Microwave-promoted syntheses of quinazolines and dihydroquinazolines from 2-aminoarylalkanone O-phenyl oximes

Article abstract of DOI:10.1021/jo900629g

(Chemical Equation Presented) A wide range of biologically active compounds contain the quinazoline ring system. A new free-radical-based method of making functionalized quinazolines is described, which relies on microwave-promoted reactions of O-phenyl oximes with aldehydes. A small set of 2-aminoaryl alkanone O-phenyl oximes was prepared and shown to produce dihydroquinazolines when mixed with an aldehyde in toluene and subjected to microwave heating. When ZnCl₂ was included in the reaction mixture, fully aromatic quinazolines were produced in high yields by a rapid and convenient process. The method worked well with alkyl, aryl, and heterocyclic aldehydes and for a variety of substituents in the benzenic part of the molecule. Similar reactions employing ketones instead of aldehydes were less efficient. Although some dihydroquinazolines did form, they were accompanied by several byproducts. Surprisingly, in each case, one of the byproducts was a quinoline derivative, and a plausible mechanism to account for this rearrangement is proposed.

Full text of DOI:10.1021/jo900629g

Microwave-Promoted Syntheses of Quinazolines and
Dihydroquinazolines from 2-Aminoarylalkanone O-Phenyl Oximes
Fernando Portela-Cubillo,† Jackie S. Scott,§ and John C. Walton*,†
School of Chemistry, UniVersity of St. Andrews, EaStChem, St. Andrews, Fife KY16 9ST, U.K., and
GlaxoSmithKline, New Frontiers Science Park, Third AVenue, Harlow, Essex CM19 5AW, U.K.
jcw@st-and.ac.uk
ReceiVed March 25, 2009
A wide range of biologically active compounds contain the quinazoline ring system. A new free-radical-
based method of making functionalized quinazolines is described, which relies on microwave-promoted
reactions of O-phenyl oximes with aldehydes. A small set of 2-aminoaryl alkanone O-phenyl oximes
was prepared and shown to produce dihydroquinazolines when mixed with an aldehyde in toluene and
subjected to microwave heating. When ZnCl2 was included in the reaction mixture, fully aromatic
quinazolines were produced in high yields by a rapid and convenient process. The method worked well
with alkyl, aryl, and heterocyclic aldehydes and for a variety of substituents in the benzenic part of the
molecule. Similar reactions employing ketones instead of aldehydes were less efficient. Although some
dihydroquinazolines did form, they were accompanied by several byproducts. Surprisingly, in each case,
one of the byproducts was a quinoline derivative, and a plausible mechanism to account for this
rearrangement is proposed.
Introduction
products. The growing importance of quinazolines in medicine
is highlighted by the huge sales of the drugs Erlotinib, which
is used in the treatment of several types tumors,6 and Prazosin,
an R-adrenergic blocker.7 Likewise, Iressa, an epidermal growth
factor receptor inhibitor, was recently approved by the U.S. Food
and Drug Administration for the treatment of lung cancer8
(Figure 1). The quinazoline unit represents a useful natural
product scaffold with demonstrated activities against numerous
disorders. The transferable nature of its properties provides a
strong rationale for the development of synthetic methods.
Quinazoline derivatives are among the most potent tyrosine
kinase and cellular phosphorylation inhibitors,1 and they also
show remarkable activity as antitubercular, antiviral, and
anticancer agents.2 They have been used as DNA ligands,3 they
bind to adenosine receptors,4 and are potent antibacterial agents.5
It is no surprise, therefore, that the quinazoline ring system forms
the basis of many pharmaceutical, agrochemical, and veterinary
† University of St. Andrews.
§ GSK Harlow.
Not surprisingly, considerable progress in synthetic methodol-
ogy applicable to quinazoline alkaloids has been made during
the past decade.9 The following are among the most important
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Leopold, W. R.; Connors, R. W.; Bridges, A. J. Science 1994, 265, 1093–1095.
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2000, 55, 725–729. (b) el-Sherbeny, M. A.; Gineinah, M. M.; Nasr, M. N.; el-
Shafeith, F. S. Arzneim. Forsch. 2003, 53, 206–213. (c) Foster, A.; Coffrey,
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C.; Henichart, J. P. Bioorg. Med. Chem. 2004, 12, 641–647.
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Bioorg. Med. Chem. 2008, 16, 7254–7263.
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H. D.; Sun, L.; Nelson, J.; McMichael, A.; Kraker, A. J.; Fry, D. W.; Denny,
W. A. J. Med. Chem. 1996, 39, 918–928. (b) Luth, A.; Lowe, W. Eur. J. Med.
Chem. 2008, 43, 1478–1488.
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4934 J. Org. Chem. 2009, 74, 4934–4942
10.1021/jo900629g CCC: $40.75  2009 American Chemical Society
Published on Web 05/18/2009

Syntheses of Quinazolines and Dihydroquinazolines
Microwave-assisted methods offer improved opportunities for
reproducibility, rapid reaction optimizations, and the potential
for discovery of new chemistry. Several examples of microwave-
assisted syntheses of the quinazoline core have also been
described. Anilines (protected as N-ethyl carbamates) with
HMTA in TFA afforded quinazolines on microwave irradiation
under pressure in a monomode reactor.19 4-Amino-2-arylquinazo-
lines were obtained from cyano-aromatic compounds with
anthranilonitrile in the presence of catalytic amounts of base.20
Microwave-assisted reactions of N-(2-cyanophenyl)-N,N-dim-
ethylformamidine derivatives and amines, with a catalytic
amount of acetic acid, gave 4-aminoquinazolines in high
yields.21 Recently, a solvent- and catalyst-free approach toward
the selective synthesis of quinazolines and benzo[g]quinazolines
from N-arylamidines with various aldehydes has been devel-
oped.22 2,4-Disubstituted quinazolines were obtained from
2-aminoacylbenzenes by N-acylation and rapid cyclization in
the presence of ammonium formate under microwave heating.23
Microwave-assisted cyclizations of 2-aminoaryl imines with
aldehydes provided good yields of novel 2,4-disubstituted
quinazolines.24 Microwave irradiations of solutions of N-arylimi-
no-4-chloro-5H-1,2,3-dithiazoles, in the presence of sodium
alkoxide, in the corresponding alcohol, gave good yields of
quinazolines even on multigram scales.25 Various derivatives
of indolo- and benzimidazo[1,2-c]quinazolines were obtained
by condensation of appropriate diamines with benzothiazole-
2-carbonitrile substituted on the benzenic part.26 Anthranilic acid
condenses with formamide under open-vessel microwave condi-
tions to yield quinazolinones.27
Radical additions to imines and related compounds are
gradually emerging as useful synthetic processes,28 although
imines can be difficult to handle because they are prone to
hydrolysis and tautomerism. Attack at the carbon of the CdN
bond is almost exclusively observed, especially for oxime ethers
and hydrazones, where the stabilizing 3-electron π-bond in the
adduct aminyl radical lowers the energy of the transition state.
