N3-Alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides

Article abstract of DOI:10.1039/c1ob05430a

Dimethylformamide dimethylacetal (DMFDMA) is widely used as a source of electrophilic one-carbon units at the formate oxidation level; however, electrophilic methylation with this reagent is previously unreported. Reaction of anthranilamide with DMFDMA at 150 °C for short periods gives mainly quinazolin-4-one. However, prolonged reaction with dimethylformamide di(primary-alkyl)acetals leads to subsequent alkylation at N³. 3-Substituted anthranilamides give 8-substituted 3-alkylquinazolin-4-ones. Condensation of anthranilamides with dimethylacetamide dimethylacetal provides 2,3-dimethylquinazolin-4-ones. In these reactions, the source of the N ³-alkyl group is the O-alkyl group of the orthoamides. By contrast, reaction with the more sterically crowded dimethylformamide di(isopropyl)acetal diverts the alkylation to the oxygen, giving 4-isopropoxyquinazolines, along with N³-methylquinazolin-4-ones where the methyl is derived from N-Me of the orthoamides. Reaction of anthranilamide with the highly sterically demanding dimethylformamide di(t-butyl)acetal gives largely quinazolin-4-one, whereas dimethylformamide di(neopentyl)acetal forms a mixture of quinazolin-4-one and N³-methylquinazolin-4-one. The observations are rationalised in terms of formation of intermediate cationic electrophiles (alkoxymethylidene-N,N-dimethylammonium) by thermal elimination of the corresponding alkoxide from the orthoamides. These are the first observations of orthoamides as direct alkylating agents.

Full text of DOI:10.1039/c1ob05430a

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PAPER
N3-Alkylation during formation of quinazolin-4-ones from condensation of
anthranilamides and orthoamides†
Amit Nathubhai,a Richard Patterson,‡a Timothy J. Woodman,a Harriet E. C. Sharp,a,b Miranda T. Y. Chui,a
Hugo H. K. Chung,a Stephanie W. S. Lau,a Jun Zheng,a Matthew D. Lloyd,a Andrew S. Thompsona and
Michael D. Threadgill*a
Received 18th March 2011, Accepted 25th May 2011
DOI: 10.1039/c1ob05430a
Dimethylformamide dimethylacetal (DMFDMA) is widely used as a source of electrophilic
one-carbon units at the formate oxidation level; however, electrophilic methylation with this reagent is
previously unreported. Reaction of anthranilamide with DMFDMA at 150 ◦C for short periods gives
mainly quinazolin-4-one. However, prolonged reaction with dimethylformamide
di(primary-alkyl)acetals leads to subsequent alkylation at N3. 3-Substituted anthranilamides give
8-substituted 3-alkylquinazolin-4-ones. Condensation of anthranilamides with dimethylacetamide
dimethylacetal provides 2,3-dimethylquinazolin-4-ones. In these reactions, the source of the N3-alkyl
group is the O-alkyl group of the orthoamides. By contrast, reaction with the more sterically crowded
dimethylformamide di(isopropyl)acetal diverts the alkylation to the oxygen, giving
4-isopropoxyquinazolines, along with N3-methylquinazolin-4-ones where the methyl is derived from
N-Me of the orthoamides. Reaction of anthranilamide with the highly sterically demanding
dimethylformamide di(t-butyl)acetal gives largely quinazolin-4-one, whereas dimethylformamide
di(neopentyl)acetal forms a mixture of quinazolin-4-one and N3-methylquinazolin-4-one. The
observations are rationalised in terms of formation of intermediate cationic electrophiles
(alkoxymethylidene-N,N-dimethylammonium) by thermal elimination of the corresponding alkoxide
from the orthoamides. These are the first observations of orthoamides as direct alkylating agents.
Introduction
Dimethylformamide dimethylacetal (DMFDMA, dimethoxy-
methyldimethylamine, 1a, Fig. 1) is a convenient electrophile
to introduce one-carbon units at the formate oxidation level.1
Condensation with primary amines and amides leads to N,N-
dimethylformamidines and N¢-acyl-N,N-dimethylformamides,
respectively;2 the latter can be cyclised to 1,2,4-triazoles
with hydrazines and to 1,3,5-triazines with guanidines.3
Methyl anthranilate condenses with 1a to give methyl 2-
(dimethylformamidino)benzoate, which, on treatment with
primary amines, furnishes 3-alkylquinazolin-4-ones.4 It also
condenses with “active” methylene groups to form N,N-
dimethylenamines. These enamines are excellent aldehyde equiva-
lents in further synthesis, particularly of a wide range of hetero-
Fig. 1 Structures of orthoamides used in this study.
cycles. For example, acetophenones condense with 1a to give 3-
dimethylaminopropenoylbenzenes; these conjugate electrophiles
react with guanidines to form 4-arylpyrimidine-2-amines1 and
with arylhydrazines to form 1,4-diarylpyrazoles.5 Condensation
of 1a with methyl groups on electron-deficient aromatic rings
is also efficient and produces 2-arylenamines; again these are
useful synthetic equivalents of arylacetaldehydes. The Ar-Me
is particularly activated in methyl 2-methyl-3-nitrobenzoate and
condensation with 1a gives an enamine. Passage of this interme-
diate through a moist silica gel column hydrolyses the enamine
and cyclises to 5-nitroisocoumarin, a key intermediate in the
synthesis of 5-aminoisoquinolin-1-one,6 an important inhibitor
of poly(ADP-ribose)polymerases-1 and -2.7 This process cannot
aMedicinal Chemistry, Department of Pharmacy & Pharmacology, Univer-
sity of Bath, Claverton Down, Bath, UK BA2 7AY. E-mail: m.d.threadgill@
bath.ac.uk; Fax: +44 1225 386114; Tel: +44 1225 386840
bBruton School for Girls, Sunny Hill, Bruton, Somerset, UK BA10 0NT
† Electronic supplementary information (ESI) available: NMR spectra of
novel compounds, NMR spectra of product mixture from reaction of 3a–c
with 1e, NMR spectra of mixture of quinazolin-4-ones formed by reaction
of 3a with 1g. See DOI: 10.1039/c1ob05430a
‡ Present address: Ascent Scientific Ltd (UK), Unit 3 Avon Riverside
Estate, Victoria Road, Avonmouth, Bristol BS11 9DB, UK.
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be extended, as condensation of the starting ester with 1d
generates an alternative enamine, leading to 3-dimethylamino-1-
methoxy-5-nitronaphthalene.8 By contrast, reactions of 1 where
the electrophilic centre is one of the methyl groups are virtually
unknown; the formation of methyl esters from carboxylic acids is
actually an incorporation of a nucleophilic MeO unit.
repeating the condensation with the corresponding O–Et reagent,
dimethylformamide diethylacetal (DMFDEA, 1b). Reaction of 7
with 1b in boiling DMF for 16 h led to the formation of the N3-
ethylquinazolin-4-one 26b but in the lower yield of 52%. Thus it is
clear that, with simple alkyl groups, the alkyl group introduced at
N3 arises from the O-alkyl groups in the reagent orthoamide and
not from the N-alkyl groups.
Synthetic approaches to quinazolin-4-ones lacking C2- and
N3-substituents have mostly involved the introduction of the 2-
C as a one-carbon electrophile to anthranilamides, although 1a
appears not to have been used for this purpose. The principal
method is to heat the anthranilic acid to high temperatures
Since our medicinal chemical interest is in quinazolinones re-
lated to 19–25, i.e. with an 8-substituent, the effect of substitution
at position-3 of the anthranilamide on the cyclocondensation to
the quinazolin-4-ones and on the new N3-alkylation of the putative
intermediate 8-substituted quinazolin-4-ones was investigated.
The substituents at the 3-position of the anthranilamides were
chosen to be diverse in electronic effect, to explore the scope fully,
ranging from the strongly electron-withdrawing nitro group in 8
to the electron-donating methoxy group in 10, through a small
alkyl in 9, a halogen in 11 and an ester in 12. The anthranilamides
8–12 were not commercially available but were synthesised from
their corresponding benzoic acids 2–6, as shown in Scheme 1. 3-
Nitroanthranilic acid 2 was treated with thionyl chloride, followed
by ammonia to give 8, presumably via a benzoxathiazine-2,4-dione
intermediate. This method failed for reactions of 3–6 but treatment
with these anthranilic acids with 1,1¢-carbonyldiimidazole at
elevated temperature, followed by reaction of the intermediate
(an N-acylimidazole or an isatoic anhydride) with ammonia
furnished the anthranilamides 9–12 for the study. As for the parent
anthranilamide 7, treatment of 8–12 with excess 1a in refluxing
DMF for 16 h furnished the corresponding N3-methylquinazolin-
4-ones 27a, 28a, 29a, 30a, 31a in very high yields. Similar
reactions of 8–11 with 1b gave the N3-ethylquinazolin-4-ones
27b, 28b, 29b, 30b but generally in lower yields. The reaction
of the methyl ester 12 with 1b gave the ethyl ester 32b, through
transesterification with ethanol generated as a leaving group from
the orthoamide during the condensation. The location of the new
alkyl group at N3 was confirmed in each case by HMBC correlation
spectra.
