Convenient selective synthesis of 5,7,8,9-tetrahydro-4H,6H-chromeno[2,3-d] [1,3]oxazin-4-ones

Article abstract of DOI:10.1007/s11172-010-0037-z

A method for the synthesis of 5,7,8,9-tetrahydro-4H,6H-chromeno[2,3-d][1,3] oxazin-4-ones was developed. The method involves acid-catalyzed acylation of substituted ethyl 2-amino-4-aryl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3- carboxylates with acetic anhy

Full text of DOI:10.1007/s11172-010-0037-z

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 479—481, February, 2009
479
Convenient selective synthesis of
5,7,8,9ꢀtetrahydroꢀ4H,6Hꢀchromeno[2,3ꢀd][1,3]oxazinꢀ4ꢀones*
Yu. M. Litvinov and A. M. Shestopalov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: amsh@ioc.ac.ru
A method for the synthesis of 5,7,8,9ꢀtetrahydroꢀ4H,6Hꢀchromeno[2,3ꢀd][1,3]oxazinꢀ4ꢀ
ones was developed. The method involves acidꢀcatalyzed acylation of substituted ethyl
2ꢀaminoꢀ4ꢀarylꢀ5ꢀoxoꢀ5,6,7,8ꢀtetrahydroꢀ4Hꢀchromeneꢀ3ꢀcarboxylates with acetic anhydride.
Key words: chromeno[2,3ꢀd][1,3]oxazinꢀ4ꢀones, ethyl 2ꢀaminoꢀ4Hꢀpyranꢀ3ꢀcarboxylates,
annulated heterocycles, acylation, acid catalysis.
The recent attention of medicinal chemists has been
attracted by high biological activities of annulated oxazinꢀ
ones.1—8 They are active as substrate inhibitors of various
proteases because the oxazinone ring can undergo
enzymeꢀcatalyzed opening to give the corresponding stable
acyl derivatives. Benzoxazinones and thienooxazinones
effectively inhibit human leukocyte elastases (responsible
for the degradation of connective tissue),1—3 herpes
proteases,4 and those of human cytomegalovirus,5 as well
as act as antiinflammatory agents and anticoagulants.6
Hydrogenated 4Hꢀpyrido[4´,3´:4,5]thieno[2,3ꢀd][1,3]oxazinꢀ
4ꢀones are active in the selective inhibition of cholesterol
esterases and acetylcholinesterase.7 Some imidazooxazinꢀ
one nucleosides are effective against HIV.8 The biological
activities of oxygen analogs of benzoxazinones (pyranoꢀ
[2,3ꢀd][1,3]oxazines) have not been examined hitherto.
The pyran ring of 2ꢀaminoꢀ4Hꢀpyrans is unstable in the
presence of aqueous protic acids,9 alcoholic solutions of
alkali metal hydroxides,10 and amines.11 It is reasonable
that the pyran ring would also undergo opening in reacꢀ
tions of pyrano[2,3ꢀd][1,3]oxazines with proteases, thus
creating additional links with the enzyme.
By selecting the reaction conditions, we developed a
method for the synthesis of 4H,6Hꢀchromeno[2,3ꢀd]ꢀ
[1,3]oxazinꢀ4ꢀones 1a—f from substituted ethyl 2ꢀaminoꢀ
4ꢀarylꢀ5ꢀoxoꢀ5,6,7,8ꢀtetrahydroꢀ4Hꢀchromeneꢀ3ꢀcarꢀ
boxylates 2a—f without preliminary hydrolysis of the ester
group. The method involves acetylation of pyrans 2a—f
with acetic anhydride in the presence of catalytic amounts
of conc. H2SO4 (Scheme 1).
Scheme 1
R = Me (a—e), H (f); Ar = Ph (a, f), 4ꢀFC6H4 (b), 4ꢀClC6H4 (c),
4ꢀBrC6H4 (d), 2,6ꢀCl2C6H3 (e).
Reagents and conditions: i, (MeCO)2O, H2SO4 (0.3 equiv.),
reflux, 2 h.
