Boron tribromide-catalyzed rearrangement of 7,7-diphenylhydromorphone to 6,7-diphenylmorphine: A novel conversion of ketones to allylic alcohols

Article abstract of DOI:10.1021/jo951526i

A novel boron tribromide-catalyzed rearrangement of ketones to allylic alcohols was discovered in the 7-phenylmorphinan-6-one system. The reaction involved the stereospecific migration of an axial 7β-phenyl (or a hydrogen) to the C-6 carbonyl carbon, followed by the elimination of the H-8 proton leading to the generation of allylic alcohols. A possible mechanistic pathway for this rearrangement is discussed.

Full text of DOI:10.1021/jo951526i

2466
J . Org. Chem. 1996, 61, 2466-2469
Bor on Tr ibr om id e-Ca ta lyzed Rea r r a n gem en t of
7,7-Dip h en ylh yd r om or p h on e to 6,7-Dip h en ylm or p h in e: A Novel
Con ver sion of Keton es to Allylic Alcoh ols
Peng Gao† and Philip S. Portoghese*
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 308 Harvard Street,
SE, Minneapolis, Minnesota 55455
Received August 17, 1995X
A novel boron tribromide-catalyzed rearrangement of ketones to allylic alcohols was discovered in
the 7-phenylmorphinan-6-one system. The reaction involved the stereospecific migration of an axial
7â-phenyl (or a hydrogen) to the C-6 carbonyl carbon, followed by the elimination of the H-8 proton
leading to the generation of allylic alcohols. A possible mechanistic pathway for this rearrangement
is discussed.
Sch em e 1
Under acidic conditions, branched or ring-constrained
ketones are liable to skeletal rearrangement.1 In a few
cases, some bicyclic ketones have been reported to
undergo Wagner-Meerwein rearrangement2 leading to
the formation of allylic compounds.3-6 Here we report
on a novel ketone to allylic alcohol rearrangement in the
7-phenylmorphinan-6-one system that is catalyzed by
boron tribromide (BBr3).
Me
N
Me N
8
Ph
Ph
Ph
7
14
6 Ph
O
BBr3, CH2Cl2
10 min
O
1
2
5
4
O
O
3
OMe
OH
1
2
Resu lts a n d Discu ssion
BBr3
CH2Cl2
2 h
When diphenylhydrocodone 1, a byproduct from the
preparation of 7-phenylhydrocodone,7 was subjected to
boron tribromide treatment at room temperature (Scheme
1), an unexpected product 3 was isolated (52%) instead
of the desired demethylation product 2. The structure
of 3 was characterized by the disappearance of the C-6
carbonyl group and the presence of an allylic alcohol
functionality. The proton COSY spectrum of 3 indicated
a proton-proton coupling pattern of H10R-H10â-H9-H14-
H8. On the basis of the observation of the positive NOE
between H5 and ortho protons of the 6-phenyl group, the
C-6 chiral center of 3 was assigned as the S configuration
(6â-phenyl).
Further investigation showed that the reaction of 1
with boron tribromide rapidly afforded the demethylation
product 2 as it was isolated as a major component (43%)
when the reaction was quenched within 10 min. How-
ever, if the reaction proceeded longer than 30 min, the
rearrangement product 3 was predominant. Compound
4 was obtained as a major product (39%) when the
reaction proceeded beyond 1 h. The stereochemistry of
the 8â-bromo group was deduced from the coupling
constant (J H8-H14 ) 9.6 Hz) which suggested a trans
Me
N
Br
Me N
Ph
Ph
Ph
Ph
OH
O
O
OH
OH
4
3
relationship for these protons.8 In addition, the C-5
proton of 4 was found to be involved in long-range
coupling (J H5-H8 ) 1.6 Hz) to the H-8 due to the presence
of the double bond between C-6 and C-7.
From independent experiments, we have found that 3
and 4 also can be prepared from 2 and 3, respectively,
under similar conditions. The formation of 4 from 3
appears to be an example of anti SN2′ reaction,9,10 which
also supports the structure assignment of 3.
Since ketone 1 has two phenyl groups at the C-7
position, 7R-methyl-7â-phenylhydrocodone7 (5) was sub-
jected to boron tribromide treatment in order to elucidate
the stereopreference for migration of the C-7 substitu-
ents. The reaction of 5 with boron tribromide (Scheme
2) afforded both ketone 6 (59%) and the rearrangement
product 7 (22%). The stereochemistry of 7 at the 6-posi-
tion was confirmed by the positive NOE between H5 and
ortho protons of the 6-phenyl group. The formation of
the 6â-phenyl isomer 7 and the absence of its 6R epimer
suggested a stereospecific migration of the 7â-phenyl
group.
