One-step hetarylation of steroids: Regioselective synthesis of new estrone derivatives

Article abstract of DOI:10.1070/MC2006v016n02ABEH002238

New estrone derivatives containing 1,2,4-triazin-5-one moieties were synthesised through direct C-C coupling of estrone 3-methyl ether with 1,2,4-triazinones.

Full text of DOI:10.1070/MC2006v016n02ABEH002238

, 2006, 16(2), 95–96
One-step hetarylation of steroids: regioselective synthesis of new estrone derivatives
Oleg N. Chupakhin, Dmitry G. Beresnev and Nadezhda A. Itsikson*
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620219 Ekaterinburg,
Russian Federation. Fax: +7 343 374 1189; e-mail: nadya@ios.uran.ru
DOI: 10.1070/MC2006v016n02ABEH002238
New estrone derivatives containing 1,2,4-triazin-5-one moieties were synthesised through direct C–C coupling of estrone 3-methyl
ether with 1,2,4-triazinones.
Steroids are a biologically important class of compounds, which
are of importance for pharmaceutical industry.1 Estrone, one
of the three naturally occurring estrogens, is of interest for
the treatment and prevention of prostate2 and breast cancer.3–5
Modification of the estrone structure, especially in A and D rings,
can bring about remarkable changes in the pharmacological
activity of estrone.6 For example, functionalization of A ring by
pharmacophore fragments results in potential steroid sulfatase
inhibition.7
Earlier, we succeeded in the functionalization of 1,2,4-tri-
azines by π-excess carbo- and heterocycles such as phenols,
crown ethers, calixpyrroles, calixarenes and resorcinarenes using
a nucleophilic attack on an unsubstituted carbon atom in azines
(AN- and SNH-processes).8 Here we propose to modify estrone
3-methyl ether by heterocyclic moieties through direct one-step
C–C coupling.
Despite of the presence of aza groups in the molecule of
3-substituted-1,2,4-triazin-5-ones, they usually do not react
with aromatic C-nucleophiles. We found that the interaction of
1,2,4-triazin-5(2H)-ones with aromatic C-nucleophiles in a mix-
ture of trifluoroacetic acid and a carboxylic acid anhydride
results in the formation of stable products of nucleophilic
addition to the unsubstituted C(6) atom of the 1,2,4-triazine
ring.9 This reaction is accompanied by acylation of the nitrogen
atom adjacent to the reaction centre. The synthesis of hetaryl-
containing estrone derivatives was achieved in a similar fashion.
Thus, using the general procedure for the reaction of 1,2,4-tri-
azin-5(2H)-ones with aromatic C-nucleophiles, the coupling of
estrone derivatives with 3-substituted-1,2,4-triazin-5-ones 2a–d
results in the formation of a difficult-to-separate mixture of the
stable regioisomeric products 3a–d, 4a–d of nucleophilic addition
to the unsubstituted C(6) atom of the triazine ring (Scheme 1).†
The formation of such a mixture can be avoided by using
previously synthesised 2-acetyl-1,2,4-triazinones 5‡ as starting
compounds. The trifluoroacetic acid-promoted reaction between
1 and 5a,b,e in refluxing chloroform afforded stable adducts.
In this case, we succeeded to carry out a regioselective reaction.
Only diastereomeric compounds 6a,b,e and 7a,b,e were syn-
thesised in a ratio of 1:1 (Scheme 2).§
It has been shown by flash chromatography of filtrate that
there are no other by-products in an Et2O solution. It is possible
†
Flash chromatography was performed on Lancaster silica gel (230–
400 mesl). All melting points are uncorrected and have been obtained on
a Boetius melting point apparatus. Elemental analyses were performed
on a Perkin Elmer 2400 CHN analyzer. The 1H NMR spectra were
recorded on a Bruker DRX 400 (400 MHz) spectrometer with TMS as
an internal standard. The 19F NMR spectra were recorded on a Tesla
(80 MHz) spectrometer with hexafluorobenzene as an internal standard.
All signals are given in ppm.
