Synthesis of 3-alkyl and arylapomorphines

Article abstract of DOI:10.1080/00397910701462773

The synthesis of 3-alkyl and arylapomorphines 18-20 has been accomplished by using the Suzuki-Miyaura cross-coupling reaction of vinyl- and allylhalide morphinanedienes or arylhalide apocodeines and arylboronic acids. Copyright Taylor & Francis Group, LLC

Full text of DOI:10.1080/00397910701462773

Synthetic Communicationsw, 37: 2549–2558, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701462773
Synthesis of 3-Alkyl and Arylapomorphines
´
´
Attila Sipos, Szilvia Debreceni, Renata Szabo,
´
´
Zsuzsanna Gyulai, and Sandor Berenyi
Department of Organic Chemistry, University of Debrecen, Debrecen,
Hungary
Abstract: The synthesis of 3-alkyl and arylapomorphines 18–20 has been accom-
plished by using the Suzuki–Miyaura cross-coupling reaction of vinyl- and allylhalide
morphinanedienes or arylhalide apocodeines and arylboronic acids.
Keywords: 3-alkyl and arylapomorphines, arylboronic acids, palladium, Suzuki
cross-coupling
Thebaine (1) is the only morphinanediene-type alkaloid of poppy. Because of
to its easily convertable structure, it is one of the most important natural raw
materials of the pharmaceutical industry. The synthesis of 7-substituted-6-
demethoxythebaine derivatives has already more than 20 years of history.
First, 7-bromo (3) and 7-chloromorphinanedienes (2), then the 7-thiocianato
derivative (4) were prepared from thebaine (1) via mesyl esters of 7-a-
substituted neopines.[1,2] The obtained morphinanedienes 2–4 were rearranged
and O-demethylated in acidic medium to form the corresponding 3-substituted
apomorphines[3–5] 8–10 (Fig. 1).
Dopamine receptor binding studies emphasize the importance of the
presence of a hydrophobic group in the proximity of 2-position of the
aporphine skeleton.[6–8] This effect correlates with the model of dopamine D2
receptors suggested by Ramsby et al., who describe the a lipophillic cavity
on the surface of the receptor near to the binding site.[9]
Received in Poland October 23, 2006
´ ´
Address correspondence to Sandor Berenyi, Department of Organic Chemistry,
University of Debrecen, Debrecen, Hungary. E-mail: bersu@delfin.unideb.hu
2549

2550
A. Sipos et al.
Figure 1. Synthesis and rearrangement of 7-substituted morphinanedienes.
In the recent article, we report the synthesis of some 3-alkyl and arylapo-
morphines with Suzuki–Miyaura cross-coupling reaction. Palladium-
catalyzed transformations of codeine and morphine were first accomplished
by Davies et al.[10,11] Palladium-catalyzed dehydroxylation reaction on
the morphinan skeleton was recently thoroughly investigated.[6] Suzuki–
Miyaura reaction on morphinans was used by Hedberg et al. for the prep-
aration of 3-aryl-3-demethoxycodeines.[12] Søndergaard et al. applied this
reaction on the aporphine skeleton for the synthesis of 2-arylaporphines
from triflates.[13] In one of our previous articles, we described a synthetic
route to 2-alkyl and arylapomorphines through this palladium-catalyzed
cross-coupling reaction of 2-bromoapocodeine.[14] Based on our latest
results, we planned to prepare the aimed apomorphines using the available
arylbromide 6 and vinylbromide 3 (Fig. 2).
Synthetic route I was based on our previously published method for the
synthesis of 2-arylapomorphines.[14] Acid-catalyzed rearrangement of
7-bromo-6-demetoxythebaine (3) into 3-bromoapocodeine (6) was first
performed, then the Suzuki–Miyaura reaction was accomplished from the
obtained haloapocodeine to yield 3-alkyl and arylapocodeines 15–17 (Fig. 3).
Figure 2. Retrosynthetic strategies.

