Synthesis of 24-phenyl-24-oxo steroids derived from bile acids by palladium-catalyzed cross coupling with phenylboronic acid. NMR characterization and X-ray structures

Article abstract of DOI:10.1016/j.steroids.2013.07.008

Palladium-catalyzed cross coupling of phenyboronic acid with acetylated bile acids in which the carboxyl functions have been activated by formation of a mixed anhydride with pivalic anhydride afforded moderate to good yield of 24-phenyl-24-oxo-steroids. U

Full text of DOI:10.1016/j.steroids.2013.07.008

Steroids 78 (2013) 1092–1097
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Synthesis of 24-phenyl-24-oxo steroids derived from bile acids
by palladium-catalyzed cross coupling with phenylboronic acid. NMR
characterization and X-ray structures
⇑
Martha C. Mayorquín-Torres, Margarita Romero-Ávila, Marcos Flores-Álamo, Martin A. Iglesias-Arteaga
Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México, DF, México
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2013
Received in revised form 3 July 2013
Accepted 24 July 2013
Available online 2 August 2013
Palladium-catalyzed cross coupling of phenyboronic acid with acetylated bile acids in which the carboxyl
functions have been activated by formation of a mixed anhydride with pivalic anhydride afforded mod-
erate to good yield of 24-phenyl-24-oxo-steroids. Unambiguous assignments of the NMR signals were
made with the aid of combined 1D and 2D NMR techniques. X-ray diffraction studies confirmed the
obtained structures.
Ó 2013 Elsevier Inc All rights reserved.
Keywords:
Bile acids
Phenylboronic acid
Palladium-catalyzed cross coupling
24-Phenyl-24-oxo steroids
1. Introduction
highly toxic cadmium salts (i.e. CdCl2), as well as the moisture-sen-
sitive phenylmagnesium bromide which low functional group tol-
The preparation of ketones is probably one of the most wide-
spread transformations in organic synthesis. In particular the syn-
thesis of phenyl ketones is involved the preparation of a wide
variety of bioactive compounds [1]. Although the preparation of
phenyl ketones can be, in general, achieved by the classical Friedel
Crafts acylation [2] the incompatibility of several functional groups
with the harsh reaction conditions that predominate in Friedel
Craft acylation has prompted the development of alternative meth-
ods mainly based on the reaction of acyl chlorides with organome-
tallic reagents [3].
erance also limits the scope of this methodology. (see Scheme. 1)
Palladium catalyzed cross couplings of carboxylic anhydrides
with arylboronic acids have emerged as a convenient alternative
for the preparation of arylketones [6]. The fact that the starting car-
boxylic anhydride can be generated in situ allowed the design of
attractive one-pot procedures for the preparation of phenylketones
in high to good yields [7]. In addition, the high stability and wide
functional group tolerance of arylboronic acid make this cross cou-
pling a versatile synthetic alternative for the synthesis of aryl
ketones.
The preparation of phenyl ketones derived from steroidal car-
boxylic acid has received limited attention, and to the best of our
knowledge it has been only achieved by treatment of the corre-
sponding acyl chloride with diphenylcadmium. Thus, treatment
of the 3b-acetate of the acyl chloride 2 with diphenylcadmiun
afforded the corresponding phenyl ketone in good yields [4]. Sim-
ilar treatment of the acyl chorides (like 4) derived from formylated
bile and nor-bile acids produced good yields of the corresponding
ketones [5]. The fact all these transformations involve the prepara-
tion and manipulation of acyl chlorides of low stability and limited
tolerance to several functional groups is a considerable disadvan-
tage of this methodology. An additional drawback of this method-
ology is that preparation of diphenylcadmiun implies the usage of
After those facts and in connection with our program on the
synthesis of potentially bioactive steroids we decided to setup ade-
quate conditions for the preparation of a collection of phenyl ke-
tones derived from several bile acids. Herein we report on the
synthesis of 24-phenyl-24-oxo steroids by palladium-catalyzed
cross coupling of bile acids and phenylboronic acid.
