Regiospecific synthesis of neuroprotective 1,4-benzoxazine derivatives through a tandem oxidation-Diels-Alder reaction

Article abstract of DOI:10.1039/c5ob00049a

The tandem oxidation-inverse electron demand Diels-Alder reaction of o-aminophenol derivatives and enamines has been accomplished at room temperature using a stoichiometric amount of manganese dioxide as the oxidant to furnish highly substituted 1,4-benzoxazine cycloadducts with complete regiochemical control. Because of its efficiency in introducing diverse elements in both cycloaddition partners, this one-pot process should allow the assembly of libraries of biologically relevant 1,4-benzoxazine derivatives. In this respect, the 3,3-diphenyl-substituted-1,4-benzoxazine derivative 3n was found to be a potent neuroprotective agent in an animal model of excitotoxic lesions in newborn mice.

Full text of DOI:10.1039/c5ob00049a

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Regiospecific synthesis of neuroprotective
1,4-benzoxazine derivatives through a tandem
Cite this: DOI: 10.1039/c5ob00049a
oxidation–Diels–Alder reaction†
Khac Minh Huy Nguyen,a Leslie Schwendimann,b,c Pierre Gressensb,c and
Martine Largeron*a
The tandem oxidation–inverse electron demand Diels–Alder reaction of o-aminophenol derivatives and
enamines has been accomplished at room temperature using a stoichiometric amount of manganese
dioxide as the oxidant to furnish highly substituted 1,4-benzoxazine cycloadducts with complete regio-
chemical control. Because of its efficiency in introducing diverse elements in both cycloaddition partners,
this one-pot process should allow the assembly of libraries of biologically relevant 1,4-benzoxazine
derivatives. In this respect, the 3,3-diphenyl-substituted-1,4-benzoxazine derivative 3n was found to be a
potent neuroprotective agent in an animal model of excitotoxic lesions in newborn mice.
Received 9th January 2015,
Accepted 3rd February 2015
DOI: 10.1039/c5ob00049a
www.rsc.org/obc
effective neuroprotective agents both in vitro and in vivo.8
Nevertheless, it seemed doubtful that this electrochemically
Introduction
1,4-Benzoxazine derivatives are an important class of hetero- induced process will ever be able to compete with more con-
cyclic compounds because of their natural occurrence and ventional chemical approaches at a preparative scale. However,
important biological activities.1 They are potential drugs for the instability of o-quinone-monoimines prohibited their
treating infections, diabetes, asthma, depression as well as efficient use as heterodienes in chemically induced IEDDA
neurodegenerative, autoimmune, inflammatory and cardio- reactions. For a long time, such reactions were mainly
vascular disorders (Fig. 1).2 Traditional syntheses of 1,4-benz- restricted to stable o-quinone-monooximes9 and o-quinone-
oxazine derivatives involve multistep processes, using monoimides.5a–d,5f,10 Recently, the synthesis of 1,4-benzox-
2-nitrophenols or 2-aminophenols as the starting materials.1,3 azine derivatives has been reported for the first time from
However, increasing interest in 1,4-benzoxazine derivatives has in situ chemically generated unstable o-quinone-monoimine
prompted the development of new concise methodologies that heterodienes, using diacetoxyiodobenzene as the oxidizing
follow diverse one-pot strategies including metal-catalyzed reagent, in the presence of vinyl ether dienophiles.11 Inspired
reactions,4 cascade (or tandem) reactions5 and microwave- by this protocol, we looked for a chemical extrapolation of our
assisted reactions.6
previous electrochemical procedure.
A few years ago, we reported an electrochemically induced
tandem oxidation–Diels–Alder reaction for the synthesis of
highly functionalized 1,4-benzoxazine and 1,4-benzodioxin
derivatives.7 In particular, the anodic oxidation of o-amino-
phenol derivatives produced unstable o-quinone-monoimine
heterodienes, which were trapped in situ by enamine dieno-
philes through regiospecific inverse-electron-demand Diels–
Alder (IEDDA) reactions to give diverse 1,4-benzoxazine deriva-
tives. Interestingly, some of these compounds proved to be
aUMR 8638 CNRS-Université Paris Descartes, Sorbonne Paris Cité, Faculté de
Pharmacie de Paris, 4 avenue de l’Observatoire, 75270 Paris cedex 06, France.
E-mail: martine.largeron@parisdescartes.fr; Fax: +33144073588; Tel: +33153739646
bInserm, U 1141, F-75019 Paris, France
cUniversité Paris Diderot, Sorbonne Paris Cité, UMRS 1141, F-75019 Paris, France
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for benzoxazine derivatives 3a–q. See DOI: 10.1039/c5ob00049a
Fig. 1 Example of important pharmaceutically active compounds pos-
sessing a 1,4-benzoxazine core.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Activated manganese dioxide is known as a mild oxidant in tures and solvents were further screened (entries 4–7), but
organic chemistry. Especially, it has been successfully used in none of the changes led to an improvement in the yield of the
combination with a nucleophilic trapping agent in tandem oxi- cycloadduct 3a. As already observed,7 strong solvation of
dation processes (TOP) for the synthesis of diverse hetero- methanol to the o-quinone-monoimine species may be
cycles.12 As an extension of this chemistry, we report herein required to enhance the electrophilicity of its quinonoid
that a stoichiometric amount of activated MnO2, in deaerated moiety, making it able to participate in the IEDDA reaction.
methanol, is sufficient to convert various o-aminophenol
Scope of the tandem oxidation–IEDDA process
derivatives, in the presence of enamine dienophiles, to highly
functionalized 1,4-benzoxazine derivatives through a tandem The optimized reaction conditions (Table 1, entry 3) were first
oxidation–IEDDA reaction under mild conditions. The syn- applied to a series of aminophenol derivatives 1a–i, in the
thetic potential of this reaction has been further explored with presence of alkylenamine 2a. Table 2 shows some examples of
the ultimate goal of developing libraries of biologically rele- the molecular diversity that can be obtained with this reaction
vant 1,4-benzoxazine derivatives.
sequence that includes a regiospecific IEDDA reaction between
the in situ generated electron-poor o-quinone-monoimine
heterodiene and the electron-rich tertiary alkylenamine dieno-
phile 2a. The more electron-rich carbon atom of enamine
dienophile 2a added to the nitrogen atom of the o-quinone-
monoimine heterodiene. In all cases (Table 2, entries 1–9), the
method was successful leading to the 1,4-benzoxazine deriva-
tives in acceptable yields ranging from 58 to 75%. Unexpect-
edly, o-aminophenol 1i (entry 9) proved to be as reactive as
electron-poor aminophenol derivatives 1a–f. This result
could indicate that the electron-rich enamine 2a was the more
active participant in the IEDDA reaction. However, when elec-
tron-rich o-aminophenol bearing methyl or methoxy groups
were oxidized in the presence of enamine 2a no identifiable
products were obtained under the same experimental
conditions.
