Diverse Isoquinoline Scaffolds by Ugi/Pomeranz-Fritsch and Ugi/Schlittler-Müller Reactions

Article abstract of DOI:10.1021/acs.orglett.9b00778

The Pomeranz-Fritsch reaction and its Schlittler-Müller modification were successfully applied in the Ugi postcyclization strategy by using orthogonally protected aminoacetaldehyde diethyl acetal and complementary electron rich building blocks. Several scaffolds, including isoquinolines, carboline, alkaloid-like tetrazole-fused tetracyclic compounds, and benzo[d]azepinone scaffolds, were synthesized in generally moderate to good yield. All our syntheses provide a short MCR-based sequence to novel or otherwise difficult to access scaffolds. Hence, we foresee multiple applications of these synthesis technologies.

Full text of DOI:10.1021/acs.orglett.9b00778

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Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diverse Isoquinoline Scaffolds by Ugi/Pomeranz−Fritsch and Ugi/
Schlittler−Muller Reactions
̈
Yuanze Wang,† Pravin Patil,† Katarzyna Kurpiewska,‡ Justyna Kalinowska-Tluscik,‡
,†
̈
and Alexander Domling*
†Drug Design, University of Groningen, Deusinglaan 1, 7313 AV Groningen, The Netherlands
‡Faculty of Chemistry, Jagiellonian University, 3 Ingardena Street, 30-060 Krakow, Poland
S
* Supporting Information
ABSTRACT: The Pomeranz−Fritsch reaction and its
̈
Schlittler−Muller modification were successfully applied in
the Ugi postcyclization strategy by using orthogonally
protected aminoacetaldehyde diethyl acetal and complemen-
tary electron rich building blocks. Several scaffolds, including
isoquinolines, carboline, alkaloid-like tetrazole-fused tetracy-
clic compounds, and benzo[d]azepinone scaffolds, were
synthesized in generally moderate to good yield. All our
syntheses provide a short MCR-based sequence to novel or
otherwise difficult to access scaffolds. Hence, we foresee
multiple applications of these synthesis technologies.
soquinoline represent as an important heterocyclic template
Iand privileged moiety in medicinal chemistry and exhibit a
wide variety of biological and pharmacological properties.1−7
The known traditional methods to construct the isoquinoline
core include the Bischler−Napieralski reaction,8 the Pictet−
Spengler reaction,9 and the Pomeranz−Fritsch reaction.10 The
Bischler−Napieralski reaction is by far the most frequently
explored isoquinoline alkaloids synthesis approach in the past
decades. The Pictet−Spengler reaction has not only been
explored as a convenient method for the asymmetric synthesis
of isoquinoline alkaloids, but also was widely used for the
synthesis of alkaloid-like polycyclic compounds by combining
with MCR chemistry in recent years.11 The Pomeranz−Fritsch
reaction is the synthesis of isoquinolines via an acid-mediated
electrophilic cyclization of benzalaminoacetals. Since the first
and concurrent report by Pomeranz and Fritsch in 1893, this
reaction has been extensively modified.12 To improve the
reaction yield, the Fischer modification involved the treatment
of benzalaminoacetal with fuming sulfuric acid. In 1948, E.
Fritsch reaction have been published.13 Inspired by the fact
that the Pictet−Spengler reaction has been successfully used in
the Ugi postcondensation strategy in our lab,11j we surmised
that the combination of Ugi reaction with Pomeranz−Fritsch
reaction and Schlittler−Muller reaction could also be attractive
̈
way to form diversified isoquinolines (Scheme 1).
We first explored the Pomeranz−Fritsch reaction as the
post-Ugi strategy. By using 3,4,5-trimethoxybenzaldehyde,
aminoacetaldehyde diethyl acetal, 4-chlorophenylacetic acid,
Scheme 1. Ugi/Pomeranz−Fritsch Reaction
Schlittler and J. Muller modified the reaction by using benzyl
̈
amines and glyoxal semiacetal as the starting material. Later on,
Bobbitt reported synthesizing the 1,2,3,4-tetrahydroisoquino-
lines by hydrogenation of the imine intermediate in situ to the
aminoacetal, which allows for the preparation of 1-, 4-, and N-
substituted isoquinolines. At the same time, Jackson described
the dehydrogenation of 1,2-dihydroisoquinoline via a N-tosyl
derivative to a fully aromatic system.
