A convenient synthesis of 3,4-dihydro-1,4-benzoxazin-2-ones

Article abstract of DOI:10.1016/j.tet.2008.04.010

3,4-Dihydro-1,4-benzoxazin-2-one was prepared for the first time by catalytic hydrogenation of 4-benzyl-3,4-dihydro-1,4-benzoxazin-2-one. A simple and efficient synthesis of 4-benzyl- and 4-alkyl-3,4-dihydro-1,4-benzoxazin-2-one derivatives from ethyl 2-(2-hydroxyphenylamino)acetate and aldehydes is described. Some considerations regarding the reactivity of 3,4-dihydro-1,4-benzoxazin-2-ones are given.

Full text of DOI:10.1016/j.tet.2008.04.010

Tetrahedron 64 (2008) 5756–5761
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A convenient synthesis of 3,4-dihydro-1,4-benzoxazin-2-ones
*
Nace Zidar, Danijel Kikelj
ˇ
ˇ
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
3,4-Dihydro-1,4-benzoxazin-2-one was prepared for the first time by catalytic hydrogenation of
4-benzyl-3,4-dihydro-1,4-benzoxazin-2-one. A simple and efficient synthesis of 4-benzyl- and 4-alkyl-
3,4-dihydro-1,4-benzoxazin-2-one derivatives from ethyl 2-(2-hydroxyphenylamino)acetate and alde-
hydes is described. Some considerations regarding the reactivity of 3,4-dihydro-1,4-benzoxazin-2-ones
are given.
Received 20 November 2007
Received in revised form 19 March 2008
Accepted 3 April 2008
Available online 8 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of 3,4-dihydro-1,4-benzoxazin-2-one (3) and then func-
tionalize it by N-alkylation using appropriate benzyl halides as
In contrast to the 2H-1,4-benzoxazin-3(4H)-one (1) and 3,4-
dihydro-2H-1,4-benzoxazine (2) scaffolds, which have been in-
tensively studied1 and are present as structural subunits of many
naturally occurring2 and synthetic3 bioactive compounds, de-
rivatives of 3,4-dihydro-1,4-benzoxazin-2-one (3) are much less
well known. While the majority of the described derivatives of 3
bear 3-alkyl4–6 or 3-alkylidene7,8 side chains, less information is
available in the literature about the 3-unsubstituted derivatives.
Moreover, a synthesis of the parent 3,4-dihydro-1,4-benzoxazin-
2-one (3) has, to our knowledge, not yet been described.
alkylating agents. In our first attempt to prepare 3 by analogy to the
synthesis of 2H-1,4-benzoxazin-3(4H)-one derivatives from 2-
aminophenols and chloroacetyl chloride,9–13 2-nitrophenol (4) and
chloroacetyl chloride (5) were reacted in the presence of triethyl-
amine to give the expected 2-nitrophenyl 2-chloroacetate (6) in
almost quantitative yield (Scheme 1). In the next step, the nitro
group was reduced to the amine by catalytic hydrogenation, using
palladium on charcoal as catalyst. This was expected to induce
a spontaneous ring closure to give the lactone 3. However, analysis
of the reaction product revealed that this did not happen and, using
ethanol as a solvent, only 2-aminophenol (7a) was isolated, which
demonstrated that the ester moiety in 6 was susceptible to alco-
holysis. For this reason, we decided to use an inert solvent such as
tetrahydrofuran, but again failed to obtain the desired product 3.
Instead, 2-chloro-N-(2-hydroxyphenyl)-acetamide (8) was un-
expectedly obtained, indicating that, following reduction of the
nitro group, oxygen to nitrogen rearrangement took place. Such
rearrangements are common with acylated 2-aminophenols and
lead to a reversible equilibrium in which the more stable isomer
predominates (Scheme 2). According to the theory of LeRosen and
Smith14,15 for predicting the composition of an equilibrium mixture
of N- and O-acylated phenols on the basis of the principle of min-
imum charge concentration, the predominance of the acetamide 8
in the reaction mixture can be explained by the possibility of
delocalization of the lone pair of electrons on the nitrogen, leading
to better equalization of charge over the molecule.
O
O
O
O
N
H
O
N
H
N
H
1
2
3
In the course of our synthetic work directed towards discovery
of new potential antibacterial drugs, we required various N-
substituted 3,4-dihydro-1,4-benzoxazin-2-one derivatives, which
could be used as starting compounds for further functionalization.
We report here the synthesis of hitherto unknown 4-benzyl- and
4-alkyl-3,4-dihydro-1,4-benzoxazin-2-ones 12–21 and the first
successful synthesis of the parent 3,4-dihydro-1,4-benzoxazin-2-
one (3).
2. Results and discussion
Since attempted cyclization of 2-nitrophenol with chloroacetyl
chloride did not result in the desired product 3, we were forced to
choose a different reaction pathway. This time 2-aminophenol (7a)
and ethyl 2-bromoacetate (9) were reacted in the presence of
potassium fluoride and the N-alkylated product 10a was obtained
(Scheme 3). We anticipated that compound 10a would be easily
converted to lactone 3, either by conventionally heating the
Our initial plan for the preparation of 4-benzyl-3,4-dihydro-1,4-
benzoxazin-2-one derivatives was first to develop a suitable
* Corresponding author. Tel.: þ386 1 476 9561; fax: þ386 1 425 8031.
E-mail address: danijel.kikelj@ffa.uni-lj.si (D. Kikelj).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.010

N. Zidar, D. Kikelj / Tetrahedron 64 (2008) 5756–5761
5757
OH
O
OH
Cl
Cl H2/Pd-C, EtOH
Et3N, CH2Cl2
Cl
+
O
O
NO2
NH2
NO2
5
4
7a
6
OH
O
H2/Pd-C, THF
Cl
N
H
8
Scheme 1.
O
OH
also not be obtained when under same conditions DMF was
replaced by N-methylpyrrolidone as solvent.
Cl
O
O
Cl
NH2
N
H
8
OH
OH
OEt
KF, DMF
Br
+
Scheme 2.
NMe2
MW: 120 °C, 30 min
O
NH2
N
H
O
11
9
7a
OH
OH
Scheme 4.
OEt
KF
DMF, 60 °C
Br
+
OEt
O
R
N
H
R
NH2
Searching for an explanation for the unsuccessful attempts to
cyclize 10a to 3,4-dihydro-2H-1,4-benzoxazin-2-one (3), we came
across the suggestion of Freedman and Frost18 that the formation of
the morpholine-2-one ring from the corresponding N-substituted
2-aminophenols is spontaneous when the nitrogen is tertiary, but
not when it is secondary. Although the presence or absence of an N-
alkyl group appears to be the dominant factor, steric and electronic
O
9
7a (R = H)
7b (R = CH3)
10a (R = H)
10b (R = CH3)
O
O
OH
OEt
N
H
N
H
effects of the substituents in the a-position of the amino group also
O
control the ring closure.19,20 Thus, it became clear that, for suc-
cessful preparation of N-substituted 3,4-dihydro-1,4-benzoxazin-
2-one derivatives, the order of the initially envisaged synthetic
steps should be reversed. The secondary amino group of ethyl 2-(2-
hydroxyphenylamino)acetate (10a) was first benzylated and the
obtained N-benzyl derivatives cyclized to 4-benzyl-3,4-dihydro-
1,4-benzoxazin-2-one derivatives 12–17. The N-benzylation step
was performed by reductive amination of benzaldehyde derivatives
with 10a, using sodium triacetoxyborohydride21 as a reducing
agent (Scheme 5). After attachment of a benzyl group, spontaneous
ring closure took place and lactones 12–17 were isolated as the sole
products. As an exception, in the reaction of 10a with 4-(dime-
thylamino)benzaldehyde, product 23 was obtained in 55% yield,
probably as a result of Hofmann–Martius rearrangement22–24 of
intermediary formed ethyl 2-((4-(dimethylamino)benzyl)-(2-hy-
droxy-phenyl)amino)acetate (22) (Scheme 6).