During the course of this research, we became aware that no
NMR data is available for this kind of compound. Hence we decided
to carry out the unambiguous assignments of the NMR signals of
the obtained compounds. Additionally, the crystal structures of
two of the obtained steroidal phenyl ketones are provided.
2. Experimental
⇑
The starting acetylated bile acids 5–9 were prepared following
the standard Ac2O/pyr/DMAP procedure. Reactions were
Corresponding author. Tel./fax: +52 (55) 56223899x44417.
E-mail address: martin.iglesias@unam.mx (M.A. Iglesias-Arteaga).
0039-128X/$ - see front matter Ó 2013 Elsevier Inc All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2013.07.008

M.C. Mayorquín-Torres et al. / Steroids 78 (2013) 1092–1097
1093
O
X
O
1, X= OH
ii
89.4%
87.52 % overall
yield steps i and ii
i
2, X= Cl
H3CCOO
H3CCOO
97.9%
2a
4a
O
O
X
3, X= OH
4, X= Cl
ii
i
HCOO
HCOO
95%
H
H
i) SOCl2; ii) (Ph)2Cd
Scheme 1. Synthesis of phenyl ketones derived from steroidal acyl chlorides.
monitored by TLC on ALUGRAMÒ SIL G/UV254 plates from MACHE-
REY-NAGEL. Chromatographic plates were sprayed with a 1% solu-
tion of vanillin in 50% HClO4 and heated until color developed.
Melting points were measured on a Melt-Temp II apparatus. Mass
spectra were registered in a thermo-electron spectrometer model
DFS (Double Focus Sector). NMR spectra were recorded in CDCl3
solution in a Varian INOVA 400 spectrometer using the solvent sig-
nal 7.26 ppm for 1H and 77.00 ppm for 13C as references. (For cop-
ies of the 1H and 13C NMR spectra see supporting information file)
NMR signals assignments in the starting materials 5–9 and the ob-
tained ketones 5a–9a were carried out with the aid of a combina-
tion of 1D and 2D NMR techniques that included 1H, 13C, (1H–1H),
1H–1H COSY, Nuclear Overhauser Effect Spectroscopy (NOESY),
Heteronuclear Single Quantum Correlation (HSQC) and Heteronu-
clear Multiple Bond Correlation (HMBC). All 2D NMR spectra were
recorded using the standard pulse sequences and parameters rec-
ommended by the manufacturer and processed and were pro-
cessed employing the MestreNova NMR processing program [See
http://mestrelab.com/].
2.1. General procedure for cross coupling
Pd(CH3COO)2 (10.05 mg, 0.045 mmol), the acetylated bile acid
(1.00 mmol), pivalic anhydride (418.25 mg, 2.25 mmol dissolved
in 4 mL of THF); H2O (0.067 mL, 67.5 mg, 3.75 mmol); phenylbo-
ronic acid (219 mg, 1.8 mmol dissolved in 2 mL of THF) and
tris(p-metoxyphenyl)phosphine (37.05 mg, 0.105 mmol) were
added in this order to a flask under sonication and the atmosphere
Table 1
Crystal data and structure refinement for compounds 7a and 8a.
