One-pot conversion of thebaine to hydrocodone and synthesis of neopinone ketal

Article abstract of DOI:10.1021/jo802454v

The ethylene glycol ketal of neopinone was prepared in a one-pot procedure by the reaction of thebaine with ethylene glyocol in the presence of p-toluenesulfonic acid. The ketal is also an intermediate in the conversion of thebaine to hydrocodone with ethylene glycol and Pd(OAc)₂, followed by hydrogenation. Additionally, a one-pot procedure for the conversion of thebaine to hydrocodone was achieved by employing palladium catalysis in aqueous medium. Palladium serves a dual purpose in this transformation, first for the activation of the dienol ether of thebaine and second as a hydrogenation catalyst. This procedure was found to be comparable to the two-step protocol which employs diimide reduction of thebaine followed by acid-catalyzed hydrolysis of the resulting 8,14-dihydrothebaine to hydrocodone. Experimental and spectral data are provided for all compounds.

Full text of DOI:10.1021/jo802454v

One-Pot Conversion of Thebaine to Hydrocodone and Synthesis of
Neopinone Ketal
Robert J. Carroll,† Hannes Leisch,† Lena Rochon,† Tomas Hudlicky,*,† and D. Phillip Cox‡
Department of Chemistry and Centre for Biotechnology, Brock UniVersity, 500 Glenridge AVenue, St.
Catharines, ON, Canada, L2S 3A1, and Noramco Inc., 503 Carr Road, Suite 200, Wilmington, Delaware 19809
thudlicky@brocku.ca
ReceiVed September 22, 2008
The ethylene glycol ketal of neopinone was prepared in a one-pot procedure by the reaction of thebaine
with ethylene glyocol in the presence of p-toluenesulfonic acid. The ketal is also an intermediate in the
conversion of thebaine to hydrocodone with ethylene glycol and Pd(OAc)2, followed by hydrogenation.
Additionally, a one-pot procedure for the conversion of thebaine to hydrocodone was achieved by
employing palladium catalysis in aqueous medium. Palladium serves a dual purpose in this transformation,
first for the activation of the dienol ether of thebaine and second as a hydrogenation catalyst. This procedure
was found to be comparable to the two-step protocol which employs diimide reduction of thebaine followed
by acid-catalyzed hydrolysis of the resulting 8,14-dihydrothebaine to hydrocodone. Experimental and
spectral data are provided for all compounds.
Introduction
production quota is 126 metric tons.3 Consumption of morphine-
derived antagonists is expected to grow with the recent approvals
of naltrexone (Vivitrex) for treatment of alcoholism, buprenor-
phine for the treatment of addiction, and methylnaltrexone for
treatment of constipation,4 induced by the use of opiate-derived
analgesics.
Thebaine, usually a minor constituent of opium latex, is
isolated as a major component from genetically engineered
hybrids introduced by the company Tasmanian Alkaloids.5
Thebaine, an ideal precursor to most C-14 hydroxylated
derivatives, is easily transformed to 14-hydroxycodeinone by
treatment with formic acid and hydrogen peroxide, according
to the procedure first used by Freund and Speyer in 1916,6 by
Seki in 1960,7 and further refined in more recent applications.8
The supply of morphine and morphine-derived products in
medicine depends on the isolation of major constituents of the
opium poppy such as morphine (1), codeine (2), and thebaine
(3) (Figure 1).1 These alkaloids can be converted by semisyn-
thesis to other medicinally useful agents such as hydrocodone
(4), oxycodone (5), naltrexone (6), and naloxone (7). Morphine
is employed in anesthesia and pain control, and in the U.S. alone,
approximately 35 tons of morphine sulfate are supplied for this
purpose. The worldwide consumption is estimated at 400 tons/
annum.2 The world market for oxycodone and hydrocodone is
estimated at more than 80 tons/annum, and the consumption of
associated antagonists in the U.S. is about 1 ton/annum, all
derived from morphine, codeine, or thebaine, whose U.S.
† Brock University.
(3) For production quotas of morphine alkaloids for the U.S., see: http://
www.deadiversion.usdoj.gov/quotas/quota_history.htm.
‡ Noramco Inc.
(1) (a) Zezula, J.; Hudlicky, T. Synlett 2005, 388. (b) Novak, B. H.; Hudlicky,
T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, 343. (c)
Butora, G.; Hudlicky, T. Organic Synthesis: Theory and Applications; Hudlicky,
T., Ed.; JAI Press: Stamford, CT, 1998; Vol. 4, pp 1-51. (d) Hudlicky, T.;
Butora, G.; Fearnley, S.; Gum, A.; Stabile, M. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1996; Vol. 18, p 43.
(2) Report of the International Narcotics Control Board for 2005, ISBN 92-
1-148209-7 ISSN 0257-3717, Page 17.
