Synthesis of novel structurally simplified estrogen analogues

Article abstract of DOI:10.1002/chem.200701600

A library of 17 novel estrogen analogues 3 and 4 containing different substituents at rings A and D (steroid nomenclature) was prepared in a five- to seven-step synthesis. The key transformation is a Sonogashira-coupling of cyclic vinyl iodides of type 7

Full text of DOI:10.1002/chem.200701600

DOI: 10.1002/chem.200701600
Synthesis of Novel Structurally Simplified Estrogen Analogues
Lutz F. Tietze,*[a] Carsten A. Vock,[a] Ilga K. Krimmelbein,[a] J. Matthias Wiegand,[a]
Linda Nacke,[a] Tokala Ramachandar,[a] Kazi M. D. Islam,[b] and Christiane Gatz[b]
Abstract: A library of 17 novel estrogen analogues 3 and 4 containing different
substituents at rings A and D (steroid nomenclature) was prepared in a five- to
seven-step synthesis. The key transformation is a Sonogashira-coupling of cyclic
vinyl iodides of type 7 or 8 with phenylacetylenes of type 9. Reduction of the keto
function in 3 led to the estradiol analogue 5.
Keywords: alkynes · estrogens ·
palladium · Sonogashira reaction ·
steroids · vinyl halides
Introduction
Several mechanisms for the estrogen-induced vessel relax-
ation have been discussed. A genomic long-term effect
might be the increased expression of important vasodilatory
enzymes such as prostacyclin- or NO-synthase. Nongenomic
effects might include the direct stimulation of NO-synthase
by estrogen binding to membrane-bound known[6] or un-
known[6,7] estrogen receptors or the interaction of estrogen
with ion channels located in endothelial smooth muscle
cells.[8] In this context, the findings of Valverde et al.[9] that
17b-estradiol (2) influences the opening of the BKCa2+ chan-
nels by binding to their extracellularly located b-subunits
have attracted much attention. The design of newestrogen
analogues that selectively interact with the b-subunits of the
BKCa2+ channels—four b-subunits (b1–b4) expressed in dif-
ferent tissues are known[10,11]—is therefore of great impor-
tance.
Steroids play very important roles in medicinal therapy of
different diseases. Among them, estrogens—for example,
naturally occurring estrone
1
and 17b-estradiol
2
(Scheme 1)—and their derivatives are of particular interest.
While they were recognized as sexual hormones quite early,
more recent investigations have shown a much broader
spectrum of biological activity of estrogens, underlining the
fundamental importance of these hormones in mammalian,
especially human, organisms. Thus, they have been identi-
fied to display a beneficial effect on blood vessels and the
coronary heart system, being responsible for a significantly
lower risk of arteriosclerotic diseases and therefore on aver-
age increased life expectancies in women.[1,2] In addition,
long-term application of estrogens has been shown to
induce coronary vessel relaxation in mammalian studies[3]
and in women during postmenopausal hormone displace-
ment therapy.[4] However, the discovery of severe long-term
side effects[5]—the induction of estrogen-dependent cancers
such as mamma carcinoma, for example—has led to a reduc-
tion in their application.
Many elegant syntheses of the characteristic steroidal
framework and of steroid analogues have been published in
the last decades.[12] A highly efficient synthesis of enantio-
pure estradiol by means of a double Heck reaction has been
developed in our group and has also recently been applied
to the synthesis of desogestrel.[13] Moreover, we have pre-
pared estradiol derivatives of modified B-ring size, in line
with the assumption that the interaction of estrone (1) and
estradiol (2) with the corresponding receptors mainly occurs
with participation of the oxygen functionalities at C-3 and
C-17 and that the steroidal activity might be adjustable
through changing the intramolecular O–O distance.[13] How-
ever, the enantioselective synthesis of estradiol derivatives is
still a challenging task, and for practical reasons research is
focusing more and more on easily accessible nonsteroidal
SERMs (selective estrogen receptor modulators) with as
[a] Prof. Dr. L. F. Tietze, Dr. C. A. Vock, Dr. I. K. Krimmelbein,
Dr. J. M. Wiegand, Dipl.-Chem. L. Nacke, T. Ramachandar
Institut für Organische und Biomolekulare Chemie der
Georg-August-Universität Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-399476
E-mail: ltietze@gwdg.de
[b] Dr. K. M. D. Islam, Prof. Dr. C. Gatz
Albrecht-von-Haller-Institut für Pflanzenwissenschaften der
Georg-August-Universität Gçttingen
[14,15]
fewstereogenic centers as possible.
Untere Karspüle 2, 37073 Gçttingen (Germany)
3670
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Chem. Eur. J. 2008, 14, 3670 – 3679

FULL PAPER
Here we present a new class of structurally simplified
nonsteroidal estrone and estradiol analogues 3–6 based on
the assumption that the B- and C-ring system of the steroi-
dal framework can be completely removed if the steric ri-
gidity is conserved by a suitable spacer: in our case an
alkyne moiety (Scheme 1). It was further anticipated that
dures,[17] in CH3CN in the presence of NEt3 at reflux gave
the desired compounds 7a–c and 8a–c in very good yields
(Scheme 3).
Scheme 3. Synthesis of 7a–c and 8a–c.
For the synthesis of phenylacetylenes 9 the iodobenzene
derivatives 10 were transformed into the corresponding phe-
nylpropargyl alcohol derivatives 14 by means of Sonogashira
reactions with propargyl alcohol followed by oxidative elim-
ination of the CH2OH groups under basic conditions
(Scheme 4). For the Sonogashira reactions we used [Pd-
AHCTRE(UGN PPh3)2Cl2] and CuI in iPr2NH or DMF, while the oxidative
cleavage of compounds 14 was performed with an excess of
activated MnO2 and KOH powder in Et2O or Et2O/CH2Cl2
in 12–90% yields.
Scheme 1. Novel estrogen analogues 3–6 based on estrone (1) and 17b-es-
tradiol (2).
the lack of steric demand due to the loss of the bulky ring
systems B and C might be partly compensated by introduc-
tion of suitable substituents R at the rings A and D (steroid
nomenclature).[16] For the synthesis of 3 and 4, retrosynthetic
analysis prompted us to use Sonogashira reactions between
the cyclic vinyl iodides 7 or 8 and the phenylacetylenes 9
(Scheme 2). Compounds 7 and 8 were synthesized from the
Scheme 2. Retrosynthetic analysis of 3 and 4.
Scheme 4. Synthesis of phenylacetylenes 9: a) propargyl alcohol, [Pd-
AHCTREUNG
corresponding substituted 1,3-cycloalkanediones by known
literature methods,[16] and phenylacetylenes 9 were prepared
from halogenated benzene derivatives 10, again by use of
Sonogashira reactions.
AHCTREUNG
As protecting groups for the phenolic compounds 9a–f we
used tert-butyl and methyl ethers, as well as the THP and
the TIPS groups. In addition to compounds 9a–f, possessing
OR substituents, we also prepared the compounds 9g and
9h, containing a NHBoc and a CF3 group, respectively. The
necessary iodophenols 10 used as starting material for the
synthesis of 9a–f were either commercially available or
were prepared from the corresponding anilines through
Sandmeyer reactions. The protection of the phenolic hy-
droxy groups was carried out by standard methods; commer-
Results and Discussion
The synthesis of the required cyclic vinyl iodides 7 and 8
was carried out according to a procedure published by Piers
et al.[16] by treatment with 13, which was prepared in situ
from PPh3 and I2. Heating of 13 with the alkylated 1,3-cyclo-
alkanediones 11a–c and 12a–c, which were either commer-
cially available or synthesized by known literature proce-
Chem. Eur. J. 2008, 14, 3670 – 3679
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3671

L. F. Tietze et al.
cially available 4-bromo-2,5-dimethylanisole and 4-iodoani-
sole were used for the synthesis of phenylacetylenes 9e and
9 f. The phenylacetylenes 9g and 9h were synthesized from
the corresponding commercially available iodo derivatives.
The synthesis of the target compounds 3 and 4 was ac-
complished through Sonogashira reactions between the
cyclic vinyl iodides 7 or 8 and the phenylacetylenes 9 to give
the protected estrone analogues 3 and 4 (Table 1). Since the
vinyl iodide functionalities in 7 and 8 are rather sensitive to
reactions with nucleophiles, the coupling was carried out
under very mild conditions, by a procedure by Tamura
et al.[18] with an excess of the tertiary amine NEt3 as base in
BF3·Et2O in Me2S. In all cases addition reactions at the
triple bond were observed, and the obtained complex mix-
tures could not usually be separated. Compound 3 f was ob-
tained from 15 f in 33% yield by treatment with BBr3 in
CH2Cl2 with subsequent purification by preparative re-
versed-phase HPLC.
A comparison of the different protecting groups at the
phenolic hydroxy group showed that the THP group has by
far the best properties wit regard to introduction, stability,
and removal. The other tested protecting groups each had at
least one disadvantage. The methyl protecting group was
easy to introduce and showed perfect stability, but its cleav-
age was problematic. The tBu group was nearly as stable as
a methyl group under reaction conditions while being easily
removable, but its introduction turned out to be quite diffi-
cult.
The tBoc group was used for the protection of the NH2
group as a carbamate in 9g and the following Sonogashira
reaction coupling could be performed without any difficul-
ties.
Finally, we also reduced the keto groups in the estrone an-
alogues to give estradiol analogues 5 and 6. As an example
we performed a selective reduction of the TIPS-protected
15d under Luche conditions[20] with NaBH4 and CeCl3 in
MeOH at room temperature to give the allylic alcohol 17 in
86% yield. Subsequent removal of the TIPS group was car-
ried out under mild conditions with CsF in CH3CN,[21] and
the desired estradiol analogue 5 was obtained in 57% yield
after chromatography on silica
DMF as solvent and [PdACHTER(UNG PPh3)2Cl2] (1.0–2.5 mol%) and CuI
(2.5–5.0 mol%) as catalyst system.
In most cases the reaction was exothermic; however, to
start the transformation, the mixture was heated slightly to
50–608C. The subsequent deprotection of the phenolic hy-
droxy group was performed under standard conditions. The
THP acetals and the tert-butyl ethers, as well as compounds
15e and 16g, each containing a N-Boc-protected amino
group, were stirred at room temperature in a solution of
CH2Cl2 containing 10–30% of CF3COOH, while the TIPS
protecting group was removed with nBu4NF·3H2O in THF
to give the estrone analogues 3d, 4d and 4e (Table 1). How-
ever, the cleavage of the methoxy group was less successful.
Here we variously used BBr3 in CH2Cl2 (alone or with addi-
tion of K2CO3 as acid scavenger), [NMe4]
+A[Al2Cl7]ꢀ in
CHTREUNG
CH2Cl2 under microwave irradiation conditions,[19] and
gel with small amounts of NEt3
Table 1. Synthesis of steroid analogues 3, 4 and 5 from 7 or 8 and 9, via 15 and 16. Reagents and conditions:
a) [Pd(PPh3)2Cl2], CuI, NEt3, DMF, RT; b) CF3COOH, CH2Cl2, RT; c) nBu4NF·3H2O, THF, 08C to RT;
d) NaBH4, CeCl3·7H2O, MeOH/Et2O, RT, 4 h, 86%; e) CsF, CH3CN, 08C to RT, 18.5 h, 57%.
to remove traces of acid. Com-
pound 5, containing an allylic
alcohol moiety, turned out to
be rather unstable in pure form,
however, decomposing quite
rapidly at room temperature
and only being stable for a
longer time when stored at
ꢀ288C. The allylic alcohols 5
and 6 are thus not suitable as
estradiol analogues due to their
instability and no further inves-
tigations were performed with
these compounds.
ACHTREUNG
Entry
n
Starting
material
Substituents
on ring A
bÞ
Substituents
on ring D
R2 =2-Cl
R2 =2-Cl
R2 =2-Cl
Products
Yield [%]
(*: over two steps)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
7a, 9a
7b, 9a
7c, 9a
7a, 9d
7a, 9g
7a, 9 f
7a, 9e
7a, 9h
8a, 9a
8b, 9a
8c, 9a
8a, 9d
8a, 9c
8a, 9b
8a, 9g
8a, 9 f
8a, 9e
R1 =OtBu
R1 =OH
R5 =Me
R5 =Et
R5 =iPr
R5 =Me
R5 =Me
R5 =Me
15a/3a
15b/3b
15c/3c
15d/3d
15e/3e
15 f
76*
70*
75*
85*
87*
93
ƒ!
bÞ
R1 =OtBu
R1 =OtBu
R1 =OH
R1 =OH
R1 =OH
ƒ!
bÞ
ƒ!
cÞ
R1 =OTIPS
R1 =NHBoc
ƒ!
bÞ
R1 =NH
ƒ!
