Efficient solid-phase synthesis of quinazoline-2-thioxo-4-ones with SynPhase(TM) lanterns

Article abstract of DOI:10.1016/S0040-4039(00)01442-8

We wish to report the efficient solid-phase synthesis of diverse quinazoline-2-thioxo-4-ones using SynPhase(TM) lanterns as solid supports. Although target compounds were obtained only with low purity using Wang resin, lanterns derivatized with long chain

Full text of DOI:10.1016/S0040-4039(00)01442-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8333–8337
Efficient solid-phase synthesis of quinazoline-2-thioxo-4-ones
with SynPhase™ lanterns
Shingo Makino,* Nobuyasu Suzuki, Eiji Nakanishi and Takashi Tsuji
Pharmaceutical Research Laboratories, Ajinomoto Co., Inc. 1-1, Suzuki-cho, Kawasaki-ku,
Kawasaki-shi 210-8681, Japan
Received 26 July 2000; revised 21 August 2000; accepted 25 August 2000
Abstract
We wish to report the efficient solid-phase synthesis of diverse quinazoline-2-thioxo-4-ones using
SynPhase™ lanterns as solid supports. Although target compounds were obtained only with low purity
using Wang resin, lanterns derivatized with long chain hydroxymethyl phenoxy linkers successfully gave
products with high purity. Furthermore, subsequent reactions of quinazoline-2-thioxo-4-ones with various
types of halides gave S-alkylated or S-arylated products with high purity, showing the usefulness of this
chemistry for synthesizing diverse quinazoline-2-thioxo-4-one libraries. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: solid-phase synthesis; quinazolines; isothiocyanates; alkylation; arylation.
Combinatorial chemistry for the synthesis of non-peptide organic compounds has emerged as
an important tool for drug discovery.1 Solid-phase synthesis of substituted heterocyclic com-
pounds has been focussed on in particular, because of their application toward a variety of drug
targets. Among various heterocycles, we were particularly interested in the synthesis of quinazo-
lines, which have shown a wide range of pharmacological activities.2 Although there have been
reports of the solid-phase synthesis of quinazolidine-2, 4-diones3 and quinazolinones,4 a synthesis
strategy to produce a wide range of quinazoline-2-thioxo-4-ones has not been reported.4b Here,
we report the solid-phase synthesis of diverse quinazoline-2-thioxo-4-ones.
Initially, the synthesis of quinazoline-2-thioxo-4-ones 7 was attempted by reaction of 4-
aminobenzoic ester 3 and 2-methoxycarbonyl phenylisothiocyanate 4 on Wang resin5 (Scheme 1).
In contrast to quinazolidine-2,4-dione synthesis using 2-methoxycarbonyl phenylisocyanate,3b
intermediate 5 smoothly cyclized without subsequent base treatment to give quinazoline-2-
thioxo-4-one 6. However, cleavage of the products with 95% TFA/H2O gave a mixture of 7 and 8.
* Corresponding author. Tel: +81-44-210-5822; fax: +81-44-210-5871; e-mail: shingo makino@ajinomoto.com
–
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01442-8

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Scheme 1. Strategy for synthesis of quinazoline-2-thioxo-4-ones on solid supports
Since the Wang resin used in the synthesis possesses a p-benzyloxybenzyl ester moiety in its
linker, the p-hydroxybenzyl cation that was released from the Wang resin in the process of the
cleavage alkylated the sulfur atom in the product. Although water molecules in the cleavage
solution usually work well for scavenging such cations, the scavenging capability was not
sufficient for compounds with moieties highly susceptible to alkylation such as thioureas. Thus,
it was necessary to evaluate other types of solid support in order to minimize the S-alkylated
byproducts. Among several Wang derivatized solid supports6 that should not generate such
S-alkylated byproducts 8, we decided to use SynPhase™ lantern (long-chain HMP),7 because (1)
it possesses stable p-hydroxymethylphenoxy valeric amide as a linker, therefore, the generation
of p-hydroxybenzyl cation would be unlikely, (2) quantification of products is easier than with
small particle resin and (3) it is easy to remove insoluble remnants of reagents after reactions.
(Because lanterns do not require small mesh filtration for washing.) Several types of polymer-
supported amines synthesized from the corresponding nitrobenzenes were converted into quina-
zoline-2-thioxo-4-ones 7 in excellent purity8 (Scheme 2, Table 1). In the case of hindered
2-aminocinnamic acid on solid support (entry 4), the cyclization did not occur at all after the
thiourea formation. The cyclization proceeded with 20% piperidine/DMF treatment to give the
quinazoline-2-thioxo-4-one derivative in high purity. The yields were not high probably because
the product was partly captured by benzyl cation on lanterns.