(4) The Electronic Orange Book, http://www.fda.gov/cder/ob/default.htm,
U.S. Department of Health and Human Services, Food and Drug Administration,
Center for Drug Evaluation and Research,Office of Pharmaceutical Science,
Office of Generic Drugs.
(5) (a) Millgate, A. G.; Pogson, B. J.; Wilson, I. W.; Kutchan, T. M.; Zenk,
M. H.; Gerlach, W. L.; Fist, A. J.; Larkin, P. J. Nature 2004, 431, 413. (b) Fist,
A. J.; Byrne, C. J.; Gerlach, W. L. US 6067749; US 6376221; US 6723894.
(6) Freund, M.; Speyer, E. J. Prakt. Chem. 1916, 94, 135.
10.1021/jo802454v CCC: $40.75
Published on Web 12/11/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 747–752 747

Carroll et al.
FIGURE 1. Opium constituents and their derivatives derived by semisynthesis.
FIGURE 2. Production of hydrocodone from thebaine and synthesis of neopinone ketals.
Most C-14 hydroxylated derivatives are accessible through this
or similar procedures. Recent guidelines from the International
Conference on Harmonization (ICH) limit the amount of R,ꢀ-
unsaturated-ketone-containing compounds in pharmaceutical
preparations necessitating new routes to Active Pharmaceutical
Ingredients (APIs) that avoid the production of such intermedi-
ates and/or impurities.9 A logical alternative intermediate for
C-14 hydroxylations is a ꢀ,γ-unsaturated species such as
neopinone and its derivatives, which still offer the potential for
functionalization of C-14 via selective transformations of the
C-8/C-14 olefin. Here we report the transformation of thebaine
to the neopinone ketals 10 and 11 and a one-pot conversion of
FIGURE 3. Deconjugation of R,ꢀ-enones via their ketals.
thebaine to hydrocodone (Figure 2).
nation at the R-position and subsequent intra- or intermolecular
trapping of the oxonium ion, as, for example, in the generation
of ketal 14 during Heathcock’s 1971 synthesis of R-bulnesene
(Figure 3).12 It is evident that protonation of 13 at the R-position
to 15 is immediately followed by rapid intramolecular closure
of 15 to 14 and that the isomerization of the ꢀ,γ-olefin into
conjugation in 16 does not occur. The probability of the
preferential formation of the deconjugated isomers such as 14
is higher when ethylene glycol (in preference to MeOH or
EtOH) is used because the trapping of oxonium ion 15 is
intramolecular.
Results and Discussion
The conversion of thebaine to neopinone ketal 12 was
demonstrated by Rapoport10 and Dauben,11 who used mercuric
acetate to activate the dienol ether at the kinetically favored
R-position, as shown in Scheme 1. Although a direct conversion
of thebaine to its ketal under acid-catalyzed equilibrium
conditions has not previously been reported, it is well-established
that dienol ethers or R,ꢀ-unsaturated ketones can be converted
to the corresponding ꢀ,γ-unsaturated ketals via kinetic proto-
(7) Seki, I. Takamine Kenkyusho Nempo 1960, 12, 52. [CA:55:38149].
(8) (a) Krassnig, R.; Hederer, C.; Schmidhammer, H. Arch. Pharm. 1996,
329, 325. (b) Francis, C. A.; Lin, Z.; Kaldahl, C. A.; Antczak, K. G.; Kumar, V.
US 2005/0038251 A1. (c) Casner, M. L.; Dung, J. S.; Keskeny, E. M.; Luo, J.;
Lo´pez, D.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 2000, 65, 4671 US
2006111383; alternative methods for C-14 hydroxylation include a photochemical
approach.
(9) (a) ICH safety guidelines (ICH S2A, 1995;ICH S2B, 1997). (b) Mueller,
L.; Mauthe, R. J.; Riley, C. M.; Andino, M. M.; De Antonis, D.; Beels, C.;
DeGeorge, J.; De Knaep, A. G. M.; Ellison, D.; Fagerland, J. A.; Frank, R.;
Fritschel, B.; Galloway, S.; Harpur, E.; Humfrey, C. D. N.; Jacks, A. S.; Jagota,
N.; Mackinnon, J.; Mohan, G.; Ness, D. K.; O’Donovan, M. R.; Smith, M. D.;
Vudathala, G.; Yotti, L. Regul. Toxicol. Pharmacol. 2006, 44, 198.
(10) Barber, R.; Rapoport, H. J. Med. Chem. 1976, 19, 1175.
(11) Dauben, W. G.; Baskin, C. P.; Van Riel, H. C. H. A. J. Org. Chem.
1979, 44, 1567.
Exposure of thebaine to ethylene glycol in chloroform in the
presence of TsOH led to its conversion to the corresponding
ketal 10 in ∼40% yield, accompanied by a minor product,
phenolic in nature, but not positively identified (Scheme 2). To
our knowledge, the unsaturated ethylene glycol ketal 10, derived
from neopinone, has not been previously reported. The ∆7-8
isomeric ketal was not detected in the reaction mixture.