* Author to whom inquires should be addressed: Phone (612) 624-
9174. Fax (612) 626-6891.
† Current address: Research Biochemicals International, One Strath-
more Road, Natick, MA 01760. Phone (508) 651-8151, ext 245. Fax
(508) 655-1315.
X Abstract published in Advance ACS Abstracts, March 1, 1996.
(1) Fry, A. Mech. Mol. Migr. 1971, 6, 113-196.
(2) Pocker, Y. In Molecular Rearrangements; P. de Mayo, Ed.;
Interscience: New York, 1963; Part I; pp 1.
(3) Libman, J .; Sprecher, M.; Mazur, Y. Tetrahedron 1969, 25, 1679-
1698.
(4) Paukstells, J . V.; Macharia, B. W. Tetrahedron 1959, 29, 1955-
1959.
(5) Bentz, H.; Subramanian, L. R.; Hanack, M.; Martinez, A. G.;
Marin, M. G.; Perezossorio, R. Tetrahedron Lett. 1977, 1, 9-12.
(6) Money, T. Nat. Prod. Rep., 1985, 2, 253-289.
(7) Gao, P.; Portoghese, P. S. J . Org. Chem. 1995, 60, 2276-2278.
(8) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. In Spectrometric
Identification of Organic Compounds, 5th ed.; J ohn Wiley & Sons
Inc.: New York, 1991; pp 196-198.
(9) Stock, G.; Kreft, A. F. I. J . Am. Chem. Soc. 1977, 99, 3850-3851.
(10) Stock, G.; Kreft, A. E. I. J . Am. Chem. Soc. 1977, 99, 3851-
3853.
0022-3263/96/1961-2466$12.00/0 © 1996 American Chemical Society

Novel Conversion of Ketones to Allylic Alcohols
J . Org. Chem., Vol. 61, No. 7, 1996 2467
Sch em e 2
To further validate this observation, the reaction of the
C-7 epimer 9 with boron tribromide was investigated
(Scheme 3). Compound 9 was obtained by methylation
reaction (15 min) led to the formation of 12 (26%). On
prolonged treatment (4 days) of 8 with boron tribromide
the R,â-conjugated ketone 14 (12%) in addition to 12 (8%)
was isolated. It should be noted that the boron tribro-
mide treatment of 8 led to the formation of a large
amount of highly polar material which resulted in the
low recovery of reaction material. A possible pathway
leading to 14 may involve rearrangement of 12 to the
allylic alcohol 13, followed by air oxidation to the ketone.
The reactions of 7-phenylmorphinan-6-ones (1, 5, 8)
with boron tribromide appear to be new examples of
Lewis acid-catalyzed ketone to allylic alcohol rearrange-
ments.1,3-6 A proposed mechanism (Figure 1) of this
rearrangement may involve the coordination of the
carbonyl group by boron tribromide (step i), which would
promote migration of the axial 7â-phenyl group (step ii).
Migration of the 7â-phenyl would be expected because it
is perpendicular to the sp2 plane of C-6 center. The
carbonium ion intermediate that is formed through this
process would be expected to eliminate the pro-S proton
(axial H8R, perpendicular to the sp2 plane of C-7) to form
the allylic product (step iii), which would yield 3 upon
hydrolysis, or afford 4 through an anti SN2′ reaction (step
iv).
Sch em e 3
of the lithium enolate of monophenyl ketone7 8 with
methyl iodide. The stereochemistry at the C-7 position
was confirmed by the positive proton NOE signals
between H5 and 7-methyl group, as well as between H14
and 7-methyl group. The stereochemistry of 9 is reason-
able in view of the fact that the â face of the enolate is
more accessable than the R face. Treatment of 9 with
boron tribromide afforded 10 (29%), together with a
minor amount (15%) of 11. The 5-methyl group of 11 is
likely derived from methyl bromide. Of significance was
the finding that no 7-methyl or 7-phenyl migration
product was isolated, supporting the idea that stereo-
electronic factors are important in the rearrangement.
The reaction of ketone 8 with boron tribromide was
also studied (Scheme 4). At room temperature, the
Sch em e 4
F igu r e 1.
