Synthesis of α-Aminocyclopropyl Ketones and 2-Substituted Benzoimidazoles from 2-Hydroxycyclobutanones and Aryl Amines

Article abstract of DOI:10.1002/adsc.202000541

We have developed one-step protocols for the preparation of a large selection of α-aminocyclopropyl ketones or benzo[d]imidazoles, by reacting 2-substituted-2-hydroxycyclobutanones with aryl amines or o-phenylenediamines, respectively. In most case the reactions proceed at room temperature and are catalyst-free. The formation of benzo[d]imidazoles is rationalized in terms of an unusual ring-closure/ring-fission process followed by aromatization. (Figure presented.).

Full text of DOI:10.1002/adsc.202000541

Title: Synthesis of α‐Aminocyclopropyl ketones and 2-Substituted
benzoimidazoles from 2-Hydroxycyclobutanones and Aryl
Amines
Authors: Lorenzo Serusi, Francesco Soddu, Federico Cuccu,
Giuseppe Peretti, Alberto Luridiana, Francesco Secci,
Pierluigi Caboni, David J. Aitken, and Angelo Frongia
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000541
Link to VoR: https://doi.org/10.1002/adsc.202000541

Advanced Synthesis & Catalysis
10.1002/adsc.202000541
UPDATE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Synthesis of α‐ Aminocyclopropyl ketones and 2-Substituted
benzoimidazoles from 2-Hydroxycyclobutanones and Aryl
Amines
a
a
a
a
Lorenzo Serusi, Francesco Soddu, Federico Cuccu, Giuseppe Peretti, Alberto
a
a
b
c
a
Luridiana, Francesco Secci, Pierluigi Caboni, David J. Aitken and Angelo Frongia *
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
Dipartimento di Scienze della Vita e dell’Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124,
b
Cagliari, Italy.
c
Université Paris Saclay, CNRS, ICMMO, CP3A Organic Synthesis Group, Bât 420, rue du Doyen Georges Poitou,
9
1405 Orsay cedex, France.
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. We have developed one-step protocols for
the preparation of large selection of α-
provides an unexpected new synthetic entry to
benzo[d]imidazoles 5.
a
aminocyclopropyl ketones or benzo[d]imidazoles, by
reacting 2-substituted-2-hydroxycyclobutanones with
aryl amines or o-phenylenediamines, respectively. In
most case the reactions proceed at room temperature
and
are
catalyst-free.
The
formation
of
benzo[d]imidazoles is rationalized in terms of an
unusual ring-closure/ring-fission process followed by
aromatization.
Keywords: carbocycles; nitrogen heterocycles;
ketones; rearrangement reactions; synthetic methods
Cyclopropylamines are a very important class of
organic molecules and a large number of synthetic
[1,2]
methods have been proposed for their synthesis.
Within this family, α-aminocyclopropyl ketones are
much less developed. One recent method for the
construction of such compounds involves the reaction
of α-arylamino ketones and vinyl sulfonium salts in
the presence of DBU,[ while more traditional
3]
[4]
approaches require multistep procedures (Scheme
Scheme 1. Literature methods for the synthesis of α-
aminocyclopropyl ketones (top). The new approach
developed in this work for the synthesis of these
compounds 3 and of benzo[d]imidazoles 5 (bottom).
1
). In the pursuit of our investigations of the reactions
[5,6]
of 2-hydroxycyclobutanone with amines,
we
envisaged that the condensation of a 2-substituted-2-
hydroxycyclobutanone 1 with an aniline might
provide an attractive route to α-aminocyclopropyl
ketones 3, taking advantage of the α-iminol
We began our studies with the benchmark reaction
rearrangement[
7]
of a transient 2-substituted-2-
between
equimolar
amounts
of
2-ethyl-2-
hydroxycyclobutyl imine A (Scheme 1). Herein we
describe the successful development of this procedure
and also disclose the discovery that the use of an o-
phenylenediamine 4 as the aryl amine partner
hydroxycyclobutanone 1a and aniline 2a, which
gratifyingly afforded α‐ aminocyclopropyl ketone 3a
in 81% yield after 2 days at room temperature in
toluene (Scheme 2). We retained these mild
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000541
conditions as standard for subsequent investigations
of the reaction scope.
(2b-g), phenyl (2h), alkoxy (2i-j), alkylthio (2k) and