2
R1 =OMe
R1 =OMe
Conclusion
R2 =3-Me, 5-Me R5 =Me
R5 =Me
15g
15h
86
85
R1 =CF3
bÞ
R1 =OtBu
R1 =OH
R2 =2-Cl
R2 =2-Cl
R2 =2-Cl
R5 =Me
R5 =Et
R5 =iPr
16a/4a
16b/4b
16c/4c
76*
55*
60*
84*
47*
57*
41*
74
A library of 17 novel estrone
analogues 3 and 4 was synthe-
sized from phenylacetylenes 9
and cyclic vinyl iodides 7 or 8
ƒ!
bÞ
R1 =OtBu
R1 =OtBu
R1 =OH
R1 =OH
ƒ!
bÞ
ƒ!
cÞ
R1 =OTIPS
R1 =OTIPS
R1 =OTHF
R1 =NHBoc
R1 =OH
R1 =OH
R1 =OH
R1 =NH
R5 =Me 16d[a]/4d
ƒ!
cÞ
R2 =2-CO2Me
R2 =Br
R5 =Me
16e/4e
ƒ!
bÞ
through
palladium-catalyzed
R5 =Me 16 f[a]/4 f
ƒ!
bÞ
R5 =Me
R5 =Me
16g/4g
16h
16i
Sonogashira reactions in five to
seven synthetic steps starting
from commercially available
materials. The compounds are
ƒ!
2
R1 =OMe
R1 =OMe
R2 =3-Me, 5-Me R5 =Me
82
[a] Compounds 16d and 16 f were not isolated, but were directly subjected to deprotection.
3672
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3670 – 3679

Estrogen Analogues
FULL PAPER
(C-1); HRMS (EI+): m/z: calcd for C7H9IO: 235.9698 [M]+; found:
235.9696.
highly stable solids and a large variety of substitution pat-
terns has been produced. Selective reduction of the keto
functionality of TIPS-protected 15d and subsequent depro-
tection gave the estradiol analogue 5, but this lacks suffi-
cient stability. The evaluation of the biological properties of
the newcompounds with regard to their steroidal activities
is currently underway.
3-Iodo-2-isopropylcyclopent-2-en-1-one (7c): The title compound was
synthesized according to General Procedure A by use of PPh3 (10.3 g,
39.2 mmol), I2 (10.5 g, 41.3 mmol), NEt3 (5.90 mL, 4.31 g, 42.6 mmol),
and 2-isopropylcyclopentane-1,3-dione (5.00 g, 35.7 mmol) in CH3CN
(400 mL). The mixture was heated for 15 h at reflux. Workup and filtra-
tion gave 7c as light yellowcrystals (6.96 g, 27.8 mmol, 78%). 1H NMR
(300 MHz, CDCl3): d=1.19 (d, J=7.0 Hz, 6H; 2-CH
2H; 5-H2), 2.82 (sept., J=7.0 Hz, 1H; 2-CH(CH3)2), 2.97 ppm (m, 2H; 4-
H2); 13C NMR (75.5 MHz, CDCl3): d=19.15 (2-CH
(CH3)2), 30.19 (2-CH-
ACHTRE(UGN CH3)2), 2.47 (m,
AHCTREUNG
AHCTREUNG
AHCTRE(UNG CH3)2), 37.52 (C-4), 39.56 (C-5), 132.5 (C-3), 154.0 (C-2), 201.9 ppm (C-
1); HRMS (EI+): m/z: calcd for C8H11IO: 249.9855 [M]+; found:
289.9850.
Experimental Section
3-Iodo-2-methylcyclohex-2-en-1-one (8a): The title compound was syn-
thesized according to General Procedure A by use of PPh3 (27.04 g,
103 mmol) in CH3CN (750 mL), I2 (27.17 g, 107 mmol), NEt3 (15.0 mL,
General methods: All reactions were performed under argon in flame-
dried flasks. THF and Et2O were dried and distilled prior to use by usual
laboratory methods, while all other solvents were used from commercial
sources and stored over molecular sieves; Petrol ether (PE) b.p. range
35–758C. All reagents obtained from commercial sources were used with-
out further purification. Thin-layer chromatography (TLC) was per-
formed on precoated silica gel SILG/UV254 plates (Macherey–Nagel),
and silica gel 60 (0.032–0.063 mm, Merck) was used for column chroma-
tography. Vanillin in methanolic sulfuric acid was used as a staining re-
agent for TLC. UV spectra were taken in CH3CN or MeOH with a
Perkin–Elmer Lambda 2 spectrometer. IR spectra were recorded as KBr
pellets or as films between NaCl plates with a Bruker IFS 25 spectrome-
11.0 g,
79.3 mmol) in CH3CN (50 mL). The mixture was heated for 10 h at
reflux. Workup and filtration gave 8a as yellowsolid (16.06 g,
108 mmol),
and
2-methylcyclohexane-1,3-dione
(10.0 g,
a
68.0 mmol, 86%). 1H NMR (300 MHz, CDCl3): d=1.93–2.02 (m, 2H; 5-
H2), 2.03 (t, J=2.0 Hz, 3H; 2-CH3), 2.46–2.53 (m, 2H; 6-H2), 3.04 ppm
(tq, J=6.0, 2.0 Hz, 2H; 4-H2); 13C NMR (50.3 MHz, CDCl3): d=21.71 (2-
CH3), 24.52 (C-5), 37.81 (C-6), 42.71 (C-4), 128.0 (C-3), 142.0 (C-2),
193.2 ppm (C-l).
2-Ethyl-3-iodocyclohex-2-en-1-one (8b): The title compound was synthe-
sized according to General Procedure A by use of PPh3 (9.72 g,
37.0 mmol), I2 (9.76 g, 38.4 mmol), NEt3 (13.1 mL, 3.94 g, 39.0 mmol),
and 2-ethylcyclohexane-1,3-dione (4.05 g, 28.9 mmol) in CH3CN
(270 mL). The mixture was heated for 17 h at reflux. Workup and filtra-
tion gave 8b as a light yellowsolid (6.54 g, 26.2 mmol, 90%). 1H NMR
(300 MHz, CDCl3): d=0.96 (t, J=7.5 Hz, 3H; 2-CH2CH3), 1.90–2.00 (m,
2H; 5-H2), 2.43–2.53 (m, 4H; 4-H2, 2-CH2CH3), 3.03 ppm (t, J=6.1 Hz,
2H; 6-H2); 13C NMR (75.5 MHz, CDCl3): d=12.29 (2-CH2CH3), 24.53
(C-5), 28.94 (2-CH2CH3), 38.12 (C-6), 42.90 (C-4), 127.2 (C-3), 147.0 (C-
2), 192.8 ppm (C-1); HRMS (EI+): m/z: calcd for C8H11IO: 249.9855
[M]+; found: 289.9854.
1
ter. H and 13C NMR spectra were recorded with Mercury 200, VXR 200,
Unity 300, Inova 500, Unity Inova 600 (Varian), or AMX 300 (Bruker)
spectrometers. Chemical shifts are reported in ppm with tetramethylsi-
lane (TMS) or the solvent as internal standard. Multiplicities of 13C NMR
peaks were determined by use of the APT pulse sequence. Mass spectra
were measured with Finnigan MAT 95, TSQ 7000, or LCQ instruments.
Elemental analysis: Mikroanalytisches Labor, Institut für Organische und
Biomolekulare Chemie, Georg-August-Universität Gçttingen. The fol-
lowing abbreviations are used: s (singlet), d (doublet), t (triplet), q (quar-
tet), quint. (quintet), sept. (septet), m (multiplet), br (broad), and combi-
nations thereof.
3-Iodo-2-isopropylcyclohex-2-en-1-one (8c): The title compound was syn-
thesized according to General Procedure A by use of PPh3 (8.83 g,
33.6 mmol), I2 (8.87 g, 34.9 mmol), NEt3 (4.90 mL, 3.58 g, 35.3 mmol),
and 2-isopropylcyclohexane-1,3-dione (4.00 g, 25.9 mmol) in CH3CN
(250 mL). The mixture was heated for 23 h at reflux. Workup and filtra-
tion gave 8c as a light yellowsolid (6.02 g, 22.8 mmol, 88%). 1H NMR
General Procedure A—Synthesis of vinyl iodides 7 and 8: I2 was added
at room temperature to a stirred solution of PPh3 in CH3CN, and stirring
was continued for 15 min, after which NEt3 (15.0 mL, 11.0 g, 108 mmol)
was added. After another 5 min of stirring the 1,3-dione 11 or 12 was
added and the solution was heated to reflux. After completion of the re-
action the solvent was evaporated in vacuo, the residue was dissolved in
Et2O (10 mLmmolꢀ1), the mixture was stirred, and the solvent was de-
canted. This procedure was repeated three times. The combined organic
layers were filtered over SiO2 with the aid of Et2O and the solvent was
then evaporated in vacuo to give the vinyl iodides 7a–c and 8a–c.
(300 MHz, CDCl3): d=1.17 (d, J=7.0 Hz, 6H; 2-CH
(m, 2H; 5-H2), 2.41–2.48 (m, 2H; 4-H2), 2.94 (sept., J=7.0 Hz, 1H; 2-
CH
(CH3)2), 3.04 ppm (t, J=6.1 Hz, 2H; 6-H2); 13C NMR (75.5 MHz,
CDCl3): d=19.84 (2-CH(CH3)2), 24.32 (C-5), 39.78 (C-6), 40.32 (2-CH-
ACHTRE(UNG CH3)2), 1.84–1.95
AHCTREUNG
AHCTREUNG
AHCTRE(UNG CH3)2), 43.72 (C-4), 127.3 (C-3), 148.8 (C-2), 192.7 ppm (C-1); HRMS
3-Iodo-2-methylcyclopent-2-en-1-one (7a): The title compound was syn-
thesized according to General Procedure A by use of PPh3 (11.5 g,
44.0 mmol) in CH3CN (400 mL), I2 (11.7 g, 46.0 mmol), NEt3 (6.50 mL,
4.75 g, 46.9 mmol), and 2-methylcyclopentane-1,3-dione (4.48 g,
40.0 mmol). The mixture was heated for 6 h at 80–908C. Workup and fil-
tration gave 7a as a yellowish white solid (8.50 g, 38.3 mmol, 96%).
1H NMR (200 MHz, CDCl3): d=1.80 (t, J=2.2 Hz, 3H; 2-CH3), 2.48–
2.55 (m, 2H; 5-H2), 2.99 ppm (tq, J=4.7, 2.3 Hz, 2H; 4-H2); 13C NMR
(50.3 MHz, CDCl3): d=12.91 (2-CH3), 36.45 (C-5), 39.02 (C-4), 133.8 (C-
3), 147.8 (C-2), 202.6 ppm (C-1); HRMS (EI+): m/z: calcd for C6H7IO:
221.9542 [M]+; found: 221.9542.
(EI+): m/z: calcd for C9H13IO: 265.0011 [M]+; found: 265.0011.
General Procedure B—Synthesis of phenylacetylenes 9: Propargyl alco-
hol and, after degassing, .[PdACTHER(UNG PPh3)2Cl2] and CuI were added at room
temperature to a stirred solution of the iodobenzene derivative 10 either
in iPr2NH or in DMF and NEt3 or in CH3CN, H2O, and NEt3. The mix-
ture was normally briefly heated to 50–608C and then stirred at room
temperature for the given time. The mixture was diluted with Et2O
(150 mL) and filtered over silica gel (20 g) with the aid of Et2O (4”
100 mL), and the filtrate was evaporated in vacuo. Activated MnO2 and
KOH powder were added at room temperature to a stirred solution of
the residue in Et2O (50–250 mL), and stirring was continued for the
given time. In some cases the treatment with MnO2 was repeated. The
mixture was filtered over a pad of silica gel with the aid of Et2O (4”
100 mL), and evaporation of the solvent in vacuo gave the title com-
pound 9.
2-Ethyl-3-iodocyclopent-2-en-1-one (7b): The title compound was synthe-
sized according to General Procedure A by use of PPh3 (11.4 g,
43.4 mmol), I2 (11.6 g, 45.6 mmol), NEt3 (6.50 mL, 4.75 g, 46.9 mmol),
and 2-ethylcyclopentane-1,3-dione (5.00 g, 39.6 mmol) in CH3CN
(400 mL). The mixture was heated for 8 h at reflux. Workup and filtra-
tion gave 7b as
a
yellowoil (8.66 g, 36.7 mmol, 93%).
1H NMR
4-tert-Butoxy-2-chloro-1-ethynylbenzene (9a): The title compound was
synthesized according to General Procedure B with 4-tert-butoxy-2-
chloro-1-iodobenzene (4.05 g, 13.0 mmol) in iPr2NH (31.5 mL) and prop-
(300 MHz, CDCl3): d=1.00 (t, J=7.5 Hz, 3H; 2-CH2CH3), 2.27 (tq, J=
7.5 Hz, 1.0 Hz, 2H; 2-CH2CH3), 2.51 (m, 2H; 5-H2), 2.96–3.02 ppm (m,
2H; 4-H2); 13C NMR (50.3 MHz, CDCl3): d=11.74 (2-CH2CH3), 20.91 (2-
CH2CH3), 36.77 (C-5), 39.08 (C-4), 133.1 (C-3), 152.4 (C-2), 202.3 ppm
argyl alcohol (2.30 mL, 2.18 g, 38.9 mmol), [Pd
ACHTRE(UNG PPh3)2Cl2] (137 mg,
195 mmol, 1.50 mol%), and CuI (74.8 mg, 393 mmol, 3.02 mol%) for
Chem. Eur. J. 2008, 14, 3670 – 3679
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3673

L. F. Tietze et al.
15.5 h, followed by MnO2 (16.95 g, 195 mmol) and KOH powder (5.47 g,
97.5 mmol) in Et2O (150 mL) for 1.5 h. This was followed by repeated
treatment with MnO2 (16.95 g, 195 mmol) and KOH powder (5.47 g,
97.5 mmol) for 30 min. Product: reddish oil (2.10 g, 10.1 mmol, 77% over
18H; 3”SiCH
2’-H), 6.78–6.85 (m, 2H; 2-H, 6-H), 7.33–7.40 ppm (m, 2H; 3-H, 5-H);
13C NMR (50.3 MHz, CDCl3): d=12.63 (3”SiCH
(CH3)2), 17.85 (3”
ACHTREUN(G CH3)2), 1.18–1.34 (m, 3H; 3”SiCHACHTER(UGN CH3)2), 2.99 (s, 1H;
AHCTREUNG
SiCHACHTRE(UNG CH3)2), 75.78 (C-2’), 83.77 (C-1’), 114.4 (C-4), 119.9 (C-2, C-6),
two steps). 1H NMR (300 MHz, CDCl3): d=1.37 (s, 9H; 4-OC
A
133.6 (C-3, C-5), 156.7 ppm (C-1); HRMS (EI+): m/z: calcd for
C17H26OSi: 274.1753 [M]+; found: 274.1753.
