Keteniminium Salts as Key Intermediates for the Efficient Synthesis of 3-Amino-Indoles and -Benzofurans

Article abstract of DOI:10.1002/hlca.201900217

Herein, we describe a high yielding approach towards the synthesis of 3-amino-indoles and -benzofurans through 6π-electrocyclization. This was made possible by taking advantage of the high reactivity of keteniminium salts, formed in-situ by treating with triflic anhydride and 2-fluoropyridine amides bearing at the α-position either an aniline or a phenoxy moiety. These mild conditions, on top of furnishing rapidly the 3-aminobenzoheteroles, allow the tolerance of various functional groups. Control experiments were carried out to highlight that the keteniminium is, indeed, in most cases, the reactive intermediate and conformational preferences of such species were investigated through a DFT study.

Full text of DOI:10.1002/hlca.201900217

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chimica acta
Accepted Article
Title: Keteniminium Salts as Key Intermediates for the Efficient
Synthesis of 3-Amino-Indoles and -Benzofurans
Authors: Alain De Mesmaeker, Dylan Dagoneau, Amandine Kolleth,
Pierre Quinodoz, Gamze Tanriver, Saron Catak, Alexandre
Lumbroso, and Sarah Sulzer-Mossé
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HELVETICA
Keteniminium Salts as Key Intermediates for the Efficient Synthesis of
-Amino-Indoles and -Benzofurans
3
a
a
a
b
b
a
Dylan Dagoneau, Amandine Kolleth, Pierre Quinodoz, Gamze Tanriver, Saron Catak, Alexandre Lumbroso,
a
,a
Sarah Sulzer-Mossé and Alain De Mesmaeker*
a
Syngenta Crop Protection AG, Crop Protection Research, Research Chemistry, Schaffhauserstrasse 101, CH-4332, Switzerland, e-mail address:
alain.de_mesmaeker@syngenta.com
b
Bogazici University, Department of Chemistry, Bebek, 34342 Istanbul, Turkey
Herein, we describe a high yielding approach towards the synthesis of 3-amino-indoles and –benzofurans via 6-electrocylization. This was made possible
by taking advantage of the high reactivity of keteniminium salts, formed in-situ by treating with triflic anhydride and 2-fluoropyridine amides bearing at
the alpha position either an aniline or a phenoxy moiety. These mild conditions, on top of furnishing rapidly the 3-aminobenzoheteroles, allow the
tolerance of various functional groups. Control experiments were carried out to highlight that the keteniminium is, indeed, in most cases the reactive
intermediate and conformational preferences of such species were investigated via a DFT study.
Keywords: Aminoindole • Aminobenzofuran • Keteniminium • Electrocyclization
In the literature, the synthesis of 3-amino-indoles and -benzofurans
Introduction
is achieved following three main strategies. The first one is the
3
-aminoindoles is a rare motif present in nature[1-4] and none of its
benzofuran analogues were isolated to the best of our knowledge (Figure
). However, both scaffolds are found in synthetic compounds showing
functionalization of the naked benzoheterole via either direct amination[14-
16]
or a nitr(os)ation / reduction sequence. [5, 17] The second is the generation
1
of the heterocyclic core followed by in-situ amination of the latter[18,19] and
attractive properties in various areas. For example, 3-aminoindole is the
core of antiviral compounds against hepatitis B virus[5] and of anti-
proliferative agents[6,7] and such anti-mitotic properties were also
observed with 3-aminobenzofuran based molecules.[8] Those benzofurans
are reported to be involved in potent ischemic cell death inhibitors[9] and
anti-microbiotics[10,11] as well as in selective fluorescent chemosensors of
the third is the one-step formation of the 3-aminobenzoheterole moiety.
In this last approach, the main reaction reported is a Thorpe-Ziegler
cyclization[6-11, 20-23] or variants[24-28] and actually only a few other methods
exist.[29-35]
Zn2+ and CN ions.