Although a variety of modifications have been introduced to
improve the Pomeranz−Fritsch strategy, it has not been
explored as often as the Bischler−Napieralski reaction and
Pictet−Spengler reaction. Only a few isolated reports on the
synthesis of isoquinoline derivatives based on Pomeranz−
Received: March 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00778
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Letter
and phenylethyl isocyanide as test substrate, the Ugi reaction
was conducted in methanol at room temperature for 15 h. As
the Ugi reaction works excellently with aliphatic aldehydes and
amines, the crude Ugi adduct 5a was directly treated with
various acid conditions (Scheme 2). It is worthy to note that
Scheme 3. Examples of N,2-Disubstituted Isoquinolines
Derivatives
Scheme 2. Optimization of Reaction Conditions
Albeit in lower yields, most of the aliphatic acids also work
except pivalic acid, which failed to give any cyclized product
from isolated Ugi adduct. The structure of 6j was confirmed by
X-ray crystallography.
Nadzan and co-workers has reported the formation of 2-
oxopiperazines by Ugi-N-acyliminium ion cyclization with
good yield using TFA as acid condition.14 Thus, potentially
there is a competition between Ugi-N-acyliminium ion
cyclization and Ugi-Pomeranz−Fritsch reaction to be expected.
To our delight, no 2-oxopiperazines product was observed in
all the acid conditions we screened, and 46% of isoquinoline
product 6a was formed when TFA was used as the acid.
However, HCOOH, CH3COOH, and 37% HCl(aq) solution in
dioxane failed to give any isoquinoline product. CH3COOH
and coc. H2SO4 were found to be a good combination for this
reaction, which afforded 6a in 30−36% yield. Methanesulfonic
acid, which has been proved to be a good acid condition for
Ugi/Pictet-sprengler reaction, also works well in our Ugi/
Pomeranz−Fritsch sequence.15 Although only trace amount of
product was formed when two equivalents of methanesulfonic
acid were used, the reaction yield increased to 35% when
methanesulfonic acid was increased to 10 equiv. Finally, 20
equiv of methanesulfonic acid in acetonitrile turned out to be
the best condition for this reaction, which afforded 6a in 52%
yield in two steps. Solventless methanesulfonic acid was
inferior.
To figure out the unexpected failure of pivalic acid in the
Ugi/Pomeranz−Fritsch reaction, we rescreened all the acid
conditions in Scheme 2. Surprisingly, we observed the
formation of the benzo[d]azepinone scaffold in good yield
when 37% HCl(aq) solution in dioxane was used as the cyclizing
acid. As a class of seven-membered N-heterocycles, benzo[d]-
azepinone scaffolds are also interesting in medicinal chemistry,
where they represent as an important class of so-called
“privileged scaffolds”.16 To show some scope, we synthesized
five compounds in 39−52% yield by changing the aldehyde
and isocyanide moiety as shown in Scheme 4. A single crystal
X-ray analysis further confirmed the structure of 8a.
Recently, we reported the isoquinoline synthesis of 10 by
̈
Ugi/Schlittler−Muller modification using an unprecedented
fast nanoscale technology.17 This efficient method was
explored to synthesize hundreds of derivatives of 10 with the
help of acoustic droplet ejection (ADE). 3,4,5-Trimethoxyl-
benzylamine, 3,4-(methylenedioxy)benzylamine, four dime-
thoxy substituted benzylamine, and thiophen-3-yl-methylamine
were used previously by us as amine component in the Ugi
reaction. To further extend the reaction scope, we further
explored some other electron rich aromatic amines (Scheme
5). To our delight, 3-methoxylbenzylamine, 4-(aminomethyl)-
2-methoxyphenol, and heterocyclic 1H-indol-2-ylmethylamine
were successfully applied by increasing the concentration of
the acid and extension of the reaction time in the
With optimized reaction conditions in hand, nine isoquino-
line products 6 were synthesized by using three aldehyde, three
isocyanide, and eight acid building blocks (Scheme 3). Both
aromatic and aliphatic isocyanides work well for this reaction.
Regardless of the acid moiety, all Ugi adducts obtained from
aromatic acid afforded isoquinolines in good to moderate yield.
B
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Scheme 4. Synthesis of Benzo[d]azepinone Scaffold
Scheme 6. Synthesis of Isoquinoline-Tetrazoles
Scheme 5. Synthesis of Isoquinoline and Carboline Scaffold
Finally, as a further application of our isoquinoline-directed
Ugi postcondensation strategy, we synthesized an alkaloid-like
tetrazole-fused tetracyclic compound by using isocyanide
prepared from amino acid ester as starting material (Scheme
7). Instead of tosyl group protection, the methyl ester from
Scheme 7. Synthesis of Tetracyclic Isoquinolines
postcyclization step. The structures of 10b and 10d were
confirmed by X-ray crystallography.
