Photoinitiated Cascade for Rapid Access to Pyrroloquinazolinone Core of Vasicinone, Luotonins, and Related Alkaloids

Article abstract of DOI:10.1021/acs.orglett.9b00858

Furylimines of aromatic o-nitro aldehydes undergo a photoinduced cascade transformation offering rapid atom- and step-economical access to complex polyheterocyclic scaffolds possessing a privileged pyrroloquinazolinone core.

Full text of DOI:10.1021/acs.orglett.9b00858

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photoinitiated Cascade for Rapid Access to Pyrroloquinazolinone
Core of Vasicinone, Luotonins, and Related Alkaloids
D. Sai Reddy and Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States
S
* Supporting Information
ABSTRACT: Furylimines of aromatic o-nitro aldehydes
undergo a photoinduced cascade transformation offering
rapid atom- and step-economical access to complex
polyheterocyclic scaffolds possessing a privileged pyrroloqui-
nazolinone core.
biologically active natural products, including alkaloids
he recent renaissance in photoredox catalysisand
vasicinone,8 tryptanthrin,9 and luotonins10 shown in Figure 1.
Tsynthetic photochemistry in generalspeaks volumes
about the ability of photoinduced reactions to access complex
molecular architectures in a minimal number of steps.1
Combining more than one step in a photoinitiated cascade
improves step-normalized growth of complexity, while
simplifying and streamlining experimental procedures.2 In
our own work we demonstrated that extended polyheterocyclic
scaffolds, rivaling the complexity indices3 of complex natural
products, could be assembled in 2−4 experimentally simple
Figure 1. Vasicinone, tryptanthrin, and luotonin B.
steps from ubiquitous chemical feedstock utilizing a photo-
chemical cascade as the key step.4
In our search for new photoinduced cascade transformations
A number of ground state reactions to access alkaloids
to access complex heterocycles, we realized that some well-
containing a pyrroloquinazolinone core are known which
known photoinduced rearrangements are absent from the
include the following: synthesis of luotonins via a radical
cascade;11 synthesis of vasicinone and related heterocycles
from (i) o-azidobenzoic acid derivatives by reductive
cyclization12 or (ii) condensation of anthranylamide and
acetoxysuccinic anhydride13or other derivatives of succinic
acid;14 access to the quinazolinone core in the luotonin
synthesis via reaction of anthranylamide with acyl chlorides15
or with quinolin-carboxaldehyde.16 Several of these ground
state syntheses of pyrroloquinazolinones are nicely summar-
ized in ref 17.
Our photoinduced cascade offers a much milder option for
construction of pyrroloquinazolinone cores. Scheme 1
illustrates the typical reaction of methyl 5-aminofuran-2-
carboxylate 2a and 3-nitropyridine-2-carbaldehyde 1d provid-
ing expeditious access to the pyrrolo-aza-quinazolinone
framework. Imines are formed under standard conditions.
The subsequent photoinduced cascade is carried out in
dichloromethane (DCM), Scheme 1.
toolbox of synthetic chemistry. One of these reactionsa
photoinduced hydrogen atom transfer from the benzylic sp3
carbon in o-nitrobenzyl systemsis widely used in photo-
removable protecting groups (PPGs) chemistry, but rarely
used in synthesis, with a notable exception of photochemical
synthesis of indazolones recently reported by Kurth and co-
workers.5 Another variation on this theme is the well-known
intramolecular redox disproportionation in o-nitrobenzalde-
hyde, which is initiated by hydrogen atom abstraction from the
sp2 carbon, resulting in the formation of o-nitrosobenzoic acid.
This reaction has been widely used for UV actinometry in the
280−410 nm range of the UV spectrum.6
We note that nitroso compounds exhibit a wealth of
synthetically useful reactivity, from aldol-like condensations to
nitroso Diels−Alder reactions yielding cyclic hydroxylamines,7
which are often reduced or undergo N−O bond scission either
photochemically or under thermal activation. In this work, we
developed a photoinduced cascade which involves a photo-
chemical generation of transient aryl nitroso species, its
intramolecular Diels−Alder reaction with a furan moiety to
furnish an oxazabicyclo[2.2.1]heptane core possessing the
labile N−O moiety with subsequent rearrangement into the
target pyrroloquinazolinone in a single step. The pyrrolo- or
pyrrolidino-quinazolinone core is a prominent feature in many
