Convenient synthetic approach to 2,4-disubstituted quinazolines

Article abstract of DOI:10.1021/ol062540s

(Chemical Equation Presented) 2,4-Dialkyl or aryl quinazolines have been prepared in three steps starting from easily available anilides. A photochemically induced Fries rearrangement of the anilides gave several ortho-aminoacylbenzene derivatives that we

Full text of DOI:10.1021/ol062540s

ORGANIC
LETTERS
2007
Vol. 9, No. 1
69-72
Convenient Synthetic Approach to
2,4-Disubstituted Quinazolines
Serena Ferrini, Fabio Ponticelli, and Maurizio Taddei*
Dipartimento di Chimica and Dipartimento Farmaco Chimico Tecnologico,
UniVersita` degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
taddei.m@unisi.it
Received October 16, 2006
ABSTRACT
2,4-Dialkyl or aryl quinazolines have been prepared in three steps starting from easily available anilides. A photochemically induced Fries
rearrangement of the anilides gave several ortho-aminoacylbenzene derivatives that were acylated at the NH2. These acylamides underwent
rapid cyclization to 2,4-disubstituted quinazolines (and benzoquinazolines) in the presence of ammonium formate under microwave activation.
This procedure is compatible with different functional groups and allowed also the preparation of new quinazolines derived from naturally
occurring amino acids.
Quinazolines have recently been the object of deep inves-
tigation due to their different biological properties. This
heterocycle is present in powerful inhibitors of the epidermal
growth factor (EGF) receptors of tyrosine kinase1 and in
molecules that show remarkable activity as anticancer,2
antiviral,3 and antitubercular agents.4 Quinazolines have also
been employed as ligands for benzodiazepine and GABA
receptors in the CNS system5 or as DNA binders.6
This large interest in medicinal chemistry stimulated the
development of new and more efficient syntheses of this class
of compounds.7 The classical synthetic approach to quinazo-
lines (the Niementowski quinazoline reaction)8 involves the
formation of the intermediate 3(H)-4-quinazolinone (derived
from antranylic acid) followed by formation of 4-chloro-
quinazoline and subsequent nucleophilic aromatic substitution
(1) Klutchko, S. R.; Zhou, H.; Winters, R. T.; Tran, T. P.; Bridges, A.
J.; Althaus, I. W.; Amato, D. M.; Elliott, W. L.; Ellis, P. A.; Meade, M.
A.; Roberts, B. J.; Fry, D. W.; Gonzales, A. J.; Harvey, P. J.; Nelson, J.
M.; Sherwood, V.; Han, H.-K.; Pace, G.; Smaill, J. B.; Denny, W. A.;
Showalter, H. D. H. J. Med. Chem. 2006, 49, 1475 and references therein.
Jung, F. H.; Pasquet, G.; Lambert-van der Brempt, C.; Lohmann, J.-J. M.;
Warin, N.; Renaud, F.; Germain, H.; De Savi, C.; Roberts, N.; Johnson,
T.; Dousson, C.; Hill, G. B.; Mortlock, A. A.; Heron, N.; Wilkinson, R.
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E.; Thompson, K.; Brightwell, S. J. Med. Chem. 2006, 49, 955. Ple, P. A.;
Green, T. P.; Hennequin, L. F.; Curwen, J.; Fennell, M.; Allen, J.; Lambert-
van der Brempt, C.; Costello, G. J. Med. Chem. 2004, 47, 871. Hennequin,
L. F.; Stokes, E. S. E.; Thomas, A. P.; Johnstone, C.; Ple, P. A.; Ogilvie,
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(2) Doyle, L. A.; Ross, D. D. Oncogene 2003, 22, 7340. Henderson, E.
A.; Bavetsias, V.; Theti, D. S.; Wilson, S. C.; Clauss, R.; Jackman, A. L.
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Rajagopalan, R. Bioorg. Med. Chem. Lett. 2002, 12, 2303.
(4) Waisser, K.; Gregor, J.; Dostal, H.; Kunes, J.; Kubicova, L.;
Klimesova, V.; Kaustova, J. Farmaco 2001, 56, 803. Kunes, J.; Bazant, J.;
Pour, M.; Waisser, K.; Slosarek, M.; Janota, J. Farmaco 2000, 55, 725.
(5) Colotta, V.; Catarzi, D.; Varano, F.; Lenzi, O.; Filacchioni, G.;
Costagli, C.; Galli, A.; Ghelardini, C.; Galeotti, N.; Gratteri, P.; Sgrignani,
J.; Deflorian, F.; Moro, S. J. Med. Chem. 2006, 49, 6015. Lewerenz, A.;
Hentschel, S.; Vissiennon, Z.; Michael, S.; Nieber, K. Drug DeV. Res. 2003,
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C.; Henichart, J. P. Bioorg. Med. Chem. 2004, 12, 641.
(7) For the most recent synthetic approaches, see: Roy, A. D.; Subra-
manian, A.; Roy, R. J. Org. Chem. 2006, 71, 382. Yoo, C. L.; Fettinger, J.
C.; Kurth, M. J. J. Org. Chem. 2005, 70, 6941. Shreder, K. R.; Wong, M.
S.; Nomanbhoy, T.; Leventhal, P. S.; Fuller, S. R. Org. Lett. 2004, 6, 3715.
Wiklund, P.; Rogers-Evans, M.; Bergman, J. J. Org. Chem. 2004, 69, 6371.
Costa, M.; Ca, N. D.; Gabriele, B.; Massera, C.; Salerno, G.; Soliani, M. J.
Org. Chem. 2004, 69, 2469. For the most recent microwave-assisted
syntheses of quinazolines, see: Liu, J.-F.; Ye, P.; Zhang, B.; Bi, G.; Sargent,
K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70, 6339.
Yoon, D. S.; Han, Y.; Stark, T. M.; Haber, J. C.; Gregg, B. T.; Stankovich,
S. B. Org. Lett. 2004, 6, 4775.
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(8) Niementowski, S. v. J. Prakt. Chem. 1895, 51, 564.
10.1021/ol062540s CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/07/2006

