Applying Gewald reaction for the preparation of some novel aminothieno derivatives featuring noroxymorphone skeletal backbone

Article abstract of DOI:10.1080/17415993.2020.1729761

A group of noroxymorphone derivatives were subjected to Gewald reaction conditions to prepare their respective aminothieno products. In refluxing piperidine/ethanol, 1a–g reacted with elemental sulfur and malononitrile to produce 2a–g in high yields. Reactions took place in one pot and completed within 4–7 h and products precipitated spontaneously in the reaction mixtures.

Full text of DOI:10.1080/17415993.2020.1729761

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: https://www.tandfonline.com/loi/gsrp20
Applying Gewald reaction for the preparation of
some novel aminothieno derivatives featuring
noroxymorphone skeletal backbone
Saeed Bagherpour, Mohammad M. Mojtahedi & M. Saeed Abaee
To cite this article: Saeed Bagherpour, Mohammad M. Mojtahedi & M. Saeed Abaee
(2020): Applying Gewald reaction for the preparation of some novel aminothieno
derivatives featuring noroxymorphone skeletal backbone, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2020.1729761
To link to this article: https://doi.org/10.1080/17415993.2020.1729761
View supplementary material
Published online: 19 Feb 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=gsrp20

JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2020.1729761
Applying Gewald reaction for the preparation of some novel
aminothieno derivatives featuring noroxymorphone skeletal
backbone
Saeed Bagherpour, Mohammad M. Mojtahedi and M. Saeed Abaee
Department of Organic Chemistry and Natural Products, Chemistry and Chemical Engineering Research
Center of Iran, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received 14 December 2019
Accepted 7 February 2020
A group of noroxymorphone derivatives were subjected to Gewald
reaction conditions to prepare their respective aminothieno prod-
ucts. In refluxing piperidine/ethanol, 1a–g reacted with elemental
sulfur and malononitrile to produce 2a–g in high yields. Reactions
took place in one pot and completed within 4–7 h and products
precipitated spontaneously in the reaction mixtures.
KEYWORDS
Noroxymorphones;
aminothiophenes;
heterocycles;
multicomponent reaction;
Gewald reaction
1. Introduction
For several millenniums, man has used natural products for health purposes and curing
diseases [1]. Modern chemistry in recent centuries has promoted this area of medicine dra-
matically by isolating active agents from various natural sources [2], elucidating their struc-
tures [3], and synthesizing their derivatives [4] to explore numerous candidate molecules
for medicinal applications. From about 1000 chemical entities that were reviewed by New-
man and Cragg [5] for their bioactivities, only 43 of them were pure natural products
and more than half of the rest were either derivatives or mimics of natural products. This
highlights very well the importance of the chemistry of semisynthetic molecules.
Since isolation [6] and structural determination [7] of morphine, many research studies
have been carried out on morphine total synthesis [8] and its conversion to semisynthetic
CONTACT Mohammad M. Mojtahedi
mojtahedi@ccerci.ac.ir
Department of Organic Chemistry and Natural
Products, Chemistry and Chemical Engineering Research Center of Iran, Pajouhesh Blvd, 17th Km Tehran-Karaj Highway,
P.O.Box 14335–186, Tehran, Iran
© 2020 Informa UK Limited, trading as Taylor & Francis Group

2
S. BAGHERPOUR ET AL.
Scheme 1. Structure of the reactants.
structures [9] in order to obtain nonracemic optically active compounds with improved
medicinal properties [10], such as treating opioid overdose [11] or dependency [12] and
alcoholism [13]. Closely related structures to morphine are noroxymorphones, which due
to having active functional groups can be explored for the synthesis of other semisynthetic
structures [14–16].
In the framework of our program on sulfur chemistry [17–19] and Gewald reaction
[20,21], we were persuaded to extend our experience to compounds with natural origin.
On this basis noroxymorphone structures shown in Scheme 1, which are semisynthetic
and biologically active, were chosen to be subjected to Gewald reaction [22,23] conditions
to obtain their aminothiophene containing structures. Search in the literature shows that
there is no precedence for this approach, and the most closely related studies are limited to
the synthesis of a few thienomorphinans [10,16].
