Photo-Fries Rearrangement of Some 3-Acylestrones in Homogeneous Media: Preparative and Mechanistic Studies

Article abstract of DOI:10.1021/acs.joc.9b00786

Irradiation of a series of 3-acylestrones under a nitrogen atmosphere in cyclohexane, acetonitrile (MeCN), and methanol (MeOH) was investigated under steady-state conditions. The molecules underwent the photo-Fries rearrangement, with concomitant homolytic fragmentation of the ester group and [1;3]-acyl migration. This pathway afforded the ortho-acyl estrone derivatives, the main photoproducts, together with estrone. During the irradiation of 3-benzoyl estrone, epimerization of estrone through the Norrish type I reaction occurred, providing lumiestrone as the photoproduct. This photoreaction involves the fragmentation of the C-α at the carbonyl group (C-17) of the steroid. On the other hand, epimerization of ortho-regioisomer 2-acetyl estrone occurred during the irradiation of 3-acetyl estrone. Photosensitization with acetone and chemical quenching with N,N,N,N-tetramethyldiazetinedioxide of the photo-Fries reaction confirmed that the photoreaction took place from the singlet excited state while the Norrish type I reaction proceeds efficiently from the triplet excited state. Solvent effects, as well as the nature of the acyl group on the photoreactions, were also studied.

Full text of DOI:10.1021/acs.joc.9b00786

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Article
The photo-Fries rearrangement of some 3-acyl estrone in
homogeneous media. Preparative and mechanistic studies.
Matías Iván Quindt, Gabriel Fransisco Gola, Javier Alberto Ramírez, and Sergio Mauricio Bonesi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00786 • Publication Date (Web): 06 May 2019
Downloaded from http://pubs.acs.org on May 11, 2019
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The photo-Fries rearrangement of some 3-acylestrone in homogeneous media. Preparative
and mechanistic studies.
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Matías I. Quindta,b, Gabriel F. Golaa,c, Javier A. Ramirez*a,c and Sergio M. Bonesi*a,b
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aUniversidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de
Química Orgánica. Buenos Aires, Argentina.
bCONICET – Universidad de Buenos Aires. Centro de Investigaciones en Hidratos de Carbono
(CIHIDECAR). Buenos Aires, Argentina.
cCONICET – Universidad de Buenos Aires. Unidad de Microanálisis y Métodos Físicos Aplicados
a Química Orgánica (UMYMFOR). Buenos Aires, Argentina
E-mail: smbonesi@qo.fcen.uba.ar; jar@qo.fcen.uba.ar
Table of content.
O
Me
H
O
Me
H
O
R = Me
R
O
O
Me
HO
Solvent
N2; 25°C
R
O
h
R = Me; Ph
h
H
Norrish Type I
reaction
Solvent
N2; 25°C
Photo-Fries
rearrangement
reaction
HO
Solvent
N2; 25°C
h
O
Me
O
O
Me
Me
O
+
H
+
R
H
H
HO
HO
HO
O
R
Abstract. Irradiation of a series of 3-acylestrones under nitrogen atmosphere in cyclohexane,
MeCN and MeOH was investigated under steady-state conditions. The molecules underwent the
photo-Fries rearrangement, with concomitant homolytic fragmentation of the ester group and [1;3]-
acyl migration. This pathway afforded the ortho-acyl estrone derivatives, the main photoproducts
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together with estrone. During the irradiation of 3-benzoyl estrone, epimerization of estrone through
the Norrish Type I reaction occurred, providing lumiestrone as the photoproduct. This photoreaction
involves the fragmentation of the C- at the carbonyl group (C-17) of the steroid. On the other
hand, epimerization of ortho-regioisomer 2-acetyl estrone occurred during the irradiation of 3-
acetyl estrone. Photosensitization with acetone and chemical quenching with N,N,N,N-
tetramethyldiazetinedioxide of the photo-Fries reaction confirmed that the photoreaction took place
from the singlet excited state while the Norrish Type I reaction proceeds efficiently from the triplet
excited state. Solvent effects, as well as the nature of the acyl group on the photoreactions, were
also studied.
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Introduction.
Steroidal sex hormones such as estrone and estradiol have attracted the attention of organic
chemists because these tetracycles possess significant physiological activity and because they
represent a clear challenge for total synthesis.1 These estrogens play a role in many biological
processes, consequently they are used as a scaffold for numerous steroidal derivatives. Not
surprisingly, compounds based on these moieties are used as drugs for the treatment of a variety of
medical conditions.2 Thus, improved methods for preparing already known derivatives and the
synthesis of new estrogen scaffolds is of considerable importance. For example, modification of
estrone at position 6, 16, or 17 positions provided novel potent inhibitors of 17-hydroxysteroids
dehydrogenase type 1 (17-HSD).3 This enzyme is expressed in all classical steroidogenic tissues
and almost all peripheral tissues, including the skin and breast. Moreover, it is highly expressed in
malignant breast cells.3
The photochemistry of steroids was thoroughly studied throughout the years,and the photochemical
work on these compounds included a considerable amount of photochemical reactions in solution
such as photorearrangement, photoaddition, photoreduction and photooxidation reactions.4 Also,
photochemical approaches have been successfully applied toward the synthesis of a variety of
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natural products, i.e. -cedrene, ingenol, estrone and ginkgolide B.5Preparative and mechanistic
studies on the photolysis of steroids, also considering the stereospecificity of the photoreaction have
been carried out.6 For example, photolysis of 5-hydroxy-5- and 5-cholestan-6-one and their 3-
acetoxy and 3-benzyloxy derivatives provided the corresponding lactones, 6-oxa-B-
homocholestan-7-ones with retention of the configuration at C-5 (see Scheme 1).6bLikewise,
Morrison and co-workers have shown that 3-(dimethylphenylsilyloxy)-5a-androstane-6,17-dione
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and its 3 isomer gave photoreduction and C- fragmentation of carbonyl group at C-17 of the
steroids (see Scheme 1). This behavior was attributed to the antenna-photosensitization through
triplet and singlet energy transfer from the arylsilyloxy group to the carbonyl groups.6g
h
AcO
HO
AcO
O
Solvent
H
O
O
3 -acetoxy-5-hydroxy-

6-oxa-B-homocholestan-7-ones
5 -cholestane-6-one

O
O
OH
O
O
O
h
+
MeCN-TEA
Me2PhSiO
3 -dimethylphenylsilyloxy-
Me2PhSiO
3 -dimethylphenylsilyloxy-
Me2PhSiO
3 -dimethylphenylsilyloxy-



5 -androstane-11,17-dione

17 -hydroxy-5 -androstan-11-one
5
-androstane-11,17-dione



O
O
Me
H
Me
H
H
H
H
h
H
Solvent
RO
RO
estrone
R = H;
lumiestrone
R = H;
estrone methyl ester
R = Me;
lumiestrone methyl ester
R = Me;
Scheme 1. Photochemistry of some steroidal derivatives.
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Estrone and its derivatives were also subjected to direct irradiation in solution and neat C-
fragmentation followed by epimerization of methyl group at C-13 through a Norrish Type I reaction
occurred (see Scheme 1). Irradiation of estrone 3-methyl ether provided lumiestrone 3-methyl ether
as the main photoproduct in 53 % yield along with seco-steroids as byproducts when anhydrous
THF was used as solvent.7 Estrone was also irradiated with UV-B (280 – 320 nm) under aerobic
conditions in acetonitrile as well as in water leading to the almost complete conversion into
lumiestrone.8Electron paramagnetic resonance spectroscopy using nitric oxide in the presence of
estrone yielded a nitroxide radical signal very close to the one reported for cyclopentanone while
nanosecond laser flash photolysis experiments showed that the conversion from estrone to
lumiestrone was rapid. These results proved that 13-epimerization of estrone was via the Norrish
type I photocleavage of a cyclic ketone moiety.8
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However, according to our knowledge, the direct irradiation (254 nm) of 3-acylestrones was not
previously investigated making this one of our reason to develop the study. Therefore, based on the
preliminary reports mentioned above and considering that the direct irradiation of estrone
derivatives was not reported yet encouraged us to undertake more extensive work for which we
chose 3-acetyl and 3-benzoylestrone as substrates (see Chart I).
O
O
H
H
O
O
H
H
H
H
O
Ph
O
1
2
Chart I. Structures of the 3-acetylestrone (1) and 3-benzoylestrone (2).
