1-Aminovinylphosphonate Esters as Substrates for the Diels-Alder Reaction: First Synthetic and Theoretical Study

Article abstract of DOI:10.1002/ejoc.201801633

The Diels-Alder reaction of 1-aminovinylphosphonate esters has been studied for the first time as a suitable procedure leading to quaternary carbocyclic α-aminophosphonates. The reaction is influenced by steric effects at the phosphonate functionality (bulky groups hinder the reaction) and electronic effects at the amino group (electron-withdrawing substituents increase the reaction rate). The exo/endo ratio is constant, and no influence of the solvent is observed. The experimental results have been rationalized by DFT methods.

Full text of DOI:10.1002/ejoc.201801633

A Journal of
Accepted Article
Title: First Synthetic and Theoretical Study of 1-
aminovinylphosphonate esters as Substrates for the Diels-Alder
Reaction
Authors: Maria Mercedes Jiménez-Andreu, Jorge Bueno-Morón,
Francisco J. Sayago, Carlos Cativiela, Tomás Tejero, and
Pedro Merino
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801633
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10.1002/ejoc.201801633
European Journal of Organic Chemistry
COMMUNICATION
First Synthetic and Theoretical Study of 1-
aminovinylphosphonate esters as Substrates for the Diels-Alder
Reaction
M. Mercedes Jiménez-Andreu,[a] Jorge Bueno-Morón,[a] Francisco J. Sayago,[a]* Carlos Cativiela,[a]*
Tomás Tejero[a] and Pedro Merino[b]*
Dedication ((optional))
Abstract: The Diels-Alder reaction of 1-aminovinylphosphonate
esters has been studied for the first time as a suitable procedure
leading to quaternary carbocyclic α-aminophosphonates. The
reaction is influenced by steric effects at the phosphonate functionality
(bulky groups hinder the reaction) and electronic effects at the amino
group (electron-withdrawing substituents increase the reaction rate).
The exo/endo ratio is constant, and no influence of the solvent is
observed. The experimental results have been rationalized by DFT
methods.
acid derivatives (Figure 1). Cyclopentadiene was used as a model
to assess the reactivity and selectivity of a variety of ,-
dehydroaminophosphonates bearing different protecting groups
in the phosphonic acid and the amine functions. The reactivity and
selectivity has been rationalized by DFT methods.
Introduction
Among non-proteinogenic amino acids, quaternary -amino acids
constitute a family of compounds which find application in several
research fields, from the development of new catalytic systems to
the synthesis of pharmaceuticals.[1] Within this context, ,-
dehydroalanines are useful precursors of quaternary carbocyclic
α-amino acids through cycloaddition reactions (Figure 1).[2]
-Aminophosphonic acids are synthetic phosphorous analogues
of α-aminoacids and their biological interest has been widely
demonstrated.[3] However, although many efforts have been
devoted to the synthesis of ,-dehydroaminophosphonates[4] as
synthetic intermediates of -aminophosphonic acids,[5] their use
as substrates for cycloaddition reactions has been scarcely
explored. Only 1,3-dipolar cycloaddition reactions with
Figure 1. ,-Dehydroalanines and 1-aminovinylphosphonate esters as
substrates for cycloaddition reactions.
Results and Discussion
Firstly, the synthesis of a series of protected ,-dehydroamino
phosphonates was considered as suitable precursors of sterically
hindered -amino phosphonic acids (AAPA). A variety of
carbamates (benzyloxycarbonyl and methoxycarbonyl groups)
and amides (benzoyl, acetyl, trifluoroacetyl and p-nitrobenzoyl
groups) were selected for this study. These groups will allow
evaluating the influence of both steric and electronic effects in the
course of the reaction as well as provide the opportunity of being
deprotected if required in a further synthesis of AAPAs.
diazoalkanes,
mainly
aimed
at
the
synthesis
of
1-aminocyclopropyl phosphonic acid derivatives, have been
reported.[5c-e, 5h]
In this paper we present the first study of the use of ,-
dehydroaminophosphonates as suitable substrates in Diels-Alder
reactions for the preparation of carbocyclic α-aminophosphonic
We envisioned the Horner-Wadsworth-Emmons (HWE) reaction
as
a
suitable procedure to prepare the targeted 1-
aminovinylphosphonate esters,[4],[6] since the starting -
aminomethyl-bisphosphonic acid, 1, can be obtained in multi-
gram scale.[7] Compound 1 was then acylated and subsequently
esterified to afford N-protected tetraalkyl aminomethylbis-
phosphonates 2a-f in yields ranging from 20 to 90% (Scheme 1).