3.31 (s, 1H; 2’-H), 6.85 (dd, J=8.6, 2.4 Hz, 1H; 5-H), 7.05 (d, J=2.4 Hz,
1H; 3-H), 7.42 ppm (d, J=8.6 Hz, 1H; 6-H); 13C NMR (75.5 MHz,
CDCl3): d=28.77 (4-OCACHTER(NGU CH3)3), 80.00, 80.16 (4-OCAHCTRE(UGN CH3)3, C-1’), 81.37
(C-2’), 116.4 (C-1), 121.8 (C-5), 124.2 (C-3), 134.1 (C-6), 136.3 (C-2),
156.7 ppm (C-4); HRMS (EI+): m/z: calcd for C12H13ClO: 208.0655 [M]+
; found: 208.0655.
5-Ethynyl-2-methoxy-1,3-dimethylbenzene (9e): The title compound was
synthesized according to General Procedure B with 4-bromo-2,6-dime-
thylanisol (4.30 g, 20.0 mmol) in iPr2NH (40 mL) and propargyl alcohol
(3.55 mL, 3.37 g, 60.1 mmol), [PdCAHTRE(UNG PPh3)2Cl2] (351 mg, 500 mmol,
2.50 mol%), and CuI (191 mg, 1.00 mmol, 5.01 mol%) at 75–858C for
6 h, followed by activated MnO2 (17.39 g, 200 mmol) and KOH powder
(5.61 g, 100 mmol) in Et2O (200 mL) for 1 h. Product: yellowliquid
(1.38 g, 8.61 mmol, 43% over two steps). 1H NMR (200 MHz, CDCl3):
d=2.25 (s, 6H; 1-CH3, 3-CH3), 2.98 (s, 1H; 2’-H), 3.72 (s, 3H; 2-OCH3),
7.17 ppm (s, 2H; 4-H, 6-H); 13C NMR (50.3 MHz, CDCl3): d=15.89 (1-
CH3, 3-CH3), 59.72 (2-OCH3), 75.94 (C-2’), 83.61 (C-1’), 117.2 (C-5),
131.1 (C-1, C-3), 132.6 (C-4, C-6), 157.7 ppm (C-2); HRMS (EI+): m/z:
calcd for C11H12O: 160.0888 [M]+; found: 160.0888.
2-(3-Bromo-4-ethynylphenoxy)tetrahydropyran (9b): The title compound
was synthesized according to General Procedure B with 2-(3-bromo-4-io-
dophenoxy)tetrahydropyran (990 mg, 2.58 mmol) in iPr2NH (5.2 mL) and
propargyl alcohol (0.460 mL, 437 mg, 7.79 mmol), [PdACTHERU(GN PPh3)2Cl2]
(45.3 mg, 64.5 mmol, 2.50 mol%), and CuI (24.6 mg, 129 mmol,
5.01 mol%) for 4 h at room temperature and 4 h at 50–608C, followed by
MnO2 (8.97 g, 100 mmol) and KOH powder (2.90 g, 51.7 mmol) in Et2O
(50 mL) for 45 min. Product: reddish brown oil (420 mg, 1.49 mmol, 58%
crude yield over two steps). 1H NMR (300 MHz, CDCl3): d=1.52–2.10
(m, 6H; 3-H2, 4-H2, 5-H2), 3.28 (s, 1H; 2’’-H), 3.61 (dtd, J=11.3, 3.9,
1.5 Hz, 1H; 6-HA), 3.82 (ddd, J=11.3, 10.0, 3.1 Hz, 1H; 6-HB), 5.42 (t,
J=2.9 Hz, 1H; 2-H), 6.95 (dd, J=8.6, 2.5 Hz, 1H; 6’-H), 7.30 (d, J=
2.5 Hz, 1H; 2’-H), 7.43 ppm (d, J=8.6 Hz, 1H; 5’-H); 13C NMR
(75.5 MHz, CDCl3): d=18.32 (C-4), 24.97 (C-5), 29.99 (C-3), 61.90 (C-6),
80.16 (C-2’’), 81.92 (C-1’’), 96.30 (C-2), 115.4 (C-6’), 117.1 (C-4’), 120.3
(C-2’), 126.0 (C-3’), 133.4 (C-4’), 157.7 ppm (C-1’).
1-Ethynyl-4-methoxybenzene (9 f): The title compound was synthesized
according to General Procedure B with 1-iodo-4-methoxybenzene
(20.0 g, 85.5 mmol) in a mixture of CH3CN (210 mL) and H2O (40 mL)
together with propargyl alcohol (14.9 mL, 14.1 g, 252 mmol), NEt3
(35.7 mL, 26.1 g, 258 mmol), PPh3 (1.12 g, 4.27 mmol, 4.99 mol%), Pd-
AHCTRE(UNG OAc)2 (479 mg, 2.13 mmol, 2.50 mol%), and CuI (814 mg, 4.27 mmol,
4.99 mol%) at room temperature without heating for 42 h. The CH3CN
was mostly removed in vacuo, and the residue was diluted with H2O
(100 mL) and extracted with Et2O (200 mL, 3”100 mL). The combined
organic layers were washed with brine (50 mL) and dried over MgSO4,
and the solvent was evaporated down to give a volume of 50–75 mL. This
was filtered over silica gel (150 g), the residue was washed with Et2O,
and the solvent was evaporated. The resulting alcohol (2.43 g, 15.0 mmol)
in Et2O (150 mL) was treated with MnO2 (13.0 g, 150 mmol) and KOH
powder (4.21 g, 75.0 mmol) at room temperature for 45 min. Product:
yellow, low-melting solid (1.76 g, 13.3 mmol, 89%). 1H NMR (300 MHz,
CDCl3): d=3.00 (s, 1H; 2’-H), 3.81 (s, 3H; 4-OCH3), 6.81–6.87 (m, 2H;
3-H, 5-H), 7.40–7.46 ppm (m, 2H; 2-H, 6-H); 13C NMR (50.3 MHz,
CDCl3): d=55.24 (4-OCH3), 75.75 (C-2’), 83.62 (C-1’), 113.9 (C-3, C-5),
114.1 (C-1), 133.5 (C-2, C-6), 159.9 ppm (C-4); HRMS (EI+): m/z: calcd
for C9H8O: 132.0575 [M]+; found: 132.0575.
2-Ethynyl-5-(triisopropylsilanyloxy)benzoic acid methyl ester (9c): The
title compound was synthesized according to General Procedure B with
2-iodo-5-(triisopropylsilanyloxy)benzoic acid methyl ester (11.00 g,
25.3 mmol) in DMF (45 mL) and NEt3 (10.9 mL, 7.96 g, 78.6 mmol) and
propargyl alcohol (4.50 mL, 4.27 g, 76.2 mmol), [PdACTHERU(GN PPh3)2Cl2] (444 mg,
633 mmol, 2.50 mol%), and CuI (241 mg, 1.27 mmol, 5.00 mol%) in DMF
(15 mL) (inverse addition) for 41 h. The reaction mixture was poured
into H2O (250 mL), and the aqueous phase was saturated with NaCl and
extracted with Et2O (4”100 mL). The combined organic layers were
washed with brine (3”50 mL) and dried over MgSO4, and the solvent
was evaporated in vacuo after addition of silica gel (20 g). The crude
product was purified by column chromatography (silica gel; Et2O/CH2Cl2
3:1 ! Et2O/CH2Cl2 5:1) to give 2-(3-hydroxyprop-1-ynyl)-5-(triisopropyl-
silanyloxy)benzoic acid methyl ester (4.23 g, 11.7 mmol, 46%) as a red
oil.
(4-Ethynylphenyl)carbamic acid tert-butyl ester (9g): The title compound
was synthesized according to General Procedure B with (4-iodophenyl)-
carbamic acid tert-butyl ester (1.60 g, 5.01 mmol) in DMF (10 mL), prop-
argyl alcohol (0.890 mL, 845 mg, 15.1 mmol), and NEt3 (2.15 mL, 1.57 g,
Activated MnO2 (10.10 g, 116 mmol) and KOH powder (3.25 g,
57.9 mmol) were added to
a solution of this compound (4.21 g,
15.5 mmol), together with [PdCATHRE(UNG PPh3)2Cl2] (35.2 mg, 50.1 mmol,
11.6 mmol) in Et2O (120 mL). The reaction mixture was stirred at room
temperature for 30 min and filtered over silica gel with the aid of Et2O
(6”50 mL), the resulting solution was filtered, and the solvent was
evaporated. The crude product was purified by column chromatography
(silica gel; PE/EE 20:1 ! PE/EE 15:1 ! PE/EE 10:1) to give the title
compound with some TIPSOH contamination (1.20 g; product/TIPSOH
ratio 2.75:1, calculated from 13C NMR signals; 3.03 mmol, 12% over two
steps) as a light red oil, which partly recrystallized to afford a red solid.
1H NMR (300 MHz, CDCl3): d=1.10 (d, J=7.1 Hz, 18H; 3”SiCH-
1.00 mol%) and CuI (19.1 mg, 100 mmol, 2.00 mol%) in DMF (2.5 mL)
(inverse addition) for 20 h. The reaction mixture was poured into ice-
cold H2O (45 mL) and extracted with Et2O (4”20 mL). The combined
organic layers were washed with brine (3”15 mL) and dried over
MgSO4, and the solvent was removed under reduced pressure. The crude
product was dissolved in Et2O, and column filtration over silica gel (30 g)
gave the slightly impure alcohol as a light brown oil (1.13 g, 4.57 mmol,
91%).
ACHTREUNG(CH3)2), 1.19–1.36 (m, 3H; 3”SiCHACHTRE(UGN CH3)2), 3.29 (s, 1H; 2’-H), 3.92 (s,
3H; 1-COOCH3), 6.97 (dd, J=8.5, 2.6 Hz, 1H; 4-H), 7.42 (d, J=2.6 Hz,
1H; 6-H), 7.49 ppm (d, J=8.5 Hz, 1H; 3-H); 13C NMR (75.5 MHz,
Activated MnO2 (3.90 g, 44.9 mmol) and KOH powder (1.26 g,
22.5 mmol) were added to a solution of the alcohol (1.11 g, 4.49 mmol) in
Et2O (45 mL), and the reaction mixture was stirred at room temperature
for 45 min. Product: colorless solid (653 mg, 3.01 mmol, 61% over two
CDCl3): d=12.57 (3”SiCHACTHERUNG(CH3)2), 17.82 (3”SiCHCAHTRE(UGN CH3)2), 52.22 (1-
steps). 1H NMR (300 MHz, CDCl3): d=1.52 (s, 9H; C
ACHTRE(UGN CH3)3), 3.02 (s,
COOCH3), 80.46 (C-2’), 82.04 (C-1’), 114.9 (C-2), 121.6 (C-6), 123.4 (C-
4), 133.8 (C-l), 136.3 (C-3), 156.3 (C-5), 166.2 ppm (1-COOCH3); HRMS
(EI+): m/z: calcd for C19H28O3Si: 332.1808 [M]+; found: 332.1808.
1H; 2’-H), 6.55 (brs, 1H; NH), 7.30–7.35 (m, 2H; 3-H, 5-H), 7.39–
7.44 ppm (m, 2H; 2-H, 6-H); 13C NMR (50.3 MHz, CDCl3): d=28.27 (C-
ACHTRE(GNU CH3)3), 77.20 (C-2’), 80.93 (CCAHRTE(UGN CH3)3), 83.52 (C-1’), 116.2 (C-4), 117.9 (C-
(4-Ethynylphenoxy)triisopropylsilane (9d): The title compound was syn-
thesized according to General Procedure B with (4-iodophenoxy)triiso-
propylsilane (1.89 g, 5.02 mmol) in iPr2NH (10 mL), propargyl alcohol
2, C-6), 133.0 (C-3, C-5), 138.9 (C-1), 152.3 ppm (COOtBu); HRMS (EI+):
m/z: calcd for C13H15NO2: 217.1103 [M]+; found: 217.1103.
