Synthesis of substituted 3,4-dihydroquinazolinonesviaa metal free Leuckart-Wallach type reaction

Article abstract of DOI:10.1039/d0ra10142g

The 3,4-dihydroquinazolinone (DHQ) moiety is a highly valued scaffold in medicinal chemistry due to the vast number of biologically-active compounds based on this core structure. Current synthetic methods to access these compounds are limited in terms of diversity and flexibility and often require the use of toxic reagents or expensive transition-metal catalysts. Herein, we describe the discovery and development of a novel cascade cyclization/Leuckart-Wallach type strategy to prepare substituted DHQs in a modular and efficient process using readily-available starting materials. Notably, the reaction requires only the addition of formic acid or acetic acid/formic acid and produces H₂O, CO₂and methanol as the sole reaction byproducts. Overall, the reaction provides an attractive entry point into this important class of compounds and could even be extended to isotopic labellingviathe site-selective incorporation of a deuterium atom.

Full text of DOI:10.1039/d0ra10142g

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Synthesis of substituted 3,4-dihydroquinazolinones
via a metal free Leuckart–Wallach type reaction†
Cite this: RSC Adv., 2021, 11, 349
Suvarna Bokale-Shivale,a Mohammad A. Amin, a Rajiv T. Sawant,a Marc Y. Stevens,a
b
a
Lewend Turanli,a Adam Hallberg,a Suresh B. Waghmode
and Luke R. Odell
*
The 3,4-dihydroquinazolinone (DHQ) moiety is a highly valued scaffold in medicinal chemistry due to the
vast number of biologically-active compounds based on this core structure. Current synthetic methods
to access these compounds are limited in terms of diversity and flexibility and often require the use of
toxic reagents or expensive transition-metal catalysts. Herein, we describe the discovery and
development of a novel cascade cyclization/Leuckart–Wallach type strategy to prepare substituted
DHQs in a modular and efficient process using readily-available starting materials. Notably, the reaction
requires only the addition of formic acid or acetic acid/formic acid and produces H2O, CO2 and
methanol as the sole reaction byproducts. Overall, the reaction provides an attractive entry point into
this important class of compounds and could even be extended to isotopic labelling via the site-selective
incorporation of a deuterium atom.
Received 1st December 2020
Accepted 3rd December 2020
DOI: 10.1039/d0ra10142g
rsc.li/rsc-advances
substituted DHQs via an N-acyliminium ion cyclization
cascade.26 This is a simple, highly attractive approach for
Introduction
accessing novel and densely substituted DHQ analogues, based
on an array of different chemistries (Scheme 1).27–31
The 3,4-dihydroquinazolinone (DHQ) moiety is a privileged
scaffold in medicinal chemistry, as such compounds containing
this unit have been reported to exhibit biological activity against
a wide range of therapeutic targets. The most signicant
compound in this class, in terms of clinical utility, is the
calcitonin gene-related peptide receptor antagonist olcegepant
(Fig. 1), which demonstrated efficacy and safety in phase II trials
as an anti-migraine agent.1,2 In addition, DHQs with potent anti-
HIV,3 anti-psychotic,4,5 anti-cancer6,7 and anti-microbial8 activi-
ties as well as potential for the treatment of cardiovascular9 and
anti-inammatory disorders10 have been disclosed. Recently
PFI-1, a potent and selective inhibitor of the bromo- and extra C-
terminal domain (BET) family of bromodomains was developed
using a fragment based approach starting from small DHQ-
containing hit.11,12 As consequence of their pervading biolog-
ical importance, numerous synthetic approaches to access this
ring system are available. These include the cyclization of o-acyl/
o-aminoanilines13–17 or o-nitrobenzylamines18 with a carbonyl
donor or the nucleophilic annulation of o-functionalized
aniline derivatives19 in addition to more recent methodologies
relying on the use of expensive transition metal catalysts20–24 or
toxic selenium and carbon monoxide.25 In 2015, we disclosed
During the course of our investigations on the reactivity of N-
acyliminium ions (I), we observed the formation of an unknown
side-product (4a) when formic acid was used as a solvent, in an
aza-Henry based cyclization cascade, in lieu of acetic acid
(Scheme 1). Subsequent characterization studies revealed that
this compound retained the DHQ core but lacked the expected
C4-substituent. The most plausible explanation for the forma-
tion of 4a is the in situ reduction of the iminium ion interme-
diate and indeed, the catalyst-free formic acid (or derivative)
mediated reduction of iminium ions was rst reported over
a
novel multicomponent strategy to assemble diversely
aDepartment of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University,
P. O. Box 574, SE-751 23 Uppsala, Sweden. E-mail: luke.odell@ilk.uu.se
bDepartment of Chemistry, Savitribai Phule Pune University (formerly Pune
University), Ganeshkhind, Pune 411 007, India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra10142g
Fig. 1 Representative biologically-active 3,4-dihydroquinazolinones.
