Ring opening of 2-(benzylamino)-2H-1,4-benzoxazin-3(4H)-ones and 2-bromo-2H-1,4-benzoxazin-3(4H)-ones

Article abstract of DOI:10.1002/hlca.200890069

Substituted 2-(benzylamino)-2H-1,4-benzoxazin-3(4H)-ones are unstable under alkaline and acidic conditions, undergoing opening of the benzoxazinone ring. 2-Bromo-2H-1,4-benzoxazin-3(4H)-ones show similar degradation under alkaline conditions, while replacement of Br at C(2) to give 2-hydroxy-2H-1,4-benzoxazin- 3(4H)-ones was observed only under mild alkaline conditions. Mechanisms of ring opening and degradation to 2-aminophenol derivatives are proposed.

Full text of DOI:10.1002/hlca.200890069

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Helvetica Chimica Acta – Vol. 91(2008)
Ring Opening of 2-(Benzylamino)-2H-1,4-benzoxazin-3(4H)-ones and
2-Bromo-2H-1,4-benzoxazin-3(4H)-ones
by Janez Ilasˇ and Danijel Kikelj*
ˇ
ˇ
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, SI-1000 Ljubljana
(phone: þ 38614769561; fax: þ 38614258031; e-mail: danijel.kikelj@ffa.uni-lj.si)
Substituted 2-(benzylamino)-2H-1,4-benzoxazin-3(4H)-ones are unstable under alkaline and acidic
conditions, undergoing opening of the benzoxazinone ring. 2-Bromo-2H-1,4-benzoxazin-3(4H)-ones
show similar degradation under alkaline conditions, while replacement of Br at C(2) to give 2-hydroxy-
2H-1,4-benzoxazin-3(4H)-ones was observed only under mild alkaline conditions. Mechanisms of ring
opening and degradation to 2-aminophenol derivatives are proposed.
Introduction. – 2H-1,4-Benzoxazin-3(4H)-ones have been studied extensively as
important heterocyclic systems for building natural [1] and designed synthetic
compounds [2]. They have frequently been utilized as suitable precursors for the
design of biologically active compounds, ranging from herbicides and fungicides to
therapeutically usable drugs, due to their rather simple preparation and various options
for further functionalization [3]. Although the chemical behavior of 2H-1,4-
benzoxazin-3(4H)-ones has been well explored, unexpected reaction products are
obtained under certain specific conditions [4]. Whereas 2,2-disubstituted 2H-1,4-
benzoxazin-3(4H)-ones 1 are relatively stable, the corresponding 2-monosubstituted
2H-1,4-benzoxazin-3(4H)-ones 2, which possess an acidic H-atom at C(2), are more
prone to various transformations [5][6].
2-Unsubstituted 2H-1,4-benzoxazin-3(4H)-ones 3 are easily prepared and are
suitable for further functionalization at C(2) among which bromination is a simple and
efficient way to transform the C(2)-atom to an electrophilic center bearing a good
leaving group, thus making 4 a good substrate for nucleophilic substitution with amines,
allowing easy access to derivatives 5 [7]. Transformation of the Br derivative 4 to 2-
hydroxy-2H-1,4-benzoxazin-3(4H)-one 6 affords the O-nucleophilic compound which
is further used for nucleophilic substitution on various electrophilic substrates, e.g.,
alkyl halides to give cyclic acetals 7 (Scheme 1).
Results and Discussion. – During our investigations in the field of 2H-1,4-
benzoxazin-3(4H)-one chemistry, we observed that opening of the 1,4-oxazin-3-one
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

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655
Scheme 1
ring sometimes compromised the outcome of the synthesis. Here, we report the results
of our studies on the ring opening of 2-bromo-2H-1,4-benzoxazin-3(4H)-ones 4 and 2-
(benzylamino)-2H-1,4-benzoxazin-3(4H)-ones 8 which proceed differently from the
ring opening of naturally occurring 2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-ones and
2-hydroxy-2H-1,4-benzoxazin-3(4H)-ones, the only studied ring opening reactions of
2-substituted 2H-1,4-benzoxazin-3(4H)-ones. Whereas a) in the transformation of 2,4-
dihydroxy-2H-1,4-benzoxazin-3(4H)-ones to benzoxazolinones the ring opening step
involves participation of the hydroxamic acid OH group [8][9], and b) ring-opening of
2-hydroxy-2H-1,4-benzoxazin-3(4H)-ones has been observed only under reductive
conditions [9][10], we demonstrate in this work that substituted 2-(benzylamino)- and
2-bromo-2H-1,4-benzoxazin-3(4H)-ones undergo ring opening and degradation to 2-
aminophenol derivatives under alkaline and acidic conditions following a different
mechanism.
The Br-atom of 2-bromo-2H-1,4-benzoxazin-3(4H)-ones 4a and 4b was smoothly
replaced by (4-cyanobenzyl)amino group in the presence of K2CO3 to give 4-{[(3,4-
dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-2-yl)amino]methyl}benzonitrile
deriva-
tives 8a and 8b as solid, stable compounds (Scheme 2). In an attempt to hydrolyze
ethyl ester 8b to the corresponding acid 8c by using 2 equiv. of NaOH in a H2O/dioxane
1:1, the benzoic acid derivative 9c and 4-formylbenzonitrile (10) were obtained instead
of the desired carboxylic acid 8c. Similarly, under alkaline conditions, the nitro
derivative 8a afforded degradation products 9a and 10 (Scheme 2).