3
10a
Scheme 3.
reaction mixture or by applying microwave radiation. Despite
several attempts in which the solvent, temperature, acid or base
catalyst and reaction time were varied, the target 3,4-dihydro-1,4-
benzoxazin-2-one (3) could not be obtained (Table 1). This was
surprising, since the isomeric 2H-1,4-benzoxazin-3(4H)-one (1) is
easily formed by cyclization of in situ formed ethyl 2-(2-
aminophenoxy)acetate.16
In an attempt to obtain 3,4-dihydro-1,4-benzoxazin-2-one (3) in
a one pot reaction by heating 2-aminophenol (7a) and ethyl 2-
bromoacetate (9) in the presence of potassium fluoride in a micro-
wave reactor at 120 ꢀC for 30 min, instead of the expected
benzoxazinone 3, 2-(2-hydroxyphenylamino)-N,N-dimethylacet-
amide (11) was obtained in moderate yield (Scheme 4). The occur-
rence of dimethylamine, which in the reaction mixture acts as
a nucleophile to form the amide 11, can be explained by partial
decomposition of DMF on intense heating.17 Compound 3 could
R2-CHO,
NaBH(OAc)3, AcOH
O
O
N
OH
OEt
R1
R1
N
H
CH2Cl2, rt
O
R2
Table 1
10
12-21
Reaction conditions applied for the attempted synthesis of 3 by cyclization of 10a
Reagent, solvent
T [ꢀC]
t
R1
R2
C6H5
C6H4-4-CN
C6H4-4-COOH
C6H4-4-OMe
C6H4-4-OH
C6H4-3-OH
Product Yield (%)
KF, DMF
KF, DMF
60
24 h
H
H
H
H
H
H
12
13
14
15
16
17
18
19
20
21
65
41
15
61
40
30
55
70
37
62
120, MWa
120, MW
100, MW
120, MW
70
30 min
25 min
20 min
20 min
24 h
5 h
24 h
20 min
30 min
K2CO3, BnEt3NþClꢁ, DMF
d, DMF
NaHCO3, DMF
NaHCO3, DMF
NaOEt, EtOH
NaH, DMF
p-TosOH, toluene
p-TosOH, 1,4-dioxane
60
CH3 C6H5
rtb
H
H
H
CH2C6H5
CH3
(CH2)7CH3
120, MW
150, MW
a
Microwave irradiation.
Room temperature.
b
Scheme 5.

5758
N. Zidar, D. Kikelj / Tetrahedron 64 (2008) 5756–5761
CHO
occurred, the dimethylamine formed in situ acted as a nucleophile
OH
NaBH(OAc)3,
AcOH
and opened the lactone ring of 3. It should thus be pointed out that
3,4-dihydro-1,4-benzoxazin-2-one (3) is unstable in the presence
of nucleophiles and undergoes ring opening.
OEt
+
N
H
CH2Cl2, rt
O
NMe2
10a
3. Conclusion
OH
OH
In conclusion, the first synthesis of 3,4-dihydro-1,4-benzoxazin-
2-one (3) was accomplished by catalytic hydrogenation of 4-ben-
zyl-3,4-dihydro-1,4-benzoxazin-2-one (12). The latter was formed
by spontaneous lactonization of ethyl N-benzyl 2-(2-hydroxy-
phenyl-amino)acetate, itself obtained by reductive amination of
benzaldehyde with ethyl 2-(2-hydroxyphenylamino)-acetate (10a).
Using the same synthetic strategy, a series of 4-alkyl- and 4-benzyl-
3,4-dihydro-1,4-benzoxazin-2-ones were prepared. These results
contribute to the chemistry of 3,4-dihydro-1,4-benzoxazin-2-ones,
which, in comparison with isomeric 2H-1,4-benzoxazin-3(4H)-
ones, have been much less explored.
N
COOEt
Me2N
N
H
COOEt
NMe2
23
22
Scheme 6.
To broaden the scope of the method, we also performed
reductive amination of 10a with some aliphatic aldehydes, which,
after spontaneous ring closure, afforded 4-alkyl-3,4-dihydro-1,4-
benzoxazin-2-one derivatives 19–21. Further, we tried to extend
the scope of our synthesis with the preparation of 3,4-dihydro-1,4-
benzoxazin-2-one derivatives bearing different substituents in the
aromatic ring. Unfortunately, successful preparation of analogues of
10a, using the method depicted in Scheme 3 was found to be
strongly dependant on the position and electronic properties of
substituents in the aromatic ring. 4-Chloro-, 5-ethoxycarbonyl-,
4-methyl- and 4-nitro-2-aminophenol were reacted with ethyl
2-bromoacetate (9) in the presence of potassium fluoride in
N,N-dimethylformamide, but only 2-amino-4-methyl-phenol gave
the expected product 10b, which was successfully transformed to
the 3,4-dihydro-1,4-benzoxazin-2-one derivative 18. In all other
cases O-alkylation and subsequent cyclization to the corresponding
3,4-dihydro-2H-1,4-benzoxazine-3-one derivatives took place.25
However, this does not preclude the application of our method to
the synthesis of 3,4-dihydro-1,4-benzoxazin-2-ones substituted in
the aromatic ring from analogues of 10 accessible in a different way.
Encouraged by the successful preparation of 4-benzyl-3,4-
dihydro-1,4-benzoxazin-2-ones 12–18, we presumed that 3 could
be obtained from 12 by hydrogenolytic cleavage of the benzyl
group. Indeed, 3,4-dihydro-2H-1,4-benzoxazin-2-one (3) was
obtained for the first time by catalytic hydrogenation of 12 using
palladium on charcoal as a catalyst (Scheme 7).
4. Experimental
4.1. General
Chemicals obtained from Aldrich Chemical Co. and Merck were
used without further purification. Analytical TLC was performed on
Merck silica gel (60 F254) plates (0.25 mm) and components visu-
alized with ultraviolet light. Column chromatography was carried
out on silica gel (particle size 240–400 mesh). Microwave assisted
reactions were performed using a CEM Discover microwave reactor
(CEM Corporation, USA). Melting points were determined on
a Reichert hot stage microscope and are uncorrected. 1H NMR
spectra and 13C NMR spectra were recorded on a Bruker AVANCE
DPX300 spectrometer in CDCl3 or DMSO-d6 solution, with TMS as
the internal standard, at 300 MHz or 75 MHz, respectively. IR
spectra were obtained on a Perkin–Elmer FTIR System Spectrum BX
spectrometer. Microanalyses were performed on a Perkin–Elmer C,
H, N analyzer 240C. Mass spectra were obtained using a VG Ana-
lytical Autospec Q mass spectrometer. All reported yields are those
of the purified products.