-
[12,13]
Scheme 1. General approach towards the synthesis of 3-amino(benzo)heteroles
using the keteniminium chemistry
Based on our previous work on the direct formation of 3-
amino(benzo)thiophenes C from easily accessible thioacetamides A,[41-43]
through
a 6π-electrocyclization involving a
keteniminium[36-40] salt
intermediate B, we are pleased to report herein the expansion of this
method towards the facile synthesis of 3-aminoindoles and 3-
aminobenzofurans E (Scheme 1).[44-45]
Figure 1. Examples of natural and synthetic 3-aminobenzoheteroles
1
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manner, such as halogens, ester, cyano or nitro, which would allow further
functionalization of the 3-aminoindoles (2g to 2l). Having those
substituents in para- or meta-positions of the aniline proved to be a non-
limiting factor and even large ortho-substituent (2f) could be inserted,
albeit in moderate yield.
Results and Discussion
3
-aminoindoles
We started our investigation with a simple N-piperidylamide 1a
bearing at the alpha position a N-methylaniline moiety. Using the
optimized conditions used previously for the sulfur series (1.1 equiv. of
triflic anhydride and 1.2 equiv. of 2-fluoropyridine at room temperature),
the expected 3-aminoindole was formed but incomplete conversion of the
starting materials was observed. This problem was simply overcome by
Of course, this methodology is not limited to the use of N-
piperidylamide derivatives. Indeed, acyclic N-substituted amides can be
used and, more importantly, mono- or di-allyl substituents on the nitrogen
are tolerated (2m and 2n) which would allow further deprotection of this
using an excess of reagents (3.3 equiv. of Tf
2
O and 3.6 equiv. of 2-FPyr)
nitrogen.[41,46,47]
and desired 2a was isolated in 80% yield.
Then, the substituent on the nitrogen of the aniline motif was
investigated and proved to be broader than expected, as shown in
Scheme 3. Indeed, this methodology is not limited to alkyl group such as
methyl, allyl or benzyl. A phenyl or even strong electron-withdrawing
groups like tosyl or nosyl could be tolerated, albeit the cyclization is
slightly slower in the two latter cases. We were also surprised to observe
formation, even in low yield, of the desired indole core 2w having a triflyl
substituent, one of the strongest electron-withdrawing group which
decreases dramatically the electron density on the nitrogen of the aniline.
Starting with a nosylated aniline, we could insert on the aromatic ring
strong electron-donating functionality such as methoxy (2y) that
otherwise would not be possible. Indeed, it was observed that, starting
from an N-methyl-paramethoxy aniline derivative, sulfonylation of the
aromatic core with triflic anhydride occurred. The decreased
nucleophilicity of the aniline caused by the nosyl prevents this side
reaction and the nosyl, being a very useful protective group, could be
replaced later with the desired substituent. Again, the N-piperidyl amide
could be replaced by diallyl-substituents and, combined with the
nosylated aniline, could afford the 3-aminoindole 2z bearing two nitrogens
with orthogonal protective groups.
Next, the goal was to extend the scope of this reaction and it proved
to be very general. As depicted in Scheme 2, high yields are obtained with
alkyl, benzyl, ester or even simple hydrogen substituents at the alpha
position of the amide, corresponding to the position 2 of the formed
indole (2a to 2d). The ester group, which activates the keteniminium
intermediate and stabilizes the final product by blocking the reactive
position 2 and by decreasing the electron density on the nitrogen (position
3), allows us to perform the reaction with electron rich or poor substituents
on the aromatic ring of the aniline (2i and 2o). In order to really determine
the limitation of this methodology, we decided not to carry out the
remaining scope with the help of this ester group but actually with the less
favorable substrates, being the unsubstituted alpha position of the amide.
By comparing the two indoles 2a and 2c, we can see a slight decrease of
the yield and it was previously observed that formation of 3-
aminobenzothiophene, unsubstituted at the position 2, was obtained also
in lower yield compared to the substituted ones.[41]
Even using the most challenging substrates, the reaction can still
tolerate electron-donating or withdrawing groups on the aromatic ring (2p
to 2r). Various functionalities can also be inserted in this ring in an efficient
Scheme 2. Access to 3-aminoindoles with variation of the substituents in -position to the amide and on the aromatic ring
2
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Scheme 3. Access to 3-aminoindoles with variation of the substituent on the aniline nitrogen
In the case of diarylamines, we wanted to study the influence of the
substituents in order to discriminate one of the two aromatic rings in the
cyclization reaction (Scheme 4). When the electronic effect is purely
inductive, such as a CF
preferentially into the cyclization step (ratio: 1.9/1.0), as expected.