Encouraged by this result, we converted 10 to 17 by hydrogena-
tion at atmospheric pressure. Acid-catalyzed hydrolysis of 17
yielded hydrocodone 4 according to a previously published
(12) Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746.
748 J. Org. Chem. Vol. 74, No. 2, 2009

One-Pot ConVersion of Thebaine to Hydrocodone
SCHEME 1. Mercuric Acetate Mediated Formation of Neopinone Ketal 12 from Thebaine (3)
SCHEME 2. Formation of Neopinone Ketal 10 and Its Conversion to Hydrocodone (4)
TABLE 1. Reaction Conditions for the Formation of Neopinone Ketal 10
entry
conditionsa
thebaine consumption (%)
yield of 10 (%)b
1
2
3
4
5
6
7
8
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, CHCl3
100
65
38 (isolated)
17
N/A
N/A
N/A
16
20
21
6
8
10
12
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, CHCl3, 4Å MS
3.3 equiv of polyphosphoric acid, 10 equiv of glycol, CHCl3
3.3 equiv of oxalic acid ·2H2O, 10 equiv of glycol, CHCl3
3.3 equiv of acetic acid (glacial), 10 equiv of glycol, CHCl3
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, EtOAc
100
100
100
100
100
100
59
100
100
100
100
100
100
100
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, EtOAc, 4Å MS
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, EtOAc, 4Å MS, 0.16 M
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, EtOAc, 4Å MS, 5 h, 0.04 M
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, EtOAc, 4Å MS, 0.04 M
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, PhMe, 40 °C
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, PhMe, 60 °C
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, PhMe, 110 °C
3.3 equiv of TsOH ·H2O, 10 equiv of glycol, 1,2-dichlorobenzene
5 equiv of TsOH ·H2O, 10 equiv of glycol, CHCl3
9
10
11
12
13
14
15
16
multiple products
8
36
17
10 equiv of TsOH ·H2O, 10 equiv of glycol, CHCl3
a All reactions were carried out at reflux of the stated solvent for 45 min unless otherwise noted. b Based on 1H NMR of crude product after
workup.
procedure.13 Subsequently, we have demonstrated that 10 can
be directly converted to 4 by means of a one-pot hydrogenation
and hydrolysis procedure.
When Pd(OAc)2, in the presence of ethylene glycol, was
used with the dual purpose of acting initially as a proton
surrogate and later as a hydrogenation catalyst, hydrocodone
was obtained in a one-pot sequence from thebaine in 17%
yield at the expense of the formation of dihydrothebainone
(19)15 (Scheme 3). Addition of Pd(OAc)2 to a solution of
thebaine in ethylene glycol and chloroform resulted in the
formation of a deep-red-colored reaction mixture. After 2 h,
the mixture was hydrogenated at 1 atm for 4 h and finally
aqueous H2SO4 in MeOH was introduced for the final
hydrolysis to 4. We assumed the intermediacy of 18 as the
species present immediately before hydrogenation and rea-
soned that the ketalization step could be avoided altogether
if an intermediate of type 20 could be generated from thebaine
in aqueous media under palladium catalysis. Indeed, treatment
of thebaine in aqueous THF with Pd(OAc)2 led rapidly to
the formation of the presumed intermediate 20 (dark red in
color), which was immediately treated with hydrogen at
atmospheric pressure to yield hydrocodone 4 in 43% yield,
with the attendant diminishment of dihydrothebainone 19.
The incompatibility of thebaine with strong protic acids is
well-documented,14 and we have observed competing acid-
induced pathways during the synthesis of 10, hence the modest
yield of the ketal, despite focused attempts at optimization of
conditions for this reaction, as summarized in Table 1.
We therefore examined alternative conditions for the conver-
sion of the enol ether of thebaine to its ketal in order to generate
10. The use of bromine as a “pseudoproton” in the presence of
ethylene glycol led to the perbrominated ketal 11 (proposed
structure, tentatively assigned by NMR and low resolution mass
spectrometry), which is potentially convertible to hydrocodone
by hydrogenation and hydrolysis (Scheme 3). Because of the
rather low yield (27%) of this material, we have not further
converted 11 to hydrocodone and pursued instead investigations
of other conditions, namely, palladium-catalyzed reactions of
the dienol ether moiety in thebaine.
(13) Trauner, D.; Bats, J. W.; Werner, A.; Mulzer, J. J. Org. Chem. 1998,
63, 5908.
(14) For examples, see: (a) Conroy, H. J. Am. Chem. Soc. 1955, 77, 5960.
(b) Batterham, T. J.; Bell, K. H.; Weiss, U. Aust. J. Chem. 1966, 19, 321, and
references cited therein.
