Synthesis of morphinans with diversely functionalized benzoxazole moieties

Article abstract of DOI:10.1007/s00706-010-0380-7

Three independent strategies have been established for the synthesis of morphinans with oxazole moieties derived from the aminophenol function of 2-aminomorphine. All the procedures possess the ability to furnish diversely substituted 2′-oxazole moieties

Full text of DOI:10.1007/s00706-010-0380-7

Monatsh Chem (2010) 141:1135–1143
DOI 10.1007/s00706-010-0380-7
ORIGINAL PAPER
Synthesis of morphinans with diversely functionalized
benzoxazole moieties
•
Levente Giran Zsuzsanna Gyulai
•
´
Sandor Antus Sandor Berenyi Attila Sipos
•
•
´
´
´
Received: 17 March 2010 / Accepted: 6 August 2010 / Published online: 2 September 2010
Ó Springer-Verlag 2010
Abstract Three independent strategies have been estab-
lished for the synthesis of morphinans with oxazole
moieties derived from the aminophenol function of 2-am-
inomorphine. All the procedures possess the ability to
furnish diversely substituted 20-oxazole moieties which are
considered significant in view of the presented density
functional studies on the spatial and electrostatic properties
of the proximal functions of the 3-hydroxyl of the mor-
phinan backbone. These data are considered important for
neuropharmacological development of potential kappa
antagonist morphinans. The second strategy was extended
to the direct vinylation of oxazoles to form more complex
benzoxazole-type morphinans.
Introduction
The synthesis of morphinan derivatives with blocked or
substituted 3-hydroxyl functions is a new and important
challenge in the medicinal chemistry of opioid alkaloids.
Neumeyer et al. [1, 2] reported the synthesis and com-
plete pharmacological characterization of thiazole- and
oxazole-fused levorphanols 1–3 and thiazolomorphine 4
(Fig. 1). Compound 1 possesses high affinity and selec-
tivity at the kappa receptor. Functional assays showed that
this congener was a full kappa but partial mu agonist.
Ligands 2 and 3 showed lower affinities at mu and kappa
receptors in comparison to the thiazolo derivative 1.
Thiazolomorphinan 4 possessed moderate affinities at mu
and delta receptors without selectivity toward either
subtype.
Keywords Alkaloids ꢀ Density functional calculations ꢀ
Heterocycles ꢀ Opioid receptor ꢀ
Palladium-catalyzed direct vinylation
Besides these efforts several N-heterocycle-fused mor-
phinans have been synthesized with divergent pharma-
cological profiles with respect to subtype selectivity and
efficacy. The main approaches involve the formation of
N-heterocyclic ring-fused morphinans with [3–9] or with-
out [10–17] the presence of a 6,14-endoetheno-type C-ring
bridged moiety.
´
Dedicated to Prof. Sandor Makleit to mark his 80th birthday.
´
´
L. Giran ꢀ Z. Gyulai ꢀ S. Antus ꢀ S. Berenyi ꢀ A. Sipos
Department of Organic Chemistry, University of Debrecen,
Debrecen, Hungary
Results and discussion
S. Antus
Research Group for Carbohydrates of the Hungarian Academy
of Sciences, P.O. Box 55, Debrecen 4010, Hungary
Herewith we report the design and synthesis of a set of
novel oxazolomorphinans based on natural morphine
instead of the synthetic analgesic levorphanol. These
derivatives were designed on the basis of computational
chemistry considerations to mimic the electronic profile of
the pharmacologically more significant members of the
presented series of morphinans 1–4. Scheme 1 presents the
retrosynthetic analysis of the proposed procedure.
Present Address:
A. Sipos (&)
Department of Pharmaceutical Chemistry,
University of Debrecen, P.O. Box 70,
Debrecen 4010, Hungary
e-mail: asipos@puma.unideb.hu
123

´
L. Giran et al.
1136
7
OH
8
Ki (nM)
6
H
17N
14
μ
δ
κ
9
N
N
N
Me
R
R
R
16
1
2
3
4
1.5 29 0.049
O
15
10
150
160
-
-
52
47
3
N3'
3
O 1'
1
1
2
N
O
O
2
S
2'
S
HN
N
2'
1'
3'
NH2
NH2
NH2
30 32 220
1
2
4
3
R = cyclopropylmethyl
Fig. 1 Recent representatives of 3-OH blocked or substituted morphinans and their affinities to opioid receptor subtypes (data from Refs. [1, 2])
Scheme 1
OH
OH
OH
OH
H
H
H
H
N
N
N
N
Me
Me
Me
Me
O
O
O
O
O
OH
OH
OH
N
NO2
NH2
R
5a
Morphine
R = NH2
5b R = H
6
7
5c
5d
R = Ph
R = 2-HO-Ph
5e R = 3-O2N-Ph
5f
R = 3-CH3O-Ph
5g
R = 2-CH3-Ph
5h R= 4-HO-Ph
Design of novel derivatives
In order to study the electrostatic properties calculations
were performed on the optimized geometries at the same
level of the DFT theory. Table 1 lists the Gasteiger–Hu¨ckel
charges [20, 21] of the most important moieties of com-
pounds 1, 2, and 5. Gasteiger–Hu¨ckel charges are empirical
atomic partial charges widely used in docking and quan-
titative structure–activity relationship (QSAR) studies on
the basis of their precise correlations with observed dipole
moments. These charges were obtained with a distance-
dependent dielectric and conjugate gradient method.
It can be concluded from these data that the charges on
the O atom of the oxazole ring vary on a broad range which
could have an interesting effect on the subtype selectivity
of ligands 5a–5h. The reason for this is the importance of
the hydrogen bond forming ability of moieties in the
proximity of position 3 of the morphinan skeleton. In
addition to this, the substitution pattern of the 20-aryl
function could also have significant impact on the spatial
position of these ligands as they can act as hydrogen bond
donors (e.g., OH, NH2) or hydrogen bond acceptors (e.g.,
OCH3, NO2).
