Br?nsted acid Catalysed Synthesis of 3-(2-Alkoxyethyl)indoles from α-Arylaminocyclobutanones and Alcohols

Article abstract of DOI:10.1002/adsc.201900175

A new Br?nsted acid catalysed solvent-free cascade reaction consisting of a ring closure-ring fission process between α-arylaminocyclobutanones and alcohols has been established, providing highly functionalised 3-(2-alkoxyethyl)indoles in good to excellent yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201900175

Title: Brønsted acid catalysed synthesis of 3-(2-alkoxyethyl)indoles
from α‐arylaminocyclobutanones and alcohols
Authors: Lorenzo Serusi, Marie Bonnans, Alberto Luridiana, Francesco
Secci, Pierluigi Caboni, Thomas Boddaert, David J. Aitken,
and Angelo Frongia
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900175
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10.1002/adsc.201900175
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Brønsted acid catalysed synthesis of 3-(2-alkoxyethyl)indoles
from α‐ arylaminocyclobutanones and alcohols
Lorenzo Serusi,a Marie Bonnans,a,b Alberto Luridiana,a Francesco Secci,a Pierluigi
Caboni,c Thomas Boddaert,b David J. Aitkenb and Angelo Frongiaa*
a
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Complesso Universitario di
Monserrato, S.S. 554, Bivio per Sestu, I-09042, Monserrato, Cagliari, Italy.
Fax : (+ 39)-070-675-4388; phone: (+ 39)-070-675-4406; e-mail: afrongia@unica.it
CP3A Organic Synthesis Group, ICMMO, CNRS UMR 8182, Université Paris Sud, Université Paris Saclay, 15 rue
b
Georges Clemenceau, 91405 Orsay cedex, France.
Dipartimento di Scienze della Vita e dell’Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124,
c
Cagliari, Italy.
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))
arylaminocyclobutanone 2[11] with an alcohol 3 would
Abstract. A new Brønsted acid catalysed solvent-free
cascade reaction consisting of a ring closure–ring fission
process between α‐ arylaminocyclobutanones and
alcohols has been established, providing highly
functionalised 3-(2-alkoxyethyl)indoles in good to
excellent yields.
lead to oxonium ion B (via A) which would undergo
ring closure to give tricyclic intermediate C followed
by
an
acid-induced
‘‘depart-and-return’’
rearrangement process, via D, to provide the target
structure 1 directly (Scheme 1). We report here on the
successful achievement of this objective.
Keywords: alcohols; carbocycles; nitrogen heterocycles;
cascade reaction; synthetic methods
Functionalized indoles constitute an important class of
nitrogen heterocycles with widespread applications.[1]
These heterocycles are found in numerous natural
products possessing diverse biological activities[2] and
represent useful building blocks for the synthesis of
other nitrogen-containing heterocycles.[3] 3-(2-
Alkoxyethyl)indoles 1 are an important sub-group of
this family, serving as valuable intermediates for the
preparation of indole-fused polycyclic compounds,[4]
including therapeutics such as pemedolac[5] and
etodolac.[6] Classical methods for the synthesis of 3-(2-
alkoxyethyl)indoles usually require multistep
procedures – typically 4-5 steps starting from an
aniline or a phenylhydrazine – and harsh conditions.[7]
More efficient methods for their preparation from
readily available precursors are clearly desirable.
Recently,[8] we established Brønsted acid catalysed
cascade reactions allowing rapid access to diversely
substituted tryptamines from anilines in one-pot metal-
free processes employing α-hydroxycyclobutanone as
a key four-carbon synthon.[9,10]
Scheme 1. Proposed reaction sequence for the direct
synthesis of (2-alkoxyethyl)indoles 1.
We began our investigations by treating a solvent-free
mixture N-methyl-N-phenyl-α-aminocyclobutanone
2a and ethanol 3a, in a sealed tube, with a panel of
Brønsted acids (Table 1). In the presence of 20 mol%
p-toluenesulfonic acid (TsOH), the reaction barely
advanced over 2 days at room temperature or at 40 °C
(entries 1,2). Increasing the temperature to 60 °C was
propitious, however, providing 1a in 67% yield (entry
3) and at 80 °C the yield improved further to a very
satisfying 88% (entry 4). When other Brønsted acid
catalysts – HI, HBr, HCl, CF3COOH, MsOH and
(PhO)2POOH – were employed in the same conditions,
the yield of 1a decreased partially or substantially
(entries 5-10).