Parameters
7a
8a
Empirical formula
Formula weight
Temperature
C
34H48O5
C34H48O5
536.72
293 (2) K
536.72
130 (2) K
Wavelength
Crystal system
Space group
0.71073 Å
Monoclinic
P 21
0.71073 Å
Orthorhombic
P 21 21 21
Unit cell dimensions
a = 13.8480 (13) Å
b = 8.1490 (6) Å
c = 14.3790 (12) Å
b = 114.422 (11)°
1477.4 (2) Å3
2
a = 6.3077 (4) Å
b = 21.1380 (14) Å
c = 23.170 (2) Å
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to theta = 26.06°
Refinement method
Data /restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Largest diff. peak and hole
3089.3 (4) Å3
4
1.206 Mg/m3
0.079 mmꢀ1
584
1.154 Mg/m3
0.076 mmꢀ1
1168
0.593 ꢁ 0.4009 ꢁ 0.1836 mm3
0.5224 ꢁ 0.5164 ꢁ 0.4351 mm3
3.44–26.06°
3.52–26.73°
ꢀ13 6 h 6 17, ꢀ10 6 k 6 9, -17 6 l 6 17
10839
ꢀ7 6 h 6 6, ꢀ26 6 k 6 23, ꢀ29 6 l 6 26
9724
5412 [R(int) = 0.0494]
99.6 %
6190 [R(int) = 0.0351]
99.3 %
Full-matrix least-squares on F2
5412/1/357
Full-matrix least-squares on F2
6190/0/357
1.041
1.011
R1 = 0.0527, wR2 = 0.0846
R1 = 0.0986, wR2 = 0.1035
0.190 and ꢀ0.199 e.Åꢀ3
R1 = 0.0558, wR2 = 0.0961
R1 = 0.1198, wR2 = 0.1197
0.184 and ꢀ0.154 e.Åꢀ3

1094
M.C. Mayorquín-Torres et al. / Steroids 78 (2013) 1092–1097
ipso
O
O
21
18
22
ortho
R3
R3
meta
para
24
20
CH3
CH3
CH3
23
OH
12
11
17
13
H3C
H3C
ortho
O
19
CH3
THF
16
meta
1
4
9
8
14
O
O
2
15
10
7
5
3
6
H3CCOO
R2
Pd (OOCCH3)2
B
R2
H3CCOO
H
H
R1
5a) R1 = R2 = R3 = H; 61 %
R1
OH
OH
5) R1 = R2 = R3 = H;
6) R1 = OOCCH3 R2 = R3 = H
7) R1 = R2 = H, R3 = OOCCH3
8) R1 = R3 = H, R2 = OOCCH3
9) R1 = H, R2 = R3 = OOCCH3
6a) R1 = OOCCH3 R2 = R3 = H; 61 %
7a) R1 = R2 = H, R3 = OOCCH3; 69 %
8a) R1 = R3 = H, R2 = OOCCH3; 83 %
9a) R1 = H, R2 = R3 = OOCCH3; 77%
(4-CH3O-C6H4)3P
Scheme 2. Synthesis of 24-oxo-24-phenyl steroids.
was purged with Ar twice. The reaction mixture was stirred under
Ar at 60 °C until TLC indicated consumption of the starting material
and the solvent was evaporated. In each case the produced dark
solids were applied to a chromatographic column that was eluted
with hexane/ethyl acetate mixtures to afford the desired phenyl
ketone.
acetyl), 0.98 (3H, d, J = 6.3 Hz, H-21), 0.92 (3H, s, H-19), 0.65
(3H, s, H-18). 13C NMR (100 MHz, CDCl3) d(ppm) 35.0 C-1, 26.3
C-2, 74.4 C-3, 32.2 C-4, 41.9 C-5, 27.0 C-6, 26.6 C-7, 35.8 C-8,
40.4 C-9, 34.6 C-10, 20.8 C-11, 40.2 C-12, 42.7 C-13, 56.5 C-14,
24.2 C-15, 28.2 C-16, 56.1 C-17, 12.0 C-18, 23.3 C-19, 35.5 C-20,
18.6 C-21, 30.5 C-22, 35.5 C-23, 201.0 C-24, 21.4 CH3 acetyl,
170.6 C@O acetyl, 137.1 ipso, 132.8 para, 128.5 meta, 128.0 orto.
MS (70 eꢀV) 478 M+ (0.23), 315 (28), 299 (13), 298 (14), 257 (20),
255 (19), 216 (11), 215 (29), 161 (14), 147 (16), 135 (12), 133
(25), 121 (25), 120 (86), 119 (12), 109 (13), 108 (11), 107 (25),
95 (23), 93 (28), 91 (16), 81 (26), 79 (18), 77 (25), 67 (15), 55
(14).
