Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

Article abstract of DOI:10.3762/bjoc.14.263

We report here on the use of ethyl nitroacetate as a glycine template to produce α-amino esters. This started with a study of its condensation with various arylacetals to give ethyl 3-aryl-2-nitroacrylates followed by a reduction (NaBH₄ and then zinc/HCl) into α-amino esters. The scope of this method was explored as well as an alternative with arylacylals instead. We also focused on various [2 + 3] cycloadditions, one leading to a spiroacetal, which led to the undesired ethyl 5-(benzamidomethyl)isoxazole-3-carboxylate. The addition of ethyl nitroacetate on a 5-methylene-4,5-dihydrooxazole using cerium(IV) ammonium nitrate was also explored and the synthesis of other oxazole-bearing α-amino esters was achieved using gold(I) chemistry.

Full text of DOI:10.3762/bjoc.14.263

Synthesis of unnatural α-amino esters using ethyl
nitroacetate and condensation or cycloaddition reactions
Glwadys Gagnot1,2,3, Vincent Hervin1,2, Eloi P. Coutant1,2, Sarah Desmons1,2,
Racha Baatallah1,2, Victor Monnot1,2 and Yves L. Janin*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2846–2852.
1Unité de Chimie et Biocatalyse, Département de Biologie Structurale
et Chimie, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex
15, France, 2Unité Mixte de Recherche 3523, Centre National de la
Recherche Scientifique, 28 rue du Dr. Roux, 75724 Paris Cedex 15,
France and 3Université Paris Descartes, Sorbonne Paris Cité, 12 rue
de l'École de Médecine, 75006 Paris, France
doi:10.3762/bjoc.14.263
Received: 09 August 2018
Accepted: 26 October 2018
Published: 15 November 2018
Associate Editor: B. Stoltz
Email:
Yves L. Janin* - yves.janin@pasteur.fr
© 2018 Gagnot et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
α-amino ester; α-nitro esters; cerium ammonium nitrate; cycloaddition;
gold(I) cyclization
Abstract
We report here on the use of ethyl nitroacetate as a glycine template to produce α-amino esters. This started with a study of its con-
densation with various arylacetals to give ethyl 3-aryl-2-nitroacrylates followed by a reduction (NaBH4 and then zinc/HCl) into
α-amino esters. The scope of this method was explored as well as an alternative with arylacylals instead. We also focused on
various [2 + 3] cycloadditions, one leading to a spiroacetal, which led to the undesired ethyl 5-(benzamidomethyl)isoxazole-3-
carboxylate. The addition of ethyl nitroacetate on a 5-methylene-4,5-dihydrooxazole using cerium(IV) ammonium nitrate was also
explored and the synthesis of other oxazole-bearing α-amino esters was achieved using gold(I) chemistry.
Introduction
In the course of our work on an original synthesis of are made from condensation reactions between aldehydes 3 or
imidazo[1,2-a]pyrazin-3(7H)-one luciferins [1], a large variety acetals 5 and ethyl nitroacetate (4). However, the high yield
of racemic α-amino esters was required to prepare a correspond- condensations with aldehydes 3 which were reported for some
ing array of analogues. As we reviewed recently, nitroacetates examples [3,4] require more than stoichiometric amounts of
are amongst the principal glycine templates used to prepare titanium tetrachloride thus leading to considerable amounts of
α-amino esters 1 [2]. The retrosynthetic pathway depicted in metal-containing chemical waste. Moreover, far lower yields
Scheme 1 requires a reduction of ethyl nitroacrylates 2, which were reported in many other instances when using this reagent
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Beilstein J. Org. Chem. 2018, 14, 2846–2852.
Table 1: Synthesis and reductions of α-nitro acrylates into α-amino
esters.
Scheme 1: α-Amino esters from ethyl nitroacetate (4).
[5,6]. In an attempt to improve the generality of this synthetic
pathway and diminish its requirement for metals, we studied
some alternatives, such as the condensations between ethyl
nitroacetate (4) and acetals 5 or other approaches further de-
scribed in the following.