However, the competition between 5-exo and 6-endo cyclization
of alkyl, aryl, and acyl radicals onto imines is intriguing.
Warkentin and co-workers29 studied the regioselectivity for the
cyclization of an aryl radical onto an aldimine receptor and
found a large 6-endo preference (Scheme 1).
FIGURE 1. Popular drugs containing the quinazoline unit.
preparative methods relying on conventional wet organic
methodology: (a) aza-Wittig and tandem aza-Wittig/6π-elec-
trocyclization procedures10 have been applied in preparations
starting from N-imidoyl iminophosphoranes.11 (b) Three-
component systems consisting of an aldehyde, morpholine, and
an aryl azide react to yield triazolines that are converted into
quinazolines by ethanolic ammonia.12 (c) Condensations of a
cyano- or nitro-activated o-fluorobenzaldenyde with an amidine
yield imines that undergo intramolecular nucleophilic aromatic
substitution at the fluorine-substituted carbon, thus affording a
variety of quinazolines.12 (d) Amidines derived from 2-unsub-
stituted 4-arylaminoquinazolines are converted to 4-arylamino-
quinazolines in good yields when heated with formic acid.13
Furthermore, 2-amino-N′-phenylbenzimidamides react with
aromatic aldehydes to yield 2-aryl-4-arylimino-2,3-dihydro-
quinazolines, which are easily oxidized to the corresponding
quinazolines with potassium permanganate.14 (e) A mild
synthesis of 2,4-dihydroxyquinazolines uses 2-aminobenzonitrile
and carbon dioxide in the presence of DBU.15 (f) The
intermediates formed from 2-aminobenzonitrile and Grignard
reagents react with acid chlorides or anhydrides to afford
quinazolines in moderate to good yields.16 (g) 6-Substituted
quinazoline-2,4-diones are readily prepared from anthranil-
amides by treatment with phosgene and can be converted to
2,4-dichloroquinazolines in excellent yields by refluxing in
phosphorus oxychloride.17 (h) A solid-supported method for the
preparation of the 2,4-diaminoquinazoline ring system has also
been developed.18
They provided evidence that formation of the C-C single
bond was favored over the corresponding C-N bond by
approximately 10 kcal/mol. In addition, the geometry inherent
in the imine functional group, with a C-CdN angle of
approximately 119°, is more suited to endo addition than is the
(9) For reviews, see: (a) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry,
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Chem. High Throughput Screening 2007, 10, 903–917. (c) Michael, J. P. Nat.
Prod. Rep. 2003, 20, 476–493. (d) Undheim, K; Benneche, T. In ComprehensiVe
Heterocyclic Chemistry; Pergamon: Oxford, 1998; Vol. 6.
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425.
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J. Org. Chem. Vol. 74, No. 14, 2009 4935

Portela-Cubillo et al.
SCHEME 2. Sequential and One-Pot Reactions of
SCHEME 1. 6-endo Preference for Ring Closure of an Aryl
Radical onto an Aldimine29
1-(2-Aminophenyl)ethanone O-Phenyl Oxime 2
alkene group with a larger angle of approximately 125°. Despite
numerous examples of radical additions to CdN bonds, there
have been only a few cases where addition occurs at the
nitrogen. In the case of imines, the “radical R-effect” is not
possible, and thus it is surprising that addition does not occur
more often at nitrogen, given the stabilization available through
interaction of the adduct R-aminyl radical with the nonbonding
electron pair on nitrogen. In the cases of additions at nitrogen
known to date, additional stabilizing groups, conformational
restriction, severe steric hindrance, or polar effects are present
to encourage attack at nitrogen.30 These and other examples31
show that intramolecular additions of alkyl, aryl, vinyl, and acyl
radicals onto imines constitute useful processes for syntheses
of aza-heterocycles. Addition of iminyl radicals onto imines has
not previously been reported, although the intramolecular version
could constitute an attractive approach for the synthesis of diaza-
heterocycles, such as quinazolines or benzopyrazoles.
Thermolyses of O-phenyl oxime ethers were shown to release
simple dialkyl- and diaryl-iminyl radicals together with phenoxyl
radicals.32 Furthermore, we recently discovered that for alkenone
O-phenyl and related oximes, microwave heating was a suitable
method for release of unsaturated iminyl radicals that ring closed
to afford a variety of aza-heterocycles in good yields.33 We
reasoned that other heterocycles could probably be made by
using O-phenyl oximes containing different types of radical
acceptors in their side chains. In particular, by use of imine
functionality in the side chain, diaza-heterocycles might be
accessible under mild, neutral conditions with all the conven-
ience and rapidity of a microwave-assisted process. The
O-phenyl oxime of 2-aminoacetophenone (2) can be made in
good yield by treatment of ketone 1 with commercially available
O-phenylhydroxylamine hydrochloride. Imines 3 could be made
by condensation of 2 with aldehydes in the conventional way
(route a, Scheme 2). However, it is known that microwave
irradiation assists imine formation,34 and the technique forms
part of a standard method for syntheses of secondary amines.35
We conjectured, therefore, that the imine-yielding step would
also be promoted by microwaves and that there was the
possibility of assimilating this with radical generation, thus
enabling the whole sequence to be combined in one pot (route
b, Scheme 2).
