A new and rapid access to homochiral 2,3-dihydro-oxazolo[2,3-b]quinazolin-5-ones

Article abstract of DOI:10.1016/S0957-4166(01)00032-5

Starting from homochiral 1,3-oxazolidine-2-thiones 1, a two-step sequence led to homotopic 2,3-dihydro-oxazolo[2,3-b]quinazolin-5-one derivatives 3. The sequence was developed and studied regarding its scope and limitations.

Full text of DOI:10.1016/S0957-4166(01)00032-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 337–340
A new and rapid access to homochiral
2,3-dihydro-oxazolo[2,3-b]quinazolin-5-ones
David Gueyrard,a Onofrio Leoni,b Sandro Palmierib and Patrick Rollina,*
aInstitut de Chimie Organique et Analytique, Universite´ d’Orle´ans, B.P. 6759, F-45067 Orle´ans, France
bIstituto Sperimentale per le Colture Industriali, MiPA, via di Corticella 133, I-40129 Bologna, Italy
Received 5 January 2001; accepted 16 January 2001
Abstract—Starting from homochiral 1,3-oxazolidine-2-thiones 1, a two-step sequence led to homotopic 2,3-dihydro-oxazolo[2,3-
b]quinazolin-5-one derivatives 3. The sequence was developed and studied regarding its scope and limitations. © 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
derivatives together with a wide range of substrates
including imidates and iminohalides3 (Fig. 1).
Within the frame of our recent studies on biotechnolog-
ical synthesis using vegetable sources1 and the reactivity
of homochiral 1,3-oxazolidine-2-thiones 1,2 we envis-
aged a short sequence for the efficient synthesis of the
corresponding 2,3-dihydro-oxazolo[2,3-b]quinazolin-5-
one derivatives 3a–f (Table 1). Many papers report on
cyclo-condensation reactions involving anthranilic acid
We have tried to extend this type of reaction to
homochiral 1,3-oxazolidine-2-thiones with a view to
providing a new access to homotopic 2,3-dihydro-oxa-
zolo[2,3-b]quinazolin-5-one derivatives of the type 3.
For example, such compounds have been previously
synthesized as intermediates in the synthesis of ana-
logues of ketanserin, a prototypic 5-HT2a and 5-HT1c
serotonin antagonist.4 In addition, it has been shown
recently that chiral analogues of ketanserin enhanced
the receptor affinity in the picomolar range by the
introduction of an a-methyl group.5
Table 1. Homochiral derivatives 3a–f produced (Fig. 2)
Entry 1a–f
R1; R2; R3; R4
2a–f (%) 3a–f (%)
1
2
3
4
5
6
OZT
(+)-(5R)-5-Vinyl-
(−)-(5S)-5-Vinyl-
(−)-(5R)-5-Phenyl- H; H; Ph; H
(+)-(4R)-4-Methyl- Me; H; H; H
(−)-(5S)-5-Methyl-5- H; H; Me; Et
ethyl-
H; H; H; H
H; H; CHꢀCH2; H 93
H; H; H; CHꢀCH2 85
55
64
68
63
62
82
80
In order to build up this tricyclic skeleton, compounds
1a–f were first reacted with benzyl bromide leading to
the formation of 2-benzylthio-1,3-oxazolines 2a–f.6
With regard to stability, the selected S-benzyl deriva-
tives were shown to be the best in the preparation of
intermediate oxazolines.7 Subsequently, the cyclization
73
78
94
Figure 1.
* Corresponding author. E-mail: patrick.rollin@univ-orleans.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00032-5

338
D. Gueyrard et al. / Tetrahedron: Asymmetry 12 (2001) 337–340
Figure 2.
reaction in the presence of anthranilic acid was per-
formed in good yields.
2.1. Typical procedure for S-alkylation
Compounds 2 were obtained according to the proce-
dure described by Nagao et al.6 which was slightly
modified.2
The results obtained with the parent 1,3-oxazolidine-2-
thione 1a and homochiral derivatives 1b–f are summa-
rized in Table 1.
2.1.1. 2-Benzylthio-D2-1,3-oxazoline 2a. See Ref. 6.
To extend the scope of the method and explore its
limitations, we completed some additional trials with
diverse 1,2-aromatic amino acids and oxazoline 2b
(Table 2). The results showed that the presence of an
electron withdrawing aromatic system in the reagent
was deleterious to the reaction. In addition, the replace-
ment of the phenyl substituent with a pyridine ring did
not allow formation of the desired compound.
2.1.2. (5R)-2-Benzylthio-5-vinyl-D2-1,3-oxazoline 2b.
