Microwave-Assisted Branching Cascades: A Route to Diverse 3,4-Dihydroquinazolinone-Embedded Polyheterocyclic Scaffolds

Article abstract of DOI:10.1021/acs.orglett.6b02774

A novel metal-free microwave-assisted branching cascades strategy for the efficient synthesis of 3,4-dihydroquinazolinone-embedded polyheterocyclic scaffolds is reported. Starting from in situ generated key N-acyliminium ion precursors, 12 distinct and skeletally diverse polycyclic frameworks were accessed in a single step/pot via adjustment of the nucleophile(s) and reaction conditions. Postcascade functionalization of these compounds was also demonstrated, proving the utility of this method in accessing structurally diverse chemical entities.

Full text of DOI:10.1021/acs.orglett.6b02774

Letter
pubs.acs.org/OrgLett
Microwave-Assisted Branching Cascades: A Route to Diverse 3,4-
Dihydroquinazolinone-Embedded Polyheterocyclic Scaffolds
Rajiv T. Sawant, Marc Y. Stevens, Christian Skold, and Luke R. Odell*
̈
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, P.O. Box
574, SE-751 23 Uppsala, Sweden
S
* Supporting Information
ABSTRACT: A novel metal-free microwave-assisted branching
cascades strategy for the efficient synthesis of 3,4-dihydro-
quinazolinone-embedded polyheterocyclic scaffolds is reported.
Starting from in situ generated key N-acyliminium ion precursors,
12 distinct and skeletally diverse polycyclic frameworks were accessed
in a single step/pot via adjustment of the nucleophile(s) and reaction
conditions. Postcascade functionalization of these compounds was
also demonstrated, proving the utility of this method in accessing structurally diverse chemical entities.
he iterative design−make−test−analyze cycle of small
molecule libraries in the quest for new bioactive chemical
Scheme 1. Proposed Metal-Free Microwave-Assisted
Branching Cascades Strategy to Diverse Polycyclic Scaffolds
T
modulators is one of the central research themes for chemists and
biologists in modern drug discovery and chemical biology.1 In the
search for skeletally and functionally diverse small molecule
libraries exploring biologically relevant chemical space, a number
of methods for library generation have been developed.2 In
particular, the field of diversity-oriented synthesis (DOS)3 has
emerged as a powerful technique to fulfill the rising demand for
novel and diverse small organic molecules to facilitate the
identification of new chemical leads.4 DOS includes different
strategies5 such as branching pathways,6 folding pathways,7 the
build-couple-pair strategy,8 the click−click−cyclize strategy,9 and
the fragment-based approach.10
Accordingly, the development of an expedient, metal-free, and
environmentally benign branching cascades protocol, requiring
shortreactiontimestogeneratediversescaffoldlibraries,wouldbe
of considerable interest.
As part of our continued interest in diversity-oriented synthesis
of N-heterocycles,19 we recently reported20 a novel approach to
highly functionalized and biologically significant21 3,4-dihydro-
quinazolinones (DHQs) based on N-acyliminium ion chem-
istry.22 We envisioned that N-acyliminium ion intermediates (I),
generatedinsitufromano-formylcarbamate electrophile(A)and
an amine nucleophile (B) under microwave irradiation, would
undergo N-acyliminium ion cyclization with an appropriate
pendant aromatic/heteroaromatic ring system to provide direct
access to diverse polyheterocyclic DHQ scaffolds (C)23 (Scheme
1). With the aim of discovering an efficient, flexible approach to
build skeletal diversity in a rapid fashion, we sought to develop a
new microwave-assisted, branching cascades protocol via a novel
cascade imine/cyclization/N-acyliminium ion cyclization reac-
tion sequence. To thebestof our knowledge, this isthe firstreport
highlighting the use of both branching cascades and microwave
irradiation to create extensive skeletal diversity requiring short
(20−30 min) reaction times. Herein, we report a highly efficient,
metal-free microwave-assisted branching cascades strategy to
access natural product-like libraries of 3,4-dihydroquinazolinone-
embedded polyheterocyclic frameworks using precursors that
The branching cascades technique11 has attracted considerable
interest over the past decade for the efficient creation of
polyfunctionalized diverse and complex framework libraries.