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removal of nitromethane led to a marked increase in yield (64%,
entry 1) most likely by suppression of competing Henry-type
side reactions. An increase in the reaction temperature and
ꢀ
time (150 C and 30 min) afforded full consumption of 1a and
the desired product was isolated in 77% yield (entry 2).
Although the amount of amine 2a could be reduced to 1.5 equiv.
without affecting the yield (entry 4) further decreases were
found to be detrimental to the reaction outcome (entry 5). In
cases where a larger excess (>1.5 equiv.) of 2a was used, puri-
cation was troublesome due to the formation of benzylforma-
mide as a side-product and in entry 5 unreacted starting
material 1a was observed (LCMS analysis). Finally, the reaction
time was probed with shorter times leading to the presence of
unreacted 1a and N-acyliminium ion I and extending the reac-
tion time afforded a lower yield (entry 6). Accordingly, the
conditions from entry 4 were chosen for further evaluation.
With the optimized reaction conditions in hand, the substrate
scope was evaluated using various o-formyl methylcarbamate and
benzyl amine derivatives (Table 2). In general, the reaction was
compatible with a wide range of substrates, affording moderate
to excellent yields of the desired DHQ products. Carbamates
bearing electron donating (4b, c) or electron withdrawing (4d–h)
substituents were well tolerated with the latter returning slightly
lower yields. The presence of an o-substituent (4c) or an N-benzyl
group (4i) was also compatible with the reaction indicating
a tolerance towards steric bulk around the carbamate center.
Similarly, the amine nucleophile scope was found to be broad
Scheme 1 Overview of previous work on the formation of substituted
DHQs via carbamate induced cyclization cascade. Initial observation
using formic acid and an overview of this work.
a century ago32,33 and is known as the Leuckart–Wallach
reaction.
Although the use of formic acid as a green and renewable
reductant in transfer hydrogen chemistry34 has received signif-
icant attention, there are surprisingly few examples utilizing the
Leuckart–Wallach reaction manifold in the literature.35–43 Real-
izing that this would provide an efficient, sustainable and
straightforward entry point into DHQ scaffolds structurally
similar to olcegepant and PFI-1, we set about further exploring
the formation of 4a. Herein, we describe the discovery and
development of novel metal-free Leuckart–Wallach type reduc-
tive cyclization cascade of o-formyl methylcarbamates for the
preparation of biologically relevant DHQs.
Table 2 Substrate scope using various o-formyl methylcarbamates
and benzyl aminesa
Results and discussion
Our study commenced with a survey of reaction conditions with
the aim of increasing the yield of DHQ 4a (Table 1). Simple
Table 1 Optimization of the reaction conditionsa
2a
(equiv.)
Entry
Temp. (ꢀC)
Time (min)
Yieldb (%)
1
2
3
4
5
6
2.0
2.0
1.7
1.5
1.3
1.5
130
150
150
150
150
150
10
30
30
30
30
50
64
77
75
83
76
67
a
Isolated yield (unless otherwise stated). Reactions were performed
with 1 equiv. aldehyde (0.28 mmol scale), 1.5 equiv. benzylamine in
a
b
c
Reaction conditions: 1 equiv. aldehyde 1a (0.28 mmol scale), 1 mL HCO2H (1 mL). Reaction conducted on 2 mmol scale. Heated at
b
HCO2H. Isolated yields.
120 ꢀC.
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with sterically and electronically diverse substrates all delivering
the target DHQ products in good to excellent yields. Notably, the
reaction was also successfully extended to heterocyclic amines to
afford the thiophene and pyridine derivatives 4n and 4o,
respectively. Finally, to investigate the potential for scalability,
the reaction was performed on a 2 mmol scale resulting in an
86% yield of 4a.
Scheme 2 Proposed reaction pathway.
