Intramolecular cyclization of 9,11-seco-estrane under friedel-crafts reaction conditions

Article abstract of DOI:10.1080/00397910801914277

An intramolecular cyclization of 17β-acetoxy-3-methoxy-9,11-seco-1,3, 5(10)-estratriene-11-oic acid under different Friedel-Crafts reaction conditions is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801914277

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Intramolecular Cyclization of
9,11‐Seco‐Estrane under Friedel–Crafts
Reaction Conditions
Atul Gupta a , Kasturi Lal a , Indra Dwivedy a & Suprabhat Ray a
a Medicinal and Process Chemistry Division , Central Drug Research
Institute , Lucknow, India
Published online: 25 Apr 2008.
To cite this article: Atul Gupta , Kasturi Lal , Indra Dwivedy & Suprabhat Ray (2008) Intramolecular
Cyclization of 9,11‐Seco‐Estrane under Friedel–Crafts Reaction Conditions, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:9, 1425-1432, DOI:
10.1080/00397910801914277
To link to this article: http://dx.doi.org/10.1080/00397910801914277
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Synthetic Communicationsw, 38: 1425–1432, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801914277
Intramolecular Cyclization of
9,11-Seco-Estrane under Friedel–Crafts
Reaction Conditions
Atul Gupta, Kasturi Lal, Indra Dwivedy, and Suprabhat Ray
Medicinal and Process Chemistry Division, Central Drug Research
Institute, Lucknow, India
Abstract: Anintramolecular cyclization of17b-acetoxy-3-methoxy-9,11-seco-1,3,5(10)-
estratriene-11-oic acid under different Friedel–Crafts reaction conditions is described.
Keywords: Friedel-Crafts reaction, seco-steroids, estrogens, Grignard reaction, intra-
molecular cyclization
Several structural modifications have been made in the steroidal framework
that were achieved either by substitution at various positions of the steroidal
nucleus or by changing its stereochemistry to get a desired drug.[1–3] Among
various modifications, substitution of aryl residue at the 11b position of an
estrane as well as a progestin, which led to the development of important
compounds 1 and 2, has been found to modulate their hormonal profile
(Figure 1).[4,5] Further, seco-steroids, another class of compounds such as 3
and 4, generally share structural features similar to those of their parent
compounds for receptor affinity and are important because of their
significant receptor affinity with the desired hormonal profile.[6–8]
Keeping these considerations in view, we targeted the synthesis of 11-aryl-
substituted 3-methoxy-9,11-seco-estra-1,3,5(10)-trienes of type 5 as modified
Received in India October 16, 2007
Address correspondence to Atul Gupta, Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow 226001, India. E-mail: atisky2001@yahoo.
co.in
1425

1426
A. Gupta et al.
Figure 1. Biologically important steroidal material.
estrogens (Figure 1). During synthesis of targeted compound 5, we noticed an
intramolecular cyclization of 17b-acetoxy-3-methoxy-9,11-seco-estra-
1,3,5(10)-triene-11-oic acid (6) under different Friedel–Crafts reaction con-
ditions. This communication presents different approaches used to synthesize
the desired compounds and an unexpected intramolecular cyclization of 17b-
acetoxy-3-methoxy-9,11-seco-1,3,5(10)-estratriene-11-oic acid (6) under
differentFriedel–Crafts reaction conditions, yieldinga cyclic ester in goodyield.
Initially the synthesis of 5 was attempted though the Grignard reaction
on methyl-17b-hydroxy-3-methoxy-9,11-seco-estra-1,3,5(10)-triene-11-car-
boxylate (7) (obtained from 17b-acetoxy-3-methoxy-9,11-seco-1,3,5(10)-
estratriene-11-oic acid 6) using phenyl magnesium bromide, which led to
the formation of 11,17b-dihydroxy-11,11-diphenyl-3-methoxy-9,11-seco-
estra-1,3,5(10)-triene (8) in 88% yield instead of the desired compound 11-
oxo-11-phenyl-9,11-seco-estra-1,3,5(10)-trien-17b-diol 3-methyl ether (9)
(5, R, R1 ¼ H, R2 ¼ CH3) (Scheme 1). Therefore, synthesis of 5 was made
though controlled addition of acid 10 (obtained by deacetylation of 6),
dissolved in dry tetrahydrofuran (THF), to the solution of phenyl lithium in
dry THF under inert reaction conditions, which gave compound 9 in 20%
yield (Scheme 2). With this approach, we were able to synthesize the
desired compound 9 (5, R, R1 ¼ H, R2 ¼ CH3); however, complexity of
the reaction with other substituted phenyl lithium and low yield prevented
us for further experimentation in this direction.
In an alternate approach, Friedel–Crafts reaction on seco-estrane acid 6
with phenol under various conditions (Scheme 3) was attempted. Friedel–
Crafts reaction of 6 with phenol in the presence of polyphosphoric acid
(PPA), boron trifluoride–etherate complex (BF3–OEt2), or anhydrous AlCl3
at a temperature ranging from 80 to 120 8C led to the formation of cyclic

