See for instance : (a) T. L. S. Kishbaugh and G. W. Gribble,
Tetrahedron Lett., 2001, 42, 4783–4785. (b) M. Victoria
Gómez, A. I. Aranda, A. Moreno, F. P. Cossío, A. de Cózar, Á.
Díaz-Ortiz, A. de la Hoz and P. Prieto, Tetrahedron, 2009, 65,
5328–5336. (c) M. Andreini, M. De Paolis and I. Chataigner,
Catal. Commun., 2015, 63, 15–20. (d) Y. Li, F. Tur, R. P. Nielsen,
H. Jiang, F. Jensen and K. A. Jørgensen, Angew. Chem. Int. Ed.,
2016, 55, 1020–1024. (e) M. Andreini, F. Chapellas, S. Diab, K.
Pasturaud, S. R. Piettre, J. Legros and I. Chataigner, Org. 16 (a) H. Usutani, Y. Tomida, A. Nagaki, H. Okamoto, T. Nokami
Biomol. Chem., 2016, 14, 2833–2839. (f) D.-F. Yue, J.-Q. Zhao,
X.-Z. Chen, Y. Zhou, X.-M. Zhang, X.-Y. Xu and W.-C. Yuan, Org.
Lett., 2017, 19, 4508–4511. (g) P. V. Santhini, A. Krishnan R, S.
A. Babu, B. S. Simethy, G. Das, V. K. Praveen, S. Varughese and
J. John, J. Org. Chem., 2017, 82, 10537–10548. (h) S. Diab, L.
Noël-Duchesneau, M. Sanselme, Y. Kondo, M. De Paolis and I.
Chataigner, Eur. J. Org. Chem., 2018, 2018, 2048–2052. (i) D.
Cao, A. Ying, H. Mo, D. Chen, G. Chen, Z. Wang and J. Yang, J.
Org. Chem., 2018, 83, 12568–12574. (j) K. Pasturaud, B. Rkein,
and J. Yoshida, J. Am. Chem. Soc. 2007, 129, 3046–3047; (b) H.
Kim, A. Nagaki and J. Yoshida, Nat. Commun. 2011, 2, 264; (c)
H. Kim, K.-I. Min, K. Inoue, D. J. Im, D.-P. Kim and J. Yoshida,
Science 2016, 352, 691–694; (d) A. Nagaki, D. Ichinari and J.
Yoshida, J. Am. Chem. Soc. 2014, 136, 12245–12248; (e) T.
Lebleu, J. Maddaluno and J. Legros, Org. Chem. Front. 2015, 2,
324–327; (f) B. Picard, B. Gouilleux, T. Lebleu, J. Maddaluno, I.
Chataigner, M. Penhoat, F.-X. Felpin, P. Giraudeau and J.
Legros, Angew. Chem. Int. Ed. 2017, 56, 7568–7572; (g) B.
Picard, K. Pérez, T. Lebleu, D. Vuluga, F. Burel, D. C.
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COMMUNICATION
Journal Name
Harrowven, I. Chataigner, J. Maddaluno and J. Legros, J. Flow
Chem., 2020, 10, 139-143.
View Article Online
DOI: 10.1039/D0OB00582G
17 M. Baumann, I. Baxendale and S. Ley, Synlett 2010, 749–752.
18 See for instance: (a) V. Sharma, P. Kumar and D. Pathak, J.
Heterocycl. Chem. 2010, 47, 491–502; (b) E. Stempel, T. Gaich,
Acc. Chem. Res. 2016, 49, 2390–2402; (c) P. H. B. França, D. P.
Barbosa, D. L. da Silva, Ê. A. N. Ribeiro, A. E. G. Santana, B. V.
O. Santos, J. M. Barbosa-Filho, J. S. S. Quintans, R. S. S. Barreto,
L. J. Quintans-Júnior, et al., BioMed Res. Int. 2014, 1–12; (d) I.
Giménez Sonsona, Synlett 2015, 26, 2325–2326; (e) T. V.
Sravanthi and S. L. Manju, Eur. J. Pharm. Sci. 2016, 91, 1–10; (f)
N. Netz and T. Opatz, Mar. Drugs 2015, 13, 4814–4914; (g) M.
E. Tanner, Nat. Prod. Rep. 2015, 32, 88–101.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB00582G
Dearomatization of 3-Cyanoindoles by (3+2) Cycloaddition: From Batch to
Flow Chemistry
CN
CN
Bn
Bn
N
TFA (cat.)
CH2Cl2
N
+
MeO
SiMe3
X
X
H
X = NTf, O
reaction time
6 equiv
73-97%
75-97%
0.5 to 2.5h
flow
3 equiv
1 min
1,3-Dipolar dearomatizing cycloaddition of 3-cyanoindoles with a non-stabilized azomethine ylide occurs in smooth
conditions, allowing the formation of functionalized tricyclic indolines in only 1 min under microflow conditions using 3
equiv of the dipole precursor vs 6 equiv in a batch macroreactor.