In a second series of experiments, diverse enamine dieno-
philes 2a–i were screened in the presence of aminophenol 1a
(Table 3). As earlier shown, the use of 3,3-disubstituted enam-
ines 2 was required for the preparation of 1,4-benzoxazine
derivatives in acceptable yields.13 As expected, tertiary alkylen-
amines 2a–c with a pronounced electron-rich character pro-
duced the desired cycloadduct in high yields (entries 1–3),
whereas the introduction of phenyl substituents resulted in
lower yields (entries 4 and 5). The cycloaddition reaction could
also be extended to less stable secondary enamines 2f–h and
afforded the 1,4-benzoxazine derivatives 3n–p (entries 6–8)
without further elimination of the 2-alkylamino chain, in con-
trast to what had been previously reported for similar cyclo-
addition reactions of enamines with heterodienes.14 Despite
its aromaticity, commercially available 2,3-dihydro-1H-cyclo-
pent[b]indole 2i with latent enamine functionality could also
participate in the IEDDA reaction giving the indolobenzox-
azine ring system in 30% yield (entry 9).
Results and discussion
Choice of the optimal reaction conditions
Our studies began by examining the oxidation of o-amino-
phenol 1a in deaerated methanol, in the presence of enamine
2a. One equivalent of 1a and 1.5 equiv. of enamine 2a,
together with a stoichiometric amount of MnO2 as the
oxidant, were a good reagent combination for the reaction.
However, the reaction progressed slowly (entry 1, Table 1),
leading after 6 h to 46% of 1,4-benzoxazine 3a as a single
regioisomer. As previously observed from electrochemical
studies,7 the basicity of the enamine dienophile 2a was not
sufficient to produce significant amounts of the phenolate
anion of 1a, which is the sole form that can be oxidized to the
o-quinone-monoimine species. Accordingly, when morpholine
was added to the bulk solution as the ancillary base (entries 2
and 3), the reaction could go to completion by acid–base equi-
librium displacement. Using 1.5 equiv. of morpholine, the
yield of 3a reached 75% in only 3 h (entry 3). Various tempera-
Table 1 Optimization of the reaction conditionsa
Morpholine
(equiv.)
Temp.
(°C)
Time
(h)
Yieldb
(%)
Entry
Solvent
In vivo biological evaluation of compound 3n
1
2
3
4
5
6
7
0
1
1.5
1.5
1.5
1.5
1.5
MeOH
MeOH
MeOH
MeOH
MeOH
CH3CN
THF
25
25
25
10
40
25
25
6
6
3
3
3
3
3
46
70
75
51
44
34
36
In a previous work, we had shown that the introduction of
3-phenyl substituents was crucial for efficient neuroprotective
activity without the manifestation of intrinsic toxicity using
in vitro assays on murine HT-22 hippocampal cell cultures.
From these results, we had identified a potential candidate A
(Fig. 2) that proved to be active in vivo in newborn mice.8 Brain
lesions induced in newborn mice by the glutamatergic agonist
S-bromowillardiine acting on kainate receptors mimic some
a Reactions were performed with 1a (0.5 mmol), 2a (0.75 mmol, 1.5
equiv.) and MnO2 (0.5 mmol, 1 equiv.), in 25 mL of deaerated solvent.
b Yields refer to chromatographically pure isolated products.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Variation of the diene part: tandem oxidation–IEDDA reaction
of diverse aminophenol derivatives 1a–i with enamine 2aa
Table 3 Variation in the dienophile part: tandem oxidation–IEDDA
reaction of aminophenol 1a with different enamines 2a–ia
Yieldb (%)
75
Entry
1
Enamine 2
Product 3
Yieldb (%)
75
Entry
1
Substrate 1
Product 3
2
3
4
74
85
60
2
3
75
74
4
5
6
68
68
62
5
56
6
7
65
69
7
8
9
60
58
62
8
9
52
30c
a Reactions were performed with 1a (0.5 mmol), enamines 2a–h
(0.75 mmol) and MnO2 (0.5 mmol, 1 equiv.) in 25 mL of deaerated
MeOH, at room temperature, for 3 h. 1.5 equiv. of morpholine was
added to the bulk solution to generate the phenolate ion of 1a. b Yields
refer to chromatographically pure isolated products. c 2.5 mmol
(5 equiv.) of indole 2i was necessary for the reaction.
a Reactions were performed with 1a–i (0.5 mmol), 2a (0.75 mmol, 1.5
equiv.) and MnO2 (0.5 mmol, 1 equiv.) in 25 mL of deaerated MeOH,
at room temperature, for 3 h. 1.5 equiv. of morpholine was added to
the bulk solution for generating the phenolate ion of 1a–i. b Yields
refer to chromatographically pure isolated products.
Our present investigation into the substrate scope led us to
aspects of white matter cysts and transcortical necrosis select another candidate 3n. The neuroprotective effects of
observed in human perinatal brain damage, especially in the benzoxazine 3n were assessed and compared with those of
case of cerebral palsy.15
compound A, together with reference benzoxazines B and C,
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
elements of diversity. The reactions proceeded under mild con-
ditions, at room temperature, with a good efficiency. The low
toxicity, low cost, and ease of handling stoichiometric amount
of activated MnO2, combined with its commercial availability,
are more attractive than the previously reported electrochemi-
cal conditions for the synthesis of the derivatives at a prepara-
tive scale. By means of the current protocol, 3,3-diphenyl-
substituted-1,4-benzoxazine 3n was identified as an effective
neuroprotective agent in newborn mice, suggesting that it
could be a potential candidate for the treatment and preven-
tion of cerebral palsy, together with probably other neuro-
degenerative disorders involving excitotoxicity as
pathomechanism.
a
Experimental section
General information
Analytical thin-layer chromatography was carried out on silica
gel Macherey-Nagel Polygram SIL G/UV 254 (0.25 mm).
Column chromatography was performed on Macherey-Nagel Si
60 M silica gel (40–63 μm).
Melting points were measured on a Köfler apparatus.