General procedure for preparation of 3-substituted 2-(1-trifluoro-
acetyl-5-oxo-1,4,5,6-tetrahydro-1,2,4-triazin-6-yl)-3-methoxy-D-hydroxy-
methylestra-1,3,5(10)-trien-17-one 3, 4. A suspension of 3-substituted-
1,2,4-triazin-5(2H)-one (0.25 mmol) and 3-methoxy-D-hydroxymethyl-
estra-1,3,5(10)-trien-17-one (0.25 mmol) in a mixture of TFA (2 ml) and
trifluoroacetic anhydride (1 ml) was stirred at 20 °C until reagents were
completely dissolved. The reaction mixture was evaporated to dryness.
The residue was mashed with diethyl ether. The obtained precipitate was
filtered off and recrystallised from methanol.
2-(1-Trifluoroacetyl-5-oxo-3-phenyl-1,4,5,6-tetrahydro-1,2,4-triazin-
6-yl)-3-methoxy-D-hydroxymethylestra-1,3,5(10)-trien-17-one 3a, 4a:
yield 75%, mp 240–242 °C. 1H NMR ([2H6]DMSO) d: 0.92, 0.96 (br. s,
3H, Me), 1.31–1.40, 1.65–2.07, 2.59–2.64 (m, 12H, CH2), 3.38–3.40
(m, 3H, CH), 3.50, 3.51, 3.57, 3.59 (s, 3H, OMe), 5.85, 5.88 (set
triaz
of singlets, 1H, C H), 6.17 (d, J 2.8 Hz), 6.69 (d, J 2.8 Hz), 6.82 (d,
sp3
J 8 Hz), 6.83 (d, J 8 Hz), 7.11–7.16 (set of signals, 2H, Ar), 7.54–7.56
(m, 3H, Ph), 7.89–7.91 (m, 2H, Ph), 11.56, 11.58, 11.65, 11.67 [s,
1H, N(4)H]. 19F NMR ([2H6]DMSO) d: 93.80, 93.71, 93.66, 93.60.
MS, m/z (FD/EI, 220 °C): 553 (M+, 40), 456 (41), 283 (100), 270 (30),
187 (20.5), 97 (29). Found (%): C, 64.79; H, 5.26; N, 7.20. Calc. for
C30H30N3O4F3 (%): C, 65.09; H, 5.46; N, 7.59.
2-(1-Trifluoroacetyl-5-oxo-3-p-tolyl-1,4,5,6-tetrahydro-1,2,4-triazin-
6-yl)-3-methoxy-D-hydroxymethylestra-1,3,5(10)-trien-17-one 3b, 4b:
yield 87%, mp 284–286 °C. 1H NMR ([2H6]DMSO) d: 0.91, 0.96 (br. s,
3H, Me), 1.61–2.14 (set of m, 12H, CH2), 2.38 (br. s, 3H, Me), 2.54–2.67
(m, 3H, CH), 3.49, 3.50, 3.56, 3.58 (s, 3H, OMe), 5.84, 5.87 (set of
triaz
singlets, 2H, C H), 6.16, 6.68 (d, J 3.2 Hz), 6.82 (d, J 8 Hz), 6.83
sp3
(d, J 8 Hz), 7.13–7.16 (2H, Ar), 7.34, 7.33, 7.80, 7.78 (set of d, 4H,
Tol, J 8.6 Hz), 11.49, 11.52, 11.59, 11.61 [s, 1H, N(4)H]. Found (%):
C, 65.58; H, 5.70; N, 7.33. Calc. for C31H32N3O4F3 (%): C, 65.61; H,
5.65; N, 7.41.