Considering that estrone derivatives 1 and 2 bear an ester group on the phenyl ring, we were
interested in studying the possible photo-Fries rearrangement induced by the direct irradiation (exc
= 254 nm) of these compounds. The photo-Fries rearrangement reaction was discovered by
Anderson and Reese9 and involves the homolytic cleavage of a carbon–heteroatom bond, i.e., C-O,
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C-S and C-N, of esters, thioesters and amides, respectively.10 The product distribution of the photo-
Fries rearrangement reaction is depicted in Scheme 2 for the case of aryl esters showing the ortho-
and para-regioisomers as well as the corresponding phenols.11 The radical mechanism of the photo-
Fries rearrangement is well established and it is known that this rearrangement occurs mainly
through the excited singlet state and the migration of the radical species takes place in the solvent
cage.12 However, most of the studies have been devoted to elucidating the mechanism of the
reaction rather than its use in synthesis. Some examples regarding the application of the photo-Fries
rearrangement in synthesis have been successfully employed in the preparation of griseofulvin,
daunomycinone and flavonoids.13 In addition, we have also contributed to the application of the
photo-Fries reaction in the preparation of 2,2-dimethyl-4-chromanone derivatives and carbazole
derivatives and recently, we have studied the effect of surfactant micelles on the photo-Fries
reaction of a variety of substituted acetamides.14
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O
OH
OH
O
OH
O
R
h
R
+
+
Solvent
25ºC
R
O
R'
R'
R'
R
R = alkyl or aryl
R' = electron donor and electron acceptor substituents
Scheme 2. The photo-Fries rearrangement of aryl esters.
Because direct irradiation of steroids was not been widely studied and taking into account that the
photo-Fries rearrangement is an easy photochemical reaction to be performed, in the present work
we examined the product distribution, triplet photosensitization and chemical quenching of the
photochemical reactions of compounds 1 and 2 (see Chart I).
Results.
Irradiation of 3-acetyl and 3-benzoylestrone in homogeneous media. Irradiation of 3-
acetylestrone (1) in non-polar and polar solvents such as cyclohexane, MeOH and MeCN with exc
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= 254 nm under N2 atmosphere provided the photoproducts expected from the photo-Fries
rearrangement, viz. formation of the ortho regioisomers (1a and 1b from 3-acetylestrone and 2a and
2b from 3-benzoylestrone), and estrone (3).We could also detect compound 4 in the reaction
mixture from 3-acetylestrone and lumiestrone (5) was found in the reaction mixture after irradiation
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of 3-benzoylestrone. The photochemical reactions are depicted in Scheme 3.
O
O
O
O
O
O
H
h
H
H
H
O
H
O
H
H
Solvent
25 ºC
H
H
H
H
H
H
H
O
H
HO
HO
HO
O
HO
O
1
3
4
5
6
O
O
O
O
O
H
h
H
H
H
H
O
Ph
HO
H
H
Solvent
25 ºC
H
H
H
H
H
H
H
H
Ph
O
HO
HO
HO
O
Ph
2
7
8
5
9
Scheme 3.The photo-Fries rearrangement of 3-acetylestrone and 3-benzoylestrone (1 – 2).
The chemical yields of the photoproducts are collected in Table 1 and is apparent from the data that
the [1;3]-migrated photoproducts, viz. compounds 3, 4 and 6 from ester 1 and 7 and 8 from ester 2,
are the main photoproducts when esters 1 and 2 are consumed in up to 98% yield. The migration of
the acyl group occurred with a poor selectivity. However, the shift of the acyl group to position 2 of
the aryl moiety is preferred over the migration of the same group to position 4 but depends on the
reaction solvent. Indeed, in cyclohexane and MeCN the (3+6)/4 and 7/8 ratios change from 3.1 to
4.9 while the ratios varied from 1 to 2 in MeOH. Steric effect due to the ring B of the steroid close
to position 4 accounts for the low selectivity of the migration of the acyl group to position 4.
Table 1. Irradiation of 3-acyl estrones in different solvents under N2 atmosphere. Yield of
photoproductsa and reaction quantum yield (R).b
Yields (%)
3-Acyl
estrones
1
Solvent
MeOH
R
3
27
4
23
5
9
6
20
0.01
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Cyclohexane
MeCN
17
36
7
34
62
47
25
14
8
36
19
15
4
11
5
15
<1
<1
17
32
9
11
NDc
12
0.05
0.05
R
0.01
0.01
0.01
MeOH
Cyclohexane
MeCN
2
aYield of photoproducts determined by 1H-NMR spectroscopy in the reaction mixture.
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Concentration of 3-acyl estrone: 5.0x10-3 M. Actinometer: KI (0.6 M), KIO3 (0.1 M) and
b
Na2B2O7.10H2O (0.01 M) in water; (I3 ) = 0.74; exc = 254 nm.;15 Error: ± 0.01. cNot Detected.
-
The quantum yields of consumption (R) of estrone derivatives (1 and 2) in non-polar and polar
solvents were also measured (see Table 1). The R values of esters 1 and 2 are 0.01 except for the
irradiations ester 1 carried out in MeCN and cyclohexane, respectively, where the R values are
0.05. However, these R values imply that the photoreaction occurred smoothly and could compete
with radiative and non-radiative pathways.
We employed UV-visible and NMR spectroscopies to follow the photochemical reaction. Figure
1(a) and (b) depict the time-resolved UV-visible absorption spectra of the photoreaction of 3-acetyl
estrone (5) in cyclohexane and MeOH. A new absorption band located at 330 nm rises with
irradiation time in both solvents. These bands were assigned to the n,* transition of the carbonyl
group of the ortho-rearranged photoproducts16 and similar spectral behavior was also observed in
MeCN. The n,* transition band was not affected by a significant shift upon solvent polarity
change.
Figure 1(c) represents the course of the photoreaction of ester 1 in MeOH measured by NMR
spectroscopy where it is apparent that the acetyl [1;3]-migration to form the photoproducts 3, 4 and
1
6 is the main process. The relative yield profile was constructed recording the H-NMR spectra of
the reaction mixture at different irradiation times after evaporation of the reaction solvent and then
dissolving the solid residue in deuterated chloroform. The aromatic protons of the steroid
derivatives (1, 3, 4, 5 and 6) were chosen as the diagnostic signals and after integration of these
signals the yields were calculated. Similar results were obtained in cyclohexane and MeCN.
Notably, the yield of estrone (5) was lower than 10% in all the solvents used. Figure 1(d) shows the
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relative formation of the ortho regioisomers (3, 4 and 6) in polar and non-polar solvents. The
relative rates of these photoproducts were similar in MeCN and cyclohexane while in MeOH was
somewhat lower. The finding leads to the conclusion that in protic polar solvent radiative and non-
radiative decay rates compete in a similar extent with the photoreaction pathway.
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(a)
(b)
1,0
0,8
0,6
0,4
0,2
0,0
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
45 min
0 min
36 min
0 min
200
250
300
350
400
200
250
300
/nm
350
400
 / nm
(c)
(d)
100
1,0
80
60
40
20
0
0,8
0,6
0,4
0,2
0,0
0,0
0,2
0,4
0,6
0,8
1,0
0
2
4
6
8
t / h
t / h
Figure 1. (a) UV-visible spectral change vs time of 1 in cyclohexane. Blue line: initial time; red
line: 45min. (b) UV-visible spectral change vs time of 1 in MeOH. Blue line: initial time; red line:
36 min. (c) Relative yield profile vs time of 1 in MeOH: ester 1 (○); 3 (∆);4 (□ ); 5 (◊); 6 (▼). (d)
Relative absorbance at 330 nm (A/A∞) of formation of ortho-rearranged photoproducts (3, 4 and 6)
in: cyclohexane (○); MeCN (∆); MeOH (□).
3-Benzoyl estrone (2) is characterized by a similar behavior compared to 3-acetyl estrone. Figure 2
resumes some representative spectroscopic results of its reactivity upon irradiation. The spectral
change of the UV-visible absorption upon irradiation time (see Figure 2a) demonstrates that the
photoreaction occurred efficiently. A new band located at 350 nm accounts for the formation of the
photoproducts 7 and 8 and was assigned accordingly to the n,* electronic transition of the new
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carbonyl groups formed during the irradiation. Likewise, H-NMR spectroscopy of the reaction
4
5
6
7
8
9
mixture at different irradiation times confirmed the main pathway of the reaction is the benzoyl
[1;3]-migration that affords 7 and 8. In addition, estrone (5) and lumiestrone (9) were also detected
in the reaction mixture, and lumiestroneis formed with yields up to 12%.
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(a)
(b)
1.2
1.0
0.8
0.6
0.4
0.2
0.0
100
80
60
40
20
0
8 min
0 min
0
1
2
3
4
t / h
200
250
300
 /nm
350
400
Figure 2. (a) UV-visible spectral change vs time of 2 in cyclohexane. Blue line: initial time; red
line: 45 min. (b) Relative yield profile vs time of 2 in Cyclohexane: ester 2 (○); 7 (∆); 8 (□); 5 (◊); 9
(▼).