(15) Moos, W. H.; Gless, R. D.; Rapoport, H. J. J. Org. Chem. 1983, 48,
227.
J. Org. Chem. Vol. 74, No. 2, 2009 749

Carroll et al.
SCHEME 3. Preparation of Hydrocodone 4 from Thebaine 3
Literature reports and patents from the 1920s16 and 1930s17
revealed that thebaine was previously converted to hydroc-
odone by hydrogenation over platinum and palladium in
acidic medium. In one report,16b “...thebaine is treated in the
presence of a catalyser, especially palladium, platinum, or
their salts in comparatively large amounts and preferably in
the form of ‘black’...” to furnish hydrocodone in unspecified
yield for the conversion. A later publication in 1935 from
Goto and Shishido17 reported the hydrogenation of thebaine
to hydrocodone, dihydrothebainone 19 and, metathebainone
2118 in acidic medium, with the yield of hydrocodone esti-
mated from the data provided being about 30%. We examined
the hydrogenation of thebaine under palladium catalysis in
detail in order to provide for optimum conditions, as shown
in Table 2, and the process was reduced to a one-pot
procedure for the conversion of thebaine to hydrocodone.
Treatment of thebaine in 10-20% aqueous HCl under 1 atm
of hydrogen in the presence of 5% w/w Pd/C (10%) provided
hydrocodone 4 in 63% yield, along with dihydrothebainone
19 (20%) and tetrahydrothebaine 22 (8%) (Scheme 3).
Tetrahydrothebaine 22 was first isolated by Schopf in 1927,19
and considerable amounts were detected in previous hydro-
genation studies of thebaine using homogeneous hydrogen
catalysts in our own laboratory.20 The formation of meta-
thebainone 21 was observed in significant amounts when
platinum on charcoal was used as catalyst (Table 2).
Conclusions
The one-pot synthesis of hydrocodone in 63% yield from
thebaine compares favorably with previously reported protocols.
Grew and Robertson21 reported 88% yield for the two-step
(16) (a) Knoll & Co DE 441613. (b) Knoll & Co GB 225,824.
(17) Goto, K.; Shishido, H. Bull. Chem. Soc. Jpn. 1935, 10, 597.
(18) (a) Cahn, R. S. J. Chem. Soc. 1933, 1038. (b) Bentley, K. W.; Dyke,
S. F.; Marshall, A. R. Tetrahedron 1965, 21, 2553.
(19) (a) Schopf, C. Ann. 1927, 452, 232. (b) Janssen, R. H. A. M.; Wijkens,
P.; Kruk, C.; Biessels, H. W. A.; Menichini, F.; Theuns, H. G. Phytochemistry
1990, 29, 3331.
(20) Leisch, H.; Carroll, R. J.; Hudlicky, T.; Cox, D. P. Tetrahedron Lett.
2007, 48, 3979.
(21) Grew, E. L.; Robertson, A. A. US 3812132.
750 J. Org. Chem. Vol. 74, No. 2, 2009

One-Pot ConVersion of Thebaine to Hydrocodone
TABLE 2. Hydrogenation of Thebaine 4 in Aqueous Acidic Solution
meta-
thebainone (21)
tetrahydro-
thebaine (22)
entry
conditionsa
hydrocodone (4)
dihydrothebainone (19)
1
2
3
4
5
6
7
Pd/C (10%), H2 (1 atm), 20% aqueous HCl, 18 h
Pd/C (10%), H2 (2 atm), 20% aqueous HCl, 18 h
PdO, H2 (1 atm), 20% aqueous HCl, 18 h
PtCl2, H2 (1 atm), 20% aqueous HCl, 18 h
Pt/C (5%), H2 (1 atm), 20% aqueous HCl, 18 h
Pd/C (10%), H2 (1 atm), 20% aqueous HCOOH, 18 h
Pt/C (1%), vanadium doped, 20% aqueous HCl,
H2 (1 atm), 18 h
63%
62%
58%
13%
40%
0%
8%
8%
14%
4%
6%
0%
0%
0%
0%
14%
0%
75%
20%
25%
19%
13%
30%
18%
5%
73%
0%
15%
a All reactions were carried out with 5 wt % of catalyst loading.
(d, J ) 1.1 Hz, 1H), 2.47 (s, 3H), 2.14 (dd, J ) 16.2, 6.4 Hz,
1H), 2.06 (td, J ) 12.5, 5.0 Hz, 1H), 1.85 (dd, J ) 12.3, 1.9
Hz, 1H); 13C NMR (CDCl3, 125.5 MHz) δ 145.6, 142.1, 138.4,
131.8, 127.2, 119.4, 113.8, 113.2, 108.1, 93.1, 66.7, 65.4, 61.2,
56.8, 45.9, 45.8, 42.2, 36.2, 32.7, 26.8; MS (EI) m/z (%) 342
(23.1), 341 (100.0), 326 (10.0), 269 (10.6), 268 (21.24), 255
(17.5), 254 (52.4), 240 (10.0), 226 (14.5), 212 (11.1), 85 (22.2),
83 (34.4), 42 (18.4); HRMS (EI) calcd for C20H23NO4 341.1627;
found 341.1621.
conversion of thebaine to hydrocodone via diimide reduction
followed by hydrolysis. In our hands, the repetition of this
procedure yielded hydrocodone in ∼65%. Our lower yield may
be rationalized by the difference in the scale of this experiment.