2. Results and discussion
We first optimized the conditions for Gewald reaction of 1a with malononitrile and sulfur
(Table 1). The best results were obtained when the three reactants were refluxed in piperi-
dine/EtOH solution (entry 1). As a result, 87% of 2a was obtained after 4 h. Use of other
alcoholic solvents (entries 2–4) led to lower yields of 2a, while water almost stopped the
reaction (entry 5). Replacement of piperidine with other amines (entries 6–8) or inorganic
bases (entries 9–10) did not lead to better results.
Next, the optimum conditions were applied to evaluate the diversity of the procedure
(Table 2). In addition to 1a (entry 1), when two N-cyclopropylmethyl derivatives 1b,c
were subjected to the conditions, 2b,c were obtained in comparable yields after 5 h (entries
2–3). Similarly noroxycodone 1d (entry 4), oxycodone 1e (entry 5), and the two N-allyl
derivatives (entries of 6–7) gave their respective products within 5–7 h.

JOURNAL OF SULFUR CHEMISTRY
3
Table 1. Optimization of the conditions for the synthesis of 2a.
Entry
Solvent
Base
Temperature (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
EtOH
piperidine
piperidine
piperidine
piperidine
piperidine
piperazine
Et3N
morpholine
K2CO3
KOH
refluxing
refluxing
80
refluxing
refluxing
refluxing
refluxing
refluxing
refluxing
refluxing
4
6
4
4
4
4
4
4
4
4
87
78
82
80
5
60
45
65
60
68
MeOH
PEG-400
n-BuOH
H2O
EtOH
EtOH
EtOH
EtOH
EtOH
10
aIsolated yield.
Table 2. Synthesis of various derivatives of 2.
Entry
Reactant
Product
Time (h)
Yield (%)a
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
4
5
5
5
6
7
6
87
90
80
87
84
80
75
1g
2g
aIsolated yield.
Figure 1. Feasible reaction pathway.
Based on the observations, a mechanism can be proposed for the reaction, where it goes
through a Knoevenagel intermediate (Figure 1). Indeed, TLC monitoring of the reactions
suggested the formation of compounds of type 2a’. To support this idea, the reaction was
stopped midway, before the addition of sulfur, to obtain 2a’. Subsequently, 2a’ was treated
separately with piperidine, ethanol, and sulfur to obtain 2a in comparable yields and time
period.

4
S. BAGHERPOUR ET AL.
3. Conclusion
In summary, we succeeded to prepare several novel semisynthetic aminothieno deriva-
tives containing the noroxymorphone skeletal backbone, using a one-pot procedure. The
products are to be studied for their biological and medicinal properties in the near future.
4. Experimental
Melting points are uncorrected. FT-IR spectra were recorded using KBr disks on a Bruker
Vector-22. NMR spectra were obtained on a FT-NMR Bruker Ultra ShieldTM (500 MHz) as
DMSO-d6 or CDCl3 solutions using TMS as internal standard reference. Elemental analy-
ses were performed using a Thermo Finnigan Flash EA 1112 instrument. MS spectra were
obtained on a Finnigan Mat 8430 apparatus at ionization potential of 70 eV. TLC experi-
ments were carried out on pre-coated silica gel plates using petroleum CHCl3/MeOH (9:1)
as the eluent. Ketones 1a,b and 1d–f were prepared using reported procedures [9,24,25].
All other reagents and starting materials were purchased from the Merck Company. Com-
pounds 1c, 1g, 2a’, and 2a–g are new and were identified based on their physical and
spectral properties.
4.1. The procedure for the synthesis of 1c and 1g
In a 3-necked flask equipped with mechanical stirrer, condenser, and thermometer, a
mixture of 14 mmol 1a (or 1f,) and K2CO3 (3.8 g, 28.0 mmol) in MeCN (50.0 mL) was
stirred at 50°C for 30 min. At this point, a solution of cyclopropylmethylbromide (2.0 mL,
21.0 mmol) in MeCN (5.0 mL) was added to the mixture dropwise and the resulting mix-
ture was refluxed for 4 h. At the end, the volatile portion of the mixture was removed under
reduced pressure and the residue was dissolved in boiling Me2CHOH (20.0 mL). The solu-
tion was mixed with activated charcoal (0.2 g) for 15 min and filtered, and the filtrate was
cooled in a water bath (5–10°C) to solidify. The solid was washed with cold Me2CHOH
(5.0 mL) and dried in oven (40–45°C) to obtain the final product 1c (89%) or 1g (84%).