However, when the CF was replaced by a nitro, which is supposedly more
3
group, the more electron-rich ring intervenes
3
electron-withdrawing, a closer ratio of 1.3/1.0 was obtained. This could be
explained by the ability of the nitro group to force the delocalization of the
lone pair of the aniline nitrogen into the nitroaromatic and putting it
preferentially in
electrocylization.
a coplanar conformation, better suited for the
Scheme 5. Access to polycyclic 3-aminoindoles
3
-aminobenzofurans
By replacing the aniline at the alpha position of the amide by a
Scheme 4. Competition reactions involving unsymmetrical diarylamines
phenoxy, like in substrate 5a, the expected 3-aminobenzofuran was
formed in high yield (69%). However, contrary to the 3-aminoindoles, the
unsubstituted (position 2) benzofuran 6e could not be formed in an
efficient manner at room temperature. Indeed, consumption of the
starting material 5e was very slow, even with an excess of reagents, and
the formation of the desired heterocycle occurred with various side
products. As depicted in Scheme 6, we assume that when R=H, the
favored conformation is I to avoid clash between the keteniminium and
the aromatic ring, therefore preventing the cyclization. On the contrary,
when R=Me, the conformer II would be preferred to avoid this time
interaction of the bulkier methyl group with the phenyl ring. In the case of
aminoindoles, the additional substituent on the nitrogen of the aniline
Finally, we were interested to know if we could form polycyclic
structures starting from an amide containing at the alpha position either a
tetrahydroquinoline or tetrahydrobenzoazepine core and this proved to be
the case (Scheme 5). With our methodology we could easily synthesize
tetrahydropyrido[1,7]indole as well as tetrahydroazepino[1,7]indole in very
good yields. It is noteworthy to mention that we could also access
efficiently tetrahydropyrido[1,2]indole 4e starting from
a
N(1)-
phenylpiperidine-2-carboxamide derivative.
3
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probably disturbs the conformer I and favors II, even when R=H. In the
computational rationalization section, we investigated the R substituent
effect on the favored conformations of the keteniminiums in Scheme 6.
With substrates 5m and 5q an interesting side reaction was
observed. Indeed, after short reaction time (2-3 hours) we could observe
and isolate a side product 7 possessing a pyridine moiety (Scheme 8). We
assume that the enamine intermediate ENA, which should afford
spontaneously the keteniminium KET, is too stabilized in those cases and
therefore favors a higher concentration of this species in the medium. The
enamine then interacts with the 2-fluoropyridinium salt in a S Ar reaction.
N
More interestingly, with longer reaction time (1-4 days), we could observe
complete conversion of this kinetic product 7 towards the desired
heterocycles 6 which means that the S Ar is actually reversible. This
N
reversibility is reasonable considering the high electrophilicity of the bis
positively charged intermediate INT presumably present in the reaction
mixture. Besides, in the case of 5m, when we replaced the 2-fluoropyridine
Scheme 6. Conformational considerations for the cyclization step
by the chloro analogue, we observed the same S Ar product 7m but
N
Despite this, the scope proved to be fairly broad and is detailed in
Scheme 7. On the position 2 of the 3-aminobenzofuran are tolerated
functionalizable alkyl chain, benzyl and even a phenyl group (6a to 6f),
which gave in the case of the nitrogen series complete decomposition of
the substrate. Heteroatoms such as alkylsulfide and sulfone can be
inserted in moderate to good yields and this is also the case with the
benzothiophene family (6p to 6r). The substrates bearing an ester group
either at the alpha position of the amide or directly on the phenoxy ring
give the corresponding 3-aminobenzofurans in excellent yields. Other
functions on the aromatic ring, such as halogens, nitrile, methylether and
nitro are again tolerated (6g to 6l). The latter function combined with the
N-diallylamide afford a 3-aminobenzofuran possessing two orthogonally
protected nitrogens. It is worth mentioning that the electronic effect of
the substituents and their position on the aromatic ring, even in ortho,
have hardly an influence on the isolation yields (6m to 6o).
further demethylation and decarboxylation of the ester moiety were also
detected. This supports the fact that nucleophilic halides are present in the
medium.