4.2. 2-Nitrophenyl 2-chloroacetate (6)
Chloroacetyl chloride (5) (1.04 mL, 13.0 mmol) was added
O
N
O
dropwise to
a stirred solution of 2-nitrophenol (4) (1.39 g,
O
O
H2/Pd-C, THF
10.0 mmol) and triethylamine (2.1 mL, 15.0 mmol) in anhydrous
dichloromethane (10 mL), cooled on ice bath. The reaction mixture
was stirred for 5 h and allowed to reach room temperature.
Dichloromethane (30 mL) was added and the organic phase was
washed successively with water (2ꢂ15 mL), saturated aqueous
NaHCO3 (2ꢂ15 mL) and brine (2ꢂ15 mL). The organic phase was
dried over Na2SO4, filtered and concentrated under reduced pres-
sure. The crude product was crystallized from EtOAc/petroleum
ether to afford 6 as white crystals (1.94 g, 90%), mp 62–63 ꢀC (lit.26
62–62.5 ꢀC); Rf¼0.27 (EtOAc/petroleum ether¼1:4). 1H NMR
N
H
3
12
Scheme 7.
In an attempt to remove the benzyl group from 12 using
ammonium formate as a hydrogen transfer agent in the presence
of Pd/C as catalyst, and when the reaction was carried out in
N,N-dimethylformamide or N-methylpyrrolidone in a microwave
reactor, 3 was not formed; instead product 11 was obtained in DMF
(Scheme 8). This reaction illustrates well the reactivity of the parent
3,4-dihydro-1,4-benzoxazin-2-one ring. Although debenzylation
(DMSO-d6, 300 MHz)
d
4.79 (s, 2H, CH2), 7.53 (dd, 1H, J5,6¼8.1 Hz,
J4,6¼1.2 Hz, 6-H), 7.60 (ddd, 1H, 3J¼8.1 Hz, 4J¼1.2 Hz, 4/5-H), 7.85
(ddd, 1H, 3J¼8.1 Hz, 4J¼1.2 Hz, 4/5-H), 8.19 (dd, 1H, J3,4¼8.1 Hz,
J3,5¼1.2 Hz, 3-H). MS (EI) m/z (%): 217 ([Mþ2]þ, 10), 215 (Mþ, 38),
188 (20), 169 (31), 139 (100), 122 (34), 109 (23), 106 (17), 92 (25), 77
(75), 63 (21).
O
N
O
OH
HCOONH4/Pd-C, DMF
MW: 120 °C, 20 min
4.3. 2-Chloro-N-(2-hydroxyphenyl)acetamide (8)
NMe2
N
H
O
To a solution of compound 6 (200 mg, 0.93 mmol) and tri-
ethylamine (0.155 mL, 1.11 mmol) in anhydrous tetrahydrofuran
(10 mL), 10% Pd–C (20 mg) was added. The reaction mixture was
11
12
Scheme 8.

N. Zidar, D. Kikelj / Tetrahedron 64 (2008) 5756–5761
5759
stirred under a hydrogen atmosphere for 1 h. The catalyst was then
filtered off and the solvent removed under reduced pressure. The
residue was dissolved in EtOAc (30 mL) and washed with water
(3ꢂ10 mL) and brine (2ꢂ10 mL). The organic phase was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
residue was separated by flash column chromatography using
EtOAc/petroleum ether (1:2) as eluent, giving a brown-white solid
(32 mg, 19%), mp 120–125 ꢀC (lit.27 137–138 ꢀC); Rf¼0.49 (EtOAc/
(4 mL) in a sealed 10 mL process vial was placed in a microwave
reactor and heated at 120 ꢀC for 30 min. The reaction mixture was
cooled to room temperature and adjusted with 1 M NaOH to pH 10.
The mixture was poured into ice/water (20 g) and stood in a re-
frigerator overnight. The precipitate was filtered off and washed
with ether, yielding 227 mg (26%) of grey solid, mp 183–187 ꢀC,
Rf¼0.42 (EtOAc/petroleum ether¼4:1); IR (KBr) 3411, 3245, 2925,
2852, 2362,1611, 1527, 1474,1452, 1419,1382, 1334,1247, 1205, 1151,
petroleum ether¼1:1). 1H NMR (DMSO-d6, 300 MHz)
d
4.38 (s, 2H,
1127, 1088, 1045, 995, 908, 830, 771, 732, 630, 593, 520, 486 cmꢁ1
1H NMR (DMSO-d6, 300 MHz)
2.90 (s, 3H, CH3), 3.01 (s, 3H, CH3),
.
CH2), 6.78 (ddd, 1H, 3J¼7.8 Hz, 4J¼1.2 Hz, 4/5-H), 6.89 (dd, 1H,
J3,4¼7.8 Hz, J3,5¼1.2 Hz, 3-H), 6.96 (ddd, 1H, 3J¼7.8 Hz, 4J¼1.2 Hz, 4/
5-H), 7.88 (d, 1H, J¼7.8 Hz, 6-H), 9.41 (br s, 1H, NH), 9.92 (s, 1H, OH).
MS (EI) m/z (%): 187 ([Mþ2]þ, 9), 185 (Mþ, 27), 136 (16), 109 (100),
80 (41).
d
3.85 (d, 2H, J¼4.5 Hz, CH2), 5.08 (t, 1H, J¼4.5 Hz, NH), 6.43 (ddd, 1H,
3J¼7.8 Hz, 4J¼1.2 Hz, 4/5-H), 6.50 (dd, 1H, J3,4¼7.8 Hz, J3,5¼1.2 Hz,
3-H), 6.61–6.69 (m, 2H, 5-H, 6-H), 9.28 (s, 1H, OH). 13C NMR (DMSO-
d6, 75 MHz)
d 34.93 (CH3), 35.27 (CH3), 44.43 (CH2), 110.25 (Ar–C),
113.15 (Ar–C), 115.93 (Ar–C), 119.53 (Ar–C), 136.71 (1/2-C), 143.91
(1/2-C), 168.83 (C]O). MS (EI) m/z (%): 194 (Mþ, 80), 149 (28), 122
(100), 95 (20), 77 (16), 72 (9), 65 (8). Anal. Calcd for C10H14N2O2: C,
61.84; H, 7.27; N, 14.42; found C, 61.81; H, 7.27; N, 14.33.
4.4. General procedure for the preparation of ethyl
2-(2-hydroxyphenylamino)acetates 10a and 10b
To a stirred suspension of 2-aminophenol 7a (1.09 g, 10.0 mmol)
or 7b (1.23 g, 10.0 mmol) and potassium fluoride (1.45 g,
25.0 mmol) in dry N,N-dimethylformamide (50 mL), ethyl 2-bro-
moacetate (1.67 g, 10.0 mmol) was added. The resulting mixture
was stirred at 60 ꢀC for 6 h and the solvent was removed under
reduced pressure. The residue was dissolved in EtOAc (60 mL) and
washed with saturated aqueous NaHCO3 (2ꢂ15 mL), water
(2ꢂ15 mL) and brine (2ꢂ15 mL). The organic phase was dried over
Na2SO4, filtered and concentrated under reduced pressure.