Themajor advantage ofthis approach isthatdiversity is generated
in a one-step/pot process by treating one or more polyfunction-
alized precursors with different reagents/reactants or under
various reaction conditions. Kumar and co-workers used
chromone-based precursors12 and more recently a de novo
branching cascades approach to access complex molecular
frameworks.13 The O’Connell and Stockman groups reported a
12-fold branching pathway to access diverse natural product-like
polycyclicscaffoldsfromasingleketo-diesterintermediate.14 Patil
and co-workers have disclosed a relay catalytic branching cascade
technique utilizing alkynoic acids or alkynols15 to access diverse
polyheterocyclic scaffolds.16 More recently, the same group
developed an electrophile-induced branching cascades strategy to
produce drug-like polyheterocycles from 2-alkynylbenzalde-
hydes.17 Despite these elegant and powerful developments,18
the existing pathways require either a battery of different reaction
conditions or expensive transition metal catalysts to generate
structural diversity. Moreover, the majority of reported trans-
formations require long reaction times, detracting from their
appeal as chemical tools to enable rapid compound optimization.
Received: September 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02774
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Scheme 2. Microwave-Assisted Branching Cascades Route to Diverse 3,4-Dihydroquinazolinone Polyheterocyclic Scaffolds
a
Reaction conditions: Unless otherwise stated, reactions were performed with 1 equiv of o-formyl carbamate (1a−1h), 1.3 equiv of amine (2a−2e,
b
c
3a−3f, 4−12) in 1 mL of AcOH, 140 °C, MW, 10−120 min. HCl salt of amine used. Two-step protocol for 26a/a′−26b/b′: (i) AcOH, MW, 140
d
°C, 1 h; (ii) DMAP, Ac2O (1.5 equiv), CH2Cl2, rt, 1 h. Two-step protocol for 36a−36c: (i) AcOH, MW, 140 °C, 20 min; (ii) POCl3, reflux, 4 h.
either are commercially available or can be easily prepared by
literature methods.20
column chromatography. In addition, a significant preference for
use of the amine nucleophile infree-base form was observed using
2b and 3e rather than the corresponding HCl salts. In both cases,
the isolated yields of products 17 and 25 were substantially higher
using the free-base nucleophile rather than the HCl salt (82% vs
54% and 86% vs 35%). Reaction of 4 with carbamates 1a and 1c
was found to be sluggish and gave DHQ scaffold 27a and 27b in
moderate to fair yields of 43% and 59%, respectively. Thiophene-
2-ethylamine 5 also reacted smoothly with different carbamates
1a−1c to produce thienoquinazolinones 28a−28c in good yield
(62−81%).Similarly,thiophene-3-ethylamine6gavetheisomeric
DHQ scaffold 29a and 29b in up to 80% yield without any side
reaction derived from competing nucleophilic attack at the 4-
position of the thiophene ring.
To further expand the scope of developed protocol, we
subjected a range of amines (7−12) to our reaction conditions to
create significant skeletal diversity. In this process, aniline
derivative 7 reacted smoothly to provide pyrroloquinazolinones
30a and 30b in 80% and 71% yield, respectively. Cascade
cyclizationoftheindolenucleuswasalsosuccessfullyinducedbya
4-aminomethylsubstituentin8tofurnishquinazolinonescaffolds
31a−31c in up to 86% yield. Aiming for seven-membered fused
polyheterocyles, we subjected amine 9 to our reaction conditions
in the presence of carbamates 1a−1c to afford azepino-
quinazolinones 32a−32c in excellent yield (91−95%). The
strategy also worked well for resorcinol amine derivative 10 to
afford seven-membered fused oxazepinoquinazolinones 33a−
33cinmoderatetogoodyield(45−72%)(Scheme2).Inaddition,
the structure of 33a was confirmed by X-ray crystallographic
analysis and shows a near perpendicular orientation of the two
aromatic rings consistent with a substantial deviation from
We began our investigation by screening various solvents, acid
promoters, temperatures, and reaction times under microwave
irradiation (see Supporting Information), and after exhaustive
optimization, we were pleased to identify productive reaction
conditions. The reaction between A and B in AcOH under
microwave irradiation at 140 °C and/or further treatment with
different reagents produced a library of skeletally diverse 3,4-
dihydroquinazolinone scaffolds (C, 16−36) with 12 distinct
frameworks (Scheme 2).