The patented process was performed on 62 g of technical
thebaine (99%), while our repetition was done on a 100 mg
scale. The major advantage of our method is the fact that the
one-pot protocol is performed in aqueous medium (as opposed
to morpholine, ethanolamine, or a mixture of 2-methoxyethanol
and ethanolamine).
The ethylene glycol derived ketal of neopinone was prepared
in modest yield (∼40%), due to the known instability of thebaine
to protic acids. The corresponding neopinone ketal derived from
methanol was prepared by Rapoport in 85% yield by treating
thebaine with Hg(OAc)2 in MeOH, followed by reduction with
borohydride or formic acid.10 Clearly, further improvements in
the preparation of neopinone ketal 10 would be required for
this material to be used for either hydrocodone synthesis via
hydrogenation and hydrolysis or the preparation of C-14
hydroxylated analogues. The hydrolysis of 8,14-dihydroneopi-
none ketal 17 was reported by Mulzer in 95%.13 Our repetition
of this procedure provided hydrocodone in ∼75% yield when
Mulzer’s conditions (3 N HCl(aq) at 90 °C) were used. The
same transformation was achieved in 77% yield by treating the
ketal intermediate with aqueous H2SO4 in methanol at room
temperature.
(5r)-Cyclic-1,2-ethanediyl acetal-4,5-epoxy-3-methoxy-17-me-
thylmorphinan-6-one (17). A solution of 10 (100 mg, 0.3 mmol)
in CHCl3 (1 mL) was treated with Pt/C (10%) under H2 (1 atm)
for 16 h. Filtration through a plug of silica and elution with
CHCl3/MeOH/NH4OH, 92:8:1 gave the title compound in
quantitative yield. Data (1H and 13C NMR spectra) for 17
matched closely to those published in the literature:13 Rf 0.55
(DCM/MeOH/NH4OH, 96:4:1); FTIR (film) νmax 2941, 2926,
2889, 1636, 1611, 1502, 1441, 1325, 1275, 1258, 1190, 1155,
1
1060, 922 cm-1; H NMR (CDCl3, 600 MHz) δ 6.67 (d, J )
8.2 Hz, 1H), 6.55 (d, J ) 8.2 Hz, 1H), 4.42 (s, 1H), 4.12 (q, J
) 6.5 Hz, 1H), 3.97 (q, J ) 5.0 Hz, 1H), 3.78-3.85 (m, 5H),
3.72 (q, J ) 6.3 Hz, 1H), 3.01-3.05 (m, 1H), 2.93 (d, J ) 18.3
Hz, 1H), 2.44 (dd, J ) 12.1, 4.3 Hz, 1H), 2.33 (s, 3H), 2.27
(dd, J ) 18.2, 5.4 Hz, 1H), 2.09-2.17 (m, 2H), 1.79 (dt, J )
12.3, 4.9 Hz, 1H), 1.56-1.66 (m, 2H), 1.41-1.50 (m, 2H), 1.08
(td, J ) 12.7, 2.2 Hz, 1H); 13C NMR (CDCl3, 125.5 MHz) δ
146.6, 142.1, 129.2, 126.5, 118.6, 113.4, 108.6, 94.4, 66.4, 64.9,
59.5, 56.5, 47.1, 43.6, 42.9, 42.6, 36.5, 33.4, 22.3, 20.1; MS
(EI) m/z (%) 344 (23.3), 343 (100.0), 342 (13.4), 329 (14.4),
256 (11.4), 244 (17.2), 198 (11.1), 99 (86.9), 59 (16.5), 55 (12.0);
HRMS (EI) calcd for C20H25NO4 343.1784; found 343.1777.
Hydrocodone 4 (from 17). A solution of compound 17 (80 mg,
0.23 mmol) in 25% (v/v) solution of H2SO4/MeOH (0.5 mL) was
was stirred for 3 h. The pH of the solution was adjusted to 11 with
saturated aq K2CO3 and extracted with CHCl3 (5 mL × 3). The
combined organic extracts were dried over Na2SO4, filtered,
concentrated, and then the crude material was purified by column
chromatography (CHCl3/MeOH/NH4OH, 98:2:1) to yield 54 mg
of hydrocodone in 77% yield. All analytical data generated for
hydrocodone synthesized in this manner are identical with those
of an authentic sample.