8335
Scheme 2.
Table 1
Synthesis of quinazoline-2-thioxo-4-ones from various aniline derivatives
Entry
NO2ꢀRꢀOH
7
9
Puritya (%)
Yieldb (%)
Puritya (%)
Yieldb (%)
1
2
4-Nitrobenzoic acid
4-Nitrocinnamic acid
3-Nitrocinnamic acid
2-Nitrocinnamic acid
4-Nitrophenol
\95
\95
\95
86
35
40
90
46
38
\95
\95
\95
83
82
76
97
76
65
3
4c
5d
\95
\95
a Reverse-phase HPLC was carried out using rapid water/acetonitrile (0.04% TFA) linear gradients from 5%
organic to 98% organic component over 5 min. Flow: 2 mL/min. Column: Waters Symmetry C18 (3.5 mm) 4.6×50
mm. HPLC purities were determined by summation of integrated HPLC peak areas at (210+3N) nm, N=0–30.
b Crude yields based on the theoretical loading weight of target molecules.
c An additional treatment with 20% piperidine/DMF for 30 min was required for cyclization of the thiourea
derivative.
d Mitsunobu reaction using DIAD/Ph3P/DCM was used instead of DIC/HOAt treatment.
Furthermore, we investigated the derivatizations of quinazoline-2-thioxo-4-ones 6 using
alkyl halides, as the S-alkylated byproducts using the Wang resin suggested that such S-alkyla-
tions could proceed easily on solid supports. After testing several bases (2,6-di-tert-
butylpyridine, K2CO3/18-crown-6, DIEA) and solvents (DCM, NMP), S-alkylation with
DIEA/NMP was found to give the best results. As shown in Table 1, the products 9 were
obtained with excellent purity using allyl bromide. Encouraged by these results, we examined
alkylations using various alkylating reagents (Scheme 2, Table 2). The following types of
alkylating reagents gave high purity products 11; allyl bromide type (entries 6, 7), benzyl
bromide type (entries 8, 9), alpha-carbonylmethyl bromide type (entries 10, 11), alkyl iodide
and bromide types (entries 12, 13, 14). Excellent results were also obtained for the SnAR
reactions (entries 15, 16). All the product structures were confirmed by ESI mass spectro-
meter. Yields of compounds in Table 2 ranged from 78 to 100% based on the theoretical
loading weights of target molecules.