For the initial study, amine 2a was reacted with eight different
carbamates (1a−1h) in AcOH at 140 °C under microwave
irradiation to afford fused 3,4-diydroquinazolinone heterocycles
16a−16h in up to 96% yield (Scheme 2). Notably, the reaction
worked well with carbamates containing halogen, electron-
donating and -withdrawing groups to afford DHQs in excellent
yields. Similarly, amines 2b−2d reacted smoothly with carbamate
1atofurnish DHQs17−19ingoodtoexcellentyields(61−83%).
The reaction also performed well with amine 2e and carbamates
1aand1btogive 20aand20binexcellentyield. Next, thescope of
tryptamine 3a was investigated with carbamates 1a, 1c, and 1h,
and we were pleased to observe the formation of fused
indoloquinazolinones 21a−21c in up to 93% yield. Furthermore,
the substituted tryptamines 3b−3e reacted efficiently with
carbamate 1a to afford pentacyclic DHQs 22−25 in up to 89%
yield. Interestingly, upon treatment with carbamate 1a and 1c,
amine 3f gave a mixture of pentacyclic acetate diastereomers 26a
(syn, 5%), 26a′ (anti, 56%) and 26b (syn, 6%), 26b′ (anti, 43%),
respectively, in satisfactory yield based on a two-step reaction
sequence. Notably, both diastereomers were easily separated by
B
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aversatilesiteforsubsequentscaffoldmodification. Toinvestigate
this strategy, the demethylation of 18 was conducted using BBr3,
and this afforded the phenolic DHQ derivative 38 in 52% yield.
Finally, to validate the proposed cascade imine/cyclization/N-
acyliminium ion cyclization reaction pathway in Scheme 1, N-
acyliminium ion (I) intermediate trapping experiments were also
performed employing Mannich-type reactions.27 We have
recently reported intermolecular Mannich-type reactions be-
tween unactivated ketones and N-acyliminium ion intermediates
to afford β-amino ketones in good yields.20b The one-step three-
component reaction between carbamate 1a, amine 2a, and
acetone (13) in AcOH gave 16a in only 52% yield along with 29%
of β-amino ketone 39a (Scheme 4). We weredelighted toobserve
formation of 39a, as it suggested the intermediacy of the putative
N-acyliminium ion(I)and, more importantly, that it ispossible to
trap this intermediate with an external nucleophile despite the
presence of a pendant arene nucleophile. Pleasingly, by changing
the solvent from AcOH to EtOH/AcOH (9:1), the competing
intramolecular cyclization could be completely suppressed and a
one-pot two-step reaction sequence afforded 39a in 94% yield
under optimal reaction conditions. Similarly, other nucleophiles
14 and 15 also produced C-4-substituted DHQs 39b and 39c in
90% and 71% yields, respectively (Scheme 4). To further validate
our mechanistic hypothesis, a two-step reaction protocol using
carbamate 1a and amine 2a in EtOH/AcOH (9:1) gave the N-
acyliminium ion (I) (confirmed by LC/MS), which upon further
heating in AcOH underwent intramolecular cyclization to afford
16a in 91% yield whereas heating in the absence of additional
AcOH provided only traces of 16a (Scheme 4). Taken together,
these results indicate that the reaction can be directed exclusively
through an intra- or intermolecular cascade sequence by simply
changing the solvent composition. Intramolecular cyclization
requires the use of stoichiometric AcOH, suggesting that further
Brønsted acid activation of the N-acyliminium ion intermediate is
required to promote intramolecular attack by the pendent arene
ring. The combination of EtOH/AcOH (9:1) allows the reaction
to be paused at the N-acyliminium ion stage and selectively
functionalized at the C4-position through the addition of external
nucleophiles even in the presence of a highly electron-rich
pendant arene moiety. These results are consistent with the
proposed mechanistic pathway depicted in Scheme 1. In addition,
the microwave-assisted reaction of amine 2b, 2d, 2e, 4, and 7 with
o-formyl carbamates 1a and 1c also showed formation of traces of
competing Pictet−Spengler28 cyclization products (confirmed by
LC/MS), which did not undergo further cyclization upon
Figure 1. 3D structure of 33a: ORTEP plot (left) and 3D structure from
conformational analysis (right).