Competition between the 5-exo and 6-endo radical ring
closures onto the CdN bond could lead to formation of 6 or 5.
It was likely, however, that the architecture of iminyl radical 4
would favor ring closure in the 6-endo mode because the
resultant aminyl radical 5 would be strongly resonance-
stabilized.
Furthermore, the 5-exo approach of the nucleophilic iminyl
radical to the nitrogen atom of the imine would be polarity-
mismatched.36 Together these two effects might lead to re-
giospecific 6-endo cyclization, despite the possible 3-electron
π-bonding interaction in 6 (Scheme 2). We report in this paper
that dihydroquinazolines and quinazolines can indeed be
prepared in good to excellent yields by microwave-promoted
reactions of 2 and related oxime ethers with a range of aldehydes
and ketones. Part of this research has previously been published
as a preliminary communication.37
(30) (a) Takano, S.; Suzuki, M.; Kijima, A.; Ogasawara, K. Chem. Lett. 1990,
315–316. (b) Viswanathan, R.; Prabhakaran, E. N.; Plotkin, M. A.; Johnston,
J. N. J. Am. Chem. Soc. 2003, 125, 163–168. (c) Bowman, W. R.; Stepheson,
P. T.; Terett, N. K.; Young, A. R. Tetrahedron Lett. 1994, 35, 6369–6372. (d)
Han, O.; Frey, P. A. J. Am. Chem. Soc. 1990, 112, 8982–8983. (e) Prabhakaran,
E. N.; Nugent, B. M.; Williams, A. L.; Nailor, K. E.; Johnston, J. N. Org. Lett.
2002, 4, 4197–4200. (f) Schiesser, C. H.; Wille, U.; Matsubara, H.; Ryu, I. Acc.
Chem. Res. 2007, 40, 303–313. (g) Tojino, M.; Otsuka, N.; Fukuyama, T.;
Matsubara, H.; Ryu, I. J. Am. Chem. Soc. 2006, 128, 7712–7713. (h) Ryu, I.;
Miyazato, H.; Kuriyama, H.; Matsu, K.; Tojino, M.; Fukuyama, T.; Minakata,
S.; Komatsu, M. J. Am. Chem. Soc. 2003, 125, 5632–5633.
(31) For reviews, see: (a) Walton, J. C. Top. Curr. Chem. 2005, 264, 163–
200. (b) Stella, L. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, p 317. (c) McCarroll, A. J.; Walton,
J. C. Angew. Chem., Int. Ed. 2001, 40, 2224–2248. (d) Bowman, W. R.; Bridge,
C. F.; Brookes, P. J. Chem. Soc., Perkin Trans. 1 2000, 1–14. (e) Baguley, P. A.;
Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072–3082.
Results and Discussion
Optimization of Dihydroquinazoline Preparation. The
O-phenyl oxime ether 2 was prepared in 76% yield as a mixture
of E and Z isomers by stirring 2-aminoacetophenone 1 with
(32) Blake, J. A.; Pratt, D. A.; Lin, S.; Walton, J. C.; Mulder, P.; Ingold,
K. U. J. Org. Chem. 2004, 69, 3112–3120.
(33) (a) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. Chem. Commun. 2007,
4041–4043. (b) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. J. Org. Chem.
2008, 73, 5558–5565.
(34) Vo-Thanh, G.; Lahrache, H.; Loupy, A.; Kim, I. J.; Cang, D. H.; Jun,
C. H. Tetrahedron 2004, 60, 5539–5543.
(35) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450–7451.
(36) Kim, S.; Yoon, K. S.; Kim, Y. S. Tetrahedron 1997, 38, 73–80.
(37) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. Chem. Commun. 2008,
2935–2937.
4936 J. Org. Chem. Vol. 74, No. 14, 2009

Syntheses of Quinazolines and Dihydroquinazolines
TABLE 1. Microwave-Assisted Reactions of Pent-4-enal with 2a at
TABLE 2. Microwave-Assisted Reactions of 2 with Aldehydes
160 °Cb
entry
solvent
time (min)
IL
yield 7ac (mol %)
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
i-PrOH
t-BuOH
15
20
25
30
35
30
30
30
emimPF6
emimPF6
emimPF6
emimPF6
emimPF6
emimPF6
none
68
74
90
94
88
81
91
83
entry
aldehyde
pent-4-enal
3-phenylpropanal
pentanal
benzaldehyde
4-methoxy-benzaldehyde
thiophene-2-carbaldehyde
dihydroquinazoline yield (mol %)
none
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
94
92
91
a [2] ) 0.15 M except for entry 6 where [2] ) 0.2 M b In each case
7a (R ) but-3-enyl) was accompanied by PhOH, but no 8 was obtained.
c 7a (R ) but-3-enyl).
72
[51]a
[46]a
a
1
Yield determined by H NMR spectroscopy.
SCHEME 3. Potential Tandem Reaction of Aminyl Radical
Intermediates
FIGURE 2. Potential products from premature H-atom abstractions.
O-phenylhydroxylamine hydrochloride in pyridine at rt. The fact
that two isomers were present did not matter because both
released the same iminyl radical on scission of their N-O bonds.
To test the annulation sequence of Scheme 2 and find the best
reaction conditions, pent-4-enal (1 equiv) and oxime ether 2 (1
equiv) in various solvents, with and without emimPF6 (1-ethyl-
3-methyl-1H-imidazol-3-ium hexafluorophosphate) as ionic
liquid (IL), were irradiated with microwaves (nominally 300
MHz) in a Biotage Initiator closed reactor. A temperature of
160 °C was chosen on the basis of previous microwave-assisted
reactions of oxime ethers.33 As Table 1 shows, with toluene as
H-atom donor solvent, dihydroquinazoline 7a (R ) but-3-enyl)
was indeed formed.
