Efficient catalyst-free four-component synthesis of novel γ-aminoethers mediated by a mannich type reaction

Article abstract of DOI:10.1021/co300105t

Herein, it is provided an efficient and one-pot procedure for the synthesis of novel and diversely substituted γ-aminoethers in good yields through a four-component process by treatment of benzylamines with polyformaldehyde and activated alkenes in alipha

Full text of DOI:10.1021/co300105t

Research Article
pubs.acs.org/acscombsci
Efficient Catalyst-Free Four-Component Synthesis of Novel
γ‑Aminoethers Mediated by a Mannich Type Reaction
Rodrigo Abonia,*,† Juan Castillo,† Braulio Insuasty,† Jairo Quiroga,† Manuel Nogueras,‡ and Justo Cobo‡
†Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia
‡Department of Inorganic and Organic Chemistry, Universidad de Jaen
́ ́
, 23071 Jaen, Spain
S
* Supporting Information
ABSTRACT: Herein, it is provided an efficient and one-pot procedure for
the synthesis of novel and diversely substituted γ-aminoethers in good
yields through a four-component process by treatment of benzylamines
with polyformaldehyde and activated alkenes in aliphatic alcohols acting
both as solvent and as etherificant agents. Reactions proceeded via a
Mannich-type reaction, where the formation of iminium ions and aminals was identified as the key intermediates to obtain the
target products.
KEYWORDS: Mannich-type reaction, alkylbenzylamines, multicomponent reactions, etherification reaction, γ-aminoethers
INTRODUCTION
■
Multicomponent reactions (MCRs) are convergent reactions,
in which three or more starting materials react to form a
product, where basically all or most of the atoms contribute to
the newly formed product,1a−d (e.g., Mannich,1e Strecker,1f
Hantzsch,1g Ugi,1h Biginelli,1i Passerini,1j and Willgerodt−
Kindler1k reactions). In an MCR, a product is assembled
according to a cascade of elementary chemical reactions. Thus,
there is a network of reaction equilibria, which all finally flow
into an irreversible step yielding the product. Applications of
MCRs in all areas of applied chemistry are very popular because
they offer a wealth of products, while requiring only a minimum
of effort. As opposed to the classical way to synthesize complex
molecules by sequential synthesis, MCRs allow the assembly of
complex molecules in one pot. Unlike the usual stepwise
formation of individual bonds in the target molecule, the
defining attribute of MCRs is the inherent formation of several
bonds in one operation without isolating the intermediates
(referred to as the bond-forming efficiency, BFE),2 changing
the reaction conditions, or adding further reagents.
Amino ethers are valuable building blocks in organic
synthesis, in particular, because they are important precursors
in the preparation of a wide variety of pharmaceutical
products.3 In the past years, a series of selective serotonin (5-
HT)-reuptake inhibitor (SSRI) antidepressants (e.g., fluexetine
and paroxetine) and selective norepinephrine (NE)-reuptake
inhibitor antidepressants (e.g., tomoxetine and viloxazine), have
been developed.4 Structural examination of such compounds
revealed that several of them contain the γ-amino ether
functionality in their structures, Figure 1, which could be
related with the biological activity displayed by such
compounds.
Figure 1. Some γ-aminoethers of biological interest.
synthesis of novel γ-aminoethers in good to excellent yield
starting from secondary benzylamines through a four-
component strategy mediated by a Mannich-type reaction.
As a result of our recent reports on the benzylamine
derivatives,5 we envisioned the possibility to obtain novel 2-
benzazepine derivatives 5,6 by the treatment of benzylamine
1{1} (1 equiv), polyformaldehyde (1.2 equiv), N-vinyl-2-
pyrrolidone 2{1} (1 equiv) in methanol 3{1} as solvent and in
the presence of L-proline (20 mol %) as organocatalyst. The
experiment afforded a light and a dense oily material after 24 h
of stirring, which was purified by column chromatography on
silica gel using a mixture CH2Cl2/MeOH (20:1) as eluent.
After analysis by spectroscopic techniques, we noticed that
formation of the desired product 5 did not occur but the
unexpected γ-aminoether 4{1,1,1} was obtained as the sole
product, Scheme 1. According to this result formation of
aminoether 4{1,1,1} involved the consumption of the methanol
used as solvent.