1H NMR and 13C NMR spectra were performed on a Bruker
AC-300 spectrometer operating at 300 and 75 MHz, respecti-
vely. Chemical shifts are expressed as δ units (parts per
million) downfield from TMS (tetramethylsilane). The
measurements were carried out using the standard pulse
sequences. The carbon type (methyl, methylene, methine, or
1
quaternary) was determined by DEPT experiments. H and 13C
Fig. 2 In vivo biological evaluation of compounds A–C and 3n in
newborn mice. The histograms represent the mean length of the neocor- NMR spectra of all compounds are included in the ESI† as a
tical lesion in the sagittal fronto-occipital axis S.E.M. Asterisks indicate
difference from control (*P < 0.05, **P < 0.01 in ANOVA with Dunnet’s
multiple comparison test). PBS: control animals injected with S-bromo-
willardiine into the cortex and white matter and ip with physiological
proof of their identity.
High-resolution mass spectra (HRMS) were performed on a
Bruker maXis mass spectrometer operating in the positive ion
mode by the “Fédération de Recherche” ICOA/CBM (FR2708)
platform.
saline; all the other experimental groups were cotreated with S-bromo-
willardiine and the selected drug at the doses indicated in mg kg−1, ip.
Chemicals were commercial products of the highest avail-
able purity and were used as supplied. 2-Aminophenol 1i and
2,3-dihydro-1H-cyclopent[b]indole 2i were commercially
available compounds. Substituted o-aminophenol starting
materials 1a–h were synthesized through previously reported
procedures.7c,17 Enamine dienophiles 2a–h were prepared by
standard methods from a mixture of aldehyde, appropriate
amine (slight excess) and toluene-p-sulfonic acid (catalytic
amount) heated at reflux in benzene for 18 h, the water being
continuously removed by means of a Dean-Stark separator.
two established neuroprotective agents both in vitro and
in vivo.16 Cotreatment with 3n protected both the white matter
and the cortical plate against the insult (Fig. 2). Furthermore,
both doses (1 and 10 mg kg−1) of A, B and 3n were neuro-
protective, while only the highest dose (10 mg kg−1) of C
yielded a significant protection in this model. Finally, in
newborn mice, 3,3-diphenyl substituted 1,4-benzoxazine 3n
proved to be more potent than benzoxazines A–C, making it a
promising candidate as a neuroprotective agent.
General procedure for the tandem oxidation–IEDDA reaction
of o-aminophenol derivatives 1a–i with enamines 2a–i
A solution of enamine (0.75 mmol, 1.5 equiv.) in deaerated
methanol (5 mL) was added to a solution of o-aminophenol
Conclusions
We have reported the successful use of in situ generated derivative (0.5 mmol, 1 equiv.) in deaerated methanol (20 mL)
o-quinone-monoimine heterodienes for a regiospecific IEDDA containing activated MnO2 (43.5 mg, 0.5 mmol, 1 equiv.) and
reaction with enamine dienophiles. The possibility of introdu- morpholine (66 μL, 0.75 mmol, 1.5 equiv.). The resulting
cing variations in both cycloaddition partners led to highly mixture was stirred at room temperature for 3 h, filtered off,
substituted 1,4-benzoxazine cycloadducts with up to five and the filtrate was evaporated under reduced pressure at
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
30 °C. The residue was purified by column chromatography 3H), 1.50 − 1.70 (m, 3H), 1.70 − 1.90 (m, 1H), 2.59 (m, 2H),
(toluene–acetone, 95/5 v/v) on silica gel to afford the desired 3.31 (m, 2H), 3.66 (m, 4H), 3.85 (s, 1H), 4.53 (s, 1H), 6.78 (s,
1,4-benzoxazine derivative.
1H), 6.83 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H); 13C{1H}
The above procedure is generally representative for all the NMR (75 MHz, CDCl3) δ 6.7, 7.5, 26.4, 26.9, 49.1, 55.8, 67.1,
products shown in Tables 2 and 3. Any deviations from this 95.1, 103.5, 115.8, 117.7, 119.7, 123.6, 132.6, 148.5; Anal. calcd
protocol are specified in the footnotes of the tables. for C17H23N3O2: C, 67.77; H, 7.64; N, 13.95. Found: C, 67.60;
[(R,S)-3,3-Diethyl-5-hydroxy-2-morpholino-3,4-dihydro-2H- H, 7.66; N, 13.89.
1,4-benzoxazin-6-yl](methyl) methanone (3a). Pale yellow solid
[(R,S)-3,3-Diethyl-2-morpholino-3,4-dihydro-2H-1,4-benzoxazin-
(125 mg, 75%): mp 138–142 °C; Rf = 0.35 (toluene–acetone, 6-yl](methyl) carboxylate (3f). White solid (104 mg, 62%): mp
1
98/2 v/v); H NMR (300 MHz, CDCl3) δ 0.82 (t, J = 7.4 Hz, 3H), 160–164 °C; Rf = 0.4 (toluene–acetone, 95/5 v/v); 1H NMR
0.97 (t, J = 7.4 Hz, 3H), 1.40 − 2.00 (m, 4H), 2.59 (m, 5H), 3.41 (300 MHz, CDCl3) δ 0.81 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz,
(m, 2H), 3.70 (m, 4H), 4.13 (s, 1H), 4.57 (s, 1H), 6.45 (d, J = 3H), 1.50 − 1.65 (m, 3H), 1.70 − 1.85 (m, 1H), 2.58 (m, 2H),
8.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 12.83 (s, 1H); 13C{1H} 3.35 (m, 2H), 3.66 (m, 4H), 3.77 (s, 1H), 3.87 (s, 3H), 4.50 (s,
NMR (75 MHz, CDCl3) δ 6.7, 7.7, 25.8, 26.2, 27.1, 49.1, 55.4, 1H), 6.81 (d, J = 8.3 Hz, 1H), 7.26 (s, 1H), 67.41 (d, J = 8.3 Hz,
67.2, 95.7, 107.1, 113.3, 120.2, 120.8, 150.2, 151.3, 203.3; 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 6.7, 7.5, 26.1, 27.0, 49.2,
HRMS (ESI+) m/z calcd for C18H26N2O4 [M + H]+ 335.1965. 51.8, 55.7, 67.2, 95.0, 114.9, 116.2, 121.3, 122.5, 131.6, 148.9,
Found 335.1966.
167.2; Anal. calcd for C18H26N2O4: C, 64.67; H, 7.78, N, 8.38.