We felt that this unusual synthetic paradigm for the
construction of substituted indoles could be further
exploited to provide an expedient access to 3-(2-
alkoxyethyl)indoles 1. We envisaged that the acid-
mediated condensation of a readily available α‐
1
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10.1002/adsc.201900175
Advanced Synthesis & Catalysis
Interestingly, three by-products were detected in
variable amounts in these test reactions: a haloethyl
derivative 4, tryptamine 5a and N-methylaniline 6. The
formation of these compounds was rationalized in
terms of two reactions pathways which compete with
the proposed mechanism (Scheme 1) for the formation
of 1a. Under acidic conditions, the α‐
aminocyclobutanone 2a may decompose into N-
methyl aniline 6 and α‐ hydroxycyclobutanone 7
Having established the optimized conditions, the
broad scope of the reaction was then demonstrated
using a selection of alcohol substrates 3 in reaction
with 2a (Scheme 3). Under the standard conditions, all
reactions implicating a primary alcohol 3a-j were
successful, highlighting the broad generality of this
protocol: good-to-excellent product selectivity (1:5a
ratio from 79:21 to >99:1) was observed, leading to
good-to-high isolated chemical yields (52-85%) of
derivatives 1a-j. Propargylic alcohol 3k also
participated in the reaction, albeit less efficiently, to
provide indole 1k (28% yield; 1k:5a ratio 37:63). The
reaction also worked well with secondary alcohols 3l
and 3m, giving 1l (82% yield; 1l:5a ratio > 99:1) and
1m (51% yield; 3m:5a ratio 82:18) respectively. Even
the sterically congested tert-butyl alcohol 3n reacted
to afford the corresponding indole 1n (58% yield;
1n:5a ratio 65:35).
following
a
known equilibration;[8] subsequent
condensation between 6 and a second equivalent of 2a
followed by the tandem ring closure-ring fission
process[8] would lead to 5a (Scheme 2). The formation
of 4 was only significant for the halogen acids, whose
conjugate bases have more nucleophilic character than
the other acids investigated. For this reason,
competition may exists for the “return” part of the
depart-and-return mechanism, whereby halide anion
adds to intermediate C, leading to 4 instead of 1a
(Scheme 2).
Table 1. Screening of a panel of Brønsted acids.[a]
En
try
1
HX
T
1a
4
5a
(%)b
6
6
2a
(°C)
R.
T.
(%) b
1
(%)b
0
(%)b ( (%)b
TsOH
0
93
2
3
4
5
6
7
8
9
TsOH
TsOH
TsOH
HI
HBr
HCl
CF3COOH
MsOH
(PhO)2POOH
40
60
80
80
80
80
80
80
80
3
67
0
0
0
14
9
28
1
0
6
23
3
30
37
49
12
0
0
0
9
0
2
6
2
41
0
91
10
0
4
8
9
8
9
4
88(79)c
52
44
8
77
50
10
[a]
43
0
53
Scheme 3. Substrate scope for alcohols. Reaction
conditions: 2a (0.571 mmol), alcohol 3 (1 mL), TsOH
(0.114 mmol). Isolated yields for 1 are given. The 1:5a ratio
was determined by GC-MS.
Reaction conditions: 2a (0.571 mmol), 3a (1 mL), HX
(0.114 mmol). [b] Determined by GC-MS. [c] Isolated yield.
Next, the scope of the reaction was probed using
different N-alkyl-N-aryl-α‐ aminocyclobutanones 2 in
reaction with allyl alcohol 3g. N-methyl substrates 2o-
q, whose N-aryl group bore an electron-donating
group at the para position, performed well and
furnished the corresponding 3-(2-allyloxyethyl)-1-
methylindoles 3o-q in 65-79% yield (3:5 ratio from
71:29 to >99:1). Substrate 2r, bearing a p-
chlorophenyl group, was also transformed
successfully into 1r (74% yield; 31r:5e ratio 92:8),
although the substrate with a p-cyanophenyl group, 1u,
failed to react. The meta substituted substrate 2s gave
a mixture of the two regioisomers 3s and 3's (r.r. =
91:9) in a moderate 44% yield (2s+2's):5g ratio 85:15).
