New heterocyclic skeletons derived from the aporphine alkaloid boldine

Article abstract of DOI:10.1081/SCC-120014990

The abundant aporphine alkaloid (S)-(+)-boldine (1) was selectively nitrosated with sodium nitrite in acetic acid affording 8-nitrosoboldine (2) which was hydrogenated catalytically to give 8-aminoboldine (3). The latter was used as the starting material for annulations with ethyl ortho-formate to afford the corresponding oxazole ("boldine-9,8-oxazole", 4), and with methyl benzoylformate giving the phenyl-oxazinone ("boldine-9,8-phenyloxazinone", 5). This later product was treated with KOH/EtOH at room temperature and converted quickly into the ring-contracted phenyloxazole ("boldine-9,8-phenyloxazole", 6) in moderate yield.

Full text of DOI:10.1081/SCC-120014990

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NEW HETEROCYCLIC SKELETONS DERIVED FROM THE
APORPHINE ALKALOID BOLDINE
Eduardo Sobarzo-Sánchez a , Carolina Jullian b , Bruce K. Cassels a & Claudio Saitz b
a Instituto Milenio para Estudios Avanzados en Biología Celular y Biotecnología and
Departamento de Química , Facultad de Ciencias , Universidad de Chile , Casilla, Santiago,
653, Chile
b Departamento de Química Orgánica y Físico-Química , Facultad de Ciencias Químicas y
Farmacéuticas , Universidad de Chile , Casilla, Santiago 1, 233, Chile
Published online: 16 Aug 2006.
To cite this article: Eduardo Sobarzo-Sánchez , Carolina Jullian , Bruce K. Cassels & Claudio Saitz (2002) NEW HETEROCYCLIC
SKELETONS DERIVED FROM THE APORPHINE ALKALOID BOLDINE, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:23, 3687-3693, DOI: 10.1081/SCC-120014990
To link to this article: http://dx.doi.org/10.1081/SCC-120014990
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 23, pp. 3687–3693, 2002
NEW HETEROCYCLIC SKELETONS
DERIVED FROM THE APORPHINE
ALKALOID BOLDINE
Eduardo Sobarzo-Sanchez,1, Carolina Jullian,2
*
Bruce K. Cassels,1 and Claudio Saitz2
1Instituto Milenio para Estudios Avanzados en Biologıa
Celular y Biotecnologıa and Departamento de Quımica,
Facultad de Ciencias, Universidad de Chile,
Casilla 653, Santiago, Chile
2Departamento de Quımica Organica y Fısico-Quımica,
Facultad de Ciencias Quımicas y Farmaceuticas,
Universidad de Chile, Casilla 233, Santiago 1, Chile
ABSTRACT
The abundant aporphine alkaloid (S)-(þ)-boldine (1) was
selectively nitrosated with sodium nitrite in acetic acid afford-
ing 8-nitrosoboldine (2) which was hydrogenated catalytically
to give 8-aminoboldine (3). The latter was used as the starting
material for annulations with ethyl ortho-formate to afford the
corresponding oxazole (‘‘boldine-9,8-oxazole’’, 4), and with
methyl benzoylformate giving the phenyl-oxazinone (‘‘boldine-
9,8-phenyloxazinone’’, 5). This later product was treated with
KOH/EtOH at room temperature and converted quickly
*Corresponding author. Fax: (56-2) 271-3888; E-mail: esobarzo@ctcinternet.cl
3687
DOI: 10.1081/SCC-120014990
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3688
SOBARZO-SANCHEZ ET AL.
into the ring-contracted phenyloxazole (‘‘boldine-9,8-phenyl-
oxazole’’, 6) in moderate yield.
Boldine (1), the major alkaloid present in leaves and bark of the Chilean
boldo tree (Peumus boldus Mol., Monimiaceae), exhibits a variety of pharma-
cological activities as an antioxidant and as a catecholamine receptor
antagonist.[1] We have previously reported semi-synthetic transformations
of boldine to afford products bearing halogen atoms at C-3 or C-3 and C-8
of the aporphine framework, some of which showed greatly increased
potency and selectivity at dopamine and adrenergic receptors.[2] As an
entry to further elaborated boldine derivatives, we carried out the nitrosation
of the alkaloid in acetic acid affording 8-nitrosoboldine (2) as only reaction
product, which opened up the possibility of synthetizing new heterocyclic
systems with benzoxazole or benzoxazinone rings fused to the aporphine
skeleton, starting from 8-aminoboldine (3) obtained by reduction of the
nitroso group.
Benzoxazoles have been prepared by heating o-aminophenols with car-
boxylic acids in the presence of condensation agents such as polyphosphoric
acid[3,4] or with ethyl orthoformate in refluxing EtOH.[5] Other options
have been based on the Pomeranz-Fritsch reaction on benzalaminoacetals
in P2O5/H2SO4;[6] by cycloaddition of azomethine ylides to 1-nitroso-2-
naphthol;[7,8] by treatment of 1-nitroso-2-naphthol and phenacylpyridinium
bromide with a NaOH solution at À30ꢀC;[9] and through the condensation of
1-amino-2-naphthols with aromatic aldehydes in the presence of pyridine in
BuOH.[10] Naphth[1,2-d]oxazoles have also been obtained as intermediate
products in the preparation of naphthalenesulfonamides as dyes for wool,
polyamide fibers and leather.[11] An easy and quick way of obtaining 2-phenyl-
benzoxazoles is based on the decomposition of naphtho- and benzoxazinones
in 10% KOH/MeOH solution.[12] These oxazinones are readily available
using a variation of Moffet’s method starting from an o-aminophenol and
methyl benzoylformate in pyridine.[13]
In this communication we describe the formation of the oxazole-
annulated ‘‘boldine-9,8-oxazole’’ (4) and the oxazinone-annulated ‘‘boldine-
9,8-phenyloxazinone’’ (5) starting from an o-aminophenol (3) derived from
boldine, and the instantaneous decomposition of 5 with a 5% ethanolic KOH
solution at room temperature to give the corresponding ‘‘boldine-9,8-phenyl-
oxazole’’ (6) (Sch. 1).
It is noteworthy that 8-aminoboldine (3) is formed from the oxazinone
(5) together with the rapid appearance of the 2-phenyloxazole (6). This
behavior is quite different from the reactivity found for benzo- and
naphthoxazinones, which require many hours at reflux temperature to