phenoxy (2l), to give the corresponding products 3b-l
(
57-85% yield). Reactions with para-substituted
anilines bearing halogens (2m-o) or electron-
withdrawing groups, such as nitro (2p),
methoxycarbonyl (2q) and cyano (2r), required a
higher reaction temperature (50 °C) but otherwise
proceeded equally well to give the adducts 3m-r (60-
8
8% yield). Alkyl substituents in other positions on
the aniline (2s-u) were well tolerated and provided
the derivatives 3s-u as anticipated (67-87% yield),
while the reaction with m-(trifluoromethyl)aniline
(
2v) required heating (50 °C) to furnish 3v (68%
yield). The reaction of 1-naphthyl amine (2w) also
provided the corresponding product 3w efficiently
(
80% yield).
We next examined the scope of the reaction using
a selection of substituted 2-hydroxycyclobutanones.
As we had hoped, both the 2-methyl and 2-phenyl
derivatives 1b and 1c reacted smoothly with aniline
2
a to deliver the functionalized α‐ aminocyclopropyl
ketones 3x and 3y in good yields (71-72%). More
highly-substituted 2-hydroxycyclobutanones are not
easy substrates to work with since they can exist in
[8]
solution as an equilibrium mixture of regioisomers;
we prepared and studied compound samples 1d/1d'
and 1e/1e' as shown in Scheme 3. We were pleased to
note that the sterically-challenged trimethylated 2-
hydroxycyclobutanone mixture 1d/1d' reacted
successfully with aniline 2a in the standard
conditions to provide 3z as a single compound in
5
8% yield, while regioisomeric mixture 1e/1e' gave
3
aa/3aa' with no diastereoselectivity but in a
satisfying 85% yield. Substrates 1f and 1g were also
employed successfully to give 3ab/3ab' and 3ac/3ac'
in lower chemical yields but with good to excellent
diastereoselectivity. To illustrate the usefulness of
this protocol, the reaction between 1a and 2a was
also conducted on a larger scale (5 mmol) to provide
3a without erosion of the yield (82%; 776 mg).
Scheme 2. Substrate scope in the synthesis of α‐
aminocyclopropyl ketones 3. Reaction conditions: 1 (0.438
mmol), 2 (0.438 mmol), toluene (0.5 mL). Isolated yield
are given. [ See Scheme 3 for substrate composition.
a]
[b]
[
c]
Performed using 5 mmol of 1 and 2.
Reactions were
[
d]
1
performed at 50 °C.
NMR analysis of the crude mixture.
configurations (cis/trans) of diastereoisomers could not be
unambiguously assigned by NOESY experiments (see ESI). Scheme 3. Highly-substituted 2-hydroxycyclobutanones
No dimerization by-products were found in the reaction
mixture.
The d. r. was determined by H
[
e]
The relative
[
f]
1d/1d'-1g used in this work.
Returning to 1a as the representative 2-
hydroxycyclobutanone, we further explored the
reaction scope using other amine partners. The
aliphatic amines benzylamine (2x) and phenylalanine
benzyl ester (2y) both reacted smoothly with 1a in
standard conditions, to provide the corresponding α‐
A wide selection of para-substituted anilines 2b-r
reacted with cyclobutanone 1a to give the desired
products 3b-r in moderate to high yields. The
transformation was successful using anilines bearing
electron-releasing functional groups, including alkyl
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000541
aminocyclopropyl ketones 3ad and 3ae with
moderate (47%) and good (81%) chemical yields,
respectively. The reactions of 1a with the secondary
aryl amines N-methylaniline (2z), diphenylamine
giving the desired product 5p in good yield (75%),
but the 2-phenyl derivative 1c gave a complex
mixture from which 5q could not be isolated.
Reaction with 1d and 1e afforded the corresponding
regioisomeric benzo[d]imidazole mixtures 5r/5r' and
5s/5s' with moderate yields (46-53%).
In an effort to access the imidazo[4,5-c]pyridine
ring system we examined the reaction between 1a
and 3,4-diaminopyridine 4p. In the standard reaction
conditions however, the target compound 5t was not
isolated; only starting materials were recovered from
the reaction mixture.
(
2aa) and carbazole (2ab) were more sluggish;
nevertheless these substrates were converted into the
corresponding α‐ aminocyclopropyl ketones 3af-ah
in acceptable yields (34-38%).
It was during the course of these studies with
