Novel route to 2-arylapomorphines

Article abstract of DOI:10.1080/00397910601039200

The synthesis of 2-arylapomorphines (1, 2) has been accomplished using a new method involving a Suzuki-type cross-coupling reaction of 2-bromoapocodeine (8) and arylboronic acids. Copyright Taylor & Francis Group, LLC.

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Novel Route to 2‐Arylapomorphines
Sándor Berényi a , Attila Sipos a , Ildikó Szabó a & Tamás Kálai b
a Department of Organic Chemistry , University of Debrecen , Debrecen,
Hungary
b Institute of Organic and Medicinal Chemistry, University of Pécs , Pécs,
Hungary
Published online: 06 Feb 2007.
To cite this article: Sándor Berényi , Attila Sipos , Ildikó Szabó & Tamás Kálai (2007) Novel Route to
2‐Arylapomorphines, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:3, 467-471, DOI: 10.1080/00397910601039200
To link to this article: http://dx.doi.org/10.1080/00397910601039200
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Synthetic Communicationsw, 37: 467–471, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601039200
Novel Route to 2-Arylapomorphines
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Sandor Berenyi, Attila Sipos, and Ildiko Szabo
Department of Organic Chemistry, University of Debrecen, Debrecen,
Hungary
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Tamas Kalai
Institute of Organic and Medicinal Chemistry, University of Pecs,
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Pecs, Hungary
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Abstract: The synthesis of 2-arylapomorphines (1, 2) has been accomplished using a
new method involving a Suzuki-type cross-coupling reaction of 2-bromoapocodeine
(8) and arylboronic acids.
Keywords: Suzuki-type cross-coupling reaction, synthesis of 2-arylapomorphines
Apomorphine derivatives modified in the 2-position are known to be effective
on dopamine receptors.[1,2] The synthesis of some 2-arylapomorphines (1, 2) has
been recently reported. These compounds, especially 2-(4-hydroxyphenyl)-
apomorphine (2), exhibited high affinity for the dopamine D2 receptor.[3]
The synthesis of compounds 1 and 2 was performed by Suzuki–
Miyaura–type reaction of the corresponding triflate-substituted aporphine
derivative originating from natural codeine.[3]
In this communication, we describe a new synthesis of 2-arylapomor-
phines (1, 2) with a Suzuki-type cross-coupling reaction by treatment of
2-bromoapocodeine (8) with the appropriate arylboronic acids. The synthesis
of 2-bromoapocodeine (8) from natural thebaine (3) was performed via 14b-
chlorocodeinone (4),[4] 14b-chlorocodeine (5), 6-O-tosyl-14b-chlorocodeine
Received in the U.K. April 4, 2006
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Address correspondence to Sandor Berenyi, Department of Organic Chemistry,
University of Debrecen, P. O. Box 20, H-4010, Debrecen, Hungary. E-mail: bersu@
delfin.unideb.hu
467

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S. Berenyi et al.
468
(6), and 6-bromo-6-demetoxythebaine (7) by our previously published pro-
cedures[5,6] (Scheme 1).
The cross-coupling of 2-bromoapomorphine (8) with appropriate aryl-
boronic acids was carried out in the presence of tetrakis (triphenylphosphine)
.
palladium(0) catalyst and Ba(OH)2 8H2O base in a solvent mixture of
1,4-dioxane–H2O (4:1). Isolated yields for 2-phenylapocodeine and 2-(4-
hydroxyphenyl)-apocodeine were found to be 81% and 79%, respectively.
2-Arylapocodeines (9, 10) were O-demethylated with a reagent mixture
of methanesulfonic acid and methionine to prepare the desired 2-phenylapo-
morphine (1) and 2-(4-hydroxyphenyl)-apomorphine (2) (Scheme 2) with a
yield of 92% and 87%, respectively.
EXPERIMENTAL
Melting points were determined with a Kofler hot-stage apparatus and are
uncorrected. Thin-layer chromatography (TLC) was performed on precoated
Merck 5554 Kieselgel 60 F254 foils using chloroform—methanol (9 : 1)
mobile phase. The spots were visualized with Dragendorff’s reagent. 1H
NMR spectra were recorded on a Bruker WP 200 SY spectrometer,
chemical shifts are reported in parts per million (d) from internal TMS, and
coupling constans (J ) are measured in Hertz.
Mass spectral measurements were performed with an Automass Multi
(ThermoQuest) instrument in the EI mode (direct inlet). The source tempera-
ture was 140 8C; ionization was 70 eV. Optical rotation was determined with a
Perkin-Elmer model 241 polarimeter. Elemental analyses (C, H, N, S) were
obtained on a Carlo Erba 1106 analyzer.
Scheme 1. (i) N-Cl-succinimide, acetone–water 2:1, 08C; (ii) NaBH4, MeOH, 08C;
(iii) TsCl, abs. pyridine, 08C; (iv) LiBr, DMF, 1008C; and (v) CH3SO2OH, 908C.