To date, the acylation of 2ꢀaminoꢀ4Hꢀpyranꢀ3ꢀcarꢀ
boxylic acid esters in the presence of pyridine has been
studied only in two research papers12,13 both reporting on
the formation of 2ꢀ(diacetylamino)ꢀ4Hꢀpyranꢀ3ꢀcarboxyꢀ
lic acid esters only. 4H,5HꢀPyrano[2,3ꢀd][1,3]oxazinꢀ
4ꢀones were obtained by acylation of substituted 2ꢀaminoꢀ
4Hꢀpyranꢀ3ꢀcarboxylic acids.14 However, these acids are
not easily accessible because of possible opening of the
pyran ring during their synthesis via hydrolysis of approꢀ
priate esters of 2ꢀaminoꢀ4Hꢀpyranꢀ3ꢀcarboxylic acids.9,10
We also studied the acylation of pyrans in the absence
of an acid catalyst. In contrast to the synthesis of oxazinꢀ
ones 1a—f, pyran 2a was exhaustively acylated at the
amino group to give ethyl 2ꢀ(diacetylamino)ꢀ7,7ꢀdiꢀ
methylꢀ5ꢀoxoꢀ4ꢀphenylꢀ5,6,7,8ꢀtetrahydroꢀ4Hꢀchroꢀ
meneꢀ3ꢀcarboxylate 3. The best yield was achieved when
the starting pyran 2a was heated in acetic anhydride alone
for 40 h (TLC) (Scheme 2).
The structures of the products obtained were confirmed
by 1H NMR, IR, and mass spectra. The IR spectra of comꢀ
pounds 1 and 3 show no absorption bands at 3400—3100 cm–1
(NH stretching). The spectra of oxazines 1a—f exhibit
* On the occasion of the 75th anniversary of the foundation
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 469—471, February, 2009.
1066ꢀ5285/09/5802ꢀ0479 © 2009 Springer Science+Business Media, Inc.

480
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Litvinov and Shestopalov
Scheme 2
contains signals for the ethyl substituent at δ 1.06—1.12
(m, 3 H, CH3) and 4.03 (m, 2 H, CH2) and for two acetyl
groups at δ 2.32 (s, 6 H).
The mass spectrum of oxazine 1a shows a molecular
ion peak (m/z 337), while the peak with maximum m/z
in the mass spectrum of 2ꢀ(diacetylamino)pyran 3 corꢀ
responds to the deaceꢀtylated fragment (m/z 383,
[M – CH3CO]+).
Thus, we demonstrated that easily accessible substiꢀ
tuted ethyl 2ꢀaminoꢀ4ꢀarylꢀ5ꢀoxoꢀ5,6,7,8ꢀtetrahydroꢀ4Hꢀ
chromeneꢀ3ꢀcarboxylates 2a—f can be used as starting
materials for the synthesis of earlier unknown oxazines
1a—f and 2ꢀ(diacetylamino)pyran 3.
Reagents and conditions: i, (MeCO)2O, reflux, 40 h.
bands at 1752—1760 (lactone carbonyl) and 1656—
1664 cm–1 (conjugated oxo group). The spectrum of comꢀ
pound 3 contains intense bands at 1736, 1724, 1708, and
1664 cm–1 (νas(N(COMe)2) and νs(N(COMe)2, conꢀ
jugated ester group, and conjugated oxo group, reꢀ
spectively).15
The 1H NMR spectra of compounds 1a—f show a
singlet for the C(5)(H)Ar proton at δ 4.61—5.51, a signal
for C(2)—Me at δ 2.32—2.36 (s, 3 H), signals for the
aromatic (δ 7.08—7.32) and aliphatic protons (two CH2
groups at δ 2.14—2.27 and 2.57—2.64 as a singlet or an
AB system). The spectrum of compound 3 additionally
Experimental
Melting points were determined on a Kofler hot stage.
