Convergent assembly of structurally diverse quinazolines

Article abstract of DOI:10.1039/c0ob00608d

A convergent and versatile Vilsmeier-Haack-based carbo-annulation strategy that exhibits an unusually elevated bond-forming efficiency has been developed. By virtue of its innovative approach, structure economy and simple execution conditions the methodol

Full text of DOI:10.1039/c0ob00608d

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COMMUNICATION
Convergent assembly of structurally diverse quinazolines†
Abel Crespo,a Alberto Coelho,a Paula M. Diz,a Franco Ferna´ndez,b Hector Novoa de Armasc and
Eddy Sotelo*a,b
Received 19th August 2010, Accepted 12th October 2010
DOI: 10.1039/c0ob00608d
A convergent and versatile Vilsmeier–Haack-based carbo-
annulation strategy that exhibits an unusually elevated bond-
forming efficiency has been developed. By virtue of its
innovative approach, structure economy and simple execu-
tion conditions the methodology reported here constitutes a
very attractive protocol that enables the rapid assembly of
structurally diverse quinazoline chemotypes.
has triggered renewed interest in molecular architectures that
incorporate the quinazoline core. Paradoxically, a critical review
of the relevant literature reveals that such a prolificacy in bioactive
quinazoline entities is supported by collections of rather limited
structural and functional diversity. Such data not only emphasize
the enormous unexplored potential of quinazoline scaffolds in
medicinal chemistry, but also highlight – the relevance of quina-
zolines notwithstanding – the fact that, although efficient, the
compendium of preparative methods to access these heterobicyclic
cores is somewhat limited.
As is common in heterocyclic synthesis praxis,4 established
preparative methods for the synthesis of quinazolines are based on
the construction of the heterocyclic scaffold starting from appro-
priately functionalized o-disubstituted benzene derivatives (e.g. 2-
aminobenzoic acids, 2-aminoarylketones, 2-aminobenzonitriles or
isatoic anhydride),4,5 those derived from Niementowsky synthesis6
and Dimroth rearrangement7 being particularly useful. A valuable
incorporation to the synthetic armamentarium targeting the
quinazoline nucleus has recently been published by Chilin,8 which
enables the rapid access to the heterobicyclic core from simple
anilines after protection as ethyl carbamates. To the best of our
knowledge, the opposite synthetic strategy (i.e. construction of the
carbonated framework from the appropriate heterocyclic scaffold)
has only been described occasionally.9 Thus, the development
of conceptually novel, convergent and practical quinazoline
syntheses remains an unmet methodological challenge for organic
chemists.
Quinazolines represent an abundant heterocyclic nucleus that is
present in diverse natural products1 as well as a chemotype found
in diverse therapeutic agents,2 among which are the prominent
drug molecules Prazosin, Gefitinib, Erlotinib, Afloqualone and
Raltitrexed (Fig. 1). The pursuit of protein kinase inhibitors3
aCombinatorial Chemistry Unit (COMBIOMED), Institute of Industrial
Pharmacy (IFI), University of Santiago de Compostela, Santiago de
Compostela 15782, Spain
bDepartment of Organic Chemistry, Faculty of Pharmacy, University of
Santiago de Compostela, Santiago de Compostela 15782, Spain. E-mail:
eddy.sotelo@usc.es; Fax: ++34-981-528093; Tel: ++34-981-563100
cPharmaceutical Sciences Department, Johnson & Johnson, Pharmaceutical
Research and Development, A Division of Janssen Pharmaceutica NV,
Turnhoutseweg 30, B-2340 Beerse, Belgium
† Electronic supplementary information (ESI) available: Detailed ex-
perimental procedures, analytical and spectroscopic data for repre-
sentative compounds. CCDC reference number 781796. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00608d
Fig. 1 Representative alkaloids and drugs incorporating the quinazoline scaffold.
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Fig. 2 Retrosynthetic scheme.