The selected acylation procedure involves the use of
triethylamine as base and treatment of the reaction crude with a
strongly-acidic cation exchange resin. This methodology differs
from the classical Schotten-Baumann procedure.[8] However, the
high water-solubility of -aminomethylbisphosphonic acid
derivatives made us to discard these reaction conditions. The
[a]
Dr. M. Mercedes Jiménez-Andreu, MSc. Jorge Bueno-Morón, Dr.
Francisco J. Sayago, Prof. Dr. Carlos Cativiela, Prof. Dr. Tomás
Tejero. Departamento de Química Orgánica, Instituto de Síntesis
Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de
Zaragoza, Zaragoza 50009, Spain.
E-mail:
jsayago@unizar.es,
cativiela@unizar.es
Homepage:
http://www.unizar.es/aminoacidosypeptidos/index.htm
[b]
Prof. Dr. Pedro Merino. Instituto de Biocomputación y Física de
Sistemas Complejos (BIFI), Universidad de Zaragoza, Zaragoza
50009, Spain.
E-mail: pmerino@unizar.es Homepage: http://www.bioorganica.es/
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201801633
European Journal of Organic Chemistry
COMMUNICATION
esterification reaction was carried out using trialkyl orthoformate
derivatives as alkylating agents, which usually compare
favourably with other procedures described in the literature.[9],[10]
presence of cesium carbonate to afford the corresponding -
amino vinylphosphonates in good to high yields (45-92%).
In addition, the synthesis of the phthalimido derivative 3h was also
attempted. In our hands, the protection of tetraethyl
aminomethylbisphosphonate with phthalic anhydride was
unsuccessful and therefore, we addressed the synthesis of the
tetramethyl derivative. Thus, hydrogenolysis of compound 2a
followed by treatment with phthalic anhydride provided a mixture
of the tetramethyl phthalimido bisphosphonate, 2h, and the
partially protected amido acid derivative (a 39% conversion in the
desired compound was observed in the NMR spectra of the
reaction crude). However, the desired compound 2h decomposed
when the crude was submitted to column chromatography
purification. Moreover, HWE olefination of the crude also led to a
complex mixture. Presumably, these results can be explained by
the high steric hindrance caused by the phosphonate groups.
The reaction of cyclopentadiene with 1-aminovinylphosphonate
esters 3a-g was then investigated. First attempts were conducted
at room temperature under neat conditions or in the presence of
Lewis acids (AlCl3, TiCl4 and EtAlCl2). However, in these
experiments no reaction was observed, or they led to
decomposition, which discards the possibility of developing a
catalytic process. After that, reactions were performed under neat
conditions, without any additive, and the temperature was
Scheme 1. Synthesis of dienophiles 3a-f. Reagents and conditions: (a)
H2O/CH3CN, Et3N, R1COX (CbzOSu for 2a and 2b, MeOCOOSu for 2c,
PhCOCl for 2d, Ac2O for 2e, p-NO2PhCOCl for 2f, dimethyl terephthalate for
2h), rt; (b) Dowex® 50WX8; (c) HC(OMe)3 for 2a, HC(OEt)3 for 2b-f, reflux; (d)
H2, 10% Pd/C, MeOH, rt; (e) TFAA, CH2Cl2, rt; (f) 37% HCHO(aq), Cs2CO3,
THF/iPrOH (THF for compounds 3f and 3g), rt.
It should be noted that the N-trifluoroacetyl derivative 2g was
obtained starting from the benzyloxycarbonyl derivative 2b after
hydrogenolysis, treatment with trifluoroacetic anhydride and
olefination (Scheme 1), given that the acylation of
aminomethylbisphosphonic acid, 1, with trifluoroacetic anhydride
failed. Finally, the N-protected ,-dehydroamino-phosphonates
3a-g were obtained by means of the HWE olefination with
formaldehyde. Thus, -aminomethylbis-phosphonates 2a-g were
treated with a 37% formaldehyde aqueous solution in the
increased (Table 1). Thus,
cyclopentadiene and N-benzyloxycarbonyl derivative 3a was
stirred at 100°C for 7 days, at which time the Diels-Alder adducts
exo-4a and endo-5a were isolated in 26% yield (entry 1). The 31
NMR spectrum of the reaction crude showed the formation of
various side-products along with the signals corresponding to the
Diels-Alder adducts 4a and 5a. Under these reaction conditions,
an 86:14 exo/endo ratio was observed (exo is referred to the
phosphonate group).