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It is worth to mention that during the irradiation of 3-acetylestrone (1) the Norrish Type I
photoreaction competes with the photo-Fries rearrangement. Epimerization of the methyl group at
C-13 of photoproduct 3 was observed in polar and non-polar solvents (for example, see Figure 1c
for the case of cyclohexane). Because photoproduct 3 is a chromophore and can absorb at 254 nm
epimerization of methyl group occurred efficiently providing compound 6 which was formed with
yields up to 32% (see Scheme 4).No epimerization of estrone and compound 4 was observed during
irradiation of ester 1. Likewise, we observed the Norrish Type I photoreaction also during the
irradiation of 3-benzoyl estrone. On the other hand, estrone (5) is a chromophore able to absorb
light, allowing it to epimerize to the corresponding lumiestrone (9) (see Scheme 4).7,8
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O
O
O
O
H
O
O
H
H
h
H
H
H
H
Solvent
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H
HO
HO
HO
3
Biradical intermediate
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9
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O
O
O
H
H
H
h
H
H
H
H
Solvent
H
H
HO
HO
HO
5
Biradical intermediate
9
Scheme 4. The Norrish Type I photoreaction of 2-acetylestrone (3) and estrone (5) in organic
solvents.
The strong photostability observed for compounds 7 and 8 during irradiation of ester 2 can be
ascribed to the formation of trans-keto tautomer in the ground state as it is depicted in Scheme 5 for
the case of 7. This tautomer is formed by the excited state intramolecular proton transfer (ESIPT)17
of the ortho-regioisomer to produce the cis-keto tautomer in the excited state. The process is
followed by deactivation with twisting of the newly produced C=C bond of the tautomer before
intersystem crossing to the triplet excited state occurs. This radiationless process of the cis-keto
tautomer gives the trans-keto tautomer in its ground state. This behavior is usually observed with -
hydroxy carbonyl compounds such as 2’-hydroxychalcones in * excited states, where the
phenolic group usually becomes more acidic and the carbonyl more basic. The ensuing
enhancement of the proton transfer favors the one-way cis-trans isomerization of 2’-
hydroxychalcones.18 Compounds 7 and 8 have a -hydroxy carbonyl and can absorb light of 254
nm, the ESIPT process causes the deactivation through radiative and non-radiative pathways.
Consequently, no Norrish Type I photoreaction does compete with these pathways. Therefore,
epimerization of these photoproducts was not observed upon irradiation of ester 2. In the case of 3-
acetyl estrone (1), photoproduct 4 showed similar behavior as it was described for photoproducts 7
and 8 while compound 3 epimerized efficiently providing 6 with yields up to 32%. This distinct
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behavior showed by compound 3 can be attributed to the non-planarity of the acetyl group with the
benzene moiety partially preventing the intramolecular hydrogen bonding between the carbonyl
group and the hydroxyl group. Therefore, the ESIPT process is not a competitive pathway, and
epimerization reaction of the carbonyl group at C-17 occur smoothly providing compound 6.
Furthermore, intramolecular triplet photosensitization from the aryl moiety to the carbonyl group at
C-17 of compound 6 is the source of the observed epimerization, in accordance with was reported
in the literature for the case of 3-dimethylphenylsilyloxyandrostanone derivatives.6g,19
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
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37
38
39
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41
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45
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49
50
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52
53
54
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56
57
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O
O
O
*
H
O
O
Ph
Ph
O
H
H
H
h
Ph
H O
O
H
H
H
H
Solvent
H
H
H
O
cis-keto form
trans-keto form
7
ESIPT process
C=C Twist
process
A
B
Radiationless
Process
O
O
H
Ph
HO
H
H
7
Scheme 5. Cis-trans keto tautomerism of compound 7.
Photosensitization and chemical quenching of the photo-Fries rearrangement of estrone
derivatives. In order to determine the multiplicity of the excited state involved in the photo-Fries
rearrangement, 3-benzoyl estrone (2) was chosen as the triplet energy acceptor probeand acetone
was chosen as the triplet energy donor. This selection lies on the known triplet energies (ET) values.
The ET of acetone20 is 74 kcal.mol-1 while 3-benzoyl estrone’s one was assumed to be similar to that
of estrone (69.4 kcal.mol-1)21, considering the benzoyl group does not influence substantially the
value. Therefore, the triplet energy transfer pathway was a thermodynamically feasible process
because the energy gap between the triplet energy values was ca.5 kcal.mol-1. Then,
photosensitization of 3-benzoyl estrone was carried out in acetone with exc = 310 nm and the
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results are shown in Table 2. It is apparent from the data collected in the table that
photosensitization of estrone 2 with acetone occurs smoothly providing the ortho-regioisomers 7
and 8 in yields lower compared to the same experiment carried out in MeOH while the yield of
estrone 5 was doubled. Noteworthy, the formation of lumiestrone 9 was not enhanced under acetone
photosensitization.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tetramethyl-1,2-diazetine dioxide (TMDO) was chosen as the triplet energy quencher (ET = 54.0
kcal.mol-1)14eowing to the energy gap between its triplet state and the one estrone 2 (ca. 15
kcal.mol-1 lower than 2).A thermodynamically feasible triplet energy transfer pathway between
these species is hence possible. Consequently, the irradiation of 3-benzoyl estrone 2 in MeOH in the
presence of increasing amounts of TMDO, the triplet energy quencher, the photo-Fries
rearrangement took place efficiently while the formation of lumiestrone 9 diminished significantly
(see Table 2). These results suggest that in the photo-Fries reaction the excited triplet state is not the
photoreactive state while the epimerization reaction of estrone 5 to lumiestrone 9 involves the triplet
excited state because TMDO quenches the reaction efficiently. These results match with the ones
present in the literature, demonstrating the involvement of a triplet excited state in the photo
epimerization reaction of cyclic ketones.6g,19,22
Table 2. Irradiation of 3-benzoyl estrone in methanol, acetone and the presence of TMDO under
N2atmosphere.a
Estrone Solvent
Additive
TMDOb (mol.dm-3)
Yields (%)
7
8
5
9
11
13
2
MeOH
----
----
5.0x10-4
1.0x10-3
1.5x10-3
34
22
27
36
14
31
15
29
18
Acetonec
MeOH
2
23
23
23
16
10
3
1
---
aYield of photoproducts determined by 1H-NMR spectroscopy in the reaction mixture.
b
Concentration of 3-benzoyl estrone: 1.0x10-3 M. Irradiation with exc = 254 nm. Tetramethyl-1,2-
diazetina dioxide. cIrradiation with exc = 310 nm.
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9
We decided to synthesize estrone methyl ether (10) as a way to assess whether the photo
epimerization of estrone 5 takes place from the triplet excited state through a Norrish type I
mechanism. Methylation of estrone (5) with KOH / DMSO / MeI (see Scheme 6)23 afforded
compound 10 that was fully characterized using physical and spectroscopic methods. Irradiation of
estrone6 in methanol with exc = 254 nm under N2 atmosphere gave the lumiestrone methyl ether
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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49
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60
(11) as the main photoproduct in 50 % yield along with compounds 12, 13 and 14 (see Scheme 6).
(a)
O
O
i) KOH, DMSO
ii) CH3I
H
H
H
H
H
H
H3CO
HO
10 (80 %)
5
H
H
O
13 (28 %)
CHO
H
H3CO
h  nm
H
H
+
H3CO
10
+
MeOH, 25ºC
H
H
H
H
H3CO
CHO
H
14 (5 %)
COOMe
H
11 (50 %)
12 (14 %)
H3CO
O
(b)
O
O
h  nm
H
H
H
H
H
Epimerization
H
H
H
H
H
11
12
10
H
CH2OH
H
Intramolecular
Hydrogen abstraction
H
O
CH2OH
H
H
H
H
H
O2
H
OMe
H
Intermolecular
Hydrogen abstraction
MeOH
H
H
O
O
14
13
Scheme 6.(a) Preparation and irradiation of estrone methyl ether 10. (b) Plausible reaction
mechanism.
Direct irradiation of estrone methyl ether (10) demonstrates that photo epimerization of methyl
group at C-13 occurs efficiently through a Norrish type I mechanism involving a biradical
intermediate (see Scheme 6(b)). Additionally, the formation of compounds 12 and 13 accounts for
inter- and intramolecular hydrogen abstraction from the same intermediate (Scheme 6(b)).