[(R,S)-3,3-Diethyl-5-hydroxy-2-morpholino-3,4-dihydro-2H- Found: C, 64.70; H, 7.80, N, 8.38.
1,4-benzoxazin-6-yl] (cyclohexyl)methanone (3b). Pale yellow
[(R,S)-3,3-Diethyl-2-morpholino-3,4-dihydro-2H-1,4-benzoxazin-
solid (151 mg, 75%): mp 152–156 °C; Rf = 0.45 (toluene– 6-yl](phenyl)methanone (3g). Yellow solid (114 mg, 60%): mp
acetone, 98/2 v/v); 1H NMR (300 MHz, CDCl3) δ 0.82 (t, J = 150–154 °C; Rf = 0.35 (toluene–acetone, 95/5 v/v); 1H NMR
7.4 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H), 1.20 − 2.00 (m, 14H), 2.63 (300 MHz, CDCl3) δ 0.83 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz,
(m, 2H), 3.26 (t, J = 5.4 Hz, 1H), 3.42 (m, 2H), 3.71 (m, 4H), 3H), 1.50 − 1.7 (m, 3H), 1.82 (m, 1H), 2.61 (m, 2H), 3.38 (m,
4.14 (s, 1H), 4.57 (s, 1H), 6.45 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2H), 3.68 (m, 4H), 3.83 (s, 1H), 4.54 (s, 1H), 6.83 (d, J = 8.1 Hz,
8.8 Hz, 1H), 13.21 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 6.7, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.17 (s, 1H), 7.48 (m, 2H), 7.57 (m,
7.7, 25.87, 25.89, 25.92, 27.1, 29.7, 29.8, 44.9, 49.1, 55.4, 67.1, 1H), 7.77 (d, J = 7.5 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3)
95.6, 106.9, 111.9, 112.3, 119.9, 120.4, 149.8, 152.0, 209.0; δ 6.7, 7.6, 26.3, 27.0, 49.2, 55.7, 67.2, 95.1, 114.4, 116.5, 123.3,
Anal. calcd for C23H34N2O4: C, 68.66; H, 8.46; N, 6.96. Found: 128.0, 129.7, 130.2, 131.6, 132.0, 138.6, 149.1, 195.8; Anal.
C, 68.60; H, 8.49; N, 6.94.
calcd for C23H28N2O3: C, 72.63; H, 7.37; N, 7.37. Found: C,
[(R,S)-3,3-Diethyl-5-hydroxy-2-morpholino-3,4-dihydro-2H- 72.49; H, 7.40; N, 7.35.
1,4-benzoxazin-6-yl] (isobutyl)methanone (3c). Yellow solid
[(R,S)-3,3-Diethyl-2-morpholino-3,4-dihydro-2H-1,4-benzoxazin-
(139 mg, 74%): mp 152–156 °C; Rf = 0.4 (toluene–acetone, 98/2 6-yl](isobutyl) carboxamide (3h). White solid (109 mg, 58%):
1
v/v); H NMR (300 MHz, CDCl3) δ 0.82 (t, J = 7.4 Hz, 3H), 0.97 mp 198–202 °C; Rf = 0.5 (ethyl acetate–petroleum ether, 50/50
1
(t, J = 7.4 Hz, 3H), 1.05 (d, J = 7.2 Hz, 6H), 1.49 − 2.00 (m, 4H), v/v); H NMR (300 MHz, CDCl3) δ 0.79 (t, J = 7.4 Hz, 3H), 0.91
2.32 (m, 1H), 2.61 (m, 2H), 2.80 (d, J = 6.9 Hz, 2H), 3.41 (m, (t, J = 7.4 Hz, 3H), 0.96 (d, J = 6.6 Hz, 6H), 1.40 − 1.65 (m, 3H),
2H), 3.70 (m, 4H), 4.13 (s, 1H), 4.56 (s, 1H), 6.43 (d, J = 8.9 Hz, 1.70 − 1.90 (m, 2H), 2.56 (m, 2H), 3.23 (m, 1H), 3.34 (m, 2H),
1H), 7.18 (d, J = 8.9 Hz, 1H), 13.08 (s, 1H); 13C{1H} NMR 3.64 (m, 4H), 3.95 (s, 1H), 4.44 (s, 1H), 6.20 (s, 1H), 6.77 (d, J =
(75 MHz, CDCl3) δ 6.7, 7.7, 22.8, 25.83, 25.88, 27.1, 46.8, 49.1, 8.2 Hz, 1H), 7.26 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 7.11 (s, 1H);
55.4, 67.2, 95.7, 106.9, 113.3, 120.26, 120.33, 150.0, 151.6, 13C{1H} NMR (75 MHz, CDCl3) δ 6.7, 7.6, 20.2, 26.2, 27.0, 28.6,
205.5; Anal. calcd for C21H32N2O4: C, 67.02; H, 8.51; N, 7.45. 47.3, 49.2, 55.6, 67.2, 94.7, 114.56, 114.63, 116.8, 127.3, 132.1,
Found: C, 66.90; H, 8.54; N, 7.40.
147.3, 167.6; Anal. calcd for C21H33N3O3: C, 67.20; H, 8.80,
[(R,S)-3,3-Diethyl-2-morpholino-3,4-dihydro-2H-1,4-benzoxazin- N, 11.20. Found: C, 66.98; H, 8.85; N, 11.12.
6-yl](methyl)methanone (3d). White solid (108 mg, 68%): mp
(R,S)-3,3-Diethyl-2-morpholino-3,4-dihydro-2H-1,4-benzoxazine
134–138 °C; Rf = 0.25 (toluene–acetone, 95/5 v/v); 1H NMR (3i). White solid (84 mg, 62%): mp 154–158 °C; Rf = 0.35
1
(300 MHz, CDCl3) δ 0.81 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz, (toluene–acetone, 98/2 v/v); H NMR (300 MHz, CDCl3) δ 0.82
3H), 1.51 − 1.61 (m, 3H), 1.70 − 1.90 (m, 1H), 2.53 (s, 3H), 2.58 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H), 1.40 − 1.9 (m, 5H),
(m, 2H), 3.35 (m, 2H), 3.65 (m, 4H), 3.83 (s, 1H), 4.52 (s, 1H), 2.61 (m, 2H), 3.36 (m, 2H), 3.66 (m, 4H), 4.44 (s, 1H), 6.53 (d,
6.83 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H), 7.33 (d, J = 8.3 Hz, 1H); J = 7.6 Hz, 1H), 6.65–6.75 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H); 13C
13C{1H} NMR (75 MHz, CDCl3) δ 6.7, 7.5, 26.18, 26.22, 27.0, {1H} NMR (75 MHz, CDCl3) δ 6.8, 7.6, 26.2, 27.1, 49.3, 55.6,
49.2, 55.7, 67.2, 95.1, 114.5, 114.7, 121.0, 130.4, 131.9, 149.3, 67.3, 94.1, 115.0, 115.2, 118.9, 120.6, 131.9, 144.6; Anal. calcd
197.1; Anal. calcd for C18H26N2O3: C, 67.92; H, 8.18; N, 8.80. for C16H24N2O2: C, 69.56; H, 8.69; N, 10.14. Found: C, 69.39;
Found: C, 67.81; H, 8.21; N, 8.77.