Extending the scope of the new reaction to larger primary
alkyl groups, heating 7–10 with the dibenzyl orthoamide 1c
gave the N-benzylquinazolin-4-ones 26c, 27c, 28c, 29c, gener-
ally in good yields, except for the nitro analogue 27c. The
condensation/alkylation can also be extended to introduce a
alkyl substituent at the 2-position, which would require an
acetamide acetal, rather than the formamide acetals used hitherto.
Reaction of the anthranilamides 7–10 with dimethylacetamide
dimethylacetal 1d in boiling DMF gave moderate yields of the
2,3-dimethylquinazolin-4-ones 26d, 27d, 28d, 29d.
In each run with orthoformamides 1a–c, formation of the
intermediate quinazolin-4-ones 19a, 21a, 22a,23a was detected
by TLC at shorter time periods but no 8-nitroquinazolin-4-one
20a was observed. This anomalous behaviour of the compounds
containing the nitro group led to a study of the reaction of
8 with 1a under milder conditions. Heating 8 with 1.2 molar
equivalents of 1a in boiling THF (ca. 65 ◦C, cf. 150 ◦C for
refluxing DMF) gave a solid which was shown by 1H and 13C NMR
spectroscopy to comprise a mixture of the acylformamidine 33,
with smaller amounts of 20a and 27a (Scheme 1). This experiment
gives significant insights into the course and mechanism of the
condensation forming the quinazolinone heterocycle and the
alkylation at N3.
◦
(>180 C) with formamide.9,10 These quinazolin-4-ones can then
be readily alkylated at 3-N with alkyl halides and potassium
hydroxide in methanol11 or under phase-transfer conditions.10
Less-used routes to N3-alkylquinazolin-4-ones include replace-
ment of the whole [N3-Ar] unit of 3-(2-cyanophenyl)quinazolin-
4-ones with primary alkylamines (by initial nucleophilic attack
on the carbonyl),12 copper(I)-catalysed reaction of N-alkyl-2-
iodobenzamides with formamidine,13 photochemical rearrange-
ments of 2-alkylcinnolinium-4-olates14 and condensation of an-
thranilic acid with primary amines and orthoesters under Lewis
acid catalysis15,16 and with alkylisocyanides.17 The way is therefore
open to examine whether 1a and its homologues can be used
as a source of electrophilic one-carbon units to convert an-
thranilamides to 3-unsubstituted quinazolin-4-ones under milder
conditions than required for the corresponding reaction with
formamide; this study also included the effect of a diversity
of substituents at the 3-position of the anthranilamide to test
sensitivity to steric bulk ortho to the amine and to electron-
withdrawing or electron-donating substituents which influence the
nucleophilicity of this amine.
Results and discussion
In an initial experiment (Scheme 1), heating anthranilamide 7
with three molar equivalents of 1a in DMF at reflux for a short
period (90 min) gave the expected quinazolin-4-one 19a in 75%
yield; in this process, the orthoamide 1a is acting purely as a
source of the 2-CH unit at the formate oxidation level. However,
during purification, the material had to be separated from a less-
polar contaminating product. Repeating the treatment of 7 with
1a but for a longer time (16 h) led to complete consumption of
the desired 19a and conversion to the less-polar material, which
was isolated in 95% yield. This was isolated and characterised by
1H NMR spectroscopy as an N-methylquinazolin-4-one or as 4-
methoxyquinazoline, with the observation of a signal integrating
for three protons at d 3.48. The structure was confirmed as 3-
methylquinazolin-4-one 26a by comparison with literature mp
1
data11 and by HMBC correlations between the methyl H NMR
signal at d 3.48 and the 2-C signal at d 148.41 and between
the methyl protons and the 4-C signal at d 160.64. The 13C
NMR spectrum had been previously assigned by reference to
1
the H spectrum using HSQC and HMBC data. The alternative
structures 1-methylquinazolin-4-one and 1-methoxyquinazoline
were inconsistent with these HMBC data. Thus 26a appeared to
arise from methylation of 19a at N3.
The question then arises as to the source and nature of the
electrophilic methylating agent; does the methyl group come
from O–Me or from N–Me of 1a? This was addressed by
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Scheme 1 Formation of N3-alkylquinazolin-4-ones 26a–d, 27a–d, 28a–d, 29a–d, 30a, b, 31a, 32b by reaction of anthranilamides 7–12 with 1a–d. Reagents
and conditions: i, SOCl2, NH3; ii, N,N¢-carbonyldiimidazole, NH3; iii, 1a, DMF, 150 ◦C; iv, 1b, DMF, 150 ◦C; v, 1c, DMF, 150 ◦C; vi, 1d, DMF, 150 ◦C;
vii, 1a, THF, reflux.
Scheme 2 shows our proposal for the mechanisms of these
novel processes with orthoamides 1a–d carrying primary O-alkyl
groups. Thermal elimination of alkoxide from 1a–d generates the
alkoxyiminium ion 34. In the parent anthranilamide 7 and in 9–
11, which lack electron-withdrawing substituents at the 3-position
ortho to the aniline NH2, this ArNH2 is the more nucleophilic
of the two nitrogens and attacks the sp2-carbon of 34 to give
tetrahedral intermediates 35–40. Another elimination of alkoxide
leads to formamidine intermediates 13–18, where the sp2 carbon
is again the electrophile in the intramolecular reaction with the
primary amide. Simple elimination of dimethylamine from the
second tetrahedral intermediates 41–46 gives the quinazolin-4-
ones 19, 21–25. The orthoamides 1 are basic and generate some
of the corresponding anion. This quinazolin-4-one anion then
attacks the cationic intermediate 34 at the O-alkyl group. This SN2-
like substitution is facilitated by DMF being an excellent leaving
group. Thus the alkoxyiminium 34 can be electrophilic either at
the central sp2 carbon or at the sp3 carbon of the O-alkyl group.
The observation that 19a can be isolated at short reaction times
and that 21a, 22a, 23a, 24a can be seen by TLC in the reaction
mixtures of longer treatment of 7, 9–12 with 1a confirms that the
methylation occurs after the formation of the quinazolin-4-one
ring and is, therefore, slower than the cyclocondensation step. The
ethylation reactions are generally slower and lower-yielding than
the methylations, consistent with steric crowding at the CH2 group
of the ethoxyiminium intermediate 34b. No effect of the electronic
nature (electron-donating, electron-neutral) of the 3-substituent
in 7,9–12 is seen in the outcome of the reaction.
The situation is different for the compounds bearing the
electron-withdrawing nitro group. Heating 8 with 1a at lower
temperature allowed 33 to be isolated as an intermediate, whereas
no formamidine could be isolated in the reaction of 7 with 1a in
boiling THF. This indicates that the nitro group deactivates the
ortho-amine to such an extent that the amide-NH2 becomes the
more nucleophilic of the two NH2 nitrogens. Condensation of 8
with 34 thus proceeds via attack of the weakly nucleophilic amide
NH2 at the sp2 electrophilic centre. The tetrahedral intermediate
35 then collapses to form the acylformamidine 33, which cyclises
to form 20a. Subsequent methylation forms 27a. Two further
experimental observations are pertinent. Firstly, 33 is unstable
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Scheme 2 Proposed mechanisms for formation of intermediate quinazolin-4-ones 19–25 and product 3-(primary)alkylquinazolin-4-ones 26–32,
demonstrating that intermediates 34 (derived from orthoamides 1) can be electrophilic formyl equivalents and electrophilic alkylating agents in the
same reaction mixture.
to column chromatography, returning to 8 rather than cyclising
to 20a; this is consistent with the very low intramolecular
nucleophilicity of the adjacent 2-NH2, with intermolecular silica-
bound water being more reactive. Secondly, 20a was not shown
as an intermediate by TLC (comparison with authentic standard
prepared from 2 and formamide) at any stage of the two-step
reaction at 150 ◦C. It was observed as a minor component of
the mixture of products of reaction of 8 with limiting amount
of 1a at lower temperature. At the higher temperature with
excess 1a, it is clear that the cyclocondensation reaction is slowed
significantly by the nitro group, such that the methylation (and,
indeed, ethylation) reactions are now faster and intermediate 20a
is consumed as soon as it is formed. With only 1.2 equivalents of 1a
and the lower temperature, the supply of bifunctional electrophile
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Scheme 3 Reaction of anthranilamides 7–10 with hindered orthoamides 1e–g. Reagents and conditions: i, 1e, DMF, 150 ◦C; ii, 1f, DMF, 150 ◦C; iii, 1g,
DMF, 150 ◦C.
34a is exhausted, as formation of 26a requires two equivalents
thereof.
corresponding N3-methylquinazolin-4-ones 26a, 28a, 29a as the
major components of the product mixtures. Similar reaction of the
nitro analogue 8 with 1e, followed by very careful chromatography,
gave only a very small pure sample of 27e.