at the pyrimidine ring.9 Although efficient, this method can
be applied to the preparation of quinazolines substituted in
position 4 with heteroatoms (N, O, S). The introduction of
C substituents in position 4 has been limited to simple alkyl
groups.10 Other syntheses of 2,4-disubstituted quinazolines
have been described starting from substituted anthranilic
acids or o-fluorobenzoyl derivatives.11 As relatively few
examples of these kinds of compounds are available, there
are still limits in preparing 2,4-disubstituted quinazolines with
large molecular diversity.12
Scheme 1
The cyclization of an amide derived from ortho-ami-
nophenone in the presence of ammonia at high temperature
(Bischler’s synthesis) is a potential alternative.13 However,
this reaction has not found a practical application due to the
harsh conditions employed, which are not compatible with
many functional and protecting groups.
Nowadays, microwave (MW) irradiation provides a solu-
tion to reactions that require heating for long periods of
time.14 Following our interest in this field,15 we decided to
explore the possibility to accomplish Bischler’s synthesis of
quinazolines under MW irradiation in the presence of a
source of NH3. Compound 1 was chosen as the model to
find the best reaction conditions. Reaction with aqueous or
ethanolic ammonia did not give any results, whereas the use
of neat HCOONH4 allowed the formation of 10 in good
yields. The reaction was carried out in a sealed vial by mixing
HCOONH4 and 1, heating at 100 °C for 3-6 min, and
maintaining the internal pressure at 150 psi.16 To have good
results, no solvent must be used in the reaction. When we
tried to introduce DMF, H2O, or MeOH to allow the reaction
to be more homogeneous, no trace of 10 was observed even
after prolonged heating. Probably HCOONH4 is decomposed
by the heating, and the NH3 formed generates the imine that
cyclizes in the acid environment due to the presence of excess
ammonium formate (at least 20 equiv). Dehydration induced
by the high temperature and the acid gives the required
quinazoline (Scheme 1).
a General reaction conditions: HCOONH4 (20 equiv), 150 W,
max internal temperature and pressure of 150 °C and 150 psi, 3-
9 min. bYields of isolated compounds. cYields relative to the
d
N-formyl derivative. Yields relative to the NHBoc derivative.
derivative. This product was probably formed by thermic
deprotection of the Boc and further reaction with the formate
ion at high temperature. In the case of compounds 13 and
18 exclusively, the N-CHO derivative was isolated, whereas
for compounds 14, 15, and 17, the N-Boc derivative was
the unique product observed. In the case of compound 16,
the N-Boc product was formed together with minor amounts
(15%) of the N-CHO.17 However, the N-Boc or the N-COH
derivative can be easily deprotected to generate the corre-
sponding amine suitable for further functionalization. To
expand this process to a larger set of molecules, we required
a general method to produce differently substituted o-
aminophenones. Few of them are in fact commercially
available, and their synthesis can be carried out via Friedel-
Crafts acylation of anilines or through multistep procedures
starting from o-nitro aromatics.18
Different amides derived from o-amino acetophenone were
prepared and cyclized, always giving good yields of the
expected products (see Scheme 1). When amides, derived
from N-Boc-protected R-amino acids, were cyclized, we
observed the formation of the corresponding N-formyl
(9) O¨ rfi, L.; Wa´czek, F.; Pato´, J.; Varga, I.; Hegymegi-Barakonyi, B.;
Houghten, R.A.; Ke´ri, G. Curr. Med. Chem. 2004, 11, 2549 and references
therein.
(10) Wiedemann, S. H.; Ellman, J. A.; Bergman, R. G. J. Org. Chem.
2006, 71, 1969. Fekner, T.; Muller-Bunz, H.; Guiry, P. J. Org. Lett. 2006,
8, 5109.
(11) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153.
(12) The reaction of a Grignard reagent with 2-aminobenzonitrile
followed by quenching with acyl chlorides is still the most general approach
to this class of compounds: Bergman, J.; Brynolf, A.; Elman, B.; Vuorinen,
E. Tetrahedron 1986, 42, 3697.
The Fries rearrangement of esters is a useful method for
the preparation of different o-hydroxy phenones with a high
level of diversity at the alkyl substituent and around the
aromatic ring.19 Unfortunately this reaction has not been
largely explored on amides as only few examples of
rearrangements starting from simple acetanilides are de-
(13) Bischler, A. H. Chem. Ber. 1891, 24, 506.
(17) The two products can be separated by flash chromatography.
(18) Im, I.; Webb, T. R.; Gong, Y.-D.; Kim, J.-I.; Kim, Y.-C. J. Comb.
Chem. 2004, 6, 207 and references therein.
(19) Taylor, C. M.; Watson, A. J. Curr. Org. Chem. 2004, 8, 2003. For
recent synthetic applications, see: Hatano, M.; Miyamoto, T.; Ishihara, K.
J. Org. Chem. 2006, 71, 6474. Jayasundera, K. P.; Watson, A. J.; Taylor,
C. M. Tetrahedron Lett. 2005, 46, 4311. Seijas, J. A.; Va´zquez-Tato, M.
P.; Carballido-Reboredo, R. J. Org. Chem. 2005, 70, 2855. Tisserand, S.;
Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem. 2004, 69, 8982.
(14) Kappe, C. O. Chimia 2006, 60, 308. Kappe, C. O.; Dallinger, D.
Nat. ReV. Drug DiscoVery 2006, 5, 51. Kappe, C. O. Angew. Chem., Int.
Ed. 2004, 43, 6250.
(15) For our last paper on the argument, see: Bianchi, I.; Forlani, R.;
Minetto, G.; Peretto, I.; Regalia, N.; Taddei, M.; Raveglia, L. F. J. Comb.
Chem. 2006, 8, 491.
(16) All the experiments under microwave irradiation were carried out
using a Discover System from CEM.
70
Org. Lett., Vol. 9, No. 1, 2007

