[4 + 2] Addition of Singlet Oxygen to Thebaine
J . Org. Chem., Vol. 65, No. 15, 2000 4677
phenylpiperidines whereas diphenylpropylamines only
retain ring A and the ethylamine chain.14 A different, and
7.52 (d, J ) 8.6 Hz, 1H), 7.17 (d, J ) 8.6 Hz, 1H), 7.03 (1H),
7.02 (1H), 5.39 (s, 1H), 3.85 (s, 3H), 3.3-3.0 (m, 2H), 2.6-2.2
1
(
m, 2H), 2.64 (s, 3H). H NMR [250.13 Mz, DMSO-d
6
, 25 °C,
very rarely explored, modification is based on the cleav-
age of rings D and E, which leads to hydrodibenzofurans
that are structurally similar to Pummerer’s ketone (36).
This class of compound is represented by 37, which
showed selectivity for µ and κ receptors in binding
assays.15
minor rotamer, δ (ppm)]: 10.14 (s, 1H), 7.84 (s, 1H), 7.51 (d,
J ) 8.6 Hz, 1H), 7.16 (d, J ) 8.6 Hz, 1H), 7.01 (s, 1H), 7.02 (s,
1
2
H), 5.35 (s, 1H), 3.85 (s, 3H), 3.3-3.0 (m, 2H), 2.6-2.2 (m,
1
6
H), 2.83 (s, 3H). H NMR [250.13 Mz, DMSO-d , 140 °C, two
rotamers, δ (ppm)]: 10.17 (s, 1H), 7.88 (s, 1H), 7.50 (d, J )
8.5 Hz, 1H), 7.13 (d, J ) 8.5 Hz, 1H), 6.98 (s, 2H), 5.33 (s,
Partially reduced dibenzofurans16 and structurally
1H), 3.93 (s, 3H). IR (CHCl ): υ
max
1670, 1610, 1570, 1290,
3
-
1
1
7
1120, 1090 cm . UV (CHCl ): λmax 318 (ꢀ ) 5509), 280 (ꢀ )
3
related compounds, such as tramadol (38) and metha-
-
3
done (39),18 are of interest due to their analgesic activity
8870), 244 (ꢀ ) 13664). CD (c ) 3.4 × 10
3
M, CH OH) λmax/nm
∆ꢀ/cm2 mol ): 358 (37.74), 322 (-150.19), 286 (43.60), 261
-1
(
(
°
and their use in the treatment of opiate-dependent drug
addiction, respectively. Although several methods de-
scribe the preparation of this class of compound, all
involve multi-stage synthesis and are nonstereoselective.
The photooxidations of thebaine described here represent
the simplest access to functionalized hydrodibenzofurans
and to 14-hydroxycodeinone described to date. In addi-
tion, the study constitutes the first report on the isolation
of an endoperoxide of a morphine alkaloid and its use in
a synthetic method.
-28.14), 234 (-87.41), 221 (11.44). Mp (amorphous solid): 103
+
C. [R]
D
: -105.3° (c 7.2 mg/mL, CHCl
3
). FAB (NBA): 344 (M
+ H, 100), 314 (13), 285 (28), 273 (18), 258 (21), 243 (14), 203
(21). MS (EI): 343 (15), 315 (8), 284 (32), 272 (29), 271 (49),
269 (11), 258 (22), 257 (38), 256 (45), 255 (10), 244 (21), 243
(27), 228 (11), 202 (43), 202 (100). HRMS (EI) C18
H
17NO
6
calcd
3
43.1051, obsd 343.1055, ∆m 0.4 mu. Anal. Calcd for C18H -
17
6
NO : C, 62.96; N, 4.08; H, 5.00. Found: C, 62.95; N, 4.10; H,
4
.98.