[h]D=+9 (c 1, CHCl3); IR (NaCl): 1605 (CꢀN); 1H
NMR: 3.63 (dd, J4b–5=7.7, Jgem=13.4, 1H, H-4b), 4.05
(t, J4a–5=9.4, 1H, H-4a), 4.27 (s, 2H, SCH2), 5.04 (m,
1H, H-5), 5.24 (d, Jvic=11.5, 1H, H-7Z), 5.56 (d, Jvic=
17.1, 1H, H-7E), 5.89 (m, J6–5=7.0, 1H, H-6), 7.26–7.49
(m, 5H, Har); 13C NMR: 36.6 (SCH2), 60.7 (C-4), 82.8
(C-5), 118.4 (ꢀCH2), 128.0, 129.0, 129.4, 137.0 (Car),
136.0 (ꢀCH), 165.5 (C-2); MS: MH+=220; HRMS
calcd for C12H13NOS: 219.0718; found 219.0723.
In summary, a concise and practical synthesis of
homochiral 2,3-dihydro-oxazolo[2,3-b]quinazolin-5-one
derivatives has been developed starting from the corre-
sponding 1,3-oxazolidine-2-thiones. This procedure
constitutes an original extension of cyclo-condensations
involving anthranilic acid.
2.1.3. (5S)-2-Benzylthio-5-vinyl-D2-1,3-oxazoline 2c.
[h]D=−13 (c 1, CHCl3); HRMS calcd for C12H13NOS:
219.0718; found 219.0727.
2.1.4. (5R)-2-Benzylthio-5-phenyl-D2-1,3-oxazoline 2d.
[h]D=+180 (c 1, CHCl3); mp=120–122°C; IR (KBr):
2. Experimental
1
1651 (CꢀN); H NMR: 3.82 (dd, J4b–5=7.9, Jgem=13.5,
1H, H-4b), 4.28 (t, J4a–5=9.7, 1H, H-4a), 4.30 (s, 2H,
Melting points were determined with a Ko¨fler hot-stage
apparatus and are uncorrected. Specific rotations were
measured at 20°C using a Perkin–Elmer polarimeter
SCH2), 5.55 (m, 1H, H-5), 7.24–7.42 (m, 10H, Har); 13
C
RMN: 36.7 (SCH2), 63.3 (C-4), 83.3 (C-5), 126.2, 128.0,
128.9, 129.1, 129.2, 129.4, 137.0, 140.6 (Car), 165.5
(C-2); MS: MH+=270; HRMS calcd for C16H15NOS:
269.0874; found 269.0881.
141. H and 13C NMR spectra were recorded in CDCl3
1
solution on a Bruker Avance DPX250 instrument oper-
ating at 250 and 62.9 MHz, respectively. The coupling
constants (J) are reported in Hz and the chemical shifts
(l) in ppm downfield from tetramethylsilane as the
internal standard. IR spectra were measured using a
Perkin–Elmer FT Paragon 1000 PC spectrometer. Mass
spectra (MS) were obtained on a Perkin–Elmer SCIEX
API 300 spectrometer (Ionspray® mode).
2.1.5. (4R)-2-Benzylthio-4-methyl-D2-1,3-oxazoline 2e.
1
[h]D=+8 (c 0.4, CHCl3); IR (NaCl): 1608 (CꢀN); H
NMR: 1.28 (d, Jvic=6.4, 3H, CH3), 3.87 (dd, J4–5b=7.7,
Jgem=7.7, 1H, H-5b), 4.18–4.27 (m, 1H, H-4), 4.26 (s,
2H, SCH2), 4.43 (dd, J4–5a=8.9, 1H, H-5a), 7.25–7.40
Table 2. Extension to diverse heterocyclic systems

D. Gueyrard et al. / Tetrahedron: Asymmetry 12 (2001) 337–340
339
(m, 5H, Har); 13C NMR: 21.8 (CH3), 36.7 (SCH2), 62.5
(C-4), 76.0 (C-5), 128.0, 129.0, 129.4, 137.0 (Car), 165.1
(C-2); MS: MH+=208; HRMS calcd for C11H13NOS:
207.0718; found 207.0716.
2.2.5. (3R)-3-Methyl-2,3-dihydro-5H-[1,3]oxazolo[2,3-b]-
quinazolin-5-one 3e. [h]D=−105 (c 1.0, CHCl3); mp=
1
90–92°C; IR: 1685 (CꢀN), 1643 (CꢀO); H NMR: 1.62
(d, Jvic=6.3, 3H, CH3), 4.31 (dd, J=8.8, J=4.0, 1H,
H-2b), 4.74 (dd, J=8.8, 1H, H-2a), 4.90 (m, 1H, H-3),
7.31 (td, J=1.3, J=8.0, 1H, H-7), 7.50 (dd, 1H, H-9),
7.66 (td, 1H, H-8), 8.16 (dd, 1H, H-6); 13C NMR: 19.0
(CH3), 51.8 (C-3), 72.9 (C-2), 119.3 (C-5a), 125.1 (C-7),
126.5 (C-9), 127.0 (C-6), 135.1 (C-8), 149.4 (C-9a),
155.6 (C-10a), 161.2 (C-5); MS: MH+=203.5; HRMS
calcd for C11H10N2O2: 202.0742; found 202.0738.