The one-pot protocol incorporating hydrogen abstraction from
toluene gave essentially quantitative production of 7a with an
equal amount of phenol in 30 min (entry 4). The latter is formed
by H-abstraction from solvent by the co-produced phenoxyl
radicals and was easily separated.
If H-atom abstraction from solvent, by an iminyl radical
generated before imine formation, had been important, then 9a
or its hydrolysis product 9b should have been obtained (Figure
2). Similarly, if H-atom abstraction from solvent by radical 4
had been faster than ring closure, then 10a or its hydrolysis
product 10b should have been detected. In practice none of 9a,b
or 10a,b was observed.
Imine production from 2 and an aldehyde will take place via
a series of equilibria involving hemiaminal formation, water
loss, and various protonation/deprotonation steps. The absence
of 9a,b shows that the equilibria must be fast in comparison
with radical generation. Evidently, the imine intermediate was
rapidly trapped by the cyclization step, but the fast imine
formation equilibria ensured a constant supply until reactant
depletion set in. At the same time, the plain fact that none of
the benzopyrazole 8 was detected confirmed the regiospecific
character of the ring closure. This can be accounted for by the
strong resonance stabilization effect in 5 and the “polarity-
mismatch” involved in formation of 6 (see above). The kinetics
of this type of ring closure have not been studied. However,
the known rate constants for 6-endo-trig cyclizations of
C-centered radicals onto CdN bonds36 and for iminyl radicals
onto CdC bonds38 suggest 4 f 5 would be a fast process at
160 °C with a rate constant at least equal to that of a C-centered
radical onto a CdC bond and probably greater because of the
resonance stabilization in 5. This is consistent with the absence
of compounds 10a,b (Figure 2) in the product mixtures.
The use of hydrogen donor solvents such as toluene or
isopropanol allowed the iminyl radical sufficient lifetime to
cyclize. Good yields were obtained in both solvents, although
isopropanol was less convenient because its low boiling point
led to the microwave vial being exposed to high pressures. The
ionic liquid emimPF6 was used together with toluene because
of the poor microwave absorption properties of this solvent.
Entries 1-5 show that at 160 °C the reaction needed an
irradiation time of 30 min to achieve complete conversion but
that at longer times side reactions/degradative processes set in.
However, for larger concentrations of precursor 2 in toluene
(entry 6) the yield fell off in 30-min reactions.
Syntheses of 2-Substituted-4-methyldihydroquinazolines.
To discover the scope of the annulation, oxime ether 2 was
reacted with a range of commercially available aldehydes under
the optimal conditions established above; the results are in Table
2. Reactions with aliphatic aldehydes (entries 1-3) delivered
the corresponding dihydroquinazolines in very high yields, and
no unreacted starting materials were found. Imine formation,
iminyl radical generation, 6-endo radical cyclization onto the
CdN bond, and H-atom abstraction from the solvent seemed
to be extremely efficient (Table 2). In the reaction of pent-4-
enal or of 3-phenylpropanal with 2, intermediate aminyl radicals
5a,b will be formed by the first ring closure. The option of
undergoing subsequent 5-exo- or 6-endo-cyclization steps to
afford polycyclo-radicals 11a,b (Scheme 3) is a clear possibility
for these species. However, none of the products derived from
11a,b were detected, even when the reaction of 5b was carried
out in the poor-H-atom-donor solvent t-BuPh, and evidently
H-atom abstraction by radicals 5a,b is too fast for the second
ring-closure step to compete. This result was not too surprising
J. Org. Chem. Vol. 74, No. 14, 2009 4937

Portela-Cubillo et al.
TABLE 4. Preparation of Quinazolines by Microwave-Assisted
SCHEME 4. DDQ Oxidation of a Dihydroquinazoline
a
Reactions of 2 with Aldehydes in the Presence of ZnCl2
because neutral aminyl radicals are not very reactive, and it is
known that their additions to alkenes are often reversible.39
Reactions of 2 with aromatic aldehydes were next examined
under the same conditions. Microwave irradiation with benzal-
dehyde gave a 72% yield of the corresponding dihydroquinazo-
1
line (entry 4). The H NMR spectrum of the total product
mixture showed quantitative production of phenol, but also
benzaldehyde, imine 9a, and the corresponding ketone 9b were
present. 4-Methoxybenzaldehyde and thiophene-2-carbaldehyde
gave dihydroquinazolines 7e and 7f in 51% and 46% yield,
respectively, as determined by NMR spectroscopy (entries 5
and 6). In both cases the 1H NMR spectrum showed a complex
mixture of components including the starting aldehydes as well
as imine 9a and ketone 9b. However, phenol was formed
quantitatively as was expected (Table 2). For the aromatic
aldehydes, the presence of unreacted starting materials suggested
that the first step of the sequence, the formation of imine 3,
was not complete. We inferred therefore, than an improvement
in the imine forming condensation would lead to an increase in
the dihydroquinazoline yields.
The dihydroquinazolines tended to slowly oxidize to the
corresponding quinazolines over a period of days when stored
in air at room temperature. The oxidation of dihydroquinazoline
7a was studied by continuously bubbling oxygen through a
solution of 7a in CDCl3 at 50 °C, the course of the oxidation
1
being monitored by H NMR spectroscopy (Table 3). Autoxi-
TABLE 3
time (h)
4
8
24
42
48
88
a 30-min reactions in PhMe at 160 °C with emimPF6 and ZnCl2 (0.3
equiv). b Isolated yields.
yield of quinazoline 12a (%)
28
32
dation was virtually complete in 48 h, but side processes had
set in, and various minor unidentified byproducts were present
in the total reaction mixture. It was desirable to find an oxidation
protocol that could bring about this conversion in high yield
and short reaction time. Microwave irradiation of dihydro-
quinazoline 7a in DCM and in the presence of DDQ for 10
min at 100 °C gave the fully aromatic quinazoline 12a in good
yield (Scheme 4).
