Synthesis and characterization of new thebaine derivatives as potential opioid agonists and antagonists: 2-[ N -(1 H -Tetrazol-5-yl)-6,14-endo-etheno-6, 7,8,14-tetrahydrothebaine-7α-yl]-5-phenyl-1,3,4-oxadiazoles

Article abstract of DOI:10.1002/jhet.1074

In this study, we report the synthesis a series of novel 2-[N-(1H-tetrazol-5-yl)-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine-7α- yl]-5-phenyl-1,3,4-oxadiazole derivatives (7a-e) which have potential opioid antagonist and agonist. The substitution reaction of 6,14-endo- ethenotetrahydrothebaine-7α-carbohydrazide with corresponding benzoyl chlorides gave diacylhydrazine compounds 4a-e in good yields. The treatment of compounds 4a-e with POCl₃ caused the conversion of side-chain of compounds 5a-e into 1,3,4-oxadiazole ring at C(7) position; thus, compounds 5a-e were obtained. Subsequently, cyanamides (6a-e) were prepared from compounds 5a-e and then compounds 7a-e were synthesized by the azidation of 6a-e with NaN₃. The structures of the compounds were established on the basis of their IR, ¹H NMR, ¹³C APT, 2D-NMR (COSY, NOESY, HMQC, HMBC) and high-resolution mass spectral data.

Full text of DOI:10.1002/jhet.1074

February 2013
Synthesis and Characterization of New Thebaine Derivatives as
Potential Opioid Agonists and Antagonists: 2-[N-(1H-Tetrazol-5-yl)-
6,14-endo-etheno-6,7,8,14-tetrahydrothebaine-7α-yl]-
5-phenyl-1,3,4-oxadiazoles
E93
*
Yilmaz Yildirir, Özgür Pamir, Serkan Yavuz, and Ali Dişli
Department of Chemistry, Faculty of Science, Gazi University, Ankara 06500, Turkey
*
E-mail: yildirir@gazi.edu.tr
Received March 7, 2011
DOI 10.1002/jhet.1074
Published online 21 February 2013 in Wiley Online Library (wileyonlinelibrary.com).
In this study, we report the synthesis a series of novel 2-[N-(1H-tetrazol-5-yl)-6,14-endo-etheno-6,7,8,14-
tetrahydrothebaine-7α-yl]-5-phenyl-1,3,4-oxadiazole derivatives (7a–e) which have potential opioid antago-
nist and agonist. The substitution reaction of 6,14-endo-ethenotetrahydrothebaine-7α-carbohydrazide with
corresponding benzoyl chlorides gave diacylhydrazine compounds 4a–e in good yields. The treatment of
compounds 4a–e with POCl3 caused the conversion of side-chain of compounds 5a–e into 1,3,4-oxadiazole
ring at C(7) position; thus, compounds 5a–e were obtained. Subsequently, cyanamides (6a–e) were prepared
from compounds 5a–e and then compounds 7a–e were synthesized by the azidation of 6a–e with NaN3. The
structures of the compounds were established on the basis of their IR, 1H NMR, 13C APT, 2D-NMR (COSY,
NOESY, HMQC, HMBC) and high-resolution mass spectral data.
J. Heterocyclic Chem., 50, E93 (2013).
INTRODUCTION
δ opioid receptor [7, 8]. Furthermore, the C rings in their
structures essentially affect the pharmacological properties of
these types of alkaloids [9, 10]. The reported pharmacological
active compounds in the literature, such as etorphine (I) has a
lipophilic substituent at position 7α of the C ring [11]. The
introduction of additional heterocyclic fragments into the
molecules of morphinan alkaloids leads to highly promising
opioids. For example, nitrogen and sulphur containing
morphinan alkaloids exhibit analgesic activity [12, 13].
1,3,4-Oxadiazoles have attracted interest in medicinal
chemistry as bioisosters of carboxylic acids, esters, and
carboxamides. Because of their metabolic profile and ability
to engage in hydrogen bonding, they are an important
class of heterocyclic compounds that have a wide range
of pharmaceutical and biological activities including
analgesic, antimicrobial, antifungal, antinflammatory,
and antihypertensive [14–16].
The nature of the substituent at the nitrogen atom in
morphine alkaloids is a significant factor on their antago-
nist activity [17]. Through of N-demethylation of the ter-
tiary amine in the opiate skeleton were pharmaceutically
useful opiates, such as diprenorphine (II) and naloxone
(III) obtained. They have been found that replacing cyclo-
propylmethyl and allyl groups with a methyl group greatly
There are at least three major types of opioid receptors
which are widely distributed in mammalian systems [1].
It is generally thought that stimulation of μ receptors
(MOR) leads to analgesic effects, respiratory depression,
and physical dependence, κ receptors (KOR) produce
analgesia and δ receptors (DOR) play a role in spinal analgesia
but are involved in other biological processes, such as immune
response [2–4]. Morphinan alkaloids and their semisynthetic
derivatives are one of the most important groups of none-
ndogenous ligands for opioid receptor and exhibit properties
of agonists and antagonists [5]. Thus, some of them are used
as narcotic analgesics and pain-killer with opioid agonist
properties; others are used as opioid antagonist for the
treatment of narcotic overdosage and opioid addiction.
These properties depend on substituents in different posi-
tions of the morphinan skeleton.
In our previous work, we successfully synthesized and
characterized a series of (1,3,4-oxadiazol-2-yl)-N-arenamine
derivates of 7α-substituted-6,14-endo-ethenotetrahydrothe-
baine [6]. It is well known that the 7α-substituted-6,14-endo-
ethenotetrahydrothebaine derivates are very strong analgesic
compounds that show high affinity for each of the μ, κ, and
© 2013 HeteroCorporation

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Y. Yildirir, Ö. Pamir, S. Yavuz, and A. Dişli
Vol 50
Figure 1. Structures of etorphine, diprenorphine, and naloxone.
increases efficacy antagonist effect particularly at MOR
[18] (Fig. 1).
and 3100 cm–1 revealing the formation of an intramolecular
hydrogen bond with a nitrogen atom of tetrazole ring. In the
1H-MNR spectra of compounds 4a–e were confirmed through
the loss of -NH2 protons (broad at 4.07 ppm) signal belonging
to compound 3, when the hydrazinocarbonyl group converted
to diacylhydrazine; instead of -NH2 protons a new signal
appeared originating from another -NH proton. In addition,
one more N-H peak which was sourced from protonated
N-Me group was shown of 4a–e. The 13C APT spectra of these
compounds contained two carbonyl peaks at the weakest field.
In the 1H NMR spectra of compounds 5a–e showed no signal
belonging to the -NH groups due to the cyclodehydration
reaction of 4a–e with POCl3. A singlet for methyl group on
N atom disappeared by the replacement of 5a–e with CNBr
in the 1H NMR spectra of 6a–e. Significant structural
information was provided by two-dimensional COSY,
NOESY, HMQC, and HMBC experiments for compound
7d. A NOESY experiment showing NOE effect of the H-5β
proton at 5.07 ppm to H-7β proton at 4.07 enabled the determi-
nation as the S configuration of the C-7. The C-3 methoxy
group (proton at 3.78 ppm / carbon at 56.44 ppm from HMQC)
showed NOE to the H-2 proton at 6.77 ppm; moreover other
methoxy group (proton at 3.54 ppm / carbon at 51.66 ppm)
showed NOE to the H-18 proton at 5.57 ppm. An HMBC
correlation from the H-17 proton at 5.86 ppm to the carbon
at 31.19 ppm, allowed assignment of C-8, on which the
two germinal protons were assigned based on HMQC
correlation 1.84 ppm (H-8α)/31.19 ppm and 2.72 ppm
(H-8β)/31.19 ppm. An HMBC correlation from the H-16eq
proton at 3.82–3.85 ppm to the carbon at 131.50 ppm, allowed
its assignment of terazole rings carbon. A tree-band HMBC
correlation between the H-2′ proton at 7.90 ppm to the carbon
at 167.41 ppm allowed its assignments as C-5 of oxadiazole
ring.
In the recent years, a lot of studies on tetrazole derivatives
have been reported. Tetrazoles have become very popular
because of their functionality and wide range of applications.
Tetrazoles may be regarded as biological equivalents of the
carboxyl group, and extensive studies on tetrazoles have been
performed in the field of medicinal chemistry [19].
We report the synthesis a series of novel 6,14-endo-
ethenotetrahydrothebaine derivatives including, tetrazole
group at nitrogen atom and 5-substituted-phenyl-1,3,
4-oxadiazole groups at C-7α position which have candi-
dates to opioid agonist and antagonist agent.
