Synthesis of 2-substituted indoles through cyclization and demethylation of 2-alkynyldimethylanilines by ethanol

Article abstract of DOI:10.1039/c9gc01880h

Herein, we demonstrated that 2-alkynyldimethylamines easily cyclize in EtOH according to a 5-endo-dig annulation into 2-substituted indoles without the aid of any additives or any metal catalysts to activate the triple bond. Thus, a variety of functionalized 2-styrylindoles, 2-arylindoles, 2-alkynylindoles, and 2-alkylindoles were prepared in high to excellent yields according to an environmentally friendly protocol. The mechanism has been explored to better understand this eco-friendly access to 2-substituted indoles and DFT calculations rationalized the role of the solvent in this N-annulation/dealkylation process.

Full text of DOI:10.1039/c9gc01880h

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DOI: 10.1039/C9GC01880H
COMMUNICATION
Synthesis of 2-Substituted Indoles through Cyclization and
Demethylation of 2-Alkynyldimethylanilines by Ethanol
Guangkuan Zhao, Christelle Roudaut, Vincent Gandon, *c,d Mouad Alami, * Olivier Provot
a
b
a
*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Herein, we demonstrated that 2-alkynyldimethylamines easily
cyclize in EtOH according to a 5-endo-dig annulation into 2-
substituted indoles without the aid of any additive or any metal
catalyst to activate the triple bond. Thus, a variety of functionalized
our previous work7:
Cl ArB(OH)2 (1.3 equiv)
Pd(PPh3)4 (8 mol %)
K2CO3 (2 equiv)
R
R
2
FG
N
N
Toluene / MeOH, (2:1)
4
8 h, 90 °C, Schlenk tube
(
E)-chloroenynes
(E)-2-styryl indoles
2
-styrylindoles, 2-arylindoles, 2-alkynylindoles, and 2-alkylindoles
this work:
R
were prepared in high to excellent yields according to an
environmentally friendly protocol. The mechanism has been
explored to better understand this eco-friendly access to 2-
substituted indoles and DFT computations rationalized the role of
the solvent in this N-annulation/dealkylation process.
EtOH, 120°C, MWI
R
R = H, Ar, alk, styryl, acrylate, vinylchloride(s)
N
N
2
-alkynyldimethylanilines 1
2-substituted indoles 2
Scheme 1. Our approaches for the synthesis of 2-substituted indoles
The success of this N,N-dimethyl-cyclization/N-demethylation
1
Introduction
process prompted us to examine the role of each reagent in this
Indoles are important heterocycles in biologically active natural transformation. To this end, we have removed one by one all of the
8
products1 and are also frequently found in various
pharmaceutical products.
reagents used in our previous protocol to transform 1a into 2a
2
,3
(Scheme 2).
Consequently, this important
structural motif has led to the development of a very large
OMe
number of synthetic methodologies. Among them, the 5-endo-
dig hetero-annulation of alkynyldimethylanilines in the
MeOH, 48 h, 90 °C, Schlenk tube
N
OMe
N
4
2
presence of electrophiles (ICl, I , ArSCl…) developed by Larock
1
a
2a (89%)
and others,5 as well as transition-metal catalyzed
transformations, played a major role in this field. In this
Scheme 2. Synthesis of (E)-2-(2-chlorovinyl)-1-methyl-1H-indole 2a from
cyclization of 1a followed by a N-demethylation reaction
6
challenging context, we recently reported the one-pot synthesis
7
of 2-styrylindoles from ortho-substituted chloroenynes. In a In the presence of only hot MeOH, we were delighted to observe the
hot toluene/MeOH mixture, using a Pd(0) catalyst, boronic acids transformation of diarylenyne 1a into indole 2a with an excellent
and K
2
2
CO
3
, 2-alkynyldimethylanilines 1 were transformed into yield (89%). Even if the N-cyclization of ortho-alkynylanilines into
-styrylindoles after successive Suzuki arylation, N-cyclization indole derivatives is well-known, to our knowledge, this result show
8
and N-demethylation reactions (Scheme 1).
that the formation of a 2-substituted-N-methylindole can be carried
out in the absence of any activating agent since a simple heating in
MeOH is sufficient to promote the N-cyclization and the N-
demethylation reactions. For comparison, Ribecai reported in 2009
the cyclization of 2-alkynylanilines into 2-substituted-1H-indoles in
a. BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ Paris-Sud, CNRS, University
Paris Saclay, 92290, Châtenay-Malabry, France
b.