In the context of a lead optimization program on the pyrimidin-
2(1H)-one framework it was required to experimentally val-
idate in silico bioactivities predicted for virtually generated
new ligands that incorporated a phenyl ring fused at positions
5,6 of the heterocyclic core [thus generating quinazolin-2(1H)-
ones 3]. Given our previous experience and the availability of
collections of pyrimidin-2-(1H)-ones (readily accessible through
Biginelli’s condensation),10 we considered the feasibility of an
unprecedented carbo-annulation strategy starting from suitably
substituted pyrimidin-2(1H)-ones (Fig. 2). It was envisioned that
submitting 5-acetyl-6-methyl-4-arylpyrimidin-2(1H)-ones (1) to a
Vilsmeier–Haack reaction11 would afford b-chloroacroleins (2),
which would undergo an intramolecular cyclization to provide a
rapid assembly of target scaffolds (Fig. 2). Herein, we document an
experimentally simple and versatile three-component reaction that
enables rapid access to diverse sets of pharmacologically relevant
chemotypes derived from the quinazoline scaffold. Moreover,
the processes highlighted in this communication represent an
unexplored one-pot pathway in which the heterobicyclic core is
assembled through a Vilsmeier–Haack-assisted carbo-annulation
strategy that employs readily accessible precursors and exhibits an
unusually elevated bond-forming efficiency. This approach provide
collections of significant structural and functional diversity in a
time- and cost-effective manner.
add to an iminium group, thus extending the carbon framework
by one unit and generating a highly reactive b-chloroacrolein (2).
In order to prove this concept it was decided to employ pyrimidin-
2(1H)-ones 1a–b (Scheme 1, R1 = H, Me) as model substrates.
These compounds were submitted to the standard experimental
conditions of the Vilsmeier–Haack reaction employing variable
equivalents (1–10) of freshly distilled phosphorus oxychloride,
different temperatures (0–90 ◦C) and reaction times (0.1–5 h).
Preliminary experimentation not only validated the feasibility
of the proposed pathway in a shorter sequence, but also revealed
remarkable facets of this chemistry that highlight its scope
and versatility in terms of the rapid generation of molecular
diversity (Scheme 1). The analytical and spectroscopic data (see
supporting information) unequivocally showed that the products
obtained during the Vilsmeier–Haack chloroformylation of 1a–
b are not the expected b-chlorovinyl aldehydes (2), but rather
diverse chemotypes derived from the quinazoline scaffold (e.g.
compounds 5, 6 and 7, Scheme 1). The structural assignment
within the series (see supporting information) was complemented
by X-ray crystallography data obtained on a monocrystal of one
representative compound (compound 7b, Fig. 3).13 Remarkably,
simple addition of freshly distilled phosphorus oxychloride to a
solution of the heterocyclic substrate in dimethylformamide at
a range of temperatures led to complete consumption of the
staring material within relatively short reaction times (0.5–2 h).
A detailed exploration of the transformation showed that slight
modifications in the experimental conditions, particularly the
reagent ratio and temperatures (see supporting information), led to
either quinazolin-2(1H)-ones (5 or 6) or 3-chloroquinazolines (7).
The feasibility of the proposed sequence relies heavily on the ef-
ficacy of the halomethyleneiminium-mediated haloformylation of
ketones that incorporate enolizable a-hydrogens.12 Such a reaction
would enable the transformation of the acetyl group at position
5 of the heterocycle into a vinyl halide that subsequently would
Scheme 1 Vilsmeier–Haack-based carbo-annulation approach to quinazolines 5–8.
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Table 1 Structure of quinazolines obtained
Compd
R4
R1
R8
Yield
5a
5b
5c
5d
6a
6b
6c
6d
6e
7a
7b
7c
7d
8
Ph
H
H
H
H
Me
Bn
Me
Me
Me
—
—
—
—
H
CHO
CHO
CHO
CHO
H
H
H
H
H
—
—
88%
65%
50%
53%
56%
47%
46%
53%
50%
76%
58%
63%
85%
74%
Ph-4-OMe
Ph-4-Cl
Ph-4-Br
Ph
Fig. 3 Ortep plot showing the crystal structure and atomic numbering
scheme for 2,5-dichloro-8-formyl-4-(4-methoxyphenyl)quinazoline (7b).