(0.890 mL, 845 mg, 15.1 mmol), [Pd
A
1-Ethynyl-4-(trifluoromethyl)benzene (9h): The title compound was syn-
thesized according to General Procedure B with 1-iodo-4-(trifluorome-
thyl)benzene (5.44 g, 20.0 mmol) in CH3CN (49 mL) and H2O (10 mL),
propargyl alcohol (3.55 mL, 3.37 g, 60.1 mmol), NEt3 (8.30 mL, 6.06 g,
1.00 mol%), and CuI (20.1 mg, 106 mmol, 2.11 mol%) for 15 h, followed
by MnO2 (4.37 g, 50.3 mmol) and KOH powder (1.41 g, 25.1 mmol) in
Et2O (50 mL) for 45 min. Product: colorless oil (1.04 g, 3.79 mmol, 75%
over two steps). 1H NMR (300 MHz, CDCl3): d=1.09 (d, J=7.0 Hz,
59.9 mmol), PPh3 (263 mg, 1.00 mmol, 5.01 mol%), PdACTHER(UNG OAc)2 (112 mg,
3674
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3670 – 3679

Estrogen Analogues
FULL PAPER
499 mmol, 2.49 mol%), and CuI (191 mg, 1.00 mmol, 5.01 mol%) for 16 h
at room temperature without heating. The CH3CN was mostly removed
under reduced pressure, and the residue was diluted with H2O (25 mL)
and brine (25 mL) and extracted with Et2O (4”25 mL). The combined
organic layers were washed with brine (10 mL) and dried over MgSO4,
and the solvent was evaporated. The crude product was dissolved in
Et2O and filtered over silica gel (75 g), which was then washed with
Et2O. Evaporation of the solvent gave the alcohol as a brown solid,
which was dissolved in Et2O (160 mL). Subsequent treatment with MnO2
(13.91 g, 160 mmol) and KOH powder (4.49 g, 80.0 mmol) at room tem-
perature for 2 h gave a light yellowsolid (1.49 g, 8.76 mmol, 90% over
two steps). 1H NMR (300 MHz, CDCl3): d=3.20 (s, 1H; 2’-H), 7.59 ppm
(s, 4H; 2-H, 3-H, 5-H, 6-H); 13C NMR (50.3 MHz, CDCl3): d=79.61 (C-
2’), 82.19 (q, J=0.7 Hz, C-1’), 123.8 (q, J=273 Hz, 4-CF3), 125.3 (q, J=
3.8 Hz, C-3, C-5), 125.9 (q, J=1.8 Hz, C-1), 130.6 (q, J=32.8 Hz, C-4),
132.4 ppm (C-2, C-6).
1.38 (s, 9H; 4’’-OC
H2), 3.01 (sept., J=7.0 Hz, 1H; 2-CH
2.2 Hz, 1H; 5’’-H), 7.08 (d, J=2.2 Hz, 1H; 3’’-H), 7.43 ppm (d, J=8.5 Hz,
1H; 6’’-H); 13C NMR (126 MHz, CDCl3): d=20.13 (2-CH
(CH3)2), 25.57
(2-CH(CH3)2), 28.77 (4’’-OC(CH3)3), 30.35 (C-4), 34.43 (C-5), 80.27 (4’’-
OC(CH3)3), 89.35 (C-1’), 102.3 (C-2’), 116.5 (C-1’’), 121.7 (C-5’’), 124.1
(C-3’’), 133.7 (C-6’’), 136.5 (C-2’’), 148.1 (C-3), 152.9 (C-2), 157.5 (C-4’’),
208.4 ppm (C-1); HRMS (EI+): m/z: calcd for C20H23ClO2: 331.14593
[M+H]+; found: 331.14596.
ACHTREUNG
AHCTREUNG
AHCTREUNG
G
ACHTREUNG
AHCTREUNG
2-Methyl-3-[4-(triisopropylsilanyloxy)phenylethynyl]cyclopent-2-enone
(15d): The title compound was synthesized according to General Proce-
dure C from phenylacetylene 9d (3.00 g, 10.9 mmol), vinyl iodide 7a
(2.31 g, 10.4 mmol), [PdACHTER(UGN PPh3)2Cl2] (146 mg, 208 mmol, 2.00 mol%), CuI
(80.0 mg, 420 mmol, 4.04 mol%) and NEt3 (1.75 mL, 1.28 g, 12.6 mmol) in
DMF (12.0 mL). After 40 h at room temperature and workup, 15d was
isolated by column chromatography (silica gel, pentane/ethyl acetate 7:1)
as a yellow-brown solid (3.71 g, 10.1 mmol, 97%). 1H NMR (300 MHz,
General Procedure C—Synthesis of protected estrogen analogues 15 and
16: NEt3 was added to a solution of the vinyl iodide 7 or 8 and the phe-
nylacetylene 9 in DMF and the reaction mixture was degassed. After ad-
CDCl3,): d=1.10 (d, J=7.0 Hz, 18H; 3”SiCH
ACHTRE(UNG CH3)2), 1.19–1.35 (m, 3H;
3”SiCH(CH3)2), 1.91 (t, J=2.2 Hz, 3H; 2-CH3), 2.43–2.49 (m, 2H; 5-
AHCTREUNG
dition of [Pd
A
H2), 2.72 (tq, J=4.7, 2.2 Hz, 2H; 4-H2), 6.84–6.90 (m, 2H; 3’’-H, 5’’-H),
7.37–7.44 ppm (m, 2H; 2’’-H, 6’’-H); 13C NMR (50.3 MHz, CDCl3): d=
9.70 (2-CH3), 12.63 (3”SiCHACHTERU(NG CH3)2), 17.84 (3”SiCHAHCTRE(UGN CH3)2), 30.11 (C-
4), 33.99 (C-5), 84.30 (C-1’), 106.2 (C-2’), 114.4 (C-1’’), 120.2 (C-3’’, C-5’’),
133.6 (C-2’’, C-6’’), 143.7 (C-3), 150.5 (C-2), 157.6 (C-4’’), 209.1 ppm (C-
1); HRMS (EI+): m/z: calcd for C23H32O2Si: 368.2172 [M+H]+; found:
368.2172.
608C and was then stirred at room temperature for the given time. After-
wards the mixture was poured into H2O and extracted with Et2O. The
combined organic layers were dried over MgSO4 or Na2SO4 and the sol-
vent was evaporated in vacuo. The residue was purified by column chro-
matography.
3-(4-tert-Butoxy-2-chlorophenylethynyl)-2-methylcyclopent-2-enone
(15a): The title compound was synthesized according to General Proce-
dure C from phenylacetylene 9a (501 mg, 2.40 mmol), vinyl iodide 7a
[4-(2-Methyl-3-oxocyclopent-1-enylethynyl)phenyl]carbamic acid tert-
butyl ester (15e): The title compound was synthesized according to Gen-
eral Procedure C from phenylacetylene 9g (689 mg, 122 mmol) dissolved
in DMF (0.50 mL), vinyl iodide 7a (669 mg, 3.01 mmol) dissolved in
(559 mg, 2.52 mmol), [PdACHTER(UGN PPh3)2Cl2] (25.5 mg, 36.4 mmol, 1.52 mol%),
CuI (14.9 mg, 78.3 mmol, 3.26 mol%), and NEt3 (0.400 mL, 292 mg,
2.88 mmol) in DMF (6.0 mL). After 16 h at room temperature and
workup, 15a was isolated by column chromatography (silica gel, pentane/
DMF (3.0 mL), [PdACHTREU(GN PPh3)2Cl2] (42.0 mg, 59.8 mmol, 1.99 mol%), CuI
(23.2 mg, 122 mmol, 4.05 mol%), and NEt3 (0.650 mL, 475 mg,
4.69 mmol). After 18 h at room temperature and workup, 15e was isolat-
ed by column chromatography (silica gel, pentane/ethyl acetate/NEt3
60:20:1!45:30:1) as a yellow-brown solid (844 mg, 2.71 mmol, 90%).
ethyl acetate 90:10) as
1H NMR (300 MHz, CDCl3): d=1.40 (s, 9H; 4’’-OC
2.0 Hz, 3H; 2-CH3), 2.45–2.51 (m, 2H; 5-H2), 2.71–2.78 (m, 2H; 4-H2),
6.90 (dd, J=8.5, 2.3 Hz, 1H; 5’’-H), 7.10 (d, J=2.3 Hz, 1H; 3’’-H),
7.45 ppm (d, J=8.5 Hz, 1H; 6’’-H); 13C NMR (50.3 MHz, CDCl3): d=
9.78 (2-CH3), 28.80 (4’’-OC(CH)3), 29.85 (C-4), 34.01 (C-5), 80.31 (4’’-
1H NMR (300 MHz, CDCl3): d=1.53 (s, 9H; C
ACHTRE(UNG CH3)3), 1.92 (t, J=
2.2 Hz, 3H; 2’’-CH3), 2.43–2.50 (m, 2H; 4’’-H2), 2.72 (tq, J=4.7, 2.2 Hz,
2H; 5’’-H2), 6.68 (brs, 1H; NH), 7.37–7.50 ppm (m, 4H; 2-H, 3-H, 5-H,
6-H); 13C NMR (75.5 MHz, CDC13): d=9.67, 9.71 (2’’-CH3), 28.17, 28.24
OCACHTREUNG(CH3)3), 89.18 (C-1’), 102.0 (C-2’), 116.3 (C-1’’), 121.7 (C-5’’), 124.0
(C-3’’), 133.8 (C-6’’), 136.5 (C-2’’), 144.9, 149.8 (C-2, C-3), 157.6 (C-4’’),
209.0 ppm (C-1); HRMS (EI+): m/z: calcd for C18H19ClO2: 302.1074
[M]+; found: 302.1068.
(C-5’’), 30.05 (C-4’’), 33.94 (CACTHREU(NG CH3)3), 80.97 (CACHTREU(GN CH3)3), 84.49 (C-2’), 105.9
(C-1’), 115.9 (C-4), 118.0 (C-2, C-6), 132.9 (C-3, C-5), 139.8 (C-1), 143.9
(C-1’’), 150.4 (C-2’’), 152.3 (COOtBu), 209.2 ppm (C-3’’); HRMS (EI+):
m/z: calcd for C19H21NO3: 311.1521 [M]+; found: 311.1521.
3-(4-tert-Butoxy-2-chlorophenylethynyl)-2-ethylcyclopent-2-enone (15b):
The title compound was synthesized according to General Procedure C
from phenylacetylene 9a (399 mg, 1.91 mmol), vinyl iodide 7b (478 mg,
3-(4-Methoxyphenylethynyl)-2-methylcyclopent-2-enone (15 f): The title
compound was synthesized according to General Procedure C from phe-
nylacetylene 9 f (1.77 g, 13.4 mmol) dissolved in DMF (10.5 mL), vinyl
iodide 7a (2.84 mg, 12.8 mmol) dissolved in DMF (12.0 mL), [Pd-
2.02 mmol), [PdACHTREUNG(PPh3)2Cl2] (20.6 mg, 29.4 mmol, 1.54 mol%), CuI
(12.5 mg, 65.7 mmol, 3.44 mol%), and NEt3 (0.320 mL, 234 mg,
2.30 mmol) in DMF (5.0 mL). After 22 h at room temperature and
workup, 15b was isolated by column chromatography (silica gel, pentane/
CH2Cl2/Et2O 70:20:10) as a light yellowsolid (486 mg, 1.53 mmol, 80%).
1H NMR (300 MHz, CDCl3): d=1.11 (t, J=7.5 Hz, 3H; 2-CH2CH3), 1.38
(s, 9H; 4’’-OCACHTREUNG(CH3)3), 2.38–2.48 (m, 4H; 5-H2, 2-CH2CH3), 2.69–2.75 (m,
2H; 4-H2), 6.88 (dd, J=8.5, 2.3 Hz, 1H; 3’’-H), 7.08 (d, J=2.3 Hz, 1H;
5’’-H), 7.43 ppm (d, J=8.5 Hz, 1H; 6’’-H); 13C NMR (75.5 MHz, CDCl3):
AHCTRE(UNG PPh3)2Cl2] (180 mg, 256 mmol, 2.00 mol%), CuI (98.0 mg, 515 mmol,
4.02 mol%), and NEt3 (2.20 mL, 1.61 g, 15.9 mmol). After 39 h at room
temperature and workup, 15 f was isolated by column chromatography
(silica gel, pentane/ethyl acetate 4:1 ! 2.5:1) as a brown solid (2.68 g,
11.8 mmol, 93%). 1H NMR (300 MHz, CDCl3): d=1.92 (t, J=2.2 Hz,
3H; 2-CH3), 2.43–2.49 (m, 2H; 5-H2), 2.72 (tq, J=4.5, 2.2 Hz, 2H; 4-H2),
3.85 (s, 3H; 4’’-OCH3), 6.87–6.94 (m, 2H; 3’’-H, 5’’-H), 7.44–7.51 ppm (m,
2H; 2’’-H, 6’’-H); 13C NMR (50.3 MHz, CDC13): d=9.72 (2-CH3), 30.10
(C-4), 33.99 (C-5), 55.35 (4’’-OCH3), 84.25 (C-1’), 106.0 (C-2’), 114.1 (C-
l’’), 114.2 (C-3’’, C-5’’), 133.6 (C-2’’, C-6’’), 143.7 (C-3), 150.5 (C-2), 160.6
(C-4’’), 209.1 ppm (C-1); HRMS (EI+): m/z: calcd for C15H14O2: 226.0994
[M]+; found: 226.1013.
d=12.48 (2-CH2CH3), 17.95 (2-CH2CH3), 28.76 (4’’-OC
ACHTRE(UNG CH3)3), 29.85 (C-
4), 34.22 (C-5), 80.27 (4’’-OC(CH3)3), 89.04 (C-1’), 101.8 (C-2’), 116.3 (C-
AHCTREUNG
1’’), 121.6 (C-5’’), 124.0 (C-3’’), 133.7 (C-6’’), 136.5 (C-2’’), 149.3, 150.1 (C-
2, C-3), 157.5 (C-4’’), 208.6 ppm (C-1); HRMS (EI+): m/z: calcd for
C19H21ClO2: 317.13028 [M+H]+; found: 317.13033.