3-Alkyl and Arylapomorphines
2551
Figure 3. Synthetic route I.
The cross-coupling was catalyzed by PdCl2(PPh3)2 or Pd(PPh3)4; no
significant difference was observed in the corresponding yields. Classic
Suzuki cross-coupling partners, boronic acids, were applied. Barium
hydroxide was found to be an appropriately strong base to accomplish the
reductive elimination step of the reaction in the solvent mixture of 1,4-
dioxane and water (ratio 4:1).
We revealed a potential second reaction route (synthetic route II) to
the products; the cross-coupling step was directly performed on 7-bromo-
6-demethoxythebaine (3, Fig. 4).
The same reaction conditions were applied in both reaction routes for the
Suzuki reactions and the rearrangement steps. Almost the same yields were
observed irrespective of the type of the basic molecule of the palladium-
catalyzed cross-coupling reaction (i.e., vinyl- and allyl-type bromo derivative
or aryl-type bromo derivative). The yields of the Suzuki–Miyaura cross-
coupling steps of the two synthetic routes are summarized in Table 1.
Figure 4. Synthetic route II.

2552
A. Sipos et al.
Table 1. Comparison of yields of synthetic routes I and II
Yield (%), synthetic
route I
Yield (%), synthetic
route II
Compound
R
15
16
-CH3
55
84
62
88
17
86
86
The conversion of apocodeines 15–17 into apomorphines 18–20 was
carried out by means of the methanesulfonic acid/methionine reagent combi-
nation, which was successfully used earlier by our laboratory[15] (Fig. 5).
The receptor binding test for the presented apomorphine derivatives
18–20 is in progress; the results and the structure–activity relationships
will be published in due course.
The Diels–Alder reactions of 7-alkyl and 7-aryl-6-demethoxythebaines
12–14 are being examined to explore the stereochemistry and the opiate
receptor affinity of the products.
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 (4:1)
1
mobile phase. The spots were visualized with Draggendorf’s reagent. H
NMR spectra were recorded on a Bruker WP 200 SY spectrometer;
chemical shifts are reported in parts per million (ppm) (d) from internal
TMS, and coupling constants (J ) are measured in Hertz. 13C NMR spectra
were recorded on a Bruker AM 360 instrument; chemical shifts are also
reported in ppm (d) and are presented for 13, 16, and 19 (R ¼ Ph). Mass
spectral measurements were performed with an Automass Multi
Figure 5. O-demethylation of 3-substituted apocodeines.

3-Alkyl and Arylapomorphines
2553
(ThermoQuest) instrument in the EI mode (direct inlet). The source
temperature was 1408C; ionization was 70 eV. Optical rotation was deter-
mined with a Perkin-Elmer model 241 polarimeter. Elemental analyses
(C, H, N, S) were obtained on a Carlo Erba 1106 analyzer.
Acid-Catalyzed Rearrangement of Morphinanediens (General
Procedure A)
A mixture of the dien (1.48 mmol) and methanesulfonic acid (5 ml) was
stirred for 20 min at 08C. Then the reaction mixture was added dropwise,
with stirring and external ice cooling, to a solution of potassium hydrogen
carbonate (10 g) in water (50 ml). After extraction with chloroform
(3 ꢀ 15 ml), the combined extracts were washed with saturated brine, dried
(MgSO4), and concentrated in vacuum. The residue was submitted to purifi-
cation by means of column chromatography (Kieselgel 40, chloroform–
methanol 1:1) to yield appropriate apocodeines.
Cross-coupling of Halo Derivatives with Aryl- and Methylboronic
Acids (General Procedure B)
A mixture of the halo-derivative (3 mmol), the aryl- or methylboronic acid
.
(3 mmol), Pd(PPh3)2Cl2 (0.15 mmol), and Ba(OH)2 8H2O (3 mmol) was
boiled in 1,4-dioxane–H2O ¼ (4:1) under reflux for 30 min. After evapor-
ation 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 aryl- and
alkyl-derivatives.
Synthetic Route I
3-Bromoapocodeine (6)
Compound 6 was prepared from 1000 mg (2.79 mmol) of 7-bromo-6-
demethoxythebaine (1) in agreement with general procedure A. White crystal-
line solid; mp. 88–908C, Yield: 950 mg (95%), Spectral data were in
agreement with previously published results.[3]
3-Methylapocodeine (15)
Compound 15 was prepared from 3-bromoapocodeine (6) in agreement with
general procedure B. Off-white crystalline solid; mp 2108C (decomposition).
Yield: 430 mg (55%), Anal. calc. for C19H21NO2 (%): C, 77.26; H, 7.17; N,