The finding that ketone 9 did not undergo the ketone
to allylic alcohol rearrangement when treated with boron
tribromide is consistent with this mechanism, as its 7R-
phenyl group occupies an equatorial position and is thus
not available to migrate. Although the 7â-methyl group
of 9 is in an axial position that is favorable for migration,
the low migratory aptitude of a methyl group compared

2468 J . Org. Chem., Vol. 61, No. 7, 1996
Gao and Portoghese
7.30-7.39 (m, 1H, H-Ph), 7.00-7.10 (m, 3H, H-Ph), 6.71-6.75
(m, 2H, H-Ph), 6.57-6.64 (2d, 2H, J ) 5.8, H-1,2), 5.74-5.75
(d, 1H, J ) 3, H-8), 4.88 (s, 1H, H-5), 3.39-3.43 (m, 1H, H-9),
3.00-3.06 (d, 1H, J ) 6, H-10), 2.65-2.70 (m, 1H, H-14), 2.40-
2.48 (dd, 1H, J ) 6, H-10), 2.37-2.43 (m, 1H, H-D ring), 2.25-
2.30 (m, 1H, H-D ring), 1.69-1.76 (m, 1H, H-D ring), 1.54-
1.70 (m, 1H, H-D ring); 13C NMR (CD3COCD3) δ 145.33,
143.21, 140.91, 139.31, 132.46, 130.76, 129.38, 129.13, 128.87,
128.38, 127.67, 127.41, 127.10, 126.27, 120.76, 117.82, 99.04,
76.06, 59.30, 46.75, 44.45, 43.10, 42.53, 36.80, 20.56; MS
(HRFAB) m/ z 438.2065 [M + H]+ (calcd for C29H27NO3 [M +
H]+ ) 438.2050). The free base 3 (84 mg, 0.19 mmol) was
treated with Et2O‚HCl in a minimum amount of CH2Cl2 and
the precipitate was recrystallized twice from MeOH-ether to
afford 3‚HCl (40 mg, 44%), mp 223 °C dec; 1H NMR (CD3OD)
δ 7.71-7.74 (m, 2H, H-Ph), 7.45-7.50 (m, 2H, H-Ph), 7.36-
7.41 (m, 1H, H-Ph), 7.07-7.15 (m, 3H, H-Ph), 6.74-6.79 (m,
4H, H-1,2 and H-Ph), 5.71-5.72 (d, 1H, J ) 2.1), 5.18 (s, 1H,
H-5), 4.20-4.23 (m, 1H, H-9), 3.30-3.34 (m, 1H, H-10), 3.19-
3.25 (m, 1H, H-11), 3.06-3.12 (m, 1H, H-11), 3.00-3.09 (dd,
1H, J ) 7.2, 20.4, H-10), 2.86-2.86 (m, 1H, H-14), 2.10-2.14
(m, 1H, H-12), 1.80-1.90 (m, 1H, H-12). The proton NMR in
CD3COCD3 has a similar pattern but the chemical shift of the
14 proton is 3.55 instead of 2.85 ppm; three D2O exchangeable
protons were observed in CD3COCD3 at: 13.2, 8.2, and 4.5
ppm; 13C NMR (CD3OCD3 at AC-300) δ 147.36 (q), 145.10 (q),
143.52 (q), 140.28 (q), 130.41 (q), 129.47 (t), 129.08 (t), 128.50
(t), 127.83 (t), 127.75 (t), 127.53 (t), 126.81 (t), 123.43 (q),
121.42 (t), 118.77 (t), 97.63 (t), 75.46 (q), 61.17 (t), 47.40 (s),
43.02 (q), 41.20 (p); 13C NMR (CD3OD): δ 147.22, 146.03,
141.41, 139.97, 139.68, 130.42, 129.34, 128.87, 128.72, 128.38,
127.69, 127.59, 126.59, 123.30, 121.11, 118.61, 97.76, 76.66,
61.47, 43.26, 40.79; 13C NMR (D2O) δ 145.84, 145.47, 140.42,
139.39, 138.53, 130.54, 129.87, 129.61, 128.77, 128.51, 128.40,
128.37, 127.72, 124.47, 121.60, 118.61, 97.27, 76.90, 61.25,
47.77, 41.54, 40.05, 33.43, 33.39, 21.61. Anal. Calcd for
C29H28NO3•HCl: C, 73.49; H, 5.95; N, 2.96. Found: C, 73.23;
H, 5.98; N, 2.73.
8â-Br om o-6,7-d id eh yd r o-4,5r-ep oxy-6,7-d ip h en yl-17-
m eth ylm or p h in a n -3-ol (4). A CH2Cl2 solution of boron
tribromide (1 M, 0.6 mL, 0.6 mmol) was added over 5 min to
a solution of 7,7-diphenylhydrocodone 1 (64 mg, 0.21 mmol)
in CH2Cl2 (1 mL). After the mixture was stirred for 2 h,
methanol (3 mL) was added and the stirring was continued
for 30 min. The solution was adjusted to pH 8 with aqueous
KHCO3 (10%) and then extracted with CH2Cl2 (3 × 25 mL).