The affinity and selectivity of morphinans toward the target
subtypes of opioid receptors are determined by two
important factors. Firstly the relative distance of the
important pharmacophores of the backbone and secondly
the quality of the pharmacologically important moieties
(i.e., the potential to interact with determining regions of
peptide moieties of the active site). Therefore, an extended
density functional theory (DFT) study was performed to
explore and compare the spatial and electrostatic properties
of compounds 1 and 2 and the outlined oxazolomorphinans
5 derived from 2-aminomorphine (6).
The optimized structures of compounds 1, 2, and 5a
were obtained at the B3LYP/6-31G(d,p) level of theory. On
the basis of the superimpositions of compounds 2 versus 5a
and 1 versus 5a made with overlaying carbons of ring A
(Fig. 2, a and b, respectively) we concluded that the most
important pharmacophores of the morphinan backbone
(N17 for ionic interactions, C3-OH/X for hydrogen bond-
ing) are very much in the same regions relative to each
other irrespective of the quality of the new heterocycle and
the presence of the 4,5-epoxy bridge between rings A and
C [18, 19]. Besides of these considerations we also con-
cluded that the spatial size of thiazole and oxazole rings are
very close.
Synthesis
Three approaches have been elaborated for the preparation
of morphine analogues possessing an oxazole moiety
123

Synthesis of morphinans with diversely functionalized benzoxazole moieties
1137
Fig. 2 Superimposition of
optimized structures of
compounds 2 and 5a (a) and
compounds 1 and 5a (b)
OH
NaNO2 /HCl
Table 1 Gasteiger–Hu¨ckel charges of atoms in the proximity of
position 3 of the morphinan skeleton calculated at the B3LYP/6-
31G(d,p) level of DFT
OH
Sn/HCl
N
N
Me
Me
O
O
Compounds Gasteiger–Hu¨ckel charges (e) on new heterocycles
Position 10
Position 20
Position 30
OH
OH
NO2
1
0.1898
-0.1580
-0.1599
-0.1643
-0.1210
-0.1164
-0.1209
-0.1235
-0.1275
-0.1247
0.1672
0.1519
0.1521
-0.0340
0.1047
0.1227
0.0873
0.0924
0.1066
0.1103
-0.1567
-0.1868
-0.1878
-0.1811
-0.1413
-0.1876
-0.1222
-0.1212
-0.1209
-0.1445
morphine
OH
2
7
H
5a
5b
5c
5d
5e
5f
5g
5h
OH
N
N
N
N
N
N
N
Me
Me
O
O
CHCl3/MeOH
OH
O
N
NH2
NH2
6
5a
Scheme 2
derived from the phenolic hydroxy group of morphinans.
These procedures were initiated from a natural starting
material, i.e., morphine, which was first nitrated. The
synthesis and structure elucidation of 2-nitromorphine (7)
[22] were started in 1911 and were undoubtedly clarified
decades later [23, 24]. We applied these classical methods
for the synthesis of 2-nitromorphine (7) [22–24]. The
reduction of compound 7 to 2-aminomorphine (6) was
performed in accordance with our previously published
procedure [25] or with the classic tin–hydrochloric acid
reagent combination [26].
OH
OH
(EtO)3CH
N
N
Me
Me
O
O
OH
O
N
NH2
H
6
5b
Scheme 3
The synthesis of aminooxazole-derived morphinan 5a
was realized in accordance with the procedure disclosed by
Wu et al. [27] using di(imidazol-1-yl)methanimine
(Scheme 2). However, the original procedure and its
applications for morphinans [2] applied THF as solvent, in
which compound 6 is practically insoluble; therefore the
reaction was carried out in a mixture of chloroform and
methanol with significantly higher yields as previously
reported, which may suggest the importance of the proper
solvation.
In the second oxazole-forming strategy o-aminophenol-
type 6 was treated with triethyl orthoformate to form
unsubstituted oxazolomorphine 5b in accordance with
the procedure reported for aporphine alkaloids [28]
(Scheme 3).
No formation of by-products was observed during
reaction. After separation of the crude product mixture of
unreacted aminomorphine 6 and product 5b by column
chromatography, compound 5b was obtained in 56% yield.
123

´
L. Giran et al.
1138
Scheme 4
OH
OH
OH
5
R
H
O
c
d
e
f
g
h
i
N
N
N
2-OH
3-NO2
3-OCH3
2-CH3
4-OH
4-NO2
Me
Me
Me
Ar
H
PIDA
O
O
O
OH
OH
O
NH2
N
N
6
R
R
5c 5i
-
worthwhile to note that the significantly shorter reaction
time could make the MW procedure a tempting choice,
even though there is a well-known limitation regarding
reaction volumes. Tricyclohexyl phosphine, as a simpler
and cheaper analogue of cyclohexyl JohnPhos, was found
to be completely ineffective in our catalytic systems,
whereas bis(t-butyl)phosphine (JohnPhos) was similarly
effective compared with the original choice. The spatially
more hindered X-Phos was found to be less effective under
the applied conditions (Scheme 6).
OH
OH
Br
CH3
N
Pd(OAc)2
K3PO4
N
Me
Me
CH3
H
O
O
1,4-dioxane:water = 95:5
Phosphine ligand
O
H
O
N
N
CH3
H
5b
CH3
5j
Scheme 5
On the basis of previous observations, the synthesis of
2-vinyloxazole-type derivatives 5j–5l was realized under
thermal conditions at 110 °C. Isolated yields were found to
be in the range of 54–75%. Lower conversions were
observed for spatially hindered vinyl derivative 5k and the
highest conversion was detected for the coupling with
(E)-b-bromostyrene due to electronic reasons.
The third strategy was based on the observations of
Prakash et al. [29] in connection with the oxidative
ring-closure of Schiff bases ortho to an unprotected
phenolic hydroxyl function. The oxidative ring-closure
was efficiently achieved with the application of (diacet-
oxyiodo)benzene (PIDA). The two-step procedure afforded
a series of novel oxazolomorphinans 5c–5i in high yields
(Scheme 4).