IR spectra were recorded on a Specord M82 spectrometer in
KBr pellets (1 : 200). 1H NMR spectra were recorded on Bruker
WMꢀ250 and Bruker ACꢀ200 instruments (250 and 200 MHz,
respectively) in DMSOꢀd6. Lowꢀresolution mass spectra were
measured on a Kratos MSꢀ30 instrument (EI, 70 eV, direct inlet
probe, ionization chamber temperature 200 °C).
The starting ethyl 2ꢀaminoꢀ4ꢀarylꢀ5ꢀoxoꢀ5,6,7,8ꢀtetrahydroꢀ
4Hꢀchromeneꢀ3ꢀcarboxylates 2a—f were prepared according to
Table 1. Yields, physical constants, and spectroscopic characteristics of compounds 1a—f and 3
Comꢀ Yield
pound (%)
M.p.
/°C
Found
Calculated
Molecular
formula
IR
1H NMR,
δ (J/Hz)
(%)
N
ν/cm–1
ν(C=O),
ν(C=C)
C
H
1a
1b
1c
75
52
48
212—214 71.25 5.72 4.09 C20H19NO4 1756,
0.98, 1.07 (both s, по 3 H, C(8)(Me)2); 2.19—2.27 (m,
2 H, CH2); 2.36 (s, 3 H, C(2)Me); 2.64 (s, 2 H, CH2);
4.61 (s, 1 H, H(5)); 7.25 (m, 5 H, Ph)
0.98, 1.07 (both s, 3 H each, C(8)(Me)2); 2.19—2.27 (m,
2 H, CH2); 2.36 (s, 3 H, C(2)Me); 2.64 (s, 2 H, CH2);
4.64 (s, 1 H, H(5)); 7.08 (m, 2 H, Ar), 7.22 (m, 2 H, Ar)
0.97, 1.06 (both s, 3 H each, C(8)(Me)2); 2.15—2.31 (m,
2 H, CH2); 2.36 (s, 3 H, C(2)Me); 2.62 (s, 2 H, CH2);
4.60 (s, 1 H, H(5)); 7.27 (d, 2 H, H(2´), H(6´), J = 7.9),
7.33 (d, 2 H, H(3´), H(5´), J = 7.8)
71.20 5.68 4.15
1664,
1624
203—205 67.35 5.13 4.09 C20H18FNO4 1756,
67.60 5.11 3.94
1668,
1628
199—201 64.78 4.63 3.91 C20H18ClNO4 1760,
64.61 4.88 3.77
1660,
1620
1d
1e
65
67
205—207 57.46 4.28 3.51 C20H18BrNO4 1752,
0.96, 1.05 (both s, 3 H each, C(8)(Me)2); 2.22
(ABꢀsystem, 2 H, CH2, J = 16.4); 2.34 (s, 3 H, C(2)Me);
2.62 (s, 2 H,CH2); 4.58 (s, 1 H, H(5)); 7.20 (d, 2 H,
H(2´),H(6´), J = 7.9); 7.46 (d, 2 H, H(3´), H(5´), J = 7.8)
1.00, 1.07 (both s, 3 H each, C(8)(Me)2); 2.07—2.30
(m, 2 H, CH2); 2.38 (s, 3 H, C(2)Me); 2.58 (s, 2 H,
CH2); 5.51 (s, 1 H, H(5)); 7.20—7.31 (m, 2 H, Ar);
7.42—7.46 (m, 1 H, Ar)
57.71 4.36 3.36
1656,
1628
247—250 58.94 4.29 3.14 C20H17Cl2NO4 1752,
59.13 4.22 3.45
1656,
1624
1f
3
62
62
243—246 69.72 4.99 4.72 C18H15NO4 1756,
1.97—2.02 (m, 2 H, CH2); 2.30 (s, 2 H, CH2);
2.34 (s, 3 H, C(2)Me); 2.63–2.81 (s, 2 H, CH2);
4.62 (s, 1 H, H(5)); 7.27 (m, 5 H, Ph)
0.93 (s, 3 H, C(7)Me); 1.06—1.12 (m, 6 H, C(7)Me +
COOCH2CH3); 2.14 (ABꢀsystem, 2 H, CH2, J = 14.7);
2.32 (s, 6 H, N(COCH3)2); 2.57 (ABꢀsystem, 2 H,
CH2, J = 17.7); 4.03 (m, 2 H, COOCH2CH3); 4.82 (s,
1 H, H(5)); 7.19—7.32 (m, 5 H, Ph)
69.89 4.89 4.53
1664,
1628
161—163 67.62 6.51 3.15 C24H27NO6 1736,
67.75 6.40 3.29
1724,
1708
1664
1640

Synthesis of 4H,5Hꢀchromeno[2,3ꢀd][1,3]oxazinꢀ4ꢀones Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
481
a standard threeꢀcomponent procedure16,17 from equimolar
amounts of malononitrile, dimedone (2a—e), or cyclohexaneꢀ
1,3ꢀdione (2f) and an appropriate aromatic aldehyde.