The most relevant spectroscopic features to confirm the
structure proposed for compound 4{1,1,1} corresponded to the
presence of CO and C−O absorption bands at 1692 and
RESULTS AND DISCUSSION
Received: August 31, 2012
Revised: November 18, 2012
Published: November 20, 2012
■
Continuing with our studies on the synthetic utility of
benzylamine derivatives,5 herein, we report a highly efficient
© 2012 American Chemical Society
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On the basis of this unexpected γ-aminoether product
4{1,1,1}, we decided to test the scope of this synthetic
methodology with benzylamines chemset 1{1−4}, terminal
alkenes chemset 2{1−4}, and alcohols chemset 3{1−5}, Figure
3, to determine the generality of this multicomponent
methodology.
Scheme 1. Synthesis of the Novel γ-Aminoether 4{1,1,1}
from the Benzylmethylamine 1{1}
(1207, 1077) cm−1, respectively, in the IR spectrum. A NCH3
signal at 2.20 ppm, six methylenic signals between 1.69 and
3.51 ppm, a singlet integrating for 3H at 3.22 ppm assigned to
the OCH3 functionality and a tiplet integrating for 1H at 5.21
ppm (t, J = 6.6 Hz) assigned to the new aza-methylacetal
proton (NCH−O), along with five (but not four if product 5
were been formed) aromatic protons are the most relevant
signals in the 1H NMR spectrum. The presence of six
methylene carbon atoms between 18.2−62.6 ppm, a NCH3
signal at 42.3 ppm, a methoxy group at 55.6 ppm, a signal of the
aza-methylacetal carbon atom (NCH−O) at 81.1 ppm, three
aromatic CH, two quaternary Cq carbon atoms and the (C
O) at 176.0 ppm in the 13C NMR spectrum, are in agreement
with the proposed structure for compound 4{1,1,1}. Finally, a
molecular ion with m/z 276 and a base peak with m/z 91
(tropylium cation), also confirmed its structure.
Since compound 4{1,1,1} possesses an asymmetric carbon
atom (i.e., the aza-acetal one), a sample of the product was
analyzed by polarimetry and HPLC using a chiral column to
determine if an asymmetric process occurred by the presence of
L-proline in the reaction media. Regrettably, product 4{1,1,1}
was optically inactive affording a racemic mixture, Figure 2. The
reaction was repeated without adding L-proline, and the results
were similar indicating L-proline did not participate in the
synthetic process.
Figure 3. Employed diversity benzylamines 1, terminal alkenes 2, and
alcohols 3 reagents for the synthesis of products 4.
To our satisfaction a set of diversely substituted γ-
aminoethers 4{1,1,1} through 4{2,4,2} was obtained as
shown in the Scheme 2. The reaction proceeded similarly
Scheme 2. General Approach for the Synthesis of the Novel
γ-Aminoethers 4
with yields in the range of 61−91%. Their structures were also
confirmed by complete spectroscopic analysis (see Supporting
Information). Table 1 summarizes the obtained results for
compounds 4{1,1,1} through 4{2,4,2}.
The presence of the aza-acetalyc functionality (NCH−O)
was the determinant structural feature in compounds 4{1,1,1}
through 4{4,1,1} which appeared in the range of (5.14−5.66
1
ppm) and (77.3−83.2 ppm) in the H and 13C NMR spectra
respectively. Meanwhile this functionality corresponds to an
acetal (OCH−O) properly for compounds 4{2,3,1} through
4{2,4,2} and appears in the range of (4.35−4.85 ppm) and
(98.3−108.5 ppm), respectively.
The general character of this approach was confirmed by
using not only primary alcohols 3 (MeOH {1}, EtOH {2},
PrOH {3} and BnOH {5}) but also secondary (iPrOH {4})
aliphatic alcohols, although reaction does not proceeded when
the tertiary tert-BuOH was used. The reaction worked well not
only with the enamines (N-vinyl-2-pyrrolidinone 2a and N-
vinylcaprolactam 2b) but also with the cyclic vinyl ethers (2,3-
Figure 2. Chromatogram of the racemic mixture of compound
4{1,1,1} separated by HPLC using a chiralpack column.
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Table 1. Synthesis of the Novel γ-Aminoethers 4{1,1,1}−4{2,4,2}
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Table 1. continued
a
Isolated yield.
dihydrofuran 2c and 3,4-dihydropyran 2d). No limitation was
found for any of the secondary amines used. The reaction
proceeded smoothly with sterically less hindered benzylmethyl-
amine 1a but also with the sterically most hindered
dibenzylamine 1d.
It is worth mentioning that this developed protocol is
strongly dependent on the high concentration of alcohol 3.
Four alternative experiments were performed to demonstrate it.