Syntheses of 2-Substituted-4-methylquinazolines. The de-
hydration step of imine formation is acid-catalyzed, and the rates
of individual steps depend on pH.40 It is known that imine
formation via microwave irradiation is promoted by inclusion
of zinc chloride.41 We hoped, therefore, that addition of ZnCl2
as a promoter would improve the product yields when less
reactive carbonyl compounds were employed. Pent-4-enal was
reacted with oxime ether 2 in the presence of ZnCl2 using the
usual microwave reaction conditions. An excellent product yield
was obtained, but the surprising outcome was that the quinazo-
line 12a was formed directly rather than the dihydroquinazoline.
Reactions with 0.1, 0.3, and 0.5 equiv of ZnCl2 indicated that
0.3 equiv was the optimal amount, and this was adopted as
standard in subsequent preparations.
To assess the scope of this new process, oxime ether 2 was
reacted with a range of aldehydes in the presence of 0.3 equiv
of ZnCl2 (Table 4). High yields of quinazolines 12a,b were
obtained with aliphatic aldehydes (entries 1 and 2) and with
aromatic aldehydes containing electron-withdrawing substituents
in the 4-position (entries 3 and 4). Somewhat lower but still
useful yields of quinazolines were obtained from aromatic
aldehydes containing electron-releasing substituents (entries 5
and 6). The low yield of entry 6 may be due to the high steric
hindrance in the formation of the imine intermediate. The
slightly better yields for aromatic aldehydes with electron-
withdrawing groups might be due to an increase in the
electrophilic character of the carbonyl group, which would favor
the nucleophilic addition of 2.
(38) Le Tadic-Biadatti, M.-H.; Callier-Dublanchet, A.-C.; Horner, J. H.;
Quiclet-Sire, B.; Zard, S. Z.; Newcomb, M. J. Org. Chem. 1997, 62, 559–563.
(39) Bowman, W. R.; Clark, D. N.; Marmon, R. J. Tetrahedron 1994, 50,
1295–1310.
(40) (a) Hine, J.; Cholod, M. S.; Chess, W. K., Jr. J. Am. Chem. Soc. 1973,
95, 4270–4276. (b) Hine, J.; Chou, Y. J. Org. Chem. 1981, 46, 649–652.
(41) Pouilhes, A.; Langlois, Y.; Chiaroni, A. Synlett 2003, 1488–1490.
The annulations also worked well with heterocyclic aldehydes
including furfural and picolinaldehyde, which gave novel and
potentially useful quinazolines 12 g,h (entries 7 and 8).
4938 J. Org. Chem. Vol. 74, No. 14, 2009

Syntheses of Quinazolines and Dihydroquinazolines
SCHEME 5. Preparation of Functionalized Quinazolines
SCHEME 6. Possible Electrocyclization Route to
Quinazolines
the precursor oxime ether 13 (R1 ) Ph, R2 ) R3 ) R4 ) H).
The reaction was carried out at rt for 24, 48, and 72 h and at 50
°C for 4 h. Unfortunately only a minimal conversion to the
desired phenyl-derivative was achieved. This lack of success
may be due to steric hindrance between one of the phenyl groups
of the 2-aminobenzophenone and the phenyl hydroxylamine.
Mechanism of Quinazoline Formation. Formation of the
fully aromatic product suggested that inclusion of the Lewis
acid ZnCl2 might have caused a change in the mechanism and
electrocyclic ring closure is worth considering. Imine 3 might
electrocyclize to give the dihydroquinazoline intermediate 15
followed by the elimination of PhOH (Scheme 6). Recently,
Trost and co-workers reported somewhat related syntheses of
substituted pyridines via 6π-electrocyclizations of oxime-dienes
with subsequent elimination of water under microwave irradia-
tion.43
However, our precursor O-phenyl oximes are known to
completely dissociate to radicals in <30 min under the micro-
wave conditions,33 so any alternative mechanism would have
to be faster than this. It is unlikely both electrocyclization and
phenol elimination could be fast enough to compete with the
radical process. Note also that phenol was formed quantitatively
in reactions with ketones, where this molecule cannot be
produced by elimination from the 2,2′-disubstituted dihydro-
quinazoline analogous to 15 (see below). None of the quinazo-
line was observed in the absence of ZnCl2, and therefore, the
Lewis acid must play an important role in the mechanism.
Recently, Lewis acids have been shown to catalyze 6-π
electrocyclizations,44 so the mechanism of Scheme 6 could not
be entirely ruled out.
A radical-based mechanism in which the ZnCl2 bonds to the
iminyl nitrogen is outlined in Scheme 7. Bonding of zinc to
the imine intermediate, followed by thermolysis of the N-O
bond, would generate the iminyl radical 16. Subsequent ring
closure would lead to amminium radical cation 17 in a process
akin to an iminium salt cyclization. The adjacent cation would
considerably lower the pKa of the H-atom at the 2-position of
the heterocycle. Proton loss would then yield 18 in a process
reminiscent of the Minisci reaction.45 Stabilized intermediate
18 might transfer an electron to the starting oxime ether to give
19 or be converted to 19 on exposure to oxygen during workup.
When the ZnCl2 is not present, the C-H at the 2-position is far
less acidic, and hence aromatization to a quinazoline does not
occur.
The efficiency of the reaction was also investigated for a set
of O-phenyl oxime ethers having different functionality in the
amino-aryl ring. The O-phenyl oxime ether 13a was prepared
in good yield (78%) from the condensation of 2-aminobenzal-
dehyde and O-phenyl hydroxylamine hydrochloride in pyridine.