4.2. Typical procedure for the synthesis of 2
A mixture of 1a (2.73 g, 8.0 mmol), malononitrile (529.0 mg, 8.0 mmol), sulfur (256.0 mg,
8.0 mmol), and piperidine (1.2 mL, 12.0 mmol) in EtOH (15.0 mL) was stirred at 80°C for
4 h until TLC showed complete disappearance of the starting materials. The product pre-
cipitated at the end of the reaction and was separated by filtration. The crude product was
purified by silica gel column chromatography using CHCl3/MeOH (9:1) as eluent to afford
the pure product. Product 2a was obtained in 87% yield (2.93 g). The product structure
was identified based on its physical and spectral characteristics.
4.3. Spectral data of new products
4.3.1. 3-(Cyclopropylmethoxy)-17-(cyclopropylmethyl)-14-hydroxy-4,5α-
epoxymorphinan-6-one (1c)
White crystal, mp 112–114°C; 1H NMR (500 MHz, CDCl3) δ 0.16–0.17 (m, 2H), 0.31–0.37
(m, 2H), 0.56–0.57 (m, 2H), 0.58–0.61 (m, 2H), 0.56–0.91 (m, 1H), 1.26–1.34 (m, 1H), 1.58

JOURNAL OF SULFUR CHEMISTRY
5
(dd, J = 2.5, 12.5 Hz, 1H), 1.66 (ddd, J = 3.5, 13.5, 14.0 Hz, 1H), 1.89 (dddd, J = 1.5, 3.0,
4.5, 11.5 Hz, 1 H), 2.16 (ddd, J = 3.0, 11.5, 12.5 Hz, 1H), 2.33 (ddd, J = 3.0, 6.0, 11.5 Hz,
1H), 2.41–2.43 (m, 3H), 2.60 (dd, J = 6.0, 18.5 Hz, 1 H), 2.70 (dd, J = 4.0, 11.5 Hz, 1H),
3.05 (ddd, J = 5.0, 14.5, 16.0 Hz, 1H), 3.07 (d, J = 18.5 Hz, 1H), 3.20 (d, J = 5.0 Hz, 1 H),
4.00 (ap d, J = 7.0 Hz, 2H), 4.67 (s, 1H), 5.25 (br s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.72 (d,
J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ = 3.2, 3.3, 3.8, 4.0, 9.4, 10.7, 22.7, 30.7,
31.5, 36.2, 43.6, 50.7, 59.2, 62.0, 70.1, 75.1, 90.3, 117.6, 119.4, 125.1, 129.6, 142.1, 145.3,
208.5; IR (KBr) 3359, 2928, 1723, 1602 cm−1; MS (70 eV) m/z 395 [M+], 354, 310, 241;
Anal. Calcd for C24H29NO4: C, 72.89; H, 7.39; N, 3.54. Found: C, 72.65; H, 7.55; N, 3.41.
4.3.2. 17-(Allyl)-3-(cyclopropylmethoxy)-14-hydroxy-4,5α-epoxymorphinan-6-
one (1 g)
White crystal, mp 108–110°C; 1H NMR (500 MHz, CDCl3) δ 0.29–0.35 (m, 2H), 0.57–0.59
(m, 2H), 1.23–-1.30 (m, 1H), 1.56 (ddd, J = 2.0, 11.0, 13.0 Hz, 1H), 1.63 (dd, J = 2.5,
16.5 Hz, 1H), 1.86 (ddd, J = 2.5, 4.5, 14.0 Hz, 1H), 2.15 (ddd, J = 3.5, 12.0, 12.5 Hz, 1H),
2.28 (ddd, J = 3.0, 6.0, 11.5 Hz, 1H), 2.38 (ddd, J = 5.0, 12.0, 12.5 Hz, 1H), 2.54–2.59 (m,
2H), 2.98–3.03 (m, 2H), 3.07 (d, J = 18.5 Hz, 1H), 3.15 (ap d, J = 5.5 Hz, 2H), 3.94 (ap
d, J = 7.0 Hz, 2H), 5.02 (s, 1H), 5.19 (d, J = 11.0 Hz, 1H), 5.23 (dd, J = 1.5, 18.0 Hz, 1H),
5.78–5.86 (m, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ = 3.2, 3.3, 10.7, 22.7, 30.5, 31.4, 36.2, 43.3, 50.6, 57.6, 62.2, 70.2, 75.1, 90.2, 117.6,
118.1, 119.4, 125.0, 129.6, 135.1, 142.1, 145.3, 208.4; IR (KBr) 3370, 2931, 1724, 1602 cm−1
;
MS (70 eV) m/z 381 [M+], 340, 296, 241; Anal. Calcd for C23H27NO4: C, 72.42; H, 7.13;
N, 3.67. Found: C, 72.45; H, 7.23; N, 3.69.
