An efficient synthesis of 2,3-diaryl (3H)-quinazolin-4-ones via imidoyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2008.07.091

A practical and efficient three step synthetic route to 2,3-diaryl (3H)-quinazolin-4-ones has been developed. The key step involves microwave-assisted condensation of an imidoyl chloride with an aryl amine. This methodology affords the products cleanly and in high yields.

Full text of DOI:10.1016/j.tetlet.2008.07.091

Tetrahedron Letters 49 (2008) 5840–5842
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Tetrahedron Letters
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An efficient synthesis of 2,3-diaryl (3H)-quinazolin-4-ones via imidoyl chlorides
*
Andrew Kalusa, Nicola Chessum, Keith Jones
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and efficient three step synthetic route to 2,3-diaryl (3H)-quinazolin-4-ones has been devel-
oped. The key step involves microwave-assisted condensation of an imidoyl chloride with an aryl amine.
This methodology affords the products cleanly and in high yields.
Received 5 June 2008
Revised 9 July 2008
Accepted 16 July 2008
Available online 22 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Table 1
The quinazolinone moiety is a widely researched scaffold in
medicinal chemistry. The quinazolinone core is found in a range
of compounds exhibiting a broad spectrum of biological effects.
These include kinase inhibition,1 anticancer,2 antimalarial,3,4 dia-
betes and obesity.5
Over the years, the broad range of biological properties of 2,3-
disubstituted (3H)-quinazolin-4-ones has prompted considerable
synthetic efforts. Although a number of synthetic methodologies
have been reported, accessing 2,3-diaryl (3H)-quinazolin-4-ones
continues to be problematic owing to the limited nucleophilicity
of aromatic amines.6–12
As part of our research programme, we needed to synthesise a
series of 2,3-diaryl (3H)-quinazolin-4-one derivatives. The most
commonly employed method for the synthesis of compounds with
this substitution pattern involves condensation of benzoxazinone 3
with an amine 4 at high temperature13,14 (Scheme 1).
Synthesis of 2,3-diaryl (3H)-quinazolin-4-ones 5 from benzoxazinones 3
Entry
Ar1
Ar2
Yielda of 5 (%)
Productb
1
4
5a
N
N
N
N
2
4
5b
N
NN
3
4
7
5c
N
N
14
5d
5
12
10
5e
5f
Benzoxazinones 3 were synthesised by the reaction of anthra-
nilic acid 1 with an acyl chloride 2 followed by dehydration. Sub-
N
sequent microwave heating of benzoxazinones
3 with an
6
aromatic amine 4 in DMF at 150 °C afforded the 2,3-disubstituted
(3H)-quinazolin-4-one 5 in low yield (Scheme 1). The results are
summarised in Table 1. The low yields obtained via this route were
ascribed to poor nucleophilicity of the aryl amines.
N
a
Isolated yield after flash chromatography and/or prep TLC.
b
All compounds were characterised by 1H NMR, 13C NMR and HRMS.
We also explored methodologies employing the diamide 9 as an
intermediate following studies which were recently reported.15,16
In this procedure, 2,3-dialkyl (3H)-quinazolin-4-ones were pre-
pared by microwave-assisted cyclocondensation of diamides.
A series of diamides 9 was prepared by condensation of the
appropriate amine with isatoic anhydride 6 followed by coupling
of the resulting amine 7 with an acyl chloride 2 or carboxylic acid
8. The isatoic anhydride 6 was prepared by reaction of anthranilic
acid 1 with triphosgene in good yield.17 The diamides 9 were con-
verted to the corresponding 2,3-diaryl (3H)-quinazolin-4-ones by
microwave heating in pyridine at 200 °C for 2 h (Scheme 2). The
yields were low to moderate (Table 2).
O
N
O
O
Ar2
Ar1
(ii)
(i)
N
OH
NH2
O
Ar1
Ar2NH2, 4
Ar1COCl, 2
N
3
1
5
Scheme 1. Reagents and conditions: (i) pyridine, rt or pyridine and then acetic
anhydride, reflux, 40–60% (ii) DMF, 150 °C, microwave.
* Corresponding author. Tel.: +44 208 722 4334; fax: +44 208 722 4047.
E-mail address: keith.jones@icr.ac.uk (K. Jones).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.091