3-(4-tert-Butoxy-2-chlorophenylethynyl)-2-isopropylcyclopent-2-enone
(15c): The title compound was synthesized according to General Proce-
dure C from phenylacetylene 9a (404 mg, 1.93 mmol), vinyl iodide 7c
3-(4-Methoxy-3,5-dimethylphenylethynyl)-2-methylcyclopent-2-enone
(15g): The title compound was synthesized according to General Proce-
dure C from phenylacetylene 9e (678 mg, 4.23 mmol) dissolved in DMF
(4.0 mL), vinyl iodide 7a (892 mg, 4.02 mmol) dissolved in DMF
(508 mg, 2.03 mmol), [PdACHTER(UGN PPh3)2Cl2] (20.8 mg, 29.7 mmol, 1.54 mol%),
CuI (11.5 mg, 60.4 mmol, 3.13 mol%), and NEt3 (0.320 mL, 234 mg,
2.30 mmol) in DMF (5.0 mL). After 16 h at room temperature and
workup, 15c was isolated by column chromatography (silica gel, pentane/
CH2Cl2/Et2O 75:20:5) as a light yellowsolid (481 mg, 1.45 mmol, 75%).
(5.0 mL), [PdACHTRE(UNG PPh3)2Cl2] (56.2 mg, 80.1 mmol, 1.99 mol%), CuI (30.9 mg,
162 mmol, 4.23 mol%) and NEt3 (0.700 mL, 511 mg, 5.05 mmol). After
7.5 h at room temperature and workup, 15g was isolated by column chro-
matography (silica gel, pentane/ethyl acetate 7:1 ! 6:1 ! 5:1) as a
yellow-brown solid (879 mg, 3.46 mmol, 86%). 1H NMR (300 MHz,
1H NMR (300 MHz, CDCl3): d=1.27 (d, J=7.0 Hz, 6H; 2-CH
ACHTRE(UNG CH3)2),
Chem. Eur. J. 2008, 14, 3670 – 3679
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3675

L. F. Tietze et al.
CDC13): d=1.92 (t, J=2.3 Hz, 3H; 2-CH3), 2.29 (s, 6H; 3’’-CH3, 5’’-
CH3), 2.43–2.48 (m, 2H; 5-H2), 2.71 (tq, J=4.7, 2.3 Hz, 2H; 4-H2), 3.74
(s, 3H; 4’’-OCH3), 7.21 ppm (s, 2H; 2’’-H, 6’’-H); 13C NMR (75.5 MHz,
CDC13): d=9.69 (2-CH3), 15.91 (3’’-CH3, 5’’-CH3), 30.06 (C-4), 33.94 (C-
5), 59.71 (4’’-OCH3), 84.15 (C-1’), 105.8 (C-2’), 117.2 (C-1’’), 131.4 (C-3’’,
C-5’’), 132.5 (C-2’’, C-6’’), 144.0 (C-3), 150.3 (C-2), 158.3 ppm (C-4’’),
209.0 (C-1); HRMS (EI+): m/z: calcd for C17H18O2: 254.1307 [M]+;
found: 254.1307.
4’’-OC
H2), 2.59 (t, J=6.1 Hz, 2H; 4-H2), 3.40 (sept., J=7.1 Hz, 1H; 2-CH-
(CH3)2), 6.88 (dd, J=8.5 Hz, 2.3 Hz, 1H; 5’’-H), 7.07 (d, J=2.3 Hz, 1H;
3’’-H), 7.40 ppm (d, J=8.5 Hz, 1H; 6’’-H); 13C NMR (50.3 MHz, CDCl3):
d=20.47 (2-CH(CH3)2), 22.52 (C-5), 28.79 (4’’-OC(CH3)3), 29.82 (2-CH-
(CH3)2), 32.00 (C-4), 39.12 (C-5), 80.22 (4’’-OC(CH3)3), 92.39 (C-1’),
99.96 (C-2’), 116.9 (C-1’’), 121.8 (C-5’’), 124.2 (C-3’’), 133.5 (C-6’’), 136.2,
136.4 (C-2’’, C-3), 147.6 (C-2), 157.2 (C-4’’), 198.1 ppm (C-1); HRMS
(EI+): m/z: calcd for C21H25ClO2: 344.1543 [M]+; found: 344.1542.
ACHTREUNG(CH3)3), 1.94–2.04 (m, 2H; 5-H2), 2.43 (dd, J=7.3, 6.1 Hz, 2H; 6-
AHCTREUNG
A
ACHTREUNG
A
ACHTREUNG
2-Methyl-3-[4-(trifluoromethyl)phenylethynyl]cyclopent-2-enone (15h):
The title compound was synthesized according to General Procedure C
from phenylacetylene 9h (1.43 g, 8.41 mmol) dissolved in DMF (7.5 mL),
vinyl iodide 7a (1.78 g, 8.02 mmol) dissolved in DMF (10.0 mL), [Pd-
2-(2-Methyl-3-oxocyclohex-1-enylethynyl)-5-(triisopropylsilanyloxy)ben-
zoic acid methyl ester (16e): The title compound was synthesized accord-
ing to General Procedure C from a mixture of phenylacetylene 9c and
TIPSOH (1.18 g; 9c/TIPSOH ratio 2.75:1, calculated from 1H NMR
data; 2.98 mmol) dissolved in a mixture of DMF (4.0 mL) and DMSO
ACHTREUNG(PPh3)2Cl2] (113 mg, 161 mmol, 2.01 mol%), CuI (61.5 mg, 323 mmol,
4.03 mol%), and NEt3 (1.34 mL, 978 mg, 9.67 mmol). After 14.5 h at
room temperature and workup, 15h was isolated by column chromatog-
raphy (silica gel, pentane/ethyl acetate 6:1) as a yellow-gray solid (1.81 g,
6.85 mmol, 85%). 1H NMR (300 MHz, CDC13): d=1.94 (t, J=2.3 Hz,
3H; 2-CH3), 2.47–2.52 (m, 2H; 5-H2), 2.76 (tq, J=4.7, 2.3 Hz, 2H; 4-H2),
7.64 ppm (s, 4H; 2’’-H, 3’’-H, 5’’-H, 6’’-H); 13C NMR (50.3 MHz, CDC13):
d=9.85 (2-CH3), 29.91 (C-4), 33.95 (C-5), 86.87 (C-1’), 103.2 (C-2’), 123.7
(q, J=273 Hz, 4’’-CF3), 125.5 (q, J=3.9 Hz, C-3’’, C-5’’), 125.8 (q, J=
1.4 Hz, C-1’’), 131.0 (q, J=33.0 Hz, C-4’’), 132.1 (C-2’’, C-6’’), 145.7 (C-3),
148.9 (C-2), 208.8 ppm (C-1); HRMS (EI+): m/z: calcd for C15H11F3O:
264.0762 [M]+; found: 264.0762.
(2.0 mL), vinyl iodide 8a (667 mg, 2.53 mmol), [PdACTHERU(GN PPh3)2Cl2] (47.7 mg,
68.0 mmol, 2.28 mol%), CuI (27.1 mg, 142 mmol, 4.77 mol%), and NEt3
(0.700 mL, 511 mg, 5.05 mmol) in DMF (6.0 mL). The reaction mixture
was briefly heated to 50–608C with a heat gun. After 22 h at room tem-
perature and workup, 16e was isolated by column chromatography (silica
gel, pentane/ethyl acetate 6:1 ! pentane/ethyl acetate 4:1) as a reddish
brown oil (658 mg, 1.49 mmol, 50%). 1H NMR (300 MHz, CDCl3): d=
1.11 (d, J=7.1 Hz, 18H; 3”SiCH
ACHTREU(NG CH3)2), 1.18–1.37 (m, 3H; 3”SiCH-
AHCTRE(UNG CH3)2), 2.04 (quint, J=6.4 Hz, 2H; 5’’-H2), 2.08 (t, J=1.8 Hz, 3H; 2’’-
CH3), 2.48 (t, J=6.4 Hz, 2H; 4’’-H2), 2.61 (tq, J=6.4, 1.8 Hz, 2H; 6’’-H2),
3.93 (s, 3H; 1-COOCH3), 7.01 (dd, J=8.6, 2.7 Hz, 1H; 4-H), 7.47 (d, J=
8.6 Hz, 1H; 3-H), 7.48 ppm (d, J=2.7 Hz, 1H; 6-H); 13C NMR
3-(4-tert-Butoxy-2-chlorophenylethynyl)-2-methylcyclohex-2-enone
(16a): The title compound was synthesized according to General Proce-
dure C from phenylacetylene 9a (4.83 g, 23.1 mmol), vinyl iodide 8a
(75.5 MHz, CDCl3): d=12.56 (3”SiCH
ACHTER(UGN CH3)2), 14.00 (2’’-CH3), 17.79
(3”SiCH(CH3)2), 22.69 (C-5’’), 31.04 (C-6’’), 37.90 (C-4’’), 52.32 (1-
AHCTREUNG
(5.20 g, 22.0 mmol), [PdACHTREUNG(PPh3)2Cl2] (232 mg, 331 mmol, 1.50 mol%), CuI
COOCH3), 91.41 (C-2’), 102.1 (C-1’), 115.1 (C-2), 121.9 (C-6), 123.5 (C-
4), 133.1 (C-1), 135.7 (C-3), 137.9, 138.7 (C-1’’, C-2’’), 156.8 (C-5), 166.1
(1-COOCH3), 198.6 ppm (C-3’’); HRMS (EI+): m/z: calcd for
C26H32O4Si: 440.2383 [M]+; found: 440.2383.
(128 mg, 674 mmol, 3.06 mol%), and NEt3 (3.72 mL, 2.71 g, 26.8 mmol) in
DMF (23.0 mL). After 26 h at room temperature and workup, 16a was
isolated by column chromatography (silica gel, pentane/ethyl acetate 9:1)
as a red oil (5.73 g, 18.1 mmol, 78%). 1H NMR (300 MHz, CDCl3): d=
1.38 (s, 9H; 4’’-OC
A
[4-(2-Methyl-3-oxocyclohex-1-enylethynyl)phenyl]carbamic acid tert-
butyl ester (16g): The title compound was synthesized according to Gen-
eral Procedure C from phenyl acetylene 9g (682 mg, 3.14 mmol) in DMF
(3.0 mL), vinyl iodide 8c (710 mg, 3.01 mmol) in DMF (4.0 mL), [Pd-
3H; 2-CH3), 2.48 (dd, J=7.3, 6.1 Hz, 2H; 6-H2), 2.59 (m, 2H; 4-H2), 6.88
(dd, J=8.6, 2.3 Hz, 1H; 5’’-H), 7.08 (d, J=2.3 Hz, 1H; 3’’-H), 7.41 ppm
(d, J=8.6 Hz, 1H; 6’’-H); 13C NMR (75.5 MHz, CDCl3): d=14.08 (2-
CH3), 22.69 (C-5), 28.79 (4’’-OC
A
ACHTRE(UNG PPh3)2Cl2] (42.1 mg, 60.0 mmol, 1.99 mol%) and CuI (24.1 mg, 127 mmol,
(4’’-OC(CH3)3), 92.39 (C-1’), 99.67 (C-2’), 116.8 (C-1’’), 121.7 (C-5’’),
A
4.20 mol%) in DMF (0.50 mL), and NEt3 (0.650 mL, 475 mg, 4.69 mmol).
124.1 (C-3’’), 133.6 (C-6’’), 136.4, 137.3, 139.1 (C-2, C-2’’, C-3), 157.2 (C-
4’’), 198.5 ppm (C-1); HRMS (EI+): m/z: calcd for C15H13ClO2: 260.0604
[M]+; found: 260.0604.
After 43 h at room temperature and workup, 16g was isolated by column
chromatography (silica gel, pentane/ethyl acetate/NEt3 90:30:1
90:60:1) as a yellow-brown solid (758 mg, 2.33 mmol, 77%). 1H NMR
(300 MHz, CDCl3): d=1.52 (s, 9H; C(CH3)3), 2.02 (quint, J=6.3 Hz, 2H;
!
