Solid-phase synthesis of 3H-Quinazolin-4-ones based on an aza Wittig-mediated annulation strategy

Article abstract of DOI:10.1055/s-1998-1971

Aza Wittig-mediated annulation provides a highly efficient and straightforward strategy for the parallel synthesis of 3H-quinazolin-4-ones on solid support. The products were recovered in good yields and exhibited excellent purities.

Full text of DOI:10.1055/s-1998-1971

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Solid-Phase Synthesis of 3H-Quinazolin-4-ones Based on an Aza Wittig-Mediated annulation
Strategy
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#
José M. Villalgordo* , Daniel Obrecht and Alexander Chucholowsky
Pharma Research. F. Hoffmann-La Roche AG, CH-4002 Basel. Switzerland
Fax: +34 972 418 150, E-mail: dqjvs@xamba.udg.es
Received 12 October 1998
Abstract: Aza Wittig-mediated annulation provides a highly efficient
and straightforward strategy for the parallel synthesis of 3H-quinazolin-
4-ones on solid support. The products were recovered in good yields and
exhibited excellent purities.
Combinatorial chemistry and related multiple synthesis technologies
toward the synthesis of small organic molecules have recently emerged
as powerful tools for lead structure identification. Thus, numerous
protocols have already been disclosed for the construction of various
1
-8
heterocyclic and other compound libraries . For most of these
protocols, the use of solid phase methods has been the technique of
9
-11
choice
.
As a part of our ongoing project devoted toward the development of
efficient solid phase methodologies for the combinatorial and parallel
synthesis of diverse heterocyclic systems11,12 we have focused our
attention on the benzopyrimidone (quinazoline) nucleus 1. (Figure 1)
Scheme 1
Figure 1
3
H-Quinazolin-4-ones of type 1 represent an interesting pharmacophore
1
3-15
that displays a wide rage of biological properties
. Therefore, an
efficient strategy for the combinatorial and parallel synthesis of this
interesting target, that allows the introduction of a high degree of
molecular diversity, would be of interest.
Herein, we report
a highly versatile solid phase synthesis of
quinazolinones 1, which efficiently combines the aza Wittig reaction
with a multidirectional cleavage process. As recent literature has
1
6-22
discussed in depth,
iminophosphoranes have been shown to be
useful intermediates in organic synthesis, particularly for the
preparation of different heterocyclic systems containing an endocyclic
C,N double bond. In these cases, an aza Wittig-mediated annulation
reaction was involved as the key step. Our working hypothesis began
with the idea that a benzoic acid derivative containing an ortho-azido 2,
or an ortho-amino group 3 would be tethered to the Merrifield resin and
would provide the starting point for the formation of the corresponding
phosphorylimine derivative 4 via a Kirsanov1 or a Staudinger
9
23
reaction respectively.
Division of the polymer bound iminophosphorane beds 4, followed by
suitable manipulations and a cyclative cleavage process from the resin,
would produce various heterocycles. We envisioned that this strategy
could be applied efficiently to create compound libraries of diverse
fused pyrimidones 5. (Scheme 1).
To prove the above mentioned hypothesis, easily available ortho-azido
2
4
benzoic acid 6 was selected as a model case. Thus, alkylative
2
5
esterification of 6, via the corresponding cesium salt , with high loaded
Merrifield resin (3.4 mmol/g) resulted in polymer-bound ortho-azido
Scheme 2

1
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ester 7. Treatment of 7 with a 5-fold excess PPh3 in THF at room
temperature produced the corresponding iminophosphorane 8 attached
to the resin (evolution of N2 clearly detected). Division of the resin
beads and subsequent aza Wittig reaction with different isocyanates at
room temperature smoothly formed the corresponding reactive
carbodiimides 9. Further division of resin-bound carbodiimides 9 and
treatment with different nucleophiles (e.g. amines, thiols) led, via
intramolecular cyclization and simultaneous cleavage from the resin, to
quinazolines 10 (together with 11, when primary, non-sterically
hindered amines were used) in good yields and excellent purities. The
formation of the polymer-bound compounds was routinely monitored by
FT-IR of the resin beds. (Scheme-2, Table 1).
phosphorylimine 8 was swollen as before, and treated with 5ml/mmol of
dry THF and
5 equiv. of the corresponding isocyanate. The
heterogeneous reaction mixture was vortexed at r.t. under Ar during 8 h.
After washing cycles as above, resin 9 was dried in high vacuum and
newly divided. Polymer-bound carbodiimide 9 was treated with 3ml/
mmol of dry THF and 1 equiv. of the corresponding nucleophile. The
reaction mixture was vortexed at 50ºC during 4h. and then at r.t.
overnight liberating compounds 11 and/or 12, that were analysed by
HPLC and isolated by simply evaporating the solvent. Compounds 10
1
26
and 11 were characterised by M.S. and H-NMR
.
In summary, we have developed a simple and efficient solid-phase
methodology that allows for a rapid synthesis of quinazoline libraries.
There is also the possibility of introducing additional functionalities on
the aromatic ring, allowing further chemical manipulations compatible
with the ester, which is linked to the Merrifield resin27. The mild
reaction conditions and the selective multidirectional cyclization make
out of this traceless linker strategy an attractive procedure toward the
synthesis of highly functionalized quinazolinones and other
heterocycles. Further developments along this line are now in progress
and will be published in due course.
When primary amines were used as the nucleophiles, the product
composition 11:12 was strongly influenced by differences in
nucleophilicity and/or sterical hindrance of the two adjacent nitrogen
atoms of the presumably formed guanidine intermediate 10 (X=NH),
(
entries b and i, Table 1). When those differences were minimal, both
possible compounds of type 11 and type 12 were generally formed in
:1 ratio (entries e, h and l, Table 1).
1
Typical experimental procedure
Acknowledgements. The authors would like to thank Mr. A Grieder
and Mr. D. Sprenger for valuable technical assistance and Dr. W. Huber
for assistance with FT-IR. Fruitful discussions with Profs. K. Müller (F.
Hoffmann-La Roche AG, Basel), J. Baldwin (Oxford), F. Diderich
Polymer-bound ortho-azide ester 7, obtained by essentially following
the experimental procedure described in ref. 25, was swollen with 5ml/
mmol of dry THF and treated with 5 equiv. of a 1M soln. of Ph P in dry
3
THF. The reaction mixture was vortexed at r.t. under Ar during 6h.
(Zürich), H.-J. Hansen (Zürich) and H. Heimgartner (Zürich) are
(
evolution of N , clearly detected) and then washed with 5ml/mmol of
2
gratefully acknowledged. JMV also thanks DGICYT (Ministerio de
Educación y Ciencia, Spain) for financial support. Project PB94-0509.
dry THF (2x), dry toluene (2x), dry CH Cl2 (2x) and pentane (2x),
repeating this washing cycle 3 times to give resin 8, that was dried in
2
high vacuum, divided up and used in the next step. Polymer-bound

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1
§
Present address: Departament de Química. Facultat de Ciències.
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Spain). E-mail: dqjvs@xamba.udg.es
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(
#
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