Convergent Route to β-Amino Acids and to β-Heteroarylethylamines: An Unexpected Vinylation Reaction

Article abstract of DOI:10.1021/acs.orglett.0c01087

Various protected β²-amino acids can be prepared by radical addition of β-phthalimido-α-xanthyl propionic acid, both as the free acid or as the ethyl ester. Successive radical additions provide access to more complex structures. In the case of the free acid, addition to certain heteroaromatics leads directly to β-heteroarylethylamines through spontaneous decarboxylation of the intermediate adduct. Forcing the decarboxylation in some cases generated a vinyl group by decarboxylative elimination of the phthalimido group.

Full text of DOI:10.1021/acs.orglett.0c01087

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Letter
Convergent Route to β‑Amino Acids and to
β‑Heteroarylethylamines: An Unexpected Vinylation Reaction
Xuan Chen and Samir Z. Zard*
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ABSTRACT: Various protected β2-amino acids can be prepared by
radical addition of β-phthalimido-α-xanthyl propionic acid, both as the
free acid or as the ethyl ester. Successive radical additions provide
access to more complex structures. In the case of the free acid, addition
to certain heteroaromatics leads directly to β-heteroarylethylamines
through spontaneous decarboxylation of the intermediate adduct.
Forcing the decarboxylation in some cases generated a vinyl group by
decarboxylative elimination of the phthalimido group.
Scheme 1. Radical-Based Route to β2-Amino Acids
he β-amino acids and their derivatives are compounds of
1
2
Tremarkable versatility. They are precursors of β-lactams,
of metabolically stable peptidomimetics,3 of various bio-
logically active substances, and of numerous ligands for
transition-metal-based catalysts.4 The β-amino acid motif is
present in a number of important natural products,5 the most
prominent of which are perhaps the anticancer taxol, the β-
lactam family of antibiotics,2 and β-lysine (or isolysine),6 a
mild antibiotic found in tears that causes lysis of many Gram-
positive bacteria.
Most of the synthetic efforts have concerned β-amino acids
with substituents on the carbon bearing the amino group,1 the
so-called β3-amino acids according to the nomenclature
introduced by Seebach.7 β2-Amino acids have attracted
comparatively less attention, despite their potential utility for
synthesis and for medicinal chemistry.8 They are also much
less readily accessible than their β2 congeners. We describe
now a convergent and flexible route to β2-amino acids that
exploits the lack of β-elimination of β-imido radicals and the
unique properties of the degenerative xanthate addition-
transfer process.9,10 An offshoot of this study is a
straightforward synthesis of β-heteroarylethylamines and an
unexpected vinylation reaction.
The conception underlying our synthetic approach is
outlined in Scheme 1. It hinges on the expectation that radical
2 derived from xanthate 1 will not undergo a β-elimination of
phthalimidyl radical 5 before adding to the alkene. This is in
contrast to the corresponding anion 6 which would readily
eliminate phthalimidyl anion 7 (PhthN = phthalimido). A
further non-negligible advantage of proceeding through radical
intermediates generated from the corresponding xanthate is
that nonactivated, electronically unbiased alkenes bearing
numerous functionalities, especially polar groups, can be
used as traps.9
The synthesis of the requisite xanthate from known bromide
911 was straightforward (Scheme 2). We were pleased to find
that, as anticipated, the addition to allyl cyanide took place
without β-scission of the phthalimide (DLP = dilauroyl
peroxide, also sold under lauroyl peroxide, Laurox, or Luperox
LP). The reaction was conducted neat, without any solvent,
and furnished adduct 4a in high yield. Other examples of
addition are provided in the same Scheme. The yields are
generally higher than typical xanthate additions and reflect
presumably the increased electrophilic character of intermedi-
ate radical 2 caused by the presence of the adjacent
Received: March 25, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01087
© XXXX American Chemical Society
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Scheme 2. Synthesis of Protected β2-Amino Acids
intermolecular additions is a unique property of the xanthate
addition-transfer and allows rapid access to complex structures
that would be very tedious to obtain by more conventional
ionic or organometallic methods.
We further found that the radical additions could be
accomplished from the free carboxylic acid 15 (Scheme 4).
Scheme 4. Synthesis of N-Protected β2-Amino Acids
phthalimide group. All the reactions were performed neat,
except for the addition to vinyl MIDA boronate (example 4g),
which was performed in ethyl acetate at a 1 M concentration.