% 1
Ar
% 6a
% 6b
a
b
c
d
e
f
–
C6H5
35c
53
21
55
51
16
6
90
92
95
67
80
94
–
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-BnOC6H4
3-MeC6H4
2-FC6H4
Results and Discussion
As depicted in Table 1, we first studied the scope of the conden-
sation between ethyl nitroacetate (4) and aryldimethylacetals
5a–s which are easily obtained in situ from the corresponding
arylaldehydes 3a–s. As seen by 1H NMR monitoring, the treat-
ment of arylaldehydes 3a–s with trimethyl orthoformate and an
acid-bearing resin in dry methanol led to full conversion into
the corresponding acetals 5a–s. Then, as reported [7,8], heating
the crude acetals 5a–s and ethyl nitroacetate (4) in the presence
of acetic anhydride afforded a mixture of compounds contain-
ing variable amounts of the expected acrylates 2a–s. No
attempts were made to purify these as they were immediately
subjected to a reduction of its double bond using sodium boro-
hydride [9,10] in refluxing isopropanol in order to properly
isolate the corresponding α-nitro esters 6a–s. Isopropanol was
used instead of ethanol in order to decrease the incidence of a
recurrent side product arising from a decarboxylation or a retro
condensation of the partially reduced ester function (this side
product was characterized in 1H NMR by two triplets at
4.6 ppm and 3.4 ppm, but eluded our purification efforts).
Moreover, one minute in refluxing isopropanol was found to be
g
h
i
3-FC6H4
0.9
13
0d
94
–
4-FC6H4
j
2-CF3C6H4
3-CF3C6H4
4-CF3C6H4
2-pyridyl
k
l
–
<5d
<5d
0d
–
m
n
o
p
q
r
–
furan-2-yl
27
–
38/48e/70f 94
furan-3-yl
34
–
88
75
56
79
58
5-methyl-furan-2-yl
5-ethyl-furan-2-yl
60
39
–
4,5-dimethyl-furan-2-yl <20
thiophen-2-yl 33
46e
–
s
aIsolated yield from 3a–s, via acetals 5a–s. bIsolated yield via the
direct condensation between 3a–s and 4. c39% yield from
(diethoxymethyl)benzene. dAs seen by 1H NMR analysis. eUsing
NaBH3CN; see text. fAlso using NaBH3CN but from pure 2n; see text.
sufficient to complete the reduction especially for the fairly acetals 5g–l featuring electron-withdrawing groups, low to non-
insoluble acrylate 2e, and also avoided most of the undesired detectable amounts of the condensations products 2g–l were ob-
transesterification byproducts that could form upon long reac- served by 1H NMR analysis, and this was reflected in the isolat-
tion times. As seen in Table 1, modest yields of compounds ed yield of the corresponding α-nitroesters 6g–i as well as the
6a–i were isolated anyway, especially for meta-substituted phe- lack of compounds 6j–l. Similarly, no condensation was ob-
nyl-bearing products 6c, 6f and 6h. Even if the reduction was served when starting with the pyridyl-bearing acetal 5m. These
less than perfect, the low yields originate from the initial con- disappointing results are plausibly due to two factors: (i) As
densation between acetals 5 and 4. Indeed, when considering mentioned above, the condensation of ethyl nitroacetate (4)
the phenyl derivative of 6a, a sobering 35% isolated yield was with aryl acetals 5 takes place along with an O-alkylation reac-
obtained, in stark contrast to the reported 95% yield published tion which leads, via a rearrangement, to the corresponding aryl
in 1980 [7]. In our hands, 1H NMR analysis of the crude con- ester byproduct [7,8]. The proportion between the C-alkylation
densation product pointed out the occurrence of the intermedi- (leading to the expected acrylate) and this O-alkylation is most
ate acrylate 2a along with a large amount of methyl benzoate, a certainly governed by the electronic effects of the substituent on
well-known side product in this reaction [7,8]. From the aryl the aryl group. Indeed, the best overall yields are observed
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Beilstein J. Org. Chem. 2018, 14, 2846–2852.
when starting from the electronically similar 2-methoxy acetal
5b or the 4-methoxy analog 5d, as well as the 4-benzyloxy
acetal 5e. (ii) Secondly, the reduction of acrylates 2a–s to com-
pounds 6a–s was achieved with sodium borohydride and the re-
sulting basic conditions could be detrimental to the stability of
some of these α-nitro acrylates. In the past, such reductions
have been achieved under fairly uncommon conditions (NaBH4
in a mixture of isopropanol and chloroform over a large propor-
tion of silica gel) [11,12]. However, when tried, no real overall
improvements were observed with these conditions. Other
series of trials were made to improve the overall yields of the
furan-bearing α-nitro esters 6n–r. We first tried to avoid the
preparation of the acetals 5n or 5o and used the previously re-
ported direct condensation between furfural (3n) and ethyl
nitroacetate (4) [13]. Unfortunately, we could not reproduce the
95% yield reported for compound 2n, and under a thoroughly
inert atmosphere (as advised) we obtained 48–53% isolated
yields at best. In any case, this approach did shorten the synthe-
tic pathway by one step and upon the reduction of the resulting
acrylates 2n or 2o using sodium borohydride, the α-nitro esters
6n and 6o were isolated in the rather modest yields indicated in
Table 1. We then focused on the model reduction of acrylate 2n
into 6n. Since all our attempts to achieve a palladium-catalyzed
hydrogenation failed, we tried other borohydride salts. The use
of tetramethylammonium borohydride did not increase the
overall yield of 6n, however, a rather substantial improvement
was observed when using sodium cyanoborohydride. Indeed,
from pure acrylate 2n, a 70% yield of 6n was obtained, and in
one pot starting from aldehyde 3n, a 48% overall yield of 6n
was achieved. Moreover, without using an inert atmosphere for
Scheme 2: Preparations of α-amino esters 10, 12 and 14.