The combined extracts were washed with water to pH 7, dried
(MgSO4), and filtered. The filtrate was evaporated under
reduced pressure, and the residue was chromatographed on a
spinning TLC plate (1 mm, silica gel, ethyl acetate) to afford
4 (27 mg, 39%): 1H NMR (CD3COCD3) δ 7.06-7.10 (m, 3H,
H-Ph), 6.93-7.00 (m, 5H, H-Ph), 6.64-6.74 (m, 4H, H-1,2 and
H-Ph), 5.42-5.43 (d, 1H, J ) 1.64, H-5), 4.78-4.81 (dd, 1H, J
) 1.64, 9.6, H-8R), 3.64-3.70 (m, 1H, H-9), 3.09-3.15 (d, 1H,
J ) 18.7, H-10), 3.02-3.06 (dd, 1H, J ) 2.82, 9.6, H-14), 2.59-
2.67 (dd, 1H, J ) 4.98, 18.7, H-10), 2.52-2.56 (dd, 1H, J )
3.98, 11.0, H-11), 2.44 (s, 3H, H-NMe), 2.26-2.35 (td, 1H, J )
3.22, 12, 12, H-D ring), 2.09-2.18(td, 1H, J ) 4.90, 12, 12,
H-D ring), 1.71-1.75 (m, 1H, H-D ring); 13C NMR (CD3COCD3)
δ 143.40 (q), 141.54 (q), 141.03 (q), 140.88 (q), 140.78 (q), 137.27
(q), 130.47 (t), 129.82 (q), 129.71 (t), 128.15 (t), 127.90 (t),
127.15 (t), 127.05 (t), 126.41 (q), 120.26 (t), 118.21 (t), 90.85
(t), 58.67 (t), 55.55 (t), 50.27 (t), 47.27 (s), 43.41 (p), 35.64 (s),
20.09 (s); MS (HRFAB) m/ z 500.1222 [M + H]+ (calcd for
C29H27NO2Br, [M + H]+ 500.1225).
to a phenyl group may be responsible for the failure of 9
to undergo the rearrangement.
Exp er im en ta l Section
Reagents were from Aldrich Chemicals unless otherwise
noted. 7,7-Diphenylhydrocodone, 7R-phenylhydrocodone, and
7â-methyl-7R-phenylhydrocodone were prepared according to
the procedures that we have reported previously.7 All reac-
tions were performed under N2. Spinning thin-layer chroma-
tography (TLC) was performed on silica gel (EM Science Silica
Gel 60, PF254). Chromatographic solvent systems are re-
ported as volume/volume ratios. NMR data were collected at
room temperature (18-20 °C) on a 300 MHz spectrometer. The
δ (ppm) scale was in reference to the deuterated solvent.
Coupling constants are reported in Hz. Proton NMR peak
assignments were derived from COSY spectra. Melting points
were determined in open capillary tubes and are uncorrected.
Elemental analysis was performed by MHW Laboratory
(Phoenix, AZ).
7,7-Dip h en ylh yd r om or p h on e (2). Boron tribromide (1
M in CH2Cl2, 0.85 mL, 0.85 mmol) was added over 5 min with
stirring to diphenylhydrocodone7 1 (120 mg, 0.27 mmol) in CH2-
Cl2 (2 mL). Stirring was continued for 10 min after addition.