In contrast to the N3-alkylations observed with orthoamides
carrying unhindered primary alkoxy groups, Scheme 3 shows
the anomalous products obtained from reactions of the an-
thranilamides 7–10 with orthoamides 1e–g, carrying isopropoxy
(secondary), t-butyl (tertiary) and neopentyloxy (hindered pri-
mary) groups, respectively. Reaction of anthranilamides 7, 9,
10 with 1e at 150 ◦C for 24 h gave mixtures which were
not chromatographically separable but which were analysed by
1H and 13C NMR. The component compounds were further
identified by COSY, NOESY, HSQC and HMBC NMR and
MS. A component of each mixture was the corresponding N3-
unsubstituted quinazolin-4-one 19a, 21a, 22a. Also observed were
the expected N3-isopropylquinazolin-4-ones 26e, 28e, 29e. The
location of the isopropyl group at the 3-position in 26e, 28e,
29e was confirmed for each example through HMBC cross-peaks
connecting the isopropyl 2-H with 2-C and 4-C of the quinazolin-
4-one and by NOE between 2-H and the isopropyl (CH3)2 and
isopropyl CH protons. Less expected was the formation of the 4-
isopropoxyquinazolines 47e, 49e, 50e by alkylation at the harder
nucleophile oxygen. Isomers 26e, 28e, 29e and 47e, 49e, 50e
were formed in approximately equimolar amounts in each case.
The structures of 47e, 49e, 50e were confirmed by the more
Moving from the moderate steric demand of the isopropyl group
to the severe crowding of the t-butyl unit, 7 was treated with five
equivalents of 1f at 150 ◦C for 24 h; this process furnished only the
N3-unsubstituted quinazolin-4-one 19a, in high yield. When 19a
was re-subjected to the same reaction conditions with a further five
equivalents of 1f for a further 24 h, chromatography of the product
mixture provided very small amounts of N3-But-quinazolin-4-one
26f and 4-ButO-quinazoline 47f, along with major recovery of
unreacted 19a. Although 1g contains primary alkoxy groups, these
are neopentyl, which should preclude both SN1-like and SN2-like
electrophilic reactions. Treatment of 7 with 1g afforded good yields
of 19a and, unexpectedly, the N3-methylquinazolin-4-one 26a.
Scheme 4 provides our mechanistic rationale for these unusual
observations. Intermediate cation 34e is generated by elimination
of isopropanol from 1e. The quinazolinone anion can be repre-
sented in two mesomeric structures, 19A–22A and 19B–22B, show-
ing that it has two potentially nucleophilic sites. When this meets
simple primary alkoxy electrophiles 34a–d, alkylation takes place
exclusively at the softer and more nucleophilic nitrogen. However,
the increased steric bulk of the secondary alkyl group drives
some of the alkylation to the more sterically accessible but more
weakly nucleophilic oxygen, giving the 4-isopropoxyquinazolines
47e–50e, in addition to the N-alkylated products 26e–29e. The
secondary alkyl electrophile in 34e may also be more “SN1-
like”/cationic in its reactivity, making it a harder electrophile with
greater propensity to react at oxygen, whereas the corresponding
1
downfield H chemical shifts of the isopropyl central protons d
5.43–5.58) and the 13C chemical shifts of the isopropyl central
carbons (d 69.84–70.01), compared to the corresponding values
for 26e, 28e, 29e (1H d 4.97–5.03; 13C d 45.09–46.19). For 49e,
an HMBC cross-peak was observed connecting the isopropyl 2-H
with the quinazoline 4-C. More unexpected was the presence of the
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oxygen cannot react as an alkylating electrophile, either by SN1 or
SN2 mechanisms. Thus the only electrophilic site in 34g is the N-
methyl, which alkylates anion 19A to form 26a. Intermediate 34f,
derived by elimination of ButOH from orthoamide 1f, may, at first
sight, be expected to behave like intermediate cation 34g and thus
condense with 7 to give 19a, which would then be methylated by
the weak N-Me electrophile to give 26a. However, by far the major
product is 19a, with traces of the N-But and O-But compounds
26f and 47f, with no N-methylation. This observation can be
rationalised, as cationic intermediate 34f has an alternative mode
of decomposition through an elimination giving 2-methylpropene
and DMF (Scheme 4). The lifetime of 34f at 150 ◦C may be long
enough to insert 2-C of the quinazoline, a rapid reaction at this
temperature, but too short to allow it to persist long enough
to carry out the slow methylation using the N-methyl groups.
Interestingly, the tertiary alkyl group of 34f should react in an
“SN1-like” manner, allowing it to alkylate the harder oxygen as
well as the softer nitrogen nucleophiles of the quinazolinone.
Conclusions
In this paper, we report that dimethylformamide di(primary-
alkoxy)acetals 1a–c and dimethylacetamide dimethylacetal 1d
can eliminate one alkoxide thermally to generate cationic in-
termediates 34a–d that can act as electrophiles at two sites.
Firstly, the predictable cyclocondensation of anthranilamides 7–
12 with 1 generates quinazolin-4-ones through attack on the
central carbon, which is sp2 in 34. This cyclocondensation also
takes place readily with 7 and the electrophilic sp2-carbon of the
corresponding cationic intermediates 34e–g, derived from more
sterically bulky diisopropoxy, di-t-butoxy and dineopentyl acetals
1e–g. Secondly, nucleophilic attack also takes place at the alkoxy
sp3 carbon of unhindered primary intermediates 34a–d, forming
3-alkylquinazolin-4-ones 26–32 from the N–H quinazolin-4-ones
19–25. This second reaction of 1 as electrophilic alkylating
agents is unprecedented. Increasing the steric bulk of the O-
alkyl substituent in the cationic intermediates 34e,g mitigates this
second electrophile but reveals a third site, the N-methyl. Reaction
of N–H quinazolin-4-one 19a with these electrophiles gives the
N3-Me quinazolin-4-one 26a as major products. These reactions
provide a useful one-pot route to N3-(primary-alkyl)quinazolin-
4-ones and point to new applications of these orthoamides as
electrophilic alkylating agents in heterocyclic and other chemistry.
Scheme
4
Proposed mechanisms for formation of 3-isopropy-
lquinazolin-4-ones 26e–29e, 4-isopropoxyquinazolines 47e–50e and
3-methylquinazolin-4-ones 26a–29a from intermediate quinazolinone an-
ions 19A–22A / 19B–22B (derived from 7–10) and electrophile 34e
(derived from 1e); proposed mechanisms for formation of 26a from 19A
and electrophile 34g (derived from 1g) and degradation of analogous
electrophile 34f (derived from 1f).
Experimental
NMR spectra were recorded on Bruker Avance III 400 and 500
spectrometers of solutions in hexadeuteriodimethylsulfoxide, ex-
cept as otherwise noted; coupling constants are given in Hz. Mass
spectra were obtained using Bruker microTOFTM spectrometers in
electrospray positive ion mode. IR spectra were obtained as KBr
discs. The stationary phase for chromatography was silica gel.
Melting points were determined using a Reichert-Jung Thermo
Galen instrument and are uncorrected. Reactions were performed
at ambient temperature, unless stated otherwise. The solvents were
evaporated under reduced pressure. Solutions in organic solvents
were dried with sodium sulfate. The brine was saturated.
primary alkyl intermediates 34a–d may be more “SN2-like” and
softer in their electrophilic reactivity, reacting only with the softer
nitrogen nucleophile. However, both reactions are slow, diverting
the nucleophiles 19A–22A to approach the alternative electrophilic
site in 34e, the intrinsically less electrophilic but less sterically
encumbered N-methyl. This process generates an iminoester as
the leaving group, in forming the 3-methylquinazolin-4-ones 26a–
29a. The steric bulk is increased further in intermediate cation
34g. This can form readily by thermal elimination of neopentyl
alcohol from 1g but the remaining neopentyl alkyl group at the
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2-Amino-3-nitrobenzamide (8)
(br), 1575 cm-1; dH 3.78 (3 H, s, Me), 6.52 (1 H, t, J 7.8, 5-H),
6.99 (0.5 H, br s, CONH), 7.28 (1 H, br s, CONH), 7.61 (0.5
H, br s, CONH), 7.77 (1 H, dd, J 7.7, 1.6, 6-H), 7.87 (1 H, dd,
J 7.9, 1.6, 4-H), 7.99 (2 H, br s, Ar-NH2); dC (HSQC/HMBC)
51.63 (Me), 110.51 (1-C), 113.21 (5-C), 116.17 (3-C), 134.56 (6-C),
134.64 (4-C), 151.59 (2-C), 167.54 (CO2Me), 170.72 (CONH2);
m/z 217.0619 (M + Na) (C9H10N2NaO3 requires 217.0589).
2-Amino-3-nitrobenzoic acid 2 (5.1 g, 28 mmol) was suspended
in tetrahydrofuran (50 mL). Thionyl chloride (5.0 g, 42 mmol)
and dimethylformamide (100 mL) were added and the mixture was
stirred for 16 h. This solution was added dropwise to aq. ammonia
(35%, 200 mL). Filtration and drying gave 8 (4.02 g, 79%) as an
◦
orange solid: mp 240–242 C (lit.18 mp 234–235 ◦C); nmax 3458,
3431, 3297, 3207, 1686, 1630, 1596, 1544, 1320 cm-1; dH 6.66 (1 H,
t, J 6.8, 5-H), 7.59 (1 H, br s, CONH), 7.94 (1 H, dd, J 6.0, 1.2, 6-
H), 8.14 (1 H, br s, CONH), 8.17 (1 H, dd, J 6.8, 1.2, 4-H), 8.64 (2
H, br s, Ar-NH2); dC (HSQC/HMBC) d 113.67 (5-C), 118.82 (3-
C), 129.40 (6-C), 132.13 (1-C), 136.41 (4-C), 146.03 (2-C), 169.93
(C O).
