'Atypical Ugi' tetrazoles

Article abstract of DOI:10.1039/c9cc09194g

Amino acid-derived isocyano amides together with TMSN₃, oxocomponents and 1° or 2° amines are common substrates in the Ugi tetrazole reaction. We surprisingly found that combining these substrates gives two different constitutional isomeric Ugi products A and B. A is the expected classical Ugi product whereas B is an isomeric product ('atypical Ugi') of the same molecular weight with the tetrazole heterocycle migrated to a different position. We synthesized, separated and characterized 22 different isomorphic examples of the two constitutional isomers of the Ugi reaction to unambiguously prove the formation of A and B. Mechanistic studies resulted in a proposed mechanism for the concomitant formation of A and B.

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'Atypical Ugi' Tetrazoles
Eman M.M. Abdelraheema,b, Imogen Goodwina, Shabnam Shaabania, Michel P. de Haana,
Katarzyna Kurpiewskac, Justyna Kalinowska-Tłuścikc, and Alexander Dömlinga*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
ABSTRACT: Amino acid-derived isocyano amides together with 1,5-Disubstituted tetrazoles are well-known bioisosteres of
TMSN3, oxocomponents and 1o or 2o amines are common carboxylic acids and cis-amides and thus widely used in
substrates in the Ugi tetrazole reaction. We surprisingly found that chemical biology and medicinal chemistry.1 One of the most
combining these substrates gives two different constitutional competitive synthetic pathways towards this important scaffold
isomeric Ugi products A and B. A is the expected classical Ugi is the Ugi tetrazole reaction (Scheme 1).2 Recently, we
products whereas B is an isomeric product (‘atypical Ugi’) of the introduced a straight forward way for the synthesis of α-, β- and
same molecular weight with the tetrazole heterocycle migrated to higher amino acid-derived isocyano amides.3 Isocyano
a different position. We synthesized, separated and characterized acetamides are very versatile building blocks and have been
22 different isomorphic examples of the two constitutional isomers used in Ugi and Passerini multicomponent reactions as well as
of the Ugi reaction to unambiguously prove the formation of A and in heterocycle syntheses, for example for the synthesis of
B. Mechanistic studies resulted in a proposed mechanism for the tetrazoles,4 imidazoles,5 iminohydantoins,6 oxazoles7 and for
concomitant formation of A and B.
the production of functional materials such as giant vesicles,8
PEGylated polymers,9 proline-like β-turn mimics,10 functional β-
sheet mimics,11 tryptase and FXa inhibitors,12 inhibitors of
hepatitis C virus NS3 protease,13 Src-family kinase p56Lck
inhibitors,14 erythropoietin mimicking small molecules,15
selenopeptido mimetics,16 hydrogels,17 polyisocyanides for
bioscaffolding,18
peptide
ligations,19
polyamines,20
spirocycles,21 functionalized fullerenes,22 natural product
sandramycin,23 dendrimers24 and artificial macrocycles25 (Fig.
1). The chemistry of isocyanoacetate and derivatives has been
recently comprehensively reviewed.26 In an ongoing effort to
synthesize diversely substituted macrocycles using isocyanide
based multicomponent reactions (IMCR), we reported the first
time use of the Ugi tetrazole variation for macrocyclic ring
closure using amino acid derived isocyanides.27
a.
Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV
Groningen, The Netherlands. * a.s.s.domling@rug.nl
b. Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt
c.
Faculty of Chemistry, Jagiellonian University, 3 Ingardena Street, 30-060 Krakow,
Poland.
† General procedures, characterization data of all the compounds and crystal
structure determination are included as Supporting Information. The Supporting
Information is available free of charge on the ACS Publications website.
See DOI: 10.1039/x0xx00000x
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Figure 1. Bioisostery of 1,5-disubstituted tetrazoles (A), tetrazole Ugi reaction (B),
isocyanoacetamide synthesis (C). Herein reported: surprising finding of two
constitutional Ugi tetrazole isomers (D).
During analysis of several X-ray structures of tetrazole products
including macrocycles, we noted beside the formation of the
expected classical tetrazole products, the formation of
constitutional isomeric Ugi products in considerable amounts
where the tetrazole heterocycle was formally migrated from
the isocyanide position to the amide position introduced by the
amino acid-derived isocyano amide (Fig. 2). Surprised by the
unexpected formation of the atypical isomer we investigated
the reaction more thoroughly and want to report here synthesis
and separation of 22 compounds, analytical and structural
evidence for the formation of both isomers, and a mechanistic
proposal.
Figure 2. Observation of the ‘atypical Ugi’ tetrazole products besides expected
products, highlighted as red and green bolded structures respectively and X-ray
structures. In 6a the red dotted line indicates an intramolecular hydrogen bond
(Trt = trityl).
We thoroughly investigated the structural influence of the
substrates and reaction conditions on the ratio of A/B.
Numerous examples were characterized by different means, 1H-
NMR, 13C-NMR, 2D COSY and HMBC, for example in Fig. 3 the
key proton which is labeled by star * correlates to 157.5 ppm
(tetrazole-C) in compound 6i and correlates to 173.7 ppm
(carbonyl-C) in compound 7i (SI). Also, multiple compounds
were characterized by unambiguous X-ray structure analyses.