P r ep a r a tion of Com p ou n d 11 fr om 10. (a ) Hydrodiben-
zofuran 10 (30 mg, 0.087 mmol) was dissolved in 50 mL of
CH Cl . The solution was irradiated as described in method
2
2
A, without oxygen or TPP, until TLC (AcOEt) indicated that
no starting material remained (7 h). Removal of solvent under
reduced pressure followed by flash chromatography (CH Cl
Exp er im en ta l Section
Gen er a l Meth od s. Reagents were purchased from Aldrich
and used without purification. Reaction solvents were purified
according to standard procedures. Chromatographic solvents
were used without purification. Thin-layer chromatography
was carried out on TLC aluminum-backed sheets of silica gel
2
2
to CH Cl /MeOH [98:2]), afforded 20 mg of 11 (88% yield). (b)
2
2
Hydrodibenzofuran 10 (35 mg, 0.100 mmol) was dissolved in
50 mL of CH Cl . The solution was irradiated as described in
2
2
method B, without oxygen or TPP, until TLC (AcOEt) indicated
that no starting material remained (45 min). Removal of
solvent under reduced pressure followed by flash chromatog-
raphy (CH Cl to CH Cl /MeOH [98:2]), afforded 26.2 mg of
6
0 F254. Visualization was achieved with Liebermann or
Hanessian reagent or iodine. Flash column chromatography
was gravity fed and carried out with silica gel 60 (230-240
mesh). NMR spectra were recorded at 250 or 300 MHz.
Multiplicity of carbon signals was determined by DEPT
experiments. Melting points are uncorrected.
Gen er a l P r oced u r e for th e P h otooxygen a tion .
Meth od A. Oxygen was bubbled through a solution of the
corresponding compound and meso-tetraphenylporphyrin
2
2
2
2
11 (95% yield).
Com p ou n d 11.
1
3
H NMR [250.13 Mz, CDCl , (major rota-
mer), δ (ppm)]: 9.97 (s, 1H), 7.86 (s, 1H), 7.73 (d, J ) 8.3 Hz,
1H), 7.66 (s, 1H), 6.95 (d, J ) 8.2 Hz, 1H), 4.10 (s, 3H), 3.59-
3.47 (m, 2H), 3.28-3.23 (m, 2H), 2.97 (s, 3H). 13C NMR [CDCl ,
3
(major rotamer), δ (ppm)]: 191.3, 163.3, 151.8, 146.0, 145.6,
(
5,10,15,20-tetraphenyl-21H,23H-porphine; TPP) in CH
2
Cl
2
, in
134.8, 131.5, 124.6, 118.9, 105.8, 56.3, 50.9, 29.9, 25.4. H NMR
1
a round-bottomed flask fitted with a cooling water-jacket. The
mixture was irradiated from a distance of 45 cm with an
Osram Ultra-Vitalux sun lamp (300 W).
[250.13 Mz, CDCl , (minor rotamer), δ (ppm)]: 10.03 (s, 1H),
3
7.85 (s, 1H), 7.74 (d, J ) 8.3 Hz, 1H), 7.56 (s), 6.93 (d, J ) 8.2
Hz, 1H), 4.09 (s, 3H), 3.59-3.47 (m, 2H), 3.28-3.23 (m, 2H),
Meth od B. Oxygen was bubbled through a solution of the
3.01 (s, 3H). 13C NMR [CDCl , (minor rotamer), δ (ppm)]:
3
corresponding compound and TPP in CH
irradiated using a 400 W high-pressure mercury lamp in a
Pyrex immersion apparatus until TLC analysis [silica gel, CH
Cl /MeOH (95:5) or ethyl acetate] showed that all the starting
material had been consumed.
2
Cl
2
. The solution was
191.0, 163.0, 150.6, 146.0, 145.7, 133.7, 131.6, 124.7, 118.9,
105.7, 56.3, 45.3, 35.0, 23.5. IE: 523 (19), 262 (100), 264 (8).
2
-
IR (CHCl ): υ
3
max
2967, 2903, 2851, 1651, 1617, 1562, 1418,
1396 cm-1. UV (CHCl ) λmax: 304, 298, 246. FAB
+
2
3
(glycerol):
263 (M + H, 19), 262 (100), 234 (7), 203 (9), 175 (22), 243 (14),
203 (21). FAB (NBA): 262 (37), 207 (24), 175 (22), 149 (62).
P r ep a r a tion of Com p ou n d 10 fr om Th eba in e (3).
