Non-hydrolytic chemoselective cleavage of Ugi tertiary amides: A mild access to N-substituted α-amino acid amides

Article abstract of DOI:10.1016/j.tetlet.2018.02.017

N-Substituted α-amino acid amides can be easily obtained in two steps using the four-component Ugi reaction followed by chemoselective cleavage of the resulting tertiary amide. The use of the sacrificial acid, 2-hydroxymethylbenzoic acid is associated to

Full text of DOI:10.1016/j.tetlet.2018.02.017

Accepted Manuscript
Non-hydrolytic chemoselective cleavage of Ugi tertiary amides: a mild access
to N-substituted α-amino acid amides.
Mariateresa Giustiniano, Sveva Pelliccia, Ettore Novellino, Gian Cesare Tron
PII:
S0040-4039(18)30184-9
https://doi.org/10.1016/j.tetlet.2018.02.017
TETL 49702
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 January 2018
5 February 2018
6 February 2018
Please cite this article as: Giustiniano, M., Pelliccia, S., Novellino, E., Tron, G.C., Non-hydrolytic chemoselective
cleavage of Ugi tertiary amides: a mild access to N-substituted α-amino acid amides., Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.02.017
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Graphical Abstract
Non-Hydrolytic Chemoselective Cleavage of
Ugi Tertiary Amides: A Mild Access To N-
Substituted α-Amino Acid Amides.
Leave this area blank for abstract info.
*
†a
†a
a
*b
Mariateresa Giustiniano, Sveva Pelliccia, Ettore Novellino and Gian Cesare Tron

1
Tetrahedron Letters
Non-hydrolytic chemoselective cleavage of Ugi tertiary amides: a mild access to
N-substituted α-amino acid amides.
*
†a
†a
a
*b
Mariateresa Giustiniano, Sveva Pelliccia, Ettore Novellino and Gian Cesare Tron
a
Dipartimento di Farmacia, Università degli Studi di Napoli “Federico II”, via D. Montesano 49, 80131 Napoli, Italy.
Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale “A. Avogadro”, Largo Donegani 2, 28100 Novara, Italy.
The authors equally contributed to this work.
b
†
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
N-substituted α-amino acid amides can be easily obtained in two steps using the four-component
Ugi reaction followed by chemoselective cleavage of the resulting tertiary amide. The use of the
sacrificial acid, 2-hydroxymethylbenzoic acid is associated to shorter reaction times, higher
yields, and safer and greener reaction conditions compared to strategies based on trifluoroacetic
acid, a toxic and environmental hazardous reagent. The optimized procedure was easily scaled
up to gram amounts.
Available online
Keywords:
Ugi reaction
α-amino acid amides
Isocyanides
2
009 Elsevier Ltd. All rights reserved.
Tertiary amides
Green reaction
N-substituted α-amino acid amides are important for both
organic and medicinal chemists due to their intrinsic potential in
both fields, exemplified by a plethora of organic transformations
other hand, one or both the amides could be hydrolyzed forming
important building blocks such as natural and unnatural N-
substituted α-amino acids (6), N-alkyl,N’-acyl α-amino acids (7),
and N-substituted α-amino acid amides (8), (Scheme 1).
1
developed on this structural element , their use in
2
organocatalysis , and their privileged structure status for the
3
induction/modulation of bioactivity . For these reasons, there is
no shortage of methods for their preparation, the most popular
4
being N-alkylation of α-aminoamides , SN
2
reaction on α-
5
haloamides with amines , amidation of N-alkyl α-amino acid
esters , Strecker reaction followed by nitrile hydrolysis and amine
coupling , ruthenium catalyzed amination of α-hydroxy amides ,
and copper catalyzed amination of α-bromocarboxamides . None
6
7
8
9
of these strategies is free from drawbacks, which range from
scarce reactivity to over-alkylation. As a result, the preparation
and the purification of N-substituted α-amino acid amides are not
trivial tasks. Compared to these strategies, the chemoselective
hydrolysis of Ugi adducts has a remarkable simplification
potential, being atom economical and environmentally benign
Scheme 1. Hydrolytic pathways of bis-amide 5.
12
(
no coupling agents or expensive transition metals are indeed
While different procedures have been reported for scaffolds
(6) and (7), the chemoselective hydrolysis of the tertiary amide
versus the secondary amide of the Ugi scaffold is still largely
unexplored. In practice, trifluoroacetic acid (9) is used as acidic
component to give the Ugi adduct 10, allowing for an easier
hydrolysis of the tertiary amide compared to the secondary one
thanks to its more electrophilic character. The hydrolysis has
1
0
required). The Ugi reaction is a four-component reaction
between an aldehyde (1), a primary amine (2), a carboxylic acid
(3), and an isocyanide (4) leading to the one pot formation of a
variously decorated racemic bis-amides (5). Usually, the reaction
is performed in methanol at room temperature and complies with
several principles of green chemistry. Only one equivalent of
water is indeed formed during this transformation and yields are
generally good, resulting in excellent green chemistry metrics in
terms of atom economy (AE), Reaction Mass Efficiency (RME),
consistency, and selectivity. Bis-amides (e.g. 5) have been long
exploited as advanced synthons for the synthesis of more
13
been reported either in basic (LiOH 50% aq., MeOH, 60°C) and
14
acid conditions (TsOH, MeOH, 50°C), or via amide reduction
1
5
using sodium borohydride, albeit in low yields (Scheme 2).
Thus, up to 8 equivalents of LiOH were requested to cleave the
trifluoroacetamide function, translating in a large amount of salts
to dispose after the reaction.
11
complex structures via post-condensation strategies. On the