The reaction also succeeded with substrate 2t, bearing
Scheme 2. Proposed competing pathways leading to the
formation of 5a and 4.
2
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10.1002/adsc.201900175
Advanced Synthesis & Catalysis
a substituent at the ortho position, to provide indole 1t
in 39% yield (1t:5h ratio=95:5).
Other N-alkyl-N-aryl-α‐ aminocyclobutanones were
examined: substrates 2v-y, with N-ethyl, hexyl, benzyl
and phenyl substituents, respectively, were all
transformed efficiently into the corresponding indoles
1v-y, in 66-76% yield (3:5 ratio from 79:21 to >99:1).
Substrate 2z, a tetrahydroquinoline derivative, also
participated in the reaction to furnish the tricyclic
product 1z in 44% yield (1z:5l ratio 94:6). Moreover,
N-ethyl-N-(α-naphthyl)-α-aminocyclobutanone 2za
was transformed into the 1H-benz[g]indole derivative
1za in a respectable 53% yield (1za:5m ratio 99:1).
Scheme 5. Two-step reaction sequence for the synthesis of
NH indoles 7.
In all of the 3-(2-alkoxyethyl)indole libraries
described above, the alkoxy moiety was provided in
the form of an alcohol. We examined the scope of the
reaction protocol further by considering the TsOH-
mediated reaction of 2a with two other types of
nucleophile (Scheme 5). Pleasingly, the reaction with
thiophenol 3' provided the requisite phenylthioethyl
derivative product 8 in good yield (74%). On the other
hand, the reaction with p-methoxyphenol 3'' gave a
low yield (16%) of the p-methoxyphenoxy derivative
9 and a significant amount of the tryptamine 5a was
formed via the competitive reaction. The lower
nucleophilicity of 3'' may explain the reactivity
erosion.
Scheme 4. Substrate scope for α‐ aminocyclobutanones.
Reaction conditions: 2 (0.571 mmol), allylic alcohol 3g (1
mL), TsOH (0.114 mmol). Isolated yields for 1 are given.
The 1:5 ratio was determined by GC-MS.
The methodology was conveniently adapted to provide
a viable synthesis of NH indoles in only two steps
(Scheme 5).[12] A selection of primary (3a, 3b, 3f) and
secondary (3l) alcohol substrates were reacted with N-
benzyl-N-phenyl--aminocyclobutanone 2k in the
standard conditions to provide N-benzyl-3-(2-
alkoxyethyl)indoles 1zb-ze in high yields (75-80%).
Competition from the formation of tryptamine 5f was
minimal. Selective debenzylation of each derivative
1zb-ze was achieved via Birch reduction, through
treatment with sodium and ammonia in THF at –50 °C,
leading smoothly to the target NH indoles 7a-d in good
to high chemical yields (75-90%). Birch reduction of
3-(2-allyloxyethyl)-1-benzylindole 1x gave 7e in a
lower yield (50%) due to a competing deallylation
reaction, testified by the concomitant formation of 1H-
indole-3-ethanol 7f (22% yield).
Scheme 6. Synthesis of indoles 8 and 9. A small amount of
toluene was added to reduce the viscosity of the reaction
mixture.