The palladium-catalyzed derivatization of unsubstituted
oxazolomorphine 5b was identified as an interesting
opportunity to significantly expand the range of moieties in
terms of steric and electronic properties similarly to the
previous application of Suzuki cross-coupling of halogen-
containing morphinans [30–33]. The optimization of the
direct vinylation of oxazolomorphinan 5b was based on a
recently reported protocol (Scheme 5) [34]. However, we
aimed to use microwave (MW) initiation besides the tra-
ditional thermal procedure and to test some structurally
similar phosphine ligands of the previously suggested
2-(dicyclohexylphosphino)biphenyl. The solvent mixture
and the base were chosen in line with our previous expe-
rience with Pd-catalyzed cross-coupling of morphinans
[30–33], whereas the reaction time and the target temper-
ature (together with MW power) were carefully optimized
with 2-(dicyclohexylphosphino)biphenyl as the phosphine
ligand and 1-bromo-2-methylpropene as the vinyl source
for both thermal and MW procedures (see footnote to
Table 2).
Conclusion
Oxazole rings were formed in three independent methods
on morphinan backbone utilizing its 3-hydroxyl function.
These derivatives and their N-cylopropylmethyl-nor coun-
terparts could be interesting pharmacologically based on
DFT-supported calculations. Versatile derivatization was
made possible by Pd-catalyzed direct vinylation of the
unsubstituted oxazolomorphinan. The optimization of the
procedure was extended to microwave-promoted condi-
tions as well.
Experimental
Melting points were determined with a Kofler hot-stage
apparatus. Thin-layer chromatography (TLC) was per-
formed on pre-coated Merck 5554 Kieselgel 60 F254 foils
using chloroform/methanol (8:2) mobile phase. The spots
were visualized with Dragendorff’s reagent. H and 13C
1
In view of the isolated yields reported in Table 2 it
could be emphasized that the application of MW promotion
had no advantage over the thermal method; however, it is
NMR spectra were recorded on a Bruker Avance DX 360
spectrometer, chemical shifts are reported in parts per
million (d) from internal TMS, and coupling constants
123

Synthesis of morphinans with diversely functionalized benzoxazole moieties
1139
recorded on PerkinElmer 16 PC FTIR spectrometer. Ele-
mental analyses (C, H, N) were obtained on a Carlo Erba
EA1108 analyzer, and the results agreed favorably with
calculated values. The MW-induced reactions were carried
out in a Discover model microwave reactor manufactured
by CEM Corporation. Controlled temperature, power,
pressure, and time settings were used for all reactions.
Table 2 Details of the optimization of the direct vinylation
Applied
phosphine
Isolated yield for
5j under thermal
conditions (%)a,c
Isolated yield for
5j under MW
conditions (%)b,c
PCy3
3
Traces
60
63
P(Cy)2
20-Amino-10,30-oxazolo-(40,50:2,3)-3-deoxymorphine
(5a, C18H19N3O3)
Cyclohexyl
JohnPhos
A solution containing 739 mg di(imidazol-1-yl)methan-
imine (4.59 mmol) and 460 mg 2-aminomorphine (6,
1.53 mmol) in 60 cm3 chloroform/methanol (2:1) was
heated at reflux under nitrogen overnight. After cooling
to room temperature, the reaction mixture was diluted with
80 cm3 ethyl acetate and washed successively with water,
saturated aqueous NH4Cl solution, and brine. The organic
layer was dried over MgSO4, filtered, and concentrated in
vacuo to afford the crude product. Further purification by
silica gel chromatography gave the desired product 5a as a
yellow solid (yield 310 mg, 60%). M.p.: 244–246 °C;
[a]2D5 = -16.4 (c = 0.1, chloroform); Rf = 0.40 (CHCl3/
MeOH = 8:2); IR (KBr): vꢀ = 3,520, 3,460, 3,370, 2,960,
52
58
44
52
P(Cy)2
iPr
iPr
iPr
X-Phos
P(tBu)2
JohnPhos
1,620, 1,350, 1,240, 1,160 cm-1 1H NMR (360 MHz,
;
a
1 equiv. of oxazole, 2 equiv. of vinyl bromide, 2 eq. of K3PO4,
5 mol% of Pd(OAc)2, and 10 mol% of phosphine in dioxane/
water (95:5) stirred in a sealed tube at 110 °C for 18 h under nitrogen
CDCl3): d = 6.52 (1H, s, H1), 5.59–5.56 (1H, m, H7),
5.34–5.32 (1H, m, H8), 5.02 (2H, br s, 20-NH2), 4.87 (1H,
dd, H5, J5,6 = 6.3 Hz, J5,7 = 1.4 Hz), 4.25–4.21 (1H, m,
H6), 3.31 (1H, dd, H9, J9,10a = 6.9 Hz, J9,14 = 2.8 Hz),
3.22 (1H, d, H10b, J = 18.3 Hz), 2.84–2.81 (1H, m, H14),
2.65 (1H, dd, H16b, J16b,16a = 13.7 Hz, J16b,15b = 4.4
Hz), 2.43 (3H, s, N-CH3), 2.30–2.27 (2H, m, H10a, H16a),
2.06 (1H, td, H15a, J15a,15b;15a,16a = 12.3 Hz, J15a,15b = 5.4
Hz), 1.83–1.79 (2H, m, H15b, C6-OH) ppm; 13C NMR
(90.6 MHz, CDCl3): d = 165.34 (C20), 140.69 (C2), 137.41
(C4), 133.60, 133.20, 133.16, 132.45, 130.51 (C3, C7, C8,
C11, C12), 109.90 (C1), 94.54 (C5), 68.12 (C9), 67.56
(C6), 48.67 (C16), 43.76, 43.54 (C13, NCH3), 41.09
(C14), 35.78 (C15), 24.90 (C10) ppm; HRMS: m/z (%) =
348.1329 (M ? Na?, 100), calculated for C18H19N3O3Na
348.1324.
b
1 equiv. of oxazole, 2 equiv. of vinyl bromide, 2 equiv. of K3PO4,
5 mol% of Pd(OAc)2, and 10 mol% of phosphine in dioxane/
water (95:5) irradiated in CEM Discover MW reactor at 140 °C
(150 W in PowerMax mode) for 10 min under nitrogen
c
The reported yields are averages of three runs
(J) are measured in Hertz. MALDI-TOF MS spectra were
recorded on a Bruker Biflex III spectrometer in the positive,
linear mode using 2,4,6-trihydroxyacetophenone as matrix.
