D-Ring modification of steroids: synthesis of isoxazole annulated steroids from des D-formyl alkyne via 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1080/00397911.2021.1955930

The reaction of 17,17-dichloro-androst-16(E)-chloromethylene with secondary amine base afforded substitution products of exocyclic D-ring ketones, in contrast to the reaction of alkaline base which cleaved steroidal D-ring to des-D formyl alkyne. The des-

Full text of DOI:10.1080/00397911.2021.1955930

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D-Ring modification of steroids: synthesis of
isoxazole annulated steroids from des D-formyl
alkyne via 1,3-dipolar cycloaddition reaction
Geetmani Singh Nongthombam & Romesh Chandra Boruah
To cite this article: Geetmani Singh Nongthombam & Romesh Chandra Boruah (2021): D-Ring
modification of steroids: synthesis of isoxazole annulated steroids from des D-formyl alkyne via 1,3-
dipolar cycloaddition reaction, Synthetic Communications, DOI: 10.1080/00397911.2021.1955930
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https://doi.org/10.1080/00397911.2021.1955930
D-Ring modification of steroids: synthesis of isoxazole
annulated steroids from des D-formyl alkyne via 1,3-dipolar
cycloaddition reaction
Geetmani Singh Nongthombam
and Romesh Chandra Boruah
Applied Organic Chemistry Group, Chemical Science & Technology Division, CSIR-NEIST, Jorhat, India
ABSTRACT
ARTICLE HISTORY
Received 25 February 2021
The reaction of 17,17-dichloro-androst-16(E)-chloromethylene with
secondary amine base afforded substitution products of exocyclic D-
ring ketones, in contrast to the reaction of alkaline base which
cleaved steroidal D-ring to des-D formyl alkyne. The des-D formyl
alkyne was employed to prepare D-ring annulated isoxazolo steroid
via 1,3-dipolar nitrile oxide cycloaddition reaction.
KEYWORDS
Steroids; isoxazole; 1,3-
dipolar cycloaddition;
b-formylenamide
GRAPHICAL ABSTRACT
Introduction
Azasteroids and its fused analogs are important class of compounds because of their
broad spectrum biological activities.[1–5] Some of the azasteroids such as abiraterone,
finasteride, dutasteride, 7-aza-des-A-steroid inhibit enzymes like 5a-reductase, 17a-
hydroxylase/17,20-yase; and deliver antitumor, benign prostatic hyperplasia, antimicro-
bial and cytotoxic activities.[6–9] Due to remarkable biological activities of heterosteroids,
continued efforts have been bestowed to develop new and versatile methodologies for
annulations of steroidal moiety with heterocycles such as pyrazole, pyridine, pyrimidine,
pyran or pyrrole rings.[10–14]
CONTACT Romesh Chandra Boruah
rc_boruah@yahoo.co.in
Applied Organic Chemistry Group, Chemical Science
& Technology Division, CSIR-NEIST, Jorhat, Assam, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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G. S. NONGTHOMBAM AND R. C. BORUAH
Scheme 1. Synthesis of 17,17-dichloro-androst-16(E)-chloromethylene (4)
Isoxazole compounds have attracted extensive interests as important heterocyclic
motif due to diverse biological activities including anti-bacterial, analgesic, anti-fungal,
anti-inflammatory, anti-microbial, anti-viral, anti-cancer, anti-tuberculosis, herbicidal,
DNA-intercalating agents and COX-2 inhibitory properties.[15–21] They also behave as
important synthetic intermediates for various difunctionalized compounds such as 2-
aminobenzophenone, c-amino alcohol, a,b-unsaturated oxime, b-hydroxy nitrile,
b-hydroxyketone and nitrile oxide.[22–26] Despite enormous biological potentials, syn-
thetic attempt for the annulation of isoxazole moiety to steroidal core received scant
attentions.[27,28]
The exocyclic steroidal conjugated ketones have shown enormous potential
as synthon for annulation of pyrazolo[1,5-a]pyrimidine,[29] pyrimidine,[30,31] and
dicyanoaniline moieties.[32] D-Ring exocyclic chloro olefins, namely, 3b-acetoxy-17,17-
dichloro-16(E)-chloromethylen-androst-5-en (4) and 3b-acetoxy-16-(E)-chloromethy-
lene-androst-5-en-16-one (5) were utilized for synthesis of a novel class of steroidal
diyne.[33] The compounds 4 and 5 were accomplished from 16-dehydropregnenolone
acetate (1) following a reported procedure,[34,35] Reaction of 1 with hydroxylamine
hydrochloride gave corresponding oxime (2), which on treatment with Vilsmeier
reagent under cold condition afforded b-formyl enamide (3). Further, reaction of 3 with
Vilsmeier reagent accomplished 4 and 5 as major and minor products respectively
(Scheme 1).
Results and discussion
Earlier, we have observed that the compound 4 in methanolic KOH under refluxing
condition led to facile ring cleavage of steroidal D-ring to afford des-D formyl alkyne
(6) (Scheme 2).[34] The ring cleavage reaction was presumed by initial abstraction of C-
16 methylene proton by strong alkali, followed by hydrolysis of geminal dichloride
group. To explore the influence of other bases on D-ring cleavage of 4, we planned to
study the possibility of ring opening reaction of 4 using secondary amines with an aim
to prepare ynamines.[36,37] However, we found that secondary amines failed to cleave
D-ring of 4 in a similar way in refluxing methanol to give ynamine 7. Further, our
attempt to react the secondary amines with 4 in DMF under thermal condition did not
afford the D-ring cleaved product.
The reaction of 4 (0.24 mmol) with pyrrolidine (0.72 mmol) in DMF at 120 ꢀC for 4 h
led to pyrrolidine substituted exocyclic conjugated ketone (8) as the sole product (90%)
instead of the expected ynamine 7. Similar treatment of piperidine with 4 resulted
piperidine substituted product (9) in high yields (75%). Surprisingly, when product 4
was treated with morpholine under identical condition, it did not give a morpholine