Overall, this approach gives rapid access to complex
polyheterocyclic scaffolds in an experimentally simple atom-
and step-economical way from readily available starting
materials. In this context, not unimportant is the fact that
Received: March 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00858
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Typical Furylimine Formation and Subsequent
Photoinduced Cascade Furnishing a Fused Pyrimidone
Table 1. Pyrroloquinazolinone Products and Isolated Yields
the recent developments in sustainable chemistry point to a
number of furan-based semiproducts as a viable biomass-
derived chemical feedstock.18
The simplicity of the experimental procedure is a prominent
feature of this short photoassisted synthetic sequence. As many
aromatic o-nitro aldehydes and acceptor-substituted furan-
amines are readily available from commercial sources, we
tested the scope of this reaction sequence and found that the
procedure is broadly applicable. Examples with isolated yields
are presented in Table 1 below. Notice that hemiaminals 4 are
racemic.
Structures of pyrroloquinazolinones 4aa, 4ba, and 4ab were
established with X-ray crystallography. The rest of the products
were characterized by solution NMR, with the DU8+
computations19 of NMR chemical shifts and spin−spin
coupling constants supporting the structure assignment. For
1
details of these computations and rmsd values matching H,
13C NMR chemical shifts and proton spin coupling constants,
see the Supporting Information.
Our mechanistic rationale for this cascade is shown in
Scheme 2. It involves intramolecular hydrogen atom
abstraction by the ortho-nitro group in benzaldimine 3aa
followed by oxygen transfer via cycloaddition/fragmentation.
This leads to the formation of nitroso amide C, which
undergoes the intramolecular hetero Diels−Alder reaction to
form D. Cyclic hydroxylamine D undergoes homolytic
fragmentation with the N,O-diradical E being reduced via H-
abstraction, presumably from the solvent (CH2Cl2). The
dehydrated open form G of the resulting hemiacetal F then
spontaneously cyclizes into the hemiaminal product 4aa. Since
the vicinal protons of the double-bond in the open form G are
expected to have very different chemical shifts and spin−spin
coupling constants from 4aa, we could confidently corroborate
that there is no open form E in the NMR spectrum of the
reaction mixture.
Monitoring the reaction by NMR reveals the intermittent
appearance of the NH proton belonging to nitroso amide C.
The Diels−Alder intermediate D was not isolated, although
very small olefinic peaks with J = 5.9 Hz observed in the
reaction mixture are consistent with the heterobicyclo[2.2.1]-
heptene CHCH moiety and may belong to this transient.20
Utilization of o-nitrobenzaldimine of 5-cyanofuranamine
(3ae) offers an atom- and step-economical pathway to the
carba-analog of luotonin B (7) as shown in Scheme 3. The
primary product of the photoinduced cascade in this case is
cyanohydrin 4ae which is expected to lose HCN and act as
dienophile 521 in the postphotochemical step, i.e. Diels−Alder
reaction with isobenzofuran (readily available as described
before22). After this experimentally simple photoinitiated one-
pot sequence, the reaction mixture in acetic acid is treated with
Zn powder.
This last step accomplishes two goals: aromatization of the
oxabenzobicyclo[2.2.1]heptane moiety in 6 and selective
B
DOI: 10.1021/acs.orglett.9b00858
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Letter
1
Experimental procedures, characterization data, H and
13C NMR spectra for all compounds, computational
details, and calculated NMR chemical shifts and
constants (PDF)
Scheme 2. Plausible Mechanistic Rationale for the
Photoinduced Cascade 3aa →4aa
Accession Codes
CCDC 1894983−1894985 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: akutatel@du.edu.
ORCID
D. Sai Reddy: 0000-0003-3471-8339
Andrei G. Kutateladze: 0000-0003-3066-517X
Notes
The authors declare no competing financial interest.
Scheme 3. Atom- and Step-Economical Synthesis of the
Carba-Analog of Luotonin B (7)
ACKNOWLEDGMENTS
This work is supported by the NIH (GM093930)
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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.9b00858.
C
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D
DOI: 10.1021/acs.orglett.9b00858
Org. Lett. XXXX, XXX, XXX−XXX