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9
Oxidation of compound 13 by residual molecular oxygen present in the reaction mixture afforded
the corresponding carboxylic acid that, in turn, reacted with MeOH to give compound 14.
Triplet quenching of the photoreaction of estrone methyl ether (10) with TMDO in methanol under
N2 atmosphere was also carried out, assuming that the triplet energy of estrone methyl ether is ca.
70 kcal mol-1, which is similar to that of estrone21 or 17-estradiol24. The results are summarized in
Table 3.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Irradiation of estrone methyl ether (10) in methanol in the presence of TMDO under
N2atmosphere.a
TMDOb (mol dm-3) Yield of 11 (%) Conversion (%)
0
55
52
31
24
91
69
38
29
5.0x10-4
1.0x10-3
1.5x10-3
aYield of photoproducts determined by 1H-NMR spectroscopy in the reaction mixture.
Concentration of 3-methoxy estrone: 1.0x10-3 M. Irradiation with exc = 254 nm. bTetramethyl-1,2-
diazetina dioxide.
As can be seen in Table 3 it is apparent that TMDO quenches efficiently the photo epimerization
reaction of estrone methyl ether 10 confirming that the photo reaction takes place from the triplet
excited state. Photosensitization of estrone methyl ether 10 in acetone (exc = 310 nm) provided
compound 11 as the sole product demonstrating again that the triplet excited state is involved in the
epimerization reaction. In this experiment, acetone is both the solvent and the photosensitizer.
Irradiation of 3-acetyl 17-norestrone (16) in homogeneous media. In order to demonstrate that
the carbonyl group (C-17) is responsible of the competitive Norrish type I reaction during the
irradiation of estrones 1 and 2, we decided to prepare 3-acetyl 17-norestrone 16 as a probe
compound. The preparation of compound 16 starts with the reaction of estrone 5 under Wolf-
Kischner conditions in dimethoxy ethane at 200 °C providing17-norestrone 15 in good yield. After
purification by column chromatography, compound 15 was acetylated with acetyl anhydride in
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pyridine at room temperature giving compound 16 in 88% yield (see Scheme 7). Both compounds
4
5
15 and 16 were fully characterized by means of physical and spectroscopic methods.
6
7
O
NH2NH2.H2O
KOH; DME
t-BuOH; 200 ºC
8
9
H
H
H
Ac2O
Py, 25ºC
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
H
H
H
H
HO
HO
O
5
15 (Yield: 91%)
16 (Yield: 88%)
O
H
H
H
h
H
H
H
H
H
Solvent
25 ºC
H
HO
O
HO
HO
17
18
15
Yield (%)
18
R
Solvent
Conv. (%) 17
15
MeOH
Cyclohexane
87
81
60
46
23
35
4
1
0.16
0.15
Scheme 7. Preparation and irradiation of 3-acetyl 17-norestrone 16.
Irradiation of 3-acetyl-17-norestrone (16) in MeOH and cyclohexane (exc = 254 nm) under N2
atmosphere provided the expected photoproducts from the photo-Fries rearrangement, viz.
formation of the ortho-regioisomers (17 and 18) and 17-norestrone (15) (see Scheme 7). No
epimerization of the photoproducts was observed because compound 16 does not bear a carbonyl
group at C-17. We determined the chemical yields using NMR spectroscopy and compounds 17 and
18 were the main photoproducts when the ester 16 was consumed in up to 87% yield (see Scheme
7). The selectivity of the acetyl migration depended on the reaction solvent used and the 17/18 ratio
was found to be 2.6 in MeOH while in cyclohexane was found to be 1.4. The photoreaction was
also followed by UV-visible spectroscopy and a new band located at 330 nm rises with irradiation
time (see Figure S1 in Supporting Information) which was assigned to the n,* transition of the
carbonyl group of the ortho-rearranged photoproducts.16
The quantum yields of consumption (R) of 16 were measured in MeOH and cyclohexane (see
Scheme 7) and were found to be similar in both solvents (ca. 0.16). Notably, ester 16 showed a R
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value16 times higher than ester 1 when the irradiation solvent was MeOH whereas in cyclohexane,
the R value was found to be 3 times higher than ester 1. This photochemical behavior can be
attributed to the absence of the carbonyl group at C-17 in ester 16 and, therefore, no competition
between the photo-Fries rearrangement and the antenna sensitization of the aryl moiety takes place
during the irradiation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation of 2-acetyl estrone (3) and 4-acetyl estrone (4) applying the photo-Fries
rearrangement. Having understood the mechanistic facets involving the irradiation of 1, we aimed
to prepare estrone derivative 3 without epimerization of ring D (see Scheme 8).25Estrone 5 was
reacted with triethylorthoformate and ethylene glycol in the presence of p-toluenesulfonic acid at 70
°C providing estrone derivative 19 in 90% yield. Then, acetylation of compound 19 with acetic
anhydride in pyridine gave compound 16 in 83%yield. Both intermediates, viz. 19 and 20, were
fully characterized by means of NMR spectroscopy.
O
O
O
O
O
HC(OEt)3
Ac2O
H
H
H
O
H
HOCH2CH2OH
p-TsOH; 70 °C
Pyridine; 0 °C
H
H
H
H
H
HO
HO
O
20 (Yield: 83%)
19 (Yield: 90%)
5
h 254 nm)
Solvent
25 ºC
O
O
O
O
O
O
H
O
H
H
H
H
H
H
H
H
HO
HO
HO
O
21
22
19
Yield (%)
Solvent
MeOH
21
22
19
HCl
MeOH
25 °C
10
20
20
27
14
16
Cyclohexane
O
O
O
H
O
H
H
H
H
H
H
H
H
HO
HO
HO
O
3
4
5
Scheme 8. Preparation and irradiation of compound 20.
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Irradiation of compound 20 in polar and non-polar solvents such as MeOH and cyclohexane with
exc = 254 nm under N2 atmosphere provided the expected photoproducts from the photo-Fries
rearrangement, viz. formation of the ortho rearranged protected photoproducts (21 and 22), and
protected estrone (19) (see Scheme 8). No epimerization of the photoproducts was observed and the
chemical yields in both solvents were determined by NMR spectroscopy (see Scheme 8). No
significant selectivity was observed for the migration of the acetyl group in both reaction solvents
used to perform the photoreaction. Indeed, the 22:21 ratio was found to be 2:1 when the solvent was
methanol while in cyclohexane the 22:21 ratio was found to be ca. 1.4:1. On the other hand, the
quantum yield of consumption (R) of ester 20 was also measured and the values depended on the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
nature of the solvent, i.e. in cyclohexane the R values was found to be 0.02 while in methanol was
doubled (R = 0.04). These values are in the same order of magnitude of those obtained for the
irradiations of ester 1 and 2 (see Table 1). The last step involved in the synthetic approach was the
deprotection reaction of photoproducts 21 and 22 under acid catalysis in methanol at room
temperature. This reaction was found to be quantitative providing products 3 and 4 in a clean
process. Also, deprotection of compound 19 under the abovementioned acidic conditions provided
estrone 5 in quantitative yield.
Discussion.
As hinted above, 3-acetyl- and 3-benzoyl estrone, 1 and 2, respectively, reacted efficiently upon
direct irradiation (254 nm) in homogeneous media (cyclohexane, MeCN and MeOH) under N2
atmosphere (see Scheme 1 and Figures 1 and 2) providing the [1;3]-migrated photoproducts along
with estrone (see Table 1). However, epimerization reaction of 3 to give compound 6 occurred
during the irradiation of 3-acetyl estrone (1) while lumiestrone (9) was formed upon irradiation of
3-benzoyl estrone (2). This behaviour shows that two reaction pathways operate during the
irradiation of 3-acyl estrone: i) the photo-Fries rearrangement reaction and, ii) the Norrish type I
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reaction. On the basis of our results, a reaction mechanism for the irradiation of 3-acyl estrone is
proposed in Scheme 9.
6
7
O
O
O
8
9
H
H
H
h
1[1]*
O
O
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
3[3]*
H
H
path (c)
H
path (a)
R
O
R
O
HO
5
kd
1; R = CH3
2; R = Ph
ISC
h
path (b)
O
O
k'd
k''d
3[5]*
path (f)
O
H
H
h
R
H
H
H
H
ISC
(R = CH3)
HO
O
HO
3; R = CH3
7; R = Ph
4; R = CH3
8; R = Ph
path (d)
O
R
H
H
O
O
H
HO
O
O
path (e)
H
path (g)
H
H
H
H
O
HO
HO
6
H
H
H
HO
9
Scheme 9. The reaction mechanism of compounds 1 and 2.