4.3.3. 5ꢀ-Amino-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5α-epoxythieno[3ꢀ,2ꢀ-
6,7]morphinane-4ꢀ-carbonitrile (2a)
1
Brown crystal, mp 310°C decomposes; H NMR (500 MHz, DMSO-d6) δ 0.13–0.14
(m, 2H), 0.46–0.52 (m, 2H), 0.86–0.87 (m, 1H), 1.50 (d, J = 12.0 Hz, 1H), 2.12 (dd,
J = 12.0, 12.5 Hz, 1H), 2.23 (ddd, J = 5.0, 12.0, 12.5 Hz, 1H), 2.33 (d, J = 6.0 Hz, 2H), 2.37
(d, J = 6.0 Hz, 2H), 2.50 (dd, J = 1.5, 1.5 Hz, 1H), 2.60–2.67 (m, 2H), 3.03 (d, J = 18.5 Hz,
1H), 3.15 (d, J = 6.0 Hz, 1H), 5.13 (s, 1H), 6.49 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 8.0 Hz,
1H), 7.06 (s, 2H), 9.04 (br s, 1H); 13C NMR (125 MHz, DMSO-d6) δ = 4.0, 4.3, 9.6, 23.0,
31.4, 31.8, 43.7, 46.4, 59.0, 61.6, 72.4, 83.1, 84.7, 116.3, 117.6, 118.9, 120.5, 124.5, 128.7,
130.9, 140.3, 143.5, 163; IR (KBr) 3443, 2923, 2199, 1462 cm−1; MS (70 eV) m/z 421 [M+],
380, 324, 277; Anal. Calcd for C23H23N3O3S: C, 65.54; H, 5.50; N, 9.97. Found: C, 65.45;
H, 5.61; N, 10.09.
4.3.4. 5ꢀ-Amino-17-(cyclopropylmethyl)-14-hydroxy-3-methoxy-4,5α-
epoxythieno[3ꢀ,2ꢀ-6,7]morphinane-4ꢀ-carbonitrile (2b)
1
Light yellow crystal; mp = 293–295°C; H NMR (500 MHz, DMSO-d6) δ = 0.12 (dd,
J = 6.0, 11.0 Hz, 2H), 0.45–0.52 (m, 2H), 0.86–0.87 (m, 1H), 1.5 (d, J = 10.0 Hz, 1H),
2.10 (dd, J = 10.0, 12.0 Hz, 1H), 2.24 (ddd, J = 5.0,12.0, 12.5 Hz, 1H), 2.30–2.40 (m, 3H),
2.49–2.52 (m, 1H), 2.62–2.70 (m, 2H), 3.05 (d, J = 18.5 Hz, 1H), 3.17 (d, J = 6.0 Hz, 1H),
3.72 (s, 3H), 4.81 (s, 1H), 5.18 (s, 1H), 6.62 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H),
7.10 (s, 2H)13C NMR (125 MHz, DMSO-d6) δ = 4.0, 4.2, 9.6, 23.0, 31.3, 31.8, 43.6, 46.3,
56.3, 59.1, 61.6, 72.3, 82.9, 85.2, 114.4, 116.2, 119.1, 120.6, 126.5, 128.6, 131.1, 142.9, 144.2,

6
S. BAGHERPOUR ET AL.
163.7; IR (KBr) 3362, 2926, 2202, 1447 cm−1; MS (70 eV) m/z 435 [M+], 394, 355, 321;
Anal. Calcd for C24H25N3O3S:C, 66.19; H, 5.79; N, 9.65. Found: C, 66.28; H, 5.90; N, 9.58.
