The synthesis of 2-amino-4(3H)-quinazolinones and related heterocycles via a mild electrocyclization of aryl guanidines

Article abstract of DOI:10.1016/j.tetlet.2018.03.034

A new method for the preparation of 2-amino-4(3H)-quinazolinones and similar fused heterocycles is described. Simply warming a mixture of an aryl guanidine and carbonyl diimidazole in acetonitrile results in formation of a putative N-amidinoisocyanate intermediate which undergoes a 6π-electron electrocyclic reaction with the aryl ring to generate the quinazolinone ring system. The mild conditions are compatible with a variety of functional groups, and the reaction is shown to be successful on multigram scale.

Full text of DOI:10.1016/j.tetlet.2018.03.034

Accepted Manuscript
The synthesis of 2-amino-4(3H)-quinazolinones and related heterocycles via a
mild electrocyclization of aryl guanidines
Zachary S. Sales, Neelakandha S. Mani, Brett D. Allison
PII:
S0040-4039(18)30331-9
https://doi.org/10.1016/j.tetlet.2018.03.034
TETL 49803
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Accepted Date:
5 March 2018
13 March 2018
Please cite this article as: Sales, Z.S., Mani, N.S., Allison, B.D., The synthesis of 2-amino-4(3H)-quinazolinones
and related heterocycles via a mild electrocyclization of aryl guanidines, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.03.034
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Tetrahedron Letters
The synthesis of 2-amino-4(3H)-quinazolinones and related heterocycles via a mild
electrocyclization of aryl guanidines
Zachary S. Sales, Neelakandha S. Mani, Brett D. Allison
aJanssen Research and Development, LLC., 3210 Merryfield Row, San Diego, CA, 92121, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new method for the preparation of 2-amino-4(3H)-quinazolinones and similar fused
heterocycles is described. Simply warming a mixture of an aryl guanidine and carbonyl
diimidazole in acetonitrile results in formation of a putative N-amidinoisocyanate intermediate
which undergoes a 6-electron electrocyclic reaction with the aryl ring to generate the
quinazolinone ring system. The mild conditions are compatible with a variety of functional
groups, and the reaction is shown to be successful on multigram scale.
Available online
Keywords:
quinazolinone
heterocycles
2009 Elsevier Ltd. All rights reserved.
electrocyclic reaction
cyclization
carbonyl diimidazole
The 4(3H)-quinazolinone ring system is a long studied
aromatic derivatives such as anthranilic acids or ortho-halo
aryl acids and their carboxyl derivatives. However, the pool
of readily available anthranilic acids and related compounds
is limited. Due to their commercial abundance and
relatively low cost, simple anilines or heteroaryl amines
would provide an advantageous feedstock for quinazolinone
preparation, yet despite decades of synthetic development,
there are few papers documenting quinazolinone synthesis
from aryl amine derivatives such as amidines or guanidines
lacking pre-installed ortho-carboxyl substitution (Scheme
1).
heteroaromatic structure (Figure 1),1 which has been the
subject of many synthetic methodology studies.2 Its
importance has been highlighted by recognition as a
privileged scaffold in natural products and medicinal
chemistry.3 Recent reviews highlight the accelerating
interest in this heterocyclic nucleus.4
The 2-amino
substituted 4(3H)-quinazolinone is also a target of particular
interest. This continuing interest is due in part to the
numerous medicinal chemistry investigations that find 2-
aminoquinazolinones with a broad range of biological
activity.5
One compound in particular, Nolatrexed
(thymitaq), has been advanced to late stage clinical trials
(Figure 1).6 The literature indicates efficient, functional
group tolerant methods to construct these heterocycles are
in demand. This letter documents a new carbonylative
annulation of N-aryl guanidines generating 2-
aminoquinazolinones by a very mild procedure using
carbonyl diimidazole (Scheme 1).
Scheme 1. General routes to quinazolinones and our approach
to 2-aminoquinazolinones.
We surmised we should be able to access the key N-
amidinoisocyanate intermediate 2 via carbonylation of an
N-aryl guanidine 1 with phosgene or a phosgene surrogate,
and this isocyanate should smoothly cyclize to the
quinazolinone by an electrocyclic 6-electron process.
Figure 1. The 4(3H)-quinazolinone ring system.
The vast majority of reported methods to build the
———
quinazolinone ring system start with ortho-disubstituted
 Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
With the exception of Zhu’s palladium-catalyzed
carbonylative cyclization of N-aryl amidines,7 the only
reports of quinazolinone preparation by annulation of
simple aniline derivatives all proceed via putative
generation of a similar isocyanate intermediate.8 But, the
