Solvent-free reaction between anthranilic acids and isocyanides: A novel approach for the synthesis of 2-unsubstituted 4(3 H)-quinazolinones

Article abstract of DOI:10.1055/s-0030-1259909

A novel synthesis of 2-unsubstituted 4(3H)-quinazolinones is described. Heating a mixture of an anthranilic acid and an isocyanide under solvent-free conditions afforded the title compounds in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259909

8
34
LETTER
Solvent-Free Reaction between Anthranilic Acids and Isocyanides: A Novel
Approach for the Synthesis of 2-Unsubstituted 4(3H)-Quinazolinones
a
a
a
a
b
S
M
ynthesis of 2-Unsubst
e
ituted 4(
3
H
h
)-Quinazolin
d
ones i Adib,* Morteza Karimzadeh, Mohammad Mahdavi, Ehsan Sheikhi, Peiman Mirzaei
a
School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
Fax +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
b
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Received 5 October 2010
methods for the synthesis of 4(3H)-quinazolinones are
therefore desirable.
Abstract: A novel synthesis of 2-unsubstituted 4(3H)-quinazolino-
nes is described. Heating a mixture of an anthranilic acid and an iso-
cyanide under solvent-free conditions afforded the title compounds There are several reports in literature concerning the reac-
in good to excellent yields.
tion between carboxylic acids and isocyanides in different
2
0
Key words: anthranilic acids, isocyanides, 2-unsubstituted 4(3H)- conditions leading to various amide types, amidine car-
quinazolinones, solvent-free synthesis, cyclizations, heterocycles
2
1
22
22
bocations, imidic structures, N-thioacetal amides, 3-
aryl-2-acyloxyacrylamides,23 and formimidate carboxy-
late mixed anhydride intermediates.24
4
(3H)-Quinazolinones, an important class of fused het-
There is only one report in the literature concerning syn-
thesis of quinazolinones from isocyanides. Descotes et al.
1
,2
erocyclic compounds, have attracted much synthetic at-
tention because of their wide range of pharmacological
and therapeutic activities such as anticancer, anti-inflam-
reported the HgCl -catalyzed reaction of a glycosyl isocy-
2
3
anide with methyl anthranilate leading to the correspond-
4
5
6
7
matory, anticonvulsant, antiulcer, and hypolipidemic.
25
ing glycosyl quinazolinone.
Some quinazolinones have been reported as potent che-
motherapeutic agents in the treatment of tuberculosis.8
Knowing the chemical and pharmacological importance
of the 4(3H)-quinazolinones and as part of our continuing
efforts on the development of new routes for the prepara-
The bioactive natural products, febrifugine and isofebri-
fugine, contain a quinazolinone moiety and possess anti-
malarial activity.
26
9
,10
tion of biologically active heterocyclic compounds, very
recently we have reported a solvent- and catalyst-free
reaction between the in situ generated amidoximes and
anthranilic acids, which resulted in 2-aryl/alkyl-4(3H)-
The importance of 2-unsubstituted 4-(arylamino)quinazo-
1
1
lines as tyrosine kinase inhibitors has meant that many
different syntheses of the 2-unsubstituted 4(3H)-
quinazolinone precursors have been performed during the
recent decade. The original Niementowski route to 2-un-
substituted 4(3H)-quinazolinones involved heating an-
thranilic acids with formamide. This procedure was then
improved by use of formamidine acetate under thermal
conditions and microwave irradiation. Other synthetic
approaches to the 2-unsubstituted 4(3H)-quinazolinones
involve dimerization of anthranilic acids under Vilsmeier
conditions, reductive cyclization of 2-azido/2-nitroben-
zoic acids by Zn–HCO NH under microwave irradia-
tion, reaction of anthranilic acid, trialkyl orthoformate,
and amines in the presence of La(NO ) ·6H O, p-tolu-
enesulfonic acid,
27
quinazolinones. Herein we report a novel synthesis of 2-
unsubstituted 4(3H)-quinazolinones. Thus, a mixture of
an anthranilic acid (1) and an isocyanide 2 was heated at
1
50 °C under solvent-free conditions to produce the cor-
responding 4(3H)-quinazolinones 3a–l in 76–92% yields
Table 1). All the reactions went to completion within two
1
2
(
1
3
14
1
hours. H NMR analysis of the reaction mixtures clearly
indicated formation of the c2o8rresponding 4(3H)-
quinazolinones in excellent yields.