Methanol (4 mL) was added and after stirring for 30 min the
solution was adjusted to pH 8 with aqueous KHCO3 (10%) and
extracted with CH2Cl2-MeOH (95/5, 4 × 25 mL). The
combined organic layer was washed with water to pH 7, dried
over anhydrous MgSO4, and filtered. The solvent was removed
under reduced pressure, and the residue was chromatographed
on a spinning TLC (1 mm silica gel plate, ethyl acetate) to
afford 2 (50 mg, 43%): IR (KBr) 3444.5, 2930, 1718.3, 1496.3,
1447.0, 1384.3, 1250.8, 1030.8, 700.3 cm-1 1H NMR (CD3-
;
COCD3) δ 7.47-7.52 (t, 2H, J ) 7.5, H-Ph), 7.31-7.419 (m,
3H, H-Ph), 7.06-7.09 (m, 3H, H-Ph), 6.60-6.64 (m, 4H, H-1,2
and H-Ph), 5.01 (s, 1H, H-5), 3.17-3.20 (m, 1H, H-9), 2.99-
3.05 (d, 1H, J ) 6, H-10), 2.67-2.72 (dd, 1H, J ) 3.9, 13.8,
H-8â), 2.57-2.64 (m, 1H, H-14), 2.39-2.47 (dd, 1H, J ) 6, 18,
H-10), 2.31-2.38 (m, 1H, H-D ring), 2.29 (s, 3H, H-NMe),
2.02-2.18 (dd, 1H, J ) 16.8, 30.3, H-8R), 2.062-2.12 (m, 1H,
H-D ring), 1.54-2.67 (dt, 1H, J ) 5.4, H-D ring), 1.45-1.51
(m, 1H, H-D ring); 13C NMR (CD3COCD3) δ 207.88, 144.84,
144.34, 140.39, 139.40, 129.29, 129.12, 128.95, 128.32, 128.22,
127.98, 126.91, 125.62, 120.47, 118.35, 91.76, 63.57, 59.34,
54.09, 47.12, 42.74, 38.45, 36.19, 35.66, 20.23; MS (HRFAB)
m/ z 438.2057 [M + H]+, (calcd for C29H28NO3 [M + H]+
)
438.2049). 7,7-Diphenylhydromorphone (2) (48 mg, 0.11 mmol)
was treated with Et2O‚HCl in a minimum amount of CH2Cl2.
The resulting precipitate was crystallized from MeOH-Et2O
1
to give 2‚HCl (48 mg, 90%): mp 240 °C dec; H NMR (CD3-
OD) δ 7.52-7.57 (t, 2H, J ) 7.2, H-Ph), 7.41-7.46 (m, 1H,
H-Ph), 7.32-7.34 (d, 2H, J ) 7.2, H-Ph), 7.07-7.09 (m, 3H,
H-Ph), 6.80 (s, 2H, H-1,2), 6.53-6.56 (m, 2H, H-Ph), 5.23 (s,
1H, H-5), 4.06-4.08 (m, 1H, H-9), 3.19-3.34 (m, 2H, H-10,
H-D ring), 3.04-3.19 (m, 2H, H-10, H-D ring), 2.91 (s, 3H,
H-NMe), 2.91-2.96 (m, 1H, H-14), 2.77-2.83 (dd, 1H, J ) 3.6,
14.7, H-8â), 2.03-2.13 (t, 1H, J ) 13.6, H-8R), 1.84-1.96 (m,
2H, H-D ring); 13C NMR (CD3OD) δ 207.77, 144.70, 143.04,
141.18, 137.96, 130.13, 129.11, 128.59, 128.55, 127.93, 127.14,
125.96, 121.65, 121.31, 119.26, 90.86, 63.28, 61.84, 45.30,
40.78, 35.06; MS (FAB) m/ z 438.2 [M + H]+; Anal. Calcd for
C29H28NO3‚HCl‚2/3H2O: C, 69.98; H, 6.36; N, 3.40; Cl, 8.61.
Found: C, 69.98; H, 6.52; N, 3.21; Cl, 8.45.
6â,7-Dip h en ylm or p h in e (3). Boron tribromide in CH2Cl2
(1 M, 1.2 mL, 1.2 mmol) was added over 5 min to a solution of
7,7-diphenylhydrocodone (1) (168 mg, 0.37 mmol) in CH2Cl2
(5 mL). After stirring for 25 min at room temperature, the
reaction was quenched with methanol (5 mL) and stirred for
30 min. The mixture was adjusted to pH 8 with aqueous
KHCO3 (10%), extracted with CH2Cl2-MeOH (95/5, 4 × 25
mL), and washed with water to pH 7. The solvent was
evaporated under reduced pressure, and the residue was
chromatographed on a spinning TLC (silica gel, 1 mm, 3/97,
MeOH-CH2Cl2) to afford 3 (84 mg, 52%): 1H NMR (CD3-
COCD3) δ 7.66-7.69 (m, 2H, H-Ph), 7.40-7.45 (m, 2H, H-Ph),
7r-Meth yl-7â-p h en ylh yd r om or p h on e (6) a n d 7-m eth yl-
6â-p h en ylm or p h in e (7). To a solution of 7R-methyl-7â-
phenylhydrocodone7 (5) (280 mg, 0.72 mmol) in CH2Cl2 was
added boron tribromide (2.8 mL, 2.8 mmol, 1 M in CH2Cl2)
over 5 min at 0 °C, and the mixture was stirred for 40 min.