RESULTS AND DISCUSSION
The target compound 2 was prepared from thebaine (1)
by Diels–Alder reaction with methyl acrylate [10, 20].
We obtained compound 3 by the treatment of compound
2 with hydrazine hydrate [21]. Then, compound 3 reacted
with benzoyl chlorid derivatives in toluene producing
diacylhydrazine compounds 4a–e. In 7α position oxadiazole
ring substituted thebaine derivatives 5a–e were obtained by
the cyclodehydration of diacylhydrazines 4a–e under the
action of POCl3 [22]. Further, 1,3,4-oxadiazole derivatives
5a–e were refluxed with cyanogen bromide in dry CHCl3 to
obtain cyanamides 6a–e. At least, the subsequent reaction of
6a–e with NaN3 and NH4Cl in dry DMF furnished tetrazole
compounds 7a–e (Scheme 1).
The structures of the products were determined by analysis
of their IR, 1H NMR, 13C APT, 2D-NMR (COSY, NOESY,
HMQC, HMBC) and high resolution mass spectra for the
molecular weights. In addition, the crystallographic structure
of the compound 2 was previously reported by our group [20].
In the IR spectra of compound 4a–e, characteristic bands of
secondary amide in the regions 3200 cm−1(N-H) were
observed, and there were no absorption bands for -NH2
belonging to compound 3. After the cyclodehydration
reactions of 4a–e with POCl3, N-H bands of amide groups
disappeared in the spectra of 7α-1,3,4-oxadiazle rings
substituted thebaine derivatives 5a–e. A special feature of the
IR spectra of the cyanamide products 6a–e was the presence
of absorption bands of cyanide groups at 2200–2225 cm−1.
N-Tetrazole compounds 7a–e had the band at between 3535
In conclusion, we have synthesized new 2-[N-(1H-Tetrazol-
5-yl)-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine-7α-yl]-
5-phenyl-1,3,4-oxadiazole (7a–e) which are potential analgesic
and evaluated their structures with spectroscopic methods.
EXPERIMENTAL
All the reagents for synthesis were commercially available and
used without further purification or purified by standard methods
before use. Melting points were determined using an Electrothermal
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis and Characterization of New Thebaine Derivatives as Potential
Opioid Agonists and Antagonists
E95
Scheme 1. Synthesize of 2‐[N‐(1H‐Tetrazol‐5‐yl)‐6,14‐endo‐etheno‐6,7,8,14‐tetrahydrothebaine‐7α‐yl]‐5‐phenyl‐1,3,4‐oxadiazoles.
9100 apparatus, uncorrected. All NMR spectra were recorded on a
Bruker 400 (1H: 400 MHz, 13C: 100 MHz) NMR spectrometer,
DMSO-d6. Chemical shift values were reported in ppm relative to that
for TMS used as an internal reference standard, J in Hz. MS were
obtained from Waters LCT Premier XE LTOF (EI TOF MS) instru-
ments. FTIR spectra were recorded on a Mattson 1000 spectrometer
using KBr pellets. The progress of reactions was monitored by TLC
using Silufol UV-254 plates. The products were isolated by column
chromatography (CC) on silica gel. The compounds 2 and 3 were
synthesized using a published method. All the physical and spectral
data were in line with the previously reported results [20, 21].
General procedure for the synthesis of compounds 4a–e. A
solution of 7α-(hydrazinocarbonyl)-6,14-endo ethenotetrahydrothebaine
3 (0.79 g, 2 mmol in 10 mL toluene) was added 2 mmol of a
corresponding benzoyl chloride compound. The reaction
mixture was boiled for 1 h and monitored with TLC. The white
crystals of adducts 4a–e after cooling were filtered. The
corresponding diacylhydrazine solid substance was recrystallized
from an appropriate solvent.
Hz, J8α,7β = 6.5 Hz, 1H, H-8α ) ppm; 13C-APT NMR (100 MHz,
DMSO-d6): δ 24.66 C(10); 30.30 C(8); 30.82 C(15); 40.84 C(7);
42.11 CH3-N; 42.53 C(14); 45.82 C(16); 46.69 C(13); 52.18 CH3O-
C(6); 56.56 CH3O-C(3); 61.18 C(9); 80.38 C(6); 91.35 C(5); 114.79
C(2); 120.41 C(1); 125.71 C(11); 125.75 C(4′) 128.35 C(18);
129.025 C(3′);132.21 C(2′); 132.37 C(12); 132.64 C(17); 132.92 C
(1′); 143.31 C(3); 148.27 C(4); 165.66 (N-C═O); 170.42 (N-C═O)
ppm; hrms (EI): 502.2317 ([M − H]+, C29H32N3O5+, calc. 502.2342).
1-[(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-
carbonyl]-2-(4′-flourobenzoyl)hydrazine hydrochloride (4b,
C29H30FN3O5.HCl). Recrystallized from methanol-chloroform.
Yield 80%; dp 266–268°C; IR (KBr): 3290 (-N-H); 3066 (═C-H);
2961 (C-H); 1657,1695 (-C═O); 1604,1623 (N-C═O) cm−1; 1H
NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H, N-H); 10.02 (s, 1H,
N-H); 9.94 (b, 1H, N-H); 7.94–7.97 (m, 2H, H-2′); 7.30–7.37 (m,
2H, H-3′); 6.75 (d, J1,2 = 8.2 Hz, 1H, H-2); 6.63 (d, J1,2 = 8.2 Hz,
1H, H-1); 5.68 (d, J17,18 = 8.8 Hz, 1H, H-18); 5.53 (d, J17,18 = 8.8
Hz, 1H, H-17); 4.75 (s, 1H, H-5β); 4.18 (d, J9α,10α = 6.2 Hz, 1H,
H-9α); 3.75(s, 3H, 3-OCH3); 3.52 (s, 3H, 6-OCH3); 3.46 (d, J10α,10β
=19.9 Hz, 1H, H-10β); 3.17–3.32 (m, 2H, H-8β, H-15ax); 2.86–
3.05 (m, 6H, H-7β, H-10α, H-16eq, N-CH3); 2.08–2.22 (m, 2H, H-
15eq, H-16ax); 1.47 (dd, J8α,8β = 12.2 Hz, J8α,7β = 6.3 Hz, 1H, H-
8α) ppm; 13C-APT NMR (100 MHz, DMSO-d6): δ 24.76 C(10);
30.72 C(8); 31.17 C(15); 42.09 C(7); 42.36 CH3-N; 43.80 C(14);
45.83 C(16); 46.63 C(13); 52.12 CH3O-C(6); 56.63 CH3O-C(3);
61.11 C(9); 80.40 C(6); 91.92 C(5); 114.68 C(2); 115.77–115.99
(JC(3′)-F = 22.0 Hz) C(3′);120.41 C(1); 125.91 C(11); 128.31 C(18);
129.45 C(1′); 130.59–130.68 (JC(2′)-F = 9.0 Hz, C(2′)); 132.46 C
(12); 132.75 C(17); 142.28 C(3); 148.22 C(4); 164.70 (N-C═O);
163.36–165.83 (JC(4′)-F = 247.0 Hz, C(4′)); 171.67 (N-C═O) ppm;
hrms (EI): 520.2250 ([M − H]+, C29H31FN3O5+, calc., 520.2248).
1-[(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-
carbonyl]-2-(4′-chlorobenzoyl)hydrazine hydrochloride (4c,
1-[(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-
carbonyl]-2-benzoylhydrazine hydrochloride (4a, C29H31N3O5.
HCl). Recrystallized from methanol-chloroform. Yield 79%; dp
247–248°C; IR (KBr): 3200 (-N-H); 3023 (═C-H); 2971 (C-H);
1
1657, 1695 (-C═O); 1600, 1628 (N-C═O) cm−1; H NMR (400
MHz, DMSO-d6): δ 10.35 (s, 1H, N-H); 9.85 (s, 1H, N-H); 9.54 (b,
1H, N-H); 7.79 (d, J2′,3′ = 7.4 Hz, 2H, H-2′); 7.48 (t, J3′,4′ = 7.4 Hz;
1H, H-4′); 7.39 (t, J2′,3′ = 7.3 Hz; 2H, H-3′); 6.66 (d, J1,2 =8.2 Hz,
1H, H-2); 6.53 (d, J1,2 =8.2 Hz, 1H, H-1); 5.61 (d, J17,18 = 8.8 Hz,
1H, H-18); 5.44 (d, J17,18 = 8.8 Hz, 1H, H-17); 4.66 (s, 1H, H-5β);
4.09 (d, J9α, 10α = 6.4 Hz, 1H, H-9α ); 3.64 (s, 3H, 3-OCH3); 3.43
(s, 3H, 6-OCH3); 3.38 (d, J10α, 10β = 18 Hz, 1H, H-10β); 3.08–3.16
(m, 2H, H-8β, H-15ax); 2.78–2.97 (m, 6H, H-7β, H-10α, H-16eq,
N-CH3); 2.00–2.07 (m, 2H, H-15eq, H-16ax); 1.40 (dd, J8α,8β = 12.7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Y. Yildirir, Ö. Pamir, S. Yavuz, and A. Dişli
Vol 50
C29H30ClN3O5.HCl). Recrystallized from ethanol-ethyl acetate.