a mixture of an excess of
P
Table 1. Diels-Alder reaction of N-acyl-1-aminovinylphosphonate esters 3a-g with cyclopentadiene.
entry
1
substrate
3a
R1
OBn
R2
Me
Me
Et
solvent
neat
T(°C)
100
time
7 d
Yield[a]
26%
32%
44%
54%
54%
51%
-
exo-4/endo-5[b]
86:14
86:14
86:14
88:12
84:16
82:18
-
2
3a
OBn
neat
160
22 h
32 h
27 h
24 h
18 h
4 h
3
3b
OBn
neat
160
4
3c
OMe
Et
neat
160
5
3d
Ph
Et
neat
160
6
3e
Me
Et
neat
160
7
3f
4-NO2C6H4
CF3
Et
neat
160
8
3g
Et
neat
160
5 h
66%
45%
65%
64%
86:14
82:18
84:16
85:15
9
3f
4-NO2C6H4
CF3
Et
EtOH/water
EtOH/water
neat
75
17 d
7 d
10
11
3g
Et
75
3g
CF3
Et
150 (MW)
1 h
[a] Isolated yield for both Diels-Alder adducts. [b] Determined by 31P NMR of the crude reaction mixture.
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10.1002/ejoc.201801633
European Journal of Organic Chemistry
COMMUNICATION
The exo/endo ratio was determined by integration of the
corresponding signals in the reaction crude 31P NMR spectrum.
The exo-/endo-stereochemistry of the isolated adducts was
assigned by 2D-NOESY experiments and the analysis of
the Diels-Alder reaction outcome as a result of a negligible
difference in polarity between the initial state and the transition
state,[14],[15] it is well known that both the reaction time and the
stereoselectivity can be dramatically influenced by polar protic or
aqueous media.[16] For instance, in the case of dehydroalanine
derivatives, significant changes in stereoselectivity are observed
when using ethanol[12] or water[17] as solvents. Consequently, the
effect of a polar protic medium was investigated for compounds
3f and 3g, in ethanol-water as a solvent at 75°C (higher
temperatures led to decomposition). Under these conditions, the
p-nitrobenzoyl derivative 3f did not lead to decomposition
(presumably due to the lower temperature used), and the adducts
exo-4f and endo-5f were obtained in 45% yield after 17 days of
reaction (entry 9) at which time no more starting material was
observed in the reaction mixture. An 82:18 exo/endo ratio was
determined. The reaction with the N-trifluoroacetyl derivative 3g
was completed after 7 days, affording the adducts 4g and 5g in a
65% yield and 84:16 exo/endo ratio. These results confirm the
limited effect exerted by including a polar solvent which, on the
other side, favours decomposition at high temperatures, forcing
the use of lower temperatures, which greatly increase the reaction
time.
3
characteristic vicinal JP-C coupling constants in the 13C NMR
spectra (see supporting information). At 160°C (entry 2) the
cycloaddition with 3a showed a complete conversion after 22 h,
and the adducts 4a and 5a were isolated in a 32% yield. The
exo/endo ratio remained unchanged and formation of side-
products was diminished. After this result, we decided to perform
the cycloaddition reactions with 3b-g at 160°C.
Reaction of the diethyl dehydroaminophosphonate 3b with
cyclopentadiene was completed in 32 h. The 31P NMR spectra of
the crude showed less formation of side-products in comparison
to that observed for compound 3a (R1 = Me), whereas the same
exo/endo ratio was observed. Indeed, adducts exo-4b and endo-
5b were obtained in a higher yield (44%, entry 3). This result
prompted us to use diethyl phosphonate derivatives instead the
corresponding dimethyl phoshonates. However, the longer
reaction times required as a result of the higher steric hindrance
of ethyl esters discourage the use of more voluminous
substituents (iPr or Ph).
The effect of the nitrogen protecting groups was then evaluated.
