COMMUNICATIONS

DOI: 10.1002/adsc.201200676

Unexpected N-Demethylation of Oxymorphone and Oxycodone

N-Oxides Mediated by the Burgess Reagent: Direct Synthesis
of Naltrexone, Naloxone, and Other Antagonists from
Oxymorphone
Lukas Werner,a Martina Wernerova,a Ales Machara,a Mary Ann Endoma-Arias,a
Jan Duchek,a David R. Adams ,a D. Phillip Cox,b and Tomas Hudlickya,*
a
Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario
L2S 3A1, Canada
E-mail: thudlicky@brocku.ca
b
Noramco, Inc., 503 Carr Road, Suite 200, Wilmington, DE 19809, USA

Received: July 30, 2012; Published online: October 4, 2012

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200676.

Abstract: N-Oxides derived from oxycodone and
O-acyloxymorphone were treated with the Burgess
reagent to provide the corresponding oxazolidines
in excellent yields. Oxazolidines derived from O-
acyloxymorphone were further hydrolyzed to nor-
oxymorphone, whose alkylation furnished naltrex-
one, naloxone, and nalbuphone, which can be con-
verted to nalbuphine, the mixed agonist-antagonist
analgesic. The entire sequence from oxymorphone
to the various antagonists was reduced to three
one-pot operations, proceeding in excellent overall
yields. In addition, quaternary salts of the oxazoli-
dines with allyl or cyclopropylmethyl groups in
fixed equatorial configurations were synthesized.
Complete spectral and experimental data are pro-
vided for all compounds.
Keywords: Burgess reagent; N-demethylation of
oxycodone and oxymorphone; N-oxides of oxyco-
done and oxymorphone; synthesis of naltrexone,
naloxone, and nalbuphone
Various morphine antagonists[1] such as naltrexone
(1),[2] naloxone (2),[3,4] and nalbuphone (3) are avail-
able by semi-synthesis from the natural opiates such
as morphine (4), codeine (5), thebaine (6), or oripa-
vine (7), (see Figure 1). These compounds are used
extensively in medicine as antagonists (naltrexone
and naloxone) and mixed agonists/antagonists (nalbu-
phine). Naltrexone has long been used for the treat-
ment of alcoholism,[5,6] and is the active ingredient in
Vivitrol, an extended release injectable suspension
for the treatment of alcoholism and opioid depend-
ence.[7] Naloxone is the active ingredient in Narcan
for the reversal of opioid overdose[8,9] and is used to
mitigate side effects in combination with buprenor-
phine[10] (Suboxone)[11] for the treatment of opioid
addiction, with tilidine[12] (Valoron N) for the treat-
ment of pain and with oxycodone[13] (Targin)[14] for
the prophylaxis and/or treatment of opioid-induced
bowel dysfunction during the treatment of pain. Nal-
buphine[15] is the active ingredient in Nubain and is
used for the treatment of pain in very low doses par-
ticularly in women.

Figure 1. Semi-synthetic opiate derivatives and their natural progenitors.

2706  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2012, 354, 2706 – 2712
Unexpected N-Demethylation of Oxymorphone and Oxycodone N-Oxides
Their synthesis from naturally occurring opiates re-
quires several steps consisting of the oxidation of the
C-14 position and the eventual, seemingly trivial oper-
ation, the replacement of an N-methyl group with cy-
clopropylmethyl, allyl, or cyclobutylmethyl and other
alkyl groups, respectively.
The introduction of the C-14 hydroxy into various
natural morphinans to produce oxycodone (8) and
oxymorphone (9) has been reduced to practice on
large scales with high degrees of efficiency by oxida-
tion of thebaine or oripavine. Methods for direct C
H oxidation at C-14 for compounds such as codeine,
morphine, or hydrocodone have been reported but
are not very efficient or practical at this time. On the
other hand, N-demethylation of natural opiates still
represents a challenge, especially in terms of efficien-
cy or the focus on environmentally benign procedures
and reagents. Many methods have been employed for
the demethylation; these include the use of cyanogen
bromide (von Braun reaction),[17] methyl or ethyl
chloroformate,[18] 1-chloroethyl chloroformate (ACE-
Cl),[19] and microbial protocols,[20] including a recently
published procedure employing fungal biotransforma-
tions.[21] The biotransformations of several morphine
alkaloids with the strain Cunninghamella echinulata
and several others produced the free amines in rea-
sonable yields and purity. Such processes, when scaled
up and improved, would have great potential as envi-
ronmentally benign N-demethylation protocols.