Quinazolin-4-one (19a)
2-Aminobenzamide 7 (500 mg, 3.7 mmol) in dimethylformamide
(18 mL) was treated with 1a (1.27 g, 10.6 mmol) at 150 ◦C
for 1.5 h. Cooling, evaporation and chromatography (ethyl
acetate/dichloromethane 1 : 4 → 2 : 3) gave 19a (410 mg, 75%)
as a white solid: mp 225–227 ◦C (lit.22 mp 221–222 ◦C); dH 7.58 (1
H, ddd, J 8.1, 7.3, 1.1, 6-H), 7.72 (1 H, ddd, J 8.1, 1.2, 0.5, 8-H),
7.87 (1 H, ddd, J 8.2, 7.2, 1.6, 7-H), 8.15 (1 H, s, 2-H), 8.18 (1 H,
ddd, J 8.0, 1.6, 0.4, 5-H), 12.3 (1 H, br, 3-H); dC (HSQC/HMBC)
122.64 (4a-C), 125.80 (5-C), 126.70 (6-C), 127.21 (8-C), 134.27
(7-C), 145.33 (8a-C), 148.77 (2-C), 160.68 (4-C).
2-Amino-3-methylbenzamide (9)
2-Amino-3-methylbenzoic acid
3 (2.93 g, 19.8 mmol) in
dry dimethylformamide (78 mL) was treated with 1,1¢-
carbonyldiimidazole (3.14 g, 19.4 mmol) at 70 ◦C under argon for
1 h, after which aq. ammonia (35%, 49 mL) was added dropwise.
The mixture was stirred for 16 h. The mixture was allowed to cool
to 20 ◦C and diluted with ethyl acetate (100 mL). Washing (water
(twice), brine (twice)), drying◦and evaporation gave ◦9 (2.14 g, 98%)
as a white solid: mp 150–152 C (lit.19 mp 147–149 C); nmax 3468,
3392, 3353, 3190, 1641, 1608, 1569 cm-1; dH 2.05 (3 H, s, Me),
6.35 (2 H, br s, Ar-NH2), 6.41 (1 H, br t, J 7.6, 5-H), 6.89 (1 H,
br s, CONH), 7.04 (1 H, d, J 6.8, 6-H), 7.34 (1 H, dd, J 8.0, 0.8,
4-H), 7.67 (1 H, br s, CONH); dC (HSQC/HMBC) 17.56 (Me),
113.59 (1-C), 114.17 (5-C), 122.99 (3-C), 126.61 (6-C), 132.67 (4-
C), 148.21 (2-C), 171.73 (C O).
3-Methylquinazolin-4-one (26a)
Amide 7 (500 mg, 3.7 mmol) in dimethylformamide (16 mL) was
treated with 1a (1.3 g, 11 mmol) at 150 ◦C for 16 h. Cooling,
evaporation and chromatography (ethyl acetate/petroleum ether,
2 : 3 → ethyl acetate) gave 26a (560 mg, 95%) as a white solid: mp
98–100 ◦C (lit.11 mp 105 ◦C); nmax 1670, 1614 cm-1; dH 3.55 (3 H, s,
Me), 7.60 (1 H, ddd, J 8.1, 7.2, 1.2, 6-H), 7.73 (1 H, ddd, J 8.2, 1.2,
0.5, 8-H), 7.87 (1 H, ddd, J 8.2, 7.1, 1.6, 7-H), 8.43 (1 H, ddd, J 8.0,
1.5, 0.5, 5-H), 8.34 (1 H, s, 2-H); dC (HSQC/HMBC) 33.49 (Me),
121.43 (4a-C), 125.82 (5-C), 126.91 (6-C), 127.12 (8-C), 134.09
(7-C), 148.10 (8a-C), 148.41 (2-C), 160.64 (4-C).
2-Amino-3-methoxybenzamide (10)
2-Amino-3-methoxybenzoic acid
4 was treated with 1,1¢-
3-Ethylquinazolin-4-one (26b)
carbonyldiimidazole, as for the synthesis of 9, to◦give 10 (80%)
as a white solid: mp 139–141 ◦C (lit.20 mp 140–141 C); nmax 3474,
3367, 3304, 3150, 1670, 1617, 1548 cm-1; dH 3.77 (3 H, s, Me),
6.23 (2 H, br s, Ar-NH2), 6.44 (1 H, t, J 8.0, 5-H), 6.85 (1 H,
dd, J 7.6, 0.8, 6-H), 7.03 (1 H, br s, CONH), 7.16 (1 H, dd, J
= 8.0, 1.2, 4-H), 7.67 (1 H, br s, CONH); dC (HSQC/HMBC)
55.53 (Me), 111.98 (6-C), 113.38 (3-C), 113.64 (5-C), 120.42 (4-C),
140.19 (1-C), 146.88 (2-C), 171.19 (C O).
Amide 7 (500 mg, 3.7 mmol) in dimethylformamide (16 mL) was
treated with 1b (1.3 g, 11 mmol) at 150 ◦C for 16 h. Cooling,
evaporation and chromatography (ethyl acetate/petroleum ether
1 : 4 → 1 : 1) gave 26b (330 mg, 52%) as a white solid: mp 110–
112 ◦C (lit.12 mp 99–101 ◦C); nmax 1676, 1613 cm-1; dH 1.27 (3 H,
t, J 7.5, Me), 3.99 (2 H, q, J 7.5, CH2), 7.52 (1 H, t, J 8.0, 6-H),
7.66 (1 H, d, J 8.0, 8-H), 7.80 (1 H, br t, J 7.5, 7-H), 8.15 (1H, br
d, J 8.0, 5-H), 8.41 (1 H, s, 2-H); dC (HSQC/HMBC) 14.49 (Me),
41.19 (CH2), 121.57 (4a-C), 125.94 (5-C), 126.92 (6-C), 127.13
(8-C), 134.15 (7-C), 147.84 (8a-C), 147.99 (2-C), 159.97 (4-C).
2-Amino-3-chlorobenzamide (11)
2-Amino-3-chlorobenzoic acid
5
was treated with 1,1¢-
carbonyldiimidazole, as for the synthesis of 9, to◦give 11 (97%)
as a white solid: mp 155–157 ◦C (lit.21 mp 161–162 C); nmax 3436,
3398, 3277, 3222, 1640, 1607, 1573, 1542 cm-1; dH 6.51 (1 H, t, J
8.0, 5-H), 6.66 (2 H, br s, Ar-NH2), 7.26 (1 H, br s, CONH), 7.34
(1 H, dd, J 7.6, 1.2, 6-H), 7.53 (1 H, dd, J 8.0, 1.6, 4-H), 7.86
(1 H, br s, CONH); dC (HSQC/HMBC) 114.89 (1-C), 115.84 (5-
C), 119.03 (3-C), 127.74 (6-C), 131.83 (4-C), 145.62 (2-C), 170.45
(C O).
3-Phenylmethylquinazolin-4-one (26c)
Amide 7 (200 mg, 1.5 mmol) was stirred at 150 ◦C with 1c (2.00 g,
7.3 mmol) in dimethylformamide (8.0 mL) for 24 h. Evaporation
and chromatography (ethyl acetate/petroleum ether 1 : 4 → 7 : 1)
gave 26c (286 mg, 82%) as a white solid: mp 117–119 ◦C; (lit.16 mp
◦
118–120 C); nmax 1674, 1604 cm-1; dH 5.20 (2 H, s, CH2), 7.29–
7.38 (5 H, m, Ph-H5); 7.55 (ddd, J 8.0, 7.0, 1.1, 6-H), 7.69 (1 H,
brd, J 8.0, 8-H), 7.84 (1 H, ddd, J 8.1, 7.0, 1.5, 7-H), 8.15 (1 H,
dd, J 8.0, 1.2, 5-H), 8.58 (1 H, s, 2-H); dC (HSQC/HMBC) 48.84
(CH2), 121.64 (4a-C), 126.11 (8-C), 127.19 (6-C), 127.26 (5-C),
127.64 and 128.64 (Ph 2,3,5,6-C4), 127.67 (Ph 4-C), 134.43 (7-C),
136.85 (Ph 1-C), 147.91 (8a-C), 148.01 (2-C), 160.09 (4-C); m/z
Methyl 2-amino-3-aminocarbonylbenzoate (12)
Methyl 2-amino-3-carboxybenzoate 6 was treated with 1,1¢-
carbonyldiimidazole, as for the synthesis of 9, to give 12 (84%)
as a white solid: mp 75–77 ◦C; nmax 3455, 3437, 3285, 3200, 1682
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495.1777 (2 M + Na) (C30H24N4NaO2 requires 495.1806); 259.0848
(M + Na) (C15H12N2NaO requires 259.0847), 237.1043 (M + H)
(C15H13N2O requires 237.1029).