4.5.2. Synthesis from 4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-
one (12)
A 10 mL process vial was charged with a solution of 4-benzyl-
3,4-dihydro-1,4-benzoxazin-2-one (12) (100 mg, 0.418 mmol) in
anhydrous N,N-dimethylformamide (1.5 mL), ammonium formate
(132 mg, 2.09 mmol) and 10% Pd–C (20 mg). The vial was sealed,
placed in a microwave reactor and heated at 120 ꢀC for 20 min. The
solvent was removed under reduced pressure and the residue
dissolved in EtOAc (30 mL). The organic phase was washed with
water (2ꢂ10 mL) and brine (2ꢂ10 mL), dried over Na2SO4, filtered
and concentrated under reduced pressure. Compound 11 was iso-
lated from the residue by flash column chromatography using
EtOAc/petroleum ether (6:1) as eluant, giving 19 mg (23%) of a grey
solid. Spectroscopic data were identical to those described above.
4.4.1. Ethyl 2-(2-hydroxyphenylamino)acetate (10a)
Yield: 90%; brown crystals; mp 90–94 ꢀC; Rf¼0.65 (EtOAc/pe-
troleum ether¼1:1); IR (KBr) 3342, 1722, 1614, 1531, 1455, 1438,
1382, 1354, 1327, 1223, 1157, 1086, 1055, 1029, 894, 850, 826, 812,
738 cmꢁ1
.
1H NMR (DMSO-d6, 300 MHz)
d
1.20 (t, 3H, J¼7.2 Hz,
CH2CH3), 3.90 (d, 2H, J¼6.0 Hz, CH2CO), 4.13 (q, 2H, J¼7.2 Hz,
CH2CH3), 4.99 (t, 1H, J¼6.0 Hz, NH), 6.36 (dd, 1H, J3,4¼7.8 Hz, J3,5
¼
4.6. General procedure for the preparation of N-alkyl/benzyl-
3,4-dihydro-2H-1,4-benzoxazin-2-ones 12–21 and ethyl 2-(4-
(4-(dimethylamino)benzyl)-2-hydroxy-phenylamino)-
acetate (23)
1.5 Hz, 3-H), 6.46 (ddd, 1H, 3J¼7.8 Hz, 4J¼1.5 Hz, 4/5-H), 6.61 (ddd,
1H, 3J¼7.8 Hz, 4J¼1.5 Hz, 4/5-H), 6.68 (dd, 1H, J6,5¼7.8 Hz, J6,4
¼
1.5 Hz, 6-H), 9.29 (s, 1H, OH). 13C NMR (DMSO-d6, 75 MHz)
d 14.02
(CH3CH2), 44.82 (NHCH2CO), 60.26 (CH3CH2), 109.77 (Ar–C), 113.49
(Ar–C), 116.42 (Ar–C), 119.52 (Ar–C), 136.54 (1/2-C), 144.06 (1/2-C),
171.22 (C]O). MS (EI) m/z (%): 195 (Mþ, 33), 122 (100), 94 (14), 77
(13), 65 (9). Anal. Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.18;
found C, 61.57; H, 6.74; N, 7.15.
To a solution of ethyl 2-(2-hydroxyphenylamino)acetate (10a)
(488 mg, 2.5 mmol) or ethyl 2-(2-hydroxy-5-methylphenylamino)-
acetate (10b) (523 mg, 2.5 mmol) and the corresponding aldehyde
(3.0 mmol for 12–18, 23; 3.5 mmol for 19–21) in dichloromethane
(15 mL), glacial acetic acid [0.21 mL (3.75 mmol) for 12–18,
23;0.43 mL (7.5 mmol) for 19–21] was added and the mixture
stirred for 30 min on ice bath. Sodium triacetoxyborohydride
[795 mg (3.75 mmol) for 12–18, 23; 1.06 g (5 mmol) for 19–21] was
added in portions. The reaction mixture was stirred overnight and
diluted with dichloromethane (15 mL) and the organic phase was
washed with saturated aqueous NaHCO3 (2ꢂ10 mL), water
(2ꢂ10 mL) and brine (2ꢂ10 mL), dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash column chromatography using EtOAc/petroleum ether or
dichloromethane/methanol as eluant, yielding pure products
12–18 and 23.
4.4.2. Ethyl 2-(2-hydroxy-5-methylphenylamino)-acetate (10b)
Yield: 55%; brown crystals; mp 114–118 ꢀC; Rf¼0.59 (EtOAc/
petroleum ether¼1:1); IR (KBr) 3398, 3033, 2985, 2870, 2344, 2361,
1820, 1714, 1607, 1531, 1443, 1374, 1318, 1258, 1100, 1019, 866, 838,
812, 795, 606 cmꢁ1 1H NMR (DMSO-d6, 300 MHz)
. d 1.20 (t, 3H,
J¼7.2 Hz, CH2CH3), 2.12 (s, 3H, ArCH3), 3.88 (d, 2H, J¼6.0 Hz,
CH2CO), 4.13 (q, 2H, J¼7.2 Hz, CH2CH3), 4.92 (t, 1H, J¼6.0 Hz, NH),
6.19 (s, 1H, 6-H), 6.24 (d, 1H, J¼7.8 Hz, 4-H), 6.55 (d, 1H, J¼7.8 Hz, 3-
H), 9.03 (s, 1H, OH). 13C NMR (DMSO-d6, 75 MHz)
d 14.02 (CH3CH2),
20.75 (Ar–CH3), 44.86 (NHCH2CO), 60.25 (CH3CH2), 110.71 (Ar–C),
113.35 (Ar–C), 116.58 (Ar–C), 127.91 (Ar–C), 136.32 (1/2-C), 141.84
(1/2-C), 171.23 (C]O). MS (EI) m/z (%): 209 (Mþ, 43), 136 (100), 109
(28), 94 (5), 91 (19), 77 (11), 65 (7). Anal. Calcd for C11H15NO3: C,
63.14; H, 7.23; N, 6.69; found C, 63.32; H, 7.36; N, 6.77.