N
O
HN
Me
H
R
N
O
2-[1-Trifluoroacetyl-3-(4-chlorophenyl)-5-oxo-1,4,5,6-tetrahydro-1,2,4-
H
H
2a–d
(F3CCO)2O/CF3COOH
triazin-6-yl]-3-methoxy-D-estra-1,3,5(10)-trien-17-one 3c, 4c: yield 52%,
1
mp 244–246 °C. H NMR ([2H6]DMSO) d: 0.93, 0.99 (br. s, 6H, Me),
H
1.27–1.33, 1.71–2.43, 2.68–2.72 (m, 12H, CH2), 3.35–3.39 (m, 3H, CH),
MeO
triaz
3.54, 3.59 (br. s, 3H, OMe), 5.14 (br. s, 1H, C H), 5.78 (d, J 2.8 Hz),
sp3
1
6.06 (br. s), 6.62–6.82 (m), 7.07–7.13 (m, 2H, Ar), 7.50 (d, J 8.5 Hz),
7.94 (d, 4H, ClC6H4, J 8.5 Hz), 11.53, 11.63 [br. s, 1H, N(4)H]. 19F NMR
([2H6]DMSO) d: 92.94, 92.95, 93.05, 93.08. MS, m/z (FD/EI, 220 °C):
588 (M+, 11), 587 (32), 490 (32), 283 (100), 187 (28), 97 (34). Found (%):
C, 61.23; H, 4.44; N, 7.14. Calc. for C30H29N3O4F3Cl (%): C, 61.28;
H, 4.97; N, 7.15.
CF3
O
O
Me
H
Me
H
R
N
O
O
N
H
H
HN
H
H
O
2-(1-Trifluoroacetyl-3-ethylthio-5-oxy-1,4,5,6-tetrahydro-1,2,4-triazin-
6-yl)-3-methoxy-D-estra-1,3,5(10)-trien-17-one 3d, 4d: yield 61%, mp 232–
MeO
MeO
O
1
234 °C. H NMR ([2H6]DMSO) d: 0.93, 0.98 (br. s, 3H, Me), 1.38 (t,
H
4a–d
3H, SCH2Me), 2.47 (q, 2H, SCH2Me), 1.27–1.47, 1.89–2.28, 2.77–2.98
N
N
CF3
(m, 12H, CH2), 3.16–3.17 (m, 3H, CH), 3.70, 3.73 (br. s, 3H, OMe),
a R = Ph
HN
triaz
5.68 (br. s, 1H, C H), 5.73 (br. s), 5.96 (br. s), 6.63–6.84 (m), 7.05–
sp3
b R = 4-MeC6H4
c R = 4-ClC6H4
d R = SEt
7.16 (m, 2H, Ar), 11.49 [br. s, 1H, N(4)H]. 19F NMR ([2H6]DMSO) d:
92.68, 92.63, 92.56, 92.54. MS, m/z (FD/EI, 190 °C): 537 (M+, 25), 440
(18), 283 (100), 187 (31), 97 (38). Found (%): C, 57.87; H, 5.93; N, 7.64.
Calc. for C26H30N3O4F3S (%): C, 58.09; H, 5.62; N, 7.82.
R
3a–d
Scheme 1
Mendeleev Commun. 2006 95

, 2006, 16(2), 95–96
to isolate an additional amount of parent 1,2,4-triazinone 2.
Attempts to separate 6 and 7 by column chromatography with a
mixture of benzene and ethyl acetate as an eluent failed.
The diastereomeric composition of 6–7a,b,e can be easily
O
Me
H
H
N
N
N
N
Ac
Ac2O
1
HN
N
determined by H NMR spectroscopy, according to the inten-
H
sities of C(6) protons of the triazine ring and the protons of the
aromatic estrone fragment. Thus, in the 1H NMR spectra of
the products of the regeoselective nucleophilic addition of estrone
methyl ether to the unsubstituted C(6) atom of the triazine ring
the H(6) signal is observed as a pair of singlets at the region
5.80–6.13 ppm, while the signal of the N(4) proton is located
as a pair of singlets or as a broad singlet at 11.00 ppm. The
aromatic protons of the estrone fragment appear as a pair of
signals. Note that the structure of 6 and 7 depends on the nature
of the substituent at the 3-position of the 1,2,4-triazinone ring.
In the case of 3-phenyl- or 3-p-tolyl-1,2,4-triazin-5-one (5a,b),
the reaction with 1 affords the 2-hetaryl-substituted estrone, but
the introduction of 3-(2-pyridyl)-substituted triazinone 5e into
the reaction leads to the isomeric 4-hetaryl-substituted estrone.