The first one consisted in repeat the reaction described in
Scheme 2 but using a mixture 1:1 mL of MeOH/ACN as
solvent. In this case, product 4{1,1,1} was isolated in 56% yield
after 24 h of stirring. Unreacted starting materials were
detected. When reaction was carried out using a mixture
0.5:1.5 mL of MeOH/ACN product 4{1,1,1} was isolated just
in 25% yield after 24 h. Unreacted starting materials were also
detected along with other minor components. In a third
experiment a mixture of 1 equiv of MeOH in ACN (2 mL) was
used as solvent. From this approach a complex mixture was
obtained after 24 h of stirring, including product 4{1,1,1} along
with unreacted aminal 7, as well as, other unidentified
components. In the fourth experiment only ACN (2 mL)
was used as solvent. In this case reaction was incomplete after
24 h of stirring, being the aminal 7 the main product.
Unreacted alkene 2{1} and other unidentified components
were detected. These finding confirms that the best reaction
Compounds 4{2,3,1} through 4{2,4,2} (entries 12 and 13,
Table 1), were obtained as mixtures of their corresponding cis
and trans diastereomers with the cis isomer the main
component for 4{2,3,1} (i.e., 71:29 cis/trans ratio). In contrast,
the trans isomer was slightly favored for 4{2,4,2} (i.e., 47:53
cis/trans ratio). In both cases the ratios were calculated from
1
the H NMR spectra of their crudes. In the case of product
4{2,3,1} we were able to separate the mixture of the two
diastereomers (91% overall yield), by column chromatography
on silica gel by using a CHCl3/MeOH (30:1) mixture as eluent.
1
Figure 4 shows the H NMR signals of the acetalyc OCH−O
protons of both cis (J = 0.75 Hz) and trans (J = 4.5 Hz)
isomers, respectively. It confirms not only their formation and
ratio (part a) but also their separation in pure components
(part b) and (part c), respectively.
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not formed. This fact may indicate that the intermolecular
nucleophilic attack of the hydroxyl group of the respective
R1OH over the species 8 proceeded faster than the intra-
molecular ring closure. Steric and conformational factors should
be determinant features in this process.
It is also remarkable, that in this one-pot protocol three new
bonds were formed in sequence during the process. This
finding is in agreement with the atomic economy and bond-
forming efficiency (BFE) concepts, which characterizes a
multicomponent reaction.2 Moreover, in the overall process
only a molecule of water is removed as byproduct which
provide also an environmentally friendly character to this four-
component procedure.
The interesting results obtained from Scheme 3 encouraged
us to investigate a variation of the protocol in order to explore a
broadest and scope of this methodology.
Our objectives were to extend the procedure to other amines
chemset 1{5−7} and phenolic derivatives chemset 3{6−9}, as
shown in Schemes 4 and 5 respectively. Thus, applying our
Figure 4. 1H NMR expansion of the signals for the acetalyc OCH−O
protons of the mixture of diastereomers of compound 4{2,3,1}. (a)
Crude mixture of both isomers. (b) Pure trans isomer. (c) Pure cis
isomer.
Scheme 4. Synthesis of the Novel γ-Aminoethers 4{5−7,1,1}
from Diethylamine 1{5}, Morpholine 1{6}, and 1,2,3,4-
Tetrahydro-isoquinoline 1{7}, Respectively
conditions to efficiently afford products 4 should involve an
excess of pure alcohols 3 acting both as solvent and as reagent.
On the basis of the literature7 and our experimental
observations, it may be suggested that synthesis of the γ-
aminoethers 4 started with the formation of the well-known
iminium ion type 6 from the reaction of the secondary amines 1
with polyformaldehyde. This species is then trapped by the
electron-rich alkene 2 via a Mannich-type reaction affording a
new cationic species 8 (stabilized by a resonant effect with the
free electronic pair of the X (N, O) atoms). Finally, the
nucleophilic intermolecular attack of the hydroxyl group of the
alcohol R1OH over species 8 afforded the γ-aminoether
derivatives 4, Scheme 3. Moreover, formation of aminals type
7 was detected in the reaction mixture but they were consumed
in the course of the reaction. A hydrolytic process toward the
iminium ion 6 may explain that. Particularly aminal 7{3} (R =
−CH2Ph) was isolated and characterized (see Supporting
Information).
Although, initially we expected an intramolecular cyclization
process (ring closure), involving the ortho-carbon atom of the
Ph-ring in the intermediate species 8 to afford the 2-
benzazepinic framework 5, see Scheme 1, such product was
Scheme 3. Proposed Mechanistic Sequence for the Formation of the Products 4 via the Iminium Ion 6
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as soon as it was formed, via an ortho-C alkylation process as
Scheme 5. Tricomponent Synthesis of the Aminals 9 from
Phenolic Derivatives 3{6−9}
showed in Scheme 6.