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NEW HETEROCYCLIC SKELETONS
3689
Scheme 1.
afford the oxazole system in good yield. However, the fast reaction of 5
under relatively mild basic conditions resulting in the ring contraction to 6
suggests the existence of a 2,3-dihydrobenzoxazole intermediate (7).
Decarboxylation of this intermediate and dehydrogenation presumably
lead to the formation of 6, while hydrolysis of 7 or of its ring-opened
precursor should give 8-aminoboldine 3 (Sch. 2).
No satisfactory, experimentally based mechanistic rationalization of
the base-catalyzed decomposition of benzo- or naphtoxazinones is available
yet. In the meantime, it seems prudent to postpone any speculations as to
why the annulated oxazinone derived from boldine shows such remarkably
enhanced reactivity.
EXPERIMENTAL
Boldine (1), isolated from P. boldus bark was crystallized from CHCl3
as the 1 : 1 complex (1-CHCl3) and used as such. Melting points were

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3690
SOBARZO-SANCHEZ ET AL.
Scheme 2.
determined on a Reichert-Jung Galen III Kofler hot stage. Optical rotations
were determined with a Schmidt-Haensch Polartronic electronic polarimeter.
Column chromatography was performed on Merck silica gel 60, 230–400
mesh, and TLC on Merck silica gel G. Microanalyses were obtained using a
Fisons EA 1108 analyzer and were carried out by the CEPEDEQ, Faculty of
Chemical and Pharmaceutical Sciences, University of Chile. NMR spectra
were recorded in DMSO-d6 using a Bruker AMX 300 instrument, operating
at 300.13 MHz (1H) or 75.48 MHz (13C). Compounds 4 to 6 were fully
characterized by concerted use of one- and two dimensional NMR
techniques as described in our previous paper.[14]
2,9-Dihydroxy-1,10-dimethoxy-6-methyl-8-nitrosodibenzo[de,g]quinoline
(2): A solution of 1-CHCl3 (2.4 g, 7.33 mmol) dissolved in HOAc (60 mL) was
treated with solid NaNO2 (0.64 g, 9.28 mmol) at room temperature. After 1 h
stirring, the mixture was poured into 100 mL cold H2O, and the aqueous
solution was adjusted to pH 8–9 with concentrated NH3, extracted with
EtOAc (4 Â 50 mL), worked up, and separated from unreacted 1 by Si gel
flash chromatography (EtOAc) to give 2 as the only reaction product (1.66 g,
64%), Rf (EtOAc) 0.4, (CHCl3-MeOH 4 : 1) 0.8. 2 crystallized in CHCl3 as
24
D
1
reddish rhombi, m.p. 128–130ꢀC; ½ꢀŠ þ231ꢀ (c 0.11, MeOH); H NMR
(DMSO-d6) ꢁ 2.20 (1H, dd, J ¼ J0 ¼ 14.0 Hz), 2.36 (3H, s), 2.39 (1H, s),