ATD ATG et Absorption Atomique, PLATINA, IC2MP- UMR 7285, Bat B 27-RdC Nord,
9
water at 200 °C under microwave heating in the absence or in the
4
rue Michel Brunet, TSA 51106, 86073 Poitiers cedex 9, France
1
0
c.
3
presence of additives (e.g. KCl, NaHCO , pyrrolidine,…), necessary
Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182,
Université
France
́
Paris-Sud, Université
́
Paris-Saclay, Bâtiment 420, 91405 Orsay cedex,
to increase yields and the scope of the cyclization reactions.
d.
Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique,
IP Paris, route de Saclay, 91128 Palaiseau cedex, France
In this paper, we wish to present our results concerning the
development of this "green" annulation/demethylation process, its
application to a wide range of functionalized substrates and also a
possible reaction mechanism which is supported by DFT calculations.
Email: vincent.gandon@u-psud.fr, mouad.alami@u-psud.fr, olivier.provot@u-
psud.fr
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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COMMUNICATION
Journal Name
Table 2. Synthesis of 2-substituted indoles
2
from 2-
2
Results and discussion
View Article Online
a
alkynyldimethylanilines 1.
DOI: 10.1039/C9GC01880H
R
Before studying the scope of this process using EtOH as only reagent,
we first examined the influence of other solvents on the cyclization
and demethylation steps of (E)-chloroenyne 1b, a poorly cooperative
substrate in which the chlorine atom, useful for further
transformations, disfavoured the 5-endo-dig annulation reaction.
The results of this solvent and experimental screening are reported
in Table 1.
EtOH, 120 °C
MWI, t
R1
R1
X
N
R
X
1
N
a, 1c-t
2a, 2c-t
Yieldb
1
1
12
o-Alkynylanilines 1c-t
Indoles 2 c-s
t (h)
2
(
%)
OMe 1a
1
2
2a
2c
90
90
N
N
OMe
Table 1. Effects of solvents and experimental conditions on the
transformation of (E)-chloroenyne 1b into 2-(2-chlorovinyl)-1-methyl-
Ac
Cl
1c
2
4
N
Ac
Cl
a
N
1
H-indole 2b.
Cl
MeO
MeO
MeO
Solvent
3
4
1d MeO
2d
2e
56
N
N
N
Cl
N
OMe
OMe
Conditions
1
20 °C
1
b
2b
MeO
MeO
MeO
MeO
Cl
1e
6
42c
N
N
Time
h)
Yieldb
(%)
40c
70
75
OMe
N
Cl
OMe
Entry
Solvent(s)
Conditions
(
Cl
5
6
7
8
9
1f
1g
1g
1h
1i
2f
2g
2h
2
2
2
85
90
88d
93
91
94
95
95
74
95
80
1
2
3
4
5
6
7
8
9
MeOH
MeOH
EtOH
Schlenk tube
MWId
MWI
48
2
Cl
N
Cl
Cl
CO2Me
2
N
N
N
CO Et
2
i-PrOH
HFIP
MWI
2
30
e
CO2Me
MWI
2
N
CO2Me
Toluene
MWI
2
0
trace
35
2
H O
MWI
2
2i 10
2j 10
2k 10
2l 10
2m 10
N
N
H
2
O/EtOH (1/1)
MWI
2
OMe
F
H
2
O/acetone (1/1)
MWI
2
40
OMe
F
N
N
aTypical reaction conditions: a mixture of 1b (0.5 mmol) was stirred in
EtOH (3 mL) at 120 °C under MWI. After completion (estimated by TLC),
the mixture was allowed to cool to room temperature and EtOH or
MeOH was removed under reduced pressure. The crude material was
1
0
1
2
1j
N
N
b
purified by silica gel column chromatography to give 2b. Isolated yield.
S
1
1
1k
1l
N
S
c
d
e
Reaction achieved at 90 °C. 30W Microwave irradiation. Complex
N
mixture.