Table 1. Three-Step Sequence for the Transformation of Anilides into 2,4-Disubstituted Quinazolines
aniline
(yield %)
amide
(yield %)
cyclization
conditions
quinazoline
(yield %)a
entry
1
R1
R2
R3
PhCH2-
TBDMSO-
19
66
20
56
21
55
21
PhCH2CH2-
24
81
25
73
36
80
27
73
28
80
29
72
30
68
31
71
150 W, 150 °C,
100 psi, 4 min
150 W, 150 °C,
100 psi, 16 min
50 W, 150 °C,
100 psi, 9 min
50 W, 150 °C,
100 psi, 10 min
100 W, 150 °C,
100 psi, 16 min
100 W, 150 °C,
100 psi, 18 min
150 W, 150 °C,
100 psi, 16 min
150 W, 150 °C,
100 psi, 9 min
R2 ) OH 32
78
2
3
5
PhCH2CH2-
TBDMSO-
TBDMSO-
TBDMSO-
p-CN-C6H4-
PhCH2CH2-
R2 ) OH 33
76
CH3(CH2)10
CH3(CH2)10
-
-
R2 ) OH 34
60b
CH3(CH2)10
-
R2 ) OH 35
72
R2 ) OH 36
6
7
CH3(CH2)10
CH3(CH2)10
-
-
TBDMSO-
TBDMSO-
21
21
73
o-Cl-C6H4-
Me2CH-
R2 ) OH 37
61c
38
51
39
74d
8
9
PhCH2CH2-
Cl
H
22
56
23
51
MeCH(NHBoc)
CbzNHCH2-
a Yields of compounds isolated by column chromatography on silica gel. b The corresponding OTBDMS derivative was isolated in 15% yield. c The
corresponding OTBDMS derivative was isolated in 18% yield. d When amide 31 was heated at 150 W, 150 °C, and 100 psi for 20 min, the quinazoline 39
with NHCO in the place of the NHBoc group was obtained.
scribed. The reaction takes place by heating in the presence
of corrosive Lewis acids that are not compatible with several
functional and protective groups such as Cbz and Boc.20
Thus, we decided to explore the possibility of doing a
photochemically induced Fries rearrangement on amide,
finding that the reaction could be effectively carried out using
a low-pressure Hg lamp at 254 nm in cyclohexane as the
solvent. Better results were obtained with MeCN, although
the reaction did not go to completion and some starting
material was recovered. The best yields were obtained using
deoxygenated MeCN and irradiating for 24 h at room
temperature. Following this procedure, compounds 19-23
were obtained in acceptable yields (see Table 1).21 Amides
24-30 were obtained by reaction with different acyl
chlorides and Et3N in CH2Cl2. Amide 31 was prepared by
coupling 23 with N-Cbz-GlyOH in the presence of DCC,
DMAP, and Et3N in DMF. These products were submitted
to microwave-assisted cyclization with HCOONH4 that
formed quinazolines 32-39 in acceptable to good yields (see
Table 1).22 During the reaction, the TBDMS protection was
removed and quinazolines 32-37 were isolated with the free
OH. The cyclization seemed to be influenced by the steric
hindrance. When R3 was an aromatic or a branched alkyl
substituent (entries 2 and 6-8), heating for more than 10 min
was necessary to obtain the product. The yields and the
conditions reported in Scheme 1 and Table 1 are relative to
reactions carried out on a 0.1 g scale of starting amides 1-9
and 24-31. However, when cyclization of 24 was repeated
on a 1.0 g scale, quinazoline 32 was isolated in 72% yield
after 20 min of heating (150 W, 150 °C, 100 psi using an
80 mL vial).
Scheme 2
(20) Balkus, K. J., Jr.; Khanmamedova, A. K.; Woo, R. J. Mol. Catal.
A: Chem. 1998, 134, 137. Abdel-Malik, M. M.; de Mayo, P. Can. J. Chem.
1984, 62, 1275. Bradshaw, J. S.; Knudsen, J. S.; Elwood, L. L. J. Org.
Chem. 1970, 35, 1219. Bellus, D.; Schaffner, K.; Higne, J. HelV. Chim.
Acta 1968, 51, 1980. Easwaramurthy, M.; Ravikumar, R.; Lakshmanan, A.
J.; Raju, G. J. Indian J. Chem. Sect. B, Org. Med. Chem. 2006, 44, 635.
(21) Different amounts of the starting material were always observed at
the end of the photo-Fries rearrangement. Increasing the reaction times gave
degradation of the starting material without increasing the formation of the
acetophenone. The yields reported (from 48 to 66%) are calculated without
considering the recovery of the starting material that pushes yields to values
of 65-80%.
(a) TFA/Et3SiH, CH2Cl2, room temperature, 12 h. (b) (R)-1-
Naphthylethylisocyanate, Py, room temperature, 12 h, (86%).
Org. Lett., Vol. 9, No. 1, 2007
71