High resolution mass spectral measurements were per-
formed with a Bruker micrOTOF-Q instrument in the ESI
mode. Optical rotation was determined with a PerkinElmer
Model 241 polarimeter with a water-jacketed 10-cm cell
and is given in units of deg cm2 g-1. IR spectra were
Scheme 6
OH
OH
Br
R2
N
R1 R2 R3
Me Me
Pd(OAc)2
K3PO4
N
R1
R3 Me
Me
5j
5k Me H
H
O
O
1,4-dioxane:water = 95:5
P(Cy)2
H
H
H
Ph
O
N
5l
O
N
R2
R3
H
R1
5j - 5l
5b
123

´
L. Giran et al.
1140
10,30-Oxazolo-(40,50:2,3)-3-deoxymorphine
(5b, C18H18N2O3)
20-Phenyl-10,30-oxazolo-(40,50:2,3)-3-deoxymorphine
dihydrochloride (5c, C24H24Cl2N2O3)
2-Aminomorphine (6, 500 mg, 1.66 mmol) was dissolved
in 25 cm3 of ethanol, and 0.5 cm3 of triethyl orthoformate
(5.5 mmol) was added to the slurry solution. This mixture
was refluxed overnight under nitrogen. The resulting
solution was evaporated to dryness, and the residue was
dissolved in ethyl acetate. The organic solution was washed
with 2 9 10 cm3 of 10% NaOH solution, dried over
MgSO4, and was evaporated to dryness to yield the oxazole
5b as yellow, pyramidal crystals. Yield 287 mg (56%),
m.p.: 218 °C (dec.); [a]D25 = -24.5 (c = 0.1, chloroform);
IR (KBr): vꢀ = 3,540, 3,310, 2,970, 1,610, 1,340, 1,240,
Pale yellow solid, yield 545 mg (85%); m.p.: [250 °C;
[a]2D5 = -6.9 (c = 0.1, methanol); IR (KBr): vꢀ ¼ 3,570;
3,380; 2,950; 1,630; 1,350; 1,250; 1,120 cmꢁ1
;
1H NMR
(360 MHz, DMSO-d6): d = 10.41–10.21 (2H, br s, 2
NH?), 7.87 (2H, dd, 2 phenyl-H, J = 8.4, 3.4 Hz),
7.42–7.31 (3H, m, 3 phenyl-H), 6.52 (1H, s, H1),
5.73–5.70 (1H, m, H7), 5.45–5.43 (1H, m, H8), 4.92 (1H,
dd, H5, J5,6 = 6.6 Hz, J5,7 = 1.6 Hz), 4.30–4.25 (2H, m,
H6, C6-OH), 3.38 (1H, dd, H9, J9,10a = 7.2 Hz, J9,14
=
2.7 Hz), 3.28 (1H, d, H10b, J = 18.0 Hz), 2.86–2.82
(1H, m, H14), 2.57 (1H, dd, H16b, J16b,16a = 14.4 Hz,
J16b,15b = 3.9 Hz), 2.46 (3H, s, N-CH3), 2.33–2.28 (2H, m,
1
1,150 cm-1; H NMR (360 MHz, CDCl3): d = 7.65 (1H,
s, H20), 6.63 (1H, s, H1), 5.61–5.58 (1H, m, H7), 5.31–5.28
(1H, m, H8), 4.81 (1H, dd, H5, J5,6 = 6.4 Hz,
J5,7 = 1.4 Hz), 4.30–4.27 (1H, m, H6), 3.33 (1H, dd, H9,
J9,10a = 7.0 Hz, J9,14 = 2.6 Hz), 3.27 (1H, d, H10b,
J = 17.9 Hz), 2.87–2.82 (1H, m, H14), 2.55 (1H, dd,
H16b, J16b,16a = 14.1 Hz, J16b,15b = 4.4 Hz), 2.50 (3H,
s, N-CH3), 2.31–2.27 (2H, m, H10a, H16a), 2.04 (1H,
td, H15a, J15a,15b;15a,16a = 12.7 Hz, J15a,15b = 5.9 Hz),
1.91–1.85 (2H, m, H15b, C6-OH) ppm; 13C NMR (90.6
MHz, CDCl3): d = 154.19 (C20), 138.28 (C2), 137.56 (C4),
133.90, 133.45, 132.76, 132.35, 131.66 (C3, C7, C8, C11,
C12), 107.38 (C1), 93.71 (C5), 67.92 (C9), 66.50 (C6), 47.91
(C16), 43.70, 43.24 (C13, NCH3), 41.79 (C14), 36.07 (C15),
25.09 (C10) ppm; HRMS: m/z (%) = 333.1221 (M ? Na?,
100), calculated for C18H18N2O3Na 333.1215.
H10a, H16a), 2.10 (1H, td, H15a, J15a,15b;15a,16a =
12.2 Hz, J15a,15b = 6.0 Hz), 1.97–1.91 (1H, m, H15b)
ppm; 13C NMR (90.6 MHz, DMSO-d6): d = 163.71
(C20), 138.84 (C2), 137.55 (C4), 134.11, 133.86, 133.55,
132.89, 132.50, 132.35, 131.88, 131.66, 130.60, 129.75,
128.77 (C3, C7, C8, C11, C12, 6 phenyl-C), 107.78 (C1),
94.24 (C5), 68.21 (C9), 66.73 (C6), 47.33 (C16), 43.59,
43.04 (C13, NCH3), 41.44 (C14), 38.01 (C15), 25.49 (C10)
ppm; HRMS: m/z (%) = 409.1533 (M ? Na?, 100),
calculated for C24H22N2O3Na 409.1528.