Recently, iron(II)- as well as iron(0)-catalyzed N-
demethylation of several morphinan N-oxides was re-
ported by Scammells.[22] Smith et al.[23] developed
a method to convert N-methylated 6-oxo-14-hydroxy-
morphinanes to the corresponding nor compounds by
treating the N-oxide with an Fe(II)-based reducing
agent in the presence of formic acid to form an oxa-
zolidine. Conversion of the N-oxide to the corre-
sponding oxazolidine works equally well irrespective
of whether the 7,8 carbon bond is unsaturated or satu-
rated. Despite a host of methods available in the liter-
ature and in patents to accomplish this task there still
exists the need for an efficient conversion of various
morphinans to the medicinally important antagonists
as well as to other N-alkyl derivatives some of which
also have increased agonist activities.
Because the conversion of natural opiates to their
C-14 hydroxy derivatives is well established it would
be convenient to provide a direct conversion of oxy-
morphone to the corresponding antagonists via N-de-
methylation and alkylation. In this paper we report
a rather unexpected reaction of the Burgess reagent[24]
with N-oxides derived from oxymorphone and oxyco-
done to the corresponding oxazolidines and a high-
yielding conversion of the former compound to nal-
trexone, naloxone, and other antagonists.
The reactivity of the Burgess reagent, long associat-
ed only with the dehydration of alcohols, has been
Adv. Synth. Catal. 2012, 354, 2706 – 2712  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
tested in a variety of ways with other functional
groups. The synthesis of cis-fused sulfamidates was ac-
complished by the reaction of the Burgess reagent
with epoxides[25] and 1,2-diols.[26] The Burgess reagent
was shown to oxidize thiols to disulfides in high
yields.[27] New applications[28] as well as more thermal-
ly stable forms of this reagent[29] are being reported,
including its chiral auxiliary version,[30] and the re-
agent has been used extensively in natural product
syntheses.[31]
We examined the reaction of oxycodone N-oxide
10, derived from oxycodone, with the Burgess reagent
and found a clean conversion to oxazolidine 12 in sig-
nificantly higher yield than that quoted in the Smith
procedure, as shown in Scheme 1.
Presumably, the intermediate iminium species 11 is,
in the absence of a nucleophile, trapped, by the C-14
hydroxy group to form the oxazolidine. Such a process
would represent the (formally) forbidden 5-endo-trig
closure. An alternative to this closure would be trap-
ping of the iminium species with triethylamine and
a subsequent SN2-type alkylation, as shown below in
Scheme 2.[32]
This was a somewhat unexpected result, especially
in view of the recent report by Scammells, in which
11 was proposed as an intermediate in the ferrocene-
catalyzed demethylation of N-oxide 10.[33] In that
report nor-oxycodone was produced in 32% yield
with 23% recovery of oxycodone. No oxazolidine for-
mation was mentioned and formaldehyde was as-
sumed to be the by-product of hydrolysis of 11. The
oxazolidine should have been observed under the
conditions of the reaction, corresponding to the re-
sults reported by Smith but perhaps it was hydrolyzed
in situ and hence escaped detection.
Presumably, with the Burgess reagent the initial sul-
fonation occurs at the site of N-oxide and not at the
C-14 hydroxy group, which then serves to either trap
Scheme 1.
asc.wiley-vch.de 2707
 COMMUNICATIONS
Scheme 2.
the iminium ion or displace the triethylammonium
salt as shown above. However, the C-14 hydroxy
group may play some role in anchimeric assitance or
delivery of the reagent to the N-oxide. Attempts to
generate the iminium species of type 11 (and thus no-
rhydrocodone) from hydrocodone N-oxide with the
Burgess reagent were not successful. The procedure is
easily reduced to a one-pot protocol providing 12 as
a hygroscopic solid that can be used without further
purification.