Ph
Ph-4-OMe
Ph-4-Cl
Ph-4-Br
Ph
Ph-4-OMe
Ph-4-Cl
Ph-4-Br
Ph
It was observed that some of the isolated compounds incorporate
a formyl group at position 8 of the heterocyclic backbone
(Scheme 1, compounds 5 and 7), probably as a consequence of
a post-annulation regiospecific Vilsmeier–Haack formylation. All
attempts to avoid the formylation at the benzene moiety of the
heterobicyclic core for the simplest model substrate [pyrimidin-
2(1H)-one 1a] failed, generating reaction mixtures in which the
formylated products were the major components. Conversely, sim-
ilar studies on the N-methyl analog (1b) revealed that formylation
at position 8 of this substrate hardly occurs (even when working
at high concentrations of the Vilsmeier–Haack reagent) and
this process regiospecifically gave the non-formylated quinazolin-
2(1H)-one 6b. These data suggest strict control of the steric
factors is required for the viability of the electrophilic aromatic
substitution by the chloromethyleneiminium salt at position 8, but
simultaneously provide valuable information from a mechanistic
point of view.
—
—
H
group at position 1, thus validating the straightforward access
to 5-chloro-4-arylquinolin-2(1H)-ones (8). Having established the
feasibility of the proposed method for the model systems, and also
having identified a set of optimal experimental conditions for each
chemotype, the robustness and scope of the methodology was
briefly assessed by employing a set of representative pyrimidin-
2-ones 1 that incorporate different aryl groups at position 4 of
the heterocyclic scaffold. These experiments provided additional
evidence to support the versatility of the developed synthetic
methodology (Table 1).
In an attempt to broaden the scope of the methodology and to
address access to non-formylated quinazolin-2(1H)-ones (8), and
taking advantage of the decisive effect of steric hindrance at posi-
tion 1 on reaction behavior, 5-acetyl-1-benzyl-6-methyl-4-aryl-3,4-
dihydropyrimidin-2(1H)-one (1c) was submitted to the previously
optimized experimental conditions (Scheme 1). It was gratifying
to verify that this reaction satisfactorily afforded 2-benzyl-5-
chloro-4-phenylquinolin-2(1H)-one (6b), thus confirming that the
previously documented reactivity profile had been maintained.
A mild cleavage protocol was employed to remove the benzyl
Encouraged by the excellent reactivity profiles and efficiency
observed in the Vilsmeier–Haack-based carbo-annulation strategy
within the pyrimidin-2(1H)-one series (1), we considered the
feasibility of a similar sequence starting from the corresponding
3,4-dihydroanalogs (Scheme 2, compounds 9). The experimental
conditions evaluated, the model substrates (9) and the compounds
isolated during this study (10–13) are shown in Scheme 2
and Table 2. As previously observed for the dehydroanalogs,
complete consumption of the starting materials (9) was achieved
within short reaction times (10–30 min) under Vilsmeier–Haack
Scheme 2 Vilsmeier–Haack-based carbo-annulation approach to 3,4-dihydroquinazolines 10–12.
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Table 2 Structures of 3,4-dihydroquinazolines obtained
Compd
10a
10b
10c
10d
11a
11b
11c
11d
12a
12b
12c
12d
12e
13
R4
Ph
R1
H
H
H
H
H
H
H
H
Me
Bn
Me
Me
Me
Me
Yield
56
53
60
57
62
55
67
62
59
66
53
58
49
53
Ph-4-OMe
Ph-4-Cl
Ph-4-Br
Ph
Ph-4-OMe
Ph-4-Cl
Ph-4-Br
Ph
Ph
Ph-4-OMe
Ph-4-Cl
Ph-4-Br
Ph
conditions. While the carbo-annulation process showed a similar
efficacy profile, slight modifications in reaction behaviour were
observed (Scheme 2). Remarkably, within this series the hetero-
cyclic scaffold is formylated at position 3 (Scheme 2), a predictable
behaviour in the light of the well documented14 nucleophilic profile
of the N-3 atom of the 3,4-dihydropyrimidin-2(1H)-one scaffold.