3-(2-Halogenoethyl)indoles are widely used in organic
synthesis,[13] so we returned to the formation of
compounds 4 from the reaction of 2a and 3a in the
presence of halogen acids (Table 1). It appeared
plausible that by increasing the amount of acid reagent
and removing the alcohol, this process might provide
a convenient access to compounds such as 4. To
examine this hypothesis, 2a was treated with 80 mol%
of each of the acids HI, HBr and HCl. Gratifyingly, the
3
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10.1002/adsc.201900175
Advanced Synthesis & Catalysis
alcohol of choice (1 mL) was stirred in a sealed tube reactor
at 80 °C for 48h. The crude mixture, without aqueous
work‐ up, was directly purified by flash column
chromatography (SiO2, petroleum ether/ether = 10:1→1:1)
to give compound 1.
corresponding 2-halogenoethyl derivatives 4a-c were
obtained in moderate-to-good yields (40-71%;
Scheme 7). This procedure also provided access to 2-
(1-methyl-3-indolyl)ethyl trifluoroacetate 4d (59%
yield). The reactions of TsOH and MsOH failed to
produce the corresponding sulphonate esters; the only
products obtained were tryptamine 5a and N-methyl
aniline 6.
General procedure for the preparation of indoles 4: A
solution of 2a (0.571 mmol) and the acid (0.456 mmol) in
toluene (0.7 mL) was stirred in a sealed tube reactor at 80 °C
for 48 h. The resulting reaction mixture was concentrated in
a vacuum, diluted with ethyl acetate and washed with
saturated NaHCO3 aqueous solution. The organic layer was
dried over anhydrous Na2SO4, filtered and concentrated to
give the crude product 4 which was purified by column
chromatography (SiO2, petroleum ether/ether = 10:1→1:1).
General procedure for the preparation of indoles 7: A
solution of N-benzylindole 1 (0.24 mmol) in THF (2 mL)
was added dropwise to a mixture of THF (2 mL) and
ammonia (3 mL) containing sodium (1.4 mmol) at –78 °C.
The mixture was stirred at –50 °C for 4 h then cooled again
to –78 °C and quenched by addition of saturated aqueous
NH4Cl solution. The solvent was evaporated under reduced
pressure, water was added and the mixture was extracted
with ether. Combined organic layers were dried over
anhydrous Na2SO4, filtered and concentrated. The residue
was purified by column chromatography (SiO2, petroleum
ether/ether = 10:1→1:1) to give indole 7.
Scheme 7. Substrate scope of indoles 4. Reaction
conditions: 2a (0.571 mmol), toluene (0.7 mL), HX (0.457
mmol). Isolated yield for 4 are given. The 4:5a ratio
determined by GC-MS. A small amount of toluene was
added to reduce the viscosity of the reaction mixture.
General procedure for the preparation of indoles 8 and
9: A solution of 2a (0.571 mmol), TsOH (0.114 mmol) and
thiophenol 3’ or para-methoxy phenol 3’’ (0.856 mmol) in
toluene (0.7 mL) was stirred in a sealed tube reactor at 80 °C
for 48 h. The crude mixture, without aqueous work‐ up, was
directly purified by flash column chromatography (SiO2,
petroleum ether/ether = 10:1→1:1) to give compound 8 or
9. Yields refer to chromatographically pure materials.
Finally, to demonstrate the synthetic utility of this
protocol, 4a was prepared as above from 2a and HI and
was reacted directly with p-methoxyaniline 3''' to
furnish the tryptamine derivative 10 in good yield
(69% for two steps; Scheme 8).
Acknowledgements
Financial support from the MIUR, Rome, by the University of
Cagliari (FIR 2016-FIR 2017) and from Regione Autonoma della
Sardegna (Progetti Biennali di Ateneo Annualità 2016) and
Fondazione Banco di Sardegna is acknowledged.
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Scheme 8. A two-step preparation of tryptamine 10.
In summary, we have developed a rapid and efficient
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Brønsted acid catalysed cascade reaction of α‐
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4
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10.1002/adsc.201900175
Advanced Synthesis & Catalysis
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the
requisite
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or
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with
α-
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ether derivative; this chemistry is restricted principally
to secondary anilines and does not work satisfactorily
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5
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Advanced Synthesis & Catalysis
UPDATE
Brønsted acid catalysed synthesis of 3-(2-
alkoxyethyl)indoles from α‐
arylaminocyclobutanones and alcohols
Adv. Synth. Catal. Year, Volume, Page – Page
Lorenzo Serusi, Marie Bonnans, Alberto Luridiana,
Francesco Secci, Pierluigi Caboni, Thomas
Boddaert, David J. Aitken and Angelo Frongia*
6
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