2554
A. Sipos et al.
4.74; O, 10.83. Found (%): C, 77.30; H, 7.15; N, 4.75; O, 10.80, [a]2D5 282 (c
0.1, chloroform); MS m/z (%) 295 (Mþ, 52%); 1H NMR (200 MHz, CDCl3)
d ¼ 8.09 (d, 1H, H1, J1,2 ¼ 9.3 Hz), 7.06 (d, 1H, H2, J1,2 ¼ 9.3 Hz), 6.75 (dd,
2H, H8, H9), 6.35 (s, 1H, OH), 3.89 (s, 3H, OCH3), 3.31–2.84 (m, 4H, H4a,
H5a, H5b, H6a), 2.81–2.32 (m, 6H, H4b, H7a, H7b, NCH3), 2.21 (s, 3H,
Ar-CH3).
3-Phenylapocodeine (16)
Compound 16 was prepared from 3-bromoapocodeine (6) in agreement with
general procedure B. White crystalline solid; mp 107–1108C. Yield:
795 mg (84%). C24H23NO2 (%): C, 80.64; H, 6,49; N, 3.92; O, 8.95. Found
(%): C, 80.67; H, 6.46; N, 3.94; O, 8.93, [a]2D5 262 (c 1.52, chloroform);
1
MS m/z (%) 357 (Mþ, 49); H NMR (200 MHz, CDCl3) d ¼ 8.26 (d, 1H,
H1, J1,2 ¼ 8.1 Hz), 7.42–7.23 (m, 5H, 23Ph), 7.21 (d, 1H, H2,
J1,2 ¼ 8.1 Hz), 6.73 (dd, 2H, H8, H9), 6.40 (s, 1H, OH), 3.88 (s, 3H,
OCH3), 3.28–2.82 (m, 5H, H4a, H5a, H5b, H6a, H7b), 2.76–2.26 (m, 5H,
H4b, H7a, NCH3); 13C NMR (90 MHz, CDCl3) d ¼ 145.97, 143.19, 141.57,
140.51, 134.86, 130.80, 130.30, 130.01, 129.20, 128.05, 127.65, 126.78,
126.01, 120.37, 118.45, 109.17 (Ar), 63.28 (C6a), 59.30 (OCH3), 53.20
(C5), 44.04 (55NCH3), 34.57 (C7), 28.53 (C4)
3-(4-Dibenzofuranyl)-apocodeine (17)
Compound 17 was prepared from 3-bromoapocodeine (6) in agreement with
general procedure B. Brown crystalline solid; mp 114–1208C. Yield:
1019 mg (86%). Anal. calc. for C30H25NO3 (%): C, 80.51; H, 5.63; N, 3.13;
O, 10.73. Found (%): C, 80.48; H, 5.65; N, 3.18; O, 10.69. [a]2D5 þ51 (c
1
0.30, chloroform); MS m/z (%) 447 (Mþ, 51); H NMR (200 MHz, CDCl3)
d ¼ 8.44 (s, 1H, H1, J1,2 ¼ 8.1 Hz), 8.11-7.29 (m, 7H, 3-Ar), 6.85 (m, 3H,
H3, H8, H9), 6.41 (s, 1H, OH), 3.94 (s, 3H, OCH3), 3.42–2.29 (m, 10H,
H4a, H4b H5a, H5b, H6a, H7a, H7b, NCH3)
Synthetic Route II
7-Methyl-6-demethoxythebaine (12)
Compound 12 was prepared from 7-bromo-6-demethoxythebaine (3) in
agreement with general procedure B. Brown crystalline solid; mp 177–
1798C. Yield: 758 mg (92%). Anal. calc. for C19H21NO2 (%): C,77.26; H,
7.17; N, 4.74; O,10.83, Found (%): C, 77.29; H, 7.14; N, 4.76 O, 10.81.
[a]2D5 2123 (c 0.15, chloroform); MS m/z (%) 295 (Mþ, 56%); H NMR
1
(200 MHz, CDCl3) d ¼ 6.68 (dd, 2H, H1, H2), 5.55–4.90 (m, 2H, H6, H8),