2,3-Dimethyl-8-nitroquinazolin-4-one (27d)
2-Amino-3-nitrobenzamide 8 (200 mg, 1.1 mmol) was stirred at
150 ◦C with 1d (441 mg, 3.3 mmol) in dimethylformamide (4.0
mL) for 5 d. Evaporation and chromatography (dichloromethane)
gave 27d (180 mg, 75%) as a pale yellow solid: mp 178–179 ◦C
(lit.25 mp 175 ◦C); dH ((CD3)2SO) 2.64 (3 H, s, 2-Me), 3.60 (3 H, s,
3-Me), 7.66 (1 H, t, J 8.0, 6-H), 8.30 (1 H, dd, J 7.6, 1.6, 7-H), 8.39
(1 H, dd, J 8.0, 1.6, 5-H); dH (CDCl3) 2.65 (3 H, s, 2-Me), 3.63 (3
H, s, 3-Me), 7.48 (1 H, t, J 8.0, 6-H), 8.00 (1 H, dd, J 7.8, 1.4, 7-H),
8.43 (1 H, dd, J 8.0, 1.5, 5-H); dH (HSQC/HMBC) (CDCl3) 24.06
(2-Me), 31.30 (3-Me), 121.85 (4a-C), 125.31 (6-C), 128.04 (7-C),
130.82 (5-C), 139.73 (8a-C), 146.29 (8-C), 157.42 (2-C), 160.72
(4-C); m/z 242.0521 (M + Na) (C10H9N3NaO3 requires 242.0542),
220.0748 (M + H) (C10H10N3O3 requires 220.0722).
2,3-Dimethylquinazolin-4-one (26d)
Amide 7 (200 mg, 1.47 mmol) was stirred at 150 ◦C with 1d
(783 mg, 5.9 mmol) in dimethylformamide (8.0 mL) for 2 d.
Evaporation and chromatography (CH2Cl2 → CH2Cl2/EtOAc
4 : 1) gave 26d (30◦mg, 12%) as a white solid: mp 110–112 ◦C
(lit.12 mp 108–109 C); nmax 1671, 1600 cm-1; dH 2.57 (3 H, s, 2-
Me), 3.53 (3 H, s, 3-Me), 7.46 (1 H, ddd, J 8.0, 6.8, 0.8, 6-H),
7.56 (1 H, brd, J 8.0 Hz, 8-H), 7.77 (1 H, ddd, J 8.4, 7.2, 1.6 Hz,
7-H), 8.09 (1 H, dd, J 8.0, 1.2 Hz, 5-H); dC (HSQC/HMBC) 23.15
(2-Me), 30.52 (3-Me), 119.70 (4a-C), 126.05 (6-C), 126.12 (5-C),
126.41 (8-C), 134.09 (7-C), 155.60 (2-C), 161.27 (4-C).
3,8-Dimethylquinazolin-4-one (28a)
3-Methyl-8-nitroquinazolin-4-one (27a)
Amide 9 was treated with 1a, as for the synthesis of 26a except
that the chromatographic eluant was ethyl acetate/petroleum ether
(1 : 4 → 3 : 7), to give 28a (0.41 g, 71%) as a white solid: mp
Amide 8 was treated with 1a, as for the synthesis of 19a except
that the chromatographic eluant was ethyl acetate/petroleum ether
(1 : 4 → 1 : 1), to give 27a (93%) as a pale yellow solid: mp 165–
167 ◦C (lit.23 mp 157 ◦C); nmax 1697, 1614, 1604, 1526, 1366 cm-1;
dH 3.49 (3 H, s, Me), 7.63 (1 H, t, J 8.6, 6-H), 8.26 (1 H, dd,
J 8.0, 1.6, 7-H), 8.34 (1 H, dd, J 8.0, 1.6, 5-H), 8.47 (1 H, s, 2-
H); dC (HSQC/HMBC) 33.86 (Me), 122.83 (4a-C), 126.56 (5-C),
127.58 (6-C), 129.64 (7-C), 139.85 (8-C), 146.45 (8a-C), 150.97
(2-C), 159.31 (4-C).
◦
151–153 C; nmax 1667, 1612, 1574 cm-1; dH 2.52 (3 H, s, 8-Me),
3.49 (3 H, s, 3-Me), 7.39 (1 H, t, J 7.5, 6-H), 7.64 (1 H, ddq,
J 8.0, 2.5, 0.5, 7-H), 7.97 (1 H, brd, J 8.0, 5-H), 8.35 (1 H, s,
2-H); dC (HSQC/HMBC) 17.02 (8-Me), 33.43 (3-Me), 121.35
(4a-C), 123.48 (5-C), 126.38 (6-C), 134.38 (7-C), 135.26 (8-C),
146.57 (8a-C), 147.37 (2-C), 160.85 (4-C); m/z 371.1450 (2 M
+ Na) (C20H20N4NaO2 requires 371.1478), 197.0680 (M + Na)
(C10H10N2NaO requires 197.0691), 175.0874 (M + H) (C10H11N2O
requires 175.0871).
3-Ethyl-8-nitroquinazolin-4-one (27b)
Amide 8 was treated with 1b, as for the synthe◦sis of 26b, to give
3-Ethyl-8-methylquinazolin-4-one (28b)
27b (89%) as a pale yellow solid: mp 143–145 C (lit.24 mp 143–
◦
144 C); nmax 1683, 1526, 1379 cm-1; dH 1.27 (3 H, t, J 7.2, Me),
Amide 9 was treated with 1b, as for the synthesis of 26b except
that the chromatographic eluant was ethyl acetate/petroleum ether
(1 : 4), to give 28b (45%) as a white solid: mp 67–69 ◦C; nmax 1678,
1607, 1574, 1456 cm-1; dH 1.25 (3 H, t, J 7.2, CH2CH3), 2.50 (3
H, s, 8-Me), 3.96 (2 H, q, J 7.2, CH2), 7.36 (1 H, t, J 7.6, 6-H),
7.63 (1 H, br d, J 7.2, 7-H), 7.96 (1 H, br d, J 8.0, 5-H), 8.39 (1
H, s, 2-H); dC (HSQC/HMBC) 14.47 (CH2CH3), 16.97 (8-Me),
41.10 (CH2), 121.53 (4a-C), 123.61 (5-C), 126.40 (6-C), 134.43 (7-
C), 135.28 (8-C), 146.47 (8a-C), 146.80 (2-C), 160.20 (4-C); m/z
211.0846 (M + Na) (C11H12N2NaO requires 211.0847), 189.1033
(M + H) (C11H13N2O requires 189.1028).
3.98 (2 H, q, J 7.2, CH2), 7.64 (1 H, t, J 7.6, 6-H), 8.26 (1
H, dd, J8.0, 1.6, 7-H), 8.35 (1 H, dd, J 8.0, 1.2, 5-H), 8.53 (1
H, s, 2-H); dC (HSQC/HMBC) 14.20 (Me), 41.74 (CH2), 123.00
(4a-C), 126.61 (5-C), 127.63 (6-C), 129.76 (7-C), 139.74 (8-C),
146.47 (8a-C), 150.43 (2-C), 158.69 (4-C); m/z 242.0535 (M + Na)
(C10H9N3NaO3 requires 242.0542), 220.0719 (M + H) (C10H10N3O3
requires 220.0722).
8-Nitro-3-(phenylmethyl)quinazolin-4-one (27c)
Amide 8 (200 mg, 1.1 mmol) was stirred at 150 ◦C with 1c (1.2 g,
4.4 mmol) in dimethylformamide (4.0 mL) for 5 d. Evaporation
and chromatography (ethyl acetate/petroleum ether 1 : 1) gave 27c
(190 mg, 61%) as pale yellow crystals: mp 189–191 ◦C; nmax 1691,
1602, 1527, 1356 cm-1; dH ((CD3)2SO) 5.27 (2 H, s, CH2), 7.36
(5 H, m, Ph-H5), 7.76 (1 H, t, J 8.0, 6-H), 8.38 (1 H, dd, J 8.0,
1.2, 7-H), 8.44 (1 H, dd, J 8.0, 1.6, 5-H), 8.78 (1 H, s, 2-H); dH
(CDCl3) 5.21 (2 H, s, CH2), 7.35 (5 H, m, Ph-H5), 7.58 (1 H,
t, J 8.0, 6-H), 8.09 (1 H, dd, J 8.0, 1.5, 7-H), 8.23 (1 H, s, 2-
H), 8.53 (1 H, dd, J 8.0, 1.5, 5-H); dC (HSQC/HMBC) (CDCl3)
50.07 (CH2), 123.74 (4a-C), 126.54 (6-C), 128.24 and 129.18 (Ph
2,3,5,6-C4), 128.52 (7-C), 128.71 (Ph 4-C), 131.08 (5-C), 134.71
(Ph 1-C), 140.46 (8a-C), 146.63 (8-C), 148.60 (2-C), 159.42 (4-
C); m/z 585.1460 (2 M + Na) (C30H22N6NaO6 requires 585.1493),
304.0686 (M + Na) (C15H11N3NaO3 requires 304.0693), 282.0879
(M + H) (C15H12N3O3 requires 282.0873).
