A synthesis of alkyl 4-alkyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates

Article abstract of DOI:10.1016/S0040-4039(01)00954-6

Reaction of ethyl 4-alkyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates with sodium hydride in dioxane affords ethyl 4-alkyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates. The structure of the products was unambiguously established b

Full text of DOI:10.1016/S0040-4039(01)00954-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5295–5297
A synthesis of alkyl
4-alkyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-
carboxylates
a
a
b
b
c
a,
&
Petra Stefanicˇ, Matej Breznik, Nina Lah, Ivan Leban, Janez Plavec and Danijel Kikelj *
aUniversity of Ljubljana, Faculty of Pharmacy, Asˇkere`eva 7, 1000 Ljubljana, Slovenia
bUniversity of Ljubljana, Faculty of Chemistry and Chemical Technology, Asˇkercˇeva 5, 1000 Ljubljana, Slovenia
cNational Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
Received 6 April 2001; revised 23 May 2001; accepted 1 June 2001
Abstract—Reaction of ethyl 4-alkyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates with sodium hydride in dioxane affords
ethyl 4-alkyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates. The structure of the products was unambiguously
1
1
established by X-ray analysis as well as by H–13C and H–15N NMR correlation spectroscopy. © 2001 Published by Elsevier
Science Ltd.
In the course of our recent work on the design and
synthesis of serine protease inhibitors and fibrinogen
receptor antagonists, derivatives of 2H-1,4-benzox-
azine-3(4H)-one have served as useful peptidomimetic
building blocks.1,2 This heterocycle furnishes a skeleton
suitable for introducing various functionalities in order
to achieve a specific spatial orientation of pharma-
cophoric groups that interact with receptors or enzyme
active sites. Among derivatives of 2H-1,4-benzoxazine-
3(4H)-one, alkyl 3-oxo-3,4-dihydro-2H-1,4-benzox-
azine-2-carboxylates3,4 are especially suitable synthons
which can be easily functionalized at positions 2 and 4,
as well as at the ester group and aromatic ring
substituents.
4-Alkyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-car-
boxylates 2 were prepared as previously reported by
phase-transfer alkylation of ethyl 3-oxo-3,4-dihydro-
2H-1,4-benzoxazine-2-carboxylate (1).3,4 Although it
had generally been assumed that alkylation of 2H-1,4-
benzoxazine-3(4H)-one derivatives occurs at the ring
nitrogen,5,6 we strove for a clear proof of the structure
of compounds 2a–f. The site of alkylation (O- versus
N-alkylation) of 1 could not be established unambigu-
ously using the usual methods of structure determina-
tion and NOESY experiments. We therefore performed
an X-ray crystallographic analysis of 2d7 which
unequivocally proved that alkylation of 1 occurred at
the ring nitrogen atom.
In this paper we report an unexpected synthesis of the
hitherto unknown ethyl 4-alkyl-2-hydroxy-3-oxo-3,4-
dihydro-2H-1,4-benzoxazine-2-carboxylates 3, which
constitute a set of new versatile peptidomimetic scaf-
folds. The structure of compounds possessing the gen-
eral structure 3 was proved by 1H–13C and 1H–15N
NMR correlation spectroscopy, as well as by X-ray
crystallography.
On alkylation of 2a–f at position 2 with alkyl halides in
dioxane, using sodium hydride as a base,4 the forma-
1
tion of a by-product, whose H NMR spectrum lacked
the signals of an additional alkyl group and of a proton
at position 2, was consistently observed. The by-prod-
ucts additionally showed an exchangeable broad singlet
at approximately 8 ppm in DMSO-d6.8 In order to
clarify the formation and structure of the side products,
the same reaction was performed with 2a–f in the
absence of alkyl halide, resulting in the formation of
compounds 3a–f, which were in all respects identical
with the aforementioned by-products.9,14
Keywords: peptidomimetic building blocks; alkyl 4-alkyl-2-hydroxy-3-
oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates; X-ray structure;
NMR correlation spectroscopy.
* Corresponding author. Fax: +386-1-4258031; e-mail: danijel.
kikelj@ffa.uni-lj.si
Comparison of NOESY spectra10 of 2a,d and 3a,d at
302 K revealed no significant differences, thus the ini-
tially assumed structure 4 was discarded. NOE cross
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00954-6