In this case the yield was almost quantitative, reflecting the
matched polarity between electrophilic radical 2 and electron-
rich vinyl MIDA boronate. The boron substituent is negatively
charged and releases electrons into the attached vinyl group.12
As can be seen upon inspection, many different functional
groups are tolerated on the alkene. One interesting case is that
of adduct 4d to vinyl pivalate (Piv = pivalate). The carbon
bearing both the xanthate and the pivalate has the oxidation
level of an aldehyde, and such compounds have a very rich
chemistry.13 In all of these additions, a 1:1 mixture of
diastereoisomers is produced. The xanthate group can be
reductively removed, which simplifies the structures, or used to
create another carbon−carbon bond and thus increase further
the complexity. Both of these possibilities are illustrated in the
sequence in Scheme 3.
This compound was prepared from bromide 14, itself obtained
from 2-phthalimidopropionic acid 13 by the classical Hell−
Volhard−Zelinsky reaction.11,17 The substitution leading to
xanthate 15 was surprisingly only modestly efficient, and more
work is still needed to improve the yield. Nevertheless, the
precursors are readily available, and sufficient quantities could
be easily secured to complete the present preliminary study.
The radical addition proceeded normally, even if the yields of
adducts 16a−d were generally slightly lower than with the
corresponding ester 1 (Scheme 4). The xanthate was
reductively removed in the first three products to give the
simpler derivatives 17a−c. The possibility of creating carbon−
carbon bonds starting with a free carboxylic acid is remarkable,
and a hallmark of radical processes, even if it has been seldom
used hitherto. Only a handful of intermolecular additions to
unactivated alkenes have been reported starting with iodoacetic
and 2-iodopropionic acids.18 In view of the numerous α-
xanthyl carboxylic acids that can in principle be made by
exploiting the Hell−Volhard−Zelinsky reaction and other
processes, such as the radical addition of a xanthate to acrylic
acid, this addition acquires a significant synthetic relevance.
Another interesting application of xanthate 15 is the direct
introduction of an ethylamine moiety into heteroaromatics. β-
(Hetero)arylethylamines represent perhaps the most important
class of substances interacting with the central nervous system
(CNS).19 A few of these compounds are pictured in Figure 1.
These can be endogenous neurotransmitters, such as
dopamine 18 and serotonin 19, or natural products with
psychedelic and hallucinogenic activity, or even synthetic drugs
such as the antidepressant venlafaxine and the antiobesity
lorcaserine. The ethylamine motif highlighted in blue can be a
simple pendant, substituted on the carbon chain or on the
nitrogen, or even part of a ring.
Scheme 3. Example of Successive Radical Additions
The addition of xanthate 1 to N-vinyl phthalimide was
conducted in ethyl acetate at a 1 M concentration (Scheme 3).
The resulting adduct 4h could, in turn, be made to add to
methyl 10-undecylenate to give a second adduct 10, also in
high yield. We had found previously that xanthates geminal to
imide groups were suitable partners for the radical addition and
provide a very powerful route to functional amines.14 Indeed,
this property was exploited to access β3-amino acids.15
Reductive elimination of the xanthate group using Barton’s
reagent16 and deprotection of the phthalimide furnished
aminomethyl substituted lactam 12, where the ring closure
occurred spontaneously. The ability to accomplish successive
The addition of xanthate 15 to a number of heteroaromatic
structures could be accomplished by using stoichiometric
B
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Scheme 6. Possible Pathway for Vinyl Formation
Figure 1. Examples of biologically active β-(hetero)arylethylamines.
amounts of peroxide.20 The initial adduct 26 underwent
spontaneous decarboxylation in some cases to furnish the
corresponding phthalimide protected β-aminoethyl derivative
(Scheme 5). This transformation is illustrated by the formation
then eliminates phthalimide in a step that restores at the same
time the aromaticity of the heteroaromatic ring. An attempt to
accomplish just the decarboxylation step without concomitant
elimination of the phthalimide by heating compound 26i
gradually was unsuccessful. Only vinyl derivative was observed
forming at 170 °C. Indeed, the decarboxylation process is
necessary for the elimination of the phthalimide. Prolonged
microwave heating of caffeine derivative 27a at the higher
temperature of 250 °C did not result in any reaction.
Furthermore, we found that, under these harsher conditions,
aliphatic acid 17e, which cannot undergo a retro-ene loss of
CO2, was converted in poor yield into acrylic acid product 32.