8-Methyl-3-phenylmethylquinazolin-4-one (28c)
Amide 9 was treated with 1c, as for the synthesis of 26c except that
the chromatographic eluant was ethyl acetate/petroleum ether
(1 : 9 → 7 : 1), to give 28c (83%) as pale buff solid: mp 143–
145 ◦C; nmax 1673, 1603 cm-1; dH 2.54 (3 H, s, 8-Me), 5.20 (2
H, s, CH2), 7.28-7.36 (5 H, m, Ph-H5), 7.43 (1 H, t, J 8.0, 6-H),
7.69 (1 H, dd, J 7.6, 1.6, 7-H), 7.99 (1 H, dd, J 8.0, 0.8, 5-H),
8.59 (1 H, s, 2-H); dC (HSQC/HMBC) 17.03 (Me), 48.79 (CH2),
121.58 (4a-C), 123.76 (5-C) 126.69 (6-C), 127.61 and 128.62 (Ph
2,3,5,6-C4), 127.64 (Ph 4-C), 134.74 (7-C), 135.47 (8-C), 136.86
(Ph 1-C), 146.37 (8a-C), 147.02 (2-C), 160.31 (4-C); m/z 523.2085
(2 M + Na) (C32H28N4Na1O2 requires 523.2104), 273.0985 (M
+ Na) (C16H14N2Na1O1 requires 273.0998), 251.1186 (M + H)
(C16H15N2O1 requires 251.1179).
6096 | Org. Biomol. Chem., 2011, 9, 6089–6099
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◦
2,3,8-Trimethylquinazolin-4-one (28d)
gave 29d (28 mg, 24%) as a white solid: mp 133 C (lit.27 mp
133–136 ◦C); dH 2.63 (3 H, s, 2-Me), 3.59 (3 H, s, 3-Me), 3.95
(3 H, s, OMe), 7.36 (1 H, dd, J 8.0, 1.2, 7-H), 7.44 (1 H, t, J
8.0, 6-H), 7.70 (1 H, dd, J 8.0, 1.2, 5-H); dC (HSQC/HMBC)
23.19 (2-Me), 30.60 (3-Me), 55.74 (O-Me), 114.35 (7-C), 117.07
(5-C), 120.73 (8-C), 126.27 (6-C), 137.68 (8a-C), 154.21 (4a-
C), 161.15 (4-C); m/z 205.0976 (M + H) (C11H13N2O2 requires
205.0977).
Amide 9 (50 mg, 0.33 mmol) was stirred at 150 ◦C with 1d (133 mg,
1.0 mmol) in dimethylformamide (1.5 mL) for 90 h. Evaporation
and chromatography (ethyl acetate/petroleum ether 1 : 4) gave◦27d
(18.9 mg, 38%) as a white solid: mp 104–108 ◦C (lit.26 mp 107 C);
dH ((CD3)2SO) 2.14 (3 H, s, 8-Me), 2.65 (3 H, s, 2-Me), 3.59 (3
H, s, 3-Me), 7.40 (1 H, t, J 8.0, 6-H), 7.68 (1 H, ddq, J 8.0, 1.2,
0.5, 7-H), 8.00 (1 H, dd, J 8.0, 1.2, 5-H); dH (CDCl3) 2.56 (3
H, s, 8-Me), 2.59 (3 H, s, 2-Me), 3.59 (3 H, s, 3-Me), 7.28 (1 H,
t, J 7.5, 6-H), 7.72 (1 H, brd, J 7.5, 7-H), 8.07 (1 H, brd, J 7.5,
5-H); dC (HSQC/HMBC) (CDCl3) 17.13 (8-Me), 23.76 (2-Me),
30.90 (3-Me), 120.07 (4a-C), 124.31 (5-C), 125.75 (7-C), 134.53 (7-
C), 135.09 (8-C), 145.84 (8a-C), 152.90 (2-C), 162.65 (4-C). m/z
399.1828 (2 M + Na) (C22H24N4NaO2 requires 399.1782), 211 (M
+ Na), 189 (M + H).
8-Chloro-3-methylquinazolin-4-one (30a)
Amide 11 was treated with 1a, as for th◦e synthesis of 26a, to ◦give
30a (63%) as a white solid: mp 160–162 C (lit.14 mp 158–159 C);
n
max 1672, 1609 cm-1; dH 3.49 (3 H, s, Me), 7.46 (1 H, t, J 7.8, 6-H),
7.92 (1 H, dd, J 7.8, 1.3, 5-H), 8.07 (1 H, dd, J 8.0, 1.2, 7-H),
8.45 (1 H, s, 2-H); dC (HSQC/HMBC) 33.69 (Me), 123.13 (4a-
C), 125.03 (5-C), 127.25 (6-C), 130.66 (7-C), 134.17 (8-C), 144.58
(8a-C), 149.27 (2-C), 160.12 (4-C).
8-Methoxy-3-methylquinazolin-4-one (29a)
Amide 10 was treated with 1a, as for the synthesis of 26a except
that the chromatographic eluant was ethyl acetat◦e, to give 29a
(64%) as a white solid: mp 177–179 ◦C (lit.9 mp 172 C); nmax 1677,
1602, 1548 cm-1; dH 3.47 (3 H, s, 3-Me), 3.88 (3 H, s, OMe), 7.31 (1
H, dd, J 8.0, 1.2, 7-H), 7.41 (1 H, t, J 8.0, 6-H), 7.66 (1 H, dd, J 8.0,
1.2, 5-H), 8.23 (1 H, s, 2-H); dC (HSQC/HMBC) 33.42 (3-Me),
55.96 (OMe), 114.63 (5-C), 116.79 (7-C), 122.52 (4a-C), 127.23
(6-C), 138.70 (8a-C), 146.97 (2-C), 154.48 (8-C), 160.50 (4-C).
8-Chloro-3-ethylquinazolin-4-one (30b)
Amide 11 was treated with 1b, as for the synthesis of 26b except
that the chromatographic eluant was ethyl acetate/petroleum ether
(1 : 4 → 3 : 7), to give 30b (58%) as a white solid: mp 127–128 ◦C
◦
(lit.24 mp 123–123.5 C); nmax 1679, 1607 cm-1; dH 1.26 (3 H, t, J
7.2, CH2CH3), 3.98 (2 H, q, J 7.2, CH2), 7.47 (1 H, t, J 8.0, 6-H),
7.93 (1 H, dd, J 7.6, 1.2, 7-H), 8.08 (1 H, dd, J 8.0, 1.6, 5-H), 8.49
(1 H, s, 2-H); dC (HSQC/HMBC) 14.31 (CH2CH3), 41.49 (CH2),
123.29 (4a-C), 125.16 (5-C), 127.29 (6-C), 130.69 (7-C), 134.23
(8-C), 144.48 (8a-C), 148.72 (2-C), 159.48 (4-C).
3-Ethyl-8-methoxyquinazolin-4-one (29b)
Amide 10 was treated with 1b, as for the synthesis of 26b except
that the chromatographic eluant was ethyl acetate/petroleum ether
(1 : 4) → EtOAc, to give 29b (43%) as a white solid: mp 115–116 ◦C
Methyl 3-methyl-4-oxoquinazoline-8-carboxylate (31a)
◦
(lit.9 mp 108 C); nmax 1680, 1604, 1570 cm-1; dH 1.24 (3 H, t, J
Amide 12 was treated with 1a, as for the synthesis of 27a, to
give 31a (66%) as a white solid: mp 180–182 ◦C; nmax 1740, 1681,
1610 cm-1; dH 3.48 (3 H, s, 3-Me), 3.86 (3 H, s, OMe), 7.54 (1 H, t,
J 7.6, 6-H), 7.95 (1 H, dd, J 7.6, 1.6, 7-H), 8.26 (1 H, dd, J 8.0, 1.6,
5-H), 8.38 (1 H, s, 2-H); dC (HSQC/HMBC) 33.57 (3-Me), 52.33
(OMe), 121.90 (4a-C), 126.36 (5-C), 128.54 (6-C), 130.65 (7-C),
133.32 (8-C), 145.35 (8a-C), 149.14 (2-C), 160.14 (4-C); MS m/z
219.0777 (M + H) (C11H11N2O3 requires 219.0769).
6.8 Hz, CH2CH3), 3.89 (3 H, s, OMe), 3.96 (2 H, q, J 6.8, CH2),
7.32 (1 H, dd, J 8.0, 1.2, 7-H), 7.42 (1 H, t, J 8.0, 6-H), 7.67 (1 H,
dd, J 8.0, 1.2, 5-H), 8.32 (1 H, s, 2-H); dC (HSQC/HMBC) 14.44
(CH2CH3), 41.16 (CH2), 55.99 (OMe), 114.73 (5-C), 116.91 (7-C),
122.68 (4a-C), 127.26 (6-C), 138.59 (8a-C), 146.39 (2-C), 154.49
(8-C), 159.85 (4-C).
8-Methoxy-3-phenylmethylquinazolin-4-one (29c)
Ethyl 3-ethyl-4-oxoquinazoline-8-carboxylate (32b)
Amide 10 was treated with 1d, as for the synthesis of 26c except
that the chromatographic eluant was ethyl acetate/petroleum ether
(2 : 3 → 7 : 1), to give 29c (72%) as a white solid: mp 121–123 ◦C
(lit.9 mp 118 ◦C); nmax 1688, 1605, 1570, 1483 cm-1; dH (COSY)
3.90 (3 H, s, OMe), 5.20 (2 H, s, CH2), 7.28–7.35 (5 H, m, Ph-
H5), 7.38 (1 H, slightly br dd, J 8.0, 1.3, 7-H), 7.47 (1 H, t, J 8.0,
6-H), 7.69 (1 H, dd, J 8.0, 1.3 Hz, 5-H), 8.51 (1 H, s, 2-H); dC
(HSQC/HMBC) 48.82 (CH2), 56.00 (OMe), 114.96 (7-C), 117.01
(5-C), 122.73 (4a-C), 127.60 (Ph 2,4,6-C3), 127.65 (6-C), 128.64
(Ph 3,5-H2), 136.85 (Ph 1-C), 138.42 (8a-C), 146.61 (2-C), 154.55
(8-C), 160.00 (4-C); m/z 555 (2 M + Na), 289.0984 (M + Na)
(C16H14N2NaO2 requires 289.0953), 267 (M + H).