The same protocol was applied to oxymorphone
(9), a more convenient starting material for the pro-
duction of various antagonists and other N-alkyl de-
rivatives. The phenol was protected as either acetate
(Ac2O was used) or ethyl carbonate (EtOCOCl was
Scheme 3.
Scheme 4.
2708 asc.wiley-vch.de  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Lukas Werner et al.
used) and the protected material was converted to N-
oxides 13a and 13b, whose exposure to the Burgess
reagent provided in high overall yields oxazolidines
15a (89–93%, 78% after crystallization) and 15b
(84%), Scheme 3.
Hydrolysis of the acetate or carbonate-protected
products 15a, b under either acidic or basic buffered
conditions furnished cleanly the free phenol (noroxy-
morphone) 16, which was alkylated to the known an-
tagonists as shown in Scheme 4. The entire process
from oxymorphone to naltrexone or naloxone can be
performed in just three operations (without purifica-
tion of intermediates) in an overall yield of 55–65%.
Finally, we have converted oxazolidine 12, derived
from oxycodone, to the quaternary salts 17 and 18
(allyl and cyclopropylmethyl, respectively). The prep-
aration of the cyclopropylmethyl salt 18 required ele-
vated temperature and DMF as the solvent. Oxazoli-
dine 15a was converted to the quaternary salts 19, 20,
and 21, respectively, as shown in Scheme 4. The alky-
lation with allyl bromide was carried out in nitrome-
thane and produced the quaternary salts 17 and 19 in
high yields. When cyclopropylmethyl bromide was
employed under these conditions only 22, the product
resulting from the opening of the oxazolidine ring
with nitromethane, was observed. The corresponding
derivative 20, containing the cyclopropylmethyl
group, was obtained in ca. 50% yield when the reac-
tion was carried out at elevated temperature in DMF
instead of nitromethane. The remaining mass balance
likely consisted of the hydrobromide of oxazolidine
15a. The cyclobutylmethyl derivative 21 could, in
principle, be obtained by a similar protocol.
Mild hydrolysis of 19 and 20 in aqueous methanol
or on wet silica gel furnished the corresponding oxa-
Adv. Synth. Catal. 2012, 354, 2706 – 2712
Unexpected N-Demethylation of Oxymorphone and Oxycodone N-Oxides
Scheme 5.
zolidine quaternary salts 23 and 24 in ca. 80% yield.
The compounds appeared to be bromide salts (vide
mass spectral analysis) although the possibility, during
the basic hydrolysis of the acetates, of ion exchange
for hydroxide and hence the equilibrium formation of
the inner salts of type 26 should be considered. All of
the salts have the alkyl substituent fixed in the equa-
torial position, as, for example, in the conformation of
(R)-methylnaltrexone. To the best of our knowledge
compounds of this type in which the C-14 hydroxy is
alkylated have not been investigated in detail for an-
tagonist/agonist activity. Further exploitation of the
chemistry described in this paper will involve the con-
version of quaternary salts such 20 or 24 directly into
(R)-methylnaltrexone by a reduction of the oxazoli-
dine bridge to a methyl group.
In preliminary experiments we attempted the re-
duction of the quaternary salt 20 under a variety of
conditions, including the activation of the C-14
oxygen with Lewis acids. We observed only the C-14
methyl ether 27 rather than (R)-methylnaltrexone, as
shown in Scheme 5. Clearly additional, and more de-
tailed, investigation is required in order to elicit the
cleavage of 20 to produce the desired quaternary salt.
Finally, we should compare the efficacy of this nal-
trexone synthesis by hydrolysis of oxazoline 15b and
alkylation of 16 versus the quaternization of 15 a and
Adv. Synth. Catal. 2012, 354, 2706 – 2712  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
hydrolysis of the salt 20 (Scheme 5). The results of
these and other endeavors will be reported in due
time.