Yield 82%; dp 286–287 °C; IR (KBr): 3190 (-N-H); 3043
(═C-H); 2942 (C-H); 1657, 1690 (-C═O); 1595, 1620
(8); 30.86 C(15); 40.72 C(7); 42.10 CH3-N; 42.55 C(14); 45.82
C(16); 46.66 C(13); 52.13 CH3O-C(6); 55.84 CH3O-C(3);
56.67 CH3O-C(4′); 61.15 C(9); 80.39 C(6); 91.29 C(5); 114.08
C(3′); 114.75 C(2); 114.80 C(2′); 120.40 C(1); 125.07 C(1′);
125.74 C(11); 128.36 C(18); 132.40 C(12); 132.66 C(17);
142.30 C(3); 148.26 C(4); 162.38 (N-C═O); 165.15 (N-C═O);
(N-C═O) cm−1 1H NMR (400 MHz, DMSO-d6): δ 10.57
;
(s, 1H, N-H); 9.99 (s, 1H, N-H); 9.42 (b, 1H, N-H); 7.90
(d, J2′,3′ = 8.5 Hz, 2H, H-2′); 7.58 (d, J2′,3′ = 8.5 Hz, 2H,
H-3′); 6.75 (d, J1,2 = 8.3 Hz, 1H, H-2); 6.63 (d, J1,2 = 8.3 Hz, 1H,
H-1); 5.71 (d, J17,18 = 8.8 Hz, 1H, H-18); 5.54 (d, J17,18 = 8.8
Hz, 1H, H-17); 4.76 (s, 1H, H-5β); 4.19 (d, J9α,10α = 6.4 Hz,
1H, H-9α); 3.73 (s, 3H, 3-OCH3); 3.51 (s, 3H, 3H, 6-OCH3);
3.45–3.51 (m, 1H, H-10β); 3.23–3.26 (m, 2H, H-8β, H-15 ax);
2,99–3.16 (m, 6H, H-7β, H-10α, H-16eq, N-CH3); 2.09–2.18
(m, 2H, H-15eq, H-16ax); 1.48 (dd, J8α,8β = 12.6 Hz, J8α,7β = 6.1
Hz, 1H, H-8α) ppm; 13C-APT NMR (100 MHz, DMSO-d6):
δ 24.66 C(10); 30.29 C(8); 30.80 C(15); 40.79 C(7); 42.08 CH3-N;
42.52 C(14); 45.81 C(16); 46.64 C(13); 52.15 CH3O-C(6); 56.51
CH3O-C(3); 61.13 C(9); 80.37 C(6); 91.28 C(5); 114.71 C(2);
120.41 C(1); 125.70 C(11); 137.06 C(4′); 128.31 C(18); 129.025 C
(3′); 129.84 C(2′); 131.64 C(1′); 132.35 C(12); 132.70 C(17);
142.28 C(3); 148.22 C(4); 164.65 (N-C═O); 170.59 (N-C═O)
ppm; hrms (EI): 536.1926 ([M − H]+, C29H31ClN3O5+, calc.,
536.1952).
170.64 C(4′) ppm; hrms (EI): 532.2430 ([M
−
H]+,
C30H34N3O+6, calc., 532.2448).
General procedure for the synthesis of compounds 5a–e.
The compounds 5a–e was synthesized using with improving of
published method [22]. A solution of corresponding compound
4a–e (1 mmol) in 5 mL POCl3 was refluxed in an oil bath for
3 h. The mixture was cooled to room temperature, poured slowly
onto about 20 g of ice and stirred for 20 min. (Caution! When
the mixture is poured onto ice, a very high exothermic reaction
occurs). The resulting suspension was basified to pH 9 with a
saturated solution of NaOH, and the precipitate was extracted
into ethyl acetate (2 × 30 mL). The extract was dried over
MgSO4 and evaporated. The residue was recrystallized from an
appropriate solvent.
2-(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-5-
phenyl-1,3,4-oxadiazole (5a, C29H29N3O4). Recrystallized
from ethyl acetate-hexane. Yield 66%; mp 208–209°C; (ref.
1-[(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-
carbonyl]-2-(4′-bromobenzoyl)hydrazine hydrochloride (4d,
C29H30BrN3O5.HCl). Recrystallized from methanol-ethyl
acetate. Yield 78%; dp 285–288°C; IR (KBr): 3358 (-N-H);
3035 (═C-H); 2957 (C-H); 1652, 1695 (-C═O); 1585, 1614
22, 210–212°C); IR (KBr): 3057(═C-H), 2971 (C-H) cm−1
;
1H NMR (400 MHz, DMSO-d6): δ 7.62–7.92 (m, 5H, H-2′,
H-3′, H-4′); 6.64 (d, J1,2 =8.2 Hz, 1H, H-2); 6.53 (d, J1,2
=8.2 Hz, 1H, H-1); 5.70 (d, J17,18 =8.7 Hz, 1H, H-17); 5.58
(d, J17,18 =8.7 Hz, 1H, H-18); 4.94 (s, 1H, H-5β); 3.93 (dd,
J7β,8β = 9.3 Hz, J7β,8α = 6.1 Hz, 1H, H-7β); 3.70 (s, 3H, 3-OCH3);
3.47 (s, 3H, 6-OCH3); 3.26 (d, J9α, 10α = 6.5 Hz, 1H, H-9α );
3.14–3.17 (m, 1H, H-8β); 3.10 (d, J10α,10β = 17.4 Hz, 1H, H-10β);
2.45–2.47 (m, 1H, H-16eq); 2.30 (s, 3H, N-CH3); 2.17–2.25 (m,
3H, 16ax, H-10α, H-15 ax); 1.73–1.74 (m, 1H, H-15eq); 1.63 (dd,
1
(N-C═O) cm−1; H NMR (400 MHz, DMSO-d6): δ 10.57 (s,
1H, N-H); 10.03 (s, 1H, N-H); 9.78 (b, 1H, N-H); 7.82 (d,
J2′,3′ = 8.2 Hz, 2H, H-2′); 7.72 (d, J2′,3′ = 8.2 Hz, 2H, H-3′); 6.76
(d, J1,2 = 8.3 Hz, 1H, H-2); 6.62 (d, J1,2 = 8.3 Hz, 1H, H-1); 5.68
(d, J17,18 = 8.8 Hz, 1H, H-18); 5.55 (d, J17,18 = 8.8 Hz, 1H, H-17);
4.75 (s, 1H, H-5β); 4,18 (d, J9α,10α = 6.2 Hz, 1H, H-9α); 3.73
(s, 3H, 3H, 3-OCH3); 3.51 (s, 3H, 6-OCH3); 3.43 (d, 1H,
J10α,10β =11.3 Hz, 1H, H-10β); 3.22–3.29 (m, 2H, H-8β, H-15 ax);
2.86 -3.05 (m, 6H, H-7β, H-10α, H-16eq, N-CH3); 2.09–2.14 (m,
2H, H-15eq, H-16ax); 1.47 (dd, J8α,8β = 12.8 Hz, J8α,7β = 6.2 Hz,
1H, H-8α) ppm; 13C-APT NMR (100 MHz, DMSO-d6): δ 24.75 C
(10); 30.27 C(8); 30.89 C(15); 40.77 C(7); 42.06 CH3-N; 42.57 C
(14); 45.83 C(16); 46.63 C(13); 52.14 CH3O-C(6); 56.53 CH3O-C
(3); 61.13 C(9); 80.86 C(6); 91.23 C(5); 114.71 C(2); 120.42 C(1);
125.73 C(1′); 126.02 C(11); 128.29 C(18); 130.48 C(3′); 131.77 C
(2′); 132.39 C(12);132.75 C(17); 142.29 C(3); 148.22 C(4); 164.89
(N-C═O); 170.59 (N-C═O); 171.61 C(4′) ppm; hrms (EI):
580.1460 ([M − H]+, C29H31BrN3O+5, calc., 580.1447).