20-(2-Hydroxyphenyl)-10,30-oxazolo-(40,50:2,3)-3-deoxy-
morphine dihydrochloride (5d, C24H24Cl2N2O4)
Yellow solid, yield 547 mg (82%); m.p.: [250 °C;
[a]2D5 = -6.2 (c = 0.1, methanol); IR (KBr): vꢀ ¼ 3,620;
3,580; 3,370; 2,950; 1,630; 1,400; 1,340; 1,250; 1,130 cmꢁ1
;
1H NMR (360 MHz, DMSO-d6): d = 10.30–10.15 (2H, br
s, 2 NH?), 9.30 (1H, br s, 200-OH), 7.45 (1H, dd, aryl-H,
J = 8.1, 4.2 Hz), 7.24–7.09 (3H, , 3 aryl-H), 6.59 (1H, s,
H1), 5.81–5.77 (1H, m, H7), 5.50–5.44 (1H, m, H8), 4.85
(1H, dd, H5, J5,6 = 7.0 Hz, J5,7 = 2.2 Hz), 4.27–4.22 (2H,
m, H6, C6-OH), 3.76–3.31 (2H, m, H9, H10b), 2.91–2.86
(1H, m, H14), 2.64 (1H, dd, H16b, J16b,16a = 14.7 Hz,
J16b,15b = 4.0 Hz), 2.51 (3H, s, N-CH3), 2.33–2.26 (2H, m,
General method for the formation of Schiff bases
2-Aminomorphine (6, 500 mg, 1.66 mmol) was dissolved
in 25 cm3 of absolute ethanol. After addition of 1.83 mmol
of the appropriate benzaldehyde the solution was refluxed
for 3 h. The ethanolic solution was evaporated to dryness,
and the crude yellow oily product was found to be pure
enough according to TLC monitoring to use it in the fol-
lowing step without further purification.
H10a, H16a), 2.17 (1H, td, H15a, J15a,15b;15a,16a
=
13.1 Hz, J15a,15b = 6.0 Hz), 1.88–1.84 (1H, m, H15b)
ppm; 13C NMR (90.6 MHz, DMSO-d6): d = 162.41
(C20), 157.34 (C200), 138.52, 138.29 (C2, C600), 137.61
(C4), 135.01, 134.22, 133.65, 132.65, 131.88, 130.66,
128.79 (C3, C7, C8, C11, C12, 2 aryl-C), 117.43 (C300),
112.51 (C100), 107.66 (C1), 94.10 (C5), 68.66 (C9), 66.39
(C6), 47.37 (C16), 43.69, 43.24 (C13, NCH3), 41.14 (C14),
38.63 (C15), 25.40 (C10) ppm; MALDI TOF: m/z = 425.3
(M ? Na?), calculated for C24H22N2O4Na 425.1.
General method for the synthesis of 20-aryl-10,30-
oxazolo-(40,50:2,3)-3-deoxymorphine hydrochlorides
(5c–5i) from Schiff bases
The Schiff base (1.66 mmol) was dissolved in 10 cm3
methanol and 550 mg (diacetoxyiodo)benzene (1.75 mmol)
was added and the mixture was stirred overnight at room
temperature. The solution was evaporated to dryness and
the residual mass was dissolved in absolute ethanol. On
dropwise addition of ethanol saturated with hydrogen
chloride the product precipitated in salt form. The HCl salt
was filtered off and was washed with ether to yield the
corresponding 20-aryloxazolo product.
20-(3-Nitrophenyl)-10,30-oxazolo-(4’,50:2,3)-3-deoxy-
morphine dihydrochloride (5e, C24H23Cl2N3O5)
Bright yellow solid, yield 601 mg (84%); m.p.: [250 °C;
[a]2D5 = -3.0 (c = 0.1, methanol); IR (KBr): vꢀ ¼ 3,550;
3,370; 2,960; 1,640; 1,550; 1,400; 1,350; 1,330; 1,260; 1,140
123

Synthesis of morphinans with diversely functionalized benzoxazole moieties
1141
1
cmꢁ1; H NMR (360 MHz, DMSO-d6): d = 10.08–9.95
H6, C6-OH), 3.40 (1H, dd, H9, J9,10a = 6.8 Hz, J9,14
2.9 Hz), 3.33 (1H, d, H10b, J = 17.5 Hz), 2.94–2.87 (1H, m,
=
(2H, br s, 2 NH?), 7.87–7.73 (2H, m, 2 aryl-H), 7.66–7.54
(2H, m, 2 aryl-H), 6.51 (1H, s, H1), 5.87–5.82 (1H, m, H7),
5.59–5.54 (1H, m, H8), 4.91 (1H, dd, H5, J5,6 = 6.8 Hz,
J5,7 = 2.4 Hz), 4.30–4.25 (2H, m, H6, C6-OH), 3.38 (1H,
dd, H9, J9,10a = 6.6 Hz, J9,14 = 2.7 Hz), 3.30 (1H, d,
H10b, J = 18.3 Hz), 2.88–2.83 (1H, m, H14), 2.63 (1H,
dd, H16b, J16b,16a = 14.7 Hz, J16b,15b = 3.7 Hz), 2.50
(3H, s, N-CH3), 2.36–2.29 (2H, m, H10a, H16a), 2.19
H14), 2.58 (1H, dd, H16b, J16b,16a = 14.5 Hz, J16b,15b
=
4.0 Hz), 2.47 (3H, s, N-CH3), 2.39–2.32 (2H, m, H10a,
H16a), 2.25 (3H, s, aryl-CH3), 2.14 (1H, td, H15a,
J15a,15b;15a,16a = 12.8 Hz, J15a,15b = 5.1 Hz), 1.90–1.84
(1H, m, H15b) ppm; 13C NMR (90.6 MHz, DMSO-d6):
d = 162.71 (C20), 138.38, 137.51, 137.40, 136.83 (C2, C4,
C100, C200), 133.80, 133.51, 133.40, 132.63, 129.55, 128.44,
128.23, 127.18, 126.93 (C3, C7, C8, C11, C12, 4 aryl-C),
107.12 (C1), 95.81 (C5), 69.64 (C9), 66.21 (C6), 46.07
(C16), 44.02, 43.87 (C13, NCH3), 42.44 (C14), 39.72 (C15),
24.72 (C10), 21.76 (aryl-CH3) ppm; MALDI TOF:
m/z = 423.1 (M ? Na?), calculated for C25H24N2O3Na 423.2.