2.1.6. (5S)-2-Benzylthio-5-ethyl-5-methyl-D2-1,3-oxazo-
line 2f. [h]D=−9 (c 2.9, CHCl3); IR (NaCl): 1606
1
(CꢀN); H NMR: 0.90 (t, Jvic=7.5, 3H, CH3), 1.37 (s,
3H, CH3), 1.67 (q, 2H, CH2), 3.53 and 3.67 (2d, Jgem
=
13.4, 2H, H-4), 4.23 (s, 2H, SCH2), 7.23–7.42 (m, 5H,
Har); 13C NMR: 8.5 (CH3), 25.4 (CH3), 33.2 (CH2),
36.4 (SCH2), 65.0 (C-4), 89.7 (C-5), 127.9, 129.0, 129.3,
137.1 (Car), 164.5 (C-2); MS: MH+=236; HRMS calcd
for C13H17NOS: 235.1031; found 235.1023.
2.2.6. (2S)-2-Ethyl-2-methyl-2,3-dihydro-5H-[1,3]oxazo-
lo[2,3-b]quinazolin-5-one 3f. [h]D=−15 (c 1.0, CHCl3);
1
mp=82–84°C; IR: 1678 (CꢀN), 1642 (CꢀO); H NMR:
2.2. Typical procedure for cyclization
1.04 (t, Jvic=7.5, 3H, CH3), 1.60 (s, 3H, CH3), 1.90 (q,
2H, CH2), 3.99 and 4.10 (2d, J=11.5, 2H, H-3), 7.30
(td, J=1.1, J=8.3, 1H, H-7), 7.47 (dd, 1H, H-9), 7.64
(td, 1H, H-8), 8.17 (dd, 1H, H-6); 13C NMR: 8.2
(CH3CH2), 25.4 (CH3), 33.3 (CH2CH3), 52.3 (C-3), 86.7
(C-2), 118.9 (C-5a), 124.7 (C-7), 126.5 (C-9), 127.0
(C-6), 135.1 (C-8), 149.7 (C-9a), 155.4 (C-10a), 161.5
(C-5); MS: MH+=231.5; HRMS calcd for C13H14N2O2:
230.1055; found 230.1063.
Compound 2b (0.305 g, 1.39 mmol) was dissolved in
ethanol (10 mL) in the presence of molecular sieves (4
,
A). Anthranilic acid (0.229 g, 1.2 equiv.) was then
added. The reaction mixture was refluxed for 18 h, then
made neutral with aqueous sodium hydrogencarbonate
and extracted with dichloromethane (3×). The com-
bined organic phases were dried over magnesium sul-
fate and concentrated in vacuo. The residue was
purified by flash chromatography (petroleum ether/
ethyl acetate 1:1) to furnish the desired compound 3b as
oil (0.202 g, 68%).
2.2.7. (2R)-8-Chloro-2-vinyl-2,3-dihydro-5H-[1,3]oxazo-
lo[2,3-b]quinazolin-5-one 4. [h]D=+48 (c 1.0, CHCl3);
mp=114–116°C; IR: 1687 (CꢀN), 1647 (CꢀO); 1H
NMR: 4.02 (dd, Jvic=7.3, Jgem=11.5, 1H, H-3b), 4.49
(dd, Jvic=8.7, 1H, H-3a), 5.39 (m, 1H, H-2), 5.47 (d,
J=10.2, 1H, ꢀCH2Z), 5.58 (d, J=17,1, 1H, ꢀCH2E),
6.01 (m, 1H, ꢀCH), 7.25 (dd, J=1.9, J=8.5, 1H, H-7),
7.47 (d, 1H, H-9), 8.04 (d, 1H, H-6); 13C NMR: 47.6
(C-3), 79.1 (C-2), 117.4 (C-5a), 121.4 (ꢀCH2), 125.8
(C-7), 126.3 (C-9), 128.3 (C-6), 133.0 (ꢀCH), 141.4
(C-8), 150.5 (C-9a), 156.2 (C-10a), 160.5 (C-5); MS:
MH+=249 and 251; HRMS calcd for C12H9ClN2O2:
248.0353 and 250.0323; found 248.0351 and 250.0319.
