One-pot synthesis of nuevamine aza-analogues by combined use of an oxidative Ugi type reaction and aza-diels-alder cycloaddition

Article abstract of DOI:10.1055/s-0033-1340218

A rapid and efficient one-pot synthesis of a series of four novel nuevamine aza-analogues is described based on the oxidative Ugi-type reaction and aza-Diels-Alder reaction as post-functionalization. A simple IBX-mediated oxidation of a secondary amine followed by isonitrile α-addition and finally an aza-Diels-Alder cycloaddition provides the desired compounds in excellent overall yields considering the short reaction time, atom economy, and the molecular complexity of the final products. This protocol presents a highly attractive procedure for the rapid generation of fused polyheterocycles. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340218

LETTER
▌403
letter
One-Pot Synthesis of Nuevamine Aza-Analogues by Combined Use of an
Oxidative Ugi Type Reaction and Aza-Diels–Alder Cycloaddition
Nuevamine Aza-Analogues
Alejandro Islas-Jácome,a Atilano Gutiérrez-Carrillo,a Miguel A. García-Garibay,b Eduardo González-Zamora*a
a
Departamento de Química, División de Ciencias Básicas e Ingeniería, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco
186, Col. Vicentina Iztapalapa, C. P. 09340, México D. F., México
Fax +52(55)58044666; E-mail: egz@xanum.uam.mx
b
Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young, Drive East, Los Angeles,
CA 90095-1569, USA
Received: 09.10.2013; Accepted after revision: 10.10.2013
dine ring systems have been granted special status in the
pharmaceutical arena. However, the synthesis of fused
pyridines has often been rather cumbersome and lengthy
even for the simplest fused pyridines.7 Nevertheless, the
Abstract: A rapid and efficient one-pot synthesis of a series of four
novel nuevamine aza-analogues is described based on the oxidative
Ugi-type reaction and aza-Diels–Alder reaction as post-functional-
ization. A simple IBX-mediated oxidation of a secondary amine fol-
lowed by isonitrile α-addition and finally an aza-Diels–Alder inclusion of a nitrogen atom in the aromatic ring could
cycloaddition provides the desired compounds in excellent overall
yields considering the short reaction time, atom economy, and the
molecular complexity of the final products. This protocol presents
eral synthetically modified analogues of compound 1
a highly attractive procedure for the rapid generation of fused poly-
heterocycles.
provide the opportunity to modulate both the pharmaco-
dynamic and kinetic properties of pyrrolopyridines.8 Sev-
have been prepared to evaluate their biological activity.9
In connection with an ongoing project and with the goal
of developing novel synthetic methodologies for gaining
rapid access to new nitrogen heterocyclic compounds, we
herein describe a rapid synthesis of a series of compounds
2 (Figure 1), which are aza-analogues of 1, based on an
oxidative Ugi type reaction and the aza-Diels–Alder cy-
cloaddition as post-condensation.
Key words: one-pot synthesis, natural products, oxidation, oxida-
tive Ugi reaction, aza-Diels–Alder cycloaddition
The natural product (±)-nuevamine 1 (Figure 1) was iso-
lated from a rare plant native of Chile (Berberis Darwinii
Hook).1 This alkaloid occupies a special place in natural
product chemistry because it was considered the first re-
ported naturally occurring compound containing the
isoindolo[1,2-a]isoquinolinone skeleton.2 Although 1 has
no known significant biological activity, several method-
ologies for its preparation have been described.3
Much research has focused on the development of new
methodologies that benefit from high synthetic efficiency
and atom economy. Multicomponent reactions (MCR),
which are defined as condensations of three or more
building blocks reacting in a one-pot process to give a fi-
nal product containing the majority of atoms derived from
all reacting molecules,10 can be used to construct complex
advanced intermediates for products with biological ac-
tivity.11 An efficient preparation of chemical libraries,
with higher yields and a minimum number of steps, can be
performed by using this kind of highly convergent
processes12 to produce pharmacologically relevant mole-
cules for biological evaluation.13
natural product
our targets
O
O
N
N
O
O
MeO
N
MeO
Bn
R
2a–d
In this context, isocyanide-based multicomponent reac-
tions (I-MCR) have become powerful synthetic tools, due
to the divalent nature of the isocyanide moiety, which can
react as either nucleophile or electrophile giving rise to a
manifold of molecular frameworks that are suitable for
further elaboration.14 This is especially true when the iso-
cyanide moiety is sequentially combined with other post-
transformation processes to increase molecular complexi-
ty or to add functional groups to the final products.15
( )-nuevamine (1)
Figure 1 Nuevamine and its aza-analogue
Nitrogen heterocyclic compounds are an integral part of
numerous drugs and natural products,4 and the majority of
them exhibit biological activity.5 Nitrogen heterocycles
are important pharmacophores in drug design, especially
pyridine derivatives, which are among the most frequently
cited heterocyclic compounds.6 In particular, fused pyri-
The Ugi reaction, which is the most used isocyanide-
based multicomponent process, allows the use of different
inputs with different substituents, thus permitting further
structural diversity. Several post-transformations of Ugi
products have been reported, including cyclocondensa-
SYNLETT 2014, 25, 0403–0406
Advanced online publication: 02.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340218; Art ID: ST-2013-R0955-L
© Georg Thieme Verlag Stuttgart · New York