Methanol (15 mL) was added, and the mixture was stirred for
another 40 min. The solution was adjusted to pH 8 with
saturated NaHCO3 (aq) and extracted with chloroform (3 ×
40 mL), and the solvent was removed to afford crude product
(290 mg). Chromatographic separation (spinning TLC, 2 mm
silica gel plate, 3% EtOH in CHCl3) afforded 6 (159 mg, 59%)

Novel Conversion of Ketones to Allylic Alcohols
J . Org. Chem., Vol. 61, No. 7, 1996 2469
and 7 (60 mg, 22%). 6: 1H NMR (CDCl3) δ 7.14-7.30 (m, 5H,
H-Ph), 6.61-6.71 (2d, J ) 8.4, 2H, H-1,2), 4.87 (s, 1H, H-5),
3.39 (m, 1H, H-9), 3.05-3.11 (d, J ) 18.3, 1H, H-10â), 2.82-
2.87 (m, 1H, H-14), 2.53-2.60 (m, 1H, H-D ring), 2.49 (s, 3H,
H-NMe), 2.42-2.49 (m, 1H, H-10R), 2.17-2.25 (m, 1H, H-8â),
1.79 (m, 1H, H-D ring), 1.16-1.66 (m, 1H, H-D ring), 1.40-
1.49 (t, J ) 13.5, 1H, H-8R), 1.14 (s, 3H, H-Me); MS (FAB)
m/ z 376.2 [M + H]+. Compound 6 (199 mg, 0.53 mmol) was
dissolved in CHCl3 (5 mL) and MeOH (2 mL) and treated with
Et2O‚HCl to afford crude hydrochloride, which then was
recrystallized (i-PrOH) to afford 6‚HCl (147 mg, 67%): mp 251
°C dec; MS (FAB) m/ z 376.2 [M - Cl]+. Anal. Calcd for
C24H25NO3‚HCl: C, 69.98; H, 6.36; N, 3.40; Cl, 8.61. Found:
C, 69.78; H, 6.52; N, 3.15; Cl, 8.43.
H-Me); 13C NMR (CDCl3) δ 215.76, 144.79, 144.17, 139.05,
129.14, 128.77, 128.62, 127.39, 125.83, 120.90, 118.29, 95.88,
59.87, 53.62, 46.88, 43.29, 39.87, 37.12, 32.10, 22.99, 20.95,
20.58; MS (FAB) m/ z 390.1 [M + H]+, m/ z 388.0 [M - H]-;
MS (HRFAB) m/ z 390.2054 (calcd for C25H28NO3 m/ z )
390.2069).
7r-P h en ylh yd r om or p h on e (12). Boron tribromide in
CH2Cl2 (1 M, 0.4 mL, 0.4 mmol) was added over 5 min to a
solution of 7R-phenylhydrocodone7 (8) (80 mg, 0.26 mmol) in
CH2Cl2 (5 mL). After stirring for 15 min at room temperature,
the reaction was quenched with methanol (5 mL) and stirred
for 30 min. The mixture was adjusted to pH 8 with aqueous
KHCO3 (10%), extracted with CH2Cl2-MeOH (95/5, 4 × 25
mL), and washed with water to pH 7. The solvent was
evaporated under reduced pressure, and the residue was
chromatographed on a spinning TLC plate (silica gel, 1 mm,
3/97, MeOH-CH2Cl2) to afford 12 (25 mg, 26%): 1H NMR
(CD3COCD3) δ 7.12-7.23 (m, 3H, 7-Ph), 6.94-6.98 (m, 2H,
H-Ph), 6.53-6.64 (2d, 2H, J ) 1.8, H-1,2), 4.95 (s, 1H, H-5),
3.89-3.95 (dd, 1H, J ) 4.2, 13.8, H-7â), 3.15-3.18 (m, 1H,
H-9), 2.97-3.03 (d, 1H, J ) 18.3, H-10), 2.83-2.89 (m, 1H,
H-14), 2.47-2.50 (m, 1H, H-D ring), 2.35 (s, 3H, H-Me), 2.29-
2.37 (dd, 1H, J ) 5.7,18.3), 2.13-2.17 (m, 1H, H-8â), 1.92-
1.99 (m, 1H, H-D ring), 1.62-1.65 (m, 1H, H-D ring), 1.55-
1.68 (m, 1H, H-8R). 7R-Phenylhydromorphone (12) (25 mg)
was treated with Et2O‚HCl in a minimum amount of CH2Cl2
(0.5 mL) and recrystallized twice from MeOH-ether to afford
12‚HCl (15 mg). 1H NMR (CD3OD): δ 7.19-7.30 (m, 3H,
H-Ph), 6.96-6.99 (m, 2H, H-ph), 6.75 (s, 2H, H-1,2), 5.119 (s,
1H, H-5), 3.96-4.02 (m, 1H, H-7â), 3.30-3.37 (m, 1H, H-D
ring), 3.20-3.25 (m, 1H, H-10), 3.02-3.11 (m, 1H, H-10), 3.00
(s, 3H, H-NMe), 2.80-2.90 (m, 1H, H-9), 2.40-2.50 (m, 1H,
H-D ring), 2.12-2.20 (m, 1H, H-8â), 1.99-2.06 (m, 1H, H-D
ring), 1.58-1.70 (m, 1H, H-8R); MS (FAB) m/ z 362 [M + H]+.