As valuable bioisosteres of carboxylic acid and cis-amide,
tetrazole is an important drug-like scaffold, which often
exhibits improved pharmacokinetics in drug discovery.18
Exploration of the Ugi-Azide MCR and postcyclization by
Hulme et al. and others has created several unique scaffolds as
exemplified by ketopiperazine-tetrazoles,19 quinoxaline-tetra-
zoles,20 azepine-tetrazoles,21 benzodiazepine-tetrazoles,22 and
lactam-tetrazoles.23 Inspired by these methodologies, we
successfully constructed the isoquinoline-tetrazoles by combin-
ing the Ugi-azide with the Pomeranz−Fritsch reaction
(Scheme 6). Initially, we subjected the Ugi-azide product 11
directly to acidic condition for cyclization. To our surprise,
however, the subsequent Pomeranz−Fritsch reaction was very
sluggish and only trace amount of product was formed. In
addition, variation of the acid condition and solvent did not
greatly improve to the reaction performance. We reasoned that
the exposed secondary amine could interfere with the reaction
and cause side reactions. Thus, we first protected the
secondary amine by a tosyl group in situ to obtain product
12, which then undergoes clean cyclization to form the
isoquinoline-tetrazoles 13. This stepwise reaction proved to be
highly superior and the desired product was isolated in good to
excellent yields. Eight diverse intermediates and products were
characterized, and the X-ray structure of 13d was obtained.
isocyanide moiety will react with the exposed secondary amine
in basic condition to form the tetrazolopyrazinone 14, followed
by the Pomeranz−Fritsch cyclization to afford tetracyclic
product 15. To support the diversity of our isoquinoline-based
scaffolds, we generated virtual libraries of each 100 randomly
generated molecules and for comparison ChEMBL using
JChem software.24 The chemical properties MW and log P
were calculated and plotted in Figure SI-1 (see Supporting
Information p S75). Moreover, an SCI-FINDER sub- and
Markush structure query revealed 8 and 9, 0 and 1, 2353 and
848, 847 and 61, 1 and 0, 0 and 0 results for the herein
described scaffolds 6, 8, 10-isoquinoline, 10-carboline, 13, and
15, respectively. Also, ChEMBL substructure searches found
one hit for scaffold 6, zero hits for scaffold 8, 422 hits for
scaffold 10-isoquinoline, 182 hits for scaffold 10-carboline, and
zero hits for scaffold 13 and scaffold 15, respectively. In
conclusion, we have developed several straightforward
methods to assemble isoquinoline derivatives, benzo[d]-
azepinone and carboline scaffold. The Ugi postcyclization
strategy is probably the most powerful tool to create structural
diversity and large compound numbers while keeping the
number of synthetic steps low. It already has gained lots of
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Letter
interest in the field of medicinal chemistry.25 Our new strategy
of Ugi/Pomeranz−Fritsch reaction is an expedited and
convergent access to skeletal diverse compounds. Significantly,
isoquinoline-tetrazoles and tetrazole-fused tetracyclic com-
pound can now be constructed in just two steps with this
method. One of the herein described reactions in a variation
already has found an application in nanoscale accelerated and
automated synthesis; however, we foresee many more
applications in the discovery of novel biologically active
compounds.17
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00778.
Experiment procedures, compounds data, NMR spectra,
HRMS and crystal structure determinations (PDF)
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Accession Codes
CCDC 1573261, 1827865, 1827938, 1828772, and 1856636
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by e-mailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: a.s.s.domling@rug.nl.
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Pravin Patil: 0000-0002-0903-8174
Justyna Kalinowska-Tluscik: 0000-0001-7714-1651
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Alexander Domling: 0000-0002-9923-8873
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ACKNOWLEDGMENTS
■
This research was financially supported to (AD) by the
National Institute of Health (NIH) (2R01GM097082-05), the
European Lead Factory (IMI) under grant agreement number
115489, the Qatar National Research Foundation (NPRP6-
065-3-012). Moreover, funding was received through ITN
“Accelerated Early stage drug dIScovery” (AEGIS, grant
agreement No 675555) and COFUND ALERT (grant
agreement No 665250), Hartstichting (ESCAPE-HF,
2018B012) and KWF Kankerbestrijding grant (grant agree-
ment No 10504). The research was carried out with the
equipment purchased thanks to the financial support of the
European Regional Development Fund in the framework of
the Polish Innovation Economy Operational Program
(contract no. POIG.02.01.00-12-023/08). We acknowledge
the China Scholarship Council for supporting Y.W.
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