alternative amine partners that we made an important
discovery. The reaction of 1a with o-
phenylenediamine 4a in standard conditions did not
produce an α‐ aminocyclopropyl ketone; instead, 2-
Finally, to illustrate the usefulness of the
methodology, the reaction between 1a and 4a was
conducted on a larger scale (4.7 mmol) to provide
adduct 5a in a slightly lower yield (71%; 671 mg).
(
3-oxopentyl)benzo[d]imidazole 5a was obtained in
7% yield. Benzo[d]imidazoles are an important
family of heterocycles and a number of synthetic
7
[9]
routes thereto have been developed. However, there
are very few reports of direct and efficient syntheses
of 2-(oxoalkyl)benzo[d]imidazoles (Scheme 4). The
most straightforward method, condensation of o-
phenylenediamine with 4-oxopentanoic acid, requires
strong acid conditions and high temperature. More
recent approaches employ an elegant metal catalyzed
cyclopropanol-Minisci reaction of the parent
heterocycle.[ Since our standard conditions are mild
and catalyst-free, we decided to apply them to
develop a new synthesis of these compounds.
[10]
11]
Scheme 4. Literature methods for the synthesis of 2-
(
oxoalkyl)benzo[d]imidazoles.
In the event, a wide variety of substituted o-
phenylenediamines 4 reacted with equimolar amounts
of cyclobutanone 1a to give the desired products
(
Scheme
5).
Six
ring-substituted
o-
phenylenediamines 4b-g were examined. The 4-
methyl (4b), 3-methyl (4c), 4-chloro (4d) and 4-
bromo (4e) derivatives provided the corresponding
benzo[d]imidazoles 5b-e in decent yields (55-66%).
For substrates bearing strong electron withdrawing
groups, 4-nitro (4f) or 4-cyano (4g), the presence of
an acid catalyst (TsOH, 20 mol%) was required to
achieve good conversions and provide the requisite
benzo[d]imidazoles 5f-g (59-71% yields). A panel of
eight N-substituted o-phenylenediamines 4h-o,
bearing primary, secondary, unsaturated alkyl or aryl
N-substituents, were all compatible with the protocol
and reacted with 1a in standard conditions to furnish
Scheme 5. Substrate scope in the synthesis of
benzo[d]imidazoles 5. Reaction conditions: 1 (0.438
mmol), 4 (0.438 mmol), toluene (0.5 mL). Isolated yield
[
a]
[b]
are given. Performed using 4.7 mmol of 1a and 4a.
The reaction was carried out in the presence of TsOH (20
[
c]
mol%). Complex mixture.
We propose a tandem ring-closure/ring-fission
mechanism for the formation of benzo[d]imidazoles 5
the
corresponding
1,2-disubstituted
(
Scheme
6).
Condensation
of
the
2-
benzo[d]imidazoles 5h-o in moderate to high yields
hydroxycyclobutanone 1 and the o-phenylenediamine
gives the α-iminol A as expected. Attack of the
(
42-84%).
4
We probed the reaction scope further using more
vicinal nitrogen leads to intermediate B which
evolves by fission and release of ring strain to give C;
this latter is readily aromatized to give 5.
complex 2-hydroxycyclobutanones (Scheme 5). o-
Phenylenediamine 4a reacted efficiently with 1b
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000541
Processi Innovativi di Sintesi” is acknowledged. We acknowledge
the CeSAR (Centro Servizi Ricerca d'Ateneo) core facility of the
University of Cagliari and Dr. Sandrina Lampis for assistance
with the generation of NMR data.
Sch
eme
6
.
Pro
pose
d
mec
hani
sm
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(
SiO
designated
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compounds.
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refer
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7
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Advanced Synthesis & Catalysis
10.1002/adsc.202000541
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5
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Advanced Synthesis & Catalysis
10.1002/adsc.202000541
COMMUNICATION
Synthesis of α‐ Aminocyclopropyl ketones and
2
-Substituted benzoimidazoles from 2-
Hydroxycyclobutanones and Aryl Amines
Adv. Synth. Catal. Year, Volume, Page – Page
Lorenzo Serusi, Francesco Soddu, Federico Cuccu,
Giuseppe Peretti, Alberto Luridiana, Francesco
Secci, Pierluigi Caboni, David J. Aitken and
Angelo Frongia*
6
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