(1H, td, H15a, J15a,15b;15a,16a = 12.7 Hz, J15a,15b
=
5.8 Hz), 1.84–1.79 (1H, m, H15b) ppm; 13C NMR
(90.6 MHz, DMSO-d6): d = 162.67 (C20), 146.94 (C300),
138.27, 137.29 (C2, C4), 135.05, 134.71, 133.92, 133.60,
132.35, 132.09, 131.88, 129.45, 128.92, 127.60 (C3, C7,
C8, C11, C12, 5 aryl-C), 107.70 (C1), 94.51 (C5), 68.14
(C9), 66.08 (C6), 46.73 (C16), 43.60, 43.42 (C13, NCH3),
42.43 (C14), 39.07 (C15), 25.28 (C10) ppm; MALDI TOF:
m/z = 454.1 (M ? Na?), calculated for C24H21N3O5Na
454.1.
20-(4-Hydroxyphenyl)-10,30-oxazolo-(40,50:2,3)-3-deoxy-
morphine dihydrochloride (5h, C24H24Cl2N2O4)
Pale yellow solid, yield 587 mg (88%); m.p.: [250 °C;
[a]2D5 = -4.6 (c = 0.1, methanol); IR (KBr): vꢀ ¼
3,640; 3,590; 3,370; 2,960; 1,640; 1,330; 1,260; 1,140 cmꢁ1
;
20-(3-Methoxyphenyl)-10,30-oxazolo-(40,50:2,3)-3-deoxy-
morphine dihydrochloride (5f, C25H26Cl2N2O4)
1H NMR (360 MHz, DMSO-d6): d = 10.28–10.10 (2H, br
s, 2 NH?), 9.23 (1H, br s, 400-OH), 7.58–7.52 (2H, m, 2
aryl-H), 7.18–7.04 (2H, m, 2 aryl-H), 6.44 (1H, s, H1),
5.80–5.71 (1H, m, H7), 5.48–5.46 (1H, m, H8), 4.84 (1H,
dd, H5, J5,6 = 7.2 Hz, J5,7 = 2.5 Hz), 4.26–4.23 (2H, m,
H6, C6-OH), 3.31–3.19 (2H, m, H9, H10b), 2.91–2.84 (1H,
m, H14), 2.57 (1H, dd, H16b, J16b,16a = 14.3 Hz,
J16b,15b = 3.7 Hz), 2.46 (3H, s, N-CH3), 2.39–2.31 (2H,
Pale yellow solid, yield 512 mg (74%); m.p.: [250 °C;
[a]2D5 = -4.9 (c = 0.1, methanol); IR (KBr): vꢀ ¼ 3,540;
3,340; 2,950; 1,630; 1,340; 1,240; 1,120 cmꢁ1
;
1H NMR
(360 MHz, DMSO-d6): d = 10.44–10.09 (2H, br s, 2
NH?), 7.37–7.10 (4H, m, 4 aryl-H), 6.47 (1H, s, H1),
5.81–5.75 (1H, m, H7), 5.54–5.50 (1H, m, H8), 4.83 (1H,
dd, H5, J5,6 = 6.9 Hz, J5,7 = 2.7 Hz), 4.33–4.29 (2H, m,
H6, C6-OH), 3.91 (3H, s, OCH3), 3.45–3.12 (2H, m, H9,
H10b), 2.90–2.84 (1H, m, H14), 2.60 (1H, dd, H16b,
J16b,16a = 14.5 Hz, J16b,15b = 4.0 Hz), 2.47 (3H, s, N-
CH3), 2.39–2.32 (2H, m, H10a, H16a), 2.14 (1H, td, H15a,
J15a,15b;15a,16a = 12.4 Hz, J15a,15b = 5.5 Hz), 1.91–1.84
(1H, m, H15b) ppm; 13C NMR (90.6 MHz, DMSO-d6):
d = 162.37 (C20), 157.04 (C300), 138.14, 137.62 (C2, C4),
136.48, 136.21, 136.11, 133.66, 132.55, 129.69, 128.76
(C3, C7, C8, C11, C12, 2 aryl-C), 121.49, 119.71 (C500,
C200), 110.28 (C100), 106.97 (C1), 94.18 (C5), 69.04 (C9),
66.11 (C6), 56.18 (OCH3), 46.32 (C16), 43.82, 43.67 (C13,
NCH3), 42.31 (C14), 39.80 (C15), 24.82 (C10) ppm;
MALDI TOF: m/z = 439.1 (M ? Na?), calculated for
C25H24N2O4Na 439.2.
m, H10a, H16a), 2.20 (1H, td, H15a, J15a,15b;15a,16a
=
12.8 Hz, J15a,15b = 5.7 Hz), 1.89–1.80 (1H, m, H15b)
ppm; 13C NMR (90.6 MHz, DMSO-d6): d = 162.73
(C20), 157.29 (C400), 138.52, 138.26 (C2, C4), 137.78
(C4), 134.62, 133.89, 132.52, 131.73, 129.03 (C3, C7, C8,
C11, C12), 117.43, 117.36 (4 aryl-C), 106.92 (C1), 93.69
(C5), 68.61 (C9), 66.41 (C6), 46.79 (C16), 43.91, 43.66
(C13, NCH3), 41.25 (C14), 38.60 (C15), 24.69 (C10) ppm;
MALDI TOF: m/z = 425.1 (M ? Na?), calculated for
C24H22N2O4Na 425.1.