In agreement with previous findings for the pyrimidin-2(1H)-one
series (1), the regiochemistry at position 8 (R8 = H or CHO) is
governed by the substitution pattern at position 1 (R1 = H, Me or
Bn) of the heterocyclic scaffold (Scheme 2). As corroborated by
the spectroscopic and analytical data, concomitant formation of
quinazolines 10 and 11 (typically in a 2 : 1 ratio) was observed
on submitting 9a to Vilsmeier–Haack conditions identical to
those used for 1a (see supporting information). An increased
regioselectivity (4 : 1) in favor of the 3,8-diformylquinazoline-2-
(1H)one 10 was obtained by modification of both the reagent
ratio and temperature (see supporting information). As previously
demonstrated for the pyrimidin-2(1H) series, regiospecific access
to non-formylated quinazoline-2(1H)-ones 11 was provided by
cleavage of the benzyl group at position 1 of 12b employing
aluminium chloride (Scheme 2). Fine tuning of the experimental
conditions in these series also enabled the preparation of 5-chloro-
1-methyl-4-phenyl-3,4-dihydroquinazolin-2(1H)-one 13 starting
from 9b. Once different experimental conditions to access the
target quinazoline chemotypes were available, these were applied
to a set of precursors that incorporated different aryl moieties at
position 4 (Table 2). It can be seen (Scheme 2) that within the
3,4-dihydropyrimidin-2(1H)-one series the transformation retains
its versatility and readily provides structurally and functionally di-
verse quinazoline frameworks (i.e. compounds 10–13, Scheme 2).
In an attempt to expand the scope of the strategy reported here,
and taking advantage of the highly diverse collections of pyrimi-
dine derivatives provided by the Biginelli reaction, we assessed the
feasibility of a similar sequence but starting from 2-thioanalogs of
previously tested substrates [e.g. pyrimidin-2(1H)-thiones 14a–b
and dihydroderivatives 15a–b]. With this aim in mind, compounds
14–15 were reacted with dimethylformamide and phosphorus
oxychloride under identical experimental conditions as for 1 and
9 (Scheme 3). In sharp contrast to the results described above,
all experiments on these compounds afforded complex reaction
mixtures from which, instead of the desired derivatives (16 and
17), low yields of the corresponding quinazolin-2(1H)-one or
3,4-dihydroquinazolin-2(1H)-one analogs (5–6 and 10–12) were
isolated. As observed experimentally, the use of milder conditions
[by performing the reactions at room temperature or below (0 ◦C)
and/or employing preformed chloromethyleneiminium salt] did
not have any effect on the reaction behavior. In an attempt to
circumvent this drawback, it was decided to mask the thiocarbonyl
moiety in the heterocyclic backbone by methylation. Thus, 1-[2-
(methylthio)-4-methyl-6-phenylpyrimidin-5-yl]ethanone (18) was
utilized as the reactive substrate under previously optimized
experimental conditions of the Vilsmeier–Haack-based carbo-
annulation strategy (Scheme 3). These experiments confirmed the
feasibility of the sequence and successfully afforded the 5-chloro-
8-formyl-2-methylthio-4-phenylquinazoline (19) in moderate yield
(52%). Further work is now in progress in our laboratory aimed
at extending this protocol to other 2-blocked pyrimidin-2(1H)-
thiones, thus facilitating the thiocarbonyl reversion once the
annulation process has finished.