To further expand the reaction scope, we sought to explore
the use of aliphatic amine nucleophiles in lieu of substituted
benzyl amines. However, during our initial scouting reactions
we noted a marked difference in reactivity, with only low levels
of conversion observed (LCMS analysis) even aer prolonged
heating times. We reasoned that this could be the result of the
higher basicity of these substrates, leading to an increase in the
proportion of unreactive ammonium cations, under the acidic
reaction conditions. To overcome this issue, we investigated
a telescoped one-pot protocol where the key N-acyliminium ion
intermediate was rst generated using the less acidic acetic
acid26 and subsequently reduced through the addition of formic
acid. As shown in Table 3, the reaction performed well with wide
range of amine nucleophiles to afford the corresponding DHQ
products 5a–5m in up to 92% yield. Pleasingly, linear, branched
and cyclic primary amines were all found to be suitable
substrates and the use of NH4OAc was also successful. When
ethanolamine was employed as the nucleophile, the corre-
sponding formate ester 5j was isolated in 81% yield and this was
readily hydrolyzed to afford alcohol 5k in an overall yield of
74%. The reaction scope could even be extended to acid-
sensitive and less-reactive nucleophiles to afford moderate
yields of the corresponding products 5l and 5m, respectively.
The synthesis of 5l is particularly noteworthy given the labile
nature of the Boc group and the elevated temperature and acidic
reaction conditions.
Based on the above results and our previous studies,26 the
reaction is believed to occur via a cascade imine/iminium ion/
Leuckart–Wallach type reaction process (Scheme 2). The reac-
tion begins with the acid-mediated formation of imine II fol-
lowed by annulation onto the pendant carbamate resulting in
the formation of cyclic N-acyl iminium ion I. Finally, reduction
of this highly electrophilic intermediate by formic acid leads to
the target DHQ products 4 and 6, in an effective and efficient
process, generating H2O, CO2 and MeOH as the only reaction
byproducts. This is the most likely set of events in the two-step
reaction (Table 3), as complete conversion to I was routinely
observed (LCMS analysis) prior to the addition of formic acid.
However, when the reaction is conducted solely in formic acid
(Tables 1 and 2) an alternative scenario where reduction of II
occurs prior to cyclization is also plausible. To further investi-
gate this possibility, we set about synthesizing an imine of type-
II and its corresponding reduced form (Scheme 3) to assess
their relevance in our reaction system.
To this end, o-formyl carbamate (1a) and benzylamine (2a)
were rst reacted under standard reductive amination condi-
tions using Na(OAc)3BH (Scheme 3). Surprisingly, formation of
amine 8 was not observed (LCMS analysis) and instead imine 7
was isolated in 48% yield. Subsequent treatment of 7 with the
more reactive NaBH4 led to formation of the desired amine
product 8. We next subjected 7 and 8 to the optimized reaction
conditions from Table 2. Interestingly, full conversion of 7 to 4a
was observed (LCMS analysis) whereas the reaction with 8 gave
the N-formyl derivative 8a as the major product (63%) and 4a
was isolated in only 5% yield. These results strongly support the
intermediacy of a cyclic N-acyl iminium ion species under both
sets of reaction conditions.
Table 3 Substrate scope with aliphatic and aromatic aminesa
Finally, the utility of our methodology was demonstrated
through the synthesis of additional, more elaborate DHQ
derivatives (Scheme 4). Firstly, we were intrigued by the possi-
bility of using deuterated formic acid to potentially enable the
site-selective introduction of a deuterium atom. The H/D
isotopic replacement is an important tool to modulate the PK/
a
Isolated yield. Unless otherwise stated, reactions were performed with
1 equiv. aldehyde (0.28 mmol scale), 1.5 equiv. amine in AcOH (1 mL)
b
c
and HCO2H (1 mL). Heated at 130 ꢀC in step 2. Treated with
d
NaOAc (10 equiv.) in EtOH at reux for 5 h. Heated at 100 ꢀC with
Scheme
3
Control experiments probing possible reaction
10 equiv. HCO2H for 30 min in step 2.
intermediates.
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Acknowledgements
The research was supported by Uppsala University and the
˚
Swedish Research Council (Vetenskapsradet 2018-05133).
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In summary, we have developed a straightforward and high-
yielding protocol for the synthesis of 3,4-dihydroquinazolinone
by a novel imine/cyclization/Leuckart–Wallach type cascade
process. Notably, the reaction is metal-free and requires only the
addition of formic acid as a dual Brønsted acid/reductant or
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