Control Experiments
We wanted to highlight that the cyclization step occurred indeed on
the keteniminium salt, and not on the iminium intermediate resulting
from the triflation of the amide. Previously, we demonstrated this by
carrying out the reaction in the absence of base.[41,43] Activation of the
amide by triflic anhydride would give rapidly the iminium IMI2 but without
the 2-fluoropyridine in the medium, the formation of the keteniminium
KET2 would occur very slowly (Table 1). By comparing the formation rates
of the product with or without base, we could determine which
intermediate is most likely the reactive one.
Scheme 7. General access to 3-aminobenzofurans
4
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Scheme 8. Proposed mechanism for the formation of side products 7
Table 1. Control experiments to highlight the formation of
a
Unfortunately, we cannot completely use this approach for the
indole series. Indeed, the starting materials bearing intrinsically a base,
the aniline, can take the role of the 2-fluoropyridine and help the
formation of the keteniminium salt. This was supported experimentally by
keteniminium salt intermediate
treating 1r exclusively with Tf O and which gave rapidly 50% of the 3-
2
aminoindole together with protonated starting aniline (entry 3). With
longer reaction time, we only observed slow decomposition of the
remaining starting materials. To overcome this issue, we replaced the
triflating reagent by the well-known amide activator POCl which cannot
3
formed efficiently a keteniminium due to the nucleophilic counter anion
chloride.[36,39,40] As expected, no aniline cyclization onto the iminium
intermediate was observed with or without base, even with higher
temperature and longer reaction time. Similarly to the benzofuran, when
electron-rich aniline was used (entry 4), partial cyclization was observed
Entry
X[a]
O
R1
R2
H
Reagent
Base
Time
2.5h
15h
2h
DP[b]
93
4
SM[b]
0
1 [
c]
a
CO
2
Me
Me
Tf
2
Tf
2
Tf
2
Tf
2
Tf
2
Tf
2
Tf
2
Tf
2
O
O
O
O
O
O
O
O
FPyr
1 [
c]
b
O
CO
2
H
/
94
0
2 [
2 [
2 [
a
d]
O
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
FPyr
92
42
67
73
51
52
0
d]
b
O
/
15h
72h
3h
54
31
d]
e]
c
O
/
with POCl , thus the Friedel-Crafts pathway involving IMI2 cannot again be
3
3 [
a
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
CF
3
CF
3
CF
3
CF
3
CF
3
FPyr
0
excluded in this case.[48] This was also supported by formation over 50% of
3 [
b
e]
/
4h
35
indole 2p by treating 1p exclusively with triflic anhydride.
3 [
c
e]
/
15h
20h
20h
2h
23
nd[g]
nd[g]
0
3 [
d
e],[f]
e],[f]
e]
POCl
POCl
FPyr
3
Competition Experiments
3 [
e
/
0
3
Next, we designed substrates in order to compare kinetically the
formation of the different aminobenzoheteroles, via 6-electrocyclization,
with the formation of cyclobutanones, obtained by intramolecular [2+2]
cycloaddition between an alkene and the keteniminium salt. Previously, in
the case of phenylsulfide, the [2+2] cycloaddition reaction was
predominant with short alkene chain (n=1 or 2) in order to form the
corresponding bicyclo[3.2.0]heptane or [4.2.0]octane systems. With
4 [
a
Me
Me
Me
Me
Me
Tf
2
Tf
2
Tf
2
O
FPyr
88
69
76
13
14
4 [
e]
b
O
O
/
4h
27
16
82
79
4 [
e]
c
/
FPyr
/
15h
15h
15h
4 [
d
e],[f]
e],[f]
POCl
3
4 [
e
POCl
3
[a]
[b]
[c]
[d]
5
5
[e]
[f]
When X=O, R =Me and when X=NMe, R =H
Yields in %
y=2.2 equiv.; z=2.4 equiv.
y=1.6 equiv.; z=1.8 equiv.
y=3.3 equiv.; z=3.6 equiv.
Reaction performed at 60°C
Non-determined
[g]
longer chain, the electrocyclization was the fastest pathway (Scheme
9 [
).