As showed in entries 2-6, shorter reaction times were needed for
In addition, we investigated the effect of microwave irradiation on
3g (entry 11). Thereby, a solution of the trifluoroacetyl derivative
3g in cyclopentadiene was subjected to 100 W constant operating
power (temperature was set to 150 ºC) for 1 hour, until
consumption of the starting aminovinylphosphonate. Apart from
the important improvement in the reaction time, no significant
changes were observer in either the yield or the exo/endo ratio,
which remained almost unchanged.
Furthermore, we also explored the synthesis of substituted
aminovinylphosphonates. However, HWE reaction of 3g with the
more voluminous aldehyde ethanal failed. The NMR spectra of
the reaction crude showed the attack of the amino group to the
aldehyde to form a hemiaminal that reverts to the starting material
when purification is attempted, thus illustrating the presence of an
equilibrium rather the formation of the corresponding substituted
alkene. Presumably, the higher steric hindrance of the aldehyde
favours the attack of the nitrogen instead of that of acidic carbon.
The reversibility of the reaction was also investigated. To this end,
amide derivatives (benzoyl and acetyl, entries
5 and 6,
respectively) in comparison with the corresponding carbamates
(benzyloxycarbonyl and methoxycarbonyl, entries 3 and 4,
respectively). The exo/endo ratios remained almost unchanged in
all cases. Such small differences indicate that the steric hindrance
of the protecting group at the amine function is not decisive in the
reaction outcome so, it can be predicted that any carbamate
including tert-butyl derivative might be used. It is worth noting that
these results differ from those of the reaction of
α,β-dehydroalanine derivatives with cyclopentadiene, where the
observed exo/endo ratios depend on the nature and the steric
hindrance of the N-acyl and ester groups. Moreover, they are
generally lower than those observed for the corresponding 1-
aminovinylphosphonate esters.[11],[12],[13]
Since differences in the steric hindrance or nature of the amine
protecting groups did not led to a significant improvement of the
reaction performance, we evaluated the influence of electronic
effects (entries 7 and 8). Admittedly, the reaction between
cyclopentadiene and compounds 3 is a typical normal demand
Diels-Alder reaction; consequently, it should be expected that the
presence of electron-withdrawing groups will tend to increase the
reaction rate. Unfortunately, the reaction of cyclopentadiene with
the p-nitrobenzoyl derivative 3f resulted in decomposition.
a
66:33 mixture of exo-4g and endo-5g was stirred in
1
cyclopentadiene at 160°C. After 5 h, the H NMR spectra of the
reaction mixture did not show any changes, concluding that the
reaction was not reversible, and that thermodynamic control can
be discarded for the observed selectivity. In this context the
reaction was also investigated computationally by DFT methods
to provide a rationale of the experimental results (for details see
SI). Admittedly, the normal demand Diels-Alder reaction with
phosphonates is less favored than the corresponding reactions
with carboxylates because of the higher electron-withdrawing
character of the latter when compared with the former, thus
explaining the longer reaction times required for the described
reactions in the present work. We located exo and endo transition
structures for the reaction of cyclopentadiene with alkenes AKb-
g equivalent to the corresponding alkenes 3b-g (the only
approximation used was replacement of Et by Me, i.e: R2 = Me).
In addition, alkenes AKa,h,i were also studied for the purpose of
comparison (see below). We calculated the energy barriers for the
reaction in gas phase and in ethanol as a solvent. The results are
However,
the
reaction
with
the
N-trifluoroacetyl
dehydroaminophosphonate 3g was completed in only 5 hours,
affording the Diels-Alder adducts exo-4g exo and endo-5g in 66%
combined yield and with a similar exo/endo ratio to those
observed before. This result represents an improvement over the
reactions with compounds 3a-e, the best chemical yield was
obtained in a shorter reaction time, and the exo-selectivity
remained unaffected.
Once we found a sufficiently reactive substrate, we expanded the
study of the reaction.
