Synthesis of Furo[3,2-g][1,4]benzoxazin-3-ones, new psoralen isosters

Article abstract of DOI:10.1002/1099-0690(200206)2002:12<1937::AID-EJOC1937>3.0.CO;2-W

Furobenzoxazin-3-one, a new tricyclic nucleus, was synthesised in two different and straightforward routes: the first route consisted of condensing a furan ring onto a preconstituted 1,4-benzoxazinone nucleus, and the other in condensing a 1,4-oxazine ring onto the appropriate benzofuran system obtained from coumarin by ring contraction. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200206)2002:12<1937::AID-EJOC1937>3.0.CO;2-W

FULL PAPER
Synthesis of Furo[3,2-g][1,4]Benzoxazin-3-ones, New Psoralen Isosters
Adriana Chilin,*[a] Alessia Confente,[a] Giovanni Pastorini,[b] and Adriano Guiotto[a]
Keywords: Antitumour agents / Nitrogen heterocycles / Ring contraction / Aromatic nitration
Furobenzoxazin-3-one, a new tricyclic nucleus, was syn-
thesised in two different and straightforward routes: the first
ing a 1,4-oxazine ring onto the appropriate benzofuran sys-
tem obtained from coumarin by ring contraction.
route consisted of condensing a furan ring onto a preconsti- ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
tuted 1,4-benzoxazinone nucleus, and the other in condens-
2002)
Introduction
trated derivative 3 in satisfactory yield (22%), along with a
small amount of dinitro derivative 2 (5%), and many un-
identified degradation products, whereas classic nitrating
agents (like nitric acid or potassium nitrate in various con-
ditions) only gave the dinitrated product, and other re-
agents, such as nitronium tetrafluoroborate, did not give
better yields than the reaction with n-pentyl nitrite. The
nitro derivative 3 was reduced by catalytic hydrogenation to
the corresponding amino derivative 4, which was directly
condensed with methyl pyruvate[10] to give 1,4-benzoxazin-
3-one (5). All attempts to isolate 4 failed, owing to rapid
oxidative degradation, with darkening of the reaction prod-
uct. Benzoxazinone 5 was then condensed with 3-chloro-2-
butanone, and the resulting ether 6 was cyclized in an acidic
Psoralens are well-known natural and/or synthetic drugs
currently used in PUVA (Psoralen plus UVA) therapy for
various skin diseases.[1] Whilst searching for new isosters of
psoralens in order to retain the high antiproliferative activ-
ity of the parent compounds but hoping to reduce the se-
vere side-effects,[2Ϫ4] we synthesised a number of tricyclic
compounds in which a carbon or an oxygen atom of the
furocoumarin nucleus was substituted by a nitrogen
atom.[5Ϫ7]
Both the photochemical behaviour of these psoralen isos-
ters in terms of their ability to photobind to DNA thymine,
and their photobiological properties, are deeply
modified.[5Ϫ8] Accordingly, we planned the synthesis of a
new tricyclic system, furo[3,2-g][1,4]benzoxazin-3-one, in
which the carbon atom at the 4-position of psoralen was
substituted by a nitrogen atom.
Results and Discussion
To build this new tricyclic system, we tried two synthetic
strategies, one consisting of condensing a furan ring onto a
preconstituted 1,4-benzoxazinone, and the other in con-
densing a 1,4-oxazine ring onto an appropriate benzofuran.
Following the first strategy, the synthesis started from 2-
methylresorcinol, because the presence of the methyl group
univocally afforded the desired product with a linear psor-
alen-like geometry. Thus, as shown in Scheme 1, resorcinol
1 was directly nitrated under mild conditions to yield com-
pounds 2 and 3: n-pentyl nitrite in ether[9] gave the mononi-
[a]
`
Dipartimento di Scienze Farmaceutiche, Universita degli Studi
di Padova,
Via Marzolo 5, 35131 Padova, Italy
Fax: (internat.) ϩ 39-049/827-5366
E-mail: adriana.chilin@unipd.it
Istituto di Chimica Biomolecolare del CNR,
Via Marzolo 3, 35131 Padova, Italy
Scheme 1. Reagents and conditions: (a) n-pentyl nitrite, diethyl
ether, room temp., 1 h, 5% (2) and 22% (3); (b) Pd/C 10%, H2, abs.