In conclusion, for the first time, a direct C–C coupling of
1,2,4-triazin-5-ones and an estrone derivative without metal cata-
lysts has been developed. Further, we hope, a new family of steroid
sulfatase inhibitors can be synthesised using the elaborated
methodology.
R
O
R
O MeO
2a,b,e
5a,b,e
1
∆
CF3COOH
R
R
N
O
O
NH
NH
Me
Me
H
N
O
O
H
H
N
N
Ac
Ac
H
H
H
MeO
MeO
6a,b,e
7a,b,e
a R = Ph
b R = 4-MeC6H4
e R = 2-Py
Scheme 2
‡
General procedure for preparation of 3-substituted 2-acyl-1,2,4-tri-
azin-5-ones 5a,b,e. A 3-substituted 1,2,4-triazin-5(2H)-one (1.7 mmol)
was dissolved by heating in 1.5 ml of acetic anhydride. The reaction
mixture was cooled and the precipitate was filtered off to give 3-substi-
tuted 2-acyl-1,2,4-triazin-5(2H)-one.
This work was supported by the Programme for Support of
Leading Scientific Schools (grant no. RF NSh 1766.2003.3),
CRDF (Rec 005) and ISTC (project no. 708).
2-Acetyl-3-phenyl-1,2,4-triazin-5-one 5a: yield 85%, mp 140–141 °C.
Found (%): C, 61.66; H, 3.98; N, 19.88. Calc. for C11H9N3O2 (%):
C, 61.40; H, 4.20; N, 19.53.
2-Acetyl-3-(p-tolyl)-1,2,4-triazin-5-one 5b: yield 92%. Found (%):
C, 63.12; H, 4.62; N, 18.16. Calc. for C12H11N3O2 (%): C, 62.87; H, 4.84;
N, 18.33.
References
1 J. B. Dence, Steroids and Peptides, Wiley-Interscience, New York, 1980.
2 F. Labrie, A. Bélanger, L. Cusan, C. Labrie, J. Simard, V. Luu-The,
P. Diamond, J.-L. Gomez and B. Candas, Endocrine-Related Cancer,
1996, 3, 243.
3 A. Picazo and R. Salcedo, J. Mol. Struct. (Theochem), 2003, 624, 29.
4 L. McCarthy-Morrogh, P. A. Townsend, A. Purohit, H. A. M. Hejaz,
B. V. L. Potte, M. J. Reed and G. Packham, Cancer Research, 2000, 60,
5441.
2-Acetyl-3-(2-pyridyl)-1,2,4-triazin-5-one 5e: yield 78%. Found, %:
C, 55.68; H, 4.01; N, 26.14. Calc. for C10H8N4O2 (%): C, 55.56; H, 3.71;
N, 25.92.
§
General procedure for the preparation of 3-substituted (1-acetyl-
5-oxy-1,4,5,6-tetrahydro-1,2,4-triazin-6-yl)-3-methoxy-D-estra-1,3,5(10)-
trien-17-ones 6, 7. A 3-substituted 2-acyl-1,2,4-triazin-5-one (0.25 mmol)
and 3-methoxyestra-1,3,5-trien-17-one (0.25 mmol) were dissolved in a
mixture of 1.0 ml of trifluoracetic acid and 2.0 ml of dichloromethane.
The reaction mixture was refluxed for 4 h. The solvent was removed
in vacuo. The oily residue was mashed by Et2O, the formed precipitate
was filtered off and dried yielding 1:1 product of hetarylation of estrone
3-methyl ether.
2-(1-Acetyl-3-phenyl-5-oxy-1,4,5,6-tetrahydro-1,2,4-triazin-6-yl)-3-
methoxy-D-estra-1,3,5(10)-trien-17-one 6a, 7a: yield 39%, mp > 255 °C.