4.6.1. 4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-one (12)
Yield: 65%; colourless oil; Rf¼0.50 (EtOAc/petroleum
ether¼1:2); IR (NaCl-film) 3525, 3388, 3063, 3030, 2813, 2624,
2362, 2336, 1774, 1696, 1611, 1584, 1502, 1453, 1393, 1339, 1291,
1213, 1162, 1147, 1113, 1026, 1052, 990, 919, 835, 744, 699 cmꢁ1. 1H
4.5. 2-(2-Hydroxyphenylamino)-N,N-dimethylacetamide (11)
4.5.1. Synthesis from 2-aminophenol (7) and ethyl 2-bromo-
acetate (9)
A suspension of 2-aminophenol (7) (500 mg, 4.58 mmol), po-
tassium fluoride (666 mg, 11.46 mmol) and ethyl 2-bromoacetate
(9) (0.512 mL, 4.58 mmol) in anhydrous N,N-dimethylformamide
NMR (DMSO-d6, 300 MHz) d 4.00 (s, 2H, CH2CO), 4.46 (s, 2H,
CH2C6H5), 6.82 (ddd, 1H, 3J¼8.1 Hz, 4J¼1.2 Hz, 6/7-H), 6.90 (dd, 1H,
J5,6¼8.1 Hz, J5,7¼1.2 Hz, 5-H), 7.00–7.08 (m, 2H, 6/7-H, 8-H), 7.30–
7.37 (m, 5H, C6H5). 13C NMR (CDCl3, 75 MHz)
d 49.65 (CH2), 53.29
(CH2), 113.08 (Ar–C), 116.83 (Ar–C), 119.86 (Ar–C), 125.13 (Ar–C),

5760
N. Zidar, D. Kikelj / Tetrahedron 64 (2008) 5756–5761
3
127.63 (20,60/30,50-C), 127.74 (Ar–C), 128.78 (20,60/30,50-C), 134.64
(Ar–C), 135.48 (Ar–C), 141.55 (Ar–C), 164.75 (C]O). MS (EI) m/z (%):
239 (Mþ, 95), 211 (42), 180 (10), 120 (48), 91 (100), 65 (30). HRMS
for C15H13NO2: calculated 239.0946; found 239.0951. Anal. Calcd for
30-H, 50-H), 6.85 (ddd, 1H, J¼7.5 Hz, 4J¼1.2 Hz, 6/7-H), 6.90 (d, 1H,
J¼7.5 Hz, 5-H), 7.05–7.11 (m, 2H, 6/7-H, 8-H), 7.20 (d, 2H, J¼8.7 Hz,
20-H, 60-H). 13C NMR (CDCl3, 75 MHz)
d 49.40 (CH2), 52.84 (CH2),
113.23 (Ar–C), 115.79 (30,50-C), 116.99 (Ar–C), 120.03 (Ar–C), 125.31
(Ar–C), 127.27 (Ar–C), 129.37 (20,60-C), 134.86 (Ar–C)þ, 141.73 (Ar–C),
155.48 (40-C), 165.43 (C]O). MS (EI) m/z (%): 255 (M , 43), 162 (14),
149 (62), 121 (28), 107 (100), 77 (12), 65 (7). Anal. Calcd for
C
15H13NO2: C, 75.30; H, 5.48; N, 5.85; found C, 74.73; H, 5.26; N,
5.94.
4.6.2. 4-(2-Oxo-2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-
benzonitrile (13)
C15H13NO3: C, 70.58; H, 5.13; N, 5.49; found C, 70.26; H, 5.04; N, 5.41.
Yield: 41%; red/brown crystals; mp 126–131 ꢀC; Rf¼0.43 (EtOAc/
petroleum ether¼1:2); IR (KBr) 2222, 1774, 1607, 1502, 1459, 1416,
1367, 1327, 1290, 1202, 1149, 1042, 998, 952, 919, 838, 821, 754,
4.6.6. 4-(3-Hydroxybenzyl)-3,4-dihydro-2H-1,4-benzoxazin-
2-one (17)
Yield: 30%; red oil; Rf¼0.34 (dichloromethane/methanol¼50:1);
IR (NaCl-film) 3392, 3071, 2849, 2254, 1770, 1683, 1614, 1504, 1456,
1344, 1293, 1218, 1157, 1113, 1054, 1028, 1000, 916, 879, 835, 782,
676 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz)
d 4.10 (s, 2H, CH2CO), 4.57
0
0
0
0
0
(s, 2H, CH2N), 6.76 (dd, 1H, J5 ,6 ¼7.8 Hz, J5 ,7 ¼1.5 Hz, 5 -H), 6.82
(ddd, 1H, 3J¼7.8 Hz, J¼1.5 Hz, 60/70-H), 6.99 (ddd, 1H, 3J¼7.8 Hz,
747, 696 cmꢁ1. 1H NMR (CDCl3, 300 MHz)
d
3.82 (s, 2H, CH2CO), 4.34
(s, 2H, CH2N), 5.55 (br s, 1H, OH), 6.78–6.91 (m, 5H, 5HAr), 7.04–7.10
(m, 2H, 2HAr), 7.24 (m, 1H, HAr). 13C NMR (CDCl3, 75 MHz)
49.69
4
4
J¼1.5 Hz, 60/70-H), 7.08 (dd, 1H, J7 ,8 ¼7.8 Hz, J6 ,8 ¼1.5 Hz, 8 -H),
0
0
0
0
0
7.56 (d, 2H, J¼8.4 Hz, 2-H, 6-H), 7.83 (d, 2H, J¼8.4 Hz, 3-H, 5-H). 13
C
d
NMR (DMSO-d6, 75 MHz)
d
51.03 (CH2), 53.02 (CH2), 110.94, 114.09,
(CH2), 53.10 (CH2), 113.17 (Ar–C), 114.51 (Ar–C), 114.90 (Ar–C),
116.85 (Ar–C), 119.67 (Ar–C), 119.87 (Ar–C), 125.34 (Ar–C), 130.06
(Ar–C), 134.53 (Ar–C), 137.31 (Ar–C), 141.40 (Ar–C), 156.27 (30-C),
165.56 (C]O). MS (EI) m/z (%): 255 (Mþ, 46), 227 (7), 134 (5), 120
(48), 108 (35), 107 (100), 94 (8), 84 (25), 77 (23), 65 (18). HRMS for
117.32, 119.63, 120.22, 125.90, 129.19 (20,60-C), 133.36 (30,50-C),
135.20, 142.03, 143.84, 165.57 (C]O). MS (EI) m/z (%): 264 (Mþ, 71),
236 (33), 120 (100), 116 (37), 93 (17), 89 (14), 65 (24). Anal. Calcd for
C
16H12N2O2: C, 72.72; H, 4.58; N, 10.60; found C, 72.53; H, 4.85; N,
10.38.
C15H13NO3: calculated 255.0895; found 255.0889.