conditions for generating the isocyanate typically are harsh
(thermolysis) or involve very reactive intermediates
(imidoyl chlorides), which may limit the practical utility of
the reaction. The only previous paper demonstrating
preparation of 2-aminoquinazolinones by annulation of N-
aryl guanidines utilizes a “pre-carbonylated” N-carboethoxy
guanidine which is activated by excess Lewis acid (5 equiv.
TMSCl) at elevated temperature.8f Our method offers an
alternative to this procedure which accomplishes in situ
carbonylation without need for additional activation or
concern for moisture sensitivity.
reaction with CDI (Table 2).
successful across a broad range of electronic perturbations
of the aryl ring.
The cyclization was
Table 2 The influence of aryl substituent on the cyclization
reaction.a
Entry
R1
Yield (%)b
1
2
3
4
5
6
OMe
Me
H
CN
CO2Me
NO2
72
91
81
58
84
52
a Reaction conditions: Guanidine (1 equiv), CDI (1.05-1.45 equiv),
ACN (0.08 M), 80 °C, 1-2 h.
The p-phenoxyphenyl guanidine 3 was prepared for
initial evaluation of carbonylating reagents for this process
(Table 1).9 Acetonitrile was found to be a favorable solvent
as the desired 2-amino-4(3H)-quinazolinone 4 precipitated
directly from the reaction mixture. The reaction with
triphosgene (entry 1) failed to provide the desired product.
Only the starting material 3 was observed along with a
product whose spectral data was consistent with a dimer of
the intermediate isocyanate resulting from intermolecular
b Isolated yield.
Next, the scope and utility of this transformation were
further explored (Table 3). Up to now, we have only shown
substrates derived from para-substituted anilines. Entries 1
and 2 show that 2-substituted and 3,4-disubstituted aryl
guanidines generate 2-aminoquinazolinones in high yield.
The 3,4-substitution pattern introduces a selectivity issue
since the two ortho sites available for cyclization are not
equivalent. In the case of entry 2, addition to the aryl ring
prefers to occur in a contrasteric sense ortho to the 3-chloro
substituent. Entries 3-6 highlight heteroaryl guanidines
which undergo clean conversion to quinazolinone-related
heterocycles. Very high selectivities can be achieved in the
cyclization event as shown in examples 4 and 6. The indole
is a good example of a substrate for which neither the
corresponding anthranilic acid nor the 2-halobenzoic acid
derivative is easily available, rendering the quinazolinone
difficult to prepare by previous methods. However, the
synthesis is made trivial with this chemistry.
[4+2] cycloaddition between two molecules of isocyanate, a
9
previously observed process.8d,
With p-nitrophenyl
carbonate, significant production of the [4+2] dimer was
again observed with a correspondingly low yield of 4.
However, diphenyl carbonate and carbonyl diimidazole
(CDI) provided high yields of product with CDI proving to
be the optimum reagent giving a very clean reaction profile
by HPLC analysis and an 89% isolated yield of 4. The
electrocyclic reaction was observed to be quite facile. At
just 40 °C, the CDI-mediated reaction of 3 proceeds to
completion in 3 days, and even at room temperature,
cyclization is still observed to some extent after an
overnight reaction (13% yield).
Table 1 The influence of carbonylating reagent on reaction
We also explored various amine substitutions that can be
successfully carried through this chemistry (entries 7-11).
Particularly noteworthy are the acid labile and thermally
labile Boc and ketal protecting groups in entries 9 and 10.
In entry 11, the unprotected ketone is not affected during
the mild cyclization process.
yield.a
As shown in entry 12, we demonstrate that this
cyclization chemistry is robust and can be scaled to
multigram quantities. On a 2 g scale, a 95% yield of the
crystalline aminoquinazolinone was isolated directly from
the reaction mixture in analytically pure form.
Entry
1
Reagent
triphosgene
Yield (%)b
0
2
3
27
80
There are some substrate limitations for this chemistry
shown in the final entry of Table 3. A tertiary amine
terminus is required on the guanidine, otherwise the distal
amine competes nucleophilically for the CDI leading to
4
89
unproductive reaction pathways.
In particular,
intermolecular urea formation was observed. Additionally,
despite numerous attempts, simple N-aryl amidines (N-
phenyl acetamidine or N-phenyl benzamidine) could not be
induced to cyclize and produce the corresponding 2-methyl
a Reaction conditions: 3, carbonylation reagent (1.05-1.1 equiv), ACN
(0.6-1.7 M), 80 °C, 2-5 h.
b Isolated yield.
or 2-phenyl-4(3H)-quinazolinones.
The CDI-mediated
cyclization appears limited to guanidine substrates;
however, within this class of substrates, this chemistry is
We prepared a series of aryl guanidines varying the
electronics of the aryl substituent and subjected them to