Intramolecular Cyclization of 9,11-Seco-Estrane
1427
Scheme 1. (a) HCl, CH3OH; (b) PhMgBr, dry ether, room temperature.
ester 11 in good yield along with other unidentified side products instead of the
desired compound 12 (R ¼ H). We had earlier observed the formation of
compound 11 from 6 and its other derivatives at elevated temperature (e.g.,
237 8C) with copper and quinoline.[9] We presumed that in this case too, temp-
erature might have played a critical role in the formation of the cyclized product
11. We therefore tried the Friedel–Crafts reaction with SnCl4 in benzene, SnCl4
(neat), and anhydrous AlCl3 in benzene at temperatures ranging from 0 8C to
room temperature (rt). Interestingly, even under such mild conditions,
formation of compound 11 in good yield was observed.
Scheme 2. 2% NaOH, CH3OH, Rt; (b) PhLi, dry THF, 0 8C.

1428
A. Gupta et al.
Scheme 3. (a) Phenol or anisole with PPA, heat; or BF3-OEt2, heat, or SnCl4, 0 8C–Rt.
When the Friedel–Crafts reaction was performed with anisole (a protected
phenol) instead of phenol, under similar reaction conditions, it also yielded 11 in
good yield. To find out any role of phenolic compound in cyclization of 6, we
stirred 6 with SnCl4 in dry benzene, SnCl4 (neat), and anhydrous AlCl3 in dry
benzene at a temperature ranging from 0 8C to rt, which gave 11 in almost
similar quantities. Thus, we concluded that the Friedel–Crafts reaction con-
ditions are sufficient for intramolecular cyclization of 6 to yield 11 in good
yield. We noticed during our experiments that the observed cyclization is repro-
ducible. The newly synthesized compounds were characterized by 1H NMR, IR,
mass spectroscopy, and microanalysis.
EXPERIMENTAL
Anhydrous reactions were performed under an inert atmosphere; the setup was
assembled and cooled under dry nitrogen. Unless otherwise noted, starting
material, reactant, and solvents were obtained commercially and used as such
or purified and dried by standard means. The reported melting points were deter-
mined in open capillaries and are uncorrected. The 1H NMR was recorded on a
Brucker Avans DRX 200 (200-MHz, FT NMR) spectrometer using TMS as
internal standard. The chemical shifts are expressed in d (ppm) values, and
coupling constants are in hertz. Multiplicities are described by the following
abbreviations: s for singlet, d for doublet, t for triplet, and bs for broad
singlet. Mass spectra were recorded on a Jeol JMS-D-300 spectrometer. The
IR spectra were recorded in KBr on a Perkin-Elmer model 881. Elemental
analyses were carried out on a Carlo-Erba EA 1108 instrument, and results
were within +0.4% of theoretical values. The purity of the products was