EtOH, room temp., 24 h; (c) methyl pyruvate, room temp., 5 h, 87%
(b ϩ c); (d) 3-chlorobutan-2-one, anhydrous K2CO3, acetone, re-
flux, 7 h, 54%; (e) conc. H2SO4, room temp., 3 h, 28%
[b]
Eur. J. Org. Chem. 2002, 1937Ϫ1940  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0612Ϫ1937 $ 20.00ϩ.50/0
1937

A. Chilin, A. Confente, G. Pastorini, A. Guiotto
FULL PAPER
medium[7] to yield 2,5,7,8-tetramethyl-3H-furo[3,2-g][1,4]-
benzoxazin-3-one (7).
This second synthetic pathway yielded the 4-azapsoralen
nucleus, although more steps were required than in the first
In the alternative route, we first built the benzofuran nuc- strategy, but with a nearly identical overall yield. In addi-
leus and then the azalactonic ring. In this case, a nitration tion, the second method yielded derivatives which were un-
reaction introducing the nitrogen atom into the final appro- substituted or monomethylated on the furan ring.
priate position was carried out on bromocoumarins 9, and
In conclusion, a new tricyclic system was synthesised in
the resulting nitrocoumarins were submitted to Perkin’s ring two different straightforward ways, with similar yields and
contraction[11,12] to afford the desired 5-nitrobenzofurans. with different degrees of substitution in the molecule.
This route was required because benzofurans are preferen-
tially nitrated on the unsubstituted or partially substituted
furan ring. Therefore, as shown in Scheme 2, the 7-hydroxy-
8-methylcoumarins 8 were reacted with bromine to yield the
corresponding 3-bromo derivatives 9, which were submitted
first to nitration and then to ring contraction in a strongly
alkaline medium. Compounds 11 were then decarb-
oxylated, yielding nitrobenzofurans 12, which were reduced
by catalytic hydrogenation to the corresponding aminoben-
zofurans 13 and directly condensed with methyl pyruvate
to give 2,5-dimethyl-3H-furo[3,2-g][1,4]benzoxazin-3-one
(14a) and 2,5,8-trimethyl-3H-furo[3,2-g][1,4]benzoxazin-3-
one (14b).
Experimental Section
Analytical TLC was performed on precoated 60 F254 silica gel
plates (0.2 mm; Merck) eluting with a CHCl3/MeOH mixture (9:1).
Column chromatography was performed using silica gel 60
(0.063Ϫ0.100 mm; Merck), eluting with CHCl3. Melting points
were determined on a Gallenkamp MFB-595-010M melting point
apparatus and are uncorrected. IR spectra were recorded on a
PerkinϪElmer 1600 FT-IR spectrometer. 1H NMR and 13C NMR
spectra were recorded at 300.13 MHz and 75.47 MHz, respectively,
on a Bruker AMX300 spectrometer with TMS as internal standard.
HR-ESI-TOF mass spectra of the final products were recorded on
a PE Biosystems Mariner 5220 spectrometer, using desipramine hy-
drochloride and dansyl-Gly-Trp as internal standards. Microana-
lyses were performed by the Microanalytical Laboratory of the De-
partment of Pharmaceutical Sciences of University of Padova and
were within Ϯ0.3%. All reagents and solvents were of commercial
quality and were used without purification.
The starting materials 8a[13] and 8b[14] were prepared according to
literature methods.
1,3-Dihydroxy-2-methyl-4-nitrobenzene (3): n-Pentyl nitrite[15] (0.8
mL, 9.6 mmol) was added to a solution of 1 (1.0 g, 8.0 mmol) in
diethyl ether (40 mL) and the mixture was kept at room temper-
ature for 1 h. The solvent was evaporated under reduced pressure
and the residue was purified by column chromatography to give 2
(0.05 g, 5%), followed by the desired product 3 (0.30 g, 22%).