planarity imparted by the benzylic sp3 center (see Figure 1).25 A
conformational analysis of 33a identified a lowest energy
conformation that was in excellent agreement with the crystal
structure (RMSD = 0.2151 Å). Conformational analyses were
then performed on representative compounds from all the
scaffolds depicted in Scheme 2, and a similar perpendicular
orientation of the DHQ and pendant aromatic rings was noted
(see Supporting Information for details). This is important, as it
showsthatthecompoundsinScheme2possessnotonlystructural
but also three-dimensional complexity, which is a key
consideration in the design of diverse compound libraries.
The pyrrole-derived amine 11 also performed well to produce
benzodiazepino DHQs 34a and 34b in 77% and 70% yield,
respectively. Gratifyingly, the reaction of 12 with carbamate 1a
and 1c provided the novel spirocycles 35a/a′ and 35b/b′ as
diastereomeric mixtures in 64% and 76% yield, respectively.
Thereafter, the diastereomers were separated by column
chromatography and carbamate 1a afforded 35a (syn, 23%)
while carbamate 1c gave 35b (syn, 33%) and 35b′ (anti, 43%),
respectively.Thespirocyclicskeletonandrelativestereochemistry
of 35b′ was confirmed by X-ray crystallographic analysis (see
Scheme 2).26 The two-pot reaction sequence of carbamates 1a
and 1c with amine 2a/2c followed by POCl3 provided the
advanced chloroquinazoline intermediates 36a (51%), 36b
(63%), and 36c (45%), respectively. The developed protocol
offersasimpleandeasyapproachfortherapidsynthesisoflibraries
of nitrogen- and oxygen-containing five-, six-, and seven-
membered fused heterocycles, including the useful 2-chloroqui-
nazolines 36a−36c and numerous halogen-bearing derivatives
(e.g., 16c, 16c, 27a, 30a) which are all highly amenable for further
elaboration into second generation libraries.
To further explore the utility of these compounds for second
generation library development, we sought to exploit the N-1
moiety,whichispresentinalmostallcompoundsinScheme2,asa
synthetichandleforpostcyclizationelaboration(Scheme3).After
some experimentation, we were pleased to identify conditions
suitable for selective N-1 alkylation and N-ethyl DHQ 37 was
prepared in70% yield bytreating scaffold 18 with ethyl iodide and
NaHatambienttemperature. ManyofthederivativesinScheme2
containalatentphenolicgroup, whichifunmaskedwould provide
Scheme 4. Mechanistic Study and Solvent-Controlled
Branching Pathway to 3,4-Dihydroquinazolinones
a
Scheme 3. Second-Generation DHQ Library Strategies
a
For structures of nucleophiles 13, 14, and 15, see Scheme 2.
C
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b02774.
■
S
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Full experimental details and characterization data (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: luke.odell@orgfarm.uu.se.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Uppsala University and we thank
Dr. Lisa Haigh (Imperial College London) and Dr. Anatoly Mish-
nev (Latvian Institute of Organic Synthesis) for assistance with
accurate mass and X-ray structure determination.
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