Amide 12 was treated with 1b, as for the synthesis of 7a except
that the chromatographic eluant was ethyl acetate/petroleum ether
(3 : 7 → 1 : 1), to give 32b (40%) as a white solid: mp 113–115 ◦C;
nmax 1727, 1672, 1606 cm-1; dH 1.26–1.32 (6 H, m, 2 ¥ Me), 3.97
(2 H, q, J 7.2, 3-CH2), 4.30 (2 H, q, J 7.2, OCH2), 7.55 (1 H,
t, J 7.6, 6-H), 7.94 (1 H, dd, J 7.6, 1.6, 7-H), 8.26 (1 H, dd,
J 8.0, 1.6, 5-H), 8.43 (1 H, s, 2-H); dC (HSQC/HMBC) 14.09
(3-CH2CH3), 14.34 (OCH2CH3), 41.34 (3-CH2), 61.05 (OCH2),
122.03 (4a-C), 126.39 (5-C), 128.47 (6-C), 131.04 (7-C), 133.12 (8-
C), 145.19 (8a-C), 148.53 (2-C), 159.51 (4-C), 166.68 (CO2); m/z
269.0939 (M + Na) (C13H14N2NaO3 requires 269.0902), 247.1132
(M + H) (C13H15N2O3 requires 247.1083).
2,3-Dimethyl-8-methoxyquinazolin-4-one (29d)
N¢-(2-Amino-3-nitrobenzoyl)-N,N-dimethylformamidine (33)
Amide 10 (95 mg, 0.57 mmol) was stirred at 150 ◦C with 1d
(230 mg, 1.7 mmol) in dimethylformamide (2.3 mL) for 24 h.
Evaporation and chromatography (ethyl acetate/methanol 19 : 1)
Amide 8 (200 mg, 1.1 mmol) was heated under reflux with 1a
(157 mg, 1.3 mmol) in tetrahydrofuran (4.0 mL) for 16 h. The
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evaporation residue, in ethyl acetate, was washed with water.
The combined aq. washings were then extracted thrice with ethyl
acetate. The combined organic extracts were dried. Evaporation
Reaction of 9 with 1e
2-Amino-3-methylbenzamide 9 was treated with 1e, as for
the reaction of with 1e, to give colourless oil,
7
a
1
gave an orange solid (221 mg). H NMR showed that the solid
which was shown by 1H NMR to comprise 21a, 28a, 8-
methyl-3-(prop-2-yl)quinazolin-4-one 28e and 8-methyl-1-(prop-
2-yloxy)quinazoline 49e (2.9 : 2.2 : 1.3 : 1.0): dH (21a) 2.5 (3 H, s,
8-Me), 7.38 (1 H, m, 6-H), 7.64 (1 H, brd, J 8, 7-H), 7.92 (1 H, m,
5-H), 8.11 (1 H, s, 2-H), 12.25 (1 H, br, 3-H); dC (HSQC/HMBC)
(21a) 17.23 (8-Me), 122.56 (4a-C), 123.5 (5-C), 126.14 (6-C),
134.62 (7-C), 146.58 (8a-C), 147 (2-C), 135.2 (8-C), 161.00 (4-
C); dH (28a) 2.5 (3 H, s, 8-Me), 3.48 (3 H, s, 3-Me), 7.38 (1 H,
m, 6-H), 7.64 (1 H, brd, J 8, 7-H), 7.92 (1 H, m, 5-H), 8.35 (1
H, s, 2-H); dC (HSQC/HMBC) (28a) 33.44 (3-Me), 17.03 (8-Me),
121.35 (4a-C), 123.5 (5-C), 126.37 (6-C), 134.36 (7-C), 135.2 (8-C),
146.58 (8a-C), 147.36 (2-C), 160.86 (4-C); dH (28e) 1.42 (6 H, d, J
7.0, CHMe2), 2.5 (3 H, s, 8-Me), 4.99 (1 H, septet, J 6.8, CHMe2),
7.38 (1 H, m, 6-H), 7.64 (1 H, brd, J 8, 7-H), 7.92 (1 H, m, 5-H),
8.48 (1 H, s, 2-H); dC (HSQC/HMBC) (28e) 17.09 (8-Me), 21.53
(CHMe2), 45.99 (CHMe2), 121.3 (4a-C), 123.87 (5-C), 126.42 (6-
C), 134.43 (7-C), 135.2 (8-C), 145.85 (8a-C), 144.3 (2-C), 159.63
(4-C); dH (49e) 1.41 (6 H, d, J 6.0, CHMe2), 2.5 (3 H, s, 8-Me), 5.43
(1 H, septet, J 6.2, CHMe2), 7.49 (1 H, dd, J 8.0, 7.5, 6-H), 7.73
(1 H, dd, J 7.0, 1.0, 7-H), 7.92 (1 H, brd, J 8.0, 5-H), 8.78 (1 H, s,
2-H); dC (HSQC/HMBC) (49e) 16.94 (8-Me), 21.20 (CHMe2),
69.84 (CHMe2), 115.92 (4a-C), 120.75 (5-C), 126.37 (6-C), 133.65
(7-C), 135.5 (8-C), 149.44 (8a-C), 153.31 (2-C), 165.78 (4-C); m/z
203.1178 (28e/49e + H) (C12H15N2O requires 203.1184), 175.0868
(28a + H) (C10H11N2O requires 175.0871), 161.0709 (21a + H)
(C9H9N2O requires 161.0715).
comprised 20a (19% yield), 27a (21% yield) and 33 (52% yield).
Spectroscopic data for 33: dH (COSY/NOESY) 3.13 (3 H, d, J 0.5,
Me trans to formamidine-H), 3.23 (3 H, s, Me cis to formamidine-
H), 6.67 (1 H, br t, J 8.0, 5-H), 8.22 (1 H, dd, J 8.5, 4-H), 8.61 (1
H, br s, N CH), 8.62 (1 H, m, 6-H); dC (HSQC/HMBC) 35.38
(Me trans to formamidine-H), 41.19 (Me cis to formamidine-H),
113.53 (5-C), 121.14 (1-C), 130.54 (4-C), 132.26 (3-C), 140.39 (6-
C), 147.31 (2-C), 160.35 (N CH), 176.82 (C O).
Reaction of 7 with 1e
2-Aminobenzamide 7 (200 mg, 1.47 mmol) was stirred at 150 ◦C
with 1e (1.29 g, 7.3 mmol) in dimethylformamide (8.0 mL) for
24 h. Further 1e (773 mg, 4.4 mmol) was added and the mixture
was stirred at 150 ◦C for 24 h. Evaporation gave a colourless oil,
1
which was shown by H NMR to comprise 19a, 26a, 3-(prop-
2-yl)quinazolin-4-one 26e and 4-(prop-2-yloxy)quinazoline 47e
(1.4 : 2.3 : 1.4 : 1.0): dH (19a) 7.53 (1 H, brt, J 8, 6-H), 7.67 (1 H,
brd, J 8, 8-H), 7.81 (1 H, brt, J 8, 7-H), 8.13 (1 H, brd, J 7.5,
5-H), 8.09 (1 H, s, 2-H), 12.5 (1 H, br, 3-H); dC (HSQC/HMBC)
(19a) 121.58 (4a-C), 123.24 (5-C), 126.8 (6-C), 127 (8-C), 134.32
(7-C), 148 (8a-C), 147.42 (2-C), 160.65 (4-C); dH (26a) 3.50 (3
H, s, 3-Me), 7.53 (1 H, brt, J 8, 6-H), 7.67 (1 H, brd, J 8, 8-H),
7.81 (1 H, brt, J 8, 7-H), 8.15 (1 H, dd, J 7.0, 1.0, 5-H), 8.37 (1
H, s, 2-H); dC (HSQC/HMBC) (26a) 33.85 (3-Me), 121.45 (4a-C),
125.84 (5-C), 126.8 (6-C), 127 (8-C), 134.21 (7-C), 148.13 (8a-C),
148.44 (2-C), 160.65 (4-C); dH (26e) 1.436 (6 H, d, J 7.0, CHMe2),
5.00 (1 H, septet, J 7.0, CHMe2), 7.53 (1 H, brt, J 8, 6-H), 7.67
(1 H, brd, J 8, 8-H), 7.81 (1 H, brt, J 8, 7-H), 8.15 (1 H, dd, J
7.0, 1.0, 5-H), 8.47 (1 H, s, 2-H); dC (HSQC/HMBC) (26e) 21.17
(CHMe2), 45.09 (CHMe2), 121.40 (4a-C), 125.83 (5-C), 126.8 (6-
C), 127 (8-C), 134.12 (7-C), 148 (8a-C), 145.35 (2-C), 159.7 (4-C);
dH (47e) 1.436 (6 H, d, J 6.4, CHMe2), 5.58 (1 H, septet, J 6.0,
CHMe2), 7.52 (1 H, brt, J 7.5, 6-H), 7.90 (1 H, brd, J 8, 8-H), 7.93
(1 H, brt, J 8, 7-H), 8.15 (1 H, dd, J 7.0, 1.0, 5-H), 8.78 (1 H, s,
2-H); dC (HSQC/HMBC) (47e) 21.53 (CHMe2), 70.01 (CHMe2),
116.1 (4a-C), 126 (5-C), 126.8 (6-C), 127.4 (8-C), 134.00 (7-C),
150.54 (8a-C), 153.34 (2-C), 165.5 (4-C); m/z 189.1018 (26e/47e +
H) (C11H13N2O requires 189.1028), 147.0546 (19a + H) (C8H7N2O
requires 147.0558).