Irradiation of 3-acyl estrone (1 and 2) with 254 nm light-source populates the singlet excited state
which is the photo reactive excited state. The triplet excited state is not involved in the photo-Fries
rearrangement of 3-acyl estrones as it was evidenced by the triplet quenching experiments with 2 in
the presence of TMDO (see Table 2). Then, homolytic fragmentation of the ester group (path (a))
occurs efficiently from the singlet excited state and competes with radiative and radiationless
processes from the same excited state (kd). After C(O)-O bond cleavage, the acyl and phenoxy
radicals are formed in the solvent cage and these species evolve to photoproducts through two
competitive pathways (paths (b) and (c) in Scheme 9). Thus, in-cage [1;3]-migration of the acyl
radicals to positions 2 and 4 affords the expected ortho-regioisomers 3 and 4 from ester 1 and 7 and
8 from ester 2 (path (b)). On the other hand, diffusion of the radical species from the solvent cage
was another viable pathway. Indeed, estrone (5) is formed after hydrogen atom abstraction of the
phenoxy radical from the solvent (path (c)). Noteworthy, the ortho-regioisomers 4, 7 and 8 were
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photo stable compounds upon irradiation with  = 254 nm. This strong photo stability is attributed
to the excited state intramolecular proton transfer (ESIPT)17 process between the proton of the
hydroxyl group and the carbonyl group attached to the aromatic ring (see Scheme 5) and a cis-trans
keto tautomerism accounts for this behavior where radiation and radiationless processes are the sole
deactivation pathways of the ortho-regioisomers. However, compound 3 undergoes photo-
epimerization reaction resulting in compound 6. This photochemical reactivity is ascribed to the
out-of-plane deviation of the acetyl group from the planarity of the aromatic ring disfavoring the
intramolecular proton transfer process and the cis-trans keto tautomerism. Direct irradiation of
compound 3 with 254 nm populated the triplet excited state of the carbonyl group (C-17) at the D
ring of the steroid because a singlet-singlet energy transfer between the aryl moiety and the
carbonyl group (C-17) occurred efficiently (see later in the text).21 Deactivation of the triplet state
through radiationless process (k’’d in Scheme 9) restores 3 in the ground state. Competitively, a
Norrish Type I photoreaction is a competitive deactivation process for triplet excited state of 3.
Thus, fragmentation of the C-C=O bond at the ring D of compound 3 (path (d)) provides the
biradical intermediate that, epimerizes the methyl group at C-13 giving compound 6 (path (e)).
Similar conclusions can be drawn for estrone3 that is converted to lumiestrone 9 (paths (f) and (g)
in Scheme 9) through a Norrish Type I reaction.6g,19,22 The results obtained in the presence of
increasing amounts of TMDO confirm that the Norrish Type I photoreaction of 10 to give
lumiestrone methyl ether 11 is inhibited. The finding supports the involvment of a triplet excited
state located on the carbonyl group (C-17) of the D ring of the steroid as the photo reactive state
(see Scheme 6 and Table 3) for this process to occur. The same conclusions can be drawn analyzing
the results of the photosensitization ( = 310 nm) of compound 10 with acetone. The reaction
demonstrates that the triplet excited state is involved in the epimerization reaction and product 11
was the sole photoproduct formed. The photochemical behavior described for compounds 3, 5 and
10 regarding the Norrish Type I reaction and consequently, the epimerization of the C-13 methyl
group are depicted in Scheme 10.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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Aryl chromophore
(antenna)
Acceptor chromophore
(C-17)
O
6
7
8

ET = 0.96
(*)S1
110 kcal.mol-1
HO
9
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
86 kcal.mol-1
O
(n,*)S1
(n,*)T1
84 kcal.mol-1
(*)T1
78 kcal.mol-1
HO
Epimerization
Reaction
TMDO
9 or 10
Quenching of the
Epimerization Reaction
S0
S0
Scheme 10. Plausible mechanism for intramolecular energy transfer for aryl antenna to the C17-
keto group of estrone (5).
Some time ago, Weinreb and Werner21 have intensely studied the photophysics of a series of
estrogen derivatives and, mainly, they found that estrone was able to give fluorescence emission
from both the phenolic moiety (em = 284 nm) and the carbonyl group (C-17) (em = 412 nm). The
only way to explain this photo physical behavior was attributed to the singlet-singlet energy transfer
from the singlet state of the phenolic moiety to the carbonyl group. Indeed, this energy transfer
process was found to proceed with a quantum yield of 0.96 and a rate constant of 2.4x109 s-1, a
value higher than the intersystem crossing process of the phenolic moiety. Therefore, excitation to
the singlet excited state of the phenolic moiety (the antenna chromophore in Scheme 10) populates
efficiently the singlet excited state of the carbonyl group (C-17; the acceptor chromophore in
Scheme 10) because it is a feasible thermodynamic process. Once this latter excited state is reached,
fluorescence emission competes with the intersystem crossing process and the triplet excited state
(n,*) of the carbonyl group is formed. Finally, C(O)-C bond cleavage occurs, and epimerization
reaction of the methyl group took place smoothly through a Norrish Type I fragmentation reaction.
Alternatively, energy transfer from the T1(*) of the phenolic moiety to the T1(n,*) of the
carbonyl group cannot be ruled out. However, Weinreb and co-workers have stated that this process
does not proceed efficiently.21 A similar Jablonski diagram can be proposed and, we are also
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convinced that operates satisfactorily, for estrone methyl ether (6) and ortho-regioisomer 3.
Therefore, the epimerization reaction of these compounds occurs from the triplet excited state
(T1(n,*)) of the carbonyl group and it was demonstrated that physical quenching of the
epimerization reaction with TMDO, a triplet quencher, proceeds efficiently.
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Direct irradiation of 3-acetyl-17-norestrone (16) with light of 254 nm in MeOH and cyclohexane
gave the ortho-regioisomers 17 and 18 in good yield but with a noticeable regioselectivity in favor
of compound 17 (see Scheme 7). However, no epimerization reaction of ortho-regioisomer 17 as
well as 17-norestrone (15) was observed because both compounds do not bear a carbonyl group at
C-17 and, as a consequence, the Norrish Type I reaction has no chance to compete with the photo-
Fries rearrangement. Indeed, the photo-Fries reaction of compound 16 occurred with quantum
yields (R) higher than those observed for esters 1 and 2 in the same solvent (compare the data
shown in Scheme 7 and Table 1). Taking into account this photochemical behavior we reasoned that
if the carbonyl group at C-17 of compound 1 would be protected as a 1,3-dioxolane derivative and
then acetylated (compounds 19 and 20 in Scheme 8, respectively) no competition of the Norrish
Type I would occur during the photo-Fries rearrangement of compound 20. Indeed, irradiation of 20
provided efficiently the ortho-regioisomers 21 and 22 in good yield without epimerization of
methyl group at C-13 (see Scheme 8). In a second step, deprotection of the ortho-regioisomers 21
and 22 under acid catalysis gave the desired 2-acetyl- (3) and 4-acetyl estrone (4) derivatives in
quantitative yield. This synthetic approach showed that in only four steps the ortho-regiosiomers 3
and 4 were prepared in good yields from estrone as the starting material, with no side epimerization.
In this synthetic scheme, the application of the photo-Fries reaction onto compound 20 represents
the crucial step. We suggest that this methodology would be useful in the preparation of other kinds
of steroid derivatives belonging to the family of estrone.
Conclusions.
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The photochemical reaction of 3-acyl estrone examined in this paper takes place efficiently
providing the expected ortho-regioisomers and estrone through the photo-Fries rearrangement.
Photosensitization and chemical quenching demonstrate that the photoreaction occurs from the
singlet excited state. The formation of the ortho-regioisomers depends on the solvent reaction and a
noticeable regioselectivity is observed in favor of 2-acetyl estrone derivatives. The C-O homolytic
cleavage that gives in-cage acyl and phenoxyl radicals competes with radiative and radiationless
excited state deactivation pathways. These radicals can couple in the solvent cage to give the
desired ortho-regioisomers (3, 4, 7 and 8 in Scheme 9) through a [1;3]-acyl migration process or
can diffuse to the bulk and give estrone. Compounds 4, 7 and 8 were found to be photo stable
photoproducts due to the efficient ESIPT processes under UV irradiation (see Scheme 5). On the
other hand, estrone, the ortho-regioisomer (3) and estrone methyl ether (10) are found to epimerize
upon irradiation with UV light (254 nm) through a Norrish Type I mechanism (see Schemes 4 and
9). This photoreaction involves the triplet excited state of the carbonyl group (C-17) at the D ring of
the steroids that is populated from the singlet excited state of the phenolic moiety through an
intramolecular energy transfer process (see Scheme 10). Finally, a four step reaction sequence was
applied to prepare the ortho-regiosiomers 3 and 4 in good yields, starting from estrone and avoiding
the epimerization of methyl group (C-13) of the D ring of the estrone moiety (see Scheme 8). This
synthetic approach shows that application of the photo-Fries reaction of compound 20 is an
alternative step to avoid the photo epimerization reaction of compound 3 to compound 6 (see
Scheme 3), suggesting its utility in organic synthesis. Further studies on the photo-Fries reaction of
3-alkyl and 3-aryl sulfonyloxyestrone derivatives are currently in progress in our laboratory and
will be reported in due course.