4.6.3. 4-(2-Oxo-2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-benzoic
acid (14)
Yield: 15%; yellow crystals; mp 245–250 ꢀC; Rf¼0.28 (dichloro-
methane/methanol/AcOH¼20:1:0.5); IR (KBr) 3480, 2840, 1951,
1766,1671, 1610, 1577, 1497, 1465, 1450,1424, 1359, 1323,1293, 1211,
1146, 1042, 1018, 957, 918, 868, 796, 759, 676, 759, 702, 676, 604,
4.6.7. 4-Benzyl-6-methyl-3,4-dihydro-2H-1,4-benzoxazin-
2-one (18)
Yield: 67%; colourless crystals; mp 93–96 ꢀC; Rf¼0.42 (EtOAc/
petroleum ether¼1:4); IR (KBr) 3850, 3500, 3067, 2917, 2860, 2803,
2358, 2338, 1960, 1764, 1608, 1506, 1454, 1506, 1454, 1370, 1287,
1208, 1146, 1078, 1031, 920, 816, 807, 761, 730, 703, 640, 570,
553, 489 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz)
d
4.07 (s, 2H, CH2CO),
483 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz)
d 2.20 (s, 3H, CH3), 3.91 (s,
4.54 (s, 2H, CH2N), 6.80–6.85 (m, 2H, 50-H, 60/70-H), 7.01 (ddd, 1H,
2H, CH2CO), 4.44 (s, 2H, CH2C6H5), 6.63 (dd, 1H, 3J¼7.8 Hz,
3
4
J¼7.8 Hz, J¼1.5 Hz, 60/70-H), 7.08 (dd, 1H, J7 ,8 ¼7.8 Hz, J6 ,8 ¼1.5 Hz,
4J¼1.2 Hz, 7-H), 6.77 (d, 1H, 4J¼1.2 Hz, 5-H), 6.95 (d, 1H, 3J¼7.8 Hz,
0
0
0
0
80-H), 7.48 (d, 2H, J¼8.4 Hz, 2-H, 6-H), 7.92 (d, 2H, J¼8.4 Hz, 3-H,
8-H), 7.29–7.37 (m, 5H, C6H5). 13C NMR (CDCl3, 75 MHz)
d 21.27
5-H), 12.90 (br s, 1H, COOH). 13C NMR (DMSO-d6, 75 MHz)
d
49.93
(CH3), 49.62 (CH2), 53.33 (CH2), 113.64 (Ar–C), 116.68 (Ar–C), 120.48
(Ar–C), 127.83 (20,60/30,50-C), 127.86 (Ar–C), 128.89 (20,60/30,50-C),
134.51 (Ar–C), 134.99 (Ar–C), 135.63 (Ar–C), 139.73 (Ar–C), 164.94
(C]O). MS (EI) m/z (%): 253 (Mþ, 60), 225 (22), 134 (96), 107 (8), 91
(100), 77 (15), 69 (9), 65 (18). Anal. Calcd for C16H15NO2: C, 75.87; H,
5.97; N, 5.53; found C, 75.78; H, 6.01; N, 5.53.
(CH2), 52.15 (CH2), 113.21 (Ar–C), 116.28 (Ar–C), 119.16 (Ar–C),
124.91 (Ar–C), 127.45 (Ar–C), 129.51 (Ar–C), 129.68 (Ar–C), 134.48
(Ar–C), 141.06 (Ar–C), 141.97 (Ar–C), 164.67 (C]O), 166.95 (C]0).
MS (ESI) m/z (%): 283 (Mþ, 20), 282 (100), 237 (8), 235 (21), 233
(28), 231 (16), 212 (11),135 (6),113 (6). Anal. Calcd for C16H13NO4: C,
67.84; H, 4.63; N, 4.94; found C, 67.60; H, 4.75; N, 4.81.
4.6.8. 4-Phenethyl-3,4-dihydro-2H-1,4-benzoxazin-2-one (19)
Yield: 70%; pink-white crystals; mp 85–88 ꢀC; Rf¼0.57 (EtOAc/
petroleum ether¼1:2); IR (KBr) 3398, 3074, 3025, 2961, 2358, 1768,
1611, 1506, 1466, 1347, 1294, 1229, 1208, 1143, 1083, 1052, 1012, 999,
918, 751, 701, 670, 566, 501, 470 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz)
4.6.4. 4-(4-Methoxybenzyl)-3,4-dihydro-2H-1,4-benzoxazin-
2-one (15)
Yield: 61%; red/brown crystals; mp 245–250 ꢀC; Rf¼0.40 (EtOAc/
petroleum ether¼1:4); IR (KBr) 1779, 1614, 1513, 1459, 1377, 1247,
1030, 916, 835, 818, 755, 672, 598, 554, 512, 472 cmꢁ1
.
1H NMR
d
2.87 (t, 2H, J¼6.0 Hz, CH2CH2C6H5), 3.38 (t, 2H, J¼6.0 Hz,
(DMSO-d6, 300 MHz)
d
3.74 (s, 3H, CH3), 3.92 (s, 2H, CH2CO), 4.37 (s,
CH2CH2C6H5), 4.06 (s, 2H, CH2CO), 6.81 (dd,1H, 3J¼8.1 Hz, 4J¼1.5 Hz,
6/7-H), 7.00 (ddd, 1H, 3Jz8.1 Hz, 4J¼1.5 Hz, 5/8-H), 7.05 (dd, 1H,
3J¼8.1 Hz, 4J¼1.5 Hz, 5/8-H), 7.10 (ddd, 1H, 3Jz8.1 Hz, 4J¼1.5 Hz, 6/
2H, CH2N), 6.84 (ddd, 1H, 3J¼7.8 Hz, 4J¼1.6 Hz, 7-H), 6.92 (d, 2H,
J¼8.5 Hz, 30-H, 50-H), 6.96 (dd, 1H, J5,6¼7.8 Hz, J6,7¼1.6 Hz, 5-H),
7.01–7.08 (m, 2H, 6-H, 8-H), 7.29 (d, 2H, J¼8.5 Hz, 20-H, 60-H). 13C
7-H), 7.20–7.33 (m, 5H, C6H5). 13C NMR (CDCl3, 75 MHz)
d 31.71
NMR (CDCl3, 75 MHz)
d
49.34 (CH2), 52.72 (CH2), 55.46 (CH3), 113.11
(CH2Ph), 50.15 (CH2), 51.13 (CH2),112.44 (Ar–C),117.11 (Ar–C),119.41
(Ar–C), 125.26 (Ar–C), 126.67 (Ar–C), 128.56 (20,60/30,50-C), 128.75
(20,60/30,50-C), 133.80 (Ar–C), 138.50 (Ar–C), 141.58 (Ar–C), 164.40
(C]O). MS (EI) m/z (%): 253 (Mþ, 23),162 (100), 134 (27), 107 (6), 91
(8), 77 (18), 65 (10). Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N,
5.53; found C, 75.71; H, 6.01; N, 5.47.
(Ar–C), 114.23 (30,50-C), 116.85 (Ar–C), 119.87 (Ar–C), 125.13 (Ar–C),
127.26 (Ar–C), 129.10 (20,60-C), 134.82 (Ar–Cþ), 141.68 (Ar–C), 159.21
(40-C),164.91 (C]O). MS (EI) m/z (%): 269 (M , 80),162 (14),149 (11),
135 (16), 121 (100), 106 (9), 91 (30), 77 (35), 65 (26). Anal. Calcd for
C
16H15NO3: C, 71.36; H, 5.61; N, 5.20; found C, 71.71; H, 5.85; N, 5.15.
4.6.5. 4-(4-Hydroxybenzyl)-3,4-dihydro-2H-1,4-benzoxazin-
2-one (16)
4.6.9. 4-Ethyl-3,4-dihydro-2H-1,4-benzoxazin-2-one (20)
Yield: 37%; orange hygroscopic oil; Rf¼0.34 (EtOAc/petroleum
ether¼1:4); IR (NaCl-film) 3523, 3318, 3070, 3045, 2976, 2876,
2815, 2628, 2344, 2330, 2021, 1770, 1694, 1611, 1584, 1504, 1470,
1461, 1394, 1379, 1340, 1292, 1205, 1127, 1100, 1042, 1021, 919,
Yield: 40%; white solid; mp 113–118 ꢀC; Rf¼0.29 (dichloro-
methane/methanol¼50:1); IR (KBr) 3408, 2361, 1747, 1636, 1614,
1595,1518,1499,1459,1451,1368,1354,1327,1289,1272,1200,1170,
1144, 1106, 1043, 1022, 960, 922, 821, 790, 735, 676, 650, 602, 564,
746 cmꢁ1
.