1
2: M.p. 133 °C. H NMR (CDCl3): δ ϭ 2.13 (s, 3 H, 2-Me), 7.74
(s, 1 H, 5-H), 11.21 (s, 2 H, OH) ppm. C7H6N2O6 (214.14): calcd.
C 39.26, H 2.82, N 13.08; found C 39.24, H 2.91, N 13.05.
1
3: M.p. 138 °C. H NMR (CDCl3): δ ϭ 2.12 (s, 3 H, 2-Me), 6.37
(d, J ϭ 9.3 Hz, 1 H, 6-H), 7.85 (d, J ϭ 9.3 Hz, 1 H, 5-H), 11.29
(s, 2 H, OH) ppm. C7H7NO4 (169.14): calcd. C 49.71, H 4.17, N
8.28; found C 49.64, H 4.11, N 8.26.
7-Hydroxy-3,8-dimethyl-1,4-benzoxazin-2-one (5):
A
catalytic
amount of Pd/C 10% was added to a solution of 3 (0.20 g,
1.2 mmol) in absolute EtOH (25 mL) and the mixture was kept at
room temperature under a slight overpressure of H2. The mixture
was stirred until 3 disappeared (24 h, TLC) and the catalyst was
then filtered off. Methyl pyruvate (0.24 g, 0.21 mL, 2.3 mmol) was
added to the filtrate and the mixture was stirred at room temper-
ature for a further 5 h. The solvent was evaporated under reduced
pressure and the residue was crystallised from MeOH to give 5
1
(0.18 g, total 87%); m.p. 245 °C. H NMR (CD3OD): δ ϭ 2.12 (s,
3 H, 8-Me), 2.33 (s, 3 H, 3-Me), 6.71 (d, J ϭ 8.7 Hz, 1 H, 6-H),
7.23 (d, J ϭ 8.7 Hz, 1 H, 5-H) ppm. C10H9NO3 (191.19): calcd. C
62.82 H 4.74 N 7.33; found C 62.85, H 4.70, N 7.36.
Scheme 2. Reagents and conditions: (a) Br2, glacial AcOH, 60 °C,
30 min, 48 and 60%; (b) HNO3, H2SO4, 0 °C, 95%; (c) KOH, di(-
ethylene glycol) ethyl ether, 98%; (d) quinoline, Cu, reflux, 30 min,
25%; (e) Pd/C 10%, H2, abs. EtOH, room temp., 2 h; (f) methyl
pyruvate, room temp., 12 h, 50% (e ϩ f)
3,8-Dimethyl-7-(1-methyl-2-oxopropoxy)-2H-1,4-benzoxazin-2-one
(6): A mixture of 5 (0.19 g, 1.0 mmol), 3-chlorobutan-2-one (0.16 g,
0.15 mL, 1.5 mmol), anhydrous K2CO3 (0.50 g) and acetone (25
mL) was refluxed until 5 disappeared (7 h, TLC). After cooling,
1938
Eur. J. Org. Chem. 2002, 1937Ϫ1940

Synthesis of Furo[3,2-g][1,4]Benzoxazin-3-ones, New Psoralen Isosters
FULL PAPER
the solid was filtered off and washed with acetone. The solvent was
evaporated under reduced pressure from the combined filtrate and
washings and the residue was purified by column chromatography
added portionwise to a solution of KOH (13.5 g, 24.0 mmol) in
di(ethylene glycol) ethyl ether (100 mL) heated at 100 °C. After
cooling, the mixture was diluted with H2O (100 mL) and neut-
ralised with 1  HCl. The obtained precipitate was collected and
1
to give 6 (0.14 g, 54%) as a gum. H NMR (CD3OD): δ ϭ 1.47 (d,
J ϭ 6.8 Hz, 3 H, 1Ј-H), 2.14 (s, 3 H, 8-Me), 2.24 (s, 3 H, 4Ј-H), crystallised from glacial AcOH.