4. R. L. Jarvest, I. L. Pinto, S. M. Ashman, C. E. Dabrowski,
A. V. Fernandez, L. J. Jennings, P. Lavery, D. G. Tew,
Bioorg. Med. Chem. Lett., 1999, 9, 443.
5ꢀArylꢀ2ꢀmethylꢀ5,7,8,9ꢀtetrahydroꢀ4H,6Hꢀchromenoꢀ
[2,3ꢀd][1,3]oxazineꢀ4,6ꢀdiones (1a—f) (general procedure).
Concentrated H2SO4 (0.09 g, 0.9 mmol) was added to a solution
of pyran 2a—f (3 mmol) in acetic anhydride (3 mL). The reaction
mixture was refluxed for 2 h (monitoring by TLC). On cooling
to 4 °C, colorless needleꢀlike crystals of products 1a—f were
filtered off, successively washed with ethanol (2 mL), water
(3×3 mL), ethanol (2 mL), and light petroleum (2 mL),
recrystallized from acetic anhydride, and dried at 150 °C to a
constant weight. The yields, physical constants, elemental
analysis data, and IR and 1H NMR spectra of compounds 1a—f
are given in Table 1.
5. I. L. Pinto, R. L. Jarvest, B. Clarke, C. E. Dabrowski,
A. Fenwick, M. M. Gorczyca, L. J. Jennings, P. Lavery, E.
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2,8,8ꢀTrimethylꢀ5ꢀphenylꢀ5,7,8,9ꢀtetrahydroꢀ4H,6Hꢀchroꢀ
meno[2,3ꢀd][1,3]oxazineꢀ4,6ꢀdione (1a). MS (EI, 70 eV), m/z
(Irel (%)): 337 [M]+ (100), 294 [M – CH3CO]+ (54), 266
[M – CH3CO – CO]+ (39), 260 [M – Ph]+ (92), 240
[M – CH3CO – C4H7]+ (71), 218 [M – CH3CO – Ph]+ (64).
Ethyl 2ꢀ(diacetylamino)ꢀ7,7ꢀdimethylꢀ5ꢀoxoꢀ4ꢀphenylꢀ
5,6,7,8ꢀtetrahydroꢀ4Hꢀchromeneꢀ3ꢀcarboxylate (3). A solution
of pyran 2a (1.02 g, 3 mmol) in acetic anhydride (3 mL) was
refluxed for 40 h (monitoring by TLC). On cooling to 4 °C, the
precipitate of product 3 that formed was filtered off, successively
washed with ethanol (2 mL), water (3×3 mL), ethanol (2 mL),
and light petroleum (2 mL), recrystallized from acetic anhydride,
and dried at 120 °C to a constant weight. The yields, physical
constants, elemental analysis data, and IR and 1H NMR spectra
of compound 3 are given in Table 1.
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MS (EI, 70 eV), m/z (Irel (%)): 383 [M – CH3CO]+ (14),
307 [M – CH3CO – Ph]+ (14), 307 [M – 2CH3CO – Ph]+ (100).
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Received November 7, 2008;
in revised form January 14, 2009