1
5
The isolated products 3 were characterized on the basis of
2
4
1
1
6
mass spectrometry, elemental analysis, IR, H NMR, and
1
3
1
7
C NMR spectroscopy,. The IR spectrum of 3l showed an
3
3
2
–
1
1
7
absorption at 1662 cm indicative of an amide function-
Bi(TFA)
immobilized on
3
1
8
19
ality. The mass spectrum of 3l displayed the molecular ion
[
nbp]FeCl4 or silica gel/FeCl . However, most of these
3
+
[
(
M ] peaks at m/z = 294 and 292, which are 18 mass units
multistep procedures have significant drawbacks such as
long reaction times, low yields of the products, harsh re-
action conditions, difficult workup, and use of expensive
and environmentally toxic catalysts, reagents, or media.
Furthermore, some of the starting materials have to be
synthesized and purified first, hence these methods are
time-consuming. The development of simple and efficient
H O) lower than that of the 1:1 adduct of 2-amino-5-
2
chlorobenzoic acid and 1,1,3,3-tetramethylbutyl isocya-
1
nide. The H NMR spectrum of 3l exhibited three sharp
singlets arising from the CMe (d = 0.81 ppm), CMe (d =
3
2
1
.75 ppm), methylene (d = 2.22 ppm) groups and the C2H
of the quinazolinone ring (d = 8.26 ppm) along with char-
acteristic signals with appropriate chemical shifts and
coupling constants for the other three aromatic H atoms.
1
13
SYNLETT 2011, No. 6, pp 0834–0836
Advanced online publication: 15.03.2011
DOI: 10.1055/s-0030-1259909; Art ID: D26810ST
©
x
x.
x
x.
2
0
1
1
The H-decoupled C NMR spectrum of 3l showed char-
acteristic signals for the tetramethylbutyl {d = 30.00
[
C(CH ) ], 31.24 [C(CH ) ], 31.93 [C(CH ) ], 48.88
3 2 3 3 3 3
Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Unsubstituted 4(3H)-Quinazolinones
835
(
CH ), 64.76 [C(CH ) ] ppm} substituent. Four signals 6, which may be cyclized under the reaction conditions to
2
3 2
were observed for the three CH of the phenylene moiety produce the isolated 4(3H)-quinazolinones 3.
and the C2H of the quinazolinone ring. The carbonyl
In conclusion, we have developed a novel reaction be-
tween anthranilic acids and isocyanides for the prepara-
tion of 4(3H)-quinazolinones, which are of potential
synthetic and pharmacological interest. Simple and readi-
ly available starting materials, good to excellent yields of
the products, fairly fast reaction times, neutral reaction
conditions, and solvent- and catalyst-free conditions are
the main advantages of this reaction. We believe this ex-
perimentally simple approach could be a useful addition
to the quinazolinones syntheses so far reported.
group resonated at d = 161.41 ppm and the other three
quaternary carbon atoms of the quinazolinone ring were
2
8
observed at appropriate chemical shifts.
Table 1 Synthesis of 4(3H)-Quinazolinones 3a–l
O
N
CO2H
R
solvent-free
N
X
+
RNC
X
150 °C, 2 h
NH2
1
2
3
a
Yield (%)b
Compd 3 R
X
Acknowledgment
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
cyclohexyl
H
90
91
92
87
90
86
90
92
87
82
85
76
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
t-Bu
H
1,1,3,3-tetramethylbutyl
cyclohexyl
H
References and Notes
4-Me
4-Me
4-Me
5-Me
5-Me
5-Me
5-Cl
5-Cl
5-Cl
(
1) (a) Rewcastle, G. W. In Comprehensive Heterocyclic
Chemistry III, Vol. 8; Katritzky, A. R.; Ramsden, C. A.;
Scriven, E. F. V.; Taylor, R. J. K., Eds.; Elsevier Science:
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t-Bu
1,1,3,3-tetramethylbutyl
cyclohexyl
g
h
i
t-Bu
(
(
(
(
1,1,3,3-tetramethylbutyl
cyclohexyl
j
k
l
t-Bu
5) Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.;
3
1,1,3,3-tetramethylbutyl
Greenwood, T. D. J. Med. Chem. 1990, 33, 161.
a
(6) Tereshima, K.; Shimamura, H.; Kawase, A.; Tanaka, Y.;
Tanimura, T.; Kamisaki, T.; Ishizuka, Y.; Sato, M. Chem.
Pharm. Bull. 1995, 43, 2021.