Intramolecular Cyclization of 9,11-Seco-Estrane
1429
checked on precoated silica-gel 60 F254 thin-layer chromatography (TLC)
plates, and the spots were visualized by inspection under short (254-nm) wave-
length UV light or by the colors developed with iodine vapors. The column
chromatography was performed on silica gel 60 (Merck).
Synthesis of Methyl-17b-hydroxy-3-methoxy-9,11-seco-estra-
1,3,5(10)-triene-11-carboxylate (7)
A mixture of 6 (1.0 g, 2.78 mmol), methanol (25 ml), and conc. HCl (0.5 ml)
was refluxed for 4 h. On completion, solvent was removed under vacuum. The
residue was treated with water and extracted with ethyl acetate. The organic
layer was washed with water, dried over anhydrous sodium sulfate, and con-
centrated. The solid thus obtained was crystallized from benzene–hexane.
Yield: 98%, mp 87–89 8C. EIMS: Mþ m/e 332; IR (cm21): 3500, 1725,
1
1600, 1580, 1500; H NMR (d): 0.93 (s, 3H, CH3), 3.69 (s, 3H, CH3), 3.77
(s, 3H, OCH3), 4.10 (m, 1H, CH), 6.32–6.88 (m, 3H, ArH). Anal. calcd. for
C20H28O4: C, 72.26; H, 8.49. Found: C, 72.15; H, 8.70.
Synthesis of 11,17b-Dihydroxy-11,11-diphenyl-3-methoxy-9,11-
seco-estra-1,3,5(10)-triene (8)
A solution of 7 (1.0 g, 3.01 mmol) in anhydrous benzene (20 ml) was added
dropwise to a magnetically stirred solution of C6H5MgBr (20.0 mmol) in
anhydrous ether (20 ml) during 1 h at 5 8C. The reaction mixture was stirred
at room temperature for another 6 h. The mixture was cooled in ice, and
saturated ammonium chloride solution was added slowly until the aqueous
layer became clean. The organic layer was separated, and the precipitated
Mg salts were washed well with ether. The combined organic extracts were
then steam-distilled to remove biphenyl. Extraction with ether followed by
washing with water, drying over anhydrous sodium sulfate, and evaporating
the solvent gave a gum, which was chromatographed over silica gel to give
8, which was crystallized from benzene–hexane.
Yield: 88%, mp 78–80 8C. EIMS: Mþ (-H2O) m/e 438; IR (cm21): 3300,
1600, 1580, 1500; 1H NMR (d): 0.46 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 4.08
(m, 2H, CH), 6.55–7.02 (m, 3H, ArH), 7.08–7.64 (m, 10H, ArH). Anal. calcd.
for C31H36O3; C, 81.54; H, 7.93. Found: C, 81.10; H, 8.14.
Synthesis of 3,17b-Dihydroxy-9,11-seco-estra-1,3,5(10)-triene-11-
oic Acid 3-Methyl Ether (10)
The acid 6 (0.50 g, 1.4 mmol) was stirred with 2% methanolic sodium
hydroxide at room temperature for 30 min. After completion of the reaction,