N
Under the conditions used in Scheme 2, 1b was transformed into
indole 2b after 48 h of reaction in a poor yield of 40% (entry 1).
Compound 1b was then heated in MeOH for 2 h at a higher
temperature of 120 °C under microwave irradiation (MWI).
Gratifyingly, after 2 h, 2b was isolated in 70% yield (entry 2). We next
replaced MeOH by EtOH, i-PrOH, hexafluoroisopropanol (HFIP),
N
N
N
N
OMe
OMe
13
1m
1n
1o
1p
1q
N
2n
2o
2p
2q
2
2
2
2
N
1
1
4
5
N
toluene and H
2
O to evaluate the influence of other solvents (entries
-7) and found that EtOH and MeOH gave nearly similar yields (70-
5%, entries 2,3). A more congested alcohol as i-PrOH allowed the
N
3
7
N
Cl
Cl
OH
expected transformation but with a poor performance (30%, entry 4), 16
while the reaction run in HFIP or toluene was inefficient (entries 5,6).
N
79
N
OH
Moreover, as it could be observed in entries 7-9, water and its
association with EtOH or acetone did not provide indole 2b with
satisfactory yields. The scope of this metal- and additive-free process
was then evaluated with a variety of N,N-dimethylanilines 1 bearing
various alkyne substrates at the ortho-position using EtOH as only
reagent at 120 °C under MWI. The results of this study are reported
in Table 2. As it can be seen, under our optimal conditions, alkynes
N
90e
1
7
N
2r 10
N
N
1
8
1r
1s
1t
N
2s
2s
2t
4
4
4
89
87
N
TMS
TMS
1
2
9
0
N
N
N
1
a, 1c-t were transformed into indoles 2a, 2c-t with excellent yields.
Br
Br
In details, diarylenynes 1a and 1c, (di)chloroenynes 1d-f and
conjugated ethyl acrylate 1g reacted well in hot EtOH or MeOH (to
avoid esterification, entry 7) under MWI to provide the expected
indoles 2a, 2c-h in good yields (entries 1-7).
88
N
a
a
Reaction conditions are identical to those described in footnote of
b
c
d
Table 1. Isolated yield. Reaction achieved at 140 °C. Reaction
achieved in MeOH. Reaction achieved at 160 °C.
e
2
| J. Name., 2012, 00, 1-3
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Journal Name
COMMUNICATION
Having in mind a deeper exploration of the structure-activity As it can be seen, heating N-methylaniline 4 at a higheVrietwemArpticeleraOtnulirnee
1
3
relationships of isoCombretastatin A4 derivatives by replacing its B- of 180 °C furnished mostly indole 2o (80%) aDccOoI:m10p.a10n3ie9d/Cw9iGthC0a1s8m80aHll
7
,14
ring with substituted-indoles, 2-chlorovinyl-indoles 2d and 2e in quantity of NH-indole 5 (9%) which is consistent with our proposition
which the chlorine atom will be useful for further transformations, of mechanism involving an ammonium intermediate and where an
were obtained in acceptable yields regardless of the configuration of ethanolate anion, in this case, acted as a base rather than a
the chloroenyne double bond (entries 3, 4). Interestingly, nucleophile. This process is less suitable for primary anilines as 3
diarylalkynes 1h-j, arylheteroarylalkynes 1k,l bearing a thiophene or since indole 5 and ketone 6, resulting from the hydration of the triple
a pyridine moiety, and diaryldiyne 1m were transformed into the bond, were obtained in equivalent quantities.
expected 2-substituted indoles 2i-n with excellent yields (entries 8-
Next, we were interested to examine the behaviour of tertiary
anilines 7 and 8 (Scheme 4) having respectively on their nitrogen
atom, two different groups (Me and Ph for 7, Me and i-Pr for 8).