J
8α,8β = 12.8 Hz, J8α,7β = 6.1 Hz, 1H, H-8α ) ppm; 13C-APT NMR
(100 MHz, DMSO-d6): δ 22.20 C(10); 33.01 C(8); 31.58 C(15);
33.92 C(7); 42.95 C(14); 43.58 CH3-N; 45.53 C(16); 47.00 C(13);
51.53 CH3O-C(6); 56.45 CH3O-C(3); 59.59 C(9); 81.40 C(6);
90.90 C(5); 113.90 C(2); 119.98 C(1); 123.99 C(1′); 126.74 C(17);
128.08 C(11); 128.65 C(3′); 129.95 C(2′); 134.42 C(12); 134.44 C
(4′); 137.24C(18); 141.77 C(3); 147.80 C(4); 164.55 (C═N);
167.56 (C═N) ppm; hrms (EI): 484.2188 ([M − H]+, C29H30N3O4+,
calc., 484.2236).
2-(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-5-
(4′-flourophenyl)-1,3,4-oxadiazole (5b, C29H28FN3O4). Recrystallized
from methanol-chloroform. Yield 60%; mp 263–265°C; IR (KBr):
1
1-[(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-
carbonyl]-2-(4′-methoxybenzoyl)hydrazine hydrochloride (4e,
C30H33N3O6.HCl). Recrystallized from methanol-ethyl acetate.
Yield 89%; dp 285–288°C; IR (KBr): 3214 (-N-H); 3033
(═C-H); 2952 (C-H); 1652, 1695 (-C═O); 1604, 1614
3057 (-C═H), 2962 (-C-H) cm−1; H NMR (400 MHz, DMSO-d6):
δ 7.96–7.99 (m, 2H, H-2′ ); 7.43–7.47 (m, 2H, H-3′ ); 6.65
(d, J1,2 = 8.2 Hz, 1H, H-2); 6.55 (d, J1,2 = 8.2 Hz, 1H, H-1);
5.69 (d, J17,18 = 8.9 Hz, 1H, H-17 ); 5.56 (d, J17,18 = 8.7 Hz, 1H,
H-18 ); 4.94 ( s, 1H, H-5β); 3.95 (dd, J7β,8β = 9.2 Hz, J7β,8α =6.7,
1H, H-7β); 3.70 (s, 3H, 3-OCH3); 3.48 (s, 3H, 6-OCH3); 3.26
(d, J9α,10α = 6.2 Hz, 1H, H-9α); 3.11 (d, J10α,10β = 18.5 Hz; 1H,
H-10β); 3.11–3.13 (m, 1H, H-8β); 2.45–2.50 (m, 1H, H-16eq );
2.33 (s, 3H, N-CH3); 2.31–2.18 (m, 3H, H-16ax, H-10α, 15ax);
1.71–1.73 (m, 1H, 15eq); 1.65 (dd, J8α.8β = 12.4 Hz, J8α.7β = 6.7
Hz, 1H, H-8α) ppm; 13C-APT NMR (100 MHz, DMSO-d6):
δ 21.67 C(10); 31.04 C(8); 32.47 C(15); 33.34 C(7); 42.43 C
(14); 43.08 CH3-N; 45.02 C(16); 46.48 C(13); 50.99 CH3O-C(6);
56.01 CH3O-C(3); 59.07 C(9); 80.88 C(6); 90.29 C(5); 113.29 C
(2); 116.62–116.84 (JC(3′)-F = 22.0 Hz) C(3′));119.49 C(1);
120.13 C(1′); 126.79 C(17); 128.12 C(11); 128.89–128.98
(JC(2′)-F = 9.0 Hz, C(2′));133.88 C(12); 137.77 C(18);
(N-C═O) cm−1 1H NMR (400 MHz, DMSO-d6): δ 10.31
;
(s, 1H, N-H); 9.85 (s, 1H, N-H); 9.27 (b, 1H, N-H); 7.85
(d, J2′,3′ = 8.8 Hz, 2H, H-2′); 7.02 (d, J2′,3′ = 8.8 Hz, 2H,
H-3′); 6.75 (d, J1,2 = 8.2 Hz, 1H, H-2); 6.63 (d, J1,2 = 8.2
Hz, 1H, H-1); 5.71 (d, J17,18 = 8.9 Hz, 1H, H-18); 5.53 (d,
J17,18 = 8.9 Hz, 1H, H-17); 4.75 (s, 1H, H-5β); 4,19 (d,
J9α,10α = 6.1 Hz, 1H, H-9α); 3.82 (s, 3H, 4′-OCH3); 3.73 (s,
3H, 3-OCH3); 3.51 (s, 3H, 6-OCH3); 3.45–3.51 (m, 1H, H-10β);
3.23–3.27 (m, 1H, H-15ax); 2.88–3.09 (m, 7H, H-7β, H-8β,
H-10α, H-16eq, N-CH3); 2.11–2.13 (m, 2H, H-15eq, H-16ax);
1.48 (dd, J8α,8β = 12.4 Hz, J8α,7β = 5.8 Hz, 1H, H-8α) ppm;
13C-APT NMR (100 MHz DMSO-d6): δ 24.71 C(10); 30.30 C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis and Characterization of New Thebaine Derivatives as Potential
Opioid Agonists and Antagonists
E97
141.24 C(3); 147.25 C(4); 165.21–162.72 (JC(4′)-F = 249.0
Hz, C(4′)); 163.32 (C═N); 167.09 (C═N) ppm; hrms (EI):
502.2071 ([M − H]+, C29H29FN3O+4, calc., 502.2142).
1,64 (dd, J8α,8β = 12.8 Hz, J8α,7β = 6.1 Hz, 1H, H-8α) ppm; 13C-
APT NMR (100 MHz, DMSO-d6): δ 22.71 C(10); 31.57 C(8);
33.02 C(15); 33.38 C(7); 43.57 CH3-N; 43.59 C(14); 45.53 C(16);
46.98 C(13); 51.48 CH3O-C(6); 55.96 CH3O-C(3); 56.55 CH3-O-
C(4′); 59.59 C(9); 81.38 C(6); 90.90 C(5); 113.87 C(2); 115.36 C
(3′); 119.96 C(1); 125.07 C(1′); 127.31 C(17); 128.64 C(11);
128.66 C(2′); 134.43 C(12); 137.17 C(18); 141.76 C(3); 147.81 C
(4); 162.34 C(4′); 164.46 (-C═N); 166.94 (-C═N) ppm; hrms
(EI): 514.2319 ([M − H]+, C30H32N3O5+, calc., 514.2342).
General procedure for the synthesis of compounds 6a–e. A
solution of corresponding compound 5a–e (0.5 mmol) and
cyanogen bromide (0.1 g, 1 mmol, Caution! cyanogen bromide
is a poison, may be fatal if inhaled or swallowed; causes burns
and severe irritation.) in 10 mL of dry chloroform were refluxed
for 24 h to obtain N-CN compounds and reaction was
monitored with TLC. The cooled reaction mixture was
evaporated, and the residue was purified by column
chromatography on silica gel using ethyl acetate/petrol ether
(2:1) as eluent. The residue was recrystallized from an
appropriate solvent.
2-(N-Cyano-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine-7α-
yl)-5-phenyl-1,3,4-oxadiazole (6a, C29H26N4O4). Recrystallized
from methanol-chloroform. Yield 54%; mp 283–285°C; IR (KBr):
3047(═C-H), 2976 (C-H), 2200 (-CN) cm−1; 1H NMR (400 MHz,
DMSO-d6): δ 7.60–7.94 (m, 5H, H-2′, H-3′, H-4′); 6.73 (d,
J1,2 = 8.2 Hz, 1H, H-2); 6.62 (d, J1,2 = 8.2 Hz, 1H, H-1); 5.70
(d, J17,18 = 8.6 Hz, 1H, H-17); 5.68 (d, J17,18 = 8.6 Hz, 1H,
H-18); 5.00 (s, 1H, H-5β); 4.13 (d, J9α,10α = 6.6 Hz, 1H, H-9α);
4.06 (dd, J7β,8β = 9.5 Hz, J7β,8α = 6.0 Hz, 1H, H-7β); 3.79 (s,
3H, 3-OCH3); 3.48 (s, 3H, 6-OCH3); 3.15-3.39 (m, 3H, H-16eq,
H-16ax, H-10α); 3.13 (d, J10α,10β = 19.2 Hz, 1H, H-10β); 2.95
(dd, J8α,8β = 11.8 Hz, J7β,8β = 9.5 Hz 1H, H-8β); 2.30–2.33 (m,
1H, H-15ax); 1.82–1.89 (m, 2H, H-8α, H-15eq) ppm; 13C-APT
NMR (100 MHz, DMSO-d6): δ 30.87 C(15); 31.15 C(8); 31.73 C
(10); 33.87 C(7); 40.81 C(14); 41.86 C(16); 46.60 C(13); 51.67
CH3O-C(6); 56.42 CH3O-C(3); 57.64 C(9); 81.13 C(6); 90.70 C
(5); 114.42 C(2); 118.41 (N-CN); 120.43 C(1); 126.77 C(4′),
123.92 C(1′); 126.56 C(12); 128.13 C(17); 128.16 C(2′); 132.37
C(3′); 132.86 C(11); 135.35 C(18); 142.19 C(3); 148.04 C(4);
164.64 (-C═N); 167.09 (-C═N) ppm; hrms (EI): 495.2023 ([M − H]+,
C29H27N4O+4, calc., 495.2032).