3a-Acetoxy-24-phenyl-5b-cholan-24-one (5a). Yied 61%, Reac-
tion time 48 h. Mp 171.5–172.7 °C (from AcOEt/CH2Cl2). 1H NMR
(400 MHz, CDCl3) d(ppm) 8.02-7.87 (2H, m, H-ortho), 7.57-7.52
(1H, m, H-para), 7.48–7.43 (2H, m, H-meta), 4.71 (1H, tt,
J = 11.4, 4.8 Hz, H-3b), 2.99 (1H, ddd, J = 16.3, 10.2, 5.0 Hz, H-
23a), 2.88 (1H, ddd, J = 15.9, 9.6, 5.9 Hz, H-23b), 2.02 (3H, s, CH3
Fig. 1. H1 NMR spectra of compound 9a.

M.C. Mayorquín-Torres et al. / Steroids 78 (2013) 1092–1097
1095
Table 2
13C NMR signals and shielding effects in the side chain of the obtained ketones.
C-17
C-18
C-20
C-21
C-22
C-23
C-24
ipso
ortho
meta
para
5
56.0
56.1
+0.1
55.9
56.1
+0.2
47.5
47.9
+0.4
55.7
55.9
+0.2
47.3
47.7
+0.4
+0.26
12.1
12.0
ꢀ0.1
12.0
12.0
0
12.4
12.4
0
11.7
11.7
0
12.3
12.3
0
35.3
35.5
+0.2
35.2
35.5
+0.3
34.6
35.0
+0.4
35.2
35.5
+0.3
34.5
34.9
+0.4
+0.32
18.2
18.6
+0.4
18.3
18.6
+0.3
17.4
17.9
+0.5
18.2
18.6
+0.4
17.5
17.9
+0.4
+0.4
30.7
30.5
ꢀ0.2
30.7
30.4
ꢀ0.3
30.6
30.3
ꢀ0.3
30.7
30.4
-0.3
31.0
35.5
+4.5
31.0
35.5
+4.5
30.9
35.6
+4.7
30.9
35.5
+4.6
30.8
35.6
+4.8
+4.62
180.4
201.0
+20.6
179.9
200.9
+21.0
180.0
200.8
+20.8
179.9
200.9
+21.0
179.4
200.8
+21.4
+20.96
–
–
–
–
5a
D
6
6a
D
7
7a
D
8
8a
D
9
137.1
–
–
137.1
–
–
137.1
–
–
137.1
–
–
128.0
–
–
128.0
–
–
128.0
–
–
128.0
–
–
128.5
–
–
128.5
–
–
128.6
–
–
128.5
–
–
132.8
–
–
132.8
–
–
132.9
–
–
132.8
–
–
ppm
ppm
ppm
ppm
ppm
30.5
30.3
ꢀ0.2
ꢀ0.26
9a
D
A
137.0
–
–
128.0
–
–
128.6
–
–
132.9
–
–
ꢀ0.02
P
D
5
ppm
AðaverageÞ ¼
3
a
,6
a
-Diacetoxy-24-phenyl-5b-cholan-24-one (6a). Yield 61%,
2H, H-23), 2.04 (s, 3H, CH3 acetyl), 2.02 (s, 3H, CH3 acetyl), 0.98
(d, J = 6.3 Hz, 3H, H-21), 0.93 (s, 3H, H-19), 0.66 (s, 3H, H-18). 13C
NMR (100 MHz, CDCl3) d(ppm) 34.6 C-1, 26.8 C-2, 74.1 C-3, 34.9
C-4, 40.9 C-5, 31.3 C-6, 71.2 C-7, 37.9 C-8, 34.1 C-9, 34.8 C-10,
20.6 C-11, 39.5 C-12, 42.7 C-13, 50.4 C-14, 23.6 C-15, 28.1 C-16,
55.9 C-17, 11.7 C-18, 22.7 C-19, 35.5 C-20, 18.6 C-21, 30.4 C-22,
35.5 C-23, 200.9 C-24, 21.4, 21.6 CH3 acetyl, 170.4, 170.6 C@O
acetyl, 137.1 ipso, 132.8 para, 128.5 meta, 128.0 ortho. MS (70
eꢀV) 416 (25), 401 (23), 313 (10), 297 (24), 296 (20), 281 (11),
256 (11), 255 (53), 253 (25), 228 (14), 213 (30), 201 (20), 199
(11), 187 (11), 185 (12), 173 (13), 171 (14), 161 (19), 159 (21),
157 (12), 147 (16), 145 (24), 143 (11), 135 (11), 134 (10), 133
(28), 131 (18), 121 (15), 120 (36), 119 (18), 117 (11), 107 (17),
106 (13), 105 (100), 95 (16), 93 (19), 91 (23), 81 (18), 79 (18), 77
(26), 67 (12), 55 (15).