4.3.5. 5ꢀ-Amino-3-(cyclopropylmethoxy)-17-(cyclopropylmethyl)-14-hydroxy-4,5α-
epoxythieno[3ꢀ,2ꢀ-6,7]morphinane-4ꢀ-carbonitrile (2c)
Light brown crystal; mp = 132–134°C; 1H NMR (500 MHz, DMSO-d6) δ = 0.13–0.14 (m,
2H), 0.19–0.23 (m, 2H), 0.48–0.49 (m, 4H), 0.86–0.88 (m, 1H), 1.14–1.15 (m, 1H), 1.50 (d,
J = 12.0 Hz, 1H), 2.07–2.11 (m, 1H), 2.22–2.23 (m, 1H), 2.24–2.26 (m, 1H), 2.28–2.32 (m,
2H), 2.66–2.68 (m, 2H), 3.04 (d, J = 18.5 Hz, 1H), 3.16–3.17 (m, 1H), 3.33 (s, 2H), 3.81
(d, J = 7.0 Hz, 2H), 5.18 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 7.09 (s,
2H);13C NMR (125 MHz, DMSO-d6) δ = 2.4, 2.5, 3.0, 3.2, 8.6, 9.9, 22.1, 25.0, 30.1, 30.8,
42.7, 45.2, 58.1, 60.6, 71.2, 73.1, 84.1, 99.0, 115.2, 115.9, 118.2, 119.6, 125.8, 127.6, 141.0,
143.6, 162.7; IR (KBr) 3312, 2921, 2201, 1444 cm−1; MS (70 eV) m/z 475 [M+], 434, 420,
217; Anal. Calcd for C27H29N3O3S: C, 68.19; H, 6.15; N, 8.84. Found: C, 68.11; H, 6.02; N,
9.01.
4.3.6. 5ꢀ-Amino-14-hydroxy-3-methoxy-4,5α-epoxythieno[3ꢀ,2ꢀ-6,7]morphinane-4ꢀ-
carbonitrile (2d)
Yellow crystal; mp = 259°C decompose; 1H NMR (500 MHz, DMSO-d6) δ = 1.22–1.35
(m, 2H), 1.34 (d, J = 10.0 Hz, 1H), 2.18 (ddd, J = 5.0, 12.0, 12.0 Hz,1H), 2.23 (d,
J = 16.0 Hz,1H), 2.34 (d, J = 16.0 Hz, 1H), 2.46–2.54 (m, 1H), 2.66 (dd, J = 5.0, 13.0 Hz,
1H), 2.93 (d, J = 18.0 Hz, 1H), 3.03–3.10 (m, 2H), 3.72 (s, 3H), 5.13 (s, 1H), 6.62 (d,
J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 7.12 (s, 2H); 13C NMR (125 MHz, DMSO-d6)
δ = 32.2, 32.3, 46.6, 55.7, 56.2, 56.7, 57.1, 72.0, 82.9, 85.6, 115.0, 116.3, 119.0, 120.5, 127.0,
128.7, 131.1, 142.9, 144.2, 163.7; IR (KBr) 3306, 2928, 2200, 1444 cm−1; MS (70 eV) m/z
381 [M+], 338, 277, 249, 216; Anal. Calcd for C20H19N3O3S: C, 62.98; H, 5.02; N, 11.02.
Found: C, 62.83; H, 5.11; N, 10.92.