AHCTREUNG
3-(4-tert-Butoxy-2-chlorophenylethynyl)-2-ethylcyclohex-2-enone (16b):
The title compound was synthesized according to General Procedure C
from phenylacetylene 9a (505 mg, 2.42 mmol), vinyl iodide 8b (630 mg,
5’’-H2), 2.04 (t, J=1.7 Hz, 3H; 2’’-CH3), 2.48 (t, J=6.3 Hz, 2H; 4’’-H2),
2.57 (tq, J=6.3, 1.7 Hz, 2H; 6’’-H2), 6.89 (brs, 1H; NH), 7.41 ppm (s,
4H; 2-H, 3-H, 5-H, 6-H); 13C NMR (75.5 MHz, CDCl3): d=13.97 (2’’-
2.52 mmol), [PdACHTREUNG(PPh3)2Cl2] (25.5 mg, 36.4 mmol, 1.50 mol%), CuI
CH3), 22.62 (C-5’’), 28.21 (C
ACHTRE(UNG CH3)3), 31.05 (C-6’’), 37.82 (C-4’’), 80.91 (C-
(14.5 mg, 76.2 mmol, 3.15 mol%), and NEt3 (0.400 mL, 292 mg,
2.88 mmol) in DMF (6.0 mL). After 19 h at room temperature and
workup, 16b was isolated by column chromatography (silica gel, pentane/
ethyl acetate 9:1) as a yellowsolid (525 mg, 1.59 mmol, 66%). 1H NMR
(200 MHz, CDCl3): d=1.06 (t, J=7.5 Hz, 3H; 2-CH2CH3), 1.39 (s, 9H;
AHCTRE(UNG CH3)3), 87.72 (C-2’), 103.5 (C-1’), 116.4 (C-4), 118.0 (C-2, C-6), 132.6 (C-
3, C-5), 137.9, 138.3, 139.5 (C-1, C-1’’, C-2“), 152.3 (COOtBu), 198.6 ppm
(C-3’’); HRMS (ESI): m/z: calcd for C20H23NO3: 326.17507 [M+H]+;
found: 326.17515.
4’’-OC
A
3-(4-Methoxyphenylethynyl)-2-methylcyclohex-2-enone (16h): The title
compound was synthesized according to General Procedure C from phe-
nylacetylene 9 f (2.10 g, 15.9 mmol) in DMF (13.5 mL), vinyl iodide 8a
6.1 Hz, 2H; 6-H2), 2.54–2.64 (m, 4H; 4-H2, 2-CH2CH3), 6.88 (dd, J=8.5,
2.3 Hz, 1H; 5’’-H), 7.08 (d, J=2.3 Hz, 1H; 3’’-H), 7.40 ppm (d, J=8.5 Hz,
1H; 6’’-H); 13C NMR (75.5 MHz, CDCl3): d=13.51 (2-CH2CH3), 21.64
(3.57 g, 15.1 mmol) in DMF (22.0 mL), [PdACHTRE(UNG PPh3)2Cl2] (212 mg, 302 mmol,
(2-CH2CH3), 22.70 (C-5), 28.80 (4’’-OC
G
2.00 mol%) and CuI (115 mg, 604 mmol, 4.00 mol%) in DMF (2.50 mL),
and NEt3 (2.52 mL, 1.84 g, 15.1 mmol). After 15 h at room temperature
and workup, 16h was isolated by column chromatography (silica gel,
80.24 (4’’-OC(CH3)3), 92.09 (C-1’), 99.12 (C-2’), 116.9 (C-1’’), 121.8 (C-
ACHTREUNG
5’’), 124.2 (C-3’’), 133.6 (C-6’’), 136.5, 136.9 (C-2’’, C-3), 145.0 (C-2), 157.2
(C-4’’), 197.9 ppm (C-1); HRMS (EI+): m/z: calcd for C20H23ClO2:
330.1387 [M]+; found: 330.1389.
CH2Cl2) as
a
light brown solid (2.69 g, 11.2 mmol, 74%). 1H NMR
(300 MHz, CDCl3): d=2.02 (quint., d=6.4 Hz, 2H; 5-H2), 2.04 (t, J=
1.8 Hz, 3H; 2-CH3), 2.47 (t, J=6.4 Hz, 2H; 6-H2), 2.57 (tq, J=6.4,
1.8 Hz, 2H; 4-H2), 3.83 (s, 3H; 4’’-OCH3), 6.85–6.92 (m, 2H; 3’’-H, 5’’-H),
7.40–7.46 ppm (m, 2H; 2’’-H, 6’’-H); 13C NMR (75.5 MHz, CDCl3): d=
13.95 (2-CH3), 22.66 (C-5), 31.09 (C-4), 37.85 (C-6), 55.28 (4’’-OCH3),
87.40 (C-1’), 103.6 (C-2’), 114.1 (C-3’’, C-5’’), 114.5 (C-l’’), 133.3 (C-2’’, C-
6’’), 137.9, 138.1 (C-2, C-3), 160.3 (C-4’’), 198.4 ppm (C-1); HRMS (EI+):
m/z: calcd for C16H16O2: 240.1150 [M]+; found: 240.1143.
3-(4-tert-Butoxy-2-chlorophenylethynyl)-2-isopropylcyclohex-2-enone
(16c): The title compound was synthesized according to General Proce-
dure C from phenylacetylene 9a (506 mg, 2.43 mmol), vinyl iodide 8c
(667 mg, 2.53 mmol), [PdACHTER(UGN PPh3)2Cl2] (26.3 mg, 37.5 mmol, 1.54 mol%),
CuI (14.3 mg, 75.1 mmol, 3.09 mol%), and NEt3 (0.400 mL, 292 mg,
2.88 mmol) in DMF (6.0 mL). After 26.5 h at room temperature and
workup, 16c was isolated by column chromatography (silica gel, pentane/
ethyl acetate 95:5) as a yellowsolid (509 mg, 1.48 mmol, 62%). 1H NMR
3-(4-Methoxy-3,5-dimethylphenylethynyl)-2-methylcyclohex-2-enone
(300 MHz, CDCl3): d=1.26 (d, J=7.1 Hz, 6H; 2-CH
A
(16i): The title compound was synthesized according to General Proce-
3676
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3670 – 3679

Estrogen Analogues
FULL PAPER
dure C from phenylacetylene 9e (662 g, 4.13 mmol) in DMF (4.0 mL),
vinyl iodide 8a (929 mg, 3.93 mmol) in DMF (5.0 mL), [PdACTHERU(GN PPh3)2Cl2]
over MgSO4, and the solvent was evaporated after addition of silica gel
(4 g). The product was isolated by column chromatography (silica gel,
pentane/ethyl acetate 2.5:1 ! 1:1) and subsequent HPLC (Kromasil
100 C18 (7 mm, 250”20 mm), CH3CN/H2O 45:55, flow12 mLmin ꢀ1) as a
yellowsolid (69.0 mg, 325 mmol, 33%).
(55.2 mg, 78.6 mmol, 2.00 mol%) and CuI (30.0 mg, 158 mmol,
4.01 mol%) in DMF (1.0 mL), and NEt3 (0.700 mL, 511 mg, 5.051 mmol).
After 18.5 h at room temperature and workup, 16i was isolated by
column chromatography (silica gel, pentane/ethyl acetate 8:1 ! 6:1) as a
yellow-green solid (863 mg, 3.22 mmol, 82%). 1H NMR (300 MHz,
CDCl3): d=2.02 (quint., J=6.4 Hz, 2H; 5-H2), 2.04 (t, J=1.9 Hz, 3H; 2-
CH3), 2.28 (s, 6H; 3’’-CH3, 5’’-CH3), 2.47 (t, J=6.4 Hz, 2H; 6-H2), 2.56
(tq, J=6.4, 1.9 Hz, 2H; 4-H2), 3.73 (s, 3H; 4’’-OCH3), 7.17 ppm (s, 2H;
2’’-H, 6’’-H); 13C NMR (50.3 MHz, CDCl3): d=13.99 (2-CH3), 15.93 (3’’-
CH3, 5’’-CH3), 22.68 (C-5), 31.10 (C-4), 37.88 (C-6), 59.75 (4’’-OCH3),
87.42 (C-1’), 103.4 (C-2’), 117.7 (C-1’’), 131.4 (C-3’’, C-5’’), 132.3 (C-2’’, C-
6’’), 137.8, 138.5 (C-2, C-3), 158.1 (C-4’’), 198.5 ppm (C-1); HRMS (EI+):
m/z: calcd for C18H20O2: 268.1463 [M]+; found: 268.1463.
Procedure b: CsF (1.40 g, 9.22 mmol) was added at 08C to a solution of
15d (1.09 g, 2.96 mmol) in CH3CN (29.0 L). After 1 min a yellowprecipi-
tate had formed. The ice bath was removed, and the mixture was stirred
for 1.5 h at room temperature. The mixture was then poured into a satu-
rated solution of NaHCO3 (150 mL) and extracted with Et2O (50 mL)
and ethyl acetate (2”50 mL). The combined organic layers were washed
with brine (2”30 mL) and dried over MgSO4, and the solvent was evapo-
rated in vacuo. The product was isolated by column chromatography
(silica gel, pentane/ethyl acetate 4:1 ! pentane/ethyl acetate 1:2 ! ace-
tone) as
a
bright yellowsolid (555 mg, 2.61 mmol, 88%). 1H NMR
General Procedure D—Deprotection of estrogen analogues 15 and 16:
CF3COOH was added at room temperature to a solution of the ether 15
or 16 in CH2Cl2. After completion of the reaction the solvent was re-
moved in vacuo.
(300 MHz, [D6]DMSO): d=1.79 (t, J=2.2 Hz, 3H; 2-CH3), 2.34–2.39 (m,
2H; 5-H2), 2.66 (tq, J=4.7, 2.2 Hz, 2H; 4-H2), 6.79–6.85 (m, 2H; 3’’-H,
5’’-H), 7.37–7.43 (m, 2H; 2’’-H, 6’’-H), 10.09 ppm (brs, 1H; 4’’-OH);
13C NMR (75.5 MHz, [D6]DMSO): d=9.40 (2-CH3), 29.58 (C-4), 33.50
(C-5), 83.74 (C-1’), 106.2 (C-2’), 111.3 (C-l’’), 115.9 (C-3’’, C-5’’), 133.6 (C-
2’’, C-6’’), 142.4 (C-3), 149.5 (C-2), 159.1 (C-4’’), 207.5 ppm (C-1); HRMS
(EI+): m/z: calcd for C14H12O2: 212.0837 [M]+; found: 212.0837.
3-(2-Chloro-4-hydroxyphenylethynyl)-2-methylcyclopent-2-enone
(3a):
The tert-butyl ether 15a was deprotected according to General Proced-
ure D with 15a (460 mg, 1.52 mmol) and CF3COOH (1.50 mL) in CH2Cl2
(15.0 mL). After the mixture had been stirred for 75 min at room temper-
ature, 3a was isolated as a yellow-green solid (354 mg, 1.43 mmol, 94%).
1H NMR (300 MHz, [D6]DMSO): d=1.82 (t, J=2.0 Hz, 3H; 2-CH3),
2.36–2.42 (m, 2H; 5-H2), 2.64–2.72 (m, 2H; 4-H2), 6.81 (dd, J=8.5,
2.3 Hz, 1H; 5’’-H), 6.97 (d, J=2.3 Hz, 1H; 3’’-H), 7.50 (d, J=8.5 Hz, 1H;
6’’-H), 10.55 ppm (brs, 1H; 4’’-OH); 13C NMR (75.5 MHz, [D6]DMSO):
d=9.42 (2-CH3), 29.33 (C-4), 33.52 (C-5), 88.19 (C-l’), 102.0 (C-2’), 111.2
(C-1’’), 115.1 (C-5’), 116.3 (C-3’’), 134.9 (C-6’’), 135.9 (C-2’’), 143.3, 148.8
(C-2, C-3), 159.9 (C-4’’), 207.5 ppm (C-1); HRMS (EI+): m/z: calcd for
C14H11ClO2: 246.0448 [M]+; found: 246.0437.
3-(4-Aminophenylethynyl)-2-methylcyclopent-2-enone (3e): The tert-
butyl ether 15e was deprotected according to General Procedure D with
15e (687 mg, 2.21 mmol) and CF3COOH (17 mL) in CH2Cl2 (40.0 mL).
After the mixture had been stirred for 1.5 h at room temperature the sol-
vent was evaporated, the residue was taken up in HCl (2m, 5 mL) and
toluene (50 mL), and the solvent was evaporated in vacuo. The proce-
dure was repeated four times. The formed hydrochloride was dissolved in
NaOH (10%, 50 mL) and ethyl acetate (50 mL). The layers were sepa-
rated, the aqueous layer was extracted with ethyl acetate (2”50 mL), and
the combined organic layers were dried over MgSO4. Evaporation of the
solvent gave 3e as a brown solid (456 mg, 2.15 mmol, 97%). 1H NMR
(300 MHz, [D6]acetone): d=1.80 (t, J=2.3 Hz, 3H; 2-CH3), 2.32–2.37
(m, 2H; 5-H2), 2.67 (tq, J=4.8, 2.3 Hz, 2H; 4-H2), 5.29 (brs, 2H; 4’’-
NH2), 6.66–6.72 (m, 2H; 3’’-H, 5’’-H), 7.24–7.30 ppm (m, 2H; 2’’-H, 6’’-
H); 13C NMR (75.5 MHz, [D4]MeOH): d=9.61 (2-CH3), 31.32 (C-4),
34.88 (C-5), 84.36 (C-1’), 110.3, 110.6 (C-2’, C-1’’), 115.4 (C-3’’, C-5’’),
134.7 (C-2’’, C-6’’), 142.5 (C-3), 151.7 (C-2), 154.3 (C-4’’), 211.7 ppm (C-
1); HRMS (EI+): m/z: calcd for C14H13NO: 211.0997 [M]+; found:
211.0997.