Compounds 3a–i were purified by precipitation in acetone from the
reaction mixture and then recrystallization from n-hexane–EtOAc;
and compounds 3j–l were purified by column chromatography using
2
8,
(7) Kurogi, Y.; Inoue, Y.; Tsutsumi, K.; Nakamura, S.; Nagao,
n-hexane–EtOAc (3:1) as eluent.
b
Isolated yield.
K.; Yohsitsugu, H.; Tsuda, Y. J. Med. Chem. 1996, 39, 1433.
8) Kuneš, J.; Bažant, J.; Pour, M.; Waisser, K.; Šlosárek, M.;
(
Janota, J. Farmaco 2000, 55, 725.
A mechanistic rationalization for this reaction is provided
in Scheme 1. On the basis of the well-established chemis-
(9) (a) Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.; Lu, G.;
Thou, T. C. Science 1946, 103, 59. (b) Koepfli, J. B.; Mead,
J. F.; Brockman, J. A. Jr. J. Am. Chem. Soc. 1947, 69, 1837.
10) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.
Tetrahedron Lett. 1999, 40, 2175.
2
9
try of isocyanides, it is reasonable to assume that the
(3H)-quinazolinones 3 result from initial protonation of
(
(
4
the isocyanide 2 by the anthranilic acid 1. Subsequent nu-
cleophilic attack of the conjugate base of the acid 4 from
amino group of the anthranilate to the isonitrilium cation
11) (a) Bridges, A. J. Chem. Rev. 2001, 101, 2541.
(b) Rewcastle, G. W.; Denny, W. A.; Showalter, H. D. H.
Curr. Org. Chem. 2000, 4, 679. (c) Bridges, A. J. Curr.
Med. Chem. 1999, 6, 825.
5
may form the iminomethyl anthranilic acid intermediate
(
12) Niementowski, S. V. J. Prakt. Chem. 1895, 51, 564.
CO2H
CO2–
(13) (a) Ballard, P.; Bradbury, R. H.; Harris, C. S.; Hennequin,
L. F. A.; Hickinson, M.; Johnson, P. D.; Kettle, J. G.;
Klinowska, T.; Leach, A. G.; Morgentin, R.; Pass, M.;
Ogilvie, D. J.; Olivier, A.; Warin, N.; Williams, E. J. Bioorg.
Med. Chem. Lett. 2006, 16, 1633. (b) Gomtsyan, A.;
Bayburt, E. K.; Schmidt, R. G.; Zheng, G. Z.; Perner, R. J.;
Didomenico, S.; Koenig, J. R.; Turner, S.; Jinkerson, T.;
Drizin, I.; Hannick, S. M.; Macri, B. S.; McDonald, H. A.;
Honore, P.; Wismer, C. T.; Marsh, K. C.; Wetter, J.; Stewart,
K. D.; Oie, T.; Jarvis, M. F.; Surowy, C. S.; Faltynek, C. R.;
Lee, C. H. J. Med. Chem. 2005, 48, 744. (c) Rocco, S. A.;
Barbarini, J. E.; Rittner, R. Synthesis 2004, 429.
+
N
+
R
C–
+
NH2
NH2 HC
N
R
R
1
2
4
5
O
N
CO2H
R
N
N
–
H2O
N
H
H
6
3
Scheme 1
Synlett 2011, No. 6, 834–836 © Thieme Stuttgart · New York

8
36
M. Adib et al.
LETTER
chromatography using n-hexane–EtOAc (3:1) as eluent.
(
14) (a) Alexandre, F. R.; Berecibar, A.; Wrigglesworth, R.;
Besson, T. Tetrahedron Lett. 2003, 44, 4455.
3-Cyclohexyl-4(3H)-quinazolinone (3a)
Yield 0.41g (90%); colorless crystals; mp 126–127 °C. IR
(KBr): 1659 (C=O), 1596, 1564, 1468, 1399, 1334, 1240,
(
b) Alexandre, F. R.; Berecibar, A.; Besson, T. Tetrahedron
Lett. 2002, 43, 3911.
–
1 1
(
(
15) Majo, V. J.; Perumal, P. T. Tetrahedron Lett. 1996, 37, 5015.
16) Kamal, A.; Reddy, K. S.; Prasad, B. R.; Babu, A. H.;
Ramana, A. V. Tetrahedron Lett. 2004, 45, 6517.
17) Narasimhulu, M.; Mahesh, K. C.; Reddy, T. S.; Rajesh, K.;
Venkateswarlu, Y. Tetrahedron Lett. 2006, 47, 4381.