We have demonstrated that a high-yielding method
for the N-demethylation of oxycodone and oxymor-
phone N-oxides becomes available by the reaction of
the N-oxides with the Burgess reagent. Several other
potential N-demethylating agents were examined for
this purpose but none were found to be more effec-
tive than the Burgess reagent. Thus oxycodone N-
oxide yielded oxazolidine 12 also on treatment with
TsCl (30%), CrO3 (44%) and DCC (50%). Treatment
of the N-oxide with CS2 or SeO2 resulted only in its
re-conversion to oxycodone.
The potential of this newly discovered reactivity of
the Burgess reagent in an improved manufacture of
opiate antagonists was demonstrated with the high-
yielding synthesis of naloxone and naltrexone from
oxymorphone. Finally, this work provides a unique
opportunity for the future exploration of biological
properties of the quaternary salts derived from the
oxazolidines.
asc.wiley-vch.de 2709
 COMMUNICATIONS
Experimental Section
3-Acetyloxymorphone N-Oxide (13a)
Oxymorphone (9) (600 mg, 1.99 mmol) was dissolved in tet-
rahydrofuran (8 mL). Solid K2CO3 (275 mg, 1.99 mmol) and
acetic anhydride (188 mL, 1.99 mmol) were then added and
reaction mixture was stirred at room temperature for 1.5 h.
TLC analysis (DCM/MeOH 95:5, double development)
showed only traces of starting material. The crude material
was subjected to the oxidation protocol without isolation
and furnished N-oxide 13 a as a solid: [a]20 D: 189.33 (c 1,
CHCl3); mp 160 8C (CHCl3); IR (KBr): n = 3449, 2968, 2938,
1764, 1726, 1685, 1654, 1627, 1495, 1444, 1373, 1287, 1219,
1193, 1161, 1111, 1044, 931, 629 cm 1; 1H NMR (CDCl3, 300
Mhz): d = 12.25 (bs, 1 H) 6.91 (d, 1 H, J = 8.4 Hz), 6.72 (d,
1 H, J = 8.1 Hz), 4.80 (s, 1 H), 3.60 (d, 1 H, J = 5.1 Hz), 3.36–
3.03 (m, 9 H), 2.31 (s, 3 H), 2.23 (td, 1 H, J = 3.0, 14.7 Hz),
1.96 (ddd, 1 H, J = 3.0, 4.8, 12.6 Hz), 1.71 (dd, 1 H, J = 3.9,
11.4 Hz), 1.58 (ddd, 1 H, J = 3.6, 14.1, 14.1 Hz); 13C NMR
(CDCl3, 75 MHz): d = 206.97, 168.31, 148.23, 133.53, 129.93,
125.90, 124.10, 119.84, 90.15, 75.44, 72.14, 61.51, 59.49, 49.77,
34.84, 32.62, 28.94, 25.82, 20.74; MS (FAB +): m/z (%) = 360
(100), 342 (20); HR-MS (FAB +): m/z = 360.14441, calcd.
for C19H22N1O6 : 360.14471.