4.3.7. 5ꢀ-Amino-14-hydroxy-3-methoxy-17-methyl-4,5α-epoxythieno[3ꢀ,2ꢀ-
6,7]morphinane-4ꢀ-carbonitrile (2e)
Brown crystal; mp = 248–250°C; 1H NMR (500 MHz, DMSO-d6) δ = 1.23–1.24 (m, 1H),
1.49 (d, J = 11.0 Hz, 1H), 2.15 (dd, J = 11.0, 11.0 Hz, 1H), 2.28 (d, J = 10.0 Hz, 1H), 2.30
(d, J = 5.0 Hz, 1H), 2.37 (s, 3H), 2.50 (s, 2H), 2.67 (dd, J = 6.5, 18.0 Hz, 1H), 2.94 (s,
1H), 3.16 (d, J = 18.0 Hz, 1H), 3.72 (s, 3H), 5.18 (s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.73
(d, J = 8.0 Hz, 1H), 7.15 (s, 2H); 13C NMR (125 MHz, DMSO-d6) δ = 3.9, 9.6, 22.9, 23.0,
31.8, 46.4, 59.0, 59.8, 61.5, 61.7, 72.4, 83.0, 84.7, 116.3, 120.4, 124.5, 128.7, 130.9, 140.3,
143.4, 163.7; IR (KBr) 3168, 2925, 2201, 1463 cm−1; MS (70 eV) m/z 395 [M+], 362, 317,
216; Anal. Calcd for C21H21N3O3S: C, 63.78; H, 5.35; N, 10.63. Found: C, 63.69; H, 5.42;
N, 10.59.
4.3.8. 17-Allyl-5ꢀ-amino-3,14-dihydroxy-4,5α-epoxythieno[3ꢀ,2ꢀ-6,7]morphinane-4ꢀ-
carbonitrile (2f)
Yellow crystal; mp = 175–177°C;1H NMR(500 MHz, DMSO-d6) δ = 1.48 (d, J = 12.0 Hz,
1H), 2.11 (ddd, J = 3.0, 12.0, 12.0 Hz, 1H), 2.22 (ddd, J = 5.0, 12.0, 12.0 Hz, 1H), 2.30
(dd, J = 12.0, 16.0 Hz, 2H), 2.49–2.55 (m, 2H), 2.60 (dd, J = 6.0, 8.5 Hz, 1H), 2.95 (d,
J = 6.0 Hz, 1H), 3.05 (d, J = 18.5 Hz, 1H), 3.12 (d, J = 6.0 Hz, 2H), 4.70 (br s, 1H), 5.14

JOURNAL OF SULFUR CHEMISTRY
7
(d, J = 10.0 Hz, 1H), 5.24 (d, J = 16.0 Hz, 1H), 5.80–5.83 (m, 1H), 6.50 (d, J = 8.0 Hz,
1H), 6.56 (d, J = 8.0 Hz, 1H), 7.08 (s, 2H), 9.10 (br s, 1H).13C NMR (125 MHz, DMSO-d6)
δ = 23.2, 31.1, 31.9, 43.5, 45.3, 57.6, 61.8, 72.6, 83.0, 84.7, 116.3, 117.6, 118.0, 118.9, 120.5,
124.6, 128.7, 130.9, 136.5, 140.3, 143.4, 163.7; IR (KBr) 3327, 2918, 2201, 1458 cm−1; MS
(70 eV) m/z 407 [M+], 366, 327, 279; Anal. Calcd for C22H21N3O3S C, 64.85; H, 5.19; N,
10.31. Found: C, 64.98; H, 5.27; N, 10.37.
4.3.9. 17-Allyl-5ꢀ-amino-3-(cyclopropylmethoxy)-14-hydroxy-4,5α-epoxythieno[3ꢀ,2ꢀ-
6,7]morphinane-4ꢀ-carbonitrile (2 g)
Light brown crystal; mp = 125°C decomposes; 1H NMR (500 MHz, DMSO-d6)
δ = 0.20–0.24 (m, 2H), 0.48–0.50 (m, 2H), 1.12–1.15 (m, 1H), 1.50 (d, J = 11.5 Hz, 1H),
2.08–2.25 (m, 1H), 2.26–2.27 (m, 1H), 2.32 (d, J = 11.5 Hz, 1H), 2.53–2.55 (m, 1H), 2.65
(dd, J = 6.0, 18.5,1H), 2.98 (d, J = 6.0, 1H), 3.10 (d, J = 18.5 Hz, 2H), 3.13–3.14 (m, 2H),
3.82 (d, J = 7.0 Hz, 2H), 4.75 (s, 1H), 5.15–5.25 (m, 3H), 5.82–5.89 (m, 1H), 6.60 (d,
J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 7.09 (s, 2H);13C NMR (125 MHz, DMSO-d6)
δ = 3.4, 3.5, 10.9, 23.3, 30.9, 31.9, 43.4, 46.2, 57.6, 61.8, 72.4, 74.1, 82.8, 85.1, 116.2, 116.8,
118.0, 119.2, 120.6, 126.8, 128.5, 131.3, 136.5, 142.0, 144.5, 163.7; IR (KBr) 3320, 2916,
2202, 1443 cm−1; MS (70 eV) m/z 461 [M+], 421, 366, 218; Anal. Calcd for C26H27N3O3S:
C, 67.66; H, 5.90; N, 9.10. Found: C, 67.44; H, 5.60; N, 10.12.