3-(2-Chloro-4-hydroxyphenylethynyl)-2-ethylcyclopent-2-enone (3b): The
tert-butyl ether 15b was deprotected according to General Procedure D
with 15b (392 mg, 1.24 mmol) and CF3COOH (1.20 mL) in CH2Cl2
(12.0 mL). After the mixture had been stirred for 15 min at room temper-
ature, 3b was isolated as a light yellow solid (283 mg, 1.09 mmol, 88%).
1H NMR (300 MHz, [D6]DMSO): d=1.02 (t, J=7.5 Hz, 3H; 2-CH2CH3),
2.30 (q, J=7.5 Hz, 2H; 2-CH2CH3), 2.35–2.41 (m, 2H; 5-H2), 2.63–2.70
(m, 2H; 4-H2), 6.80 (dd, J=8.6 Hz, 2.3 Hz, 1H; 5’’-H), 6.96 (d, J=2.3 Hz,
1H; 3’’-H), 7.47 (d, J=8.6 Hz, 1H; 6’’-H), 10.55 ppm (brs, 1H; 4“-OH);
13C NMR (75.5 MHz, [D6]DMSO): d=12.20 (2-CH2CH3), 17.42 (2-
CH2CH3), 29.39 (C-4), 33.76 (C-5), 88.01 (C-1’), 101.9 (C-2’), 111.3 (C-
1’’), 115.1 (C-5’’), 116.3 (C-3’’), 134.9 (C-6’’), 136.0 (C-2’’), 148.6 (C-2, C-
3), 159.9 (C-4’’), 207.3 ppm (C-1); HRMS (ESI): m/z: calcd for
C15H13ClO2: 261.06768 [M+H]+; found: 261.06767.
3-(2-Chloro-4-hydroxyphenylethynyl)-2-methylcyclohex-2-enone
(4a):
The tert-butyl ether 16a was deprotected according to General Proced-
ure D with 16a (5.33 g, 16.8 mmol) and CF3COOH (16.7 mL) in CH2Cl2
(167 mL). After the mixture had been stirred for 80 min at room temper-
ature, 4a was isolated as
a yellow solid (4.26 g, 16.3 mmol, 97%).
3-(2-Chloro-4-hydroxyphenylethynyl)-2-isopropylcyclopent-2-enone (3c):
The tert-butyl ether 15c was deprotected according to General Proced-
ure D with 15c (418 mg, 1.27 mmol) and CF3COOH (1.30 mL) in CH2Cl2
(13.0 mL). After the mixture had been stirred for 15 min at room temper-
ature, 3c was isolated as a light yellow solid (349 mg, 1.27 mmol, quant.).
1H NMR (300 MHz, [D6]DMSO): d=1.20 (d, J=7.0 Hz, 6H; 2-CH-
1H NMR (300 MHz, [D6]DMSO): d=1.87–1.98 (m, 5H; 5-H2, 2-CH3),
2.38 (t, J=6.6 Hz, 2H; 6-H2), 2.50–2.56 (m, 2H; 4-H2), 6.77 (dd, J=8.6,
2.3 Hz, 1H; 5’’-H), 6.93 (d, J=2.3 Hz, 1H; 3’’-H), 7.43 (d, J=8.6 Hz, 1H;
6’’-H), 10.48 ppm (brs, 1H; 4’’-OH); 13C NMR (75.5 MHz, [D6]DMSO):
d=13.72 (2-CH3), 22.18 (C-5), 30.29 (C-4), 37.23 (C-6), 91.26 (C-1’),
99.83 (C-2’), 111.6 (C-1’’), 115.0 (C-5’’), 116.2 (C-3’’), 134.8 (C-6’’), 135.9,
136.8, 137.4 (C-2, C-2’’, C-3), 159.6 (C-4’’), 197.1 ppm (C-1); HRMS
(ESI): m/z: calcd for C15H13ClO2: 261.06768 [M+H]+; found: 261.06781.
ACHTREUNG
ACHTREUNG
6.96 (d, J=2.3 Hz, 1H; 3’’-H), 7.47 (d, J=8.5 Hz, 1H; 6’’-H), 10.61 ppm
(brs, 1H; 4’’-OH); 13C NMR (75.5 MHz, [D6]DMSO): d=19.98 (2-CH-
ACHTREUNG(CH3)2), 25.04 (2-CHACHTREUNG(CH3)2), 29.85 (C-4), 33.99 (C-5), 88.21 (C-1’), 102.4
(C-2’), 111.3 (C-l’’), 115.1 (C-5’’), 116.3 (C-3’’), 134.8 (C-6’’), 136.0 (C-2’’),
147.5 (C-3), 151.3 (C-2), 159.9 (C-4’’), 207.2 ppm (C-1); HRMS (EI+):
m/z: calcd for C16H15ClO2: 274.0761 [M]+; found: 274.0759.
3-(2-Chloro-4-hydroxyphenylethynyl)-2-ethylcyclohex-2-enone (4b): The
tert-butyl ether 16b was deprotected according to General Procedure D
with 16b (454 mg, 1.37 mmol) and CF3COOH (1.36 mL) in CH2Cl2
(13.6 mL). After the mixture had been stirred for 80 min at room temper-
ature, 4b was isolated as a yellow solid (318 mg, 1.16 mmol, 84%).
1H NMR (300 MHz, [D6]DMSO): d=0.96 (t, J=7.5 Hz, 3H; 2-CH2CH3),
1.87–1.98 (m, 2H; 5-H2), 2.39 (t, J=6.7 Hz, 2H; 4-H2), 2.46 (q, J=
7.5 Hz, 2H; 2-CH2CH3), 2.53 (t, J=6.1 Hz, 2H; 4-H2), 6.79 (dd, J=8.6,
2.4 Hz, 1H; 5’’-H), 6.94 (d, J=2.4 Hz, 1H; 3’’-H), 7.44 (d, J=8.6 Hz, 1H;
6’’-H), 10.50 ppm (brs, 1H; 4’’-OH); 13C NMR (75.5 MHz, [D6]DMSO):
d=13.25 (2-CH2CH3), 20.97 (2-CH2CH3), 22.17 (C-5), 30.31 (C-4), 37.43
(C-6), 90.82 (C-1’), 99.27 (C-2’), 111.6 (C-1’’), 115.0 (C-5’’), 116.2 (C-3’’),
134.7 (C-6’’), 135.9, 136.5 (C-2’’, C-3), 143.3 (C-2), 159.6 (C-4’’),
3-(4-Hydroxyphenylethynyl)-2-methylcyclopent-2-enone
(3d)—Proce-
dure a: A solution of BBr3 (1.0m in CH2Cl2, 3.50 mL, 3.50 mmol) was
added dropwise at ꢀ788C to a solution of 15 f (227 mg, 1.00 mmol) in
CH2Cl2 (10.0 mL). The reaction mixture was slowly warmed to room
temperature over 14 h, and a saturated solution of NH4Cl (20 mL) and
H2O (5 mL) was then added. The mixture was stirred for 15 min at room
temperature and then extracted with ethyl acetate (30 mL, 2”20 mL).
The combined organic layers were washed with brine (20 mL) and dried
Chem. Eur. J. 2008, 14, 3670 – 3679
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3677

L. F. Tietze et al.
196.7 ppm (C-1); HRMS(EI): m/z: calcd for C16H25ClO2: 274.0761 [M]+;
found: 274.0761.
1.93 (t, J=1.6 Hz, 3H; 2’’-CH3), 1.94 (quint., J=6.2 Hz, 2H; 5’’-H2), 2.39
(t, J=6.2 Hz, 2H; 4’’-H2), 2.53 (tq, J=6.2, 1.6 Hz, 2H; 6’’-H2), 3.83 (s,
3H; 1-COOCH3), 7.01 (dd, J=8.5, 2.7 Hz, 1H; 4-H), 7.29 (d, J=2.7 Hz,
1H; 6-H), 7.48 (d, J=8.5 Hz, 1H; 3-H), 10.44 ppm (brs, 1H; 5-OH);
13C NMR (75.5 MHz, [D6]DMSO): d=13.66 (2’’-CH3), 22.21 (C-5’’), 30.40
(C-6’’), 37.25 (C-4’’), 52.17 (1-COOCH3), 90.41 (C-2’), 102.1 (C-1’), 111.7
(C-2), 116.8 (C-6), 119.4 (C-4), 133.2 (C-1), 135.8 (C-3), 137.3, 137.4 (C-
1’’, C-2’’), 158.5 (C-5), 165.6 (1-COOCH3), 197.3 ppm (C-3’’); HRMS
(EI+): m/z: calcd for C17H16O4: 284.1049 [M]+; found: 284.1049.
3-(2-Chloro-4-hydroxyphenylethynyl)-2-isopropylcyclohex-2-enone (4c):
The tert-butyl ether 16c was deprotected according to General Proced-
ure D with 16c (418 mg, 1.21 mmol) and CF3COOH (1.21 mL) in CH2Cl2
(12.1 mL). After the mixture had been stirred for 75 min at room temper-
ature, 4c was isolated as
1H NMR (300 MHz, [D6]DMSO): d=1.18 (d, J=7.1 Hz, 6H; 2-CH-
(CH3)2), 1.83–1.94 (m, 2H; 5-H2), 2.35 (dd, J=7.2, 6.1 Hz, 2H; 6-H2),
2.54 (t, J=6.0 Hz, 2H; 4-H2), 3.32 (sept., J=7.1 Hz, 1H; 2-CH(CH3)2),
a beige solid (337 mg, 1.17 mmol, 96%).
ACHTREUNG
AHCTREUNG
3-(2-Bromo-4-hydroxyphenylethynyl)-2-methylcyclohex-2-enone (4 f): So-
nogashira coupling was carried out according to General Procedure C
with phenylacetylene 9b (400 mg, 1.42 mmol) in DMF (1.2 mL), vinyl
6.79 (dd, J=8.6 Hz, 2.3 Hz, 1H; 5’’-H), 6.94 (d, J=2.3 Hz, 1H; 3’’-H),
7.42 (d, J=8.6 Hz, 1H; 6’’-H), 10.49 ppm (brs, 1H; 4’’-OH); 13C NMR
(75.5 MHz, [D6]DMSO): d=20.27 (2-CH
ACHTRE(UNG CH3)2), 22.01 (C-5), 29.13 (2-
iodide 8a (279 mg, 1.18 mmol) in DMF (1.5 mL), [PdACHTREUNG(PPh3)2Cl2]
CH(CH3)2), 31.29 (C-4), 38.39 (C-6), 91.06 (C-1’), 100.2 (C-2’), 111.7 (C-
ACHTREUNG
(12.6 mg, 18.0 mmol, 1.50 mol%) and CuI (7.10 mg, 37.0 mmol,
3.20 mol%) in DMF (0.30 mL), and NEt3 (0.260 mL, 190 mg, 1.88 mmol).
After 20 h at room temperature and workup, 16 f was purified by column
chromatography (silica gel, pentane/ethyl acetate/NEt3 15:1 ! 100:20:1).
The intermediate product 16 f was deprotected according to General Pro-
cedure C with CH2Cl2 (20 mL) and CF3COOH (2.0 mL) at room temper-
ature. After the mixture had been stirred at room temperature for 30 min
and the solvent had been evaporated, the product 4 f was isolated by re-
1’’), 115.0 (C-5’’), 116.3 (C-3’’), 134.6 (C-6’’), 135.8, 135.9 (C-2’’, C-3),
146.0 (C-2), 159.6 (C-4’’), 197.0 ppm (C-1); HRMS (EI+): m/z: calcd for
C17H17C1O2: 288.0917 [M]+; found: 288.0917.
3-(4-Hydroxyphenylethynyl)-2-methylcyclohex-2-enone
(4d)—Proce-
dure a: A solution of BBr3 (1.0m in CH2Cl2, 1.00 mL, 1.00 mmol) was
added dropwise at ꢀ788C to a solution of 16h (80.6 mg, 335 mmol) in
CH2Cl2 (5.0 mL). The reaction mixture was stirred at ꢀ788C for 20 min
and at room temperature for 2.25 h. The mixture was poured into H2O
(50 mL), brine (20 mL) was then added, and the mixture was extracted
with ethyl acetate (4”20 mL). The combined organic layers were washed
with brine (15 mL) and dried over MgSO4, and the solvent was evaporat-
ed under reduced pressure. KOtBu (194 mg, 1.73 mmol) was added at
room temperature to a solution of the crude product in tBuOH (4.0 mL).