In an attempt to transform 8a to the N-Boc-protected derivative 11a, required as a
key intermediate for our synthesis of potential antithrombotic compounds [11],
(Boc)2O in the presence of Et3N was employed. Although reaction conditions were

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Helvetica Chimica Acta – Vol. 91(2008)
Scheme 2
mild, the expected carbamate 11a was not obtained and, once more, 4-formylbenzoni-
trile (10) was isolated, as well as the ring-opened compound 13a (Scheme 3). This
reaction demonstrated that ring opening of 8a occurred even under mild alkaline
conditions. However, the benzoxazine ring was not completely decomposed, probably
due to the less vigorous conditions and stabilization through carbamate formation.
Ring cleavage of 8a and 8b observed in alkaline medium prompted us to apply acidic
conditions for the hydrolysis of 8b in order to preserve the heterocyclic ring. Thus, for
the synthesis of N-Boc-protected carboxylic acid 11c, a two-step procedure was
envisaged. In the first step, acid hydrolysis of 8b (6m HCl, reflux, overnight) was
Scheme 3

Helvetica Chimica Acta – Vol. 91(2008)
657
performed, followed by neutralization and treatment with (Boc)2O. Again, the desired
product 11c was not obtained, and the isolated products were identified as 3,4-dihydro-
2-hydroxy-4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylic acid (6c) and tert-butyl N-
(4-cyanobenzyl)carbamate (12; Scheme 3).
Formation of 4-formylbenzonitrile (10) and carbamate 13a (Scheme 3), as well as
2-aminophenol derivatives 9a and 9c (Scheme 2) provided an insight into the
mechanism of ring-opening degradation of hemiaminals 8. The amino group clearly
plays the key role in the instability of 2-aminobenzoxazinones 8a and 8b since the
benzoxazinone ring of the analogous 2-hydroxy and 2-alkoxy compounds, 6b and 7b,
respectively, was stable under alkaline conditions. Thus, quantitative yields of
carboxylic acids 6c and 7c was obtained on alkaline hydrolysis of ethyl esters 6b and
7b, respectively (Scheme 4).
Scheme 4
Interestingly, the 2-aminophenol derivatives 9a and 9c were also obtained as the
main products (besides 6a and 6c) of the attempted replacement of the Br-atom in 4a
and 4b by a OH group under alkaline conditions (NaOH in H2O/dioxane 1:1;
Scheme 5). However, since the hemiacetals 6 are stable under alkaline conditions, ring
degradation of 4a and 4b must have taken place before substitution of the Br-atom. The
2-OH derivatives 6a and 6b could be obtained from 4a and 4b, respectively, as the main
products under mild alkaline conditions (2 equiv. aq. NaHCO3), whereas, in more
concentrated solution, the dimeric compounds 14a and 14b were obtained as side
products. The conversion of bromo compounds 4a and 4b to alcohols 6a and 6b,
respectively, without formation of dimers 14a and 14b, was achieved by using BaCO3
[12] instead of NaHCO3 (Scheme 5).
Reaction mechanisms which could explain the formation of 4-formylbenzonitrile
(10) and 4-(aminomethyl)benzonitrile (21) from 8a and 8b, respectively, under alkaline
and acidic conditions are proposed in Schemes 6 and 7, respectively. Under alkaline
conditions, after abstraction of an acidic H-atom in 8 and following delocalization of the
negative charge to give 15 as an intermediate, ring opening takes place, and the
resulting imine 16 undergoes tautomerization to 17. Under mild alkaline conditions, 17
is hydrolyzed to give 4-formylbenzonitrile (10) and the N-(2-hydroxyphenyl)glycine
derivative 18 which was trapped as the N-Boc derivative 13a (see Scheme 3). Under
stronger alkaline conditions, 17 is fragmented, probably by participation of the
phenolate anion, to give isolated 2-(methylamino)phenol derivative 9 and 4-formyl-
benzonitrile (10). In contrast to O,N-acetals 8, cyclic hemiacetals 6a – 6c were found to
be stable under alkaline conditions. Although no ring-opened aldehyde forms of 6a – 6c

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Helvetica Chimica Acta – Vol. 91(2008)
Scheme 5
could be detected, a minor cleavage of hemiacetals 6a – 6c to the corresponding
aldehydes cannot be excluded.
Under acidic conditions, the basis of heterocyclic ring instability is the aminal
group. To account for the mechanism of the ring-cleavage step, we propose protonation
of the aminal at the O-atom [13] to give O-protonated O,N-acetal 19, which undergoes
ring-opening. The resulting iminium ion 20 is hydrolyzed to give 4-(aminomethyl)-
benzonitrile (21) and aldehyde 22, which undergoes then cyclization [8][9] to yield a
3,4-dihydro-2-hydroxy-4-methyl-3-oxo-2H-1,4-benzoxazin-7-carboxylic acid (6c).
Conclusions. – In contrast to 2-hydroxy- and 2-alkoxy-2H-1,4-benzoxazin-3(4H)-
ones, the synthetically available 4-{[(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-2-
yl)amino]methyl}benzonitrile derivatives 8, comprising a structure of cyclic hemi-
aminal ethers, were found to be unstable under both alkaline and acidic conditions.