2-(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-5-
(4′-chlorophenyl)-1,3,4-oxadiazole (5c, C29H28ClN3O4).
Recrystallized from methanol-chloroform. Yield 66%; mp
278–280°C; IR (KBr): 3040(═C-H), 2928 (C-H) cm−1 1H
;
NMR (400 MHz, DMSO-d6): δ 7.90 (d, J2′,3′ = 8.6 Hz, 2H,
H-2′); 7.68 (d, J2′,3′ = 8.6 Hz, 2H, H-3′); 6.65 (d, J1,2 = 8.2
Hz, 1H, H-2); 6.56 (d, J1,2 = 8.2 Hz, 1H, H-1); 5.70 (d, J17,18
= 8.8 Hz, 1H, H-17); 5.56 (d, J17,18 = 8.8 Hz, 1H, H-18); 4.94
(s, 1H, H-5β); 3.95 (dd, J7β,8β = 9.4 Hz, J7β,8α = 6.1 Hz, 1H,
H-7β); 3.70 (s, 3H, 3-OCH3); 3.47 (s, 3H, 6-OCH3); 3.25 (d,
J9α, 10α = 6.3 Hz, 1H, H-9α); 3.16 (d, J10α,10β = 17.9 Hz, 1H,
H-10β); 3.13–3.15 (m, 1H, H-8β); 2.17–2.31 (m, 4H, H-16eq,
H-16ax, H-10α, H-15ax); 2.09 (s, 3H, N-CH3); 1.71–1.74 (m,
1H, H-15eq); 1,65 (dd, J8α,8β = 12.8 Hz, J8α,7β = 6.1 Hz, 1H,
H-8α) ppm; 13C-APT NMR (100 MHz, DMSO-d6): δ 22.30 C
(10); 30.68 C(8); 31.04 C(15); 33.38 C(7); 42.43 C(14);43.08
CH3-N; 45.02 C(16); 46.49 C(13); 51.01 CH3O-C(6);. 55.90
CH3O-C(3); 59.07 C(9); 81.88 C(6); 90.29 C(5); 113.31 C(2);
119.49 C(1); 122.32 C(1′); 126.79 C(17); 128.05 C(3′);
128.08 C(11); 129.65 C(2′); 133.88 C(12); 136.54 C(4′)
136.79 C(18); 141.25 C(3); 147.26 C(4); 163.32 (-C═N);
167.27 (-C═N) ppm; hrms (EI): 518.1886 ([M − H]+,
C29H29ClN3O+4, calc., 518.1847).
2-(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-5-
(4′-bromophenyl)-1,3,4-oxadiazole (5d, C29H28BrN3O4).
Recrystallized from methanol-ethyl acetate. Yield 65%, mp
275–278°C; IR (KBr): 3061 (═C-H), 2952 (C-H) cm−1 1H
;
NMR (400 MHz, DMSO-d6): δ 7.86 (d, J2′,3′ = 8.7 Hz, 2H,
H-2′); 7.82 (d, J2′,3′ = 8.7 Hz, 2H, H-3′); 6.65 (d, J1,2 = 8.2
Hz, 1H, H-2); 6.55 (d, J1,2 = 8.2 Hz, 1H, H-1); 5.69 (d, 1H,
J17,18 = 8.8 Hz, H-17); 5.56 (d, 1H, J17,18 = 8.8 Hz, H-18);
4.94 (s, 1H, H-5β); 3.95 (dd, J7β,8β = 9.4 Hz, J7β,8α = 6.3 Hz,
1H, H-7β); 3.70 (s, 3H, 3-OCH3); 3.46 (s, 3H, 6-OCH3);
3.26 (d, J9α, 10α = 6.2 Hz, 1H, H-9α); 3.14 (d, J10α,10β = 16.8
Hz, 1H, H-10β); 3.12–3.11 (m, 1H, H-8β); 2.45–2.47 (m, 1H,
H-16eq); 2.31 (s, 3H, N-CH3); 2.17–2.28 (m, 3H, H-16ax, H-10α,
H-15ax,); 1.72–1.70 (m, 1H, H-15eq); 1,63 (dd, J8α,8β = 12.8 Hz,
J8α,7β = 6.3 Hz, 1H, H-8α) ppm; 13C-APT NMR (100 MHz,
DMSO-d6): δ 22.68 C(10); 31.03 C(8); 32.47 C(15); 33.37 C(7);
42.42 C(14); 43.07 CH3-N; 45.02 C(16); 46.48 C(13); 51.00
CH3O-C(6); 55.90 CH3O-C(3); 59.06 C(9); 80.88 C(6); 90.28 C(5);
113.30 C(2); 119.50 C(1); 122.64 C(1′); 125.43 C(11); 126.78 C
(17); 128.12 C(12); 128.25 C(3′); 132.58 C(2′); 133.87 C(4′)
136.81 C(18); 141.25 C(3); 147.25 C(4); 163.45 (-C═N);
2-(N-Cyano-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine-
7α-yl)-5-(4′-flourophenyl)-1,3,4-oxadiazole(6b, C29H25FN4O4).
Recrystallized from ethylacetate-hexan. Yield 50%; mp 296–298°
C; IR (KBr): 3050 (-C═H), 2938 (-C-H), 2200 (-CN) cm−1
;
1H NMR (400 MHz, DMSO-d6): δ 7.94–7.98 (m, 2H, H-2′);
7,43–7.49 (m, 2H, H-3′); 6.72 (d, J1,2 = 8.2 Hz, 1H, H-2); 6.62
(d, J1,2 = 8.2 Hz, 1H, H-1); 5.69 (d, J17,18 = 8.9 Hz, 1H, H-17);
5.65 (d, J17,18 = 8.9 Hz, 1H, H-18); 4.99 (s, 1H, H-5β); 4.14
167.49 (-C═N) ppm; hrms (EI): 562.1343 ([M
−
H]+,
C29H29BrN3O+4, calc., 562.1341).
2-(6,14-endo-Etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-5-(4′-
methoxyphenyl)-1,3,4-oxadiazole (5e, C30H31N3O5). Recrystallized
from methanol-ethyl acetate, Yield: 60%; mp 168–170°C; IR (KBr):
3033 (═C-H), 2966 (C-H) cm−1; 1H NMR (400 MHz, DMSO-d6): δ
7.86 (d, J2′,3′ = 8.8 Hz, 2H, H-2′); 7.15 (d, J2′,3′ = 8.8 Hz, 2H, H-3′);
6.65 (d, J1,2 = 8.1 Hz, 1H, H-2); 6.55 (d, J1,2 = 8.1 Hz, 1H, H-1);
5.69 (d, 1H, J17,18 = 8.6 Hz, H-17); 5.67 (d, 1H, J17,18 = 8.6 Hz,
H-18); 4.99 (s, 1H, H-5β); 3.92 (dd, J7β,8β = 9.2 Hz, J7β,8α = 6.1
Hz, 1H, H-7β); 3.85 (s, 3H, 4′-OCH3); 3.71 (s, 3H, 3-OCH3);
3.46 (s, 3H, 6-OCH3); 3.25 (d, J9α, 10α = 6.3 Hz, 1H, H-9α); 3.15
(d, J10α,10β = 17.8 Hz 1H, H-10β); 3.11–3.13 (m, 1H, H-8β);
2.46–2.45 (m, 1H, H-16eq); 2.34 (s, 3H, N-CH3); 2.14–2.31
(m, 3H, H-16ax, H-10α, H-15ax,); 1.74–1.71 (m, 1H, H-15eq);
(d, J9α,
= 5.9 Hz, 1H, H-9α); 4.06 (dd, J7β,8β = 9.4 Hz,
10α
J
7β,8α= 5.9 Hz, 1H, H-7β); 3.71 (s, 3H, 3-OCH3); 3,47 (s,
3H, 6-OCH3); 3.37-3.20 (m, 3H, H-16eq, H-16ax, H-10α);
3.12 (d, J10α,10β = 18.6 Hz, 1H, H-10β); 2.94 (dd, J8α,8β = 12.6 Hz,
J7β,8β = 9.4 Hz, 1H, H-8β); 2.29–2.37 (m, 1H, H-15ax); 1.81–1.88
(m, 2H, H-15eq, H-8α) ppm 13C-APT NMR (100 MHz,
DMSO-d6): δ 30.38 C(15); 30.63 C(8); 31.23 C(10); 33.38 C
(7); 41.37 C(14); 41.40 C(16); 46.11 C(13); 51.17 CH3O-C(6);
55.93 CH3O-C(3); 57.16 C(9); 80.61 C(6); 90.19 C(5); 113.95
C(2); 116.84–116.61 (JC3′-F = 23.0 Hz, C(3′)); 117.93 (CN);
119.96 C(1); 120.10 C(1′); 126.06 C(12); 126.61 C(17);
128.94–129.03 ( JC(2′)-F = 9.0 Hz, C(2′)); 132.35 C(11);
141.70 C(3); 134.87 C(18); 147.52 C(4); 162.76–165.25
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E98
Y. Yildirir, Ö. Pamir, S. Yavuz, and A. Dişli
Vol 50
(JC4′-F = 249.0 Hz, C(4′)); 163.43 (C═N);166.63 (C═N) ppm;
hrms (EI): 513.1958 ([M − H]+, C29H26FN4O4+, calc., 513.1938).