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Scheme 2. Ring cleavage and substitution reactions of 17,17-dichloro-androst-16(E)-chloromethy-
lene (4)
substituted adduct; instead afforded exocyclic 3b-acetoxy-16-(Z)-hydroxymethylene-
androst-5-en-17-one (10) as the sole product (85%) (Scheme 2). All the products were
characterized by high resolution spectral data.
1
The H NMR of compound 8 and 9 exhibited multiplet signals at d 3.54-3.50 and d
3.41-3.35 integrating for four methylene protons adjacent to nitrogen atom of pyrrolidine
and piperidine ring respectively. The exocyclic olefinic proton of 8 and 9 showed singlet
signals at d 7.41 and 7.28 respectively. In 13C{1H}NMR, signals of C-17 carbonyl carbon
for compound 8 and 9 were appeared at d 208.8 and d 209.6 respectively; along with five
olefinic carbon signals at d 208.8, 170.4, 141.8, 139.9, 121.9, 103.3 for compound 8; and d
208.8, 170.4, 144.8, 140.0, 121.8, 101.4 for compound 9. The HRMS showed molecular
mass ion peak for compound 8 at m/z 412.2855(Mþþ1) and for compound 9 at 426.3008
1
(Mþþ1). On the other hand, H NMR of compound 10 showed absence of chemical shift
of methylene protons at the aliphatic region. The hydrogen bonded hydroxyl proton
appeared at d 9.77 and exocyclic olefinic proton showed chemical shift at d 7.07. The
13C{1H}NMR of compound 10 exhibited cyclopentanone carbonyl carbon signal at d
215.1 with other five olefinic carbons at d 170.7, 158.5, 140.2, 122.0, 112.6. The HRMS
showed molecular mass ion peak for compound 10 at m/z 359.2227 (Mþþ1).
The formation of the product 10 may be proposed due to initial displacement of
three chloro groups of 4 with two morpholine molecules to form a quaternary iminium
salt (A), followed by hydrolysis to form 17-keto-16-morpholinomethylene intermediate
(B). Under thermal condition it facilitated nucleophilic attack of a hydroxyl group at
the electron deficient exocyclic conjugated carbon to yield compound 10 with loss of