Reaction time 24 h. Mp. 120.6–122.2 °C (from CH2Cl2). 1H NMR
(400 MHz, CDCl3) d(ppm) 7.97-7.92 (m, 2H, H-ortho), 7.55 (t,
J = 7.3 Hz, 1H, H-para), 7.45 (t, J = 7.5 Hz, 2H, H-meta), 5.14 (dt,
J = 12.1, 4.7 Hz, 1H, H-6b), 4.70 (ddd, J = 15.9, 11.0, 4.6 Hz, 1H, H-
3b), 2.98 (ddd, J = 15.2, 10.0, 5.0 Hz, 1H, H-23a), 2.93-2.84 (m, 1H,
H-23b), 2.03 (s, 3H, CH3 acetyl), 2.01 (s, 3H, CH3 acetyl), 0.97 (d,
J = 5.7 Hz, 3H, H-21), 0.97 (s, 3H, H-19), 0.65 (s, 3H, H-19). 13C
NMR (100 MHz, CDCl3) d(ppm) 35.0 C-1, 26.4 C-2, 73.7 C-3, 26.2
C-4, 45.3 C-5, 70.9 C-6, 31.3 C-7, 34.6 C-8, 39.9 C-9, 36.0 C-10,
20.7 C-11, 39.9 C-12, 42.9 C-13, 56.2 C-14, 24.1 C-15, 28.2 C-16,
56.1 C-17, 12.0 C-18, 23.2 C-19, 35.5 C-20, 18.6 C-21, 30.4 C-22,
35.5 C-23, 200.9 C-24, 21.4, 21.4 CH3 acetyl, 170.5, 170.5 C@O acet-
yl, 137.1 ipso, 132.8 para, 128.5 meta, 128.0 ortho. MS (70 eꢀV) 373
(14), 297 (29), 296 (26), 255 (28), 253 (13), 228 (10), 213 (22), 173
(10), 161 (13), 159 (19), 147 (11), 145 (19), 133 (25), 131 (11), 121
(18), 120 (80), 119 (10), 107 (15), 105 (100), 95 (15), 93 (14), 81
(15), 77 (16).