O
HN
N
N
H
*
N
N
N
O
HN
N
N
*
NH
N
N
7i
6i
1H-1H COSY
1H- 13C HMBC
Figure 3. 1H-1H COSY and 1H-13C HMBC correlations to differentiate between
compounds 6i and 7i.
The dependency of the formation of A and B on the α−amino
acid isocyanide was investigated with glycine, phenylalanine,
2 | J. Name., 2012, 00, 1-3
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tryptophan and valine. Thus, we synthesized several different isolation of the toxic and explosive hydrogen azide.
amino acid-derived isocyanides as their amides, by simply Unfortunately, no difference in A to B ratio was observed using
mixing the amine and isocyanoester under solvent-free different azide sources.
R1
N
N
N
R
H
2
N
O
N
N
TMSN3
O
O
N
conditions and generally could obtain the isocyanoamides in
good to excellent yields (Scheme 1). However, no influence of
the amino acid side chain towards A/B selectivity was observed.
Isocyanoamides are α-acidic and the pKa of an amide is 2-4 units
lower than the corresponding ester.26 Moreover, anionic
α−isocyanides are important intermediates in several
heterocycle formations such as oxazoles or oxazolidines.28 To
investigate the potential involvement of such isocyano
R3
N
UT-4CR
N
N
H
R3
NC
X
N
X
+
NH2
R3
R
N
R1
R2
H
m
O
MeOH, rt, 12 h
n
NH
H
m
m
n
R1
3
4
5
6
7
R2
(Regioisomer B)
(Regioisomer A)
N
N
O
O
N
N N
N
N
H
N
N
N
N
H
N
H
N
N
N
N
N
NH
Ph
N
N
H
Ph
Ph
N
NH
NH
Ph
Ph
O
Cl
N
H
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
Cl
6a, 24%
7a,16%
6b, 29%
7b, 21%
N
N
N
N
N
N
O
N
H
O
N
N
N
O
O
N
HN
HN
N
N
N
N
N
MeO
MeO
MeO
HN
N
H
NH
N
NH
NH
MeO
carbaniones
we
reacted
blocked
α,α−dimethyl
7d, 19%
Cl
6d
, 53%
6c, 44%
7c, 17%
Cl
F
isocyanoacetamide 3f. However, even with this isocyanide,
unable to form carbanions, the formation of A and B was
observed. Thus, an isocyano carbanion-based mechanism could
be ruled out.
N
F
F
N
N
N
F
F
N
N
O
H
HN
O
N
NH
N
NH
HN
N
N
HN
O
N
N
HN
F
NH
N
N
N
N
N
O
N
N
7e, 14%
6f, 44%
6e, 65%
7f, 14%
N
H
N
More elucidating was the investigation of the dependency on
the distance between the isocyanide and the amide group, e.g.
derived from α−, β−, γ− amino acids. As shown above, all α-
amino acid derived isocyanoacetamides 3a- 3f gave mixtures of
A and B (Scheme 2). Also, β-amino acid β-alanine-derived
isocyanide 3g and 3h gave A and B, although only small amounts
of B were formed (Scheme 3). Even more pronounced with γ-
amino acid derived 3i and 3j and with δ-amino acid derived 3k
no B could be detected anymore by SFC analysis of the crude
reaction. Thus, a clear dependence of the A/B ratio on the
distance between the amide group and the isocyanide was
established.
N
N
N
Cl
Cl
O
HN
O
HN
NH
HN
O
N
N
N
HN
N
N
N
N
O
N
N
N
N
N
HN
NH NH
HN
NH
6g, 62%
7g, 13%
6h, 49%
7h, 25%
NH
O
N
N
H
N
N
H
N
N
O
N
N
NH
HN
N
N
NH
NH
HN
O
HN
N
HN
N
N
O
HN
N
N
N
N
N
6i, 31%
7i, 23%
6j, 25%
7j, 15%
N
N
N
N
O
N
H
NH
HN
O
N
HN
H
NH
N
N
N
N
6k, 43%
7k, 19%
Scheme 2: ‘Crazy Ugi’ tetrazole products beside expected products from α-amino
acid derived isocyanoacetamides, highlighted as red and green bolded structures
respectively.
O
solventless
NC
MeOOC
NC
n
+
R1
NH2
R1
N
X
X
m
rt
H
n
m
1
2
3
O
O
O
NC
NC
NC
NC
The formation of A and B dependent on the reaction
temperature was investigated by SFC-MS as shown in Fig. 1 in
the SI. The change of the temperature of the reaction from
room temperature to 0 °C and -10 °C showed a slight increase
in the formation of the minor product B. Thus we speculate that
the minor product is the thermodynamic product, however it
did not greatly change the overall distribution of the
major/minor product. Several X-ray structures of the two
products A and B involving different substituents provide
unambiguous proof of the formation and give some first insight
into possible solid-state conformations (Figure 2 and Figure 4).