Reaction of 10 with 1e
2-Amino-3-methoxybenzamide 10 was treated with 1e, as
for the reaction of 7 with 1e, to give a colourless oil,
which was shown by 1H NMR to comprise 22a, 29a,
8-methoxy-3-(prop-2-yl)quinazolin-4-one 29e and 8-methyl-1-
(prop-2-yloxy)quinazoline 50e (1.0 : 2.6 : 1.4 : 1.2): dH (22a) 3.892
(3 H, s, OMe), 7.35 (1 H, brd, J 8.0, 7-H), 7.45 (1 H, t, J 8.0, 6-H),
7.66 (1 H, dd, J 8.0, 1.0, 5-H), 8.20 (1 H, s, 2-H), 12.2 (1 H, br, 3-
H); dC (HSQC/HMBC) (22a) 55.85 (OMe), 123.5 (4a-C), 114.89
(5-C), 116.92 (7-C), 127.28 (6-C), 138.00 (8a-C), 147.0 (2-C), 154.4
(8-C), 160.52 (4-C); dH (29a) 3.49 (3 H, s, 3-Me), 3.898 (3 H, s,
OMe), 7.35 (1 H, brd, J = 8.0 Hz, 7-H), 7.45 (1 H, t, J = 8.0 Hz,
6-H), 7.690 (1 H, dd, J = 8.5, 1.0 H, 5-H), 8.31 (1 H, s, 2-H); dC
(HSQC/HMBC) (29a) 33.42 (3-Me), 55.91 (OMe), 114.72 (5-C),
116.76 (7-C), 122.50 (4a-C), 127.28 (6-C), 138.66 (8a-C), 147.02
(2-C), 154.46 (8-C), 160.52 (4-C); dH (29e) 1.43 (6 H, d, J 6.0,
CHMe2), 3.901 (3 H, s, OMe), 4.97 (1 H, septet, J 7.0, CHMe2),
7.35 (1 H, brd, J 8.0, 7-H), 7.45 (1 H, t, J 8.0, 6-H), 7.691 (1 H, dd,
J 8.5, 1.0, 5-H), 8.39 (1 H, s, 2-H); dC (HSQC/HMBC) (29e) 21.16
(CHMe2), 46.19 (CHMe2), 55.85 (OMe), 116.52 (5-C), 114.89 (7-
C), 122.50 (4a-C), 127.28 (6-C), 138.01 (8a-C), 143.90 (2-C), 154.4
(8-C), 159.60 (4-C); dH (50e) 1.42 (6 H, d, J 7.0, CHMe2), 3.95
(3 H, s, OMe), 5.55 (1 H, septet, J 6.0, CHMe2), 7.39 (1 H, dd,
J 8.0, 1.0, 7-H), 7.56 (1 H, dd, J 8.5, 7.5, 6-H), 7.64 (1 H, dd, J
8.5, 1.2, 5-H), 8.72 (1 H, s, 2-H); dC (HSQC/HMBC) (50e) 21.55
(CHMe2), 56.0 (OMe), 69.91 (CHMe2), 112.88 (7-C), 114.09 (5-
C), 116.92 (4a-C), 127.53 (6-C), 142.29 (8a-C), 152.92 (2-C), 155.4
Reaction of 8 with 1e; synthesis of
8-nitro-3-(prop-2-yl)quinazolin-4-one (27e)
2-Amino-3-nitrobenzamide 8 (25 mg, 0.14 mmol) was stirred at
150 ◦C with 1e (115 mg, 0.66 mmol) in DMF (0.55 mL) for
4 d. Evaporation and chromatography (ethyl acetate/petroleum
ether 1 : 4) gave 27e (0.7 mg, 3%) as a pale yellow solid: mp 165–
167 ◦C; dH 1.50 (6 H, d, J 6.8, 2 ¥ Me), 5.03 (1 H, septet, J
6.8, CHMe2), 7.74 (1 H, t, J 8.0, 6-H), 8.36 (1 H, dd, J 8.0,
1.6, 7-H), 8.45 (1 H, dd, J 8.0, 1.6, 5-H), 8.67 (1 H, s, 2-H); m/z
489.1461 (2 M + Na) (C22H22N6NaO6 requires 489.1499), 256.0685
(M + Na) (C11H11N3NaO3 requires 256.0693), 234.0890 (M + H)
(C11H12N3O3 requires 234.0873).
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(8-C), 165.39 (4-C); m/z 241.0945 (29e/50e + Na) (C12H14N2NaO2
requires 241.0953), 219.1130 (29e/50e + H) (C12H15N2O2 requires
219.1134), 191.0817 (29a + H) (C10H11N2O2 requires 191.0820),
177.1658 (22a + H) (C9H9N2O2 requires 177.0664).
Bath (CR@B). Part of this work was performed as MPharm
undergraduate degree projects by MTYC, HHKC, SWSL and JZ
at the University of Bath.
Notes and references
Reaction of 7 with 1f: quinazolin-4-one (19a),
3-(1,1-dimethylethyl)quinazolin-4-one (26f) and
4-(1,1-dimethylethoxy)quinazoline (47f)
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Amide 7 (200 mg, 1.5 mmol) was stirred at 150 ◦C with 1g
(1.49 g, 7.3 mmol) in dimethylformamide (8.0 mL) for 24 h.
Evaporation and chromatography (ethyl acetate/petroleum ether
1 : 4) gave 19a (170 mg, 79%), with data as above. This material
(160 mg, 1.1 mmol) was stirred at 150 ◦C with 1g (1.49 g,
7.3 mmol) in ethyl acetate (8.0 mL) for 24 h. Evaporation and
chromatography (ethyl acetate/petroleum ether 4 : 1) gave crude 4-
(1,1-dimethylethoxy)quinazoline 26f (3.0 mg, 1.4%) as a colourless
gum: dH (COSY/NOESY) 1.75 (9 H, s, But), 7.68 (1 H, ddd, J
8.2, 6.6, 1.5, 6-H), 7.91 (1 H, brd, J 8 Hz, 8-H), 7.94 (1 H, ddd,
J 8.4, 6.6, 1.5, 7-H), 8.13 (1 H, ddd, J 8.2, 1.4, 0.6, 5-H), 8.79
(1 H, s, 2-H); dC (HSQC/HMBC) 27.84 (Me3), 82.80 (CMe3),
117.00 (4a-C), 123.57 (5-C), 127.19 (6-C), 127.36 (8-C), 133.67
(7-C), 150.49 (8a-C), 153.74 (2-C), 165.65 (4-C); m/z 203.1179 (M
+ H) (C12H15N2O requires 203.1184). Further elution gave 3-(1,1-
dimethylethyl)quinazolin-4-one 47f (21 mg, 9%), as a pale yellow
solid: mp 75–78 ◦C (lit.4 mp 68-74 ◦C); dH (COSY/NOESY) 1.74
(9 H, s, But), 7.57 (1 H, ddd, J 8.1, 7.2, 1.2, 6-H), 7.70 (1 H, brd, J
8, 8-H), 7.94 (1 H, ddd, J 8.2, 7.1, 1.6, 7-H), 8.21 (1 H, ddd, J 8.0,
1.5, 0.4, 5-H), 8.47 (1 H, s, 2-H); dC (HSQC/HMBC) 27.99 (Me3),
60.47 (CMe3), 122.39 (4a-C), 126.14 (5-C), 126.58 (8-C), 126.75
(6-C), 134.10 (7-C), 145.18 (2-C), 147.20 (8a-C), 161.14 (4-C); m/z
203.1185 (M + H) (C12H15N2O requires 203.1184). Further elution
gave recovered 19a (67 mg, 41%), with properties as above.
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with 1g (1.69 g, 7.3 mmol) in dimethylformamide (8.0 mL) for
24 h. Evaporation and chromatography (ethyl acetate/petroleum
ether 1 : 1) gave a colourless gum, which was shown by 1H NMR
to comprise 19a and 26a (10 : 1).
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Acknowledgements
We thank Dr Anneke Lubben (University of Bath) for the mass
spectra and Kristin Marshall (Bruton School for Girls) for helpful
discussions. We are very grateful to the Nuffield Foundation
for financial support under the Science Bursary Programme for
Colleges and Schools and to the Association for International
Cancer Research and Cancer Research UK for project grants.
MDT, MDL and AST are members of Cancer Research at
24 Netherlands Patent, NL6403115, 1964.
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