(5aR,8aS,11aR,11bS)-2-Acetoxy-5,5a,9,10-tetrahydro-
6,11b-ethano-7H-furo[2’,3’,4’,5’:4,5]phenanthroACHTUNGRE[9,8a-
d]oxazol-11ACHTUNGRE(11aH)-one (15a): One-Pot Protocol
Oxymorphone (9) (600 mg, 1.99 mmol) was dissolved in tet-
rahydrofuran (8 mL). Solid K2CO3 (275 mg, 1.99 mmol) and
acetic anhydride (188 mL, 1.99 mmol) were then added and
the reaction mixture was stirred at room temperature for
1.5 h. TLC analysis (DCM/MeOH 95:5, double develop-
ment) showed only traces of starting material. The reaction
mixture was then cooled to approximately 48C (ice bath)
and a cold (4 8C) solution of mCPBA (446 mg, 1.99 mmol;
77% purity) in dichloromethane (6 mL) was added dropwise
over a period of 1 min. [The solution of mCPBA was pre-
pared by dissolving 669 mg mCPBA (77%) in dichlorome-
thane (9 mL) and adding MgSO4 (670 mg). The mixture was
agitated several times over a period of 30 min and cooled in
an ice-bath to 4 8C]. After stirring for 1 h a white precipitate
of N-oxide formed and the reaction mixture was cooled to
20 8C. Burgess reagent (593 mg, 2.49 mmol) in dichlorome-
thane (7 mL) was then cannulated at 20 8C into the reac-
tion mixture over a period of 2 min. The reaction mixture
was allowed to warm to 10 8C (3 h total reaction time) and
then diluted with ethyl acetate (100 mL) and washed with
an aqueous NaHCO3 solution (2  20 mL). The combined
aqueous layer was re-extracted with ethylacetate (2  20 mL)
and the combined organic layers were dried over MgSO4,
filtered, and concentrated to afford of reasonably pure (92–
95%) 15a; yield: 636 mg (93%). Crystallization of the prod-
uct from a mixture of EtOH/i-PrOH (1:1, 2 mL) from 25 8C
to 5–10 8C, afforded 520 mg (76%) of 15a. Repetition of the
experiment on a 1-g scale yielded 15a (78%) as a solid. Rf =
0.7 (DCM/MeOH/NH4OH 90:8:2); [a]20 D: 84.1 (c 1,
CHCl3); mp 179–182 8C (i-PrOH); IR (KBr): n = 2954, 2892,
2864, 2834, 1765, 1722, 1624, 1494, 1445, 1370, 1339, 1317,
1216, 1201, 1185, 1158, 1073, 1009, 958, 930, 889, 781 cm 1;
2710 asc.wiley-vch.de  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Lukas Werner et al.
1
H NMR (CDCl3, 600 MHz): d = 6.90 (d, 1 H, J = 8.2 Hz),
6.76 (d, 1 H, J = 8.4 Hz), 4.73 (d, 1 H, J = 6.0 Hz), 4.70 (d,
1 H, J = 6.0 Hz), 4.69 (s, 1 H), 3.37 (d, 1 H, J = 19.2 Hz), 3.27
(d, 1 H, J = 7.8 Hz), 3.17 (dd, 1 H, J = 7.8, 19.2 Hz), 2.89
(ddd, 1 H, J = 4.8, 14.4, 14.4 Hz), 2.80 (m, 2 H), 2.45–2.30 (m,
5 H), 1.98 (ddd, 1 H, J = 3.3, 4.2, 13.8 Hz), 1.67 (ddd, 1 H, J =
3.1, 14.4, 14.4 Hz), 1.56 (m, 1 H); 13C NMR (CDCl3,
150 MHz): d = 206.36, 168.57, 147.49, 132.45, 129.76, 128.65,
123.49, 119.97, 91.25, 86.53, 77.00, 63.95, 52.40, 44.23, 37.09,
34.09, 30.28, 27.13, 20.83; MS (+ EI): m/z (%) = 341 (8), 299
(100), 243 (7); HR-MS (+ EI): m/z = 341.12606, calcd. for
C19H19N1O5 : 341.12632.
Noroxymorphone (16)
A. Acetic acid buffer: Oxazolidine 15a (0.1 g, 0.29 mmol)
was suspended in AcOH/NH3 buffer (pH 9, 10% w/w,
1.5 mL) and heated for 16 h at 50 8C. The reaction mixture
was then cooled to room temperature and stirred for an ad-
ditional 2 h. A light brown precipitate was filtered off and
dried to afford noroxymorphone 16 as a brownish solid;
yield: 69 mg (82%); mp > 300 8C (lit > 300 8C).[34]
B. Ammonium carbonate buffer: Oxazolidine 15a (0.2 g,
0.57 mmol) was suspended in NH4HCO3/NH3 buffer (pH 9,
10% w/w, 1 mL) and heated for 16 h at 50 8C. The reaction
mixture was then cooled to room temperature and stirred
for an additional 2 h. The light brown precipitate was fil-
tered and dried to afford noroxymorphone 16 as a brownish
solid; yield: 131 mg (78%); mp > 300 8C.