Whereas, under alkaline conditions, the product of decomposition of 8a and 8b was 4-
formylbenzonitrile, ring cleavage under acidic conditions afforded 4-(aminomethyl)-
benzonitrile, in addition to 2-(methylamino)phenol or 2-hydroxy-2H-1,4-benzoxazin-
3(4H)-one derivatives, respectively. In 2-bromo-4-methyl-2H-1,4-benzoxazin-3(4H)-
one derivatives 4a and 4b, the Br-atom could be replaced with a OH group only under
mild alkaline conditions, while, under stronger alkaline conditions, a similar ring-
opening degradation yielded also 2-(methylamino)phenol derivatives. These observa-

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659
Scheme 6
tions will help to devise optimal strategies for the synthesis of 2-substituted 2H-1,4-
benzoxazin-3(4H)-ones which are pharmaceutically valuable intermediates.
Experimental Part
General. All chemicals were obtained from Aldrich Chemical Co. and Fluka, and were used without
further purification. All reported yields are yields of purified products. Solvents were used without
purification or drying, unless otherwise stated. Anh. solvents were prepared according to literature
procedures [14]. 4-Methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one and ethyl 4-methyl-3-oxo-3,4-dihydro-
2H-1,4-benzoxazine-7-carboxylate were synthesized from the corresponding 2-aminophenols and
chloroacetyl chloride (ClCH2COCl) by analogy to published procedures [15]. Anal. TLC: Merck silica
gel (60 F254 ) plates (0.25 mm), visualization with UV light. Column chromatography (CC): silica gel
(Merck, particle size 240 – 400 mesh). Microwave assisted reactions were performed on a CEM Discover

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Scheme 7
microwave reactor (CEM Corporation, USA). M.p.: Reichert hot stage microscope; uncorrected. IR
Spectra: Perkin-Elmer 1600 FT-IR spectrometer; KBr pellets, in cmÀ1. NMR Spectra: at 300 MHz (1H)
and 75 MHz (13C) on a Bruker Avance-DPX-300 spectrometer in CDCl3 or (D6)DMSO soln. with TMS
as the internal standard; assignments of 13C-NMR spectra on the basis of HMQC and HMBC
experiments. MS: VG Analytical Autospec Q mass spectrometer; in m/z (rel. %). Elemental analyses:
Perkin-Elmer C,H,N analyzer 240 C.
Synthesis of 4-Methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (3a) and Ethyl 3,4-Dihydro-4-methyl-3-
oxo-2H-1,4-benzoxazine-7-carboxylate (3b). Step 1. ClCH2COCl (3.50 ml, 44 mmol) was added dropwise
to a stirred, ice-bath cooled mixture of the corresponding 2-aminophenol derivative (40 mmol) in a
biphase mixture of AcOEt (150 ml) and sat. NaHCO3 soln. (50 ml). After 1h, the org. phase was
separated, and the aq. phase was extracted with AcOEt (3 Â 40 ml). The combined org. fractions were
dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was dissolved in
DMF (20 ml), and the soln. was heated in a sealed vial in a microwave reactor (35 min, 1208/10 bar,
10 W) and poured into 800 ml of H2O/ice. The precipitate was filtered of and dried at 608.
7-Nitro-2H-1,4-benzoxazin-3(4H)-one. Prepared from 2-amino-5-nitrophenol (40.0 mmol, 6.16 g).
Yield: 6.91g (89%). The spectral data were identical to those reported in [9].
Ethyl 3,4-Dihydro-3-oxo-2H-1,4-benzoxazine-7-carboxylate. Prepared from ethyl 4-amino-3-hydroxy-
benzoate (40.0 mmol, 7.24 g). Yield: 8.33 g (94.1%). Brown crystals. M.p. 199 – 2018. IR: 3413, 3072, 1716,
1
1687, 1610, 1424, 1282, 1098, 1050, 762. H-NMR ((D6)DMSO): 11.03 (br. s, NH); 7.57 (dd, J ¼ 8.2, 1.8,
HÀC(6)); 7.43 (d, J ¼ 1.8, HÀC(8)); 6.98 (d, J ¼ 8.2, HÀC(5)); 4.64 (s, 2 HÀC(2)); 4.27 (q, J ¼ 7.1,
MeCH2); 1.29 (t, J ¼ 7.1, MeCH2). 13C-NMR ((D6)DMSO): 165.9, 165.8 (COOEt, C(3)); 143.7 (C(8a));
132.6 (C(7)); 125.3 (C(4a)); 124.8 (C(6)); 117.5 (C(8)); 116.5 (C(5)); 67.5 (C(2)); 61.5 (MeCH2O); 15.0

Helvetica Chimica Acta – Vol. 91(2008)
661
(MeCH2O). MS (FAB): 222 (20, [M þ H]þ), 154 (100), 137 (74). Anal. calc. for C11H11NO4 (221.21): C
59.73, H 5.01, N 6.33; found: C 59.76, H 5.12, N 6.27.
Step 2. A suspension of the corresponding 7-substituted 2H-1,4-benzoxazin-3(4H)-one (15.20 mmol)
from Step 1, K2CO3 (5.25g, 38.00 mmol), benzyl(triethyl)ammonium chloride (0.35 g, 1.52 mmol) and
MeI (0.96 ml, 15.44 mmol) in MeCN (60 ml) was stirred overnight at r.t. The suspension was filtered, and
the filtrate was evaporated under reduced pressure. The obtained residue was dissolved in AcOEt
(100 ml) and washed successively with 10% citric acid (2 Â 50 ml), sat. NaHCO3 soln. (2 Â 50 ml), and
sat. NaCl soln. (1 Â 50 ml). The org. phase was dried (Na2SO4), and the solvent was evaporated under
reduced pressure.
Compound 3a. Prepared from 7-nitro-2H-1,4-benzoxazin-3(4H)-one (15.2 mmol, 2.95 g). Yield:
2.97 g (94%). The spectral data were identical to those reported in [16].