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G. S. NONGTHOMBAM AND R. C. BORUAH
Scheme 3. Plausible mechanistic pathway for formation of 16-(Z)-hydroxymethylene-epiandroster-
one (10).
morpholine. The facile loss of morpholine group in B may be attributed due to weak
basicity of morpholine (pKa value 8.36), which makes the exocyclic conjugated carbon
of C-16 methylene group electron deficient and more vulnerable to hydrolysis (Scheme
3). On the other hand, strong basicity of pyrrolidine (pKa value 11.27) and piperidine
(pKa value 11.22) probably inhibit them from nucleophilic attack of hydroxyl group for
the loss of pyrrolidine and piperidine moieties, due to comparative electron rich exocy-
clic conjugated carbon of C-16 methylene group, to afford compounds 8 and 9.[38] We
have also repeated the reaction under control experimental condition using anhydrous
DMF in presence of activated molecular sieves 4 Å but we failed to obtain 10 (moni-
tored from TLC). However, addition of few drops of water to the reaction mixture led
to the formation of 10 (monitored from TLC). So, we concluded that water from solv-
ent might be responsible for conversion of the morpholine intermediates to product 10.
Due to our continuing interests on heterosteroids,[39] we desired to study the 1,3-
dipolar cycloaddition reaction of des-D formyl alkyne (6) bearing aldehyde and alkyne
as interesting difunctional group. For this, first we converted compound 6 to corre-
sponding aldoxime (11) by treating with hydroxylamine hydrochloride in methanol
1
under reflux condition. The alkyne aldoxime (11) was obtained in 82% yield. The H
NMR showed the absence of aldehyde proton signal at d 9.99 and presence of an imine
proton appeared at d 8.03 as singlet; and HRMS showed molecular ion peak at 392.1993
(Mþþ1). Finally, treatment of des-D alkyne aldoxime (11) with chloramine-T in reflux-
ing methanol afforded D-ring annulated isoxazolo steroid (12) in 65% yields. The reac-
tion proceeded via intramolecular 1,3-cycloaddition reaction of in situ generated nitrile
oxide (C) with alkyne group. The product 12 was characterized by high resolution spec-
1
tral analysis. In H NMR, the cycloadduct 3b-acetoxy-30-chloro-androst[16,17-d]isoxa-
zole-5-ene (12) showed the absence of imine proton at d 8.03. The characteristic C-3
methine proton was appeared as a multiplet at d 4.56-4.50 and the C-5 olefinic proton
was observed as a doublet at d 5.33 (J ¼ 5.5 Hz). Also, the 13C{1H}NMR exhibited the
characteristic carbonyl carbon signal of 3-acetoxy group at d 170.4; and five olefinic car-
bons were observed at d 164.6, 154.7, 139.9, 127.1, 121.7.

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Scheme 4. Intramolecular 1,3-dipolar cycloaddition of des-D formyl alkyne (6) to isoxazolo ste-
roids (12).
However, we failed to obtain the expected isoxazoline cycloadduct 14 by intramolecu-
lar nitrone 1,3-dipolar cycloaddition reaction of des-D formyl alkyne (6) in a similar
way by using methyl hydroxylamine hydrochloride; rather we could isolate a product
which was identified as the intermediate des-D alkyne nitrone (13). The 1H NMR
exhibited a characteristic singlet proton signal at d 8.09 for imine proton of nitrone.
The 13C{1H}NMR showed characteristic 3-acetoxy carbonyl carbon signal at d 170.5 and
five olefinic carbon signals for compound 13 were appeared at d 148.2, 145.9, 139.9,
129.3 and 121.8. The HRMS exhibited the molecular ion peak at m/z 406.2155. The N-
methyl nitrone intermediate 13 was found to be sufficiently stable and did not partici-
pate in the intramolecular cycloaddition reaction even at high thermal condition of
refluxing xylene.
Conclusion
In summary, we utilized 17,17-dichloro-androst-16(E)-chloromethylene as a synthon for
the preparation of pyrrolidine and piperidine substituted exocyclic conjugated ketones
in high yields. The reaction of morpholine with 17,17-dichloro-androst-16(E)-chloro-
methylene led to exocyclic hydroxy methylene product. We demonstrated that
contrary to alkaline base, the secondary amine bases failed to cleave the D-ring of
17,17-dichloro-androst-16(E)-chloromethylene. The des-D formyl alkyne, derived from
17,17-dichloro-androst-16(E)-chloromethylene by alkaline hydrolysis, was employed for
1,3-dipolar nitrile oxide cycloaddition to accomplish D-ring annulated isoxazolo steroid.
Our attempt to accomplish intramolecular cycloadduction reaction using methyl
hydroxylamine rather afforded the des D-steroidal nitrone as a stable isolable product.
Experimental section
1
Melting points were determined on a Bu€chi B-540 melting point apparatus. The H and
13C{1H} NMR spectra were recorded at ambient temperature on a 500 MHz (125 MHz
for 13C{1H}) NMR spectrometer. NMR experiments are reported in d units, parts per
million (ppm), and were referenced to CDCl3 (d 7.26 or 77.0 ppm) as the internal
standard. The coupling constants J are given in Hz. The FTIR spectra were recorded in
a Spectrum 100 Perkin Elmer spectrometer using CHCl3. Column chromatography was