5-Bromo-2-aminoactophenone was obtained by treatment of
2-aminoacetophenone with NBS in the presence of sulfonic-
acid-functionalized silica as a heterogeneous catalyst.42 The
standard condensation gave the corresponding bromo-oxime
ether 13e in 67% yield. The 1-(2-amino-4,5-dimethoxyphe-
nyl)ethanone O-phenyl oxime 13f was obtained from condensa-
tion of the commercially available 4,5-dimethoxy-2-acetophe-
none with phenyl hydroxylamine hydrochloride. The reaction
mixture was stirred for 24 h at rt, but a disappointing 46% yield
resulted. The reaction was also carried out at 50 °C for 3 h, but
numerous byproducts were formed, probably from scission of
the N-O bond. The best result of the condensation (63%) was
achieved by stirring the starting materials for 48 h at rt in
pyridine. The slowness of this reaction may be due to the
presence of three electron-releasing groups in the acetophenone
ring.
Microwave irradiation of the unsubstituted oxime ether 13a
with aliphatic, aromatic, and heterocyclic aldehydes gave good
yields of 2-substitued quinazolines (Scheme 5, a-d). The
interesting building block 14d is of special interest. Reaction
of 6-bromopiperonal with the oxime ether 13d gave the
quinazoline 14d in 71% yield, despite the presence of the large
Br atom and a good electron-donating substituent, the dioxole,
in the aromatic aldehyde. Both factors could have inhibited
imine formation by steric hindrance and electronic effects
respectively. The result demonstrated the healthy flexibility of
this one-pot process. Similarly, the bromo-oxime ether 13e and
benzaldehyde afforded the 6-bromo-substituted quinazoline 14e
in an excellent yield (Scheme 5). Furthermore, dimethoxy-oxime
ether 13f reacted with 4-bromo- and 4-nitro-benzaldehydes,
giving quinazolines 14f and 14g in high yields of 80% and 91%,
respectively.
The possibility of making 4-phenyl quinazolines was also
examined. In this case, 2-aminobenzophenone was reacted with
O-phenyl hydroxylamine hydrochloride in pyridine to prepare
(43) Trost, M.; Gutierrez, A. C. Org. Lett. 2007, 9, 1473–1476.
(44) Bishop, L. M.; Barbarow, J. E.; Bergman, R. G.; Trauner, D. Angew.
Chem., Int. Ed. 2008, 47, 8100–8103.
(45) (a) Fontana, F.; Minisci, F.; Barbosa, M. C. N.; Vismara, E. J. Org.
Chem. 1991, 56, 2866–2869. (b) Minisci, F.; Recupero, F.; Punta, C.; Gambarotti,
C.; Antonietti, F.; Fontana, F.; Pedulli, G. F. Chem. Commun. 2002, 2496–2497.
(42) Das, B.; Ventateswarly, K.; Krishnaiah, M.; Holla, H. Tetrahedron Lett.
2006, 47, 8693–8697.
J. Org. Chem. Vol. 74, No. 14, 2009 4939

Portela-Cubillo et al.
SCHEME 7. Possible Role of ZnCl2 in Quinazoline
Formation
respectively (entries 3 and 4). The total reaction mixture of
the Lewis acid mediated process was studied by H NMR
1
and GC/MS, which showed a complex mixture including
phenol, imine 9a, ketone 9b, and six additional major peaks.
The spectrum of the first eluted component (M+ ) 158)
matched the library spectrum of 2,4-dimethylquinazoline 24a
(91% confidence level). The second eluted component (M+
) 174) was probably the dihydroquinazoline 23a. The
quantitative formation of phenol was also of note. Its presence
supported the generation of the phenoxyl radical and hence
the radical mechanism. If a 6π-electrocyclization had taken
place, analogous to that shown in Scheme 6, anisole should
have been produced in the elimination step. However, no
1
anisole was detected by GC/MS or H NMR spectroscopy.
Elimination of a methyl radical from aminyl radical 22 under
the MW conditions probably accounts for the experimental
finding of the fully aromatic quinazoline 24a (Scheme 7). A
major surprise was that the mass spectrum of the third eluted
component (M+ ) 157) matched the library spectrum of 2,4-
dimethylquinoline 30a (94% confidence level). The fourth
component remained unidentified, but the final two compo-
nents with longer retention time had mass spectra identical
to those of quinazoline 24c and quinoline 30c (see below).
Mixtures from reactions of oxime ether 2 with the alkaloid
tropinone were also studied, but NMR and GC/MS showed
that none of the desired dihydroquinazoline was formed.
Surprisingly, 2,2,4-trimethyl-1,2-dihydroquinazoline 23a was
isolated in 21% yield. This implies major degradation of
tropinone and/or the initial products under microwave
irradiation.
TABLE 5. Yields of Dihydroquinazolines from Reactions of
Ketones with 2
Microwave irradiation of 2 with acetophenone under the usual
conditions gave again a complex mixture of compounds. The
GC/MS showed the presence of unreacted starting material,
phenol, imine 9a, and ketone 9b, together with six additional
major components and several minor ones. The first and second
of these (M+ ) 221 and 220, respectively) were probably
dihydroquinazoline 23b and quinazoline 24b. The mass spec-
trum of the third component (M+ ) 219) matched the library
spectrum of 2-phenyl-4-methylquinoline 30b at the 95% con-
fidence level. There were two additional components with longer
retention times (M+ ) 234, 235 respectively), which we identify
as quinazoline 24c and quinoline 30c respectively (Scheme 8).
The presence of unreacted ketone, imine 9a, and its hydrolysis
product 9b in the total reaction mixture confirmed that imine
formation was not very efficient. This may be due to the high
sensitivity of the imine condensation to steric hindrance.
a MW at 160 °C for 30 min of 0.1 M solns. in PhMe with emimPF6.
b A: without ZnCl2. B: with 0.3 equiv of ZnCl2. c Isolated yields except
d
1
as indicated. Determined from H NMR of total reaction mixtures.