The mixture was stirred for 15 min at room temperature, then heated in
a microwave for 20 min at 608C, and then poured into HCl (2m, 40 mL)
and extracted with ethyl acetate (3”20 mL). The combined organic
layers were washed with brine (15 mL) and dried over MgSO4, and the
solvent was evaporated. The product was isolated by column chromatog-
raphy (silica gel, pentane/ethyl acetate 1:1) as a yellowsolid (49.1 mg,
217 mmol, 65%).
crystallization from THF/cyclohexane as
a yellowsolid (204 mg,
668 mmol, 57% over two steps). 1H NMR (300 MHz, [D6]DMSO): d=
1.94 (quint., J=6.3 Hz, 2H; 5-H2), 1.95 (t, J=1.7 Hz, 3H; 2-CH3), 2.39
(t, J=6.3 Hz, 2H; 6-H2), 2.54 (tq, J=6.3, 1.7 Hz, 2H; 4-H2), 6.83 (dd, J=
8.6, 2.4 Hz, 1H; 5’’-H), 7.11 (d, J=2.4 Hz, 1H; 3’’-H), 7.45 (d, J=8.6 Hz,
1H; 6’’-H), 10.50 ppm (brs, 1H; 4’’-OH); 13C NMR (75.5 MHz,
[D6]DMSO): d=13.84 (2-CH3), 22.19 (C-5), 30.30 (C-4), 37.23 (C-6),
90.51 (C-1’), 101.6 (C-2’), 113.8 (C-1’’), 115.4 (C-5’’), 119.3 (C-3’’), 125.7
(C-2’’), 134.9 (C-6’’), 136.8, 137.4 (C-2, C-3), 159.5 (C-4’’), 197.2 ppm (C-
1); HRMS (EI+): m/z: calcd for C15H13BrO2: 304.0099 [M]+; found:
304.0099.
3-(4-Aminophenylethynyl)-2-methylcyclohex-2-enone (4g): A solution of
16g (735 mg, 2.26 mmol) in CF3COOH (4.0 mL) and CH2Cl2 (40 mL)
was stirred for 20 min at room temperature. The solvent was evaporated
and the residue was dissolved in ethyl acetate (150 mL). The organic
layer was washed with a saturated solution of NaHCO3 (2”20 mL) and
brine (20 mL) and dried over MgSO4, and the solvent was evaporated.
Compound 4g was isolated by column chromatography (silica gel, pen-
Procedure b: Sonogashira coupling was carried out according to General
Procedure B with phenylacetylene 9d (640 mg, 2.10 mmol) in DMF
(1.6 mL), vinyl iodide 8a (472 mg, 2.00 mmol) in DMF (3.0 mL), [Pd-
ACHTREUNG(PPh3)2Cl2] (21.4 mg, 30.5 mmol, 1.52 mol%) and CuI (12.2 mg, 64.1 mmol,
3.20 mol%) in DMF (0.40 mL), and NEt3 (0.500 mL, 365 mg, 3.61 mmol).
After 15.5 h at room temperature and workup, 16d was purified by
column chromatography (silica gel, pentane/ethyl acetate 15:1 ! 12:1).
tane/ethyl acetate 2.5:1
!
pentane/ethyl acetate/NEt3 60:40:1) as a
yellowsolid (271 mg, 1.20 mmol, 53%). Starting material 16g was also
isolated (179 mg, 550 mmol, 24%). 1H NMR (300 MHz, CDCl3): d=2.00
(quint., J=6.3 Hz, 2H; 5-H2), 2.03 (t, J=1.8 Hz, 3H; 2-CH3), 2.46 (t, J=
6.3 Hz, 2H; 6-H2), 2.56 (tq, J=6.3, 1.8 Hz, 2H; 4-H2), 3.96 (brs, 2H; 4’’-
NH2), 6.59–6.67 (m, 2H; 3’’-H, 5’’-H), 7.25–7.34 ppm (m, 2H; 2’’-H, 6’’-
H); 13C NMR (75.5 MHz, CDCl3): d=13.90 (2-CH3), 22.68 (C-5), 31.19
(C-4), 37.87 (C-6), 87.03 (C-1’), 105.0 (C-2’), 111.5 (C-1’’), 114.6 (C-3’’, C-
5’’), 132.3 (C-2’’, C-6’’), 137.4, 138.5, 147.6 (C-2, C-3, C-4’’), 198.6 ppm (C-
1); HRMS (EI+): m/z: calcd for C15H15NO: 225.1154 [M]+; found:
225.1154.
TBAF·3H2O (1.26 g, 3.99 mmol) in THF (15 mL) was added at room
temperature to a solution of the intermediate product in THF (25 mL).
The mixture was stirred at 08C for 30 min and at room temperature for
another 30 min, and was then diluted with H2O (80 mL) and extracted
with ethyl acetate (3”40 mL). The combined organic layers were washed
with brine (3”20 mL) and dried over Na2SO4, and the solvent was evapo-
rated after addition of silica gel (5 g). The product 4d was isolated by
column chromatography (silica gel, pentane/ethyl acetate 3:1 ! 1:1) as a
light yellowsolid (381 mg, 1.68 mmol, 84% over two steps).
1H NMR
(300 MHz, [D6]DMSO): d=1.91 (t, J=1.9 Hz, 3H; 2-CH3), 1.92 (quint.,
J=6.4 Hz, 2H; 5-H2), 2.38 (t, J=6.4 Hz, 2H; 6-H2), 2.51 (tq, J=6.4,
1.9 Hz, 2H; 4-H2), 6.77–6.83 (m, 2H; 3’’-H, 5’’-H), 7.32–7.38 (m, 2H; 2’’-
H, 6’’-H), 10.03 ppm (brs, 1H; 4’’-OH); 13C NMR (75.5 MHz,
[D6]DMSO): d=13.65 (2-CH3), 22.19 (C-5), 30.46 (C-4), 37.23 (C-6),
86.83 (C-1’), 103.8 (C-2’), 111.7 (C-1’’), 115.8 (C-3’’, C-5’’), 133.3 (C-2’’, C-
6’’), 136.7, 137.3 (C-2, C-3), 158.9 ppm (C-4’’), 197.1 (C-1); HRMS (EI+):
m/z: calcd for C15H14O2: 226.0994 [M]+; found: 226.1017.
2-Methyl-3-(4-triisopropylsilanyloxyphenylethynyl)cyclopent-2-enol (17):
Compound 15d (921 mg, 2.50 mmol), dissolved in MeOH (10 mL), was
added at room temperature to a stirred solution of CeCl3·7H2O (3.22 g,
8.64 mmol) in MeOH (25 mL). Et2O (10 mL) was then added and stirring
was continued for 20 min. NaBH4 (114 mg, 3.01 mmol) was added por-
tionwise every 5 min over 20 min, and the reaction mixture was stirred
for 110 min at room temperature. After addition of another portion of
NaBH4 (58 mg, 1.5 mmol) and stirring for another 60 min a third portion
of NaBH4 (82 mg, 2.2 mmol) was added, and the mixture was stirred for
60 min at room temperature. The mixture was poured into H2O
(150 mL), stirred for 15 min, and extracted with Et2O (4”50 mL). The
combined organic layers were washed with brine (40 mL) and dried over
Na2SO4, and the solvent was evaporated in vacuo after addition of silica
gel (6 g). Column chromatography (silica gel, pentane/ethyl acetate 7:1)
gave 17 as a yellowoil (801 mg, 2.16 mmol, 86%). 1H NMR (500 MHz,
5-Hydroxy-2-(2-methyl-3-oxocyclohex-1-enylethynyl)benzoic acid methyl
ester (4e): TBAF·3H2O (1.35 g, 4.28 mmol) was added at 08C to a solu-
tion of 16e (629 mg, 1.43 mmol) in THF (25 mL). The solution was
stirred for 30 min at 08C and for 35 min at room temperature, and was
then diluted with H2O (50 mL) and brine (30 mL) and extracted with
ethyl acetate (4”50 mL). The combined organic layers were washed with
brine (2”30 mL) and dried over MgSO4, and the solvent was evaporated
after addition of silica gel (5 g). The product 4e was isolated by column
chromatography (silica gel, pentane/ethyl acetate 1.5:1) as a light yellow
solid (379 mg, 1.33 mmol, 93%). 1H NMR (300 MHz, [D6]DMSO): d=
CDCl3): d=1.09 (d, J=7.4 Hz, 18H; 3”SiCH
3”SiCH(CH3)2), 1.51 (brs, 1H; 1-OH), 1.67–1.75 (ddt, 1H; 5-HA), 1.94–
1.96 (brm, 3H; 2-CH3), 2.31–2.40 (m, 1H; 5-HB), 2.39–2.47 (brm, 1H; 4-
ACHTRE(UNG CH3)2), 1.21–1.30 (m, 3H;
AHCTREUNG
3678
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3670 – 3679

Estrogen Analogues
FULL PAPER
HA), 2.59–2.67 (m, 1H; 4-HB), 4.66–4.71 (brm, 1H; 1-H), 6.80–6.85 (m,
c) P. J. Shughrue, M. V. Lane, I. J. Merchenthaler, J. Comp. Neurol.
1997, 388, 507–525.
2H; 3’’-H, 5’’-H), 7.30–7.35 ppm (m, 2H; 2’’-H, 6’’-H); 13C NMR
(126 MHz, CDCl3): d=12.63 (3”SiCH
(CH3)2), 13.14 (2-CH3), 17.85 (3”
[12] Examples: a) R. L. Funk, K. P. C. Vollhardt, J. Am. Chem. Soc.
1977, 99, 5483–5484; b) R. L. Funk, K. P. C. Vollhardt, J. Am.
Chem. Soc. 1979, 101, 215–217; c) R. L. Funk, K. P. C. Vollhardt, J.
Am. Chem. Soc. 1980, 102, 5253–5261; d) W. Oppolzer, K. Bättig,
M. Petrzilka, Helv. Chim. Acta 1978, 61, 1945–1947; e) W. Oppolzer,
D. A. Roberts, T. G. C. Bird, Helv. Chim. Acta 1979, 62, 2017–2021;
f) K. C. Nicolaou, W. E. Barnette, P. Ma, J. Org. Chem. 1980, 45,
1463–1470; g) G. H. Posner, M. Hulce, Tetrahedron Lett. 1984, 25,
379–382; h) J. L. Charlton, M. M. Alauddin, Tetrahedron 1987, 43,
2873–2889; i) T. Doi, K. Shimizu, T. Takahashi, J. Tsuji, K. Yama-
moto, Tetrahedron Lett. 1990, 31, 3313–3316; j) T. Kametani, Pure
Appl. Chem. 1979, 51, 747–768; k) T. Kametani, H. Nemoto, Tetra-
hedron 1981, 37, 3–16; l) D. H. Kim, K. Kim, Y. K. Chung, J. Org.
Chem. 2006, 71, 8264–8267; m) W. Z. Li, K. Wei, Org. Lett. 2004, 6,
1333–1335; n) Z. Yang, D. Shannon, V. Truong, P. Deslongshamps,
Org. Lett. 2002, 4, 4693–4696; o) J. Wçlfling, ꢁ. Frank, G. Schneid-
er, L. F. Tietze, Angew. Chem. 1999, 111, 151–152; Angew. Chem.
Int. Ed. 1999, 38, 200–201; p) J. Wçlfling, ꢁ. Frank, G. Schneider,
L. F. Tietze, Eur. J. Org. Chem. 2004, 90–100; q) E. Mernyak, G.
Schneider, R. Herbst-Irmer, M. Kubas, J. Wçlfling, Steroids 2006,
558–564.
SiCH(CH3)2), 33.04 (C-5), 33.71 (C-4), 80.17 (C-1), 84.47 (C-1’), 94.37 (C-
ACHTREUNG
2’), 115.8 (C-1’’), 120.0 (C-3’’, C-5’’), 121.5 (C-3), 132.9 (C-2’’, C-6’’), 147.0
(C-2), 156.3 ppm (C-4’’); HRMS (EI+): m/z: calcd for C23H34O2: 370.2328
[M]+; found: 370.2328.
3-(4-Hydroxyphenylethynyl)-2-methylcyclopent-2-enol (5): CsF (836 mg,
5.50 mmol) was added at 08C to
a stirred solution of 17 (757 mg,
2.04 mmol) in CH3CN (20 mL). Stirring was continued for 5 h at room
temperature, CsF (800 mg, 5.27 mmol) was again added, and stirring was
continued for another 13.5 h. The mixture was then poured into a saturat-
ed solution of NaCl (100 mL) and extracted with ethyl acetate (2”
50 mL), dichloromethane (50 mL), and Et2O (3”50 mL). The combined
organic layers were washed with brine (2”30 mL) and dried over
MgSO4, and the solvent was evaporated in vacuo. The product was isolat-
ed by column chromatography (silica gel, Et2O) as a bright yellowsolid
(249 mg, 1.16 mmol, 57%). 1H NMR (500 MHz, [D6]acetone): d=1.62–
1.70 (m, 1H; 5-HA), 1.87–1.89 (brm, 3H; 2-CH3), 2.21–2.28 (m, 1H; 5-
HB), 2.29–2.38 (brm, 1H; 4-HA), 2.47–2.55 (m, 1H; 4-HB), 4.01 (brs, 1H;
1-OH), 4.59–465 (brm, 1H; 1-H), 6.80–6.85, 2H; 3’’-H, 5’’-H), 7.27–7.32
(m, 2H; 2’’-H, 6’’-H), 8.75 ppm (brs, 1H; 4’’-OH); 13C NMR (75.5 MHz,
[D6]acetone): d=13.34 (2-CH3), 33.54 (C-5), 34.23 (C-4), 79.59 (C-1),
84.96 (C-1’), 94.62 (C-2’), 115.2 (C-l’’), 116.4 (C-3’’, C-5’’), 120.6 (C-3),
133.7 (C-2’’, C-6’’), 148.9 (C-2), 158.5 ppm (C-4’’); HRMS (EI+): m/z:
calcd for C14H14O2: 214.0990 [M]+; found: 212.0990.
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Received: October 10, 2007
Published online: March 10, 2008
Chem. Eur. J. 2008, 14, 3670 – 3679
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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