6
G. S. NONGTHOMBAM AND R. C. BORUAH
performed using EM Silica gel 60 (100–200 mesh). High resolution mass spectra
(HRMS) were obtained using a Xevo XS QT of mass spectrometer, Waters
ACQUITY UHPLC.
General procedure for reaction of secondary amines with 17,17-dichloro-androst-
16(E)-chloromethylene (4)
In a dry round bottom flask (50 ml) was taken a mixture of 4 (0.24 mmol) and pyrrole/
piperidine/morpholine (0.72 mmol) in DMF (10 mL). The reaction mixture was heated
to 120 ꢀC for 4 h. On completion of reaction, it was extracted with chloroform and
washed with water, followed by drying over anhydrous Na2SO4. Removal of solvent
under reduced pressure and purification using column chromatography gave the
desired products.
Preparation of b-acetoxy-(16,17)-ethyn-17-chloro-des-D-androst-5-en-13-aldox-
ime (11)
To compound 6 (0.26 mmol) in methanol (30 ml) was added NH2OH.HCl (0.58 mmol)
and KH2PO4 (0.22 mmol). It was refluxed for 3 h and after completion of reaction the
solvent was removed under reduced pressure. Neutralization with NaHCO3 solution fol-
lowed by chloroform work up and purification by column chromatography gave 11.
Preparation of b-acetoxy-3’-chloro-androst[16,17-d]isoxazolo-5-ene (12)
To a solution of compound 11 (0.20 mmol) in methanol (10 ml) in a dry round-bottom
flask was added chloramine-T (0.22 mmol). The reaction mixture was refluxed for 2 h to
complete the reaction. Removal of solvent under reduced pressure and purification of
the product using column chromatography afforded isoxazole 12.
Preparation of b-acetoxy-(16,17)-ethyn-17-chloro-des-D-androst-5-en-13-(N-methyl)
nitrone (13) from des-D formyl alkyne (6)
To a solution of compound 6 (0.26 mmol) in methanol (30 ml) was added
CH3NHOH.HCl (0.48 mmol) and KH2PO4 (0.22 mmol). After reflux for 4 h and on
completion of reaction, solvent was removed under reduced pressure. The crude solid
was treated with dilute NaHCO3 solution, followed by chloroform work up, removal of
solvent and purification of the product using column chromatography afforded 13.
Acknowledgments
GSN thanks CSIR, New Delhi for award of RA and financial support under Emeritus Scientist
scheme, CSIR. The authors are thankful to the Director, CSIR-NEIST, Jorhat for his
keen interests.
Funding
RCB thanks CSIR, New Delhi for award of Emeritus Scientist, CSIR [ES1516Y2144].

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ORCID
Geetmani Singh Nongthombam
http://orcid.org/0000-0002-4683-6810
Romesh Chandra Boruah
http://orcid.org/0000-0003-2641-2284
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