Scheme 6. Proposed Mechanistic Sequence for the
Formation of Aminals 9
The above results confirm that the ortho-carbon atoms of the
phenolic derivatives 3{6−9} possess a much higher nucleo-
philic character not only than the terminal alkenes 2 but also
than their hydroxyl functionality of themselves. For that reason
the C-alkylation proceeded instead of the O-alkylation in all
entries of the Scheme 5. Resonant effects in the phenolic
structures should support this finding.
A further exploration of the scope and limitations of this
methodology consisted in trying the reaction with secondary
anilines 1{8−9} (instead of secondary benzylamines) and
benzyl thiol 3{10} (instead of alcohols) and using the
pyrrolidone 2{1} as the electron-rich alkene, as showed in
Scheme 7. In the first case (entry 1), reactions were carried out
in MeOH and stirred for 10 days. In both cases reactions were
much slower than when benzylamines are used (see Supporting
Information). For aniline 1{8}, the reaction was not complete
after this time and a difficult to separate mixture of unreacted
starting materials along with several products was obtained.
procedure to diethylamine 1{5} and the heterocyclic amines
morpholine 1{6} and 1,2,3,4-tetrahydro-isoquinoline 1{7}
instead of benzylamine 1{1} in MeOH 3{1}, successfully
afforded the corresponding γ-aminoethers 4{5,1,1}, 4{6,1,1},
and 4{7,1,1} in 74%, 81%, and 63% isolated yields, respectively,
Scheme 4 (see Supporting Information).
In the case of the phenolic derivatives 3{6−9}, Scheme 5, the
reaction was initially tried with amine 1{3}, polyformaldehyde,
alkene 2{1} and 1-naphthol 3{6} instead of methanol 3{1}, in
ACN as an aprotic solvent.
Reaction was monitored by TLC and although a new
product was formed, consumption of alkene 2{1} was not
observed. After purification of the crude by column
chromatography and spectroscopic analysis, the obtained
product corresponded to the new aminal 9{3,6} in 91% yield,
but not to the expected naphthyl γ-amino ether derivative
4{3,1,6}. Repetition of this reaction without alkene 2{1}
afforded the same product 9{3,6} in similar yield. An extension
of this result to 2-naphthol 3{7}, 8-hydroxyquinoline 3{8}, 2,3-
dihydroxynaphthalene 3{9} and the amine 1{1} instead of
1{3}, showed the same behavior affording the corresponding
aminals 9{3,7}, 9{3,8}, the 2:1 adduct 9{3,9} and 9{1,7} in
89%, 92%, 73% and 89% yield, respectively, Scheme 5.
Formation of aminals 9 suggests that the relative
nucleophilicity of the phenolic derivatives 3{6−9} toward the
iminium species 6 was higher than that for the activated alkene
2{1} (i.e., k1 ≫ k2, Scheme 6). The iminium ion 6 was trapped
1
The H, 13C NMR, and DEPT spectra of the crude allowed us
to identify the expected γ-amino ether 4{8,1,1} as a minoritary
product in 18% yield approximately (see Supporting
Information). For aniline 1{9} reaction was complete after
this time but a mixture of products was obtained again. After
performing a careful column chromatography to this crude, it
was possible to isolate the tetrahydroquinoline 10 in 16% yield
but not the corresponding γ-amino ether. Possible formation of
product 10 should be explained through an aza-Diels−Alder
type cycloaddition (Povarovs reaction)8 between the iminium
ion type 6 (R = −Ph) and the alkene 2{1} without participation
of MeOH. Alternatively an intramolecular cyclization of the
carbocation type 8 (R = −Ph) could also afford the product 10.
Preferred formation of the six-member ring should be the
driving force in this process.
In the case of the reaction of benzylamine 1{1} with benzyl
thiol 3{10} (entry 2), regrettably, this approach does not
afforded the desired γ-aminothioether 4{1,1,10}. Although
reaction proceeded faster that when alcohols were used (about
18 h, see Supporting Information), the N,S-acetal 119 was
obtained as the main component (about 42% isolated yield) of
a mixture of products. Selective formation of this side-product
could be explained by the fact that the trapping of the iminium
ion 6 by the benzyl thiol occurred preferentially to the alkene
2{1}. Higher nucleophilicity of the −SH function in 3{10} over
the double bond of alkene 2{1} should support this finding.