1
3). Alkyl groups on the alkyne triple bond were also well tolerated
in this process as indole derivatives 2o-q and azaindole 2r were
obtained in good yields (entries 14-17). A terminal alkyne such as 1r
was well tolerated to give 1-methyl-1H-indole 2s in a good 89 % yield
nBu
EtOH, 120 °C
nBu
nBu
(entry 18) In entries 19 and 20, we noted that silylated alkynes 1s,t
R
MWI, 10 h
N
N
N
were also transformed into indole derivatives 2s,t with good yields,
but the TMS-group did not survive under these conditions. To
summarize this study, this protocol is found to be practical for a
R
7
8
R = Ph
R = i-Pr
2o 0 %
2o 91 %
not formed
Scheme 4. Cyclization attempts of anilines 7 and 8 under MWI in EtOH
variety of alkyne substrates in which
a great number of
functionalized group are well tolerated. Intrigued by the large scope
of this transformation, we then checked that there were no traces of
metals (Pd and Cu) in our samples since alkynes 1 were prepared
according to Sonogashira and Suzuki reactions.
After heating 7 in EtOH for 10 h at 120 °C under MWI irradiation, we did
not observed any transformation of the poorly nucleophilic and
encumbered diphenylmethylaniline 7, which was totally recovered
unchanged. On the contrary, under similar conditions, a careful
1
examination of the crude mixture by H NMR revealed that aniline 8 was
We thus purified diarylenyne 1i one (sample 1, S1), two (S2) and
successfully transformed into N-methylindole 2o (91 %) with no trace of
2-butyl-1-isopropylindole. In this case, it is reasonable to think that the
ethanolate anion formed during this process acted as base to
eliminate 1-propene rather than a nucleophile (see Scheme 6).
three times (S3) on silica gel. These three samples were then reacted
1
5
16
in hot EtOH under MWI, using new magnetic stir bars and new
microwave tubes in view of their transformation into the expected
2
-arylindole 2i (Fig. 1).
To gain mechanistic insight into cyclization/demethylation process
observed with dimethylanilines, a series of experiments was then
conducted. First, o-hexynyldimethylaniline 1n was heated in EtOH for
EtOH, 120 °C
OMe
OMe
MWI, 10 h
N
N
1
i
2i
2
hours at 120 °C under MWI in the presence of 1 equiv of 2,2,6,6-
tetramethylpiperidinyl-N-oxyl (TEMPO), a well-established radical
1
7
scavenger. The presence of TEMPO did actually significantly alter
the yield in indole 2o (84% vs 95% without TEMPO), which does not
support a radical pathway.
D
MeOD, 120 °C
MWI, 10 h
N
1
N
h
(D)-2i
Scheme 5. Synthesis of (D)-2i
Our second interrogation concerned the activation of the alkyne
triple bond as EtOH or MeOH were the only reagents used in this
Fig 1. Synthesis of 2i from metal-free samples of 1i
The results indicated that these samples (S1, S2 and S3) gave similar protocol. Therefore, we have heated diarylalkyne 1h in MeOD at 120
yields in 2i (88, 90 and 92% respectively). The quantity of residual °C under MWI (Scheme 5). In the crude mixture, after 10 h of reaction,
traces of Pd and Cu in these samples was quantified by atomic we observed the unique formation of (D)-2i indicating that MeOD
absorption after mineralization of the samples. The results, obtained may activate the alkyne triple bond of 1h. Next, to demonstrate the
with internal standards, indicated that no traces of Cu in the three fundamental role of EtOH or MeOH as being also the nucleophilic
samples (below 5 ppb if any) and that Pd quantities were also reagents responsible for the N-demethylation step, we performed
negligible (7 (S1), 3 (S2) and 1 ppb (S3), respectively).
other experiments on ortho-substituted anilines 1u and 1v in which
the nitrogen atom is included into a ring (Scheme 6).
Encouraged by these results, we turned our attention to examining
primary and secondary anilines 3 and 4 (Scheme 3).
H
H
OR
5
-endo-dig
pyrolidinium
ring-opening
R1
H
cyclization
N
R1
R1
O
nBu
EtOH, 180 °C
MWI, 10 h
EtOH, 180 °C
MWI, 10 h
N
nBu
ROH, 140 °C
N
RO
nBu
nBu
nBu
R
MWI, time
OR
N
H
R = H
N
H
R = Me
N
N
H
NH2
1
u R= Bu
I
2u (R= Et, R1 = Bu, 10 h, 85%)
2
3
4
: R = H
: R = Me
6
(43%)
5 (45%)
2o (80%)
5 (9%)
1v R = Ph
v (R = Me, R1 = Ph, 25 h, 71%)
Scheme 3. Reactions of anilines 3 and 4 in hot EtOH under MWI.