2.37 (s, 3 H, 3-Me), 4.90 (q, J ϭ 6.8 Hz, 1 H, 2Ј-H), 6.75 (d, J ϭ 6-Hydroxy-7-methyl-5-nitrobenzofuran-2-carboxylic Acid (11a):
8.9 Hz, 1 H, 6-H), 7.38 (d, J ϭ 8.9 Hz, 1 H, 5-H) ppm. C14H15NO4 Colourless needles (3.7 g, 98%); m.p. 294 °C. 1H NMR
(261.28): calcd. C 64.36, H 5.79, N 5.36; found C 64.39, H 5.81,
N 5.35.
([D6]DMSO): δ ϭ 2.50 (s, 3 H, 7-Me), 7.79 (s, 1 H, 3-H), 8.46 (s,
1 H, 4-H), 10.74 (s, 1 H, OH) ppm. C10H7NO6 (237.17): calcd. C
50.64, H 2.97, N 5.91; found C 50.65, H 2.99, N 5.99.
2,5,7,8-Tetramethyl-3H-furo[3,2-g][1,4]benzoxazin-3-one (7): A so-
lution of 6 (0.14 g, 0.54 mmol) in conc. H2SO4 (5 mL) was stirred
at room temperature until the starting product had disappeared
(3 h, TLC). The mixture was poured onto ice and H2O (50 mL),
neutralised with 10% NaHCO3 and extracted with EtOAc (3 ϫ 25
mL). The dried (Na2SO4) organic phase was concentrated under
reduced pressure. The residue was purified by column chromato-
graphy and crystallised from MeOH to give 7 (0.04 g, 28%); m.p.
204 °C. IR (KBr): ν˜ ϭ 2915, 1730, 1635, 1575, 1430, 1160, 1120,
6-Hydroxy-3,7-dimethyl-5-nitrobenzofuran-2-carboxylic Acid (11b):
1
Colourless needles (3.9 g, 98%); m.p. 300 °C. H NMR (CD3OD):
δ ϭ 2.43 (s, 3 H, 7-Me), 2.55 (s, 3 H, 3-Me), 8.39 (s, 1 H, 4-H)
ppm. C11H9NO6 (251.20): calcd. C 52.59, H 3.61, N 5.58; found C
52.61, H 3.67, N 5.54.
General Procedure for the Synthesis of 6-Hydroxy-7-methyl-5-nitro-
benzofurans (12): A mixture of 11 (15.0 mmol), quinoline (20 mL)
and Cu powder (1.0 g) was refluxed for 30 min. After cooling, the
mixture was diluted with EtOAc (50 mL), the solid was filtered off
and the filtrate was extracted with 1  HCl (4 ϫ 50 mL). The dried
(Na2SO4) organic layer was concentrated under reduced pressure
and the residue purified by column chromatography.
1
955, 910, 760 cmϪ1. H NMR (CDCl3): δ ϭ 2.10 (s, 3 H, 5-Me),
2.34 (s, 3 H, 2-Me), 2.46 (s, 3 H, 7-Me or 8-Me), 2.49 (s, 3 H, 7-
Me or 8-Me), 7.47 (s, 1 H, 9-H) ppm. 13C NMR (CDCl3): δ ϭ
154.30 (C-3), 153.62 (C-5a), 152.98 (C-4a), 151.69 (C-7), 142.60 (C-
2), 128.04 (C-8a and C-9a), 115.20 (C-9), 110.51 (C-5), 108.66 (C-
8), 21.47 (2-Me), 12.37 (7-Me), 8.36 (8-Me), 8.26 (5-Me) ppm.
6-Hydroxy-7-methyl-5-nitrobenzofuran (12a): Off-white powder
1
(0.72 g, 25%); m.p. 70 °C. H NMR (CDCl3): δ ϭ 2.25 (s, 3 H, 7-
HRMS: m/z
ϭ 244.0972 (calcd. for C14H14NO3 244.0968).