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Scheme 7. Exploration of the Reactivities of Anilines and Thiols toward the Synthesis of Other Product 4 Analogs
In summary, as a consequence of an unplanned reaction we
have implemented an efficient and multicomponent approach
for the synthesis of the novel and diversely substituted γ-
aminoethers 4 in good to excellent yields from a one-pot four-
component procedure. This approach involved the trapping of
the iminium ion 6 (formed in situ) by an activated alkene 2
through a Mannich-type reaction. The subsequent attack of the
corresponding alcohol 3{1−5} used as solvent toward the new
carbocation species formed 8 afforded the isolated products 4.
In the case of phenolic derivatives 3{6−9} aminals 9 were
obtained instead of the corresponding γ-aminoethers 4. The
fact that three new bonds were formed in only one step and the
releasing of water as the unique byproduct, gives to this
approach an outstanding bond-forming efficiency, as well as a
remarkable environmentally friendly quality.
General Procedure for the Synthesis of the γ-
Aminoethers 4. A mixture of amine 1 (0.200 mg of each),
polyformaldehyde (1.5 mmol), and the activated alkene 2 (1.1
mmol) was dissolved in the corresponding alcohol (R1OH) 3
(2 mL). The solution was stirred at room temperature for 24 h
until the starting amine 1 was not detected by TLC (revealed
with an ethanolic solution of vanillin-sulfuric acid). After the
excess of solvent was removed under reduced pressure, the oily
material obtained was purified by column chromatography on
silica gel, using a mixture of CH2Cl2/MeOH (20:1) as eluent.
Synthesis of the Aminals 9. A mixture of dibenzylamine
1{3} (150.0 mg, 0.76 mmol), polyformaldehyde (34.0 mg, 1.13
mmol), the corresponding phenolic compound 3{6−9} (0.76
mmol), and alkene 2{1} (0.76 mmol or without it) was
dissolved in ACN (2 mL). The solution was stirred at room
temperature for 12 h until the starting amine 1{3} was not
detected by TLC. The solvent was removed under reduced
pressure and the crude was purified by column chromatography
on silica gel using a CHCl3/MeOH (30:1) mixture as eluent. In
the case of product 9{1,7} it was used amine 1{1} instead of
1{3}. For the bis-aminal 9{3,9}, the reaction was optimized by
using a mixture of 2,3-dihydroxynaphthalene 3{9} (1 equiv),
dibenzylamine 1{3} (2 equiv), and polyformaldehyde (2.5
equiv).
EXPERIMENTAL PROCEDURES
■
General. Melting points were determined on a Buchi
̈
melting point B-450 apparatus and are uncorrected. IR spectra
were recorded on a Shimadzu FTIR 8400 spectrophotometer in
1
KBr disks and films. H and 13C NMR spectra were recorded
on a Bruker Avance 400 spectrophotometer operating at 400
and 100 MHz, respectively, and Bruker AC 300 operating at
300 and 75 MHz respectively, and using CDCl3 as solvent and
tetramethylsilane as internal standard. Mass spectra were run
on a SHIMADZU-GCMS 2010-DI-2010 spectrometer (equip-
ped with a direct inlet probe) operating at 70 eV. Low
resolution mass spectra (MS) were recorded on ion trap Bruker
Esquire 6000, equipped with an electrospray source (ESI).
Solvent used is methanol (Sigma Aldrich, chromasolv for
HPLC). Microanalyses were performed on an Agilent
elemental analyzer and the values are within 0.4% of the
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, compound characterization
data, and 1H, 13C NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
■
theoretical values. Silica gel aluminum plates (Merck 60 F254
)
Corresponding Author
were used for analytical TLC. The starting amines 1{1−3,5−9},
alkenes 2, polyformaldehyde, alcohols 3{1−5}, thiol 1{10}, and
naphthol derivatives 3{6−9} were purchased from Aldrich,
Fluka, and Acros (analytical reagent grades) and were used
without further purification. Owing to amine 1{4} is
commercially unavailable, it was synthesized by a reductive
amination from 3,4-dimethoxyphenethylamine and 3,4,5-
trimethoxybenzaldehyde, following a similar procedure as
described previously.5a
*E-mail: rodrigo.abonia@correounivalle.edu.co
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank COLCIENCIAS, Universidad del Valle-Project
Number CI-7812, the Spanish “Consejeria de Innovacion
Ciencia y Empresa, Junta de Andalucia” and “Centro de
́
́
,
́
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1
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