3a,7a,12a-Triacetoxy-24-phenyl-5b-cholan-24-one (9a). Yield
77%, Reaction time 45 h. Mp. 106.2–108.4 °C (from acetone). 1H
NMR (400 MHz, CDCl3) d(ppm) 7.94 (dd, J = 8.4, 1.3 Hz, 2H, H-
ortho), 7.58-7.53 (m, 1H, H-para), 7.49-7.42 (m, 2H, H-meta),
5.11 (m, 1H, H-12b), 4.91 (m, 1H, H-7b), 4.57 (ddd, J = 15.6, 11.3,
4.3 Hz, 1H H-3b), 3.02-2.84 (m, 2H, H-23), 2.14 (m, 3H, CH3 acetyl),
2.08 (s, 3H, CH3 acetyl), 2.05 (s, 3H, CH3 acetyl), 0.92 (s, 3H, H-19),
0.88 (d, J = 6.3 Hz, 3H, H-21), 0.74 (s, 3H, H-18). 13C NMR
(100 MHz, CDCl3) d(ppm) 34.6 C-1, 26.9 C-2, 74.1 C-3, 34.7 C-4,
41.0 C-5, 31.3 C-6, 70.7 C-7, 37.8 C-8, 28.9 C-9, 34.3 C-10, 25.6
C-11, 75.4 C-12, 45.1 C-13, 43.4 C-14, 22.9 C-15, 27.3 C-16,
47.7 C-17, 12.3 C-18, 22.6 C-19, 34.9 C-20, 17.9 C-21, 30.3 C-22,
35.6 C-23, 200.8 C-24, 21.4, 21.5, 21.6 CH3 acetyl, 170–4, 170.5,
170.5 C@O acetyl, 137.0 ipso, 132.9 para, 128.6 meta, 128.0 ortho.
MS (70 eꢀV) 313 (16), 295 (16), 294 (12), 254 (19), 253 (91), 251
(15), 211 (12), 199 (12), 197 (11), 187 (12), 171 (13), 161 (15),
159 (18), 157 (15), 145 (18), 143 (17), 133 (11), 131 (11), 120
(19), 119 (11), 117 (12), 107 (15), 106 (10), 105 (100), 95 (11),
93 (15), 91 (19), 81 (14), 79 (15), 77 (30), 67 (11), 60 (11).
3a,12a-Diacetoxy-24-phenyl-5b-cholan-24-one (7a). Yield 69%,
Reaction time 26 h. Mp. 136.1–137.3 °C (from benzene). 1H NMR
(400 MHz, CDCl3) d(ppm) 7.94 (ddd, J = 8.5, 2.2, 1.2 Hz, 2H, H-
ortho), 7.57-7.52 (m,1H H-para), 7.48-7.42 (m, 2H, H-meta), 5.12-
5.07 (m, 1H, H-12b), 4.69 (ddd, J = 15.9, 11.2, 4.6 Hz, 1H, H-3b),
2.97 (ddd, J = 14.9, 9.9, 4.9 Hz, 1H, H-23a), 2.92 – 2.80 (m, 1H, H-
23b), 2.10 (s, 3H, CH3 acetyl in 12), 2.02 (s, 3H CH3 acetyl in 3),
0.90 (s, 3H, H-19), 0.87 (d, J = 6.3 Hz, 3H, H-21), 0.73 (s, 3H, H-
18). 13C NMR (100 MHz, CDCl3) d(ppm) 34.7 C-1, 26.6 C-2, 74.2
C-3, 32.3 C-4, 41.8 C-5, 27.4 C-6, 25.9 C-7, 35.6 C-8, 34.4 C-9,
34.0 C-10, 26.9 C-11, 75.9 C-12, 45.1 C-13, 49.4 C-14, 23.5 C-15,
25.6 C-16, 47.9 C-17, 12.4 C-18, 23.1 C-19, 35.0 C-20, 17.9 C-21,
30.3 C-22, 35.6 C-23, 200.8 C-24, 21.4, 21.4 CH3 acetyl, 170.5,
170.5 C@O acetyl, 137.1 ipso, 132.9 para, 128.6 meta, 128.0 ortho.
MS (70 eꢀV) 416 (11), 356 (14), 315 (11), 298 (15), 297 (68), 296
(26), 283 (15), 256 (17), 255 (76), 253 (19), 213 (12), 201 (11),
187 (15), 173 (12), 161 (29), 160 (11), 159 (16), 147 (25), 145
(21), 135 (13), 134 (18), 133 (24), 131 (14), 121 (17), 120 (30),
119 (17), 109 (12), 107 (22), 106 (11), 105 (100), 95 (17), 93
(20), 91 (18), 81 (19), 79 (14), 77 (21), 67 (12), 55 (12).