Compound 3b. Prepared from ethyl 3,4-dihydro-3-oxo-2H-1,4-benzoxazine-7-carboxylate (3.36 g,
15.2 mmol). Yield: 3.29 g (92%). Pink crystals. M.p. 107 – 1088. IR: 2983, 1717, 1684, 1615, 1508, 1386,
1
1296, 1147, 886, 760. H-NMR ((D6)DMSO): 7.66 (dd, J ¼ 8.4, 1.9, HÀC(6)); 7.46 (d, J ¼ 1.9, HÀC(8));
7.26 (d, J ¼ 8.4, HÀC(5)); 4.72 (s, 2 HÀC(2)); 4.29 (q, J ¼ 7.1, MeCH2); 3.30 (s, MeN); 1.31 (t, J ¼ 7.1,
MeCH2). 13C-NMR ((D6)DMSO): 165.7 (COO); 165.0 (C(3)); 145.2 (C(8a)); 134.5 (C(4a)); 125.6
(C(7)); 124.9 (C(6)); 117.3 (C(8)); 116.2 (C(5)); 67.8 (C(2)); 61.6 (MeCH2); 28.7 (MeN); 15.0 (MeCH2).
FAB-MS: 236 (100, [M þ H]þ), 190 (21), 154 (48), 136 (41), 71 (45), 55 (47). Anal. calc. for C12H13NO4
(235.24): C 61.27, H 5.57, N 5.95; found: C 61.31, H 5.69, N 5.93.
Synthesis of Compounds 4a and 4b. The corresponding 2H-1,4-benzoxazin-3(4H)-one 3 (10.0 mmol)
was suspended in 200 ml of CCl4. Under stirring and irradiation with a 500-W lamp, a soln. of Br2
(10.1 mmol) in 50 ml of CCl4 was added dropwise over 30 min at r.t. After stirring for an additional 1.5 h
at r.t., the solvent was removed under reduced pressure. Products were additionally dried at 408.
2-Bromo-4-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (4a). Prepared from 4-methyl-7-nitro-2H-
1,4-benzoxazin-3(4H)-one (2.09 g, 10.0 mmol). Yield: 2.87 g (100%). Gray powder. M.p. 172 – 1748. IR:
3414, 3066, 1698, 1605, 1521, 1422, 1342, 1230, 1080, 919, 808, 745, 628. 1H-NMR (CDCl3, 300 MHz): 8.19
(dd, J ¼ 9.0, 2.5, HÀC(6)); 8.03 (d, J ¼ 2.5, HÀC(8)); 7.23 (d, J ¼ 9.0, HÀC(5)); 6.86 (s, HÀC(2)); 3.53 (s,
MeN). 13C-NMR (CDCl3, 75 MHz): 159.3, 144.3, 140.3, 135.0, 121.2, 115.1, 114.8, 76.2, 29.7. EI-MS: 288
(23, Mþ, 81Br), 286 (22, Mþ, 79Br), 207 (100), 179 (78), 133 (81). Anal. calc. for C9H7BrN2O4 (287.07): C
37.66, H 2.46, N 9.76; found: C 37.88, H 2.50, N 9.66.
Ethyl 2-Bromo-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylate (4b). Prepared from
ethyl 3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylate (2.35 g, 10.0 mmol). Yield: 3.14 g
(100%). White powder. M.p. 144 – 1478. IR: 3136, 1719, 1666, 1613, 1512, 1477, 1393, 1319, 1292, 1212,
1142, 1094, 1027. 1H-NMR ((D6)DMSO): 7.70 (dd, J ¼ 8.5, 1.8, HÀC(6)); 7.51( d, J ¼ 1.8, HÀC(8)); 7.32
(d, J ¼ 8.5, HÀC(5)); 5.64 (s, HÀC(2)); 4.29 (q, J ¼ 7.1, MeCH2); 3.33 (s, MeN); 1.30 (t, J ¼ 7.1, MeCH2).
13C-NMR ((D6)DMSO): 164.9 (COO); 161.9 (C(3)); 141.3 (C(8a)); 132.9 (C(4a)); 124.8 (C(7)); 124.6
(C(6)); 117.9 (C(8)); 115.2 (C(5)); 90.0 (C(2)); 60.9 (MeCH2O); 28.1(MeN); 14.1( MeCH2O). FAB-
MS: 316 (49, [M þ H]þ, 81Br), 314 (45, [M þ H]þ, 79Br), 234 (85), 206 (28), 154 (100), 136 (86). Anal.
calc. for C12H12BrNO4 (314.13): C 45.88, H 3.85, N 4.46; found: C 45.70, H 3.95, N 4.21.
Synthesis of Compounds 8a and 8b. A suspension of 4a or 4b (10.0 mmol), 4-(aminomethyl)benzo-
nitrile (1.32 g, 10 mmol) and K2CO3 (1.38 g, 10.0 mmol) in anh. THF (150 ml) was stirred at 608 for 2 h.
The mixture was cooled and poured into H2O/ice (600 ml). The precipitate was filtered off and dried at
608. The crude product was recrystallized from EtOH.
4-{[(3,4-Dihydro-4-methyl-7-nitro-3-oxo-2H-1,4-benzoxazin-2-yl)amino]methyl}benzonitrile (8a).