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Table 2
Alkylation of the quinazoline-2-thioxo-4-one with various alkyl- and arylhalide
Entry
RꢀX
11
Purity (%)
Yield (%)
6
7
8
9
10
11
12
13
14
15
16
Allyl bromide
Cinnamyl bromide
\95
\95
\95
\95
\95
\95
\95
\95
87
82
67
85
94
78
88
95
91
100
79
79
2,6-Difluorobenzyl bromide
2-(Bromomethyl)naphthalene
Methyl bromoacetate
4-Methoxyphenacyl bromide
Iodomethane
1-Iodo-3-methylbutane
(2-Bromoethyl)benzene
2,4-Dinitrofluorobenzene
2-Fluoro-5-nitrobenzaldehyde
\95
92
In conclusion, we have successfully developed a strategy for the solid-phase synthesis of
quinazoline-2-thioxo-4-ones. Treatment of amines with 2-methoxycarbonylphenyl isothiocyanate
usually gave the corresponding quinazoline-2-thioxo-4-ones. In some cases, treatment with base
was required for the cyclization. Importantly, careful selection of solid support linkers is critical
to avoid S-alkylation. Furthermore, the subsequent S-alkylations and S-arylations of quinazo-
line-2-thioxo-4-ones were performed with a wide range of reagents to give products with
excellent purity.
References
1. Reviews: (a) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555. (b) Booth, S.; Hermkens, P. H. H.;
Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1998, 54, 15385.
2. (a) de Laszlo, S. E.; Quagliato, C. S.; Greenlee, W. J.; Patchett, A. A.; Chang, R. S. L.; Lotti, V. J.; Chen, T.-B.;
Scheck, S. A.; Faust, K. A.; Kivlighn, S. S.; Schorn, T. S.; Zingaro, G. J.; Siegl, P. K. S. J. Med. Chem. 1993,
36, 3207–3210. (b) Hutchinson, J. H.; Cook, J. J.; Brashear, K. M.; Breslin, M. J.; Glass, J. D.; Gould, R. J.;
Halczenko, W.; Holahan, M. A.; Lynch, R. J.; Sitko, G. R.; Stranieri, M. T.; Hartman, G. D. J. Med. Chem.
1996, 39, 4583–4591.
3. (a) Buckman, B. O.; Mohan, R. Tetrahedron Lett. 1996, 37, 4439–4442. (b) Gouilleux, L.; Fehrentz, J.-A.;
Winternitz, F.; Martinez, J. Tetrahedron Lett. 1996, 37, 7031–7034. (c) Gorddeev, M. F.; Hui, H. C.; Gordon, E.
M.; Patel, D. V. Tetrahedron Lett. 1997, 38, 1729–1732. (d) Shao, H.; Colucci, M.; Tong, S.; Zhang, H.;
Castelhano, A. L. Tetrahedron Lett. 1998, 39, 7235–7238.
4. (a) Mayer, J. P.; Lewis, G. S.; Curtis, M. J.; Zhang, J. Tetrahedron Lett. 1997, 38, 8445–8448. (b) Villalgordo, J.
M.; Obrecht, D.; Chucholowsky, A. Synlett 1998, 1405–1407. (c) Cobb, J. M.; Fiorini, M. T.; Goddard, C. R.;
Theoclitou, M.-E.; Abell, C. Tetrahedron Lett. 1999, 40, 1045–1048.
5. Wang resin (p-benzyloxybenzyl alcohol, 100–200 mesh, loading 0.87 mmol/g) was purchased from Novabiochem
(http://www.nova.ch).
6. If compounds were derivatized from, e.g. 4-(bromomethyl)phenoxyethyl polystyrene available from Nov-
abiochem, such byproducts should not be generated.
7. SynPhase™ lanterns are available from Mimotopes (Clayton, Victoria, Australia). The type of Lantern used in
this report was SP-PS-D-HMP (long chain hydroxymethyl phenoxy linker), loading 35 mmol/lantern.
.

8337
8. Representative procedure. The p-nitrobenzoic acid bearing SynPhase™ (SP-PS-D-HMP, loading 35 mmol/lantern)
was put into 2.5 mL syringes.9 After reduction of the nitro group with SnCl2·2H2O/NMP/EtOH (1.0 g/2.0 mL/0.1
mL) for 16 h, the lantern was washed with DMF (2 mL×3) and DCM (2 mL×3), and dried under vacuum for
1 h. The amino group was reacted with 2-methoxycarbonyl phenylisothiocyanate/NMP (193 mg/2 mL) at
ambient temperature for 16 h, and the lantern was washed with DMF (2 mL×3) and DCM (2 mL×3), and dried
under vacuum for 1 h. Additionally, the lantern was reacted with allylbromide/DIEA/NMP (0.5 mmol/174 mL/2
mL) for 16 h and washed with DMF (2 mL×3) and DCM (2 mL×3). The lantern was treated with 95% TFA/H2O
for 1 h and the solution was concentrated with Genevac evaporater.10 The residue was dissolved with 50%
CH3CN/H2O and lyophilized to give the product (Table 2, entry 6) in 82% yield based on the theoretical loading
1
weight of the target molecule. H NMR (Varian VXR-300S, 300 MHz, CDCl3): l 3.87 (dd, J=6.9, 0.9 Hz, 2H),
5.16 (d, J=10.2 Hz, 1H), 5.32 (dd, J=17.0, 1.3 Hz, 1H), 5.87–6.10 (m, 1H), 7.26–7.47 (m, 3H), 7.64 (d, J=8.4
Hz, 1H), 7.74–7.80 (m, 1H). MS m/z 339 (M+1)+.
9. Disposable polypropylene/polyethylene syringes are available from Aldrich (Milwaukee, WI).
10. Genevac HT-8 available from Genevac Limited (Farthing road, Ipswich, IP1 5AP, UK).
.
.