A. Kalusa et al. / Tetrahedron Letters 49 (2008) 5840–5842
5841
tions.19 The resulting amide 11 was subsequently treated with
thionyl chloride to afford imidoyl chloride 12 in quantitative yield.
The imidoyl chloride 12 can be stored under argon and remained
stable for several days. The imidoyl chloride 12 was condensed
with a series of amines 4 in pyridine under microwave heating at
200 °C to afford the desired 2,3-diaryl (3H)-quinazolin-4-ones
(Scheme 3). The results are summarised in Table 3.
O
O
O
(ii)Ar2NH2, 4
Ar2
O
(i)
N
OH
NH2
H
O
N
H
NH2
7
6
1
(iii) Ar1COCl
or Ar1COOH
2
8
O
O
Ar2
Table 3
Ar2
Ar1
N
Synthesis of 2,3-diaryl quinazolin-4-ones 5 from imidoyl chloride 12
(iv)
N
H
Ar1
Ar2
Yielda of 5 (%)
Productb
NH
Entry
N
O
Ar1
1
85
5c
9
5
N
N
N
Scheme 2. Reagents and conditions: (i) triphosgene, THF, 0 °C to rt, 89%; (ii)
dimethylacetamide, 110 °C, DMAP; (iii) triethylamine, CHCl3, 40 °C or HATU, DIPEA,
DMF, rt; (iv) pyridine, microwave, 200 °C, 2 h.
2
3
87
83
5d
5e
Table 2
Synthesis of 2,3-substituted (3H)-quinazolin-4-ones 5 from diamide 9
N
Entry
1
Ar1
Ar2
Yielda of 5 (%)
Productb
4
88
5g
23
5g
N
N
N
N
N
N
5
6
85
79
5i
N
N
2
3
52
35
5h
5i
N
N
Br
O
5k
7
8
77
68
5l
N
N
4
47
5j
OMe
a
Isolated yield after flash chromatography.
b
All compounds were characterised by 1H NMR, 13C NMR and HRMS.
5m
OMe
OMe
Although the second route involving dehydration of diamide 9
gave access to several 2,3-diaryl (3H)-quinazolin-4-ones 5, a more
efficient and general route was sought. We were attracted by
recent work reported by a group at Albany Molecular Research.18
They described a highly stereoselective synthesis of 2,3-disubsti-
tuted (3H)-quinazolin-4-ones involving reaction of an imidoyl
chloride with a chiral amino acid. We envisaged that we could syn-
thesise 2,3-diaryl (3H)-quinazolin-4-one derivatives by reacting an
imidoyl chloride with aryl amines and subsequent ring closure.
The imidoyl chloride 12 was synthesised by acylation of methyl
anthranilate 10 with an acyl chloride 2 under standard condi-
9
74
5n
N
N
10
11
87
64
5o
5p
N
N
12
13
66
51
5q
5r
O
O
N
N
O
O
O
(i)Ar1COCl, 2
(ii)
N
N
NH2
NH
Ar1
10
11
O
14
15
80
40
75
5s
5t
5v
O
O
N
O
Br
Ar2
(iii) Ar2NH2
N
N
N
N
N
Ar1
nBu
Ar1
Cl
5
16
12
a
Isolated yield after flash chromatography.
Scheme 3. Reagents and conditions: (i) CHCl3, triethylamine, 40 °C, (ii) thionyl
chloride, reflux, (iii) pyridine, microwave, 200 °C.
b
Characterised by 1H NMR, 13C NMR and HRMS.