18) Khosropour, A. R.; Mohammadpoor-Baltork, I.;
Ghorbankhani, H. Tetrahedron Lett. 2006, 47, 3561.
19) Chari, M. A.; Shobha, D.; Mukkanti, K. Catal. Commun.
1172, 1132, 1024, 956, 894, 805, 766, 695 cm . H NMR
(300.1 MHz, CDCl ): d = 1.20–2.04 [m, 10 H, CH(CH ) ],
3
2 5
4.77–4.86 [m, 1 H, CH(CH ) ], 7.49 (dd, J = 7.2, 7.4 Hz, 1
2
5
(
(
(
(
H, CH), 7.68 (d, J = 7.6 Hz, 1 H, CH), 7.74 (dd, J = 7.0, 7.9
Hz, 1 H, CH), 8.12 (s, 1 H, CH), 8.31 (d, J = 8.0 Hz, 1 H,
1
3
CH). C NMR (75.5 MHz, CDCl ): d = 25.27, 25.89 and
3
32.60 (3 × CH ), 53.54 (NCH), 121.93 (C), 126.95, 127.10,
2
127.24, 134.10 and 143.91 (5 × CH), 147.50 (C), 160.70
+
2006, 7, 787.
(C=O). MS (EI): m/z (%) = 228 (24) [M ], 192 (7), 181 (5),
20) (a) Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron
Lett. 2007, 48, 6137. (b) Stockdill, J. L.; Wu, X.;
171 (4), 160 (7), 147 (100), 129 (8), 118 (10), 102 (5), 90 (7),
77 (9), 67 (14), 55 (16), 41 (22). Anal. Calcd for C H N O
1
4
16
2
Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 5152.
21) Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Keshipour, S.;
Khavasi, H. R. Tetrahedron Lett. 2010, 51, 4091.
(228.29): C, 73.66; H, 7.06; N, 12.27. Found: C, 73.6; H, 7.2;
N, 12.1.
(
(
(
(
6-Chloro-3-cyclohexyl-4(3H)-quinazolinone (3j)
Yield 0.43 g (82%); colorless crystals; mp 137–138 °C.
IR (KBr): 1668 (C=O), 1597, 1552, 1465, 1388, 1358, 1320,
22) Wu, X.; Li, X.; Danishefsky, S. J. Tetrahedron Lett. 2009,
50, 1523.
–
1 1
23) Basso, A.; Banfi, L.; Galatini, A.; Guanti, G.; Rastrelli, F.;
Riva, R. Org. Lett. 2009, 11, 4068.
24) (a) Li, X.; Yuan, Y.; Berkowitz, W. F.; Todaro, L. J.;
1240, 1137, 1072, 1022, 947, 895, 822, 775 cm . H NMR
(300.1 MHz, CDCl ): d = 1.25–1.97 [m, 10 H, CH(CH ) ],
3
2 5
4.76–4.84 [m, 1 H, CH(CH ) ], 7.60 (d, J = 8.8 Hz, 1 H,
2 5
Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 13222.
CH), 7.63 (dd, J = 2.1, 8.8 Hz, 1 H, CH), 8.11 (d, J = 2.1 Hz,
1 H, CH), 8.26 (s, 1 H, CH). C NMR (75.5 MHz, CDCl3):
1
3
(b) Hou, J. L.; Ajami, D.; Rebek, J. Jr. J. Am. Chem. Soc.
2
008, 130, 7810. (c) Restorp, P.; Rebek, J. Jr. J. Am. Chem.
d = 25.22, 25.28, and 32.56 (3 × CH ), 53.59 (NCH), 122.97
2
Soc. 2008, 130, 11850.
(C), 126.30 and 128.95 (2 × CH), 132.88 (C), 134.52 and
144.08 (2 × CH), 146.02 (C), 159.68 (C=O). MS (EI): m/z
(
(
25) Marmet, D.; Boullanger, P.; Descotes, G. Tetrahedron Lett.
(%) = 264 (8) [M+ Cl], 262 (22) [M Cl], 228 (5), 205 (3),
181 (100), 163 (4), 147 (18), 136 (7), 124 (5), 110 (5), 97 (4),
82 (9), 67 (20), 55 (18), 41 (23). Anal. Calcd for
37
+ 35
1
980, 21, 1459.