3-Alkyl and Arylapomorphines
2555
3.89 (s, 3H, OCH3), 3.82–2.59 (m, 5H, H5, H10a, H10b, H16a, H16b), 2.52
(s, 3H, NCH3), 2.38–1.21 (m, 6H, 7-CH3, H9a, H15a, H15b)
7-Phenyl-6-demethoxythebaine (13)
Compound 13 was prepared from 7-bromo-6-demethoxythebaine (3) in
agreement with general procedure B. White crystalline solid; mp 92–958C.
Yield: 678 mg (68%). Anal. calc. for C24H23NO2 (%): C, 80.64; H, 6.49; N,
3.92; O, 8.95, Found (%): C, 80.68; H, 6.45; N, 3.95; O, 8,92. [a]2D5 2312
1
(c 2.12 chloroform); MS m/z (%) 357 (Mþ, 72%); H NMR (200 MHz,
CDCl3) d ¼ 7.39–7.09 (m, 5H, 7-Ph), 6.58 (dd, 2H, H1, H2), 5.95 (s, 1H,
H8), 5.84 (d, 1H, H6, J5-6 ¼ 3.0 Hz), 5.58 (s, 1H, H5, J5-6 ¼ 3.0 Hz), 3.81
(s, 3H, OCH3), 3.71–3.20 (m, 2H, H10a, H10b), 2.91–2.54 (m, 3H, H9a,
H16a, H16b), 2.43 (s, 3H, NCH3), 2.30–1.68 (m, 2H, H15a, H15b); 13C
NMR (90 MHz, CDCl3) d ¼ 145.00 (C4), 142.99 (C3), 141.28 (C7), 133.39
(C14), 132.27 (C12), 130.85 (C11), 128.35, 128.21, 127.68, 127.28, 126.79,
126.07 (7-Ar), 118.87 (C1), 118.32 (C8), 113.88 (C6), 112.80 (C2), 90.00
(C5), 61.52 (C9), 56.41 (OCH3), 46.24 (C16), 43.50 (C13), 42.48
(55NCH3), 37.55 (C15), 29.29 (C10).
7-(4-Dibenzofuranyl)-6-demethoxythebaine (14)
Compound 14 was prepared from 7-bromo-6-demethoxythebaine (3) in
agreement with general procedure B. Yellow crystalline solid; mp 81–
858C. Yield: 986 mg (79%). Anal. calc. for C30H25NO3 (%): C, 80.51; H,
5.63; N, 3.13; O, 10.73. Found (%): C, 80.55; H, 5.67; N, 3.10; O, 10.68;
[a]2D5 2202 (c 0.44, chloroform); MS m/z (%) 447 (Mþ, 80%); H NMR
1
(200 MHz, CDCl3) d ¼ 8.08–7.12 (m, 7H, 7-Ar), 6.68 (dd, 2H, H1, H2,),
6.39 (d, 1H, H6, J5-6 ¼ 2.2 Hz), 6.31 (s, 1H, H8), 5.76 (d, 1H, H5,
J5-6 ¼ 2.2 Hz), 3.91 (s, 3H, OCH3), 3.55–2.65 (m, 4H, H10a, H10b, H16a,
H16b), 2.55 (s, 3H, NCH3), 2.52–1.81 (m, 3H, H9a, H15a, H15b).
3-Methylapocodeine (15)
Compound 15 was prepared from 7-methyl-6-demethoxythebaine (12)
according to general procedure A. Yield: 470 mg (62%); all the physical
and spectral data are in agreement with the details presented in synthetic
route I.
3-Phenylapocodeine (16)
Compound 16 was prepared from 7-phenyl-6-demethoxythebaine (13)
according to general procedure A. Yield: 597 mg (88%); all the physical
and spectral data are in agreement with the details presented in synthetic
route I.