the initial condensation between furfural (3n) and ethyl nitro- indium(III) chloride [15] as a Lewis acid catalyst [16] without
acetate (4) the overall yield of 6n dropped to 37% even when any solvent at room temperature pointed out a complete conver-
using sodium cyanoborohydride. The optimized conditions sion into acylal 7 overnight. A similar reaction using pivaloyl
were then applied to aldehyde 3r and afforded a significantly anhydride and either indium(III) chloride or tetrafluoroboric
improved 46% yield of 6r, in comparison with our single trial acid as a catalyst had to be heated at 60 °C for a few hours to
via 5r, which ended up with less than 20% of an impure sample secure a similar conversion into pivalal 8. From intermediates 7
of 6r. Finally, from the isolated α-nitro esters 6a–s, their reduc- and 8, and as previously reported in the case of malonates
tion into the corresponding α-amino esters 1a–s, using zinc and [17-19], we then hoped for an improvement of their condensa-
hydrochloric acid in ethanol usually proceeded in good yield, tion with ethyl nitroacetate (4). The 1H NMR monitoring of the
although care had to be taken during work-up as zinc com- reaction between compounds 7 or 8 and ethyl nitroacetate (4) in
plexes required the addition of an excess of ammonia to fully the presence of a catalytic amount of indium(III) chloride
break in the course of the extraction.
pointed out the occurrence of tangibly more of the expected
acrylate 2j, although along with many byproducts. Indeed, in a
In an attempt to overcome the lack of condensation between typical experiment, upon reduction of the crude reaction prod-
ethyl nitroacetate (4) and electron-poor substrates 5j–l, we uct obtained from 8 and ethyl nitroacetate (4), a discouraging
focused on the model preparation of the trifluoromethyl-bear- 13% yield of the corresponding α-nitro ester 6j was isolated.
ing α-nitro ester 6j from acylals 7 depicted in Scheme 2. As The use of α-nitro esters to obtain disubstituted α-amino esters
well reviewed [14], acylals can be prepared from aldehydes and such as compound 10 via an alkylation step has been described
anhydrides using a variety of acids as catalysts. In our [20]. In order to reach such α-amino esters, we tried their prepa-
case, 1H NMR monitoring of the reaction between 2-(trifluoro- ration via a C-methylation of α-nitroester 6a in DMF using so-
methyl)benzaldehyde (3j) and acetic anhydride using dium hydride and methyl iodide. Upon purification, this gave
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Beilstein J. Org. Chem. 2018, 14, 2846–2852.
46% of the nitro compound 9 with 94% purity (as assessed by
1H NMR). Despite this modest yield, the ensuing reduction
using zinc and hydrochloric acid in ethanol overnight gave a
sufficient amount of the (pure) target phenyl-bearing α-amino
ester 10 which had been previously obtained by catalytic hydro-
genation using palladium [20]. The same transformation se-
quences were used starting with compound 6n and provided the
furan-bearing α-amino ester 12 in 32% overall yield via the
nitro compound 11. We also investigated the reported [4] 1,4-
addition of a methyl on compound 2n to prepare the β-methyl-
ated derivative 13. In our hands, a rather modest 43% yield of
the expected adduct 13 was achieved from purified acrylate 2n.
Again, the ensuing reduction of 13 using zinc and hydrochloric
acid gave the target α-amino ester 14 in an 85% yield.