The present expedient route to (hetero)arylmines comple-
ments the approach recently described by Jui and co-workers,
where (hetero)arylmines were prepared by (hetero)aryl radical
addition to enamides.22
Scheme 5. Synthesis of N-Protected Heteroarylethylamines
It is further noteworthy that radical reactions have almost
never been used for the synthesis of β2-amino acids. Indeed, a
literature search revealed reports by only two research groups,
where a radical in position-2 of a β-amino acid or ester was
generated and captured. In both cases, an intramolecular
reaction is involved (34 → 35 and 37 → 38 in Scheme 7).23
Scheme 7. Literature Examples of β3-Amino Acid Esters
Obtained by Radical Cyclization
of compounds 27a−g in moderate yield. Interestingly, the
reaction with pyrrole gave rise to both the monoadduct 27e
and bis-adduct 27f, the latter being the major product.
In contrast to the case of 3-methylindole (adduct 27g), the
reaction with ethyl 2-indolecarboxylate did not result in
spontaneous decarboxylation, and carboxylic acid 26h was
isolated in 60% yield. Addition to 6-phenyl imidazo[2,1-
b]thiazole also did not result in decarboxylation and furnished
efficiently compound 26i. Not only was the yield significantly
higher than average, but the product crystallized directly from
the reaction mixture and was isolated by simple filtration. This
reaction was easily scaled up (1.2 g); albeit, the yield was
somewhat lower (60%). Interestingly, when we attempted to
decarboxylate both 26h and 26i by briefly heating a solution in
N-methylpyrrolidone (NMP) in a microwave oven at 220−230
°C,21 the reaction furnished cleanly vinyl derivatives 28 and
29, respectively.
Xanthates provide an opportunity for intermolecular additions,
even to unactivated alkenes. This results in a versatile, modular,
and flexible route to a broad variety of β2-amino acids, thus
considerably expanding the range of attainable structures. As
stated in the introduction, β2-amino acids are much less
accessible than the more common β3-amino acids. Further-
more, the same xanthate 15 serves to prepare β2-amino acids
and β-heteroarylethylamines, both of which are valuable for
medicinal chemists. The cheapness and ready availability of the
reagents, the mildness of the experimental conditions, and the
compatibility with many functionalities, especially polar
groups, are significant practical advantages.
A possible explanation for the vinyl formation is provided in
Scheme 6. At the high temperature required to decarboxylate
adducts 26 which do not spontaneously extrude carbon
dioxide, the retro-ene reaction leads to intermediate 30 which
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01087.
■
sı
Experimental procedures, full spectroscopic data, and
1
copies of H and 13C NMR for all new compounds
(PDF)
(8) (a) Lelais, G.; Seebach, D. β2-Amino AcidsSyntheses,
Occurrence in Natural Products, and Components of β-Peptides.
Biopolymers 2004, 76, 206. (b) Nagula, G.; Huber, V. J.; Lum, C.;
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Impact of the Degenerative Transfer of Xanthates on Synthetic
Planning. Isr. J. Chem. 2017, 57, 202. (b) Quiclet-Sire, B.; Zard, S. Z.
Fun with Radicals: Some New Perspectives for Organic Synthesis.
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AUTHOR INFORMATION
Corresponding Author
■
̀
Samir Z. Zard − Laboratoire de Synthese Organique, CNRS
UMR 7652 Ecole Polytechnique, 91128 Cedex Palaiseau,
France; orcid.org/0000-0002-5456-910X;
Email: samir.zard@polytechnique.edu
Author
̀
Xuan Chen − Laboratoire de Synthese Organique, CNRS UMR
7652 Ecole Polytechnique, 91128 Cedex Palaiseau, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01087
(10) For an account of the discovery of this process, see: (a) Zard, S.
Z. The Genesis of the Reversible Radical Addition-Fragmentation-
Transfer of Thiocarbonylthio Derivatives from the Barton-McCombie
Deoxygenation. A brief Account and some Mechanistic Observations.
Aust. J. Chem. 2006, 59, 663 For a discussion of the mechanism, see:.
(b) Zard, S. Z. Radical Alliances: Solutions and Opportunities for
Organic Synthesis. Helv. Chim. Acta 2019, 102, No. e1900134.
(c) Zard, S. Z. Some Intriguing Mechanistic Aspects of the Radical
Chemistry of Xanthates. J. Phys. Org. Chem. 2012, 25, 953.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the China Scholarship Council for a scholarship to
X.C. and Mrs. Sophie Bourcier and Mr. Vincent Jactel (both at
Ecole Polytechnique) for HRMS measurements.
̈
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DEDICATION
■
This article is dedicated with respect to the memory of
Professors Dieter Enders (RWTH Aachen University) and
Albert van Leusen (University of Groningen).
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