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Experimental.
Materials and equipment. Estrone, acetyl chloride, acetic anhydride, benzoyl chloride, pyridine,
tetramethyl-diazodiazetine dioxide and acetone were obtained from commercial sources.
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Spectroscopic grade solvents were used as received. Pyridine was distilled and stored over KOH
pellets. Melting Points were determined with a Fisher Jones apparatus and are not corrected. 1H and
13C NMR spectra were recorded in CDCl3on a 500 MHz spectrometer; chemical shifts ( are
reported in parts per million (ppm), relative to signal of tetramethylsilane, used as internal standard.
2D NMR spectra (HSQC and HMQC sequences) were recorded in CDCl3 on a 500 MHz
spectrometer. Coupling constant (J) values are given in Hz. The measurements were carried out
using standard pulse sequences. The UV-visible spectra were measured with a Shimadzu UV-1203
spectrophotometer using two-faced stoppered quartz cuvettes (1 mm x 1 mm) at 298 K. HR-MS
(ESI) analyses were performed on a Bruker micrOTOF-Q-11 instrument. Quadrupole – time of
flight analyzer that provides exact masses with an error less than 3 ppm in EM and less than 5 ppm
in EM/MS.
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General procedure for the synthesis of esters 1 and 2.To a solution of estrone (1.85 mmol) in
pyridine (10 mL) chilled in an ice-bath, acetic anhydride for 1 or benzoyl chloride for 2 (2.22
mmol) was added dropwise 10 min under stirring. After the addition of the acylating reagents, the
solution was stirred at 25 ºC until TLC control showed total consumption of estrone. Then, the
reaction mixture was extracted with dichloromethane (10 mL) and washed with a solution of diluted
HCl (10 mL). The organic phase was then washed three times with water, dried over Na2SO4,
filtrated and evaporated under vacuum. The solid residue was washed with 10 ml of cold methanol
(0/5 °C) and dried in the air. The corresponding esters were obtained in excellent yields (>90%).
Compounds 1 and 2 were characterized by comparison with the physical constant (m.p.) and
spectroscopic data (1H and 13C NMR) reported in the literature.
17-Oxoestra-1,3,5(10)-trien-3-yl acetate (1). White solid (0.54 g, 93%). M.p.: 126 - 127ºC (lit. 125 -
1
126ºC26). H NMR (500 MHz, CDCl3): δ 7.28 (d, J = 8.5 Hz, 1H, H-1), 6.85 (dd, J = 8.5, 2.6 Hz,
1H, H-2), 6.81 (d, J = 2.6 Hz, 1H, H-4), 2.94 – 2.86 (m, 2H, H-6), 2.51 (dd, J = 19.0, 8.8 Hz, 1H,
H-16), 2.43 – 2.38 (m, 1H, H-11), 2.32 – 2.25 (m, 1H, H-9), 2.28 (s, 3H, H-20), 2.14 (dt, J = 18.6,
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8.9 Hz, 1H, H-16'), 2.09 – 1.94 (m, 3H, H-12, H-7 and H-15), 1.68 – 1.40 (m, 6H, H-7', H-14, H-8,
H-12', H-11' and H-15'), 0.91 (s, 3H, H-18).13C{1H} NMR (126 MHz, CDCl3):δ 220.8 (C-17),
169.9 (C-19), 148.6 (C-3), 138.1 (C-5), 137.5 (C-10), 126.5 (C-1), 121.7 (C-4), 118.8 (C-2), 50.5
(C-14), 48.1 (C-13), 44.3 (C-9), 38.1 (C-8), 35.9 (C-16), 31.6 (C-12), 29.5 (C-6), 26.4 (C-11), 25.8
(C-7), 21.7 (C-15), 21.2 (C-20), 13.9 (C-18).
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17-Oxoestra-1,3,5(10)-trien-3-yl benzoate (2). White solid (0.67 g, 95%). M. p.: 217-219ºC (lit. 217
- 220ºC27).1H NMR (500 MHz, CDCl3):δ 8.20 (d, J=7.53 Hz, 2H, H-22), 7.67 – 7.60 (t, 1H, J = 7.3
Hz, H-24), 7.51 (t, J = 7.7 Hz, 2H, H-23), 7.34 (d, J = 8.5 Hz, 1H, H-1), 6.99 (dd, J = 8.4, 2.6 Hz,
1H, H-2), 6.95 (d, J = 2.6 Hz, 1H, H-4), 2.98 – 2.92 (m, 2H, H-6), 2.52 (dd, J = 19.1, 8.7 Hz, 1H,
H-16), 2.43 (dq, J = 11.5, 3.1, 2.1 Hz, 1H, H-11), 2.32 (td, J = 10.9, 3.8 Hz, 1H, H-9), 2.16 (dt, J =
18.6, 8.8 Hz, 1H, H-16), 2.10 – 1.96 (m, 3H, H-12, H-7 and H-15), 1.70 – 1.43 (m, 6H, H-7', H-14,
H-8, H-12', H-11' and H-15'), 0.93 (s, 3H, H-18).13C{1H} NMR (126 MHz, CDCl3):δ 220.9 (C-17),
165.6 (C-20), 148.9 (C-3), 138.2 (C-5), 137.5 (C-10), 133.6 (C-24), 130.2 (C-22), 129.7 (C-21),
128.6 (C-23), 126.6 (C-1), 121.8 (C-4), 119.0 (C-2), 50.5 (C-14), 48.1 (C-13), 44.3 (C-9), 38.1 (C-
8), 36.0 (C-16), 31.7 (C-12), 29.5 (C-6), 26.5 (C-11), 25.9 (C-7), 21.7 (C-15), 13.9 (C-18).
General procedure for the synthesis of estrone methyl ether (10). Powdered KOH (21.7 mmol)
was added to DMSO (12 ml) and the solution was stirred for 5 min. Then, estrone (5.5 mmol) was
added to the solution followed by the addition of MeI (11 mmol). The reaction mixture was stirred
for ca. 1 hr until TLC control showed total consumption of estrone. The reaction mixture was
poured into water (100 ml) and extracted with dichloromethane (3 x 10 mL). The combined organic
layers were washed with water, dried over Na2SO4, filtrated and evaporated under vacuum. The
white solid residue was recrystallized from ethyl acetate to give the desired compound 10.
3-Methoxyestra-1,3,5(10)-trien-17-one (10). White solid (4.94 g, 80 %). M.p.: 143-145ºC (lit.
142ºC28). 1H NMR (500 MHz, CDCl3): δ 7.21 (dd, J = 8.6, 1.1 Hz, 1H, H-1), 6.72 (dd, J = 8.6, 2.8
Hz, 1H, H-2), 6.65 (d, J = 2.8 Hz, 1H, H-4), 3.78 (s, 3H, CH3O), 2.96 – 2.85 (m, 2H, H-6), 2.50
(ddd, J = 19.0, 8.8, 0.9 Hz, 1H, H-16), 2.43 – 2.37 (m, 1H, H-11), 2.26 (td, J = 10.7, 4.4 Hz, 1H, H-
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9), 2.14 (dt, J = 18.9, 8.9 Hz, 1H, H-16), 2.09 – 1.92 (m, 3H, H-12, H-7 and H-15), 1.68 – 1.37 (m,
6H, H-7', H-14, H-8, H-12', H-11' and H-15'), 0.91 (s, 3H, H-18). 13C{1H} NMR (126 MHz,
CDCl3):  221.1 (C-17), 157.7 (C-3), 137.9 (C-5), 132.1 (C-10), 126.4 (C-1), 114.0 (C-4), 111.7 (C-
2), 55.3 (C-19), 50.5 (C-14), 48.1 (C-13), 44.1 (C-9), 38.5 (C-8), 36.0 (C-16), 31.7 (C-12), 29.8 (C-
6), 26.7 (C-7), 26.0 (C-11), 21.7 (C-15), 14.0 (C-18).