2-(N-Cyano-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine-
7α-yl)-5-(4-chlorophenyl)-1,3,4-oxadiazole (6c, C29H25ClN4O4).
Recrystallized from methanol-ethyl acetate. Yield 54%; mp
297–299°C; IR (KBr): 3057(═C-H), 2942 (C-H), 2209 (-CN) cm−1;
1H NMR (400 MHz, DMSO-d6): δ 7.93 (d, J2′, 3′ = 8.5 Hz,
CH3O-C(4′); 57.65 C(9); 81.11 C(6); 90.73 C(5); 114.45 C(2);
115.38 C(3′); 116.32 (CN); 118.42 C(1′); 120.43 C(1); 126.57 C(12);
128.16 C(17); 128.60 C(2′); 132.89 C(11); 135.30 C(18); 142.20 C
(3); 148.06 C(4); 162.39 (C═N); 164.56 (C═N); 166.50 C(4′) ppm;
hrms (EI): 525.2125 ([M − H]+, C30H30N4O5+, calc., 525.2138).
General procedure for the synthesis of compounds 7a–e.
A solution of corresponding compound 6a–e (0.3 mmol) in 5 mL
DMF were added NaN3 (0.19 g, 3 mmol) and NH4Cl (0.15 g, 3
mmol). The mixture was heated for 4 h under reflux, and the
reaction completion was checked by TLC. After refluxing, the
reaction mixture was cooled to room temperature and
evaporated under reduced pressure. The residue product was
extracted with ethyl acetate-water (30:10 mL). The organic layer
was dried over MgSO4 and the solvent evaporated. The crude
product was recrystallized from an appropriate solvent.
2H, H-2′); 7.70 (d, J2′,
= 8.5 Hz, 2H, H-3′); 6.72 (d,
3′
J1,2 = 8.2 Hz, 1H, H-2); 6.62 (d, J1,2 = 8.2 Hz, 1H, H-1);
5.70 (d, J17,18 = 8.7 Hz, 1H, H-17); 5.67 (d, J17,18 = 8.8 Hz,
1H, H-18); 4,99 (s, 1H, H-5β); 4.14 (d, J9α,10α = 6.2 Hz, 1H,
H-9α); 4.07 (dd, J7β,8β = 9.3 Hz, J7β,8α = 6.1 Hz, 1H, H-7β);
3.72 (s, 3H, 3-OCH3); 3.47 (s, 3H, 6-OCH3); 3.28–3.35 (m,
3H, H-16eq, H-16ax, H-10α); 3.12 (d, J10α,10β = 18.9 Hz,
1H, H-10β); 2.93 (dd, J8α,8β = 12.6 Hz, J7β,8β = 9.3 Hz 1H,
H-8β); 2.30–2.33 (m, 1H, H-15ax); 1.81–1.88 (m, 2H, H-15eq,
H-8α) ppm; 13C-APT NMR (100 MHz, DMSO-d6): δ 30.88 C(15);
31.73 C(8); 31.14 C(10); 33.91 C(7); 40.38 C(14); 41.87 C(16);
46.61 C(13); 51.68 CH3O-C(6); 56.43 CH3O-C(3); 57.65 C(9);
81.13 C(6); 90.69 C(5); 114.46 C(2); 118.42 (CN); 120.46 C(1);
122.77 C(1′); 126.57 C(12); 128.10 C(17); 128.60 C(3′); 130.15 C
(2′); 132.85 C(11); 135.41 C(18); 137.11 C(4′), 142.20 C(3);
148.03 C(4); 163.93 (C═N); 167.32 (C═N) ppm; hrms (EI):
529.1669 ([M − H]+, C29H26ClN4O+4, calc., 529.1643).
2-[N-(1H-Tetrazol-5-yl)-6,14-endo-etheno-6,7,8,14-
tetrahydrothebaine-7α-yl]-5-phenyl-1,3,4-oxadiazole (7a,
C29H27N7O4). Recrystallized from ethyl acetate-hexane, Yield:
50%; mp 195–198°C; IR (KBr): 3395–3171 (-N-H); 3043
(═C-H), 2928 (C-H) cm−1 1H NMR (400 MHz, DMSO-d6):
;
δ 7.62–7.94 (m, 5H, H-2′, H-3′, H-4′); 6.74 (d, J1,2 = 8.2
Hz, 1H, H-2); 6.63 (d, J1,2 = 8.2 Hz, 1H, H-1); 5.81 (d, 1H,
J17,18 = 8.6 Hz, H-17); 5.68 (d, 1H, J17,18 = 8.6 Hz, H-18);
5.02 (s, 1H, H-5β); 4.68 (d, J9α,
= 6.5 Hz, 1H, H-9α);
10α
2-(N-Cyano-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine-
7α-yl-5-(4′-bromophenyl)-1,3,4-oxadiazole(6d, C29H25BrN4O4).
Recrystallized from ethylacetate-hexane, Yield 56%; mp 316–317°C;
3.99 (dd, J7β,8β = 9.2 Hz, J7β,8α = 6.6 Hz, 1H, H-7β); 3.70–3.79
(m, 4H, H-16eq, 3-O-CH3); 3.40 (s, 3H, 6-OCH3); 3.04–3.20
(m, 2H, H-16ax, H-10α); 2.93 (d, J10α,10β = 20.3 Hz, 1H,
H-10β); 2.82 (dd, J8α,8β = 12.5 Hz, J7β,8β = 7.7 Hz, 1H, H-8β);
2.30–2.37 (m, 1H, H-15ax,); 1.95–1.98 (m, 1H, H-15eq); 1,80
(dd, J8α,8β = 12.5 Hz, J8α,7β = 6.6 Hz, 1H, H-8α) ppm;
13C-APT NMR (100 MHz, DMSO-d6): δ 30.30 C(10);
31.24 C(8); 32.18 C(15); 33.48 C(7); 42.05 C(14); 44.05
C(16); 46.60 C(13); 51.67 CH3O-C(6); 54.87 CH3O-C(3);
56.42 C(9); 81.13 C(6); 90.88 C(5); 113.06 C(4′); 114.87
C(2); 114.90 C(3′); 118.27 C(1′); 120.43 C(1); 127.14 C
(11); 128.13 C(18); 128.86 C(2′); 132.36 (N═C-N);
133.58 C(12); 135.60 C(17); 140.04 C(3); 148.06 C(4);
164.38 (-C═N); 168.89 (-C═N) ppm; hrms (EI): 538.2211
([M − H]+, C29H28N7O+4, calc., 538.2203).