Microwave-Promoted Reactions of 2 with Ketones. It was
anticipated that 2,2′-disubstituted dihydroquinazolines could be
prepared by the analogous reaction of oxime ether 2 with
ketones. The ring-closed aminyl radical should abstract hydrogen
from toluene solvent to give the 2,2′-disubstituted dihydro-
quinazoline together with an equal amount of phenol in the same
way as shown in Scheme 2. The absence of an H-atom at the
2-position of these dihydroquinazolines would prevent their
oxidation to quinazolines. To assess the scope and limitations
of this annulation, reactions of 2 with several ketones were
carried out in toluene, without (A) and with (B) ZnCl2 under
microwave irradiation (Table 5).
A promising result was achieved from reaction of 2 with
cyclohexanone, which afforded an excellent yield of the
spirodihydroquinazoline 20a, with and without ZnCl2 (entries
1 and 2). When the reaction was carried out with acetone,
yields of the dihydroquinazoline 23a were dramatically lower
at 36% and 45% in the absence and presence of ZnCl2,
To explain the formation of these compounds, it was
conjectured that precursor 2 could react with the ketone 9b to
give the imine 21c. Subsequent generation of the iminyl radical
and 6-endo cyclization onto the imine could give aminyl radical
22c. Dihydroquinazoline 23c would be obtained by hydrogen
abstraction from the solvent. The related quinazoline 24c was
presumably formed by elimination of a methyl radical (Scheme
8).
The most intriguing aspect of this reaction was the apparent
formation of products containing the quinoline ring, i.e., 30a-c.
A tentative mechanism to account for this is also shown in
Scheme 8. Imines 21 will be in equilibrium with their enamine
tautomers 25. Generation of iminyls 26 could be followed by
favored [1,5]-hydrogen migrations giving the aza-allyl radicals
27; 6-exo ring closures of 27 onto the newly formed imine bonds
would produce aminyl radicals 28. Hydrogen abstraction from
4940 J. Org. Chem. Vol. 74, No. 14, 2009

Syntheses of Quinazolines and Dihydroquinazolines
SCHEME 8. Mechanism for Reaction of 2 with Ketones
FIGURE 3. Imines from 2 with acetophenone and 1-(2-aminophe-
nyl)ethanone.
for the syntheses of disubstituted dihydroquinazolines. The
reactions generally gave complex mixtures of numerous com-
pounds. It was also shown that when reactions were carried out
with more sterically demanding ketones, such as acetophenone,
the complexity of the total reaction mixture increased as a result
of the poor efficiency of imine formation.
Conclusions
The results show that 2-(aminoaryl)alkanone O-phenyl oximes
are excellent precursors for quinazoline derivatives. They react
in one pot, with aliphatic aldehydes, in microwave-assisted
reactions yielding dihydroquinazolines. When more sterically
demanding aldehydes were used, the yield dropped dramatically.
The precursor O-phenyloximes are easily made in one step from
the corresponding carbonyl and O-phenyl hydroxylamine in
good yields and can be stored indefinitely. Nevertheless, it was
found that electronic and steric hindrance effects played an
important role in the success of this condensation reaction.
When ZnCl2 was included in the mixture, quinazolines were
obtained instead of dihydroquinazolines. The process is of wide
scope and works well with alkyl, aryl, and heterocyclic types
of aldehydes. The reaction has all the advantages associated
with microwave chemistry. The process is rapid, high-yielding,
reproducible, neutral, and comparatively mild. The methodology
was successful in syntheses of quinazolines with high steric
demand such as 4-methyl-2-(6-phenylbenzo[d][1,3]dioxol-5-
yl)quinazoline 12f and 2-(6-bromobenzo[d][1,3]dioxol-5-
yl)quinazoline 14f. Quinazolines with heterocycles as substit-
uents were also prepared in good yields. On the other hand,
although this methodology was extremely effective for the
preparation of quinazolines from aldehydes, it does not appear
to be a suitable method in the preparation of dihydroquinazolines
from ketones. Apart from the reaction with cyclohexanone,
complex mixtures of several compounds were obtained instead.
the solvent and subsequent elimination of ammonia could then
yield the quinolines 30 (Scheme 8).
This mechanism for formation of quinazoline 24c and
quinoline 30c implied that oxime ether 2 might react on its own,
without any ketone being present, under the usual microwave
reaction conditions in toluene with ionic liquid and ZnCl2. When
this control experiment was carried out, the 2-(4-methylquinazo-
lin-2-yl)aniline 24c was isolated in 41% yield; dihydroquinazo-
line 23c could not be isolated, but a minor peak in the GC/MS
with the correct mass confirmed that it was formed. The
quinoline 30c was also isolated in 18% yield and its identity
confirmed from its NMR spectra.
Ketone 9b is formed either by hydrolysis of imine 9a or by
direct hydrolysis of precursor 2. It should therefore be a minor
component, particularly in the early stages of the reaction. If
the mechanism of Scheme 8 is correct, oxime ether 2 condenses
with 9b to give imine 21c even though 1 equiv of the added
ketone (acetone or acetophenone) is present. A tentative
explanation of this selectivity may be that the aryl-amino group,
as well as imine nitrogen, might interact with the ZnCl2 present
in the reaction medium to favor 21c against intermediates 21b
(or 21a) (Figure 3).
Experimental Section
Typical Procedure for Preparation of O-Phenyl Oximes:
1-(2-Aminophenyl)ethanone O-Phenyl Oxime (2). O-Phenyl
hydroxylamine hydrochloride (2.15 g, 15 mmol) was dissolved in
anhydrous pyridine (40 mL) under N2 at room temperature, and
1-(2-aminophenyl)ethanone (2.0 g, 15 mmol) was added in one
portion. The resulting solution was stirred at rt overnight, and the
progress of the reaction was monitored by TLC (EtOAc/ hexane,
1:2). Upon completion, the reaction mixture was poured into water
(40 mL) and extracted with EtOAc (3 × 30 mL), and the combined
organic phases were washed several times with saturated, aqueous
CuSO4 solution to remove any traces of pyridine. The solution was
then dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (5% EtOAc/
1
hexane) affording a dark orange oil (2.54 g, 76%). H NMR (400
MHz, CDCl3) δ 2.56 (3H, s, CH3), 5.72 (2H, s, NH2), 6.80 (2H,
m, CH), 7.10 (1H, tt, J ) 7.2, 1.1 Hz, CH), 7.22 (1H, t, J ) 7.7
Hz, CH), 7.28 (2H, m, CH), 7.39 (2H, t, J ) 7.2 Hz, CH), 7.49
It was clear from the results described above that reaction of
oxime ether 2 with ketones did not constitute a general method
J. Org. Chem. Vol. 74, No. 14, 2009 4941

Portela-Cubillo et al.