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General procedure for the synthesis of estra-1,3,5(11)-trien-3-ol (14) and estra-1,3,5(10)-trien-
3-yl acetate (16).To a solution of 0.51 g of KOH (9.25 mmol) in 3.5 ml of diethylene glycol was
added a solution of 0.5 g of estrone (1.85 mmol) in butanol and 0.28 g of hydrazine hydrate (5.6
mmol). After refluxing the reaction mixture for about 0.5 h the mixture water-butanol was drained
from the condenser and the temperature allowed rising to 200 °C while refluxing was continued for
additional 2 hr. Then, the reaction mixture was cooled, diluted with water and poured slowly into 2
ml of 6 N HCl solution. An amorphous solid separated from the solution which was filtered,
washed with cold water and finally, purified by flash chromatography on silica gel with hexane and
ethyl acetate mixtures to give compound 15. Acetylation of compound 15 with acetic anhydride in
pyridine was performed by the procedure previously described giving compound 16 as a white solid
after purification by flash chromatography on silica gel with hexane and ethyl acetate mixtures.
Estra-1,3,5(10)-trien-3-ol (15). White solid (0.45 g, 91%). M.p.: 134 - 135ºC (lit. 134 -
134.5ºC25a).1H NMR (500 MHz, CDCl3):δ 7.17 (d, J=8.38 Hz, 1H, H-1), 6.63 (dd, J= 2.79 and 8.42
Hz, 1H, H-2), 5.57 (d, J=2.61 Hz, 1H, H-4), 2.77-2.89 (m, 2H, H-6), 2.16-2.30 (m, 2H), 1.05-1.94
13
(m, 13H), 0.75 (s, 3H, H-18). C{1H}NMR (126 MHz, CDCl3):δ 153.2 (C-3), 138.5 (C-5), 133.4
(C-10), 126.7 (C-1), 115.4 (C-4), 112.7 (C-2), 53.7 (C-14), 44.2 (C-9), 41.2 (C-13), 40.6 (C-17),
39.3 (C-8), 38.9 (C-12) , 29.9 (C-6), 28.2 (C-7), 26.9 (C-11) , 25.4 (C-15). 20.7 (C-16). 17.7 (C-18).
Estra-1,3,5(10)-trien-3-yl acetate (16). White solid (0.46 g, 88%). M.p.: 109-110ºC (lit. 104 -
105ºC29).1H NMR (500 MHz, CDCl3):δ 7.32 – 7.28 (m, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 6.79
(dd, J = 2.4, 1.1 Hz, 1H), 2.93-2.80 (m, 2H, H-6), 2.31 – 2.20 (m, 2H), 2.28 (s, 3H, H-20, CH3),
1.11-1.96 (m, 13H), 0.74 (s, 3H, H-18).13C{1H} NMR (126 MHz, CDCl3):δ 170.0 (C-19), 148.4 (C-
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3), 138.6 (C-5), 138.5 (C-10), 126.6 (C-1), 121.6 (C-4), 118.6 (C-2), 53.7 (C-14), 44.3 (C-9), 41.1
(C-13), 40.6 (C-17), 38.9 (C-12 and 8), 29.8 (C-6), 28.0 (C-7), 26.7 (C-11), 25.4 (C-15), 21.3 (C-
20), 20.7 (C-16), 17.7 (C-18).
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General procedure for the synthesis of (8R,9S,13S,14S)-13-methyl-6,7,8,9,11,12,13,14,15,16-
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decahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-3-ol
(8R,9S,13S,14S)-13-methyl-6,7,8,9,11,12,13,14,15,16-
(19)
and
decahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-3-yl acetate (20). To
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suspension of estrone (0.33 g, 1.12mmol) in triethylorthoformate (3 ml, 18 mmol) and ethylene
glycol (0.2 ml, 3.7 mmol), a catalytic amount of p-TsOH was added, and the mixture was gently
heated at 70°C until the suspension became a clear solution (1 h). The warm reaction mixture was
then poured into a saturated solution of sodium bicarbonate. A white solid separated from the
reaction solution which was filtered off, washed with water and dried in the air. The acetylation
reaction of compound 19 was carried out with acetic anhydride in pyridine according to the
procedure previously described and, after recrystallization of the white solid residue from methanol,
compound 20 was obtained.
(8R,9S,13S,14S)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-
17,2'-[1,3]dioxolan]-3-ol (19). White solid (0.32 g; 90%). M.p.: 183 - 185ºC (lit. 180 - 181ºC30).1H
NMR (500 MHz, CDCl3):δ 7.15 (d, J= 8.35 Hz, 1H, H-1), 6.62 (dd, J= 8.35 y 2.85 Hz, 1H, H-2),
6.56 (d, J= 2.71 Hz, 1H, H-4), 4.97 (s, 1H, OH-3), 3.99 - 3.87 (m, 4H, OCH2CH2O), 2.86 - 2.76 (m,
2H, H-6 and H-6'), 2.30 (m, 1H), 2.21 (td, J = 11.1 and 4.2 Hz, 1H), 2.03 (ddd, J=2.98, 11.65 and
14.27 Hz, 1H), 1.90-1.73 (m, 4H), 1.63 -1.23 (m, 6H), 0.88 (s, 3H, H-18).13C{1H} NMR (126
MHz,CDCl3):δ 153.5 (C-3), 138.4 (C-5), 132.8 (C-10), 126.6 (C-1), 119.6 (C-17), 115.4 (C-4),
112.8 (C-2), 65.4 y 64.7 (OCH2CH2O), 49.5 (C-14), 46.3 (C-13), 43.7 (C-9), 39.2 (C-8), 34.4 (C-
16), 30.9 (C-12), 29.8 (C-6), 27.1 (C-7), 26.3 (C-11), 22.5 (C-15), 14.5 (C-18).
(8R,9S,13S,14S)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-
17,2'-[1,3]dioxolan]-3-yl acetate (20). White crystalline solid (0.30 g, 0.84 mmol, 83%), mp 250 -
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251ºC (lit. 146 - 248ºC29). H RMN (500 MHz, CDCl3):δ 7.28 (dd, J = 8.5 Hz, 1.1 Hz, 1H, H-1),
6.84 (dd, J = 8.5, 2.6 Hz, 1H, H-2), 6.78 (d, J = 2.50 Hz, 1H, H-4), 3.99 – 3.86 (m, 4H,
OCH2CH2O), 2.89 – 2.82 (m, 2H, H-6 y H-6'), 2.35 - 2.24 (ddt, J = 11.1, 4.4, 2.3 Hz, 2H), 2.28 (s,
3H, H-20), 2.03 (ddd, J = 14.1, 11.4, 2.9 Hz, 1H), 1.93 – 1.73 (m, 4H), 1.66 - 1.60 (m, 1H), 1.57 –
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1.29 (m, 5H), 0.88 (d, J = 0.7 Hz, 3H, H-18). C{1H} RMN (126 MHz, CDCl3):δ 167.0 (C-19),
148.5 (C-3), 138.4 (C-5), 138.2 (C-10), 126.5 (C-1), 121.6 (C-4), 119.5 (C-17), 118.6 (C-2),
65.4and 64.7 (OCH2CH2O), 49.5 (C-14), 46.2 (C-13), 43.9 (C-9), 38.8 (C-8), 34.3 (C-16), 30.8 (C-
12), 29.8 (C-6), 26.9 (C-7), 26.1 (C-11), 22.5 (C-15), 21.3 (C-20), 14.4 (C-18).
Photoirradiations
General procedure for the irradiations of 3-acyl estrone derivatives. Stock solutions of esters
(1, 2, 10, 16and 20; 0.106 mmol) were prepared in different organic media (250 mL). The
photoirradiations of the esters were carried out as follow: i) analytical scale: a 2 mL aliquot of
solution was placed in a stoppered 3 mL quartz cell and deaerated with argon for 20 min; ii)
preparative scale: a 65 mL aliquot was placed in a stoppered 100 mL Erlenmeyer quartz flask and
deaerated with argon for 30 min. The quartz cell as well as the Erlenmeyer quartz flask was placed
in a home-made optical bench provided with eight lamps. In all the experiments the solutions of the
esters were stirred during the irradiation process. Irradiations with exc= 310 nm were carried out
with four phosphorous coated lamps (HelioQuartz, each of 18 Watts) that give a nearly parallel
beam at 310 nm. Irradiations with exc= 254 nm were carried with eight germicide lamps (Philips,
each of 20 Watts). The progress of the reaction was monitored by three different methods: (i) UV-
visible spectroscopy; (ii) TLC [eluent: hexane-ethyl acetate (8: 2 v/v); spots were visualized with
UV light (254 and 366 nm) and with cerium molybdate stain (Hanessian’s stain)] and (iii) 1HNMR
spectroscopy. In order to isolate, purify and characterize the photoproducts, preparative photolysis
(preparative scale) was conducted according to the following procedure. A solution of estrone
derivative (0.106 mol) in cyclohexane (65 mL) was placed in a stoppered Erlenmeyer quartz flask
and was irradiated with stirring under N2 atmosphere employing the optical bench above described.