1
IR (KBr): 3059(═C-H), 2978 (C-H), 2122 (-CN) cm−1; H NMR
(400 MHz, DMSO-d6): δ 7.92 (d, J2′, 3′ = 8.9 Hz, 2H, H-2′); 7.87
(d, J2′, 3′ = 8.9 Hz, 2H, H-3′); 6.78 (d, J1,2 = 8.2 Hz, 1H, H-2); 6.68
(d, J1,2 = 8.2 Hz, 1H, H-1); 5.75 (d, J17,18 = 8.8 Hz, 1H, H-17);
5.71 (d, J17,18 = 8.8 Hz, 1H, H-18); 5.05 (s, 1H, H-5β); 4.19 (d,
J9α,10α = 5.9 Hz, 1H, H-9α); 4.13 (dd, J7β,8β = 9.5 Hz, J7β,8α = 6.3
Hz, 1H, H-7β); 3.78 (s, 3H, 3-OCH3); 3.53 (s, 3H, 6-OCH3);
3.20–3.48 (m, 3H, H-16eq, H-16ax, H-10α); 3.17 (d, J10α,10β = 18.8
Hz, 1H, H-10β); 2.98 (dd, J8α,8β = 12.5 Hz, J7β,8β = 9.5 Hz 1H,
H-8β); 2.39–2.43 (m, 1H, H-15ax); 1.87–1.94 (m, 2H, H-15eq,
H-8α) ppm; 13C-APT NMR (100 MHz, DMSO-d6): δ 30.38 C
(15); 30.64 C(8); 31.23 C(10); 33.42 C(7); 40.33 C(14); 41.37
C(16); 46.11 C(13); 51.18 CH3O-C (6); 55.94 CH3O-C (3);
57.15 C(9); 80.62 C(6); 90.19 C(5); 113.95 C(2); 117.92
(CN); 119.96 C(1); 122.60 C(1′); 125.48 C(4′), 126.07 C(12);
127.59 C(17); 128.21 C(3′); 132.35 C(11); 132.57 C(2′);
134.91 C(18); 141.70 C(3); 147.53 C(4); 163.54 (C═N);
2-[N-(Tetrazol-1H-5-yl)-6,14-endo-etheno-6,7,8,14-
tetrahydrothebaine-7α-yl]-5-(4′-flourophenyl)-1,3,4-oxadiazole
(7b, C29H26FN7O4). Recrystallized from methanol. Yield 55%;
mp 263–266°C; IR (KBr): 3328–3223 (-N-H), 3066 (-C═H),
1
2947 (-C-H) cm−1; H NMR (400 MHz, DMSO-d6): δ 7.96–8.04
166.83 (C═N) ppm; hrms (EI): 573.1136 ([M
−
H]+,
(m, 2H, H-2′); 7.43 -7.48 (m, 2H, H-3′); 6.72 (d, J1,2 = 8.3 Hz,
1H, H-2); 6.58 (d, J1,2 = 8.3 Hz, 1H, H-1); 5.80 (d, 1H,
J17,18 = 8.7 Hz, H-17); 5.67 (d, 1H, J17,18 = 8.7 Hz, H-18);
5.02 (s, 1H, H-5β); 4.67 (d, J9α, 10α = 5.9 Hz, 1H, H-9α); 4.01
(dd, J7β,8β = 8.8 Hz, J7β,8α = 5.9 Hz, 1H, H-7β); 3.71–3.79 (m,
4H, H-16eq, 3-OCH3); 3.45 (s, 3H, 6-OCH3); 3.15–3.23 (m,
2H, H-16ax, H-10α); 2.85 (d, J10α,10β = 15.2 Hz, 1H, H-10β);
2.69 (dd, J8α,8β = 10.0 Hz, J7β,8β = 7.4 Hz, 1H, H-8β); 2.41–2.50
(m, 1H, H-15ax,); 1.91–1.95 (m, 1H, H-15eq); 1,78 (dd,
J8α,8β = 12.9 Hz, J8α,7β = 6.1 Hz, 1H, H-8α) ppm; 13C-APT
NMR (100 MHz, DMSO-d6): δ 31.12 C(10); 31.20 C(8);
31.27 C(15); 33.90 C(7); 42.06 C(14); 45.43 C(16); 47.35 C
(13); 51.65 CH3O-C(6); 55.38 CH3O-C(3); 56.44 C(9); 81.30
C(6); 90.77 C(5); 114.32 C(2); 117.03 C(11); 117.12–117.34
(JC3′-F = 22.0 Hz, C(3′)); 120.42 C(1); 120.63 C(1′); 128.17 C
(18); 129.41–129.59 (JC2′-F = 9.0 Hz, C(2′)); 130.15 (N═C-N);
133.32 C(12); 135.90 C(17); 142.09 C(3); 148.00 C(4);
165.73–163.24 (JC4′-F = 249.0 Hz, C(4′)); 166.89 (C═N);
C29H26BrN4O+4, calc., 573.1137).
2-(N-Cyano-6,14-endo-etheno-6,7,8,14-tetrahydrothebaine-7α-yl)-
5-(4′-methoxyphenyl)-1,3,4-oxadiazole (6e, C30H29N4O5).
Recrystallized from ethyl acetate-hexane, Yield: 50%; mp 175–177°C;
1
IR (KBr): 3057 (═C-H), 2942 (C-H), 2209 (-CN) cm−1; H NMR
(400 MHz, DMSO-d6): δ 7.86 (d, J2′, 3′ = 8.8 Hz, 2H, H-2′); 7.15
(d, J2′, 3′ = 8.8 Hz, 2H, H-3′); 6.73 (d, J1,2 = 8.2 Hz, 1H, H-2); 6.62
(d, J1,2 = 8.2 Hz, 1H, H-1); 5.68 (d, J17,18 = 8.8 Hz, 1H, H-17); 5.65
(d, J17,18 = 8.8 Hz, 1H, H-18); 4,99 (s, 1H, H-5β); 4.14 (d,
J9α,10α = 6.0 Hz, 1H, H-9α); 4.01 (dd, J7β,8β = 9.5 Hz, J7β,8α = 6.1
Hz, 1H, H-7β); 3.85 (s, 3H, 4′-OCH3); 3.79 (s, 3H, 3-OCH3); 3.47
(s, 3H, 6-OCH3); 3.19–3.39 (m, 3H, H-16eq, H-16ax, H-10α); 3.12
(d, J10α,10β = 18.9 Hz, 1H, H-10β); 2.92 (dd, J8α,8β = 12.6 Hz, J7β,8β
= 9.5 Hz 1H, H-8β); 2.29–2.37 (m, 1H, H-15ax); 1.82–1.87 (m, 2H,
H-15eq, H-8α) ppm; 13C-APT NMR (100 MHz, DMSO-d6): δ 30.90
C(15); 31.16 C(8); 31.73 C(10); 33.83 C(7); 41.86 C(14); 41.92 C
(16); 46.60 C(13); 51.64 CH3O-C(6); 55.98 CH3O-C(3); 56.44
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis and Characterization of New Thebaine Derivatives as Potential
Opioid Agonists and Antagonists
E99
167.22 (C═N) ppm; hrms (EI): 556.2103 ([M − H]+,
3.48 (s, 3H, 6-OCH3); 3.15–3.24 (m, 2H, H-16ax, H-10α); 2.87
(d, J10α,10β = 18.8 Hz, 1H, H-10β); 2.72 (dd, J8α,8β = 12.7 Hz, J7β,8β
= 9.2 Hz, 1H, H-8β); 2.29–2,33 (m, 1H, H-15ax,); 1.91–1.94 (m,
1H, H-15eq); 1,77 (dd, J8α,8β = 12.7 Hz, J7β,8α = 6.1 Hz, 1H, H-8α)
ppm; 13C-APT NMR (100 MHz, DMSO-d6): δ 31.13 C(10); 31.19
C(8); 31,28 C(15); 33.89 C(7); 40,62 C(14); 42,07 C(16); 47,35 C
(13); 51.63 CH3O-C(6); 55.40 CH3O-C(3); 55.97 CH3O-C(4′);56.48
C(9); 81.30 C(6); 90.85 C(5); 112.10 (N═C-N); 114.38 C(2);
115.83 C(3′); 116.43 C(1′); 120.40 C(1); 127.06 C(11); 128,19 C
(18); 128.57 C(2′); 133.36 C(12); 135.83 C(17); 142,10 C(3);
148.04 C(4); 162.38 (-C═N); 164.53 (-C═N); 166.59 C(4′) ppm;
hrms (EI): 568.2296 ([M − H]+, C30H30N7O5+, calc., 568.2308).
C29H27FN7O+4, calc., 556.2109).