2
Tetrahedron
(16), was investigated as the model reaction. The Ugi reaction
was carried out in methanol at 60°C and it was completed in less
then 2 h, affording the expected Ugi adduct 17 in 85% yield after
chromatographic purification (Scheme 4). For comparison, when
the same reaction was carried out with trifluoroacetic acid, the
reaction required 2 days, and the yield was only 43%. With the
model compound in hands, we evaluated the chemoselective
cleavage of the tertiary amide vs the secondary amide, by stirring
1
7 in a 4N HCl solution in 1,4-dioxan. After 10 minutes,
Scheme 2. Hydrolysis of trifluoroacetamide 10: a) LiOH 50%
aq., MeOH, 60°C; b) TsOH, MeOH, 50°C.
complete conversion of the Ugi adduct 17 to the amine
hydrochloride 18 and phtalide 13 was observed. The same
reaction, when performed in methanolic 3N HCl, was only
slightly slower (30 minutes).
Despite the undoubted appeal of this method, Sci-Finder®
Scholar only lists 33 cases of Ugi adduct formed using
trifluoracetic acid, and 15 examples of selective hydrolysis of the
tertiary trifluoroacetamide to N-substituted α-amino acid amides.
Several reasons seemingly underlie this paucity of
documentation. Thus, trifluoroacetic acid is a very strong acid
with a pKa of -0.25. This strong acidity can be devastating for
acid sensitive substrates. For example, isocyanides can be easily
hydrolyzed to formamides in the presence of trifluoroacetic acid
16
and water . Moreover, the trifluoroacetate ion is less
nucleophilic compared to the classical carboxylic acids used in
the Ugi reaction, resulting in higher reaction time (2 days) and
reduced yields. Scale-up problems should also be considered.
Trifluoroacetic acid, indeed, is a strong corrosive and toxic
substance, which requires special storage, handling and
equipment when used in a chemical plant. Finally, during the
hydrolytic cleavage of the trifluoroacetamide, trifluoracetic acid
is again formed. This acid is completely miscible in water and it
is not biodegradable posing important environmental burden also
1
7
because it cannot be incinerated due to the generation of HF .
Given the organic and medicinal chemistry relevance of N-
substituted α-amino acids, we have explored the identification of
a more practical, safer, greener and economical approach based
on the replacement of trifluoracetic acid with 2-hydroxy-
methylbenzoic acid (11). We had already reported the use of
this acid as sacrificial component in the Mumm-like
Scheme 4. Ugi reaction and selective acidic cleavage of 17.
To test the robustness of this novel synthetic approach, the
reaction was scaled to gram amounts (10 mmol), affording the
amine 18 in 48% overall yield (2 steps) and 97% purity without
chromatographic purification (see Supporting Information for
HPLC analysis). The scope of this strategy was then evaluated
using different amines, aldehydes, and isocyanides (Figure 1) and
the results are reported in Table 1.
18
rearrangement where it behaves as a molecule of water, paving
the way to the overall generation of bis-(β-aminoamides) via an
Ugi-like reaction based on symmetrical secondary diamines as
starting materials. A water-like behavior was also demonstrated
19
in the synthesis of α-aminocarbonyl hydrazones and α-
20
hydroxyamides . We were therefore confident that the use of 2-
hydroxymethylbenzoic acid in a Ugi reaction with primary amine
should follow the classic Mumm rearrangement, with formation
of the desired Ugi adduct 12. Under acidic conditions, the
hydroxymethylene moiety ortho to the tertiary amide should
promote, by anchimeric assistance, the counter-thermodynamic
2
1
alcoholysis of the amide function , preserving the more delicate
secondary amide on the other side of the molecule and giving the
phthalide (13) as the sole by-product. This could then be
recovered and re-transformed in 2-hydroxymethylbenzoic acid by
18
lactone hydrolysis under basic conditions (Scheme 3).
Figure 1. Starting aldehydes, isocyanides and amines used.
Scheme 3. Ugi reaction with 2-hydroxymethylbenzoic acid,
and acidic cleavage of 12.
Both aromatic electron-rich (16, 19, 21, 24, and 25) and
electron-poor aldehydes (20 and 22) have been successfully used
as well as aliphatic ones (23, 27, and formaldehyde 26). When
ketones were used in the Ugi reaction, the cleavage of the
To test this hypothesis, the combination of 11,
cyclohexylisocyanide (14), hexylamine (15) and p-anisaldehyde