Prepared from 4a (2.87 g, 10.0 mmol). Yield: 2.91 g (86%). Brown powder. M.p. 204 – 2068. IR: 3306,
3088, 2228, 1677, 1598, 1498, 1341, 1134, 894, 745. 1H-NMR ((D6)DMSO): 7.97 (dd, J ¼ 8.9, 2.4, HÀC(6));
7.76 (d, J ¼ 8.2, HÀC(3’), HÀC(5’)); 7.47 – 7.50 (m, HÀC(8), HÀC(2’), HÀC(6’)); 7.39 (d, J ¼ 8.9,
HÀC(5)); 5.42 (d, J ¼ 11.0, HÀC(2)); 4.48 – 4.56 (m, NHCH2); 3.95 – 4.09 (m, NHCH2); 3.35 (s, MeN).
13C-NMR (CDCl3, 75 MHz): 161.5; 146.3; 142.5; 142.1; 135.7; 131.9; 128.6; 118.8; 118.1; 115.6; 112.7;
109.4; 85.9; 47.9; 28.7. EI-MS: 339 (4, [M þ H]þ), 321 (6), 168 (85), 131 (100), 116 (72). Anal. calc. for
C17H14N4O4 · 1ꢁ4 H2O (338.32): C 59.56, H 4.26, N 16.34; found: C 59.67, H 4.37, N 16.13.
Ethyl 2-[(4-Cyanobenzyl)amino]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylate
(8b). Prepared from 4b (3.13 g, 10.0 mmol). Yield: 3.21 g (88%). Yellow powder. M.p. 152 – 1558. IR:

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3451, 3278, 2228, 1715, 1677, 1611, 1509, 1397, 1286, 1159, 1027, 907, 818, 726. 1H-NMR ((D6)DMSO): 7.75
(d, J ¼ 8.2, HÀC(3’), HÀC(5’)); 7.66 (dd, J ¼ 8.5, 1.9, HÀC(6)); 7.48 (d, J ¼ 8.2, HÀC(2’), HÀC(6’)); 7.28
(d, J ¼ 8.5, HÀC(5)); 7.22 (d, J ¼ 1.9, HÀC(8)); 5.31( d, J ¼ 10.7, HÀC(2)); 4.34 – 4.42 (m, NHCH2); 4.30
(q, J ¼ 7.1, MeCH2); 3.92 – 4.07 (m, NHCH2); 3.35 (s, MeN); 1.33 (t, J ¼ 7.1, MeCH2). 13C-NMR
((D6)DMSO): 165.8 (COO); 162.7 (C(3)); 147.4 (C(1’)); 142.7 (C(8a)); 134.6 (C(3’); C(5’)); 132.8
(C(4a)); 129.6 (C(2’); C(6’)); 125.8 (C(7)); 124.6 (C(6)); 119.8 (CN); 119.0 (C(8)); 116.2 (C(5)); 110.3
(C(4’)); 86.7 (C(2)); 61.6 (MeCH2); 48.9 (NHCH2); 29.4 (MeN); 15.1 (MeCH2). EI-MS: 365 (4, Mþ), 320
(25), 235 (75), 222 (45), 195 (100), 116 (62). Anal. calc. for C20H19N3O4 (365.38): C 65.74, H 5.24, N
11.50; found: C 65.59, H 5.41, N 11.21.
Alkaline Hydrolysis of 8a and 8b. A soln. of 8a or 8b (1.0 mmol) and 1m NaOH (2.0 ml for 8a; 4.0 ml
for 8b) in dioxane/H2O 1:1(50 ml) was stirred for 6 h at r.t. The pH was adjusted with 1 m HCl to 3, and
the solvent was removed under reduced pressure. The residue was separated by CC (silica gel; CH2Cl2/
MeOH 20 :1 ! 9 :1) to give 9a (119 mg, 71%) and 10 (26 mg, 20%; starting from 8a), and 9c (35 mg,
21%) and 10 (89 mg, 68%; starting from 8b).
Data of 4-Formylbenzonitrile (10). The product was in all respects (m.p., TLC, 1H-NMR, MS)
identical to an authentic sample (Sigma-Aldrich).
Data of 2-(Methylamino)-5-nitrophenol (9a). Red crystals. M.p. 177 – 1798. IR: 3402, 1614, 1552,
1486, 1296, 1199, 855, 749. 1H-NMR ((D6)DMSO): 10.26 (s, OH); 7.72 (dd, J ¼ 9.0, 2.4, HÀC(4)); 7.47 (d,
J ¼ 2.4, HÀC(6)); 6.48 (d, J ¼ 9.0, HÀC(3)); 6.42 (br. q, J ¼ 4.8, NH); 2.83 (d, J ¼ 5.3, Me). 13C-NMR
((D6)DMSO): 146.5, 143.7, 136.0, 119.6 (C(4)); 107.9 (C(6)); 107.2 (C(3)); 30.1 (Me). EI-MS: 168 (100,
Mþ), 138 (44), 122 (25), 94 (24). HR-MS: 168.0535 (Mþ, C7H8N2Oþ3 ; calc. 168.0535).
Data of 3-Hydroxy-4-(methylamino)benzoic Acid (9c). White crystals. M.p. 180 – 1838. IR: 3318,
1675, 1609, 1423, 1271, 1158, 958, 766, 715, 628. 1H-NMR ((D6)DMSO): 11.90 (br. s, COOH); 9.50 (br. s,
OH); 7.37 (dd, J ¼ 8.3, 1.8, HÀC(6)); 7.23 (d, J ¼ 1.9, HÀC(2)); 6.42 (d, J ¼ 8.3, HÀC(5)); 5.51(br. s,
NH); 2.75 (br. s, Me). 13C-NMR ((D6)DMSO): 168.6 (CO); 143.8, 143.8 (C(3), C(4)); 124.0 (C(6)); 117.4
(C(1)); 114.2 (C(2)); 108.1 (C(5)); 30.2 (Me). EI-MS: 167 (100, Mþ), 152 (25), 150 (19), 124 (18). Anal.
calc. for C8H9NO3 (167.16): C 57.48, H 5.43, N 8.38; found: C 57.71, H 5.51, N 8.40.