42]
In the case of benzofuran, and by starting with an electron-deficient
In the case of the phenyl ether, the [2+2] was still favored when n=1,
phenol (Table 1, entry 1), we could observe a dramatic decrease of the
product yield in the absence of base, despite a much longer reaction time.
This confirms that the keteniminium is required for the reaction to occur
efficiently. However, when an electron-rich phenol (entry 2) was employed,
we can see slow but decent conversion to the desired product. In this case,
the cyclization via a 6-electrocylization with the keteniminium KET2 is
probably the fastest pathway, but the competitive Friedel-Crafts addition
onto the iminium intermediate IMI2 cannot be excluded.
giving a mixture of two regioisomers,[43,49] but when n=2, no cycloadduct
was observed and the 3-aminobenzofuran was the only isolable product.
With the aniline derivative, in each case, no product arising from a [2+2]
cycloaddition was observed and only formation of the desired indoles,
together with an unexpected side ketoamide product, were isolated.
5
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Scheme 9. Intramolecular competition reactions between formation of 3-aminobenzoheteroles and [2+2] cycloadducts
aniline.[50] In our present case, the Friedel-Crafts was the fastest pathway
compared to the other processes, with isolation of the cyclic enone in 79%
yield, albeit a tiny amount of cycloadduct was observed in the reaction
mixture.[51]
Those observations are not surprising considering that the 6-
electrocyclization is dependent on the electron density of the aromatic
ring, with the aniline being electronically the richest and the thiophenol
the most deficient.
With these experiments, we can already deduce that formation of
the 3-aminoindoles are faster than the corresponding benzofurans and the
latter are faster than the benzothiophenes. However, we were interested
to confirm this by directly putting in competition the aniline, phenol and
thiophenol (Scheme 10). Unfortunately, substrates bearing at the alpha
position of the amide an aniline and either a phenol or thiophenol proved
to be unstable and decomposed under the reaction conditions.
Nonetheless, we were able to submit under the typical conditions the
substrate bearing both phenol and thiophenol and, as expected, the 3-
aminobenzofuran was the only product formed.
Scheme 11. Intramolecular competition between 6-electrocylization and Friedel-
Crafts reactions
Computational Rationalization
The conformational preferences of the R substituted keteniminium
intermediates (R=H, CH ) depicted in Scheme 6 were computationally
3
investigated in order to elucidate the R substituent’s effect on the
electrocyclization reaction. All optimizations were performed at the M06-
2X[52-53] / 6-31+G(d,p) [41-42,46-47,54] with IEF-PCM[55-56] in dichloromethane
Scheme 10. Attempts to compare directly the formation rates of the different 3-
aminoheteroles
) as implemented in Gaussian 16 (G16, Revision A.03)[57]. Energy
Cl
(
CH
2
2
refinements were carried out using double hybrid B2PLYP[58] functional in
order to accurately evaluate the relative Gibbs free energies. In case of
R=H, the computed data revealed that the relative Gibbs free energies of
the open I and closed II conformations are isoenergetic (Figure 2).
Structurally, C-C-O bond angle of the closed conformation II (124.8°,
Figure 2) is larger than a regular trigonal planar bond angle and the C-H-π
stacking distances (4.41 Å and 4.46 Å) are also quite large in the closed
conformer II, somewhat destabilizing this conformation. Moreover, a C-H-
π interaction (CH···π distance = 3.58 Å) contributes to the stabilization of
the open conformer I. Hence, the conformational equilibrium shifts
slightly towards the open conformation I. Conversely, for the methyl
substituent, the closed conformation II is energetically strongly preferred
Finally, we wanted to submit a substrate bearing a styrenic
diarylamine 17 as depicted in Scheme 11. Such scaffold, upon treatment
with triflic anhydride and 2-fluoropyridine, could produce in theory several
products. Indeed, formation of two different 3-aminoindoles (18, 19) could
occur, by reaction of each aromatic ring in a 6-electrocyclization, but not
only. Formation of a cyclobutanone 21 or a 7-membered cyclic enone 20,
arising respectively from a [2+2] cycloaddition or Friedel-Crafts reaction of
the styrenic double bond with the keteniminium salt, has to be considered.