Thebaine (3) (200 mg, 0.64 mmol) and TPP (20 mg, 0.03 mmol)
+
MS (EI): m/z 261 (6), 243 (8), 232 (6), 204 (4), 203 (15), 202
were dissolved in 150 mL of CH
2
Cl
2
, and the solution was
(100), 189 (29). HRMS (EI): C H NO calcd 261.1001, obsd
1
4
15
4
irradiated, as described in method A, until TLC indicated that
no starting material remained (90 min). Removal of the solvent
under reduced pressure, followed by flash chromatography
261.1005, ∆m 0.4 mu. Anal. Calcd for C H NO : C, 64.36;
1
4
15
4
N, 5.36; H, 5.78. Found: C, 64.34; N, 5.33; H, 5.77.
P r ep a r a tion of Com p ou n d 26. The methyl vinyl ketone
adduct of thebaine 25 (60 mg, 0.157 mmol) was combined with
TPP (3 mg, 0.004 mmol) in 50 mL of CH Cl , and the solution
2 2 2 2
[hexane/CH Cl (50:50) to CH Cl /MeOH (98:2)], afforded 136
mg (62%) of 10 as a yellow solid.
2
2
Com p ou n d 10. H NMR (250.13 Mz) and 13C NMR in
1
was irradiated and oxygenated for 11h 20 min. Removal of
solvent under reduced pressure followed by flash chromatog-
raphy afforded 57 mg (98%) of the N-demethylated methyl
vinyl adduct of thebaine 26.
1
CDCl
3
can be found in Table 1. H NMR [250.13 Mz, DMSO-
6
d , 25 °C, major rotamer, δ (ppm)]: 10.09 (s, 1H), 7.84 (s, 1H),
Com p ou n d 26. 1H NMR [250.13 MHz, CDCl
, δ (ppm)]:
(
14) Reference 1c, pp 139-213.
3
(15) Labidalle, S.; Zhang, Y. M.; Moskowitz, H.; Thal, C.; Miocque,
6.64 (d, J ) 8.2 Hz, 1H), 6.54 (d, J ) 8.2 Hz, 1H), 5.92 (d, J )
M.; Degryse, M.; Fortin, M.; Delevall e´ e, F. Eur. J . Med. Chem. 1989,
4, 385.
16) (a) Zhang, Y. M.; Boukaache, A.; Mayrargue, J .; Moskowitz, H.;
8
3
.9 Hz, 1H), 5.53 (d, J ) 8.9 Hz, 1H), 4.55 (s, 1H), 3.81 (s,
2
13
H), 3.60 (s, 3H), 3.3-1.2 (m, 10H), 2.15 (s, 3H). C NMR
(
3
[CDCl , δ (ppm)]: 209.0, 147.9, 141.8, 135.6, 133.8, 127.8, 126.0,
Miocque, M.; Thal, C. Synth. Commun. 1992, 22, 1403. (b) Labidalle,
S.; Min, Z. Y.; Reynet, A.; Moskowitz, H.; Vierfond, J .-M.; Miocque, M.
Tetrahedron 1988, 44, 1159. (c) id. Tetrahedron 1988, 44, 1171.
119.4, 113.5, 95.0, 81.1, 60.0, 56.5, 53.4, 50.4, 47.3, 45.4, 43.1,
33.1, 30.5, 29.8, 22.5. MS (EI): m/z 368 (3), 367 (8), 352 (2),
(
17) (a) Salazar, L. A.; Mart ´ı nez, R. V.; L o´ pez-Mu n˜ oz, F. J . Drug
Dev. Res. 1995, 36 (3), 119. (b) Raffa, R. B. Am. J . Med. 1996, 101(1A),
0S.
18) (a) Kreek, M. J . Pharmacol. Biochem. Behav. 1997, 573, 551.
b) Brackbill, R. M.; MacGowan, R. J .; Rugg, D. Am. J . Drug. Alcohol
Abuse 1997, 233, 397.
3
1
3
24 (3), 296 (1), 215 (6), 214 (8), 192 (11), 189 (6), 150 (12),
48 (13), 121 (16), 115 (9). HRMS (EI):
22 4
C H25NO obsd
4
67.1770, calcd 367.1784, ∆m 1.4 mu.
P r ep a r a tion of Com p ou n d 31. To a stirred solution of
(
(
thebaine (3) (200 mg, 0.64 mmol) in dry nitromethane (4 mL)