Acid Hydrolysis of 8b. Compound 8b (1.095 g, 3.0 mmol) and 6m HCl (30 ml) in dioxane (30 ml)
were refluxed overnight. The soln. was then cooled and neutralized with 3m NaOH. (Boc)2O (720 mg,
3.3 mmol) and NaHCO3 (504 mg, 6 mmol) were added, and the soln. was stirred at r.t. overnight. The
dioxane was removed under reduced pressure, the pH was adjusted to 3.5, and the products were
extracted with AcOEt (3 Â 40 ml). The combined org. fractions were dried (Na2SO4) and the solvent
evaporated under reduced pressure. The residue was separated with CC (CH2Cl2/MeOH 50 :1 ! 9 :1 ) to
give 6c (288 mg, 43%) and 12 (432 mg, 62%).
Data of 4-Methyl-3-oxo-3,4-dihydro-2-hydroxy-2H-1,4-benzoxazine-7-carboxylic Acid (6c). White
crystals. M.p. 249 – 2518. IR: 3163, 1701, 1612, 1478, 1388, 1241, 1148, 1026, 926, 805, 760, 515. 1H-NMR
((D6)DMSO): 12.89 (s, COOH); 8.12 (s, OH); 7.70 (dd, J ¼ 8.4, 1.9, HÀC(6)); 7.51( d, J ¼ 1.9, HÀC(8));
7.30 (d, J ¼ 8.4, HÀC(5)); 5.65 (s, HÀC(2)); 3.34 (s, MeN). 13C-NMR ((D6)DMSO): 167.4; 162.8; 142.2;
133.5; 126.8; 125.2 (C(6)); 119.0 (C(8)); 115.9 (C(5)); 91.0 (C(2)); 29.0 (MeN). EI-MS: 223 (25, Mþ), 194
(100). Anal. calc. for C10H9NO5 (223.18): C 53.82, H 4.06, N 6.28; found: C 54.13, H 4.13, N 6.34.
Data of tert-Butyl (4-Cyanobenzyl)carbamate (12). White crystals. M.p. 90 – 928. IR: 3351, 2977,
2228, 1675, 1504, 1366, 1246, 1160, 1053, 872, 846, 784. 1H-NMR ((D6)DMSO): 7.80 (d, J ¼ 8.2, HÀC(3),
HÀC(5)); 7.50 (br. t, J ¼ 6.1, NH); 7.43 (d, J ¼ 8.2, HÀC(2), HÀC(6)); 4.21( d, J ¼ 6.1, CH2); 1.40 (s, t-
Bu). 13C-NMR (CDCl3, 75 MHz): 156.3 (CO); 145.1 (C(1’)); 132.8 (C(3’); C(5’)); 128.2 (C(2’); C(6’));
119.2 (CN); 111.5 (C(4’)); 80.4 (Me3C); 44.6 (CH2); 28.7 (3 Me). EI-MS: 233 (32, [M þ H]þ), 177 (70),
116 (35), 57 (100). Anal. calc. for C13H16N2O2 (232.28): C 67.22, H 6.94, N 12.06; found: C 66.88, H 6.95, N
12.46.
Attempted Boc Protection of 8a. A soln. of (Boc)2O (1.31 g, 6 mmol) in THF (25 ml) was added
dropwise to a stirred soln. of 8a (1.69 g, 5 mmol), 4-(dimethylamino)pyridine (100 mg, 0.8 mmol), and
Et3N (707 mg, 7 mmol), cooled on ice bath. The mixture was stirred overnight at r.t., THF was removed
under reduced pressure, and the obtained residue was dissolved in AcOEt (100 ml) and washed
successively with 5% citric acid (2 Â 25 ml) and brine (1 Â 25 ml). The org. phase was dried (Na2SO4),

Helvetica Chimica Acta – Vol. 91(2008)
663
and the solvent was evaporated under reduced pressure. The crude product was separated by radial
chromatography (petroleum ether/AcOEt 3 :1) to give 13a (666 mg, 41%) and 10 (334 mg, 51%).
Data of tert-Butyl {2-[(2-Hydroxy-4-nitrophenyl)(methyl)amino]-2-oxoethyl}carbamate (13a).
White crystals. M.p. 101 – 1038. IR: 3366, 1677, 1529, 1353, 1246, 1163, 1082, 956, 816, 736. 1H-NMR
((D6)DMSO): 11.08 (br. s, OH); 7.77 (d, J ¼ 2.5, HÀC(3)); 7.74 (dd, J ¼ 8.4, 2.5, HÀC(5)); 7.52 (d, J ¼
8.4, HÀC(6)); 6.76 (t, J ¼ 5.8, CONH); 3.49 (br. s, CH2); 3.10 (s, MeN); 1.35 (s, t-Bu). 13C-NMR
((D6)DMSO): 169.4 (CONMe); 156.4 (NHCOO); 154.6, 148.2, 136.5 (C(1), C(2), C(4)); 131.2 (C(6));
115.6 (C(5)); 112.2 (C(3)); 78.8 (Me3C); 42.8 (CH2); 36.4 (MeN); 29.03 (3 Me). FAB-MS: 326 (41, [M þ
H]þ), 270 (95), 226 (58), 169 (32), 57 (100). Anal. calc. for C14H19N3O6 · 3ꢁ4 H2O (325.32): C 50.98, H 5.96,
N 12.74; found: C 50.94, H 6.12, N 12.61.