20-(4-Nitrophenyl)-10,30-oxazolo-(40,50:2,3)-3-deoxy-
morphine dihydrochloride (5i, C24H23Cl2N3O5)
Bright yellow solid, yield 587 mg (82%); m.p.: [250 °C;
[a]2D5 = -2.6 (c = 0.1, methanol); IR (KBr): vꢀ ¼ 3,550;
3,360;2,970; 1,630;1,570;1,550; 1,410;1,350;1,340; 1,270;
1
20-(2-Methylphenyl)-10,30-oxazolo-(40,50:2,3)-3-deoxy-
morphine dihydrochloride (5g, C25H26Cl2N2O3)
Yellow solid, yield 478 mg (72%); m.p.:[250 °C; [a]D25
1,140 cmꢁ1; H NMR (360 MHz, DMSO-d6): d = 10.21–
10.05 (2H, br s, 2 NH?), 8.21–8.10 (4H, m, 4 aryl-H), 6.60
(1H, s, H1), 5.84–5.78 (1H, m, H7), 5.51–5.47 (1H, m, H8),
4.87 (1H, dd, H5, J5,6 = 6.9 Hz, J5,7 = 2.6 Hz), 4.30–4.23
(2H, m, H6, C6-OH), 3.39 (1H, dd, H9, J9,10a = 6.8 Hz,
J9,14 = 2.7 Hz), 3.28 (1H, d, H10b, J = 18.5 Hz),
=
-5.8 (c = 0.1, methanol); IR (KBr): vꢀ ¼ 3,540; 3,330;
2,950; 1,640; 1,550; 1,340; 1,250; 1,130 cmꢁ1 1H NMR
;
(360 MHz, DMSO-d6): d = 10.23–9.79 (2H, br s, 2
NH?), 7.51–7.17 (4H, m, 4 aryl-H), 6.41 (1H, s, H1),
5.87–5.79 (1H, m, H7), 5.51–5.47 (1H, m, H8), 4.77 (1H,
dd, H5, J5,6 = 6.8 Hz, J5,7 = 3.0 Hz), 4.29–4.24 (2H, m,
2.90–2.84 (1H, m, H14), 2.63 (1H, dd, H16b, J16b,16a
14.3 Hz, J16b,15b = 3.6 Hz), 2.46 (3H, s, N-CH3),
=
2.32–2.24 (2H, m, H10a, H16a), 2.09 (1H, td, H15a,
123

´
L. Giran et al.
1142
J15a,15b;15a,16a = 12.7 Hz, J15a,15b = 5.8 Hz), 1.89–1.80
(1H, m, H15b) ppm; 13C NMR (90.6 MHz, DMSO-d6):
d = 163.12 (C20), 148.37 (C400), 138.27, 137.66 (C2, C4),
136.48 (C100), 134.92, 134.11, 133.60, 132.35, 131.18,
129.66, 128.41 (C3, C7, C8, C11, C12, 4 aryl-C), 106.61
(C1), 94.68 (C5), 67.94 (C9), 66.28 (C6), 46.74 (C16),
43.71, 43.48 (C13, NCH3), 42.31 (C14), 39.53 (C15), 25.23
(C10) ppm; MALDI TOF: m/z = 454.1 (M ? Na?), cal-
culated for C24H21N3O5Na 454.1.
d = 6.48 (1H, s, H1), 5.87–5.81 (1H, m, H7), 5.57 (1H,
d, H200, J = 2.3 Hz), 5.38–5.27 (2H, m, H8, H200), 4.71
(1H, dd, H5, J5,6 = 6.4 Hz, J5,7 = 1.9 Hz), 4.31–4.26 (1H,
m, H6), 3.35–3.23 (2H, m, H9, H10b), 2.89–2.85 (1H, m,
H14), 2.60 (1H, dd, H16b, J16b,16a = 14.2 Hz, J16b,15b
=
4.2 Hz), 2.48 (3H, s, N-CH3), 2.33–2.29 (2H, m, H10a,
H16a), 2.20 (3H, s, C100-CH3), 1.97 (1H, td, H15a,
J15a,15b;15a,16a = 12.4 Hz, J15a,15b = 5.4 Hz), 1.91–1.85
(1H, m, H15b, C6-OH) ppm; 13C NMR (90.6 MHz,
CDCl3): d = 151.95 (C20), 138.47 (C2), 137.62 (C4),
133.35, 133.06, 132.72, 130.18, 128.71, 128.10 (C3, C7,
C8, C11, C12, C100), 118.70 (C200), 107.20 (C1), 95.25
(C5), 69.01 (C9), 65.27 (C6), 47.30 (C16), 44.04, 43.87
(C13, NCH3), 41.23 (C14), 35.73 (C15), 28.44 (C200-CH3),
25.55 (C10) ppm; HRMS: m/z (%) = 373.1535 (M ? Na?,
100), calculated for C21H22N2O3Na 373.1528.
General procedure for Pd-catalyzed vinylation
The direct (hetero)vinylation reactions were carried out in a
sealed tube at 110 °C for 18 h under nitrogen. A solution of
oxazolomorphinan 5a (0.35 mmol) was allowed to react
with vinyl bromide (2 equiv.) with 4 mg palladium acetate
(0.017 mmol), 144 mg potassium phosphate (0.70 mmol),
and 12 mg 2-(dicyclohexylphosphino)biphenyl (10 mol%)
in 3 cm3 1,4-dioxane/water (95:5). After filtration on Cel-
ite and concentration in vacuo, the crude product was
purified by column chromatography on silica gel using a
chloroform/methanol (8:2) as the eluent to afford the 20-
vinyloxazole derivatives 5j–5l.