2556
A. Sipos et al.
3-(4-Dibenzofuranyl)-apocodeine (17)
Compound 17 was prepared from 7-(4-dibenzofuranyl)-6-demethoxythebaine
(14) according to general procedure A. Yield: 848 mg (86%); all the physical
and spectral data are in agreement with the details presented in synthetic
route I.
O-Demethylation of 3-Substituted Apocodeines to Yield
Corresponding 2-Substituted Apomorphines (General Procedure C)
A mixture of 3-substituted apocodeine (4.562 mmol), methionine (1 g,
6.702 mmol), and methanesulfonic acid (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 the corre-
sponding apomorphines.
3-Methylapomorphine Hydrochloride (18)
Compound 18 was prepared from 3-methylapocodeine (15) according to
general procedure C. White crystalline solid; mp 200–2058C (HCl salt,
decomposition). Yield: 283 mg (56%). Anal. calc. for C19H22ClNO2 (%): C,
68.77; H; 6.68; Cl, 10.68; N, 4.22; O, 9.64. Found (%): C, 68.75; H, 6.70;
N, 4.25; Cl, 10.70; O, 9.60, [a]2D5 252 (c 0.10, DMSO); MS m/z (%) 331
(Mþ, 63); 1H NMR (200 MHz, DMSO-d6) d ¼ 9.05 (s, 1H, OH), 8.20
(d, 1H, H1, J1-2 ¼ 7.8 Hz), 7.16 (d, 1H, H2, J1-2 ¼ 7.8 Hz), 3.25–1.95
(m, 13H, H4a, H4b, H5a, N-CH3, Ar-CH3 H5b, H6a, H7a, H7b).
3-Phenylapomorphine Hydrochloride (19)
Compound 19 was prepared from 3-phenylapocodeine (16) according to
general procedure C. Green crystalline solid; mp 205–2108C (HCl salt).
Yield: 381 mg (60%). Anal. calc. for C24H24ClNO2 (%): C, 73.18; H, 6.14;
Cl, 9.00; N, 3.56; O, 8.12. Found (%): C, 73.21; H, 6.10; N, 3.53; Cl, 9.04;
1
O, 8.12. [a]2D5 264 (c 0.20, ethanol); MS m/z (%) 3.93 (Mþ, 64); H NMR
(200 MHz, DMSO-d6) d ¼ 11.24 (s, 1H, OH), 9.82 (s, 1H, OH), 8.44
(d, 1H, H1, J1-2 ¼ 7.8 Hz), 7.58–7.12 (m, 6H, H2, 3-Ph), 6.78 (dd, 2H, H8,
H9), 4.34 (dd, 1H, H6a), 3.46–2.48 (m, 9H, H4a, H4b, H5a, N-CH3, H5b,
H7a, H7b); 13C NMR (90 MHz, DMSO-d6) d ¼ 145.07, 143.44, 140.09,
139.46, 131.73, 129.26, 128.97, 128.69, 128.60, 127.56, 127.46, 127.01,
124.77, 119.65, 118.60, 114.57 (Ar), 61.78 (C6a), 51.17 (C5), 41.05
(55NCH3), 30.64 (C7), 25.04 (C4).

3-Alkyl and Arylapomorphines
2557
3-(4-Dibenzofuranyl)-apomorphine Hydrochloride (20)
Compound 20 was prepared from 3-(4-dibenzofuranyl)-apocodeine (17)
according to general procedure C. Green crystalline solid; mp .2408C
(HCl salt). Yield: 392 mg (44%). Anal. calc. for C30H26ClNO3 (%): C,
74.45; H, 5.41; Cl, 7.33; N, 2.89; O, 9.92. Found (%): C, 74.48; H, 5.39;
Cl, 7.30; N, 2.91; O, 9.92. [a]2D5 þ48 (c 0.20, methanol); MS m/z (%) 483
(Mþ, 32); 1H NMR (200 MHz, DMSO-d6) d ¼ 9.95 (s, 1H, OH), 9.08
(s, 1H, OH), 8.55 (d, 1H, H1, J1-2 ¼ 9.5 Hz), 8.31 (d, 1H, H2, J1-2
¼
9.5 Hz), 7.84–7.41 (m, 7H, 3-Ar), 6.87 (dd, 2H, H8, H9), 4.45 (dd, 1H,
H6a), 4.20–2.41 (m, 9H, H4a, H4b, H5a, H5b, H7a, H7b, NCH3).
ACKNOWLEDGMENTS
´
The authors are grateful for the substantial discussion with Sandor Antus and
for the financial support from the National Science Foundation (Grant OTKA
Reg. Nos. T049436 and NI61336).
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