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monitored by TLC and HNMR spectroscopy. When total conversion of the starting material was
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reached, the photolyzed solution was evaporated carefully to dryness under vacuum. The yellowish
solid residue obtained was worked up by silica gel column chromatography (eluent: hexane 100%
followed by hexane-ethyl acetate mixtures). From the eluted fractions, the photoproducts were
isolated and characterized by mean of physical and spectroscopic methods.
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2-Acetyl-3-hydroxyestra-1,3,5(10)-trien-17-one (3).White solid (0.018 g, 17%). M. p.: 162 - 163ºC
(lit. 160-162ºC31).1H NMR (500 MHz, CDCl3 ):δ 12.04 (s, 1H, OH), 7.60 (d, J = 1.3 Hz, 1H, H-1),
6.70 (s, 1H, H-4), 2.97 – 2.83 (m, 2H, H-6), 2.60 (s, 3H, H-21), 2.52 (dd, J = 19.0, 8.7 Hz, 1H, H-
16), 2.44 – 2.39 (m, 1H, H-11), 2.24 (td, J = 10.7, 4.3 Hz, 1H, H-11), 2.15 (dt, J = 18.9, 8.9 Hz, 1H,
H-16'), 2.10 – 1.97 (m; 3H; H-12, H-7 and H-15), 1.66 – 1.41 (m; 6H; H-7', H-14, H-8, H-12', H-11'
y H-15'), 0.92 (s, 3H, H-18). 13C{1H} NMR (126 MHz, CDCl3):δ 220,9 (C-17); 204,1 (C-20); 160,3
(C-3); 147,0 (C-10); 131,0 (C-5); 127,4 (C-1); 118,0 (C-2); 117,8 (C-4); 50,5 (C-14); 48,0 (C-13);
43,7 (C-9); 38,2 (C-8); 35,9 (C-16); 31,6 (C-12); 29,9 (C-6); 26,6 (C-21); 26,3 (C-7); 26,1 (C-11);
21,7 (C-15); 13.9 (C-18).
4-Acetyl-3-hydroxyestra-1,3,5(10)-trien-17-one (4). Pale yellow solid (0.026 g, 25%). M.p.: 195 -
196ºC. 1H NMR (500 MHz, CDCl3):δ 10.45 (s, 1H, H-19), 7.34 (d, J= 8.80 Hz, 1H, H-1), 6.81 (d,
J= 8.80 Hz, 1H, H-2), 3.16 - 3.09 (m, 1H, H-6), 2.94 (ddd, J = 16.7, 5.6, 2.9 Hz, 1H, H-6'), 2.63 (s,
3H, H-21), 2.52 (dd, J= 18.90 y 9.16 Hz, 1H, H-16), 2.38 - 2.34 (m, 1H, H-11), 2.27 - 2.23 (m, 1H,
H-9), 2.16 (dt, J = 19.0, 8.9 Hz, 1H, H-16'), 2.08-2.03 (m, 2H, H-7, H-15), 1.98 - 1.96 (m, 1H, H-
12), 1.69 - 1.47 (m, 5H, H-14, H-15', H-8, H-12', H-11'), 1.44 - 1.36 (m, 1H, H-7'), 0.93 (s, 3H, H-
18). 13C{1H} NMR (126 MHz, CDCl3):δ 220.7 (C-17), 206.8 (C-20), 157.8 (C-3), 136.8 (C-5),
131.8 (C-10), 131.7 (C-1), 123.8 (C-4), 115.9 (C-2), 50.4 (C-14), 48.2 (C-13), 44.7 (C-9), 37.9 (C-
8), 36.0 (C-16), 33.5 (C-21), 31.8 (C-12), 30.1 (C-6), 26.4 (C-11), 26.3 (C-7), 21.6 (C-15), 14.1 (C-
+
18). HMRS ESI [M + H]+Calcd for C20H25O3 313.1798, found 313.1804.
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(13)-2-Acetyl-3-hydroxyestra-1,3,5(10)-trien-17-one (6). White solid (0.015 g, 17% ). M.p.: 160-
163ºC. 1H NMR (500 MHz, CDCl3 ):δ 12.03 (s, 1H, OH), 7.58 (s, 1H, H-1), 6.68 (s, 1H, H-4), 2.89
– 2.80 (m, 2H, H-6), 2.59 (s, 3H, H-21), 2.43 – 2.21 (m, 4H, H-16, H-12, H-9 and H-11), 2.20 –
2.09 (m, 3H, H-16’, H-7 and H-15), 1.98 – 1.92 (m, 1H, H-15’), 1.74 – 1.79 (m, 1H, H-14), 1.49 –
1.37 (m, 2H, H-12’ and H-7’), 1.07 (s, 3H, H-18), 1.04 – 0.99 (m, 1H, H-11’), 0.95 – 0.89 (m, 1H,
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H-8). C{1H} NMR (126 MHz, CDCl3):δ 221.6 (C-17), 204.2 (C-20), 160.2 (C-3), 147.3 (C-10),
131.1 (C-5), 127.9 (C-1), 118.2 (C-2), 117.5 (C-4), 50.3 (C-13), 49.5 (C-14), 41.8 (C-9), 41.3 (C-
8), 33.6 (C-16), 32.2 (C-12), 30.2 (C-6), 28.3 (C-7), 28.3 (C-11), 26.7 (C-21), 25.2 (C-18), 21.2 (C-
+
15).HMRS ESI [M + H]+Calcd for C20H25O3 313.1798, found 313.1806.
2-benzoyl-3-hydroxyestra-1,3,5(10)-trien-17-one (7). White solid (0.093 g, 62%). M.p.: 188-190ºC.
1H RMN (500 MHz. CDCl3):δ 11.87 (s, 1H, H-19), 7.67 (d, J = 6.96 Hz, 2H, H-22), 7.59 (dd, J =
7.49 and 7.35 Hz, 1H, H-24), 7.52 (dd, J = 7.77 and 7.35 Hz, 2H, H-23), 7.49 (s, 1H, H-1), 6.81 (sa,
1H, H-4), 3.00 - 2.89 (m, 2H, H-6), 2.50 (dd, J= 8.7, 19 Hz, 1H, H-16), 2.21 - 2.10 (m, 3H, H-9, H-
16 and H-11), 2.08 - 2.00 (m, 2H, H-15 and H-7), 1.92 - 1.86 (m, 1H, H-12), 1.67 - 1.54 (m, 2H, H-
15' and H-8), 1.51 - 1.38 (m, 4H, H-14, H-11', H-7' and H-12'), 0.90 (s, 3H, H-18). 13C{1H} RMN
(126 MHz. CDCl3):δ 220.7 (C-17), 201.3 (C-20), 161.2 (C-3), 146.9 (C-10), 138.3 (C-21), 131.9
(C-24), 130.8 (C-5), 130.6 (C-1), 129.2 (C-22), 128.5 (C-23), 117.8 (C-4), 117.4 (C-2), 50.5 (C-14),
48.0 (C-13), 43.7 (C-9), 38.3 (C-8), 35.9 (C-16), 31.5 (C-12), 30.0 (C-6), 26.3 (C-7), 25.8 (C-11),
+
21.7 (C-15), 13.9 (C-18).HMRS ESI [M + H]+Calcd for C25H27O3 375.1955, found 375.1959.
4-Benzoyl-3-hydroxyestra-1,3,5(10)-trien-17-one (8). The NMR spectra showed a mixture of two
conformers, which are expected to originate from de rotation of the benzoyl group. Pale yellowish
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solid (0.028 g, 19%).M.p.: 148 - 150ºC. The data belongs to the major conformer. H NMR (500
MHz, CDCl3):δ 7.80 (d, J= 6.9 Hz, 1H, H-22), 7.59 (t, 1H, H-24), 7.47 (t. J=7.8 Hz, 1H, H-23),
7.31 (d, J=8.4 Hz, 1H, H-1), 6.82 (d, J=8.5 Hz, 1H, H-2), 2.57 - 2.43 (m, 3H, H-6 and H-16), 2.41 -
2.33 (m, 1H, H-12), 2.23 (td, J= 4.0 and 10.4 Hz, 1H, H-9), 2.11 (dt, J= 8.8, 19.3 Hz, 1H, H-16),
2.03 - 1.92 (m, 2H, H-12 and H-15), 1.83 - 1.74 (m, 1H, H-7), 1.63 - 1.43 (m, 5H, H-14, H-11, H-
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