Experimental Section
(5r)-Cyclic-1,2-ethanediyl acetal-8,14-didehydro-4,5-epoxy-3-
methoxy-17-methylmorphinan-6-one (10). Thebaine (0.5 g, 1.6
mmol) was dissolved in CHCl3 (0.9 mL), and freshly distilled
ethylene glycol (1.0 g, 16.1 mmol) was added. To this biphasic
mixture was added TsOH · H2O (1.0 g, 5.3 mmol) under vigorous
stirring. The reaction mixture was heated to reflux for 45 min,
cooled to 0 °C, and the pH was adjusted to 11 with saturated aq
K2CO3. The solution was extracted three times with CHCl3 (5
mL), and the organic layers were combined. Drying over
anhydrous Na2SO4, filtration, and evaporation of the solvent
provided a dark yellow residue, which was purified by flash
column chromatography (CHCl3/MeOH/NH4OH, 98:2:1) to
provide the title compound as a pale yellow oil in 38% yield: Rf
0.55 (DCM/MeOH/NH4OH, 96:4:1); FTIR (film) νmax 3407,
3031, 2924, 2903, 2833, 2791, 1634, 1603, 1504, 1448, 1325,
1277, 1258, 1165, 1050, 1035, 825 cm-1; 1H NMR (CDCl3, 600
MHz) δ 6.74 (d, J ) 8.2 Hz, 1H), 6.64 (d, J ) 8.2 Hz, 1H),
5.56 (d, J ) 5.6 Hz, 1H), 4.70 (s, 1H), 4.28 (q, J ) 6.2 Hz,
1H), 3.93 (q, J ) 6.8 Hz, 1H), 3.86-3.90 (m, 4H), 3.81 (q, J )
6.2 Hz, 1H), 3.64 (d, J ) 3.64 Hz, 1H), 3.26 (d, J ) 18.1 Hz,
1H), 2.67-2.78 (m, 2H), 2.61 (dd, J ) 12.6, 4.6 Hz, 1H), 2.50
Hydrocodone 4 (One-Pot Procedure from 10). A solution of 10
(45 mg, 0.13 mmol) in MeOH (90 µL) was treated with Pt/C (10%)
(1 mg) under H2 (1 atm) for 12 h. A 25% (v/v) solution of H2SO4/
MeOH (0.5 mL) was added to the reaction solution, which was
stirred for 3 h. The pH of the solution was adjusted to 11 with
saturated aq K2CO3 and extracted with CHCl3 (5 mL × 3). The
combined organic extracts were dried over Na2SO4, filtered,
concentrated, and then the crude material was purified by column
chromatography (CHCl3/MeOH/NH4OH, 98:2:1) to yield hydroc-
odone in 75% yield. All analytical data generated for hydrocodone
synthesized in this manner are identical with those of an authentic
sample.
Hydrocodone 4 (One-Pot Procedure from Thebaine). To the-
baine 3 (100 mg, 0.32 mmol) dissolved in THF (1 mL) and H2O
(22) The use of thebaine and other morphinans was carried out in accordance
with Health Canada guidelines and procedures [licence # 2006/7531].
J. Org. Chem. Vol. 74, No. 2, 2009 751

Carroll et al.
(1 mL) was added Pd(OAc)2 (72 mg, 0.32 mmol). After 2 h at
room temperature, the orange-red reaction solution contained no
thebaine as evidenced by TLC. Hydrogen was introduced to the
reaction vessel by use of a balloon, and the mixture was stirred for
4 h. Removal of the balloon and filtration of the suspension through
a plug of silica (CHCl3/MeOH/NH4OH, 92:8:1) gave the crude
products 4 and 19 in a ratio of 3:4. Purification of the crude material
was achieved by column chromatography (CHCl3/MeOH/NH4OH,
98:2:1) to yield 4 in 43% and 19 in 52% yield. All analytical data
generated for hydrocodone synthesized in this manner are identical
with those of an authentic sample of hydrocodone. Data (1H and
13C NMR spectra) for 19 are identical to those published in the
literature.15
compounds, which were purified by flash column chromatography
(CHCl3/MeOH/NH4OH, 98:2:1) to give hydrocodone 4 (63%),
dihydrothebainone 19 (20%), and tetrahydrothebaine 22 (8%). Data
for 22 (13C NMR spectra) are identical to those published in the
literature.19
(5r,6r)-4,5-Epoxy-3,6-dimethoxy-17-methylmorphinan (Tet-
rahydrothebaine 22): Rf 0.50 (DCM/MeOH/NH4OH, 96:4:1); FTIR
(film) νmax 3429, 2933, 2835, 1635, 1609, 1504, 1440, 1337, 1277,
1258, 1152, 1105, 1057 cm-1; 1H NMR (CDCl3, 600 MHz) δ 6.71
(d, J ) 8.2 Hz, 1H), 6.58 (d, J ) 8.2 Hz, 1H), 4.68 (d, J ) 5.0 Hz,
1H), 3.85 (s, 3H), 3.50-3.54 (m, 2H), 3.46 (s, 3H), 3.09-3.12
(m, 1H), 2.98 (d, J ) 18.5 Hz, 1H), 2.51-2.57 (m, 1H), 2.39-2.45
(m, 4H), 2.21-2.32 (m, 2H), 1.89 (dt, J ) 12.5, 4.9 Hz, 1H), 1.72
(dd, J ) 11.3, 1.1 Hz, 1H), 1.37-1.54 (m, 3H); 13C NMR (CDCl3,
125.5 MHz) δ 147.1, 141.8, 129.9, 126.4, 118.4, 113.5, 89.3, 76.9,
59.9, 58.2, 56.5, 46.9, 42.9, 42.3, 39.9, 37.1, 24.3, 20.1, 19.4; MS
(EI) m/z (%) 316 (18.3), 315 (87.3), 300 (42.5), 178 (15.0), 86
(68.8), 85 (75.8), 84 (97.1), 83 (100), 70 (18.3), 49 (30.5), 47 (53.5),
42 (19.9); HRMS (EI) calcd for C19H25NO3 315.1834; found
315.1831.