26) (a) Adib, M.; Ansari, S.; Feizi, S.; Bijanzadeh, H. R. Synlett
010, 921. (b) Adib, M.; Ansari, S.; Fatemi, S.; Bijanzadeh,
2
H. R.; Zhu, L. G. Tetrahedron 2010, 66, 2723. (c) Adib,
M.; Ansari, S.; Feizi, S.; Asgarian Damavandi, J.; Mirzaei,
P. Synlett 2009, 3263. (d) Adib, M.; Mahdavi, M.; Ansari,
S.; Malihi, F.; Zhu, L. G.; Bijanzadeh, H. R. Tetrahedron
Lett. 2009, 50, 7246. (e) Adib, M.; Sheibani, E.; Bijanzadeh,
H. R.; Zhu, L. G. Tetrahedron 2008, 64, 10681. (f) Adib,
M.; Sayahi, M. H.; Ziyadi, H.; Zhu, L. G.; Bijanzadeh, H. R.
Synthesis 2008, 3289. (g) Adib, M.; Mohammadi, B.;
Bijanzadeh, H. R. Synlett 2008, 3180. (h) Adib, M.;
Mohammadi, B.; Bijanzadeh, H. R. Synlett 2008, 177.
C H ClN O (262.74): C, 64.00; H, 5.75; N, 10.66. Found:
C, 63.9; H, 5.7; N, 10.6.
6-Chloro-3-(1,1,3,3-tetramethylbutyl)-4(3H)-
quinazolinone (3l)
1
4
15
2
Yield 0.44 g (76%); colorless crystals; mp 118–119 °C.
IR (KBr): 1662 (C=O), 1592, 1560, 1467, 1362, 1324, 1285,
–
1 1
1219, 1128, 1075, 918, 835, 805, 754, 712 cm . H NMR
(500.1 MHz, CDCl ): d = 0.81 [s, 9 H, C(CH ) ], 1.75 [s, 6
3
3 3
H, C(CH ) ], 2.22 (s, 2 H, CH ), 7.56 (d, J = 8.9 Hz, 1 H,
3
2
2
CH), 7.60 (dd, J = 2.2, 8.9 Hz, 1 H, CH), 8.20 (d, J = 2.2 Hz,
1
3
(
i) Adib, M.; Sayahi, M. H.; Ziyadi, H.; Bijanzadeh, H. R.;
1 H, CH), 8.26 (s, 1 H, CH). C NMR (125.8 MHz, CDCl3):
Zhu, L. G. Tetrahedron 2007, 63, 11135.
27) Adib, M.; Ansari, S.; Mohammadi, A.; Bijanzadeh, H. R.
Tetrahedron Lett. 2010, 51, 30.
d = 30.00 [C(CH ) ], 31.24 [C(CH ) ], 31.93 [C(CH ) ],
3
2
3 3
3 3
(
(
48.88 (CH ), 64.76 [C(CH ) ], 124.13 (C), 126.23 and
2 3 2
128.55 (2 × CH), 132.66 (C), 134.34 and 144.84 (2 × CH),
+
28) General Procedure for the Preparation of Compounds
145.85 (C), 161.41 (C=O). MS (EI): m/z (%) = 294 (1) [M
3
7
+ 35
3a–l
Cl], 292 (3) [M Cl], 235 (8), 180 (100), 163 (9), 153 (8),
A mixture of the appropriate anthranilic acid (2 mmol) and
isocyanide (2.2 mmol) was stirred at 150 °C for 2 h. Progress
of the reaction was indicated by TLC monitoring. Next, the
reaction mixture was cooled to r.t. and acetone (2 mL) was
added, and stirring was continued for 10 min at ambient
temperature. The precipitate was filtered and washed with
cold acetone (2 mL), and the product was recrystallized from
n-hexane–EtOAc (1:1). Compounds 3a–i were purified by
this procedure, and compounds 3j–l were purified by column
138 (7), 124 (6), 112 (26), 97 (68), 69 (10), 57 (54), 41 (31).
Anal. Calcd for C H ClN O (292.81): C, 65.63; H, 7.23; N,
9.57. Found: C, 65.7; H, 7.4; N, 9.4.
1
6
21
2
(29) (a) Dömling, A. Chem. Rev. 2006, 106, 17. (b) Dömling,
A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3169. (c)Ugi,I.
Isonitrile Chemistry; Academic Press: London, 1971.
(d) Walborsky, H. M.; Periasamy, M. P. In The Chemistry of
Functional Groups, Suppl. C; Patai, S.; Rappaport, Z., Eds.;
Wiley: New York, 1983, Chapt. 20, 835–837.
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