H, 8.73; N, 10.11.
[(R,S)-3,3-Diethyl-2-morpholino-3,4-dihydro-2H-1,4-benzoxazin-
[(R,S)-3,3-Dimethyl-5-hydroxy-2-morpholino-3,4-dihydro-2H-
6-yl]carbonitrile (3e). White solid (103 mg, 68%): mp 1,4-benzoxazin-6-yl](methyl)methanone (3j). Yellow solid
156–160 °C; Rf = 0.35 (toluene–acetone, 95/5 v/v); 1H NMR (113 mg, 74%): mp 153–157 °C; Rf = 0.35 (toluene–acetone,
(300 MHz, CDCl3) δ 0.81 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 95/5 v/v); 1H NMR (300 MHz, CDCl3) δ 1.26 (s, 3H), 1.41 (s,
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
3H), 2.59 (s, 3H), 2.62 (m, 2H), 3.36 (m, 2H), 3.69 (m, 4H), 3.90 120.6, 121.5, 124.7, 124.9, 126.56, 126.62, 127.0, 127.1, 127.2,
(s, 1H), 4.52 (s, 1H), 6.47 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 128.3, 128.4, 142.8, 143.6, 144.1, 146.7, 151.6, 203.4; Anal.
1H), 12.84 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 26.1, 26.2, calcd for C27H24N2O3S: C, 71.05; H, 5.26; N, 6.14. Found: C,
28.3, 48.8, 50.9, 67.2, 96.9, 107.2, 113.3, 120.5, 120.9, 150.0, 70.83; H, 5.27; N, 6.12.
151.5, 203.3; Anal. calcd for C16H22N2O4: C, 62.74; H, 7.19;
N, 9.15. Found: C, 62.47; H, 7.21; N, 9.11.
[(R,S)-2-[(2,2-Dimethoxy)ethylamino]-3,3-diphenyl-5-hydroxy-
3,4-dihydro-2H-1,4-benzoxazin-6-yl](methyl)methanone (3p).
[(R,S)-5-Hydroxy-2-morpholino-3-spiro-1′-cyclohexyl-3,4- Pale yellow solid (117 mg, 52%): mp 64–68 °C; Rf = 0.3
1
dihydro-2H-1,4-benzoxazin-6-yl](methyl)methanone (3k). Pale (toluene–acetone, 95/5 v/v); H NMR (300 MHz, CDCl3) δ 2.40
yellow solid (144 mg, 83%): mp 68–72 °C; Rf = 0.45 (toluene– (broad s, 1H), 2.53 (s, 3H), 2.85–3.10 (m, 2H), 3.22 (s, 3H), 3.24
1
acetone, 95/5 v/v); H NMR (300 MHz, CDCl3) δ 1.30–1.90 (m, (s, 3H), 4.32 (t, J = 5.7 Hz, 1H), 5.15 (s, 1H), 5.77 (s, 1H), 6.37
10H), 2.56 (s, 3H), 2.58 (m, 2H), 3.39 (m, 2H), 3.66 (m, 4H), (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.15–7.55 (m, 10H),
4.27 (s, 1H), 4.58 (s, 1H), 6.42 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 12.98 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 26.2, 46.9, 53.4,
8.8 Hz, 1H), 12.81 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) 54.2, 62.4, 89.3, 104.2, 109.0, 113.5, 120.6, 121.4, 126.6, 127.0,
δ 21.3, 21.5, 25.4, 26.1, 34.2, 34.7, 48.9, 52.0, 67.1, 96.3, 107.0, 127.1, 128.2, 128.5, 143.0, 144.2, 146.8, 151.6, 203.5; Anal.
113.2, 120.0, 120.7, 150.0, 151.4, 203.1; Anal. calcd for calcd for C26H28N2O5: C, 69.64; H, 6.25; N, 6.25. Found: C,
C19H26N2O4: C, 65.89; H, 7.51; N, 8.09. Found: C, 66.09; H, 69.49; H, 6.28; N, 6.24.
7.51; N, 8.11.
[1-Hydroxy-6H,11H-5a,10b-propanoindolo[2,3-b][1,4] benzox-
[(R,S)-3,3-Diphenyl-5-hydroxy-2-morpholino-3,4-dihydro-2H- azin-2-yl](methyl) methanone (3q). Pale pink solid (48 mg,
1
1,4-benzoxazin-6-yl](methyl) methanone (3l). Pale yellow solid 30%): mp 144–148 °C; Rf = 0.4 (toluene–acetone, 95/5 v/v); H
(143 mg, 60%): mp 158–162 °C; Rf = 0.45 (toluene–acetone, 95/ NMR (300 MHz, CDCl3) δ 1.75–2.45 (m, 6H), 2.51 (s, 3H), 4.60
1
5 v/v); H NMR (300 MHz, CDCl3) δ 2.51 (s, 3H), 2.54 (m, 2H), (broad s, 2H), 6.41 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H),
3.30–3.40 (m, 6H), 4.98 (s, 1H), 5.57 (s, 1H), 6.48 (d, J = 8.8 Hz, 6.76 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.08 (d, J =
1H), 7.10–7.44 (m, 11H), 12.90 (s, 1H); 13C{1H} NMR (75 MHz, 8.8 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 12.7 (s, 1H); 13C{1H} NMR
CDCl3) δ 26.1, 49.1, 63.3, 67.0, 94.7, 107.2, 113.4, 120.0, 121.8, (75 MHz, CDCl3) δ 22.7, 26.2, 38.3, 41.5, 70.5, 107.2, 113.6,
126.7, 126.8, 126.98, 127.02, 128.0, 128.4, 144.0, 145.8, 150.0, 120.6, 121.5, 124.7, 124.9, 126.56, 126.62, 127.0, 127.1, 127.2,
151.9, 203.2; Anal. calcd for C30H26N2O4: C, 75.31; H, 5.44; 128.3, 128.4, 142.8, 143.6, 144.1, 146.7, 151.6, 203.4; Anal.