Novel Route to 2-Arylapomorphines
469
Figure 1.
Cross-Coupling of 2-Bromoapocodeine (8) with Arylboronic Acids
(General Procedure)
A mixture of 2-bromoapocodeine (1130 mg, 3.137 mmol), arylboronic acid
.
(3.137 mmol), Pd(PPh3)4 (184 mg, 0.159 mmol), and Ba(OH)2 8H2O
(990 mg, 3.137 mmol) was boiled in 1,4-dioxane–H2O (4:1) under reflux
for 30 min. After evaporation at reduced pressure, the residue was dissolved
in chloroform (20 ml) and filtered. The filtrate was evaporated, and the
residue was purified by flash chromatography (silica, chloroform–methanol
1:1) to yield compounds 9 or 10.
2-Phenylapocodeine (9)
White crystalline solid; mp 85–888C; yield: 910 mg (81.2%); anal. calc. for
C24H23NO2 (%): C, 78.88; H, 6.34; N, 3.84; O, 10.94; found (%): C, 78.62;
H, 6.30; N, 3.99; O, 11.09; [a]2D5 2145.7 (c 0.5, chloroform); MS m/z (%)
1
357 (Mþ, 8), 356 (10), 312 (22), 277 (35), 154 (100); H NMR (200 MHz,
CDCl3) d ¼ 8.55 [d, 1H, H1, J(1,3) ¼ 4.8], 7.81–7.51 (m, 2H, 2-Ar),
.
Scheme 2. (i) Arylboronic acid, Pd(PPh3)4, Ba(OH)2 8H2O, 1,4-dioxane–H2O 4:1,
1008C, 30 min; (ii) CH3SO2OH, methionine, 908C, 4 h.

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S. Berenyi et al.
470
7.50–7.19 (m, 4H, 2-Ar, H3), 6.80 (dd, 2H, H8-9), 6.32 (s, 1H, OH), 4.02
(s, 1H, H6a), 3.91 (s, 3H, OCH3), 3.45–3.08 (m, 4H, H4a, H5a, H5b, H7a),
2.90–2.52 (m, 5H, H4b, H7b, NCH3).
2-(4-Hydroxyphenyl)-apocodeine (10)
White crystalline solid; mp 130–1318C; yield: 922 mg (78.7%); anal. calc.
for C24H23NO3 (%): C, 77.19; H, 6.21; N, 3.75; O, 12.85; found (%): C,
77.51; H, 6.22; N, 3.61; O, 12.66; [a]2D5 2101.4 (c 0.75, chloroform); MS
1
m/z (%) 373 (Mþ, 68), 372 (100), 312 (27), 304 (31), 280 (75); H NMR
(200 MHz, CDCl3) d ¼ 8.50 [d, 1H, H1, J(1,3) ¼ 3.9], 7.75 (s, 1H, OH),
7.51 (d, 2H, 2-Ar, Jortho ¼ 9.8), 7.23 (s, 1H, H3), 6.87–6.69 (m, 4H, H8-9,
2-Ar), 6.25 (s, 1H, OH), 4.15 (s, 1H, H6a), 3.95 (s, 3H, OCH3), 3.72 (s, 1H,
H5a), 3.40–3.05 (m, 4H, H4a, H5b, H7a, H7b), 2.82–2.52 (m, 4H, H4b, NCH3).
O-Demethylation of 2-Arylapocodeins (9 and 10) to Yield
Corresponding 2-Arylapomorphines (1 and 2) (General Procedure)
A
mixture of 2-arylapocodeine (1000 mg), methionine (1000 mg,
6.702 mmol), and CH3SO2OH (4 ml) was boiled at 908C for 4 h. After
cooling, the pH of the mixture was set to 10 by concentrated NH3 solution
and extracted with chloroform (3 ꢀ 15 ml). The organic layers were
collected, washed with saturated NaCl solution, dried over anhydrous
MgSO4, and evaporated. The residue was subjected to silica-gel column
chromatography. Elution with chloroform–methanol (1:1) gave 1 and 2.
2-Phenylapomorphine Hydrochloride (1)
Yield: 818 mg (92.2%); mp .2308C (HCl salt); spectral data were in
agreement with previously published results.[3]
2-(4-Hydroxyphenyl)-apomorphine Hydrochloride (2)
Yield: 762 mg (87.2%); mp .2308C (HCl salt); spectral data were in
agreement with previously published results.[3]
ACKNOWLEDGMENT
The authors thank the National Science Foundation for financial support of
this work (Grant OTKA Reg. No. T049436).

Novel Route to 2-Arylapomorphines
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