1
Data of 10. Compound 10 was in all respects (m.p., TLC, H-NMR, MS) identical to an authentic
sample (Sigma-Aldrich).
Alkaline Hydrolysis of Ethyl 3,4-Dihydro-3-oxo-2H-1,4-benzoxazine-7-carboxylates 6b and 7b. A
soln. of 6b or 7b (1mmol) and 2 ml of 1m NaOH in EtOH/H2O 1:1(50 ml) was stirred for 6 h at r.t. The
pH was then adjusted to 1with 1 m HCl, the precipitate was filtered off and dried at 608. The
corresponding carboxylic acids 6c and 7c were obtained in 96 and 94% yield, resp.
Data of 6c. Yield: 214 mg (96%) The spectral data of 6c were identical to those described above.
Data of 2-[(4-Cyanobenzyl)oxy]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylic Acid
(7c). Yield: 317 mg (94%) The spectral data of 7c were identical to those reported in [9].
Synthesis of 6a, 6b, and 6c. Method A (with NaOH). A soln. of 4a (1.0 mmol) and 1m NaOH
(1.2 ml), or 4b (1mmol) and 1m NaOH (10 ml) in dioxane/H2O 1:1(50 ml) was stirred overnight at r.t.
The pH was then adjusted to 3 with 1m HCl, and the solvent was evaporated under reduced pressure. The
crude products were separated by radial chromatography using petroleum ether/AcOEt 1:1 as eluant
giving 6a (123 mg, 55%) and 9a (50 mg, 30%), or 6c (14 mg, 6%) and 9c (135 mg, 81%), resp.
Method B (with NaHCO3). A soln. of 4a or 4b (10 mmol) in THF (300 ml) was added dropwise, over
a period of 1h, to a soln. of NaHCO 3 (1.68 g, 20 mmol) in THF/H2O 4 :1(400 ml). The solvent was then
evaporated under reduced pressure. The products obtained from 4a were separated by recrystallization
from H2O or AcOEt to give 6a (1.37 g, 61%) and 14a (1.12 g, 26%). Products obtained from 4b were
separated by recrystallization from EtOH/AcOEt mixture to give 6b (2.16 g, 86%) and 14b (388 mg,
8%).
Method C (with BaCO3). A suspension of 4a or 4b (10.0 mmol) and BaCO3 (11.0 mmol) in H2O
(150 ml) was refluxed for 15 min, cooled to r.t., and extracted with AcOEt (3 Â 40 ml). The combined
org. fractions were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to
yield 6a (2.06 g, 92%) or 6b (2.36 g, 94%), resp.
The spectral data of 9a, 6c, and 9c were identical to those given above.
Data of 2-Hydroxy-4-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (6a). Yellow powder. M.p. 183 –
1868. IR: 3401, 1613, 1552, 1468, 1455, 1432, 1397, 1260, 1199, 1170, 1088. 1H-NMR ((D6)DMSO): 8.37 (d,
J ¼ 6.2, OH); 7.98 (dd, J ¼ 9.0, 2.6, HÀC(6)); 7.82 (d, J ¼ 2.6, HÀC(8)); 7.40 (d, J ¼ 9.0, HÀC(5)); 5.72 (d,
J ¼ 6.2, HÀC(2)); 3.37 (s, MeN). 13C-NMR ((D6)DMSO): 162.6 (C(3)); 143.5 (C(7)); 142.4 (C(8a));
135.7 (C(4a)); 119.5 (C(6)); 116.3 (C(5)); 113.5 (C(8)); 91.0 (C(2)); 29.3 (MeN). EI-MS: 224 (13, Mþ),
195 (100), 149 (45). Anal. calc. for C9H8N2O5 (224.17): C 48.22, H 3.60, N 12.50; found: C 48.25, H 3.56, N
12.56.
Data of Ethyl 3,4-Dihydro-2-hydroxy-4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylate (6b). Violet
crystals. M.p. 147 – 1488. IR: 3126, 1717, 1656, 1614, 1513, 1394, 1286, 1247, 1154, 1043, 762, 701. 1H-NMR
((D6)DMSO): 8.15 (s, OH); 7.71 (dd, J ¼ 8.4, 1.9, HÀC(6)); 7.53 (d, J ¼ 1.9, HÀC(8)); 7.32 (d, J ¼ 8.4,
HÀC(5)); 5.66 (s, HÀC(2)); 4.30 (q, J ¼ 7.1, MeCH2); 3.35 (s, MeN); 1.32 (t, J ¼ 7.1, MeCH2). 13C-NMR
((D6)DMSO): 164.8, 161.8, (COO, C(3)); 141.3, 132.8, 124.8 (C(4a), C(8a), C(7)); 124.0 (C(6)); 117.8
(C(8)); 115.1 (C(5)); 90.0 (C(2)); 60.6 (MeCH2); 28.0 (MeN); 14.0 (MeCH2). EI-MS: 251(31, Mþ), 222
(100), 206 (25), 194 (48). Anal. calc. for C12H13NO5 (251.24): C 57.37, H 5.22, N 5.58; found: C 57.65, H
5.25, N 5.80.