4.3.10. 17-(Cyclopropylmethyl)-3,14-dihydroxy-4,5α-epoxymorphinan-6-
ylidenemalononitrile (2aꢀ)
1
Light brown crystal; mp = 170–171°C H NMR (500 MHz, DMSO-d6) δ 0.34–0.37 (m,
1H), 0.40–0.44 (m, 1H), 0.57–0.60 (m, 1H), 0.66–0.69 (m, 1H), 0.99–1.07 (m, 1H), 1.54
(d, J = 12.0 Hz, 1H), 1.91 (d, J = 17.0 Hz, 1H), 2.02 (dd, J = 6.0–17.0 Hz, 1H), 2.38–2.42
(m, 1H), 2.58–2.62 (m, 1H), 2.79–2.82 (m, 1H), 2.99–3.03 (m, 2H), 3.26 (d, J = 18.0 Hz,
2 H), 3.26–3.50 (m, 1H), 3.69–3.72 (m, 1H), 4.59 (s, 1H), 4.77 (s, 1H), 6.50 (d, J = 8.0 Hz,
1H), 6.62 (d, J = 8.0 Hz, 1H), 9.08 (br s, 1H); 13C NMR (125 MHz, DMSO-d6) δ = 3.0, 5.7,
6.1, 21.5, 23.3, 27.5, 29.2, 46.5, 47.4, 57.2, 61.1, 69.7, 85.6, 86.6, 112.1, 112.6, 118.7, 121.1,
121.2, 128.3, 140.8, 142.9, 181.8; IR (KBr) 3265, 2167, 2103, 1623 cm−1; MS (70 eV) m/z
389 [M+], 348, 320, 243; Anal. Calcd for C23H23N3O3: C, 70.93; H, 5.95; N, 10.79; Found:
C, 70.81; H, 6.02; N, 10.88.
Acknowledgement
S. B. would like to thank TEMAD Pharmaceutical Company for providing some of the required
chemicals.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Mohammad M. Mojtahedi http://orcid.org/0000-0002-0452-590X

8
S. BAGHERPOUR ET AL.
References
[1] Genilloud O, Vicente F, editors. Drug discovery from natural products. Cambridge: Royal
Society of Chemistry; 2012.
[2] Chin Y-W, Balunas MJ, Chai HB, et al. Drug discovery from natural sources. AAPS J.
2006;8:E239–E253.
[3] Imperatori F, Barlozzari G, Scardigli A, et al. Leishmanicidal activity of green tea leaves and
pomegranate peel extracts on L. infantum. Nat Prod Res. 2019;33:3465–3471.
[4] Werner L, Wernerova M, Machara A, et al. Unexpected N-demethylation of oxymorphone and
oxycodone N-oxides mediated by the burgess reagent: direct synthesis of naltrexone, naloxone,
and other antagonists from oxymorphone. Adv Synth Catal. 2012;354:2706–2712.
[5] Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 Years. J Nat
Prod. 2007;70:461–477.
[6] Reed JW, Hudlicky T. The quest for a practical synthesis of morphine alkaloids and their
derivatives by chemoenzymatic methods. Acc Chem Res. 2015;48:674–687.
[7] Rice KC. Synthetic opium alkaloids and derivatives. A short total synthesis of ( )-
dihydrothebainone, ( )-dihydrocodeinone, and ( )-nordihydrocodeinone as an approach to
a practical synthesis of morphine, codeine, and congeners. J Org Chem. 1980;45:3135–3137.