very tolerant of a variety of functional groups and structural
variations.
expect this procedure will be very useful, and given the
demonstration of large scale guanidine synthesis,10b,c it is
also a very practical route to multigram quantities of 2-
aminoquinazolinones.11
The 2-amino-4(3H)-quinazolinone synthesis presented in
this communication provides a mild and convenient entry
into this heterocycle from N-aryl guanidines. The reaction
does not require inert atmosphere conditions, and it is not
sensitive to atmospheric moisture. With the variety of
available methods for N-aryl guanidine preparation,10 we
Table 3 Scope of the CDI-mediated cyclizationa
Yield
Entry Product(s)
1
Entry Product(s)
8
Yield (%)b
68
(%)b
89
2
3
87:13c 76d
9
84
86
82
10
4
95:5c
69d
74e
11
88
5
6
7
12
13
95f
0
>99:1 65d
57
a Reaction conditions: guanidine (1 equiv), CDI (1.05-1.5 equiv), ACN (0.05-0.2 M), 80 °C, 1-5 h.
b Isolated yield.
c Ratio determined by 1H NMR spectroscopy.
d Combined yield of the regioisomers.
e Isolated product was not pure. Yield is estimated from the 1H NMR spectrum of the unpurified product.
f This reaction was run on 2 g scale.
Acknowledgments
The authors thank Dr. Xiaohu Deng for providing several
guanidine substrates included in this manuscript.
1. Armarego, W. L. F. Fused Pyrimidines, Part 1,
Quinazolines; Brown, D. J., Ed.; Interscience; New
York, 1967.
Supplementary Material
References and Notes
2. Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P.
J. Tetrahedron 2005, 61, 10153-10202.

4
3. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Current
Opinion in Chemical Biology 2010, 14, 347-361.
was collected by vacuum filtration, washed with
additional acetonitrile, and allowed to dry. Yields of
precipitated product were recorded. The solubility of
the products in acetonitrile was not monitored, and
therefore, variability in reaction yields may be due to
solubility differences between compounds rather than
4. (a) He, L.; Li, H.; Chem, J.; Wu, X-F RSC Adv. 2014, 4,
12065-12077. (b) Maiden, T. M. M.; Harrity, J. P. A.
Org. Biomol. Chem. 2016, 14, 8014-8025.
(c)
Rohokale, R. S.; Kshirsagar, U. A. Synthesis 2016, 48,
1253-1268.
reaction performance.
6-Phenoxy-2-(piperidin-1-
yl)quinazolin-4(3H)-one (4). 1H NMR (400 MHz,
DMSO-d6):  ppm 11.26 (bs, 1H), 7.45-7.37 (m, 2H),
7.37-7.32 (m, 2H), 7.33-7.29 (m, 1H), 7.20-7.14 (m,
1H), 7.07-7.01 (m, 2H), 3.67-3.52 (m, 4H), 1.65-1.47
(m, 6H). 13C NMR (150 MHz, DMSO-d6):  ppm
156.8, 151.7, 130.1, 126.3, 123.5, 118.6, 117.4, 113.2,
45.8, 25.0, 23.9. MS calc’d. for C19H19N3O2, 321.15;
found, m/z 322.0 [M+H]+.
5. (a) Pendergast, W.; Johnson, J. V.; Dickerson, S. H.;
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(d) Hess, H.-J.; Cronin, T. H.; Scriabine, A. J. Med.
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Angew. Chem. Int. Ed. 2007, 46, 8266-8269. (f) Liu, H.;
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693-705.
7. Ma, B.; Wang, Y.; Peng, J.; Zhu, Q. J. Org. Chem.
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Chem. 1982, 19, 171-176. (b) Samaraj, L. I.; Bondar,
V. A.; Derkatsch, G. I. Angew. Chem. Int. Ed. Engl.
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Goerdeler, J.; Richter, R. Synthesis 1978, 760-762. (e)
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9. See supplementary material
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11. Typical experimental procedure for CDI-mediated
cyclizations: The aryl or heteroaryl guanidine (1
equiv) was combined with CDI (1.05-1.1 equiv) in a
round bottom reaction flask. Acetonitrile (~0.1-0.2 M)
was added, and the open reaction was stirred in an oil
bath at the desired temperature (usually 80 °C).
Crystalline product began precipitating within minutes.
The reaction was monitored by HPLC. If starting
guanidine remained after ~2 h, 0.1 equiv aliquots of
CDI were added with continued monitoring until the
starting material was consumed. The reaction was
allowed to cool to room temperature, and the product

5
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The synthesis of 2-amino-4(3H)-
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quinazolinones and related heterocycles via a
mild electrocyclization of aryl guanidines
Zachary S. Sales, Neelakandha S. Mani, Brett D. Allison

6
Tetrahedron
Highlights
1. 2-Amino quinazolinones and related
heterocycles can be prepared in efficient fashion by
very simply warming N-aryl or N-heteroaryl
quanidines in the presence of carbonyl diimidazole
(CDI).
2. The mild reaction conditions tolerate a variety of
functional groups allowing a diverse array of
quinazolinones to be prepared.
3. The method is scalable to multigram and likely
larger reaction scales.
4. This chemistry allows quinazolinones to be
prepared from simple aryl or heteroaryl amine
derivatives without pre-activation or pre-
substitution of the position ortho to the aryl amine.