2-[N-(Tetrazol-1H-5-yl)-6,14-endo-etheno-6,7,8,14-
tetrahydrothebaine-7α-yl]-5-(4′-cholorophenyl)-1,3,4-oxadiazole
(7c, C29H26ClN7O4). Recrystallized from methanol-chlorofom
Yield: 58%; mp 268–270°C; IR (KBr): 3471–3200 (-N-H), 3057
(═C-H), 2942 (C-H) cm−1; 1H NMR (400 MHz, DMSO-d6):
δ 8.00 (d, J2′,3′ = 8.5 Hz, 2H, H-2′); 7.75 (d, J2′,3′ = 8.5 Hz, 2H,
H-3′); 6.78 (d, J1,2 = 8.2 Hz, 1H, H-2); 6.65 (d, J1,2 = 8.2 Hz, 1H,
H-1); 5.86 (d, 1H, J17,18 = 8.8 Hz, H-17); 5.74 (d, 1H, J17,18 = 8.8
Hz, H-18); 5.08 (s, 1H, H-5β); 4.78 (d, J9α, 10α = 5.6 Hz, 1H,
H-9α); 4.05 (dd, J7β,8β = 9.3 Hz, J7β,8α = 6.1 Hz, 1H, H-7β);
3.72–3.83 (m, 4H, H-16eq, 3-OCH3); 3.49 (s, 3H, 6-OCH3);
3.22–3.30 (m, 2H, H-16ax, H-10α); 2.90 (d, J10α,10β = 17.1 Hz,
1H, H-10β); 2.82 (dd, J8α,8β = 12.7 Hz, J7β,8β = 9.3 Hz 1H, H-8β);
2.40–2.45 (m, 1H, H-15ax); 1.99–2.02 (m, 1H, H-15eq); 1,85 (dd,
Acknowledgments. The authors gratefully acknowledge financial
support from the Scientific and Technical Research Council of
Turkey (TUBITAK, Project No. 107T676). They also thank the
Turkish Grain Board (TMO) for the supply of thebaine.
J
8α,8β = 12.7 Hz, J8α,7β = 6.1 Hz, 1H, H-8α) ppm; 13C-APT NMR
(100 MHz, DMSO-d6): δ 28.96 C(10); 30.68 C(8); 30.76 C(15);
33.41 C(7); 40.07 C(14); 41.55 C(16); 46.85 C(13); 51.14
CH3-O-C(6); 54.87 CH3-O-C(3); 55.92 C(9); 80.80 C(6); 90.23
C(5); 113.79 C(2); 114.23 (N═C-N); 119.92 C(1); 122.27 C
(1′);126.51 C(11); 127.66 C(18); 128.06 C(3′);129.64 C
(2′);132.79 C(12); 135.43 C(17); 136.56 C(4′); 141.58 C(3);
147.48 C(4); 163.38 (-C═N); 166.89 (-C═N) ppm; hrms (EI):
572.1801 ([M − H]+, C29H27ClN7O+4, calc., 572.1813).
REFERENCES AND NOTES
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Bradley, P. B.; Portoghesse, P. S.; Hamon, M. Pharmacol Rev 1996, 48,
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[5] Kalinin, V. N.; Shishkov, I. V.; Moiseev, S. K.; Shults, E. E.;
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Chim Acta 2006, 89, 861.
[6] Yavuz, S.; Yildirir, Y. Helv Chim Acta 2010, 93, 2406.
[7] Lewis, J. W.; Husbands, S. M. J Med Chem 2004, 43, 139.
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717.
[9] Maat, L.; Woudenberg, R. H.; Meuzelaar, G. J.; Linders, J. T.
M. Bioorg Med Chem 1999, 7, 529.
[10] Bentley, K. W.; Hardy, D. G. J Am Chem Soc 1967, 89, 3267.
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1972, 20, 85.
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E.; Knapp, B. I.; Neumeyer, J. L. J Med Chem 2007, 50, 2747.
[13] Liu, C. H.; Zhong, B.; Liu, C.; Wu, B.; Gong, Z. Acta Chim
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Chem 2006, 71, 9584.
[15] Tully, W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R. J
Med Chem 1991, 34, 2060.
[16] Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur J Med Chem 2000,
35, 267.
2-[N-(Tetrazol-1H-5-yl)-6,14-endo-etheno-6,7,8,14-
tetrahydrothebaine-7α-yl]-5-(4′-bromophenyl)-1,3,4-oxadiazole
(7d, C29H26BrN7O4). Recrystallized from methanol. Yield: 60%;
mp 261–264°C; IR (KBr): 3385–3138(N-H), 3052(═C-H), 2961
(-C-H) cm–1 1H NMR (400 MHz, DMSO-d6): δ 7.90 (d,
;
J2′, 3′ = 8.8 Hz, 2H, H-2′); 7.84 (d, J2′, 3′ = 8.8 Hz, 2H, H-3′); 6.77
(d, J1,2 = 8.0 Hz, 1H, H-2); 6.63 (d, J1,2 = 8.0 Hz, 1H, H-1); 5.86 (d,
1H, J17,18 = 8.7 Hz, H-17); 5.73 (d, 1H, J17,18 = 8.7 Hz, H-18); 5.07
(s, 1H, H-5β); 4.73 (d, J9α, 10α = 6.3 Hz, 1H, H-9α); 4.07 (dd,
J7β,8β = 6.4 Hz, J7β,8α = 7.1 Hz, 1H, H-7β); 3.70–3,85 (m, 4H,
H-16eq, 3-OCH3); 3.54 (s, 3H, 6-OCH)3; 3.22–3,28 (m, 2H, H-16ax,
H-10α); 2.93 (d, J10α,10β = 16.7 Hz, 1H, H-10β); 2.72 (dd, 1H,
J8α,8β = 12.5 Hz, J7β,8β = 6.4 Hz, 1H, H-8β); 2.39–2.43 (m,
1H, H-15ax); 1.97–1.99 (m, 1H, H-15eq); 1,84 (dd, J8α,8β = 12.5 Hz,
J7β,8α = 7.1 Hz, 1H, H-8α) ppm; 13C-APT NMR (100 MHz,
DMSO-d6): δ 31.13 C(10); 31.19 C(8); 31.27 C(15); 33.89 C(7);
40.07 C(14); 45.44 C(16); 47.35 C(13); 51.66 CH3O-C(6); 56.44
CH3O-C(3); 56.48 C(9); 81.30 C(6); 90.85 C(5); 114.31 C(2);
120.40 C(1); 123.12 C(1′); 127.23 C(11); 128.14 C(18); 128.68 C
(3′); 131.50 (N═C-N); 133.07 C(2′); 133.32 C(4′); 135.96 C(17);
135.98 C(12); 142.18 C(3); 147.99 C(4); 164.00 (-C═N);
167.41 (-C═N) ppm; hrms (EI): 616.1323 ([M − H]+,
C29H27BrN7O+4, calc., 616.1308).
2-[N-(Tetrazol-1H-5-yl)-6,14-endo-etheno-6,7,8,14-
tetrahydrothebaine-7α-yl]-5(4′-methoxyphenyl)-1,3,4-oxadiazole
(7e, C30H29N7O5). Recrystallized from methanol-ethyl acetate,
Yield: 65%; mp 228–230°C; IR (KBr): 3385–3138 (N-H), 3052
(═C-H), 2961(-C-H) cm–1; 1H NMR (400 MHz, DMSO-d6,
δ, ppm): δ 7.85 (d, J2′,3′ = 8.8 Hz, 2H, H-2′); 7.14 (d, J2′,3′ = 8.8
Hz, 2H, H-3′); 6.71 (d, J1,2 = 8.2 Hz, 1H, H-2); 6.58 (d, J1,2 = 8.2
Hz, 1H, H-1); 5.80 (d, 1H, J17,18 = 8.7 Hz, H-17); 5.67 (d, 1H,
J17,18 = 8.7 Hz, H-18); 5.00 (s, 1H, H-5β); 4.66 (d, J9α, 10α = 6.4
Hz, 1H, H-9α); 3.97 (dd, J7β,8β = 9.2 Hz, J7β,8α = 6.1 Hz, 1H,
H-7β); 3.84 (s, 3H, 4′-OCH3); 3.71–3.79 (m, 4H, H-16eq, 3-OCH3);
[17] Lenz, G. R.; Evans, S. M.; Walters, D. E.; Hopfinger, A. J.
Opiates; Academic Press: Orlando, 1986.
[18] Nogrady, T. Medicinal Chemistry–A Biochemical Approach;
Oxford University Press: Oxford, UK, 1988.
[19] Jin, T.; Kamijo, S.; Yamamoto, Y. Tetrahedron Lett 2004, 45,
9435.
[20] Odabasoglu, M.; Yavuz, S.; Pamir, Ö.; Yildirir, Y.; Büyükgüngör,
O. Acta Crystalogr 2009, 65, o864.
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1969, 2235.
[22] Bentley, K. W.; Burton, M.; Uff, B. C. J Med Chem 1984, 27,
1276.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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