To avoid the recourse to more rare and/or expensive hetero-
cyclic aldehydes, we also tried synthetic approaches based on
[2 + 3] cycloadditions. As depicted in Scheme 3, the carbon
dioxide-producing reaction [21] between two equivalents of
ethyl nitroacetate (4) and styrene (15), gave the isoxazoline 16
in a 72% yield as a latent α-amino ester [22-24]. From this com-
pound, a reductive cleavage of the isoxazoline ring was initi-
ated using palladium over charcoal and a large excess of ammo-
nium formate in refluxing ethanol. The analysis of the resulting
mixture by LC/MS and 1H NMR pointed out the occurrence of
the expected [25] oxime 17 but along with an unexpected
sizable proportion of the α-amino ester 18. Accordingly, the
(filtrated) ethanolic solution was then treated with zinc and
hydrochloric acid in ethanol to complete the reduction and the
amino ester 18 was isolated in a 72% yield. In order to illus-
trate the synthetic potential of the isoxazoline 16 as an already
Scheme 3: Syntheses of α-amino ester 18 and piperazinediones
23a,b.
protected amino acid moiety, we prepared the piperazine-2,5- report [28] describing [2 + 3] cycloadditions between chloro-
diones 23a,b in four steps. This was achieved by the hydrolysis oxime 26 and other methylene-bearing compounds, its reaction
of the ester function of 16, followed by its coupling with with compound 25 gave the spiroacetal 27. However, in the
glycine or phenylalanine ethyl esters (respectively 20a and 20b) present case this cycloadduct was only detectable by 1H NMR
using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium analysis of the crude reaction mixture. Indeed, a slow ring-
tetrafluoroborate (TBTU) as a coupling agent to give the corre- opening reaction took place upon standing in solution to mainly
sponding amides 21a,b. The isoxazole ring of these compounds give the isoxazole isomer 28 along with much less of the target
was then cleaved using palladium and ammonium formate to oxazole-bearing α-hydroximino ester 29. Extensive trials to
give the corresponding oximes which were immediately alter the selectivity of the ring opening using heat, adsorption
reduced into amines 22a,b, using zinc and hydrochloric acid, over silica, acids (BF3·OEt2, AcOH) or bases (NEt3, LDA,
and a thermal cyclization of these crude products gave EtONa) all failed to change the ratio of compounds 28 and 29,
the piperazine-2,5-diones 23a,b in, respectively, 31 and which were isolated in 5 and 28% yield, respectively. Despite
40% overall yield from compound 16.
the potential synthetic interest [29,30] of isoxazole 28, we did
not pursue this further, but focused on another approach involv-
A second [2 + 3] cycloaddition-based approach is described in ing an oxidative addition of ethyl nitroacetate (4) on the
Scheme 4. It started with the preparation of the methylene-bear- methylene-bearing dipolarophiles 25 mediated by cerium(IV)
ing dipolarophile 25 from propargylamide 24 using gold(I) ammonium nitrate (CAN). This was inspired by reports
chemistry, which turned out to be tolerant to a wide variety of describing CAN-mediated carbon–carbon bond formation reac-
dry solvents (dichloromethane, tetrahydrofuran, toluene, tions between ethyl nitroacetate (4) and tri-O-acetylglycals
dimethylformamide, or acetonitrile) [26,27]. As for a related [31,32] or other sugar-derived alkenes [33]. We first tried the
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Beilstein J. Org. Chem. 2018, 14, 2846–2852.
We then resorted to a different approach to prepare the oxazole-
bearing α-amino ester 36 from 2,4,5-trimethyloxazole (33). De-
protonation of this compound was achieved using lithium diiso-
propylamide (LDA) and this was followed by the addition of
diethyl oxalate to give a mixture of compounds including the
ketoester 34. Then, treatment of this mixture with hydroxyl-
amine allowed the isolation of the target α-hydroximino ester 35
in a 7% overall yield. Two dimensional NMR experiments con-
firmed the depicted structure for compound 35 and trace
amounts of the other isomers were detected in other chromato-
graphic fractions but could not be fully purified. In any case,
from the α-hydroximino ester 35, a reduction using zinc and
hydrochloric acid gave the target oxazole-bearing α-amino ester
36.
Finally, as depicted in Scheme 5, the oxazole-bearing α-amino
ester 43 was prepared from the aspartic acid derivative 37
through the propargylamide 38 followed by a gold(I)-catalyzed
cyclization to form the oxazoline derivative 40. Concerning the
amidation step, propargylamide 38 was obtained in 78% yield
provided that an excess of triethylamine was avoided (other-
wise, as determined by a control experiment, substantial
amounts of the relatively stable succinyl derivative 39 [34] re-
sulting from a triethylamine-triggered cyclization of 38 were
isolated) [35-37]. The treatment of compound 38 with a catalyt-
ic amount of gold(I) in warm toluene provided us with the oxa-
zoline 40 in an 80% yield. However, this compound turned out
to be unstable, either on standing, probably because of an autox-
idation, as reported in other instances [27], or in CDCl3, proba-
bly because of acid traces. To achieve its isomerization, a litera-
ture search pointed out the use of an excess of DBU and heat
[38,39]. However, boiling compound 40 in toluene in the pres-
ence of an excess of DBU led, after chromatography, to only
Scheme 4: Syntheses of α-hydroximino ester 29 and α-amino ester
36.