4-Hydroxy-3-methoxy-17-methylmorphinan-6-one (Dihydrothe-
bainone 19): Rf 0.35 (DCM/MeOH/NH4OH, 96:4:1); FTIR (film)
νmax 3401, 2935, 2839, 2243, 1710, 1604, 1583, 1483, 1439, 1277,
1228, 1062, 922 cm-1; 1H NMR (CDCl3, 600 MHz) δ 6.68 (d, J )
8.3 Hz, 1H), 6.60 (d, J ) 8.3 Hz, 1H), 4.25 (dd, J ) 13.3, 2.5 Hz,
1H), 3.82 (s, 3H), 3.13-3.16 (m, 1H), 2.98 (d, J ) 18.5 Hz, 1H),
2.76 (dd, J ) 18.5, 6.0 Hz, 1H), 2.60-2.64 (m, 1H), 2.46 (s, 3H),
2.41-2.45 (m, 1H), 2.31 (dt, J ) 12.8, 3.2 Hz, 1H), 2.23-2.28
(m, 2H), 2.12 (td, J ) 12.0, 4.1 Hz, 1H), 2.05 (s, 1H), 1.84-1.93
(m, 3H), 1.68 (qd, J ) 13.2, 5.0 Hz, 3H); 13C NMR (CDCl3, 125.5
MHz) δ 210.7, 145.1, 144.8, 129.7, 122.6, 118.5, 109.0, 57.0, 56.1,
50.4, 46.4, 44.3, 42.1, 41.0, 40.9, 38.0, 27.0, 23.8; MS (EI) m/z
(%) 302 (11.6), 301 (56.2), 300 (18.0), 242 (10.3), 164 (53.3), 88
(11.2), 86 (64.3), 84 (100.0), 60 (19.3), 59 (16.7), 49 (19.7), 47
(23.5), 45 (24.7), 44 (13.3), 43 (34.7), 42 (17.8); HRMS (EI) calcd
for C18H23NO3 301.1678; found 301.1671.
4-Hydroxy-3-methoxy-17-methyl-14,15-cyclo-13,15-seco-morphin-
5(13)-en-6-on (meta-Thebainone 21). Thebaine (100 mg, 0.32
mmol) was dissolved in an aq solution of 20% HCl (0.5 mL)
and Pt/C (1 wt %), and doped vanadium (16 mg) was added.