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P. Stefanicˇ et al. / Tetrahedron Letters 42 (2001) 5295–5297
5296
peaks were observed between aromatic H-5 and the
methyl group in 2a and 3a, which, after integration,
gave similar proton–proton distances (approx. 0.3 nm)
in each structure. Similarly, 2d and 3d exhibited NOE
cross peaks between the aromatic proton H-5 and the
CH2 of the benzyl group, indicating that these protons
must be close to each other. No other relevant NOEs
were observed in NOESY spectra so that, due to lack
of restraints, the structure of 3a–f could not be unam-
biguously determined (Scheme 1).
ppm, thus indicating that in 3a the hydroxyl group
must be bound at position 2. The structure of 3a
suggested on the basis of these NMR experiments was
unambiguously confirmed by X-ray analysis of the crys-
tals obtained from 3a (Fig. 1).7
Although a detailed mechanistic study has not been
undertaken, the conversion of 2a–f into 3a–f can be
regarded as an oxidation of the C-2 enolate anion by
traces of air which might be present in the reaction
mixture giving 3a–f in equilibrium with the ring-opened
phenolate-ketone. An SN2-type displacement of a phen-
oxide by OH− followed by ring-closure is, although
theoretically possible, very unlikely.15 We have found
that the reaction proceeds similarly using either solid
sodium hydroxide in dioxane or aqueous sodium
hydroxide; in both cases an intense transient violet
coloration indicating the intermediate formation of a
phenolate anion was observed. Elaboration of this reac-
tion under various conditions and the use of com-
pounds 3a–f as novel peptidomimetic scaffolds are
currently in progress in our laboratory and will be
reported in due course.
Detailed structure determination of 3a in deuterochlo-
1
1
roform, using both H–13C and H–15N NMR correla-
tion spectroscopy and HSQC11 and HMBC12 pulse
sequences with gradients for coherence selection, confi-
rmed its structure unequivocally by a consistent set of
through bond proton–carbon and proton–nitrogen cor-
relations over two and three bonds. In particular, the
correlation of N-4 at −255 ppm13 with 5-H and protons
1
of the 4-methyl group was observed in a H–15N corre-
1
lation experiment. A similar H–13C correlation experi-
ment revealed connectivities between the exchangeable
broad singlet at 5.12 ppm and carbonyl carbon atoms
at 161 and 167 ppm, as well as quaternary carbon at 93
Scheme 1. (a) RBr, BTEAC, K2CO3, CH3CN, 60°C; (b) NaH, dioxane, rt.
Figure 1. ORTEP diagrams of 2d and 3a.