N, 5.86. Found: C, 75.45; H, 5.45; N, 5.87.
calcd for C19H18N2O3: C, 70.81; H, 5.59; N, 8.69. Found: C,
[(R,S)-3,3-Diphenyl-5-hydroxy-2-(N-methyldioxolan)methyl 70.58; H, 5.63; N, 8.67.
amino-3,4-dihydro-2H-1,4-benzoxazin-6-yl](methyl) methanone
In vivo biological assay
(3m). Pale yellow solid (129 mg, 56%): mp 144–148 °C; Rf =
0.25 (toluene–acetone, 95/5 v/v); 1H NMR (300 MHz, CDCl3)
Neonatal mice. At postnatal day 5, Swiss mouse pups were
δ 2.50 (s, 3H), 2.58 (s, 3H), 2.96 (m, 2H), 3.71–3.80 (m, 4H), anesthetized with isoflurane for intracerebral (ic) and intra-
4.50 (s, 1H), 4.97 (s, 1H), 5.93 (s, 1H), 6.45 (d, J = 8.8 Hz, 1H), peritoneal (ip) injections.15,18 Intracerebral injections were per-
7.10–7.50 (m, 11H), 12.86 (s, 1H); 13C{1H} NMR (75 MHz, formed using a 26-gauge needle mounted on a calibrated
CDCl3) δ 26.0, 37.6, 57.8, 63.3, 64.5, 64.8, 94.2, 104.6, 107.2, microdispenser. The needle was inserted 2 mm under the
113.2, 120.0, 121.7, 126.7, 126.9, 127.0, 127.9, 128.3, 143.8, external surface of scalp skin in the frontoparietal area of the
146.1, 150.2, 151.8, 203.1; Anal. calcd for C27H28N2O5: C, right hemisphere 2 mm from the midline in the lateral–medial
70.43; H, 6.09; N, 6.09. Found: C, 70.34; H, 6.11; N, 6.09.
plane and 3 mm (in the rostro-caudal plane) from the junction
[(R,S)-3,3-Diphenyl-5-hydroxy-2-(2-methoxy)ethylamino-3,4- between the sagittal and lambdoid sutures. Two 1 μl boluses
dihydro-2H-1,4-benzoxazin-6-yl](methyl)methanone (3n). Pale were injected at a 30 s interval.
yellow solid (136 mg, 65%): mp 96–100 °C; Rf = 0.35 (ethyl
Fifteen μg S-bromo-willardiine (Tocris, Bristol, UK), diluted
acetate–petroleum ether, 25/75 v/v); 1H NMR (300 MHz, CDCl3) in phosphate buffer saline (PBS), were injected ic. Immediately
δ 2.60 (s, 3H), 2.90–3.10 (m, 2H), 3.24 (s, 3H), 3.41 (s, 2H), 5.13 following ic injection, 1 or 10 mg kg−1 compound C (n = 8 and
(s, 1H), 5.80 (s, 1H), 6.40 (d, J = 8.8 Hz, 1H), 7.10–7.60 (m, 6, respectively), 1 or 10 mg kg−1 compound B (n = 6 and 15,
11H), 12.97 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 26.3, 44.9, respectively), 0.1, 1 or 10 mg kg−1 compound A (n = 8, 7 and 9,
58.6, 62.4, 72.6, 89.5, 109.0, 113.5, 120.6, 121.4, 126.6, 127.0, respectively), and 1 or 10 mg kg−1 3n (n = 10 in both groups)
127.1, 128.2, 128.4, 143.0, 144.3, 146.9, 151.5, 203.5; HRMS diluted in PBS containing 10% dimethylsulfoxide (DMSO),
(ESI+) m/z calcd for C25H26N2O4 [M + H]+ 419.1965. Found were administered ip. Controls received ip PBS containing
419.1963.
10% DMSO alone (n = 19).
[(R,S)-3,3-Diphenyl-5-hydroxy-2-(1-thienyl)methylamino-3,4-
Five days later, the surviving pups were sacrificed and their
dihydro-2H-1,4-benzoxazin-6-yl](methyl)methanone (3o). White brains fixed in formalin. Coronal serial sections, 15 μm thick,
solid (157 mg, 69%): mp 166–170 °C; Rf = 0.3 (toluene); 1H were cut and every third section was stained with cresyl-violet.
NMR (300 MHz, CDCl3) δ 2.56 (s, 3H), 4.21 (m, 2H), 5.22 (s, The brain was completely and serially sectioned from the
1H), 5.79 (s, 1H), 6.44 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 2.6 Hz, frontal pole to the occipital lobes. In theory, neocortical and
1H), 6.94 (m, 1H), 7.10–7.50 (m, 13H), 12.99 (s, 1H); 13C{1H} white matter lesions can be defined by the maximal length of
NMR (75 MHz, CDCl3) δ 26.2, 43.7, 62.3, 87.5, 109.0, 113.6, three orthogonal axes: the lateral–medial axis (in a coronal
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
plane), the radial axis (also in a coronal plane, from the pial
surface to the lateral ventricle) and the fronto-occipital axis (in
a sagittal plane). Due to the difficulty of accurately evaluating
the degree of damage to neurons in the neocortical layers in
the epicenter of the lesion focus, the radial axis did not appear
as an objective measure of the lesion size. In previous
studies,15,18 we had shown an excellent correlation between
the maximal size of the radial and fronto-occipital diameters
of the excitotoxic lesions. Based on these observations, we seri-
ally sectioned the entire brain in the coronal plane. This per-
mitted an accurate and reproducible determination of the
maximal sagittal fronto-occipital diameter (which is equal to
the number of sections where the lesion was present multi-
plied by 15 µm) and was as an index of the volume of the
lesion. Statistical analyses were performed by analysis of var-
iance (ANOVA) with Dunnet’s multiple comparison of means
test. The results were expressed as means S.E.M.