3
corresponding Ugi products was not able to afford the desired N-
substituted α,α-di-substituted-α-amino acid amides, and only
degradation of the starting materials was observed. On the other
hand, aliphatic (15, 37, and 38), benzylic (34, 35, and 36) and
aromatic amines (39) were tolerated, and the N-substituted
aniline proved to be stable to the reaction conditions. Finally,
primary (31), secondary (14), and tertiary (30) isocyanides, and
also benzylisocyanide 32 were used as inputs, and all the
corresponding amides in the Ugi products, including the acid-
labile tert-butyl and 1,1,3,3-tetramethylbutyl- radicals, resulted to
be completely orthogonal to the tertiary amide readily affording
the desired N-substituted-α-amino acid amides, except for 4-
methoxyphenylisocyanide 33, which gives products 51 and 52
with low yields and sluggish TLC.
intramolecular cleavage of the tertiary amide from the Ugi
reaction was of critical relevance. The cleavage of the tertiary
amide of Ugi bis-amides was performed under mild acidic
condition that left the more hydrolytically labile secondary amide
unscathed. Beyond the literature reported methodologies based
22
on a catalytic three-component Ugi reactions , selective
hydrolysis or cleavage of Ugi four component reactions amides is
23
still considered a challenging task , as amides are poor
electrophiles due to resonance stability of the amide bond, and
the selective cleavage of C-N bond generally requires enzymes.
Herein, we provided an efficient and green synthetic approach,
where the 2-hydroxymethylbenzoic acid used in the Ugi reaction
can be considered a recyclable and atom efficient protecting
group of bis-amides.
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgments
Financial support from University of Naples Federico II and
University of Piemonte Orientale, Novara, is acknowledged.
M. G. acknowledges AIRC (MFAG 18793).
References and notes
1
.
(a) For some selected examples see: Calvo L, González-Ortega A,
Navarro R, Pérez M, Sañudo MC. Synthesis 2005;3152-3158; (b)
Ooi T, Takeuchi M, Kato D, et al. J Am Chem Soc.
2
005;127:5073-5083; (c) Dumbris SM, Díaz DJ, McElwee-White
L. J Org Chem. 2009;74:8862-8865; (d) Scott WL, Zhou Z,
Martynow JG, O’Donnell MJ. Org Lett. 2009;11:3558-3561; (e)
Blid J, Brandt P, Somfai P. J Org Chem. 2004;69:3043-3049.
Xu Y, Córdova A. Chem Commun. 2006;460-462.
For some examples see: (a) Chiesi P, Ventura P, Delcanale M, et
al. 1998, WO9803472; (b) Faggi E, Luis SV, Alfonso I. RSC Adv.
2
3
.
.
2
013;3:11556-11565; (c) LeTiran A; Stables JP, Kohn H. Bioorg
Med Chem 2001;9:2693-2708; (d) Ghidini, E.; Delcanale, M.; De
Fanti, R.; et al. Bioorg Med Chem. 2006;14:3263-327; (e)
Famiglini V, Coluccia A, Brancale A. Future Med. Chem.
2
013;5:2141-2156.
4
.
(a) Kobayashi, J.; Hirasawa, H.; Ozawa, T.; et al. Bioorg Med
Chem. 2017;25:727-742; (b) Abdel-Magid AF, Carson KG, Harris
BD, et al. J Org Chem. 1996;61:3849-3862.
5
6
7
.
.
.
Smith HK, Beckett RP, Clements JM, et al. Bioorg Med Chem
Lett. 2002;12:3595-3599.
Xu K-X, Wu X-J, He Y-B, et al. Tetrahedron: Asymmetry
2
005;16:833-839.
(a) Ishitani H, Komiyama S, Hasegawa Y, Kobayashi S. J Am
Chem Soc. 2000;122:762-766; (b) Iyer MS, Gigstad KM, Namdev
ND, Lipton M. J Am Chem Soc. 1996;118:4910-4911.
Zhang M, Imm S, Bähn S, et al. Angew Chem Int Ed.
8
9
.
.
Table 1. Library of synthesized N-substituted-α-amino acid
amides. (a: Yields in parentheses are referred to the Ugi reaction
after chromatographic purification).
2
011;50:11197-11201.
Ishida S, Takeuchi K, Taniyama N, et al. Angew Chem Int Ed.
2017;56:11610-11614.
1
1
0. (Dömling A, Ugi I. Angew Chem Int Ed. 2000;39:3168-3210.
1. (Akritopoulou-Zanze I, Djuric SW. Heterocycles 2007;73:125-
146.
Any attempt to further purify them proved fruitless,
suggesting stability problems. It is important to highlight that the
conversion of the Ugi products has been always quantitative, and
the final N-substituted-α-amino acid amides have been isolated as
hydrochloride salts in different yields (Table 1) after trituration.
Evaporation of the organic solvents used for the trituration gave
quantitatively the phthalide, which could be easily recycled
through basic hydrolysis, preserving the greenness and the
perfect atom economy of the Ugi four components reaction. In
summary, we have developed a fast, green, waste less, and
scalable synthesis of N-substituted α-amino acid amides. The use
of 2-hydroxymethylbenzoic acid as an efficient component both
for the synthesis of the Ugi adduct and for the chemoselective
1
2. (a) Cioc RC, Preschel HD, van der Heijden G, et al. Chem Eur J.
2
016;22:7837-7842; (b) van der Heijden G, (Sjaak) Jong JAW,
Ruijter E, Orru RVA. Org. Lett. 2016;18:984-987; (c) Chandgude
AL, Li J, Dömling A. Asian J Org Chem. 2017;6:798-801; (d)
Giustiniano M, Basso A, Mercalli V, et al. Chem Soc Rev.
2017;46:1295-1357; (e) Costa SPG, Maia HLS, Pereira-Lima
SMMA. Org Biomol Chem. 2003;1: 1475-1479; (f) Takashi Y,
Noboru M, Teiji T, et al. Chem Lett. 1987;16:723-726.
1
1
3. Lesma G, Bassanini I, Bortolozzi R, et al. Org Biomol Chem.
2
015;13:11633-11644.
4. Narendra N, Vishwanatha TM, Nagendra G, Sureshbabu VV.
Tetrahedron 2012;68:1992-2000.
15. White TD. 2012, PCT Int. Appl., 2012030258.