This synthetic procedure can also be applied to the
synthesis of benzoquinazolines,23 starting from 1-naphthyl-
amine. Amide 41 was prepared and submitted to photo-Fries
rearrangement to give compound 42 that was coupled with
3,3-dimethylbutanoyl chloride and finally cyclized to 44 in
51% overall yield (Scheme 3).
Scheme 3
In conclusion, we have developed a simple and rapid
method for the synthesis of 2,4-disubstituted quinazolines
and benzoquinazolines including enantiomerically pure
quinazolines derived from naturally occurring amino acids.
Moreover, compounds such as 39 can be considered as
conformationally constrained scaffolds for the preparation
of quinazoline arrays for hit discovery.
(a) Low-pressure Hg lamp, 254 nm, MeCN, 36 h, 65%. (b)
Me3CCH2COCl, CH2Cl2, Et3N, room temperature, 2 h (92%). (c)
HCOONH4, microwaves, 150 W, 150 °C, 100 psi, 14 min (86%).
Acknowledgment. The work was financially supported
by the University of Siena as a PAR project 2005.
To verify that racemization did not occur during the photo-
Fries rearrangement and the microwave-assisted cyclization,
the full synthetic procedure was repeated on the anilide derived
from racemic Boc-Val-OH. The Boc was removed from the
quinazoline. (R,S)-15 was obtained, and free amine reacted
with (R)-1-naphthylethylisocyanate to give diastereomeric
(RS,R)-40 (Scheme 2). The 1H NMR 400 MHz spectrum of
(RS,R)-40 showed a marked difference in the resonances of the
methyl groups due to the presence of two diastereoisomers.
When compound (S,R)-40 was prepared using 15, derived
from L-Val, the NMR spectrum showed that racemization
occurred in less than 10%.
Supporting Information Available: Experimental gen-
eral procedure and characterization of compounds 10-23,
32-39, 40, 42, and 44. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL062540S
(22) The effective formation of the quinazoline ring was determined by
ES/MS analysis and by comparison of the 1H NMR spectra with the
corresponding amides.
(23) For a recent synthesis of benzoquinazolines, see: Marzaro, G.;
Chilin, A.; Pastorini, G.; Guiotto, A. Org. Lett. 2006, 8, 255.
72
Org. Lett., Vol. 9, No. 1, 2007