1430
A. Gupta et al.
the reaction mixture was acidified with 5% HCl. On acidification, a solid pre-
cipitated that was filtered, washed with water, and dried under suction. The
solid was obtained in 80% yield and used as such in the subsequent step.
Synthesis of 11-Oxo-11-phenyl-9,11-seco-estra-1,3,5(10)-trien-17b-
diol 3-Methyl Ether (9)
17b-Hydroxy-3-methoxy-9,11-seco-1,3,5(10)-estratrien-11-oic acid (10) (0.50 g,
1.6 mmol) in dry THF (5 ml) was added to the stirred solution of the phenyl
lithium (16.0 mmol) in dry ether (10 ml) at 0 8C under an inert atmosphere.
Stirring was continued for another 1 h, and the reaction mixture was poured
dropwise into ice water (50 ml), made acidic with dil. HCl, extracted with
ether, and worked up in the usual manner. An oily residue was obtained,
which on chromatography over silica gel gave compound 9 in 20% yield.
Yield: 20%, mp 108–110 8C. FABMS: 378; IR (cm21): 3400, 1675, 1608,
1440, 1370, 1038, 746, 687; 1H NMR (d): 1.01 (s, 3H, CH3), 1.45 (m, 2H, CH2),
1.54 (bs, 4H, CH2), 1.77 (m, 1H, CH), 2.05 (m, 1H, CH), 2.65–2.73 (m, 4H,
CH2), 2.87 (bs, 2H, CH2), 3.81 (s, 3H, OCH3), 4.12 (m, 1H, CH), 4.42 (bs,
1H, OH), 6.67–6.75 (m, 2H, ArH), 7.01 (d, J ¼ 8.00 Hz, 1H, ArH),
7.49–7.54 (m, 3H, ArH), 7.99 (d, J ¼ 8.00 Hz, 1H, ArH). Anal. calcd. for
C25H30O3: C, 79.33; H, 7.99. Found: C, 79.62; H, 7.72.
Synthesis of 17b-Hydroxy-3-methoxy-9,11-seco-estra-1,3,5(10)-
trien-11-oic Acid 11,17-Lactone (11)
Method A
In a round-bottomed flask, a mixture of acid 6 (0.50 g, 1.4 mmol), phenol
(0.14 g, 1.4 mmol), and boron–diethyl ether complex (BF3–OEt2, 1.5 ml)
was heated under reflux for 6–8 h. The reaction mixture was then poured
onto ice-cold water and extracted with ethyl acetate. The organic layer was
then dried over anhydrous sodium sulfate and concentrated. The crude
material on chromatography yielded pure compound 11 in 60% yield.
Yield: 60%, mp 82–84 8C (lit. 84–86 8C[9]). FABMS: 300; IR (cm21):
1
2925, 1774, 1610, 1502, 1462; H NMR (d): 1.14 (s, 3H, CH3), 1.68–2.45
(m, 6H, CH2), 2.50 (s, 2H, CH2), 2.71–2.82 (m, 4H, CH2), 3.77 (s, 3H,
OCH3), 4.45 (m, 1H, CH), 6.61–6.70 (m, 2H, ArH), 6.96 (d, J ¼ 8.00 Hz,
1H, ArH).
Method B
A mixture of acid 6 (0.50 g, 1.4 mmol), phenol (0.14 g, 1.5 mmol), and poly-
phosphoric acid (10 g) was taken in a round-bottomed flask. The reaction

Intramolecular Cyclization of 9,11-Seco-Estrane
1431
mixture was heated for 10–12 h on a water bath at 90–100 8C. The reaction
mixture was then poured onto ice, extracted with ethyl acetate, and washed
with sodium bicarbonate, and water until neutral. The organic layer was
dried over sodium sulfate and concentrated. The oily residue on chromato-
graphy yielded pure compound 11 in 50% yield.
Method C
A mixture of acid 6 (0.50 g, 1.4 mmol) and phenol (1.40 g, 1.5 mmol) in dry
benzene (10 ml) was strried with SnCl4 (6 ml) at a temperature ranging from
0 8C to rt for 10 h. The reaction mixture was then poured onto ice and
extracted with ethyl acetate. The organic layer was washed with sodium bicar-
bonate and water untill neutral and concentrated after drying over sodium
sulfate. The oily residue was then crystallized from ethyl acetate–hexane,
which gave 11 in 60% yield.
CONCLUSIONS
In conclusion, this communication describes an intramolecular cyclization of
17b-acetoxy-3-methoxy-9,11-seco-1,3,5(10)-estratriene-11-oic acid under
different Friedel–Crafts reaction conditions, yielding a cyclic ester in good
yield.
ACKNOWLEDGMENTS
Atul Gupta is thankful to the Council of Scientific and Industrial Research,
Government of India, India, for the senior research fellowship and to Sophis-
ticated Analytical and Instrumentation Facilities (SAIF), Central Drug
Research Institute, for spectroscopic studies.
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