Firstly, the effect of the solvent was addressed. Although it is
generally accepted that the solvent does not significantly affect
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10.1002/ejoc.201801633
European Journal of Organic Chemistry
COMMUNICATION
collected in Figure 2. The observed values for energy barriers are
in a good agreement with the experimental observations. The
lower energy barrier corresponds to AKg (13.2 kcal/mol)
corroborating the best result obtained with 3g. Similarly, AKf
showed also a low barrier (13.6 kcal/mol), whereas the more
electron-rich alkene AKi exhibited a higher barrier (14.2 kcal/mol),
as expected. Little influence was observed by moving from gas
phase to ethanol as solvent, the former presenting lower barriers,
in agreement with an apolar concerted reaction. In all cases, the
exo adduct was predicted to be the preferred one although the
differences with endo adducts predicted that the latter might be
obtained as minor isomers. Finally, similar results were obtained
for AKe (14.8 kcal/mol) and AKh (14.8 kcal/mol) demonstrating
the absence of steric effects of the amino protecting group. The
geometry of the transition structures evidenced differences
between endo and exo approaches (see SI). Whereas the less
favoured endo transition states showed to be clearly concerted,
Figure 3 illustrates both endo- and exo-TSg (the most favoured
reaction) in which the asynchronicity is exemplified with distances
of 1.97 and 2.65 Å for the C-C forming bonds in the most favored
one (exo-TSg). A topological analysis of non-covalent interactions
(NCI) confirmed H-F interactions that might also be responsible of
the enhanced stability of exo-TSg. Such interactions are not
observed in the case of endo-TSg.
the preferred exo transition structures showed
a marked
asynchronicity, based on the different lengths of forming bonds.
Figure 3. Optimized (b3lyp-d3bj/def2svp) geometries for endo- and exo-TSg
(top) and NCI topological analysis of exo-TSg (bottom).
Conclusions
In conclusion, it has been demonstrated that 1-
aminovinylphosphonate esters can be used as suitable
substrates in Diels-Alder reactions leading to quaternary α-
aminophosphonates. The reaction has some limitations, including
the lack of reactivity or decomposition when conducted in the
presence of a Lewis acids. Also, while the substituent at the amino
group has no steric influence in the stereochemical course of the
reaction, the presence of bulky substituents at the phosphonate
function slowers the reaction. Since differences are already
observed by moving from methyl to ethyl phosphonates, a cyclic
phosphonate is not expected to show different results than those
observed for Me or Et derivatives. These disappointing results
prevent the use of chiral catalysts or auxiliaries to induce
asymmetry, a subject that will require further investigations. On
the other hand, the reaction takes place with good chemical yields
in shorter reaction times by placing electron-withdrawing groups
at the amino functionality. In particular, the trifluoroacetyl group,
which can be easily removed, provided the best results. Moreover,
the microwave-promoted reaction significantly shortened the
Figure 2. Energy barriers (b3lyp-d3bj/def2tzvp) for the reactions between
cyclopentadiene and alkenes AKa-i.
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10.1002/ejoc.201801633
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COMMUNICATION
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Acknowledgments
This work was supported by the Ministerio de Economía y
Competitividad (grants CTQ2013-40855-R to C.C. and CTQ2016-
76155-R to P.M.) and the Gobierno de Aragón–FSE (Biological
and Computational Chemistry Group E34_R17 and Aminoacids
and Peptides Group E19_17R). M.M.J.-A. thanks the Gobierno
de Aragón-FSE for predoctoral grant. The authors thankfully
acknowledge the resources from the supercomputers "Memento"
and “Cierzo”, technical expertise and assistance provided by BIFI-
ZCAM (Universidad de Zaragoza, Spain).
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Keywords: Diels Alder reaction • Olefination • Phosphorous
compounds • Density functional calculations • Strained
molecules
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[3]
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10.1002/ejoc.201801633
European Journal of Organic Chemistry
COMMUNICATION
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1-aminovinylphosphonate esters have
been studied as Diels-Alder reaction
substrates for the first time. The
influence on the course of the reaction
of substituents and protecting groups
on the phosphonate and amine
1-aminovinylphosphonate esters*
M. Mercedes Jiménez-Andreu, Jorge
Bueno-Morón, Francisco J. Sayago,*
Carlos Cativiela* Tomás Tejero and
Pedro Merino*
functions has been considered and
rationalized by DFT methods.
Page No. – Page No.
First Synthetic and Theoretical Study
of 1-aminovinylphosphonate esters
as Substrates for the Diels-Alder
Reaction
*one or two words that highlight the emphasis of the paper or the field of the study
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Author(s), Corresponding Author(s)*
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Title
Text for Table of Contents (about 350 characters)
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.