conditions described in the literature (0 °C, mixture of metha-
nol and dimethylformamide as a solvent), without much success
in our case. Quite a few trials followed, changing the solvent to
a dichloromethane/dimethylformamide mixture or dimethyl-
formamide alone, or modifying the reaction conditions (at room
temperature, 0 °C or −20 °C), but none resulted in a flagrant
improvement. Indeed, as precisely described in the experimen-
tal part, the (impure) target nitroester 30 was isolated once in a
disappointing 22% yield and quite a few byproducts were
noticed. A control experiment omitting the ethyl nitroacetate (4)
allowed us to identify amongst these: the oxazole derivative 31
resulting from an isomerization of 25 as well as alcohol 32 re-
sulting from an oxidation of compound 25. Accordingly, this
greatly dampened our hope to improve this transformation
(trials with manganese(III) acetate were not successful either).
Scheme 5: Synthesis of α-amino ester 43.
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Beilstein J. Org. Chem. 2018, 14, 2846–2852.
24% of the benzyl ester 41. Since, amongst few side reactions, Acknowledgements
we suspected a benzylester cleavage, we undertook this reac- This work was supported by the Agence Nationale de la
tion under argon in ethanol at 110 °C using a microwave reactor Recherche (ANR), grant ANR-11-CRNT-0004, in the context
along with only one equivalent of DBU and these changes pro- of the investment program ‘GLOBAL CARE’, an association of
vided us with the ethyl ester 42 in a 51% yield. Finally, a far the Instituts Carnot ‘Pasteur-Maladies Infectieuses’, ‘Curie-
more simple procedure was found by just adding a catalytic Cancer’, ‘Voir et Entendre’, ‘Institut du Cerveau et de la moelle
amount of hydrogen chloride in 1,4-dioxane to the toluene solu- Épinière’ and the ‘Consortium pour l’Accélération de l’Innova-
tion containing compound 40. This afforded, after overnight tion et de son Transfert dans le domaine du Lymphome’
stirring, the isomerized compound 41 in a 69% yield. Finally, (CALYM). This project also benefited from the Valoexpress
the deprotection of the amine function was achieved with the funding call of the Institut Pasteur. Prof. Christian Bréchot, Dr.
use of an excess of hydrogen chloride in 1,4-dioxane to give the Muriel Delepierre and Dr. Daniel Larzul, from the Institut
target α-amino ester 43.
Pasteur are acknowledged for their interest and support.
ORCID® iDs
Conclusion
Glwadys Gagnot - https://orcid.org/0000-0002-5778-995X
Eloi P. Coutant - https://orcid.org/0000-0002-5571-7442
Yves L. Janin - https://orcid.org/0000-0003-3019-9842
In the course of our attempts to extend the use of ethyl nitro-
acetate (4) to prepare α-amino ethyl esters via condensation
reactions with aldehydes 3 or dimethylacetals 5, some severe
limitations were encountered. Indeed, the ubiquitous occur-
rence of aryl methyl esters, arising from an unwanted O-alkyl-
ation of ethyl nitroacetate (4), plagued all our efforts to improve
the latter synthetic pathway [2]. This side reaction pretty much
limited the approach to electron-rich substrates and even our
attempts to use the acylals 7 or 8, easily made from 2-trifluo-
romethylbenzaldehyde (3j), were very moderately successful.
Such phenomenon probably accounts for the modest yields re-
ported in many instances even when using titanium tetra-
chloride to achieve this condensation [5,6]. Concerning the
reduction of the nitroacrylates 2 into the α-nitro esters 6,
tangible but still modest yield improvements were observed
when using sodium cyanoborohydride instead of sodium boro-
hydride in some cases. This actually illustrates the sensitivity of
this reduction which, along with the condensation, are quite
limiting. As described above, the recourse to cycloaddition-
based approaches allowed us to explore some original chem-
istry aiming at the preparation of oxazole-bearing α-amino
esters which was of interest per se. Indeed, the previously unre-
ported acid-catalyzed conditions to achieve the isomerization of
the methylene-bearing oxazoline 40 into oxazole 41 should be
useful in many other instances. In any case, as described in a
following report [40], to overcome some of the limitations de-
scribed here, we then focused on an exhaustive investigation of
malonate-based strategies and reached an even more diverse set
of α-amino esters.
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