1H NMR (DMSO-d6, 300 MHz)
d
1.10 (t, 3H, J¼6.9 Hz,
553, 518, 494, 569 cmꢁ1
.
1H NMR (CDCl3, 300 MHz)
d
3.76 (s, 2H,
CH2CH3), 3.32 (q, 2H, J¼6.9 Hz, CH2CH3), 3.95 (s, 2H, CH2CO), 6.80
CH2CO), 4.31 (s, 2H, CH2N), 5.18 (br s, 1H, OH), 6.84 (d, 2H, J¼8.7 Hz,
(ddd, 1H, 3Jz7.8 Hz, 4J¼1.5 Hz, 6/7-H), 6.92 (dd, 1H, 3J¼7.8 Hz,

N. Zidar, D. Kikelj / Tetrahedron 64 (2008) 5756–5761
5761
4J¼1.5 Hz, 5/8-H), 7.04 (dd, 1H, 3J¼7.8 Hz, 4J¼1.5 Hz, 5/8-H), 7.07
(ddd, 1H, 3Jz7.8 Hz, 4J¼1.5 Hz, 6/7-H). 13C NMR (CDCl3, 75 MHz)
2H, J¼2.1 Hz, CH2), 6.22 (br s, 1H, NH), 6.73 (ddd, 1H, 3J¼7.8 Hz,
4J¼1.2 Hz, 6/7-H), 6.84 (dd, 1H, J5,6¼7.8 Hz, J5,7¼1.2 Hz, 5-H), 6.94–
d
11.10 (CH3), 38.14 (CH2), 49.09 (CH2), 114.68 (Ar–C), 117.80 (Ar–C),
6.99 (m, 2H, 8-H, 6/7-H). 13C NMR (DMSO-d6, 75 MHz)
d 45.23
124.72 (Ar–C), 125.19 (4a/8a-C), 125.81 (Ar–C), 140.35 (4a/8a-C),
165.00 (C]O). MS (EI) m/z (%): 177 (Mþ, 18), 163 (43), 148 (100), 135
(73), 122 (10), 120 (25), 106 (12), 97 (8), 91 (30), 79 (27), 77 (34),
65(18). HRMS for C10H11NO2: calculated 177.0790; found 177.0791.
Anal. Calcd for C10H11NO2$0.125H2O: C, 66.93; H, 6.32; N, 7.81;
found C, 67.00; H, 6.46; N, 7.80.
(CH2), 115.72 (5-C), 117.13 (8-C), 119.42 (7-C), 125.68 (6-C), 135.29
(8a-C), 141.61 (4a-C), 166.04 (C]O). MS (EI) m/z (%): 149 (Mþ, 70),
122 (8), 121 (45), 120 (100), 93 (12), 91 (5), 69 (7), 65 (15), 63 (5), 52
(6). HRMS for C8H7NO2: calculated 149.0477; found 149.0480. Anal.
Calcd for C8H7NO2: C, 64.42; H, 4.73; N, 9.39; found C, 64.63; H,
4.53; N, 9.15.
4.6.10. 4-Nonyl-3,4-dihydro-2H-1,4-benzoxazin-2-one (21)
Acknowledgements
Yield: 62%; orange hygroscopic oil; Rf¼0.74 (EtOAc/petroleum
ether¼1:4); IR (NaCl-film) 3309, 3045, 3070, 2952, 2925, 2853,
2361, 2343, 1778, 1697, 1612, 1503, 1462, 1340, 1290, 1206, 1162,
This work was supported by the European Union FP6 Integrated
Project EUR-INTAFAR (Project No. LSHM-CT-2004-512138) and the
Slovenian Research Agency (grant No. P1-208-0787). The authors
1128, 1043, 919, 834, 743 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz)
d 0.86
(t, 3H, J¼6.6 Hz, CH2CH3), 1.25–1.31 (m, 12H, 6ꢂCH2), 1.51–1.56 (m,
2H, NCH2CH2), 3.21 (t, 2H, J¼7.8 Hz, NCH2CH2), 3.96 (s, 2H, CH2CO),
6.79 (ddd, 1H, 3Jz8.0 Hz, 4J¼1.5 Hz, 6/7-H), 6.89 (dd, 1H, 3J¼8.1 Hz,
4J¼1.5 Hz, 5/8-H), 7.03 (dd, 1H, 3J¼7.8 Hz, 4J¼1.5 Hz, 5/8-H), 7.06
(ddd, 1H, 3Jz8.0 Hz, 4J¼1.5 Hz, 6/7-H). 13C NMR (CDCl3, 75 MHz)
ˇ
thank Mr. Janez Ilas for donation of ethyl 4-amino-3-hydroxy-
benzoate and Prof. Roger Pain for critical reading of the manuscript.
References and notes
d
14.07 (CH3), 22.62 (CH2), 26.73 (CH2), 26.85 (CH2), 29.17 (CH2),
ˇ
ˇ
ˇ
1. Ilas, J.; Stefanic Anderluh, P.; Sollner Dolenc, M.; Kikelj, D. Tetrahedron 2005, 61,
7325–7348.
29.22 (CH2), 29.40 (CH2), 31.80 (CH2), 43.14 (CH2), 49.44 (NCH2CO),
114.84 (Ar–C), 117.83 (Ar–C), 124.69 (Ar–C), 125.46 (4a/8a-C), 125.75
(Ar–C), 140.35 (4a/8a-C), 165.11 (C]O). MS (EI) m/z (%): 275 (Mþ,
61), 247 (34), 191 (14), 177 (12), 162 (100), 148 (11), 134 (69), 120
(22), 55 (19). HRMS for C17H25NO2: calculated 275.1885; found
275.1892. Anal. Calcd for C17H25NO2$0.25H2O: C, 72.95; H, 9.18; N,
5.00; found C, 72.88; H, 9.38; N, 4.78.
2. Sicker, D.; Schulz, M. Studies in Natural Products Chemistry: Part H; Atta-ur-
Rahman, H. E. J., Ed.; Elsevier: Oxford, 2002; Vol. 27, pp 185–232.
3. Teller, J. Houben–Weyl Methods of Organic Chemistry, Hetarenes IV, Six-Membered
and Larger Hetero-Rings with Maximum Unsaturation; Schaumann, E., Ed.; Georg
Thieme: Stuttgart, 1997; Vol. E9a, pp 141–177.
4. Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45,
6751–6755.
5. Wolfer, J.; Bekele, T.; Abraham, C. J.; Dogo-Isonagie, C.; Lectka, T. Angew. Chem.,
Int. Ed. 2006, 45, 7398–7400.
6. Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2006, 71, 2099–2106.
7. Kozminykh, V. O.; Igidov, N. M.; Kozminykh, E. N. Russ. J. Org. Chem. 2003, 39,
863–868.