Chem., 2010, 53, 5827; (i) M. Ilic, C. Kontogiorgis,
D. Hadjipavlou-Litina, J. Ilas and D. Kikelj, Bioorg. Med.
Chem. Lett., 2011, 21, 4705; ( j) A. N. Matralis,
M. G. Katselou, A. Nikitakis and A. P. Kourounakis, J. Med.
Chem., 2011, 54, 5583; (k) V. P. Patil, V. L. Markad,
K. M. Kodam and S. B. Waghmode, Bioorg. Med. Chem.
Lett., 2013, 23, 6259; (l) G. Sonia, K. K. Thachil,
M. K. Parameswaran and R. T. Kochupappy, Med. Chem.
Res., 2014, 23, 1320.
3 For a selected report on the synthesis of 1,4-benzoxazine
derivatives, see: J. Ilas, P. Stefanic Anderluh, M. Sollner
Dolenc and D. Kikelj, Tetrahedron, 2005, 61, 7325 and refer-
ences therein.
4 For selected recent examples, see: (a) B. Gabriele,
G. Salerno, L. Veltri, R. Mancuso, Z. Li, A. Crispini and
A. Bellusci, J. Org. Chem., 2006, 71, 7895; (b) X. Xu,
L. Liang, J. Liu, J. Yang, L. Mai and Y. Li, Tetrahedron Lett.,
2009, 50, 57; (c) Z. Liu and Y. Chen, Tetrahedron Lett., 2009,
50, 3790; (d) R. K. Rao, A. B. Naidu and G. Sekar, Org. Lett.,
2009, 11, 1923; (e) D. Chen, G. Shen and W. Bao, Org.
Biomol. Chem., 2009, 7, 4067; (f) S. Bhadra, L. Adak,
S. Samanta, A. K. M. Maidul Islam, M. Mukherjee and
B. C. Ranu, J. Org. Chem., 2010, 75, 8533; (g) F. Melkonyan,
A. Topolyan, A. Karchava and M. Yurovskaya, Tetrahedron,
2011, 67, 6826; (h) K. Brahma, A. Kumar Sasmal and
C. Chowdhury, Org. Biomol. Chem., 2011, 9, 8422;
(i) K. E. O. Ylijoki and E. P. Kündig, Chem. Commun., 2011,
47, 10608; ( j) R. K. Rao and G. Sekar, Tetrahedron: Asymmetry,
2011, 22, 948; (k) J. S. Cannon, A. C. Olson, L. E. Overman
and N. S. Solomon, J. Org. Chem., 2012, 77, 1961;
(l) J. W. Zhang, Q. Cai, Q. Gu, X.-X. Shi and S.-L. You, Chem.
Commun., 2013, 49, 7750; (m) M. Nagarjuna Reddy and
K. C. Kumara Swamy, Org. Biomol. Chem., 2013, 11, 7350;
(n) B. Liu, M. Yin, H. Gao, W. Wu and H. Jiang, J. Org. Chem.,
2013, 78, 3009.
5 For selected examples, see: (a) K. C. Nicolaou, Y. L. Zhong
and P. S. Baran, Angew. Chem., Int. Ed., 2000, 39, 622;
(b) K. C. Nicolaou, K. Sugita, P. S. Baran and Y. L. Zhong,
Angew. Chem., Int. Ed., 2001, 40, 207; (c) K. C. Nicolaou,
P. S. Baran, Y. L. Zhong and K. Sugita, J. Am. Chem. Soc.,
2002, 124, 2212; (d) K. C. Nicolaou, K. Sugita, P. S. Baran
and Y. L. Zhong, J. Am. Chem. Soc., 2002, 124, 2221;
(e) M. Largeron, A. Neudörffer, M. Vuilhorgne, E. Blattes
and M.-B. Fleury, Angew. Chem., Int. Ed., 2002, 41, 824;
(f) J. Wolfer, T. Bekele, C. J. Abraham, C. Dogo-Isonagie
and T. Lectka, Angew. Chem., Int. Ed., 2006, 45, 7398;
(g) J.-F. Bower, P. Szeto and T. Gallagher, Org. Lett., 2007, 9,
3283; (h) J. Iqbal, N. D. Tangellamudi, B. Dulla and
S. Balasubramanian, Org. Lett., 2012, 14, 552;
(i) M. S. Deshmukh, B. Das and N. Jain, RSC Adv., 2013, 3,
22389; ( j) S. K. Singh, A. K. Bajpai and R. Saini, Tetrahedron
Lett., 2013, 54, 7132; (k) L. Chouguiat, R. Boulcina,
B. Carboni, A. Demonceau and A. Debache,
Tetrahedron Lett., 2014, 55, 5124; (l) G. Choudhary,
R. T. Naganaboina and R. K. Peddinti, RSC Adv., 2014, 4,
17969.
Acknowledgements
We thank CNRS, Inserm together with Paris Descartes and
Paris Diderot Universities for financial support.
Notes and references
1 For recent reviews on biologically active 1,4-benzoxazine
derivatives, see: (a) B. Achari, S. B. Mandal, P. K. Dutta and
C. Chowdhury, Synlett, 2004, 2449 and references
therein; (b) F. A. Macias, D. Marin, A. Oliveros-
Bastidas and J. M. G. Molinillo, Nat. Prod. Rep., 2009, 26,
478.