Scheme 6. Synthesis of indoles 2u,v and possible mechanism.
J. Name., 2013, 00, 1-3 | 3
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COMMUNICATION
Journal Name
When 1u,v were heated in EtOH or MeOH under MWI, we were very full pathway could be calculated. It can be seen tVhieawtAtrthicele Oranltinee-
pleased to observe the formation of 2u and 2v demonstrating the determining step is the first one in all caseDs.OTI:h1e0.l1o0w39e/sCt9bGaCr0ri1e8r8f0oHr
fundamental role of MeOH or EtOH in the last alkylation/dealkylation this first step is 24.4 kcal/mol. It corresponds to a cluster of 4 MeOH.
steps (demethylation in the case of dimethylanilines). A possible Clearly, the formation of a network of H-bonded molecules has a
reaction mechanism is proposed in Scheme 6. First, the nitrogen positive impact on the cyclization, but the effect is not linear as the
atom of the pyrrolidine reacts with the triple bond (possibly activated barrier increases with n > 4. Focusing on n = 4, the cyclization step is
by EtOH) according to a 5-endo-dig cyclization to give intermediate I. endergonic by 18.5 kcal/mol (Scheme 8). The next step, the proton
Then, EtOH as solvent or possibly an ethanolate species generated transfer connecting B4 to C4, is achieved through a transition state
during the cyclization process reacts on one of the methylene groups that has a lower energy than B4. This unusual situation is typical of
close to the ammonium center by SN
intermediate to promote 2u,v.
2
to open the pyrrolidinium what is referred to as a collapse mechanism and means that B4 is a
very unstable intermediate, which, if it exists, is immediately
transformed into C4. This species is less stable than A4 by 3.6
Density functional theory (DFT) calculations were carried out to
understand the origin of the activation of the substrates under the
reaction conditions. The above experiments having put aside the
intervention of radical species, the main issue to address was the
feasibility of an ionic mechanism triggered by just the solvent. The
kcal/mol. What funnels the reaction towards the final product is the
dealkylation step. The corresponding transition state TSC4D4, lies 20.2
kcal/mol above A4. This step is strongly exergonic, D4 being located
at -35.2 kcal/mol on the free energy surface. Overall, the calculated
free energies of activation are realistic with regard to the
experimental conditions and the reaction is a highly favorable
process. The free energy profile and the geometry of the
intermediates and transition states with n = 4 are displayed in
Scheme 8. The MeOH molecule that donates its proton to the vinyl
anion does not become the methanolate of the cluster. It is
simultaneously reprotonated by the nearby MeOH molecule, which
is in turn reprotonated by the third one. The proton transfer stops
here, leaving the third molecule of the cluster as a doubly H-bonded
1
8
Gaussian 09 software package was used for the calculations. Gas
1
9
phase geometry optimization was carried out at the M06-2X /6-
2
0
3
1G(d,p) level of theory with the grid=ultrafine keyword.
TSAnBn
TSCnDn
Bn
TSBnCn
Me
Me
O
H
O
H
Me
N
Me
O
H
n-1
O
H
n-1
Cn
0
.0
Me
O
H
2
methanolate. The SN step could not be achieved from this
Me
O
n-1
N
An
H
N
methanolate but from the less hindered tail MeOH, which is
simultaneously deprotonated by the methanolate. Looking at higher
clusters in Table 3 (n = 5, 6), similar characteristics can be drawn,
notably regarding the instability of Bn and its straightforward
collapse to Cn. However, the n = 4 case appears to be the best
compromise in terms of free energy for the entire process. This does
Dn
H
Me
4
not mean that only linear (MeOH) clusters are active species in
O
H
N
solution for this reaction, but the feasibility of an ionic mechanism
based on the simple activation of the substrate by methanol
aggregates is validated by these computations.
n-1
O
Me
Scheme 7. Computed Steps.