5842
A. Kalusa et al. / Tetrahedron Letters 49 (2008) 5840–5842
4. Takeuchi, Y.; Koike, M.; Azuma, K.; Nishioka, H.; Abe, H.; Kim, H.-S.; Wataya, Y.;
As shown in Table 3, both aromatic and heteroaromatic amines
Harayama, T. Chem. Pharm. 2001, 49, 721–725.
underwent cyclocondensation with imidoyl chlorides 12 in good to
excellent yields. Anilines carrying electron-withdrawing groups
gave good yields (entry 6). Weakly nucleophilic aminopyridines
also reacted successfully (entry 10) even when sterically hindered
(entry 4). 5-Bromo-2-aminopyridine (Table 3, entry 15) gave only a
moderate yield, possibly due to the presence of an electron-with-
drawing bromine in the 5 position. The presence of a methyl group
ortho to the amino group did not affect cyclocondensation (Table 3,
entries 4 and 5). In contrast to the microwave reaction, conven-
tional heating of the imidoyl chloride 12 with an aromatic amine
under reflux for 24 h gave the corresponding 2,3-diaryl (3H)-qui-
nazolin-4-ones in low yields along with side products. This new
method offers a considerable improvement in yields in comparison
to the previous two routes discussed. For example, compounds 5c
and 5e were obtained in 85% and 83% yields, respectively, from the
corresponding imidoyl chloride. Using the previously reported
routes, yields of only 7% and 12%, respectively, were obtained.
In summary, we have developed a practical and efficient route
to 2,3-diaryl (3H)-quinazolin-4-ones. The key step is the cyclocon-
densation of imidoyl chloride 12 with an aryl amine using micro-
wave conditions.19 This procedure was used to synthesise a
series of 2,3-diaryl substituted (3H)-quinazolin-4-ones for biologi-
cal screening in our research programme.
5. Rudolph, J.; Esler, W. P.; O’Connor, S.; Coish, P. D. G.; Wickens, P. L.; Brands, M.;
Bierer, D. E.; Bloomquist, B. T.; Bondar, G.; Chen, L.; Chuang, C.-Y.; Claus, T. H.;
Fathi, Z.; Fu, W.; Khire, U. R.; Kristie, J. A.; Liu, X.-G.; Lowe, D. B.; McClure, A. C.;
Michels, M.; Ortiz, A. A.; Ramsden, P. D.; Schoenleber, R. W.; Shelekhin, T. E.;
Vakalopoulos, A.; Tang, W.; Wang, L.; Yi, L.; Gardell, S. J.; Livingston, J. N.;
Sweet, L. J.; Bullock, W. H. J. Med. Chem. 2007, 50, 5202–5216.
6. Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.; Kim, H. S.; Wataya, Y.;
Harayama, T. Tetrahedron 2001, 57, 1213–1218.
7. Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773–2777.
8. Wang, L.; Xia, J.; Qin, F.; Qian, C.; Sun, J. Synthesis 2003.
9. Xue, S.; McKenna, J.; Shieh, W.-C.; Repic, O. J. Org. Chem. 2004, 69, 6474–
6477.
10. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh, M. Tetrahedron Lett. 2005,
46, 7051–7053.
11. Errede, L. A. J. Org. Chem. 1976, 41, 1763–1765.
12. Komaraiah, A.; Sailu, B.; Reddy, P. S. N. Synth. Commun. 2008, 38, 114–
121.
13. Shcherbakova, I.; Balandrin, M. F.; Fox, J.; Ghatak, A.; Heaton, W. L.; Conklin, R.
L. Bioorg. Med. Chem. Lett. 2005, 15, 1557–1560.
14. Wang, S.; Ryder, H.; Pretswell, I.; Depledge, P.; Milton, J.; Hancox, T. C.; Dale, I.;
Dangerfield, W.; Charlton, P.; Faint, R.; Dodd, R.; Hassan, S. Bioorg. Med. Chem.
Lett. 2002, 12, 571–574.
15. Liu, J.-F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.; McElory, E.; Brown,
M. Tetrahedron Lett. 2005, 46, 1241–1244.
16. Kostakis, I. K.; Elomri, A.; Seguin, E.; Iannelli, M.; Besson, T. Tetrahedron Lett.
2007, 48, 6609–6613.
17. Coppola, Gary M. Synthesis 1980, 505–536.
18. Zhichkin, P.; Kesicki, E.; Treiberg, J.; Bourdon, L.; Ronsheim, M.; Ooi, H. C.;
White, S.; Judkins, A.; Fairfax, D. Org. Lett. 2007, 9, 1415–1418.
19. General procedure for synthesis of imidoyl chloride 12: Thionyl chloride (5 mL)
was added to methyl 2-(picolinamido)benzoate (0.36 g, 1.4 mmol), and the
resulting mixture was heated at 70 °C for 24 h. The excess thionyl chloride was
removed under reduced pressure, and the crude product was dried under high
vacuum at 70 °C for 30 min to afford a pale yellow solid in quantitative yield.
General procedure for synthesis of 2,3-diarylsubstituted quinazolin-4-ones:
Pyridine (1.5 mL) was added to imidoyl chloride 12 (0.328 g, 1.19 mmol) and
p-toluidine (0.191 g, 1.78 mmol), and the resulting mixture was heated at
200 °C in a Biotage Initiator SixtyTM microwave for 30 min. The excess pyridine
was removed under reduced pressure, and the residue was purified by flash
chromatography (silica; DCM–ether; 1:1) to afford 2-(pyridin-2-yl)-3-p-
tolylquinazolin-4(3H)-one 5e (0.31 g, 83%), as a white solid: mp 206–207 °C;
dH (500 MHz; CDCl3); 2.31 (3H, s, methyl C–H), 7.07–7.11 (4H, m, aryl C–H),
7.21 (1H, dd, J = 7.8, 4.8 Hz, aryl C–H), 7.52 (1H, d, J = 7.8 Hz, aryl C–H), 7.59
(1H, t, J = 7.8 Hz, aryl C–H), 7.67 (1H, m, aryl C–H), 7.85 (1H, m, aryl C–H), 7.90
(1H, d, J = 7.9 Hz, aryl C–H), 8.41 (1H, d, J = 7.9 Hz, aryl C–H), 8.46 (1H, d,
J = 4.8 Hz, aryl C–H); dC (125 MHz; CDCl3) 21.1(CH3), 121.5, 123.8, 124.4, 127.3,
127.7, 127.8, 128.7, 129.5, 134.6, 134.7, 136.5, 138.3, 147.1, 148.8, 153.1, 153.4,
162.1 (C@O); LCMS (ESI): Rt = 4.14 min: m/z 314.12 ([M+H]+, 100%); HRMS
found 314.1278, C20H16N3O [M+H]+ requires 314.1288.
Acknowledgements
This work was supported by Cancer Research UK [CRUK]
programme grant number CC309/A8274. We also thank Dr. Amin
Mirza and Mr Meirion Richards for their assistance with NMR
and mass spectrometry.
References and notes
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