To further challenge the Vilsmeier–Haack-based carbo-
annulation strategy in terms of robustness and versatility, the
possibility of increasing the diversity of the collections obtained
by introducing a bromine atom15 at positions 2 and 5 of the
heterocyclic backbone was assessed (Scheme 4). With this aim,
model substrates (1a–b and 9a–b) were reacted with phosphorus
oxybromide under previously optimized experimental conditions
(Scheme 4). It was gratifying to find that both precursors rapidly
underwent the Vilsmeier–Haack-assisted carbo-annulation to
furnish the target structures (Table 1, 20–22) and the previously
observed reactivity profiles were maintained, albeit with a slightly
reduced efficiency.
Although it is premature to propose a detailed mecha-
nism at this stage, based on the above results a prelimi-
nary plausible mechanistic proposal for the herein documented
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Scheme 3 Vilsmeier–Haack-based carbo-annulation approach to quinazoline 19.
Scheme 4 Use of POBr3 in the Vilsmeier–Haack-based carbo-annulation approach to quinazoline derivatives.
Vilsmeier–Haack–based carboannulation strategy is presented
in Scheme 5. The overall transformation would start with the
halogenation and subsequent addition of an iminium group to
the acetyl group of the heterocycle, mediated by the Vilsmeier
reagent, to generate a highly reactive b-halovinyliminium salt (A)
which rapidly undergoes an intramolecular cyclization followed by
elimination, thus generating the bicyclic heteroaromatic system
(C). Once the carbo-annulation process has occurred – and
depending on the substitution pattern at position 1 and the nature
of the heterocycle (3,4-dihydro or aromatized) – the activated
positions (e.g. 8 and/or 3) undergoes regioselective Vilsmeier–
Haack formylation. Finally, high temperatures and excess of the
reagent promotes thedehydrohalogenation of quinazoline-2-(1H)-
ones 5 or 20a to generate the corresponding 2-haloquinazolines (7
or 22).
reaction,16 e.g. its high atom economy and inherent bond-forming
efficiency. In particular, these processes elicit an unusually elevated
bond-forming efficiency,17 i.e. the number of bonds that are formed
in one process. Some of the procedures described here involve
the formation of up to 6 new bonds (7 if the in situ generation
of the formylating reagent is considered) in a convergent and
operationally simple synthetic methodology. An additional feature
of the transformation concerns its contribution in terms of the
rapid generation of skeletal and functional diversity (structure
economy).16 As can be seen, the role of the Vilsmeier–Haack
reagent is not limited to its integration in the halocarbonated
framework of the heterocyclic core. In addition, the synergistic
exploitation of both the scaffold reactivity and variation of the
experimental conditions enables the diversity contribution of the
halomethyleneiminium salt to be maximized. This broad scope
enables formyl and halogens (Cl or Br) to be incorporated at dif-
ferent positions of the quinazoline ring, both groups constituting
The quinazoline synthesis reported here has two distinctive
attributes derived from its intrinsic nature as a multicomponent
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Scheme 5 Plausible mechanism of the herein described Vilsmeier–Haack-based carbo-annulation approach to quinazoline derivatives.
new reactive centres for additional diversification. Further work
is in progress in our laboratories to study the biological activity of
the herein described derivatives, as well as to evaluate the extension
of this strategy to the synthesis of other heterobicyclic privileged
scaffolds.
In summary, a convergent and versatile Vilsmeier–Haack-based
carbo-annulation strategy that exhibits an unusually elevated
bond-forming efficiency has been developed. By virtue of this
innovative approach, structure economy, readily available starting
materials, and simple conditions the herein documented method-
ology constitutes a very attractive protocol that enables the
rapid assembly of collections of structurally diverse quinazoline
chemotypes in a cost- and time-effective manner.
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Acknowledgements
This work was financially supported by the Fondo Europeo de De-
sarrollo Social (FEDER) and the Galician Government (Project:
09CSA016234PR). E. Sotelo is the recipient of a Consolidation
Group Research Grant from the Conselleria de Educacio´n (Xunta
de Galicia). E. Sotelo and A. Coelho are research fellows of
the Isidro Parga Pondal program (Xunta de Galicia, Spain).
The crystallographic work was developed by H. Novoa during
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