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NEW HETEROCYCLIC SKELETONS
3691
2.6 (1H, m), 2.74 (1H, dd, J ¼ 14.4 Hz, J0 ¼ 3.8 Hz), 2.9 (3H, m), 3.6 (3H, m),
3.90 (3H, s), 6.61 (1H, s), 8.03 (1H, s); 13C NMR (DMSO-d6) ꢁ 28.99, 29.03,
44.08, 53.35, 57.19, 60.39, 62.11, 113.7, 116.2, 120.9, 124.1, 125.5, 129.7, 138.7,
141.0, 144.0, 147.7, 150.3. Anal. calcd for C19H20N2O5 . 0.7 CHCl3: C, 54.60;
H, 4.81; N, 6.37%. Found: C, 54.41; H, 4.90; N, 7.30%.
2,9-Dihydroxy-1,10-dimethoxy-6-methyl-8-aminodibenzo[de,g]quinoline
(3): A solution of 2 (0.316 g, 0.88 mmol) dissolved in EtOH (120 mL) was
catalytically hydrogenated over 10% Pd/C (60 mg) at 50 psi and room
temperature. After 2.5 h, the mixture was filtered over Celite and concen-
trated to give a brown residue. After work up as before, 3 (0.312 g, 100%)
24
crystallized from C6H6 as gray needles, m.p. 177–179ꢀC; ½ꢀŠD þ189ꢀ (c 0.094,
MeOH); H NMR (DMSO-d6) ꢁ 1.85 (1H, dd, J ¼ J0 ¼ 13.8 Hz), 2.33 (1H,
1
m), 2.46 (3H, s), 2.5 (1H, m), 2.7 (1H, m), 2.9 (2H, m), 3.16 (1H, dd,
J ¼ 14.3 Hz, J0 ¼ 4.0 Hz), 3.50 (3H, s), 3.77 (3H, s), 6.48 (1H, s), 7.36 (1H,
s); 13C NMR (DMSO-d6) ꢁ 27.75, 28.81, 44.12, 53.21, 56.05, 59.51, 62.69,
101.7, 114.2, 115.0, 122.9, 125.9, 127.4, 128.7, 132.7, 133.8, 143.2, 145.8,
149.4. Anal. calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18%. Found:
C, 66.24; H, 6.46; N, 8.27%.
1,11-Dimethoxy-2-hydroxy-6-methyloxazolo[4,5-k]5,6,6a,7-tetrahydro-
4H-dibenzo[de,g]quinoline (4): A solution of 3 (0.150 g, 0.44 mmol) dissolved
in EtOH (20 mL) was treated with ethyl ortho-formate (1.5 mL, 9 mmol) and
refluxed with stirring for 48 h under N2. After concentrating the solution
under reduced pressure, the residue was chromatographed on Si gel (4 : 1
CHCl3–MeOH) affording 4 (0.138 g, 89%), Rf 0.65, which crystallized from
C6H6 as brownish white needles, m.p. 189–191ꢀC; ½ꢀŠ þ227ꢀ (c 0.069,
18
D
1
MeOH); H NMR (DMSO-d6) ꢁ 2.3 (2H, m), 2.44 (3H, s), 2.5 (1H, m),
2.84 (1H, dd, J ¼ 14.1 Hz, J0 ¼ 4.0 Hz), 2.9 (2H, m), 3.58 (3H, s), 3.66
(1H, dd, J ¼ 14.0 Hz, J0 ¼ 4.0 Hz), 3.99 (3H, s), 6.61 (1H, s), 8.01 (1H, s),
8.71 (1H, s), 9.18 (1H, s); 13C NMR (DMSO-d6) ꢁ 27.13, 27.98, 43.13, 52.11,
55.50, 59.02, 61.23, 107.5, 114.8, 120.0, 125.3, 128.3, 128.7, 136.9, 138.7,
142.1, 142.6, 148.8, 153.3. Anal. calcd for C20H20N2O4: C, 68.17; H, 5.72;
N, 7.95%. Found: C, 67.93; H, 5.82; N, 8.02%.
1,12-Dimethoxy-2-hydroxy-6-methyl-9-phenyl-10H-oxazin[5,6-k]5,6,6a,7-
tetrahydro-4H-dibenzo[de,g]quinoline-10-one (5): A solution of 4 (0.166 g,
0.49 mmol) in EtOH (30 mL) was treated with methyl benzoylformate
(0.6 mL, 4 mmol) and refluxed with stirring for 48 h under N2. After con-
centrating under reduced pressure, the residue was chromatographed on
Si gel (4 : 1 CHCl3–MeOH) to give 5 (0.131 g, 60%), Rf 0.77, which crystal-
lized from C6H6 as yellowish needles, m.p. 202–203ꢀC; ½ꢀŠ þ242ꢀ (c 0.091,
17
D
MeOH); H NMR (DMSO-d6) ꢁ 2.20 (dd, J ¼ 14.0 Hz, J0 ¼ 3.8 Hz, 1H), 2.3
1
(1H, m), 2.46 (3H, s), 2.6 (1H, m), 2.9 (3H, m), 3.62 (3H, s), 3.96 (3H, s),
4.17 (1H, dd, J ¼ 14.0 Hz, J0 ¼ 3.8 Hz), 6.65 (1H, s), 7.6 (3H, m), 8.18 (1H, s),