Me), 6.56 (d, J ϭ 2.3 Hz, 1 H, 3-H), 7.47 (d, J ϭ 2.3 Hz, 1 H, 2-
H), 8.00 (s, 1 H, 4-H), 10.75 (s, 1 H, OH) ppm. C9H7NO4 (193.16):
calcd. C 55.96, H 3.65, N 7.25; found C 56.00, H 3.66, N 7.22.
6-Hydroxy-3,7-dimethyl-5-nitrobenzofuran (12b): Off-white powder
C14H13NO3 (243.26): calcd. C 69.12, H 5.39, N 5.76; found C
69.12, H 5.43, N 5.75.
General Procedure for the Synthesis of 3-Bromo-7-hydroxy-8-
methylcoumarins (9): A solution of Br2 (6.4 g, 40.0 mmol) in glacial (0.77 g, 25%); m.p. 105 °C. 1H NMR (CDCl3): δ ϭ 2.23 (d, J ϭ
AcOH (25 mL) was added dropwise at 60 °C to a solution of 8
1.2 Hz, 3 H, 3-Me), 2.42 (s, 3 H, 7-Me), 7.42 (q, J ϭ 1.2 Hz, 1 H,
(40.0 mmol) in glacial AcOH (150 mL), and the mixture was stirred 2-H), 8.16 (s, 1 H, 4-H), 10.98 (s, 1 H, OH) ppm. C10H9NO4
for an additional 15 min. After cooling, the obtained precipitate
was collected and crystallised from EtOH.
(207.19): calcd. C 57.97, H 4.38, N 6.76; found C 57.92, H 4.42,
N 6.76.
3-Bromo-7-hydroxy-8-methylcoumarin (9a): White needles (5.0 g,
48%); m.p. 220 °C. 1H NMR ([D6]acetone): δ ϭ 2.27 (s, 3 H, 8-
Me), 6.94 (d, J ϭ 8.6 Hz, 1 H, 6-H), 7.39 (d, J ϭ 8.6 Hz, 1 H, 5-
H), 8.30 (s, 1 H, H-4), 9.34 (s, 1 H, OH) ppm. C10H7BrO3 (255.07):
calcd. C 47.09, H 2.76, Br 31.33; found C 47.12, H 2.79, Br 31.36.
3-Bromo-7-hydroxy-4,8-dimethylcoumarin (9b): White needles
General Procedure for the Synthesis of Methyl-3H-furo[3,2-g]-
[1,4]benzoxazin-3-one (14): A catalytic amount of Pd/C 10% was
added to a solution of 12 (3.5 mmol) in absolute EtOH (50 mL)
and the mixture was kept at room temperature under a slight over-
pressure of H2. After stirring for 2 h, the catalyst was filtered off
and methyl pyruvate (0.72 g, 0.64 mL, 7.0 mmol) was added to the
filtrate. The mixture was stirred at room temperature for 12 h and
then the solvent was evaporated under reduced pressure. The res-
idue was purified by column chromatography and crystallised
from MeOH.
1
(6.4 g, 60%); m.p. 270 °C. H NMR ([D6]DMSO): δ ϭ 2.25 (s, 3
H, 8-Me), 2.62 (s, 3 H, 4-Me), 6.99 (d, J ϭ 8.9 Hz, 1 H, 6-H), 7.61
(d, J ϭ 8.9 Hz, 1 H, 5-H), 10.59 (s, 1 H, OH) ppm. C11H9BrO3
(269.10): calcd. C 49.10, H 3.37, Br 29.69; found C 49.11, H 3.47,
Br 29.65.
2,5-Dimethyl-3H-furo[3,2-g][1,4]benzoxazin-3-one (14a): Pale yellow
needles (37 mg, 50%); m.p. 184 °C. IR (KBr): ν˜ ϭ 3125, 2925, 1720,
General Procedure for the Synthesis of 3-Bromo-7-hydroxy-8-
methyl-6-nitrocoumarins (10): A mixture of HNO3 (1.4 mL) and
H2SO4 (1.5 mL) was added dropwise at 0 °C to a solution of 9
(20.0 mmol) in conc. H2SO4 (20 mL). The mixture was poured onto
ice and H2O (200 mL) and the precipitate was collected and washed
with H2O. The solid was crystallised from MeOH.