Anal. Calcd for C23H23NO3‚HCl‚1.5H2O: C, 65.01; H, 6.40; N,
3.29. Found: C, 65.16; H, 6.36; N, 3.29.
7r-P h en ylh yd r om or p h on e (12) a n d 6,7-Did eh yd r o-
4,5r-ep oxy-17-m eth yl-7-p h en ylm or p h in a n -6-on e (14). Re-
action of 7R-phenylhydrocodone 8 with boron tribromide. 7R-
Phenylhydrocodone7 (8) (220 mg, 0.587 mmol) in CH2Cl2 (10
mL) was treated with boron tribromide (1 M in CH2Cl2, 2.4
mL) at room temperature for 4 days under N2. Methanol (25
mL) was added, and the mixture was stirred for 30 min at
room temperature and then refluxed for 30 min. The solution
was adjusted to pH 8 with saturated NaHCO3 (aq) and
extracted with chloroform (4 × 30 mL). The organic layers
were combined and washed with water (20 mL), and the
solvent was removed under reduced pressure. The residue was
subjected to spinning TLC separation (silica gel, 2 mm plate)
by eluting with EtOH (5%) in CHCl3 to afford R,â-unsaturated
ketone 14 (26.8 mg, 12.7%) and 7R-phenylhydromorphone (12)
(17.8 mg, 8.3%). 14: 1H NMR (CDCl3) δ 7.18-7.23 (m, 3H,
H-Ph), 7.05-7.08 (m, 2H, H-Ph), 6.81 (d, J ) 1.8, 1H, H-8),
6.48-6.60 (2d, J ) 8.1, 2H, H-1,2), 4.82 (s, 1H, H-5), 3.51-
3.54 (dd, J ) 3, 5.7, 1H, H-9), 3.36-3.38 (m, 1H, H-14), 3.03-
3.09 (d, J ) 18.0, 1H, H-10), 2.40 (m, 3H, H-NMe), 1.54 (s,
3H, H-Me); 13C NMR (CDCl3) δ 193.3, 147.7, 143.1, 139.5,
136.9, 130.6, 128.9, 128.8, 128.6, 128.4, 128.2, 126.1, 120.5,
117.9, 90.08, 59.50, 47.01, 43.54, 43.01, 41.40, 34.44, 30.36,
20.64; IR (KBr) 1733.8 (m, CdO) cm-1; MS (FAB) m/ z 360.2
[M + H]+; MS (HRFAB) m/ z 359.1524 (calcd for C23H21NO3
m/ z ) 359.1521).
1
7: H NMR (CDCl3) δ 7.19-7.43 (m, 5H, H-Ph), 6.53-6.64
(2d, J ) 7.8, 2H, H-1,2), 5.34 (m, 1H, H-8), 4.82 (s, 1H, H-5),
3.43 (m, 1H, H-9), 3.01-3.07 (d, J ) 18.9, 1H, H-10â), 2.77
(m, 1H, H-14), 2.54-2.57 (m, 1H, H-D ring), 2.46 (s, 3H,
H-NMe), 2.41-2.54 (m, 1H, H-D ring), 2.37 (m, 1H, H-10R),
1.85 (m, 1H, H-D ring), 1.65-1.70 (m, 1H, H-D ring), 1.56 (s,
3H, H-Me); 13C NMR (CDCl3) δ 19.92 (p), 21.07 (s), 36.21 (t),
41.30 (s), 43.43 (p), 43.91 (s), 47.37 (p), 59.80 (t), 75.41 (t), 97.35
(t), 118.32 (t), 120.92 (t), 124.81 (t), 126.29 (q), 127.03 (t),
128.24 (t), 129.36 (t), 131.42 (q), 139.21 (q), 141.82 (q), 143.56
(q), 144.80 (q); MS (FAB) m/ z 376.2 [M + H]+. 7-Methyl-6â-
phenylmorphine 7 (60 mg, 0.16 mmol) was dissolved in
CHCl3-MeOH (4 mL, 3:1), and Et2O‚HCl was added to afford
crude hydrochloride which was recrystallized (i-PrOH--Et2O)
to afford 7‚HCl (41 mg, 62%): mp ) 237 °C dec; MS (FAB)
m/ z 376.2 [M-Cl]+. Anal. Calcd for C24H25NO3‚HCl: C, 69.98;
H, 6.36; N, 3.40; Cl, 8.61. Found: C, 69.98; H, 6.52; N, 3.21;
Cl, 8.45.