20-(E-2-Phenylethenyl)-10,30-oxazolo-(40,50:2,3)-3-deoxy-
morphine (5l, C26H24N2O3)
Yellow solid, yield 108 mg (75%); m.p.: 212–214 °C;
[a]2D5 = -18.5 (c = 0.1, chloroform); Rf = 0.62 (CHCl3/
MeOH = 8:2); IR (KBr): vꢀ ¼ 3,530; 3,320; 3,080; 3,030;
1
2,980; 1,620; 1,440; 1,330; 1,250; 670 cmꢁ1; H NMR (360
MHz, CDCl3): d = 7.37–7.12 (5H, m, aryl-H), 6.91 (1H, d,
H200, J = 14.6 Hz), 6.79 (1H, d, H100, J = 14.5 Hz), 6.51
(1H, s, H1), 5.87–5.80 (1H, m, H7), 5.36–5.33 (1H, m, H8),
4.81 (1H, dd, H5, J5,6 = 6.4 Hz, J5,7 = 1.9 Hz), 4.34–4.30
(1H, m, H6), 3.34–3.28 (2H, m, H9, H10b), 2.90–2.86 (1H,
m, H14), 2.54 (1H, dd, H16b, J16b,16a = 14.1 Hz,
J16b,15b = 4.4 Hz), 2.44 (3H, s, N-CH3), 2.29–2.23 (2H,
20-(2-Methylprop-1-enyl)-10,30-oxazolo-(40,50:2,3)-3-deoxy-
morphine (5j, C22H24N2O3)
Pale yellow solid, yield 80 mg (63%); m.p.: 232–234 °C;
[a]2D5 = -21.4 (c = 0.1, chloroform); Rf = 0.56 (CHCl3/
MeOH = 8:2); IR (KBr): vꢀ ¼ 3,530; 3,310; 3,030; 2,990;
1
1,620; 1,330; 1,300; 1,240; 680 cmꢁ1; H NMR (360 MHz,
CDCl3): d = 6.53 (1H, s, H1), 6.21 (1H, s, H100), 5.81–5.77
(1H, m, H7), 5.34–5.30 (1H, m, H8), 4.79 (1H, dd, H5,
J5,6 = 6.3 Hz, J5,7 = 1.7 Hz), 4.31–4.29 (1H, m, H6),
3.33–3.26 (2H, m, H9, H10b), 2.89–2.84 (1H, m, H14),
m, H10a, H16a), 2.05 (1H, td, H15a, J15a,15b;15a,16a =
12.2 Hz, J15a,15b = 5.2 Hz), 1.99–1.90 (2H, m, H15b,
C6-OH) ppm; 13C NMR (90.6 MHz, CDCl3): d = 154.66
(C20), 138.61 (C2), 137.68, 137.30 (C4, C1000), 133.62,
133.49, 133.11, 132.81, 129.30, 128.92, 128.81, 128.58,
128.31, 127.53, 127.11 (C3, C7, C8, C11, C12, C200, 5 aryl-
C), 109.50 (C100), 107.32 (C1), 93.91 (C5), 68.62
(C9), 66.22 (C6), 47.48 (C16), 44.03, 43.62 (C13,
NCH3), 41.66 (C14), 35.81 (C15), 25.59 (C10) ppm;
HRMS: m/z (%) = 435.1671 (M ? Na?, 100), calculated
for C26H24N2O3Na 435.1685.
2.50 (1H, dd, H16b, J16b,16a = 14.4 Hz, J16b,15b
=
4.6 Hz), 2.39 (3H, s, N-CH3), 2.29–2.22 (2H, m, H10a,
H16a), 2.01 (1H, td, H15a, J15a,15b;15a,16a = 12.4 Hz,
J15a,15b = 5.4 Hz), 1.95–1.88 (1H, m, H15b), 1.80 (3H, s,
C200-CH3), 1.78–1.68 (4H, m, C200-CH3, C6-OH) ppm; 13C
NMR (90.6 MHz, CDCl3): d = 152.15 (C20), 144.54
(C200), 139.22 (C2), 138.16 (C4), 133.63, 133.26, 132.43,
128.72, 128.33, (C3, C7, C8, C11, C12), 121.72 (C100),
106.84 (C1), 94.27 (C5), 68.23 (C9), 65.98 (C6), 47.13
(C16), 43.91, 43.46 (C13, NCH3), 41.66 (C14), 35.81
(C15), 25.65, 25.09 (C10, C200-CH3), 21.70 (C200-CH3)
ppm; HRMS: m/z (%) = 387.1690 (M ? Na?, 100),
calculated for C22H24N2O3Na 387.1685.
Computational procedure
We carried out the geometry optimization at Becke’s three-
parameter hybrid (B3LYP) levels [35–38] in the DFT with
the basis set 6-31G(d,p) using Gaussian 03 [39]. The sol-
vent effect was not considered. The models for morphine
and codeine obtained at the B3LYP/6-31G(d,p) level were
very much in accordance with X-ray data [40, 41].
20-(Prop-1-en-2-yl)-10,30-oxazolo-(40,50:2,3)-3-deoxy-
morphine (5k, C21H22N2O3)
Off-white solid, yield 66 mg (54%); m.p.: 220–222 °C;
[a]2D5 = -23.2 (c = 0.1, chloroform); Rf = 0.60 (CHCl3/
MeOH = 8:2); IR (KBr): vꢀ ¼ 3,530; 3,320; 3,040; 2,990;
Acknowledgments The authors are grateful to the National Science
Foundation (Grant OTKA reg. no. K81701) for the financial support.
1,630; 1,310; 670 cmꢁ1
;
1H NMR (360 MHz, CDCl3):
123

Synthesis of morphinans with diversely functionalized benzoxazole moieties
1143
´ ´ ´
24. Bognar R, Gaal DG (1963) Magy Kem Foly 69:17; Chem Abstr
59:1969b
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