1H NMR ([2H6]DMSO) d: 0.89, 0.90 (s, 3H, Me), 1.55–1.61, 1.72–2.10
(m, 12H, CH2), 2.23, 2.26 (s, 3H, Ac), 2.54–2.61, 2.73–2.77 (m, 3H,
CH), 3.56, 3.58 (s, 3H, OMe), 5.95, 5.97 (s, 1H, Cstrpi3azH), 6.64, 7.03
(br. s, 2H, Ar), 7.51–7.53 (m, 3H, Ph), 7.88–7.92 (m, 2H, Ph), 11.36,
11.38 [s, 1H, N(4)H]. MS, m/z (FD/EI, 230 °C): 499 (M+, 41), 456 (100),
310 (20), 174 (37), 104 (28), 97 (5). Found (%): C, 71.98; H, 6.93;
N, 8.12. Calc. for C30H33N3O4 (%): C, 72.12; H, 6.66; N, 8.41.
2-(1-Acetyl-5-oxy-3-p-tolyl-1,4,5,6-tetrahydro-1,2,4-triazin-6-yl)-3-
methoxy-D-estra-1,3,5(10)-trien-17-one 6b, 7b: yield 42%, mp 287–288 °C.
1H NMR ([2H6]DMSO) d: 0.89, 0.90 (s, 3H, Me), 1.55–1.64, 1.76–1.83
(m, 12H, CH2), 2.06–2.11 (m, 3H, CH), 2.20, 2.23 (s, 3H, Ac), 2.37
(br. s, 3H, Me), 2.55–2.56, 2.66–2.68 (m, 3H, CH), 3.55, 3.58 (s, 3H,
OMe), 5.95, 5.97 (s, 1H, Cstrpi3azH), 6.63, 7.02 (br. s, 2H, Ar), 7.31, 7.41,
7.79, 7.80 (d, 4H, Tol, J 8 Hz), 11.30, 11.32 [s, 1H, N(4)H]. Found (%):
C, 72.45; H, 7.17; N, 7.95. Calc. for C31H35N3O4 (%): C, 72.49; H, 6.87;
N, 8.18.
5 S. Ahmed, K. James and C. P. Owen, Biochem. Biophys. Res. Commun.,
2002, 294, 180.
6 M. M. Acanski, S. Jovanovic-Santa and L. R. Jervic, J. Serb. Chem.
Soc., 2003, 68, 57.
7 D. S. Fischer, L. W. Lawrence Woo, M. F. Mahon, A. Purohit, M. J. Reed
and B. V. L. Potter, Bioorg. Med. Chem., 2003, 1685.
8 O. N. Chupakhin, V. N. Charushin and H. C. van der Plas, Nucleophilic
Aromatic Substitution of Hydrogen, Academic Press, San Diego, 1994.
9 G. L. Rusinov, D. G. Beresnev, N. A. Itsikson and O. N. Chupakhin,
Heterocycles, 2001, 55, 2349.
4-[1-Acetyl-3-(2-pyridyl)-5-oxy-1,4,5,6-tetrahydro-1,2,4-triazin-6-yl)-
3-methoxy-D-estra-1,3,5(10)-trien-17-one 6e, 7e: yield 63%, mp > 255 °C.
1H NMR ([2H6]DMSO) d: 0.95, 0.96 (s, 3H, Me), 1.63–1.66, 1.84–2.08
(m, 12H, CH2), 2.23, 2.26 (s, 3H, Ac), 2.45, 2.69, 3.13 (m, 3H, CH),
3.41, 3.43 (s, 3H, OMe), 6.10, 6.14 (s, 1H, Cstrpi3azH), 6.72, 6.76 (2d, 1H,
Ar, J 8.8 Hz), 7.08, 7.09 (2d, 1H, Ar, J 8.8 Hz), 7.55–7.58 (m, 1H, Py),
7.97–8.01 (m, 1H, Py), 8.15–8.18 (m, 1H, Py), 8.67 (m, 1H, Py), 10.58
(br. s, 1H, NH). MS, m/z (FD/EI, 240 °C): 500 (M+, 4), 457 (19), 310 (16),
283 (16), 218 (100), 175 (91), 105 (50), 97 (8). Found (%): C, 69.81;
H, 6.82; N, 11.28. Calc. for C29H32N4O4 (%): C, 69.60; H, 6.42; N, 11.20.
Received: 12th September 2005; Com. 05/2576
96 Mendeleev Commun. 2006