Naltrexone (1)
Cyclopropylmethyl bromide (64 mg, 0.479 mmol) and Et3N
(45 mL, 0.327 mmol) were added to a suspension of noroxy-
morphone 16 (100 mg, 0.348 mmol) in a mixture of N-
methyl-2-pyrrolidinone/H2O (10:1 v/v, 0.35 mL). The reac-
tion vessel was purged with argon and the mixture stirred at
70 8C for 2 h. After 2 h additional Et3N (45 mL, 0.327 mmol)
was added and the mixture was stirred for additional 6 h at
70 8C. The reaction mixture was then cooled to room tem-
perature, diluted with dichloromethane (15 mL) and washed
with aqueous saturated NaHCO3 (3  3 mL). The aqueous
layer was re-extracted with dichloromethane (5 mL) and the
combined organic layers were dried over MgSO4. Column
chromatography of the residue (DCM/MeOH 4:1) afforded
naltrexone (1) as a white solid; yield: 103 mg (87%); mp
173–175 8C (acetone); mp 159–161 8C (MeOH). [lit. mp 174–
176 8C (acetone)[35]]; the material was identical in all re-
spects to the material described in the literature.[36] Rf = 0.42
(EtOAc/MeOH 4:1); [a]20 D: 207.00 (c 1, CHCl3); IR
(CHCl3): n = 3568, 3359, 3010, 2931, 2834, 1723, 1620, 156,
1317, 1146, 1058, 943 cm 1; 1H NMR (600 MHz, CDCl3): d =
6.74 (d, J = 8.1 Hz, 1 H), 6.60 (d, J = 8.1 Hz, 1 H), 5.82 (bs,
1 H, OH), 4.74 (s, 1 H), 3.21 (d, J = 5.9 Hz, 1 H), 3.11–3.03
(m, 2 H), 2.72 (dd, J = 12.0, 4.8 Hz, 1 H), 2.58 (dd, J = 18.4,
6.0 Hz, 1 H), 2.49–2.39 (m, 3 H), 2.34 (ddd, J = 14.5, 3.0,
3.0 Hz, 1 H), 2.18 (ddd, J = 12.2, 3.8, 3.8 Hz, 1 H), 1.91 (m,
1 H), 1.66 (ddd, J = 14.2, 14.2, 3.3 Hz, 1 H), 1.59 (ddd, J =
12.8, 2.7 Hz, 1 H), 0.88 (m, 1 H), 0.57 (m, 2 H), 0.16 (m, 2 H);
13
C NMR (150 MHz, CDCl3): d = 210.02, 142.51, 138.80,
129.05, 124.25, 119.90, 117.91, 90.60, 70.32, 62.01, 59.21,
51.07, 43.60, 36.21, 31.36, 30.65, 22.62, 9.42, 4.02, 3.81; MS
(+ EI): m/z (%) = 47 (15), 55 (41), 84 (100), 110 (12), 202
Adv. Synth. Catal. 2012, 354, 2706 – 2712
Unexpected N-Demethylation of Oxymorphone and Oxycodone N-Oxides
(5), 256 (12), 286 (7), 300 (15), 341 (64); HR-MS: m/z =
341.16320, calcd. for C20H23NO4 : 341.1627.