1620, 1575, 1340, 1140, 1100, 1010, 870, 760 cmϪ1 1H NMR
.
(CDCl3): δ ϭ 2.52 (br. s, 6 H, 2-Me and 5-Me), 6.79 (d, J ϭ 2.2
Hz, 1 H, 8-H), 7.64 (d, J ϭ 2.2 Hz, 1 H, 7-H), 7.69 (s, 1 H, 9-H)
ppm. 13C NMR (CDCl3): δ ϭ 154.65 (C-3), 153.97 (C-5a), 152.43
(C-4a), 147.07 (C-7), 143.12 (C-2), 128.47 (C-9a), 124.67 (C-8a),
118.02 (C-9), 109.66 (C-5), 107.45 (C-8), 21.51 (2-Me), 8.52 (5-Me)
ppm. HRMS: m/z ϭ 216.0664 (calcd. for C12H10NO3 216.0655).
C12H9NO3 (215.21): calcd. C 66.97, H 4.21, N 6.51; found C 66.99,
H 4.23, N 6.49.
3-Bromo-7-hydroxy-8-methyl-6-nitrocoumarin (10a): Pale yellow
1
crystals (5.7 g, 95%); m.p. 194 °C. H NMR (CDCl3): δ ϭ 2.40 (s,
3 H, 8-Me), 8.04 (s, 1 H, 4-H), 8.18 (s, 1 H, 5-H), 11.21 (s, 1 H,
OH) ppm. C10H6BrNO5 (300.07): calcd. C 40.03, H 2.02, Br 26.63,
N 4.67; found C 40.01, H 2.00, Br 26.59, N 4.72.
2,5,8-Trimethyl-3H-furo[3,2-g][1,4]benzoxazin-3-one (14b): Pale yel-
low needles (40 mg, 50%); m.p. 182 °C. IR (KBr): ν˜ ϭ 3100, 2925,
3-Bromo-7-hydroxy-4,8-dimethyl-6-nitrocoumarin (10b): Yellow
1
crystals (5.9 g, 95%); m.p. 265 °C. H NMR (CDCl3): δ ϭ 2.41 (s,
1725, 1620, 1575, 1350, 1130, 1070, 860, 760 cmϪ1 1H NMR
.
3 H, 8-Me), 2.64 (s, 3 H, 4-Me), 8.36 (s, 1 H, 5-H), 11.17 (s, 1 H,
OH) ppm. C11H8BrNO5 (314.10): calcd. C 42.16, H 2.56, Br 25.44,
N 4.46; found C 42.08, H 2.60, Br 25.45, N 4.46.
(CDCl3): δ ϭ 2.26 (d, J ϭ 1.2 Hz, 3 H, 8-Me), 2.54 (s, 3 H, 2-Me
or 5-Me), 2.56 (s, 3 H, 2-Me or 5-Me), 7.48 (q, J ϭ 1.2 Hz, 1 H,
7-H), 7.65 (s, 1 H, 9-H) ppm. 13C NMR (CDCl3): δ ϭ 154.95 (C-
3), 154.08 (C-5a), 152.13 (C-4a), 143.39 (C-7), 143.18 (C-2), 128.17
General Procedure for the Synthesis of 6-Hydroxy-7-methyl-5-nitro-
benzofuran-2-carboxylic Acids (11): Compound 10 (16.0 mmol) was (C-9a), 126.52 (C-8a), 116.59 (C-8), 116.35 (C-9), 109.52 (C-5),
Eur. J. Org. Chem. 2002, 1937Ϫ1940 1939

A. Chilin, A. Confente, G. Pastorini, A. Guiotto
FULL PAPER
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230.0826 (calcd. for C13H12NO3 230.0813). C13H11NO3 (229.24):
calcd. C 68.11, H 4.84, N 6.11; found C 68.09, H 4.82, N 6.15.
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