2.2.1. 2,3-Dihydro-5H-[1,3]oxazolo[2,3-b]quinazolin-5-
one 3a. See Ref. 4.
2.2.2. (2R)-2-Vinyl-2,3-dihydro-5H-[1,3]oxazolo[2,3-b]-
quinazolin-5-one 3b. [h]D=+55 (c 1.0, CHCl3); IR: 1694
1
(CꢀN), 1613 (CꢀO); H NMR: 4.02 (dd, 1 H, Jgem
=
11.3, Jvic=7.3, H-3b), 4.48 (dd, 1H, Jvic=8.8, H-3a),
5.36 (m, 1H, H-2), 5.43 (d, 1H, J=10.5, ꢀCH2z), 5.56
(d, 1H, J=17.0, ꢀCH2E), 6.00 (m, 1H, J=6.5, ꢀCH),
7.28 (t, 1H, J=7.6, H-7), 7.47 (d, 1H, H-9), 7.63 (t, 1H,
H-8), 8.11 (d, 1H, H-6); 13C NMR: 47.6 (C-4), 78.8
(C-5), 118.8 (Car), 121.0 (C-7), 125.1, 126.5, 126.8 and
135.1 (CHar), 133.3 (C-6), 149.2, 155.4 and 161.1 (Car);
MS: MH+=215; HRMS calcd for C12H10N2O2:
214.0742; found 214.0747.
2.2.8. (2R)-7-Methyl-2-vinyl-2,3-dihydro-5H-[1,3]oxazo-
lo[2,3-b]quinazolin-5-one 5. [h]D=+64 (c=1.0, CHCl3);
mp=110–112°C; IR: 1686 (CꢀN), 1643 (CꢀO); 1H
NMR: 2.40 (s, 3H, CH3), 4.01 (dd, Jvic=7.2, Jgem
=
11.3, 1H, H-3b), 4.48 (dd, Jvic=8.5, 1H, H-3a), 5.35 (m,
1H, H-2), 5.43 (d, J=10.5, 1H, ꢀCH2Z), 5.55 (d, J=
17.3, 1H, ꢀCH2E), 6.00 (m, J=6.6, 1H, CH), 7.37 (d,
J=8.3, 1H, H-9), 7.44 (dd, J=1.9, 1H, H-8), 7.88 (sl,
1H, H-6); 13C NMR: 21.4 (CH3), 47.7 (C-3), 78.7 (C-2),
118.6 (C-5a), 121.0 (ꢀCH2), 135.1 (C-7), 126.4 (C-9 and
C-6), 133.4 (ꢀCH), 136.6 (C-8), 147.2 (C-9a), 155.0
(C-10a), 161.2 (C-5); MS: MH+=229; HRMS calcd for
C13H12N2O2: 228.0899; found 228.0892.
2.2.3. (2S)-2-Vinyl-2,3-dihydro-5H-[1,3]oxazolo[2,3-b]-
quinazolin-5-one 3c. [h]D=−60 (c 1.0, CHCl3); HRMS
calcd for C12H10N2O2: 214.0742; found 214.0750.
2.2.4. (2R)-2-Phenyl-2,3-dihydro-5H-[1,3]oxazolo[2,3-b]-
quinazolin-5-one 3d. [h]D=+79 (c 1.0, CHCl3); mp=
174–176°C; IR: 1683 (CꢀN), 1646 (CꢀO); 1H NMR:
4.22 (dd, Jvic=7.8, Jgem=11.5, 1H, H-3b), 4.74 (dd,
Jvic=8.8, 1H, H-3a), 5.93 (m, 1H, H-2), 7.32 (td, J=
1.1, J=8.0, 1H, H-7), 7.42 (s, 5H, Har), 7.53 (dd, 1H,
H-9), 7.67 (td, 1H, H-8), 8.16 (dd, 1H, H-6); 13C NMR:
49.8 (C-3), 79.5 (C-2), 119.1 (C-5a), 125.2 (C-7), 126.2
(Car), 126.7 (C-9), 127.1 (C-6), 129.6 (Car), 135.3 (C-8),
137.1 (Car), 149.4 (C-9a), 155.5 (C-10a), 161.1 (C-5);
MS: MH+=265; HRMS calcd for C16H12N2O2:
264.0899; found 264.0908.
Acknowledgements
The authors thank the French M.E.N.R.T. for a grant
(D.G.). We also thank the EU for financial support
through the B.O.P. Project (FAIR CT 95-0260).

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D. Gueyrard et al. / Tetrahedron: Asymmetry 12 (2001) 337–340
Glennon, R. A. J. Med. Chem. 1992, 35, 4903.
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