Naloxone (2)
Allyl bromide (56 mg, 0.463 mmol) and Et3N (45 mL,
0.327 mmol) were added to a suspension of noroxymor-
phone 16 (100 mg, 0.348 mmol) in a mixture of N-methyl-2-
pyrrolidone/H2O (10:1 v/v, 0.35 mL). The reaction vessel
was purged with argon and the mixture was stirred at 70 8C
for 2 h. At that time additional Et3N (45 mL, 0.327 mmol)
was added and the mixture was stirred for additional 7.5 h
at 70 8C. The reaction mixture was then cooled to room tem-
perature, diluted with dichloromethane (15 mL), and
washed with aqueous saturated NaHCO3 (3  3 mL). The
aqueous layer was re-extracted with dichloromethane
(5 mL) and the combined organic layers were dried over
MgSO4. Column chromatography of the crude material
(DCM/MeOH 4:1) afforded naloxone (2) as a white solid;
yield: 96 mg (84%); mp 181–182 8C (ethyl acetate). [lit. mp
173- 175 8C,[37] 179.5 8C (toluene)[38]]. The material was
identical in all respects to the material described in the liter-
ature.[39]
Nalbuphone (3)
A slurry of noroxymorphone 16 (220 mg, 0.766 mmol),
sodium hydrogen carbonate (77 mg, 0.92 mmol), cyclobutyl-
methyl bromide (160 mg, 1.07 mmol) and N-methyl-2-pyrro-
lidone (1 mL) was stirred under a nitrogen atmosphere at
90 8C for 19 h. The reaction mixture was cooled and
quenched with water (10 mL). The quenched reaction mix-
ture pH was adjusted to pH 9 and the product was extracted
with dichloromethane (3  5 mL). The combined organic
layers were washed with water, brine and dried over
MgSO4. Column chromatography afforded nalbuphine (3)
as a white solid; yield: 180 mg (66%); mp 170–172 8C (ace-
tone) [lit. 173–174 8C (chloroform)];[40] Rf = 0.64 (EtOAc/
MeOH 4:1); [a]20 D: 180.44 (c 1.0, MeOH); IR (CHCl3): n =
3561, 3454, 2966, 2931, 2830, 1720, 1616, 1457, 1318, 1142,
1057, 944 cm 1; 1H NMR (600 MHz, CDCl3): d = 6.74 (d, J =
8.0 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 5.64 (bs, 1 H, OH),
4.72 (s, 1 H), 3.11 (d, J = 18.4 Hz, 1 H), 3.04 (ddd, J = 14.4,
14.4, 3.6 Hz, 1 H), 2.92 (d, J = 4.9 Hz, 1 H), 2.57 (m, 5 H),
2.42 (ddd, J = 12.4, 12.4, 4.4 Hz, 1 H), 2.33 (d, J = 14.4 Hz,
1 H), 2.20 (ddd, J = 12.0, 12.0, 2.2 Hz, 1 H), 2.11 (m, 2 H),
1.95 (m, 1 H), 1.90 (m, 2 H), 1.87 (m, 2 H), 1.66 (ddd, J =
13.6, 13.6, 2.2 Hz, 1 H), 1.56 (d, J = 12.6 Hz, 1 H); 13C NMR
(150 MHz, CDCl3): d = 209.68, 143.45, 138.69, 129.02, 124.34,
119.87, 117.71, 90.58, 70.31, 62.74, 60.48, 50.93, 43.74, 36.18,
33.73, 31.32, 30.69, 27.00, 26.79, 22.96, 18.76; MS (FAB +):
m/z (%) = 41 (27), 69 (9), 98 (5), 300 (88), 355 (38), 356
(100); HR-MS: m/z = 356.18552, calcd. for C21H26NO4 :
356.1856.
Supporting Information
Experimental and spectral data for compounds 1, 3, 12, 13a,
b, 15a, b, 16, 17, 18, 19, 22, and 23 are available in the Sup-
porting Information.
Adv. Synth. Catal. 2012, 354, 2706 – 2712  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Acknowledgements
The authors are grateful to the following agencies for finan-
cial support of this work: Noramco, Inc., Natural Sciences
and Engineering Research Council of Canada (NSERC)
(Idea to Innovation and Discovery Grants), Canada Research
Chair Program, Canada Foundation for Innovation (CFI),
Research Corporation, TDC Research, Inc., TDC Research
Foundation, Brock University, and the Ontario Partnership
for Innovation and Commercialization (OPIC). We also
thank Dr. Thomas Bader, Dr. Alfred Stutz, Dr. Harald Hof-
meier, and Dr. Hansueli Bichsel, Labor fuer Prozess For-
schung, University of Zurich, for providing their procedure
for N-alkylation of nor-morphinans.
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