It was demonstrated previously that the selectivity between these two
latter outcomes was dependent on the electron density of the starting
6
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over the open conformation I (ΔGrel=3.1 kcal/mol) favoring the formation
of the benzofuran derivative. The methyl group also sterically prevents the
rotation of the lowest energy conformer II to the open conformer I.
Conclusions
Herein we have reported an efficient and general route for the
synthesis of 3-amino-indoles and -benzofurans from easily accessible
acetamides, bearing respectively an aniline and a phenoxy group. The mild
reaction conditions allow the tolerance of a wide range of functional
groups and this method is not limited by the electronic or steric effect of
the aromatic substituents. We demonstrated that the reaction requires in
most cases a keteniminium salt intermediate to occur. However, it was
shown that the cyclization directly onto the iminium intermediate cannot
be neglected when electron-rich anilines or phenols were employed.
Competition experiments were also conducted in order to confirm the
ease of formation of the different 3-aminobenzoheteroles with indole
being the fastest and benzothiophene the slowest, with benzofuran in
between. Additionally, effect of R substituent on the conformational
preference of the keteniminiums and their propensity toward
electrocyclization were discussed via a DFT study.
Moreover, in Figure 3 non-covalent interactions (NCI) including C-H-π and
cation-π were also investigated using the NCIplot program.[59] Cation-π
interaction distances of the methyl substituted closed conformer II is
3.94Å whereas this distance for –H substituted conformer II is 4.02Å. This
is due to the more positive cation of the methyl substituted keteniminium,
the cation interacts with the quadrupole of phenyl more strongly and
stabilizes the closed conformation II leading to the formation of 3-
aminobenzofuran (6a) in the methyl substituted case. A full computational
study thoroughly investigating the factors (heteroatom, substituent effect,
etc.) influencing keteniminium electrocyclizations is currently underway.
Experimental Section
General Procedure for the Synthesis of 3-Aminoindoles 2 and 4
In a dried flask under argon charged with a solution of amide 1 or 3 (0.40-
0
.50 mmol, 1.0 equiv.) in CH
temperature 2-fluoropyridine (3.6 equiv.) and then, over a period of 20-
0 min, triflic anhydride (3.3 equiv.). The resulting mixture was stirred at
room temperature until complete consumption of the starting materials
from 2 h to 7 h). The reaction was then diluted with CH Cl , quenched
with a saturated aqueous solution of NaHCO until pH 8-9 and stirred
vigorously for 30 min at room temperature. The two layers were separated
and the aqueous phase was extracted with CH Cl (x2). The combined
organic layers were dried over Na SO , filtered and concentrated under
2
Cl
2
(c = 0.12 M) was added dropwise at room
3
(
2
2
Figure 2. Optimized structures and relative free energies of the Ket intermediates.
3
2 2
B2PLYP/6-31+G(d,p)//M06-2X/6-31+G(d,p) in CH Cl .
2
2
2
4
reduced pressure. Purification of the crude by flash column
chromatography on silica gel (Cyclohexane/EtOAc: from 95/5 to 70/30)
afforded desired 3-aminoindole 2 or 4.
General Procedure for the Synthesis of 3-Aminobenzofurans 6
In a dried flask under argon charged with a solution of amide 5 (0.50-
0
.60 mmol, 1.0 equiv.) in CH
temperature 2-fluoropyridine (1.2-2.4 equiv.) and then, over a period of
5-25 min, triflic anhydride (1.1-2.2 equiv.). The resulting mixture was
stirred at room temperature until complete consumption of the starting
materials (from 2 h to 6 h). The reaction was then diluted with CH Cl
quenched with a saturated aqueous solution of NaHCO until pH 8-9 and
stirred vigorously for 30 min at room temperature. The two layers were
separated and the aqueous phase was extracted with CH Cl (x2). The
combined organic layers were dried over Na SO filtered and
concentrated under reduced pressure. Purification of the crude by flash
2
Cl
2
(c = 0.12 M) was added dropwise at room
1
2
2
,
3
Figure 3. The non-covalent interaction (NCI) plots of the optimized structures. The
NCI isosurface value= 0.5 au using SCF densities.
2
2
2
4
,
7
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column chromatography on silica gel (Cyclohexane/EtOAc: from 95/5 to
[9]
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