8. Semenova, T. D.; Krasnykh, O. P. Russ. J. Org. Chem. 2005, 41, 1222–1227.
9. Huang, W.; Zhang, P.; Zuckett, J. F.; Wang, L.; Woolfrey, J.; Song, Y.; Jia, Z. J.;
Clizbe, L. A.; Su, T.; Tran, K.; Huang, B.; Wong, P.; Sinha, U.; Park, G.; Reed, A.;
Malinowski, J.; Hollenbach, S. J.; Scarborough, R. M.; Zhu, B. Y. Bioorg. Med.
Chem. Lett. 2003, 13, 561–566.
10. Maag, H.; Sui, M.; Zhao, S. H. WO Patent Appl. WO2004/041792, 2004.
11. Johnson, C.N.; Rami, H.K.; Thewlis, K.; Stemp, G.; Thompson, M.; Vong, A. K. K.
U.S. Patent Appl. 2004/063704, 2004.
12. Vianello, P.; Bandiera, T. U.S. Patent 6,750,215, 2004.
13. Friberg, B. L. M.; Koch, K. N.; Tolf, B.-R.; Skjaerbaek, N. WO Patent Appl.
03057672, 2003.
4.6.11. Ethyl 2-(4-(4-(dimethylamino)benzyl)-2-
hydroxyphenylamino)acetate (23)
Yield: 55%; yellow crystals; mp 103–109 ꢀC; Rf¼0.25 (dichloro-
methane/methanol¼20:1); IR (KBr) 3454, 1740, 1618, 1533, 1516,
1473, 1435, 1373, 1350, 1333, 1298, 1280, 1249, 1210, 1155, 1144,
1045, 1025, 960, 933, 910, 862, 811, 798, 616, 518 cmꢁ1
.
1H NMR
(DMSO-d6, 300 MHz)
d
1.19 (t, 3H, J¼7.2 Hz, CH2CH3), 2.83 (s, 6H,
N(CH3)2), 3.61 (s, 2H, ArCH2Ar), 3.86 (d, 2H, J¼6.0 Hz, CH2CO), 4.12
(q, 2H, J¼7.2 Hz, CH2CH3), 4.82 (t, 1H, J¼6.0 Hz, NH), 6.27 (d, 1H,
J¼8.1 Hz, 6-H), 6.46 (d, 1H, J¼8.1 Hz, 5-H), 6.47 (s, 1H, 3-H), 6.64 (d,
2H, J¼8.7 Hz, 30-H, 50-H), 6.97 (d, 2H, J¼8.7 Hz, 20-H, 60-H), 9.16 (s,
14. LeRosen, A. L.; Smith, E. D. J. Am. Chem. Soc. 1948, 70, 2705–2709.
15. LeRosen, A. L.; Smith, E. D. J. Am. Chem. Soc. 1949, 71, 2815–2818.
16. Macı
´as, F. A.; Marı´n, D.; Oliveros-Bastidas, A.; Chinchilla, D.; Simonet, A. M.;
1H, OH). 13C NMR (DMSO-d6, 75 MHz)28
d 14.00 (CH3), 39.59, 44.98,
60.16, 109.60, 112.55 (30-C, 50-C), 113.97, 119.28, 128.94 (20-C, 60-C),
129.72, 130.25, 134.44, 143.98, 148.67, 171.23 (C]O). MS (EI) m/z
(%): 328 (Mþ, 80), 282 (14), 255 (100), 240 (6),134 (24),127 (12),121
(8). HRMS for C19H25N2O3: calculated 329.1865; found 329.1870.
Anal. Calcd for C19H24N2O3$0.1H2O: C, 69.11; H, 7.39; N, 8.48; found
C, 68.97; H, 7.33; N, 8.40.
Molinillo, J. M. G. J. Agric. Food Chem. 2006, 54, 991–1000.
17. Tumkevicius, S.; Urbonas, A.; Vainilavicius, P. Chem. Heterocycl. Comp. 2000, 36,
841–846.
18. Freedman, H. H.; Frost, A. E. J. Org. Chem. 1958, 23, 1292–1298.
19. Lutz, R. E.; Freek, J. A.; Murphey, R. S. J. Am. Chem. Soc. 1948, 70, 2015–2023.
20. Griffin, E. C.; Lutz, R. E. J. Am. Chem. Soc. 1956, 21, 1131–1137.
21. Abdel-Magid, A. F.; Mehrman, S. Org. Process Res. Dev. 2006, 10, 971–1031.
22. Hofmann, A. W.; Martius, C. A. Ber. 1871, 4, 742–748.
23. Hofmann, A. W. Ber. 1872, 5, 720–722.
4.7. 3,4-Dihydro-2H-1,4-benzoxazin-2-one (3)
24. Magnus, P.; Turnbull, R. Org. Lett. 2006, 8, 3497–3499.
25. 6-Chloro-2H-1,4-benzoxazin-3(4H)-one (mp 213–216 ꢀC, lit.29 213 ꢀC), ethyl
3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylate (mp 197–198 ꢀC, lit.30
199–201 ꢀC) and 6-nitro-2H-1,4-benzoxazin-3(4H)-one (mp 235–237 ꢀC, lit.31
235–239 ꢀC) were identified by comparison with authentic samples.
26. Holmquist, B.; Bruice, C. T. J. Am. Chem. Soc. 1969, 91, 2982–2985.
27. Smith, E. D.; Mayasandra, V. S. J. Org. Chem. 1980, 45, 1715–1717.
28. In the 13C NMR spectrum of 19, the signal of the N(Me)2 group is positioned
under the signal of the solvent.
4-Benzyl-3,4-dihydro-1,4-benzoxazin-2-one (12) (500 mg,
2.09 mmol) was dissolved in dry THF (8 mL),10% Pd/C (100 mg) was
added and the reaction mixture was stirred under a hydrogen at-
mosphere for 1 h. The catalyst was filtered off, solvent was removed
under reduced pressure and the crude product was purified by flash
column chromatography using EtOAc/hexane (1:2) as eluant, giving
156 mg (50%) of white crystals, mp 79–83 ꢀC; Rf¼0.27 (EtOAc/
hexane¼1:2); IR (KBr) 3458, 1901, 1760, 1636, 1616, 1593, 1503,
1434, 1336, 1300, 1266, 1242, 1184, 1112, 1061, 938, 918, 748, 691,
29. Thuillier, G.; Laforest, J.; Bessin, P.; Bonnet, J.; Thuillier, J. Eur. J. Med. Chem. 1975,
10, 37–42.
ˇ
30. Ilas, J.; Kikelj, D. Helv. Chim. Acta, in press.
ˇ
ˇ
ˇ
31. Anderluh, M.; Cesar, J.; Stefanic, P.; Kikelj, D.; Janes, D.; Murn, J.; Nadrah, K.;
Tominc, M.; Addicks, E.; Giannis, A.; Stegnar, M.; Sollner Dolenc, M. Eur. J. Med.
Chem. 2005, 40, 25–49.
605, 552, 522, 470 cmꢁ1 1H NMR (DMSO-d6, 300 MHz)
. d 3.96 (d,