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3692
SOBARZO-SANCHEZ ET AL.
8.26 (2H, s), 9.27 (1H, s); 13C NMR (DMSO-d6) ꢁ 26.70, 28.32, 43.69, 52.67,
56.18, 59.68, 61.66, 113.1, 115.8, 125.1, 126.0, 127.3, 128.3, 128.6, 128.8,
129.1, 129.3, 131.1, 134.6, 135.2, 143.4, 144.0, 149.4, 150.0, 151.5. Anal.
calcd for C27H24N2O5: C, 71.04; H, 5.30; N, 6.14%. Found: C, 70.59;
H, 5.46; N, 6.26%.
1,11-Dimethoxy-2-hydroxy-6-methyl-9-phenyloxazolo[4,5-k]5,6,6a,7-
tetrahydro-4H-dibenzo[de,g]quinoline (6): A solution of 5 (0.101 g, 0.22 mmol)
in EtOH (100 mL) was treated with a 5% KOH-EtOH solution (0.45 mL) at
room temperature. Immediately the yellowish solution changed to a clear
orange color. Stirring was stopped within 30 s and the solution was immedi-
ately concentrated under reduced pressure. The residue was taken up in
100 mL H2O, and the aqueous solution was adjusted with concentrated
NH3 to pH 8–9 and extracted with CHCl3. After purifying the mixture by
Si gel flash chromatography (4 : 1 CHCl3–MeOH), 3 (40 mg, 53%), Rf 0.10
and 6 (32 mg, 34%), Rf 0.74 were obtained, the latter crystallizing in
cyclohexane–benzene as beige needles, m.p. 179–181ꢀC; ½ꢀŠ þ225ꢀ (c 0.24,
16
D
1
MeOH); H NMR (DMSO-d6) ꢁ 2.4 (2H, m), 2.48 (3H, s), 2.5 (1H, m), 2.9
(3H, m), 3.60 (3H, s), 3.73 (1H, dd, J ¼ 14.0 Hz, J0 ¼ 3.6 Hz), 4.03 (3H, s),
6.62 (1H, s), 7.6 (3H, m), 8.01 (1H, s), 8.2 (2H, m), 9.19 (1H, s); 13C NMR
(DMSO-d6) ꢁ 27.17, 27.97, 43.18, 52.12, 55.49, 59.03, 61.19, 107.7, 114.8,
119.7, 125.2, 125.3, 125.9, 126.8, 128.4, 128.7, 128.8, 131.3, 137.6, 140.4,
141.8, 142.7, 148.8, 161.5. Anal. calcd for C26H24N2O4: C, 72.88; H, 5.65;
N, 6.54%. Found: C, 72.54; H, 5.48; N, 6.52%.
ACKNOWLEDGMENTS
This work was funded by the Presidential Chair in Science
(B.K.C., Chile, 1996). The principal author is grateful to Fundacion Andes
for a doctoral fellowship.
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Received in the USA November 25, 2001

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