(1H, dd, J ) 7.7, 1.4 Hz, CH); 13C NMR δ 14.1 (CH3), 114.8,
118.8, 117.0 (CH), 117.6 (C), 122.3, 129.4, 129.5, 130.3 (CH),
146.2, 159.4, 160.4 (C); IR 3474, 3345, 1613, 1593 cm-1; HRMS
calcd for C14H15N2O (MH+) 227.1183; found 227.1184.
Typical Procedure for ZnCl2-Promoted Quinazoline Prepa-
rations: 2-(But-3-enyl)-4-methylquinazoline (12a). Pent-4-enal
(36.9 mg, 0.44 mmol) was added to a solution of 1-(2-aminophe-
nyl)ethanone O-phenyl oxime (100 mg, 0.44 mmol) in toluene (0.15
M) containing anhydrous ZnCl2 (17 mg, 0.13 mmol) and emimPF4
(100 mg, 0.46 mmol) in a microwave vessel (2-5 mL). The vessel
was sealed and subjected to microwave irradiation for 30 min at
160 °C in a Biotage Initiator system. After cooling, the ionic liquid
was filtered off, and the toluene was removed under reduced
pressure. The residue was purified by flash column chromatography
(5% EtOAc/hexane), affording the desired product as a yellow oil
Typical Procedure for 4-Methyldihydroquinazoline Prepara-
tions: 2-(But-3-enyl)-4-methyl-1,2-dihydroquinazoline (7a). Pent-
4-enal (37.0 mg, 0.44 mmol) was added to a solution of 1-(2-
aminophenyl)ethanone O-phenyl oxime 2 (100 mg, 0.44 mmol) in
toluene (0.15 M) and emimPF4 (100 mg, 0.46 mmol) in a
microwave vessel (2-5 mL). The vessel was sealed and subjected
to microwave irradiation for 30 min at 160 °C in a Biotage Initiator
system (nominally 300 MHz). After cooling the ionic liquid was
filtered off, and the toluene was removed under reduced pressure.
The residue was purified by flash column chromatography (25%
EtOAc/hexane) affording the desired product as a yellow oil (83.1
mg, 94%). 1H NMR (400 MHz, CDCl3) δ 1.84 (2H, m, CH2), 2.20
(2H, m, CH2), 2.23 (3H, s, CH3), 3.90 (1H, s, NH), 4.77 (1H, t, J
) 5.8 Hz, CH), 4.92 (1H, m, CH2), 5.01 (1H, dq, J ) 17.0, 1.8
Hz, CH2), 5.80 (1H, m, CH), 6.45 (1H, dd, J ) 8.0, 0.8 Hz, CH),
6.63 (1H, td, J ) 7.6, 1.1 Hz, CH), 7.1 (1H, m, CH), 7.21 (1H, dd,
J ) 7.7, 1.3 Hz, CH); 13C NMR δ 21.0 (CH3), 28.11, 34.5 (CH2),
67.9, (CH), 112.9 (CH), 114.1 (CH2), 117.0 (CH), 117.5 (C), 125.3,
1
(79.0 mg, 91%). H NMR (400 MHz, CDCl3) δ 2.60 (2H, q, J )
8.0 Hz, CH2), 2.87 (3H, s, CH3), 3.09 (2H, m, CH2), 4.92-5.01
(2H, m, CH2), 5.88 (1H, m, CH), 7.48 (1H, ddd, J ) 8.2,6.9, 1.2
Hz, CH), 7.76 (1H, ddd, J ) 8.4, 6.9, 1.4 Hz, CH), 7.88 (1H, d, J
) 8.3 Hz, CH), 7.98 (1H, d, J ) 8.3 Hz, CH); 13C NMR δ 22.0
(CH3), 38.8 (CH2), 39.3 (CH2), 115.2 (CH2), 122.5 (C), 125.0, 126.7,
128.5, 133.6 (CH), 137.9 (CH), 149.9, 166.1, 168.1 (C); IR 1617,
1561 cm-1; HRMS calcd for C13H15N2 (MH+) 199.1235: found
199.1234
Acknowledgment. We thank GSK and EaStChem for
financial support and Dr. M. C. Clarke and Prof. R. Morris for
loaning microwave reactors.
131.7 (CH), 137.6 (CH), 144.7, 161.9 (C); IR 3302, 1611 cm-1
HRMS calcd for C13H17N2 (MH+) 201.1392; found 201.1390.
;
Typical Procedure of Oxidation of Dihydroquinazolines to
Quinazolines: 2-(But-3-enyl)-4-methylquinazoline (12a). A solu-
tion of 2-(but-3-enyl)-4-methyl-1,2-dihydroquinazoline (7a) (50 mg,
0.25 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (68 mg,
0.30 mmol) in DCM (4 mL) was placed in a microwave vial and
was irradiated for 10 min at 100 °C. The solvent was removed
under reduced pressure. The residue was purified by column
chromatography (5% EtOAc/hexane), giving the desired product
as a brown oil (49 mg, 83%).
Supporting Information Available: General procedures.
Preparation and characterization of dihydroquinazolines and
quinazolines. 1H and 13C NMR spectra for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO900629G
4942 J. Org. Chem. Vol. 74, No. 14, 2009