The reaction mixture was stirred under 1 atm of H2 at rt for
12 h, after which time the reaction mixture was basified with
NH4OH and extracted three times with DCM (2 mL). The organic
layers were combined, dried over anhydrous sodium sulfate, and
filtered. Evaporation of the solvent gave a mixture of compounds,
which was purified by flash column chromatography (DCM/
MeOH, 200:1 to 200:4) to give 14 mg (15%) of hydrocodone 4,
5 mg (5%) of tetrahydrothebaine 22, and 72 mg (75%, 90%
purity) of meta-thebainone 21: Rf 0.50 (DCM/MeOH/NH4OH,
96:4:1); IR (film) νmax 3306, 2927, 2851, 2782, 1727, 1650, 1601,
(5r)-1,7,10-Tribromocyclic-1,2-ethanediyl acetal-8,14-didehy-
dro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-one (11). The-
baine (50 mg, 0.16 mmol) was dissolved in THF (1 mL), and freshly
distilled ethylene glycol (100 mg, 1.61 mmol) was added. Bromine
(103 mg, 0.64 mmol) was added in a single portion, and the reaction
mixture was stirred for 10 h. A saturated aqueous solution of
Na2SO3 was added to remove excess bromine. The reaction was
cooled to 0 °C, and the pH was adjusted to 11 with saturated aq
K2CO3. The reaction solution was extracted five times with CHCl3
(5 mL), and the organic extracts were combined and dried over
anhydrous Na2SO4. Filtration and evaporation of the solvent gave
a crude mixture that was further purified by flash column chroma-
tography (CHCl3/MeOH, 200:1) to provide the title compound in
27% yield: Rf 0.60 (DCM/MeOH/NH4OH, 96:4:1); FTIR (film) νmax
2391, 2937, 2891, 1654, 1632, 1611, 1487, 1435, 1287, 1203, 1160,
1479, 1441, 1349, 1266, 1183, 1092, 1002 cm-1 1H NMR
;
(CDCl3, 600 MHz) δ 6.83 (d, J ) 8.0 Hz, 1H), 6.69 (d, J ) 8.0
Hz, 1H), 6.50 (s, 1H), 3.90 (s, 3H), 2.94-2.99 (m, 1H),
2.69-2.82 (m, 2H), 2.57 (dd, J ) 14.9, 3.6 Hz, 1H), 2.50-2.55
(m, 1H), 2.33 (s, 3H), 2.22-2.29 (m, 2H), 2.05-2.15 (m, 2H),
2.00 (ddd, J ) 13.3, 5.4, 2.1 Hz, 1H), 1.51-1.58 (m, 1H); 13C
NMR (CDCl3, 150 MHz) δ 199.6, 158.4, 145.5, 131.4, 126.2,
120.4, 118.7, 113.9, 111.7, 73.1, 56.2, 55.3, 46.6, 40.4, 35.0,
33.9, 33.8, 30.6; MS (EI) m/z (%) 299 (7.8), 149 (16.2), 88
(10.7), 86 (62.8), 84 (100), 57 (11.1), 49 (17.4), 47 (21.1), 43
(10.8); HRMS (EI) calcd for C18H21NO3 299.1521, found
299.1518.
1
1125, 1089, 1051, 909 cm-1; H NMR (CDCl3, 600 MHz) δ 6.92
(s, 1H), 5.88 (d, J ) 6.4 Hz, 1H), 5.25 (s, 1H), 4.61 (d, J ) 6.4
Hz, 1H), 3.94-3.99 (m, 1H), 3.88 (s, 3H), 3.81-3.87 (m, 1H),
3.61-3.64 (m, 1H), 3.11 (d, J ) 18.6 Hz, 1H), 3.04 (s, 3H),
2.70-2.79 (m, 1H), 2.56-2.68 (m, 2H), 2.50 (s, 3H), 2.37-2.43
(m, 1H), 1.76 (dd, J ) 12.8, 2.3 Hz, 1H); 13C NMR (CDCl3, 125.5
MHz) δ 145.2, 143.1, 132.3, 126.5, 117.0, 116.3, 112.0, 98.4, 92.0,
77.2, 64.4, 62.0, 60.1, 57.0, 49.5, 46.4, 45.3, 41.9, 35.1, 30.3; MS
(EI) m/z (%) 531 (M+ - CH2CH2O), 451, 435, 420, 407, 301, 217
(15.7), 216 (80.7), 188 (53.7), 187 (100), 171 (22.3), 145 (13.4),
118 (10.9), 117 (22.0), 90 (13), 86 (19.7), 84 (24.4), 78 (15.6), 71
(10.5), 57 (11.7), 55 (13.7), 47 (12.2), 44 (28.1), 43 (40.7), 42 (12.3),
41 (32.9).
Acknowledgment. The authors are grateful to Noramco, Inc.,
TDC Research, Inc., the Natural Sciences and Engineering
Research Council of Canada (NSERC), Canada Foundation for
Innovation (CFI), Ontario Innovation Trust (OIT), Research
Corporation, and Brock University for financial support of this
work. We also thank Brian Bullen, Chem Actives, Inc., and
Tasmanian Alkaloids, Inc., for the provision of morphine
alkaloids.22
1
Supporting Information Available: H NMR spectra of
Hydrocodone 4 via Pd/C Hydrogenation of Thebaine 3. The-
baine (100 mg, 0.32 mmol) was dissolved in 20% HCl (500 µL),
and Pd/C (10 wt %, 5 mg) was added. The reaction mixture was
stirred under H2 (1 atm) at room temperature for 12 h, then it was
made alkaline with NH4OH and extracted three times with DCM
(2 mL). The organic layers were combined, dried over sodium
sulfate, and filtered. Evaporation of the solvent gave a mixture of
compounds 3, 4, 10, 11, 17, 19, 21, and 22, and 13C NMR
spectra of compounds 10, 11, 17, 19, 21, and 22. This material
is available free of charge via the Internet at http://pubs.acs.
org.
JO802454V
752 J. Org. Chem. Vol. 74, No. 2, 2009