Data of 2,2’-Oxybis(4-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (14a). The product gave two
spots on TLC (Rf 0.32 and 0.43; silica gel, CH2Cl2/MeOH 50 :1). 1H-NMR showed the presence of two
diastereoisomers. The lower spot was isolated and characterized. Red crystals. M.p. 273 – 2768. IR: 3446,

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Helvetica Chimica Acta – Vol. 91(2008)
1602, 1529, 1489, 1303, 1249, 1211, 1156, 1106, 1076. 1H-NMR ((D6)DMSO): 8.00 (dd, J ¼ 8.9, 2.5,
HÀC(6), HÀC(6’)); 7.78 (d, J ¼ 2.5, HÀC(8), HÀC(8’)); 7.04 (d, J ¼ 8.9, HÀC(5), HÀC(5’)); 5.97 (s,
HÀC(2), HÀC(2’)); 3.42 (s, 2 MeN). EI-MS: 430 (6, Mþ), 400 (4), 208 (100), 179 (80), 133 (53). HR-
MS: 430.0770 (Mþ, C18H14N4Oþ9 ; calc. 430.0761).
Diethyl 2,2’-Oxybis(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-7-carboxylate) (14b). The
product was obtained as a mixture of diastereoisomers showing two spots on TLC (Rf 0.31and 0.44;
silica gel, CH2Cl2/MeOH 50 :1) and duplication of some resonances in the 1H-NMR spectrum. The lower
spot was isolated and characterized. Gray crystals. M.p. 249 – 2538. IR: 2987, 1716, 1615, 1514, 1385, 1290,
1249, 1102, 990, 766. 1H-NMR ((D6)DMSO): 7.75 (dd, J ¼ 8.5, 1.9, HÀC(6), HÀC(6’)); 7.71( d, J ¼ 1.9,
HÀC(8), HÀC(8’)); 7.33 (d, J ¼ 8.5, HÀC(5), HÀC(5’)); 6.11 (s, HÀC(2), HÀC(2’)); 4.33 (q, J ¼ 7.1, 2
MeCH2); 3.38 (s, 2 MeN); 1.35 (t, J ¼ 7.1, 2 MeCH2). EI-MS: 484 (5, Mþ), 439 (13), 250 (40), 234 (100),
206 (59), 178 (30). Anal. calc. for C24H24N2O9 (484.46): C 59.50, H 4.99, N 5.78; found: C 59.13, H 5.00, N
5.78.
This work was supported financially by the Slovenian Research Agency (Grant No. P1-0208). The
authors thank Prof. Roger Pain for critical reading of the manuscript.
REFERENCES
[1] D. Sicker, M. Schulz, Stud. Nat. Prod. Chem. 2002, 27, 185.
[2] J. Teller, in ꢂ Houben-Weyl Methods of Organic Chemistry, Hetarenes IV, Six-Membered and Larger
Hetero-Rings with Maximum Unsaturationꢃ, Ed. E. Schaumann, Georg Thieme, Stuttgart, 1997,
Vol. E 9a, pp. 141 – 177.
ˇ
ˇ
ˇ
[3] J. Ilas, P. Stefanic Anderluh, M. Sollner Dolenc, D. Kikelj, Tetrahedron 2005, 61, 7325.
ˇ
[4] J. Ilas, N. Lah, I. Leban, D. Kikelj, Tetrahedron Lett. 2008, 49, 222.
ˇ
ˇ
ˇ
[5] P. Stefanic, K. Turnsek, D. Kikelj, Tetrahedron 2003, 59, 7123.
ˇ
ˇ
[6] P. Stefanic, M. Breznik, N. Lah, I. Leban, J. Plavec, D. Kikelj, Tetrahedron Lett. 2001, 42, 5295.
[7] D. Sicker, B. Prꢄtorius, G. Mann, L. Meyer, Synthesis 1989, 21 1 .
[8] E. E. Smissman, M. D. Corbett, N. A. Jenny, O. Kristiansen, J. Org. Chem. 1972, 37, 1700.
[9] J. Atkinson, P. Morand, J. T. Arnason, H. M. Niemeyer, H. Bravo, J. Org. Chem. 1991, 56, 1788.
[10] A. Chatterjee, N. J. Sharma, J. Banerji, S. C. Basa, Indian J. Chem., Sect. B 1990, 29, 132.
ˇ
ˇ
ˇ
[11] P. Anderluh Stefanic, M. Anderluh, J. Ilas, J. Mravljak, M. Sollner Dolenc, M. Stegnar, D. Kikelj, J.
Med. Chem. 2005, 48, 3110.
[12] J. A. Gavin, M. E. Garcia, A. J. Benesi, T. E. Mallouk, J. Org. Chem. 1998, 63, 7663.
[13] R. A. McClelland, J. Am. Chem. Soc. 1978, 100, 1844.
[14] H. G. O. Becker, W. Berger, G. Domschke, E. Fanghꢄnel, J. Faust, M. Fischer, F. Gentz, K. Gewald,
R. Gluch, R. Mayer, K. Müller, D. Pavel, H. Schmidt, K. Schollberg, K. Schwetlick, E. Seiler, G.
Zeppenfeld, ꢂOrganikum: Organisch-chemisches Grundpraktikumꢃ, 21th edn., Wiley-VCH, Wein-
heim, 2001.
[15] G. Caliendo, E. Perissutti, V. Santagada, F. Fiorino, B. Severino, D. Cirillo, R. di Villa Bianca, L.
Lippolis, A. Pinto, R. Sorrentino, Eur. J. Med. Chem. 2004, 39, 815.
[16] C. Gluchowski, U.S. Patent 5,091,528, 1992, p. 10. (Chem. Abstr. 1993, 118, 234070).
Received December 6, 2007