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P. Stefanicˇ et al. / Tetrahedron Letters 42 (2001) 5295–5297
5297
In conclusion, an important feature of our finding is
that ethyl 4-alkyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-
benzoxazine-2-carboxylates 3 can be obtained in one
step from 4-alkyl-3-oxo-3,4-dihydro-2H-1,4-benzox-
azine-2-carboxylates. The novel compounds 3a–f are
interesting peptidomimetic building blocks which offer
numerous possibilities of functionalization.
related compounds. The details of both structures (CIF
files) will be deposited in the Cambridge Structural
Database.
8. The chemical shift of the exchangeable proton was
approximately 5.2 ppm in CDCl3. The by-product was
generally obtained in 5–10% yield.
9. The crude yields of 3a–f ranged from 25 to 55%.
10. Jeener, J.; Meier, B. H.; Bachmann, P.; Ernst, R. R. J.
Chem. Phys. 1979, 71, 4546–4553.
Acknowledgements
11. Bodenhausen, G.; Ruben, D. J. Chem. Phys. Lett. 1980,
69, 185–189.
12. Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W.
Magn. Reson. Chem. 1993, 31, 287–292.
13. Relative to MeCN (l=−135.83 ppm) as external
reference.
This work was supported financially by the Ministry of
Science and Technology of the Republic of Slovenia,
through grants P1-502-002-00 and P1-511-103-00. The
authors wish to thank Professor Roger Pain for critical
reading of the manuscript.
14. Preparation of compound 3a (typical procedure):
To a stirred solution of ethyl 4-methyl-3-oxo-3,4-dihydro-
2H-1,4-benzoxazine-2-carboxylate 2a (0.470 g, 2.0 mmol)
in 1,4-dioxane (15 mL) cooled to 10°C, sodium hydride
(0.057 g, 2.4 mmol) was added under an argon atmo-
sphere. The reaction mixture was allowed to warm to
ambient temperature and stirred for an additional 5 h.
The solvent was evaporated in vacuo and the residue
dissolved in diethyl ether (15 mL). The solution was
rinsed with 0.1 M HCl (2×10 mL), dried over anhydrous
Na2SO4 and the solvent was removed in vacuo. The crude
product was purified by column chromatography on sil-
ica gel using dichloromethane/methanol (100/1) as eluant
to give analytically pure ethyl 4-methyl-2-hydroxy-3-oxo-
References
1. Goodman, M.; Ro, S. In Burger’s Medicinal Chemistry
and Drug Discovery; Wolff, M. E., Ed. Peptidomimetics
for drug design. John Wiley & Sons Inc.: New York,
1995; pp. 803–861.
2. Giannis, A.; Ru¨bsam, F. Adv. Drug Res. 1997, 29, 1–78.
3. Techer, H.; Pesson, M.; Dursin, M. C. R. Acad. Sc. Paris
Serie C 1969, 269, 154–157.
4. Rutar, A.; Kikelj, D. Synth. Commun. 1998, 28, 2737–
2749.
5. Marfat, A.; Carta, M. P. Synthesis 1987, 515–517.
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3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate 3a as
a
white amorphous solid; yield: 0.115 g (23%); mp 98–
101°C; IR (KBr): w 3376, 2991, 1750, 1675, 1609, 1502,
1394, 1294, 1229, 1140, 1048, 979, 860, 753, cm−1 1H
;
7. Compound 2d crystallizes from ethanol/acetonitrile and
forms colorless prismatic crystals in the monoclinic space
NMR (300 MHz, DMSO-d6): l 1.22 (t, 3H, J=7.16 Hz,
CH2CH3), 3.31 (s, 3H, N-CH3), 4.25 (q, 2H, J=7.16 Hz,
,
group P21/c with unit cell parameters a=8.4058(1) A,
CH2CH3), 7.05–7.18 (m, 3H, Ar-H
6 ), 7.23–7.26 (m, 1H,
,
,
b=16.7340(2) A, c=10.9222(3) A, i=99.2473(4)°. Com-
pound 3a crystallizes from dichloromethane/petrolether
and forms prismatic colorless crystals in the orthorhom-
bic space group Pn21c with unit cell parameters a=
Ar-H), 8.55 (s, 1H, -OH) ppm; MS (70 eV, EI): m/z (%)
6
6
251 (M+, 28), 235 (45), 189 (6), 178 (62), 150 (23), 94 (33),
77 (100), 65 (80). Anal. calcd for C12H13NO5: C, 57.37;
H, 5.22; N, 5.48%. Found: C, 57.00; H, 5.14; N, 5.40%.
15. The authors wish to express their gratitude to the referee
for his helpful suggestion concerning the reaction mecha-
nism.
,
,
,
10.2460(2) A, b=10.3464(2) A, c=10.9830(2) A.
Diffraction data were collected at 150(1) K with Mo Ka
radiation and CCD detector. The bond lengths and
angles are normal and in agreement with the values for
.