Correction to the Gibbs free energy was computed at 393.15 K. The
values presented include solvent correction obtained with the PCM21
Conclusions
solvation model for methanol. This solvent was chosen rather than In summary, a variety of 2-substituted indoles 2 were prepared in
EtOH to save computer time, as it provides similar experimental high yields from the annulation/demethylation process of 2-
results. The model substrate is presented in Scheme 7. Its cyclization alkynyldimethylanilines. A simple heating of these compounds
was studied in the presence of H-bonded methanol clusters (MeOH)
of various sizes (n = 1-6). Linear clusters were privileged to be able various N-methylindoles with high yields. This approach, which does
n
readily accessible in EtOH allowed rapid and efficient access to
2
2
to bridge the reactive sites. We found three steps starting from the not require metal catalysts or additives, and which is applicable to
molecular system An comprising the substrate and (MeOH)
optimized together: i) a 5-endo-dig cyclization yielding the vinyl anion perfect harmony with the requirements of modern environmentally
ammonium species Bn, ii) a proton transfer from the (MeOH) cluster friendly chemistry.
to the vinyl anion center to give the H-bonded methylate/ammonium
n
different types of alkynes bearing various functional groups, is in
n
species Cn, and iii) SN
Dn.
2
reaction to give the final dealkylated product
Conflicts of interest
There are no conflicts to declare.
The relative free energies of the computed intermediates and
transition states are collected in Table 3 as a function of n, taking An
as a reference. With only one MeOH molecule (n = 1), the cyclization
Acknowledgments
of A1 into B1 requires a high free energy of activation of 29.9 Authors gratefully acknowledge support of this project by CNRS, Univ.
kcal/mol and is markedly endergonic by 27.2 kcal/mol. No other Paris-Sud, and by La Ligue Nationale Contre le Cancer through an
steps could be computed. With n = 2, the first barrier is 26.4 kcal/mol, Equipe Labellisée 2014 grant. Guangkuan Zhao thank the Chinese
which is significantly lower than with n = 1. The cyclization is Scholarship Council for Ph.D. fundings. Our laboratory is a member
endergonic by 23.4 kcal/mol. The deprotonation step could not be of the laboratory of excellence LERMIT supported by a grant from
computed. The SN step was achieved through a transition state lying ANR (ANR-10-LABX-33).
2
at 26.9 kcal/mol above A2. Product D2 is obtained in a strongly
exergonic fashion, as it lies 38.7 kcal/mol below A2. With n = 3-6, the
4
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DOI: 10.1039/C9GC01880H
COMMUNICATION
Table 3. Free energies (G393, kcal/mol) of the computed species shown in Scheme 7.
n
1
2
3
4
5
6
TSAnBn
29.9
26.4
26.0
24.4
28.3
27.5
Bn
TSBnCn
-
-
14.8
15.1
18.2
16.3
Cn
-
16.7
8.1
3.6
3.0
1.7
TSCnDn
-
26.9
24.1
20.2
19.9
22.9
Dn
-
-38.7
-39.2
-35.2
-31.5
-28.6
27.2
23.4
20.0
18.5
20.8
19.5
TSA4B4
4.4
TSC4D4
0.2
2
2
TSB4C4
18.5
15.1
3.6
0.0
B4
C4
A4
-35.2
D4
Scheme 8. Free energy profile (G393, kcal/mol) for n = 4; Geometry of the intermediates and transition states (distances in Å)
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Please Gd roe en no tC ha ed mj u iss tt r my argins
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5 Achieving these cyclization reactions under an argon
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| J. Name., 2012, 00, 1-3
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Green Chemistry
View Article Online
DOI: 10.1039/C9GC01880H
2
2
-Alkynyldimethylanilines Cyclization: A Metal and Additive-free Access to
-Substituted Indoles
Guangkuan Zhao, Christelle Roudaut, Vincent Gandon, Mouad Alami, Olivier Provot
EtOH is the ideal reagent to transform with high yields 2-alkynyldimethylanilines into 2-substituted
indoles without the need of metal catalysts or additives.
R
H
EtOH, 120 °C
MWI
R1
R
R1
Me
N
X
N
X
Me
Me
Metal- and additive-free process
5
-endo-dig annulation
dealkylation reaction
high yields, 23 exemples
R = styryl, vinylchloride, acrylate, Ar, HetAr, Alk, H,...