[8] Kok GB, Scammells PJ. Improved synthesis of 14-hydroxy opioid pharmaceuticals and inter-
mediates. RSC Adv. 2012;2:11318–11325.
[9] Endoma-Arias MAA, Cox DP, Hudlicky T. General method of synthesis for naloxone, nal-
trexone, nalbuphone, and nalbuphine by the reaction of grignard reagents with an oxazolidine
derived from oxymorphone. Adv Synth Catal. 2013;355:1869–1873.
[10] Ronzoni S, Cerri A, Dondio G, et al. Synthesis and NMR characterization of a novel class of
thienomorphinans. Org Lett. 1999;1:513–516.
[11] Barton ED, Colwell CB, Wolfe T, et al. Efficacy of intranasal naloxone as a needleless alternative
for treatment of opioid overdose in the prehospital setting. J Emerg Med. 2005;29:265–271.
[12] Rinner U, Hudlicky T. Synthesis of morphine alkaloids and derivatives. In: Knölker HJ, editor.
Alkaloid synthesis. Topics in current chemistry Vol. 309. Berlin: Springer; 2011. p. 33–66.
[13] O’Brien CP, Volpicelli LA, Volpicelli JR. Naltrexone in the treatment of alcoholism: a clinical
review. Alcohol. 1996;13:35–39.
[14] Olofson RA, Schnur RC, Bunes L, et al. Selective N-dealkylation of tertiary amines with vinyl
chloroformate: an improved synthesis of naloxone. Tetrahedron. Lett. 1977;18:1567–1570.
[15] Ninan A, Sainsbury M. An improved synthesis of noroxymorphone. Tetrahedron. 1992;48:
6709–6716.
[16] Ananthan S. Southern research institute, Pyridomorphinans, thienomorphinans and use
thereof; United States Patent US 7,534,799 B2; [2009 May 19].
[17] Abaee MS, Ehteshami F, Forghani S, et al. Facile one-pot synthesis of novel dicyanoani-
lines fused to dithiane ring via a pseudo-four-component reaction. J Iran Chem Soc.
2017;14:1151–1157.
[18] Pourabdi L, Osati F, Mojtahedi MM, et al. A convenient one-pot synthesis of thiopyrano[4,3-
b]pyran derivatives under LiOH·H2O/EtOH/ultrasonic conditions. J Sulfur Chem. 2017;38:
34–42.
[19] Abaee MS, Forghani S, Mojtahedi MM, et al. Efficient synthesis of novel bis(arylmethylidenes)
of the 2,2-dimethyl-1,3-dithian-5-one system. J Sulfur Chem. 2016;37:683–691.
[20] Abaee MS, Hadizadeh A, Mojtahedi MM, et al. Exploring the scope of the Gewald reaction:
expansion to a four-component process. Tetrahedron Lett. 2017;58:1408–1412.
[21] Mojtahedi MM, Abaee MS, Mahmoodi P, et al. Convenient synthesis of 2-aminothiophene
derivatives by acceleration of Gewald reaction under ultrasonic aqueous conditions. Synth
Commun. 2010;40:2067–2074.
[22] Huang Y, Dömling A. The Gewald multicomponent reaction. Mol Diversity. 2011;15:3–33.
[23] Kavitha K, Srikrishna D, Dubey PK, et al. An efficient one-pot four-component Gewald
reaction: synthesis of substituted 2-aminothiophenes with coumarin–thiazole scaffolds under
environmentally benign conditions. J Sulfur Chem. 2019;40:195–208.

JOURNAL OF SULFUR CHEMISTRY
9
[24] Machara A, Cox DP, Hudlicky T. Direct synthesis of naltrexone by palladium-catalyzed
N-demethylation/acylation of oxymorphone: the Benefit of C-H activation and the intramolec-
ular acyl transfer from C-14 hydroxy. Adv Synth Catal. 2012;354:2713–2718.
[25] Itov Z, Kuznetsov VF, Voitsekhovski I. Cody laboratories, Inc. Synthesis of oxycodone
hydrochloride. United States Patent US 9,062,062 B1; [2015 Jun 23].