2 For selected recent examples, see: (a) P. Stefanic Anderluh,
M. Anderluh, J. Ilas, J. Mravljak, M. Sollner Dolenc,
M. Stegnar and D. Kikelj, J. Med. Chem., 2005, 48, 3110;
(b) F. Schiaffella, A. Macchiarulo, L. Milanese,
A. Vecchiarelli, G. Costantino, D. Pietrella and
R. Fringuelli, J. Med. Chem., 2005, 48, 7658; (c) J. Ilas,
Z. Jakopin, T. Borstnar, M. Stegnar and D. Kikelj, J. Med.
Chem., 2008, 51, 5617; (d) E. N. Koini, P. Papazafiri,
A. Vassilopoulos, M. Koufaki, Z. Horvath, I. Koncz, L. Virag,
G. J. Papp, A. Varro and T. Calogeropoulou, J. Med. Chem.,
2009, 52, 2328; (e) X. Li, N. Liu, H. Zhang, S. E. Knudson,
R. A. Slayden and P. J. Tonge, Bioorg. Med. Chem. Lett.,
2010, 20, 6306; (f) T. Bouyssou, C. Hoenke, K. Rudolf,
P. Lustenberger, S. Pestel, P. Sieger, R. Lotz, C. Heine,
F. H. Büttner, A. Schnapp and I. Konetzki, Bioorg. Med.
Chem. Lett., 2010, 20, 1410; (g) A. Wang, C. P. Prouty,
P. D. Pelton, M. Yong, K. T. Demarest, W. V. Murray and
G.-H. Kuo, Bioorg. Med. Chem. Lett., 2010, 20, 1432;
(h) S. M. Bromidge, R. Arban, B. Bertani, S. Bison,
M. Borriello, P. Cavanni, G. Dal Forno, R. Di-Fabio,
D. Donati, S. Fontana, M. Gianotti, L. J. Gordon, E. Granci,
C. P. Leslie, L. Moccia, A. Pasquarello, I. Sartori, A. Sava,
J. M. Watson, A. Worby, L. Zonzini and V. Zucchelli, J. Med.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
6 (a) W. M. Dai, X. Wang and C. Ma, Tetrahedron, 2005, 61, 12 For reviews, see: (a) R. J. K. Taylor, M. Reid, J. Foot and
6879; (b) G. Feng, J. Wu and W. M. Dai, Tetrahedron, 2006,
62, 4635; (c) X. Xing, J. Wu, G. Feng and W. M. Dai, Tetra-
hedron, 2006, 62, 6774; (d) E. Zhang, T. Xu, D. Wang,
S. A. Raw, Acc. Chem. Res., 2005, 38, 851 and references
therein; (b) V. Jeena and R. S. Robinson, RSC Adv., 2014, 4,
40720 and references therein.
T. Huang, M. Yuan, J. Li and Y. Zou, RSC Adv., 2014, 4, 13 E. Blattes, M.-B. Fleury and M. Largeron, Electrochim. Acta,
10022. 2005, 50, 4902.
7 (a) E. Blattes, M.-B. Fleury and M. Largeron, J. Org. Chem., 14 For selected examples, see: (a) Y. Omote, A. Tomotake and
2004, 69, 882; (b) D. Xu, A. Chiaroni and M. Largeron, Org.
Lett., 2005, 7, 5273; (c) D. Xu, A. Chiaroni, M.-B. Fleury and
M. Largeron, J. Org. Chem., 2006, 71, 6374.
8 E. Blattes, B. Lockhart, P. Lestage, L. Schwendimann,
P. Gressens, M.-B. Fleury and M. Largeron, J. Med. Chem.,
2005, 48, 1282.
9 (a) A. Mc Killop and T. S. B. Sayer, J. Org. Chem., 1976, 41,
1079; (b) D. N. Nicolaides, R. Wajih Awad and E. A. Varella,
J. Heterocycl. Chem., 1996, 33, 633; (c) D. N. Nicolaides,
C. Bezergiannidou-Balouctsi, R. Wajih Awad, K. E. Litinas,
E. Malamidou-Xenikaki, A. Terzis and C. P. Raptopoulou,
J. Org. Chem., 1997, 62, 499.
10 (a) H. W. Heine, B. J. Barchiesi and E. A. Williams, J. Org.
Chem., 1984, 49, 2560; (b) D. S. C. Black, D. C. Craig,
H. W. Heine, N. Kumar and E. A. Williams, Tetrahedron
Lett., 1987, 28, 6691; (c) H. W. Heine, C. Olsson,
J. D. Bergin, J. B. Foresman and E. A. Williams, J. Org.
C. Kashima, J. Chem. Soc., Perkin Trans. 1, 1988, 1988, 151;
(b) M. S. South, L. Terri, M. D. Jakuboski, M. D. Westmeyer
and D. R. Dukesherer, J. Org. Chem., 1996, 61, 8921;
(c) R. C. Boruah, S. Ahmed, U. Sharma and J. S. Sandhu,
J. Org. Chem., 2000, 65, 922; (d) R. M. Jones, C. Selenski
and T. R. R. Pettus, J. Org. Chem., 2002, 67, 6911;
(e) V. N. Kozhevnikov, D. N. Kozhevnikov, T. V. Nikitina,
V. L. Rusinov, O. N. Chupakhin, M. Zabel and B. König,
J. Org. Chem., 2003, 68, 2882; (f) D. R. Soenen,
J. M. Zimpleman and D. L. Boger, J. Org. Chem., 2003, 68,
3593.
15 (a) S. L. Tahraoui, S. Marret, C. Bodénant, P. Leroux,
M. A. Dommergues, P. Evrard and P. Gressens, Brain
Pathol., 2001, 11, 56; (b) I. Husson, B. Mesplès, P. Bac,
J. Vamecq, P. Evrard and P. Gressens, Ann. Neurol., 2002,
51, 82; (c) I. Sfaello, O. Baud, A. Arzimanoglou and
P. Gressens, Neurobiol. Dis., 2005, 20, 837.
Chem., 1987, 52, 97; (d) H. W. Heine, W. C. Schairer, 16 (a) M. Largeron, B. Lockhart, B. Pfeiffer and M.-B. Fleury,
J. A. Suriano and E. A. Williams, Tetrahedron, 1988, 44,
3181; (e) H. W. Heine, J. A. Suriano, C. Winkel, A. Burik,
C. M. Taylor and E. A. Williams, J. Org. Chem., 1989, 54,
J. Med. Chem., 1999, 42, 5043; (b) M. Largeron, B. Mesples,
P. Gressens, R. Cechelli, M. Spedding, A. Le Ridant and
M.-B. Fleury, Eur. J. Pharmacol., 2001, 424, 189.
5926; (f) G. Desimoni, G. Faita and P. P. Righetti, Tetrahe- 17 (a) H. Aichaoui, I. Lesieur and J.-P. Hénichart, Synthesis,
dron, 1991, 47, 5857; (g) H. W. Heine, D. K. Williams,
J. L. Rutherford, J. Ramphal and E. A. Williams, Hetero-
1990, 679; (b) R. Lok, R. E. Leone and A. J. Williams, J. Org.
Chem., 1996, 61, 3289.
cycles, 1993, 35, 1125; (h) H. W. Heine, M. G. La Porte, 18 (a) S. Marret, R. Mukendi, J. F. Gadisseux, P. Gressens and
R. H. Overbaugh and E. A. Williams, Heterocycles, 1995, 40,
743.
11 N. Bodipati and R. K. Peddinti, Org. Biomol. Chem., 2012,
10, 1958.
P. Evrard, J. Neuropathol. Exp. Neurol., 1995, 54, 358;
(b) P. Gressens, S. Marret, J. M. Hill, D. E. Brenneman,
I. Gozes, I. Fridkin and P. Evrard, J. Clin. Invest., 1997, 100,
390.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015