The plausible mechanism of the reaction is shown in Scheme 4.
It is conceivable that initially the condensation of the oxo-
component and amino group affords the Schiff base. Then,
nucleophilic addition of carbenoid C atom of the isocyanide
onto the iminium group followed by the addition of the azide
anion onto the C atom of the nitrilium ion and 1,5-dipolar
electrocyclization leads to the formation of regioisomer A. On
the other hand, the nucleophilic addition of carbenoid C atom
of the isocyanide onto the iminium group with the addition of
the O atom of amide group onto the C atom of the nitrilium ion
formed oxazolidine intermediate which followed by the
N
H
N
N
H
H
Cl
O
3a
3b
3c
, 98%
, 88%
O
, 99%
O
O
O
N
H
NC
NC
N
H
N
H
NH
NC
3d
3e
3f
, 94%
, 97%
O
, 90%
O
O
NC
N
H
NC
N
N
H
H
3g
3h
3i
, 79%
, 85%
, 50%
Cl
NC
O
O
NC
O
N
H
N
H
N
H
NC
NC
HN
3j
3k
3l
, 70%
, 65%
, 95%
Scheme 1: Structures and yields of isocyano amides synthesized and used in this
study.
Next, we investigated the formation of A and B in dependency
of the azide source. In the original description of the tetrazole
multicomponent reaction, Ugi used stock solutions of hydrogen
azide in benzene or alternatively amine hydrochloride together
with sodium azide. Later, TMS-azide was introduced as a safe in
situ hydrogen azide which now completely superseded the
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R2
NH+
H
R3
-N N+ N-
N
R2
NH
R3
addition of the azide anion leads to the formation of
N
R2
N
N
N
H
C-
R3
regioisomer B.
N
N
N
N+
O
N+
R2
N
N
R2 R1
N
R1
N
N
O
N
N
H
O
O
R3
O
N
O
N
+
+
N
R3
TMSN3
NH2
N
O
UT-4CR
H
NC
X
N
N
H
R3
+
R1
N
X
+
R
N
NH
NH
H
O
MeOH, rt, 12 h
NH
H
n
R1
NH
R2
R1
m
R1
R3
m
m
n
R1
regioisomer A
R2
3
4
5
6
7
(Regioisomer B)
(Regioisomer A)
O
R2NH2
N
N
NC
H
R1
N
N
N
N
Cl
N
N
O
N
H
N
N
N
R3CHO
N
HN
H
O
N
N
Cl
O
NH
Cl
NHTrt
N
H
R2
NH+
R2
6l, 66%
6m, 52%
6n, 46%
R3
O+
NH
S
C-
N+
N
R3
N
N
H
N
N
N
R3
H
N
N
N
NH
O
N
N
N
N
N
R3
N
HN
R1
N
R2
N
H
N
N
N
O
R1
N
R2
N
NHTrt
H
H
N
R1
O
-N
H
NH
B
O
N+
N
O
R1
N-
N
O
N
regioisomer B
NH
N
NH
6o, 70%
6p, 60%
6q, 77%
N
Scheme 4. Proposed mechanistic explanation of the formation of the two
tetrazole isomers.
N
N
CF3
NHTrt
O
N
NHTrt
HN
O
O
N
H
N
N
N
N
NH
HN
N
N
N
N
Acknowledgments
6x, 53%
6y, 42%
6z, 35%
Scheme 3: Tetrazole products from β− and γ−-amino acid derived isocyanoacetamides,
highlighted as red and green bolded structures respectively (Trt = trityl).
S. S. was supported by postdoctoral research fellowship from
Kankerbestrijding (KWF grant agreement No. 10504). The work
was financially supported by NIH 2R01GM097082-05, the IMI
(grant agreement No.115489), European Union’s Seventh
Framework Programme (FP7/2007-2013), EFPIA companies’ in-
kind contribution, by the European Union's Horizon 2020
research and innovation programme under MSC, ETN
“Accelerated Early stage drug dIScovery” (No 675555, CoFund
ALERT, No 665250), European Regional Development Fund in
the framework of the Polish Innovation Economy Operational
Program (POIG.02.01.00-12-023/08).
Figure 4. X-ray structures for some ‘normal’ Ugi tetrazole products.
Notes and references
Similar oxazolidine intermediates were also previously
postulated in a macrocyclization and peptide formation.29 In
conclusion, we report for the first time a competing Ugi
tetrazole reaction with commonly used isocyanoamides as
substrates. We investigated in detail the reaction by performing
many different substrate combinations, reaction conditions,
reagent conditions and standard chemical analyses and
multiple crystal structures. Based on our results and literature
analysis we propose a competing mechanism which is based on
an intramolecular carbonyl oxygen attack to the isocyanide and
addition to the imine via a five- or six-membered intermediate.
This α-adduct intermediate preferentially reacts with the azide
ion to ultimately cyclize to the ‘atypical Ugi’ product. The
knowledge of this side reaction in the context of the Ugi
tetrazole reaction is of high importance since it is an often-used
reaction in the chemical community.
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