4
Tetrahedron
1
6. We have observed that cyclohexylisocyanide in the presence of
eq of TFA and 1 eq of water is completely hydrolyzed to the
corresponding formamide in less then 10 minutes.
20. Serafini M, Griglio A, Oberto E, et al. Tetrehedron Lett.
2017;58:4786-4789.
1
21. Osby JO, Martin MG, Ganem B. Tetrahedron Lett. 1984;25:2093-
2096.
22. Pan SC, Listꢀ B. Angew Chem Int Ed. 2008;47:3622 –3625
23. Hie L, Fine Nathel NF, Shah TK, et al. Nature 2015;524:79-83.
1
1
1
7. Johnson (Ed.) DS, Li (Ed.) JJ. The art of drug synthesis, 2007,
John Wiley & Sons, Inc., Hoboken, New Jersey.
8. La Spisa F, Feo A, Mossetti R, Tron GC. Org Lett. 2012;14:6044-
6
047.
9. Giustiniano M, Mercalli V, Novellino E, Tron GC. RSC Adv.
016;6:34913-34920; Giustiniano M, Meneghetti F, Mercalli V, et
2
al. Org Lett. 2014;16:5332-5335.
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CHEMOSELECTIVE CLEAVAGE
ATOM ECONOMY
RECYCLABLE SYNTHON
WASTELESS AND SCALABLE
SYNTHESIS
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SAFE AND GREEN REACTION
CONDITIONS