404
A. Islas-Jácome et al.
LETTER
tion,16 radical cyclization,17 SNAr18 and SN2 reactions,19
cycloaddition,20 and metathesis reactions.21 In this way,
we recently focused on the preparation of libraries of syn-
thetically nitrogenated analogues of important natural
products by using I-MCR processes, such as Ugi type re-
actions combined with other post-functionalization tech-
niques involving free-radicals,22 Pummerer,23 and Pictet–
Spengler cyclizations.24
N
N
N
6a R =
6b R =
6c R =
O
OMe
N
OMe
6d R =
Me
Zhu and co-workers25 reported an efficient 2-iodoxyben-
zoic acid (IBX) mediated Ugi type reaction. They com-
bined the methodology reported by Nicolaou,26 in which
secondary amines are oxidized by IBX to obtain imines,
with the classical Ugi four-component reactions (Ugi-
4CR).27 The new methodology was named the oxidative
Ugi type reaction or oxi-Ugi reaction. Two more exam-
ples were recently developed in this area. The first was re-
ported by Che and co-workers,28 in which a singlet-
oxygen based oxidation was combined with the Ugi-4CR.
The second, reported by Xie and co-workers,29,30 involved
the use of a copper peroxide system to oxidize tertiary
amines during two different multicomponent processes,
Ugi-4CR and Ugi-3CR.
O
R
CN
Bn
IBX
4
6a–d
NH
NH
THF
reflux
THF
reflux
3
5
O
O
NH
NH
O
C
N
N
O
R
9
THF
reflux
O
The classic Ugi-3CR is carried out by combining amines
and aldehydes with isocyanides in a sequential one-pot
process. The use of an amine and aldehyde can be re-
placed by the use of an imine, which can be generated in
situ by oxidation of N-alkyl amines. In this context, we
herein show the combined use of an oxidative Ugi type re-
action derived from the Ugi-3CR with an aza-Diels–Alder
cycloaddition as a post-condensation process that can be
used to prepare a series of nuevamine aza-analogues.
H
8a–d
R
7a–d
O
R
O
COOH
R
N
N
N
– CO2
– H2O
O
N
The synthesis started with regioselective oxidation by us-
ing IBX (4) of the commercially available 1,2,3,4-tetrahy-
droisoquinoline (3) in THF at reflux to obtain the 3,4-
dihydroisoquinoline iminium ion (5; Scheme 1). Subse-
quently, α-isocyano α-benzyl acetamides 6a–d were add-
ed to obtain the intermediates 7a–d, respectively, which,
after ring-chain tautomerization, gave 5-aminooxazoles
8a–d. Maleic anhydride (9) was then added and the 5-ami-
nooxazoles 8a–d, underwent intermolecular acylation fol-
lowed by intramolecular aza Diels–Alder cycloaddition31
to afford the oxa-bridged intermediates 10a–d.32
Dehydration33 and decarboxylation34 then occurred to
yield nuevamine aza-analogues 2a–d in excellent overall
yields.35
2a 42%
2b 57%
2c 53%
2d 29%
10a–d
Scheme 1 One-pot synthesis of the nuevamine aza-analogues 2a–d
the optimization process may be that although 2-iodoso-
benzoic acid (12, IBA),26 which is formed in situ after ox-
idation, serves to transform imine 11 into iminium ion 5
(which, in turn, promotes the formation of the final prod-
uct), the presence of IBA may also promote the formation
of 4-benzyl-5-morpholine oxazole 13 by protonation/rear-
rangement of the ring-chain of isocyanide 6 (Scheme 2).
O
O
To optimize the reaction, a series of experiments were
performed based on the isocyanoacetamide 6a. The first
was performed free of catalysts, whereby 42% yield of the
desired product was observed. Lithium bromide was used
to dehydrate the reaction media,33 but the yield remained
42%. Ammonium chloride was added to promote the Ugi
reaction,36 however the observed yield was 40%. Scandi-
um(III) triflate was employed to activate the imine37 but
the yield remained 44%; finally the reaction was per-
formed by using MW as a heat source at 100 °C in a sealed
MW tube (75 W) and, again, the yield did not improve.
One possible rationalization for the observed yield during
– H2O
O
+
+
O
NH
N
I
I
3
11
OH
O
HO
12: IBA
4: IBX
O
H
O
+
O
I
N
O
;
N
NH
5
O
Bn
13
Scheme 2 Oxidation of amine 3 into the iminium ion 5
Synlett 2014, 25, 403–406
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nuevamine Aza-Analogues
405
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In addition, with the idea of making the methodology suit-
able for the use of noncommercial or expensive aryl sub-
stituted 1,2,3,4-tetrahydroisoquinolines, we were able to
prepare the starting material 3 from the commercially
available phenethylamine and paraformaldehyde by a
Pictet–Spengler reaction38 with 40% yield. Thus, the one-
pot process (oxi-Ugi and aza-Diels–Alder) can be preced-
ed by the Pictet–Spengler tetrahydroisoquinoline synthe-
sis to generalize the synthetic methodology. As a matter of
fact, by using this two-step process, a series of aryl-substi-
tuted aza-analogues of nuevamine is being prepared and
the results will be published as soon as possible.
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In summary, a new series of nuevamine aza-analogues
were prepared in excellent overall yields considering its
molecular complexity. Six new chemical bonds and four
fused rings were formed by means of three simple syn-
thetic operations from readily available building blocks in
a one-pot process. To the best of our knowledge, this
methodology represents the first example of the combined
use of an oxidative Ugi type 3CR with aza-Diels–Alder
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Acknowledgment
Financial support from Consejo Nacional de Ciencia y Tecnología
(CONACyT) is gratefully acknowledged (grants, 51346-Q and
156801), as is the scholarship awarded to Dr. A. Islas-Jácome
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Synlett 2014, 25, 403–406