7â-Meth yl-7r-p h en ylh yd r ocod on e (9). To a solution of
7R-phenylhydrocodone7 (8) (220 mg, 0.58 mmol) in THF (15
mL) was added lithium bis(trimethylsilyl)amide (1 M in THF,
2.0 mL, 2.00 mmol) and 12-crown-4 (100 mg, 0.57 mmol) at
-23 °C, and the resulting solution was stirred for 5 min.
Methyl iodide (123 mg, 0.86 mmol) was added over 5 min, and
the reaction was stirred for 23 h. Triethylamine (3 mL) was
added, and the resulting mixture was kept at 50-60 °C for 4
h. Upon filtration, the filtrate was removed at reduced
pressure and the residue was subjected to spinning TLC
separation (silica gel, 1 mm) with the elution of EtOH (4%) in
CHCl3 to afford compound 9 (48%). 1H NMR (CDCl3) δ 7.18-
7.26 (m, 3H, H-Ph), 6.99-7.00 (m, 2H, H-Ph), 6.68-6.67 (2d,
J ) 8.1, 2H, H-1,2), 5.05 (s, 1H, H-5), 3.91 (s, 3H, H-OMe),
3.38 (m, 1H, H-9), 3.05-3.12 (d, J ) 18.3, 1H, H-10), 2.59 (s,
3H, H-NMe), 1.70 (s, 3H, H-Me); MS (FAB) m/ z 390.1 [M +
H]+.
7â-Meth yl-7r-p h en ylh yd r om or p h on e (10) a n d 5â,7â-
d im eth yl-7r-p h en ylh yd r om or p h in e (11). A CH2Cl2 solu-
tion (1 M) of boron tribromide (0.6 mL, 0.6 mmol) was added
over 5 min to a solution of 7â-methyl-7R-phenylhydrocodone
(9) (60 mg, 0.15 mmol) in CH2Cl2 at 0 °C. After stirring for
45 min, methanol (10 mL) was added, and the mixture was
stirred for 1 h. The solution was washed with saturated
NaHCO3 (aq) and extracted with chloroform (3 × 30 mL), and
the solvent was removed in reduced pressure. Chromato-
graphic separation on a spinning TLC (1 mm silica gel plate,
eluted with EtOH (1%) in CHCl3 afforded 10 (17 mg, 29%) and
11 (9 mg, 15%). 10: 1H NMR (CDCl3) δ 7.19-7.25 (m, 5H,
H-Ph), 6.94-6.97 (2d, J ) 8.4, 2H, H-1,2), 4.93 (s, 1H, H-5),
3.26 (m, 1H, H-9), 3.02-3.09 (m, 1H, H-10â), 2.46 (s, 3H,
H-NMe), 1.61 (s, 3H, H-Me); MS (FAB) m/ z 376.1 [M + H]+,
m/ z 374.1 [M - H]-. Compound 10 was dissolved in CHCl3
(3 mL), treated with Et2O‚HCl, and filtered. After recrystal-
lization twice from i-PrOH, 10‚HCl was collected: mp ) 234-
240 °C dec; MS (FAB) m/ z 376.2 [M - Cl]+. Anal. Calcd for
C24H25NO3‚1.5HCl: C, 66.45; H, 6.18; N, 3.22. Found: C,
66.51; H, 5.89; N, 3.19.
Ack n ow led gm en t. We thank the National Institute
on Drug Abuse for funding this research.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of 4, 9, 11, and 14 (4 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
11: 1H NMR (CDCl3) δ 7.15-7.22 (m, 3H, H-Ph), 6.78-6.81
(m, 2H, H-Ph), 6.66-6.76 (2d, J ) 7.8, 2H, H-1,2), 3.27-3.28
(m, 1H, H-9), 2.99-3.06 (d, J ) 18.3, 1H, H-10â), 2.79-2.85
(m, 1H), 2.66-2.71 (m, 1H), 1.69 (s, 3H, H-Me), 1.61 (s, 3H,
J O951526I