406
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LETTER
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60 min, maleic anhydride (9; 1.062 mmol, 1.2 equiv) was
added. After 30 min, the reaction mixture was filtered and
the solvent was removed under reduced pressure. The crude
material was dissolved in CH2Cl2 (5.0 mL) and washed with
sat. aq NaHCO3 (3 × 15 mL) followed by an excess of brine.
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column chromatography (hexane–EtOAc, 2:1 v/v) to afford
the desired nuevamine aza-analogue 2a (42% yield) as a
white solid. Mp 63 °C; Rf = 0.18 (hexane–EtOAc, 2:1). 1H
NMR (500 MHz, CDCl3): δ = 8.10–8.06 (m, 1 H, ArH), 7.83
(s, 1 H, ArH), 7.35–7.32 (m, 3 H, ArH), 7.30–7.27 (m, 1 H,
ArH), 7.23–7.19 (m, 3 H, ArH), 7.16–7.13 (m, 1 H, ArH),
5.58 (s, 1 H, CH), 4.61–4.56 (m, 1 H, CHH), 4.46 (d, J =
14.2 Hz, 1 H, CHH), 4.32 (d, J = 14.2 Hz, 1 H, CHH), 3.85–
3.80 (m, 4 H, 2 × CH2), 3.48–3.42 (m, 1 H, CHH), 3.10–3.02
(m, 1 H, CHH), 2.87–2.82 (m, 4 H, 2 × CH2), 2.81–2.76 (m,
1 H, CHH). 13C NMR (125 MHz, CDCl3): δ = 166.6 (C=O),
161.4 (ArC), 159.1 (ArC), 148.0 (ArC), 139.7 (ArC), 133.8
(ArC), 132.8 (ArC), 129.4 (ArC), 129.2 (ArC), 128.5 (ArC),
127.6 (ArC), 127.1 (ArC), 126.6 (ArC), 126.4 (ArC), 124.8
(ArC), 123.7 (ArC), 67.4 (CH2), 59.4 (CH), 53.2 (CH2), 40.2
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Synlett 2014, 25, 403–406
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