2.2. X-ray crystallography
Crystals of compounds 7a and 8a mounted on glass fiber were
studied with an Oxford Diffraction Gemini ‘‘A’’ diffractometer with
3a,7a-Diacetoxy-24-phenyl-5b-cholan-24-one (8a). Yield 83%,
Reaction time 45 h. Mp. 153.7–154.9 °C (from CH2Cl2). 1H NMR
(400 MHz, CDCl3) d(ppm) 7.97-7.93 (m, 2H, H-ortho), 7.54 (ddd,
J = 6.7, 3.9, 1.3 Hz, 1H, H-para), 7.48-7.42 (m, 2H, H-meta), 4.87
(m, 1H, H-7b), 4.58 (tt, J = 11.4, 4.4 Hz, 1H, H-3b), 3.03-2.83 (m,
a CCD area detector (kMoK = 0.71073 Å, monochromator: graphite)
a
source equipped with a sealed tube X-ray source. Unit cell
constants were determined with a set of 15/3 narrow frame/runs
(1° in
x) scans. A data set consisted of 303 and 127 frames of

1096
M.C. Mayorquín-Torres et al. / Steroids 78 (2013) 1092–1097
7a
8a
Fig. 2. Crystal structures of the 24-oxo-24-phenyl steroids 7a and 8a with the thermal ellipsoids drawn at 50% of probability.
intensity data collected for 7a and 8a respectively with a frame
width of 1° in , a counting time of 5 s/frame, and a crystal-to-
detector distance of 55.00 mm. The double pass method of scan-
ning was used to exclude any noise. The collected frames were
integrated by using an orientation matrix determined from the
narrow frame scans.
in moderate to good yields (Scheme 2). All attempts at producing
the cross coupling employing non acetylated bile acids were
unsuccessful, presumably by consumption of the pivalic anhydride
by reaction with the hydroxyl groups. The adequate conditions
acid for the cross coupling were found to be [Pd(CH3COO)2
0.045 mmol; pivalic anhydride 2.25 mmol; H2O 3.75 mmol; phen-
x
CrysAlisPro and CrysAlis RED software packages [8] were used
for data collection and data integration. Analysis of the integrated
data did not reveal any decay. Final cell constants were determined
by a global refinement of 3034 and 1886 reflections (h < 26.7°) for
7a and 8a respectively. Collected data were corrected for absor-
bance by using Analytical Numeric Absorption Correction [9] using
a multifaceted crystal model based on expressions upon the Laue
symmetry using equivalent reflections. Structure solution and
refinement were carried out with the programs SHELXS97 and
SHELXL97 [10]. Molecular graphics were generated with ORTEP-3
for Windows and the software used to prepare material for publi-
cation was WinGX [11].
Full-matrix least-squares refinement was carried out by mini-
mizing (Fo2– Fc2)2. All non-hydrogen atoms were refined aniso-
tropically. Hydrogen attached to carbon atoms were placed in
geometrically idealized positions and refined as riding on their par-
ent atoms, with C–H = 0.93–1.00 Å with Uiso (H) = 1.2Ueq(C) for aro-
matic, methylene and methyne groups, and Uiso (H) = 1.5 Ueq(C) for
methyl group. Crystal data and experimental details of the struc-
ture determination are listed in Table 1 [12].
ylboronic
acid
1.8 mmol,
tris(p-metoxyphenyl)phosphine
0.105 mmol] ꢁ mmol after a series of iterative experiments in
which the relation of substrate and each reagent were changed.
The introduction of the 24-phenyl-24-oxo moiety can be easily
verified by the presence of the 1H NMR signals associated to the
phenyl group. In addition the signals of the diasterotopic pair of
protons attached to C-23 characterize the NMR spectra of the ob-
tained compounds (see Fig. 1 and Supplementary information file).
The introduction of the 24-phenyl-24-oxo moiety only produces
significant downfield shifts of the signals associated to C-23 and
C-24 compared to those of the starting carboxylic acids (see Table 2
and Supplementary information file). In addition the presence of
the 13C signals associated to the aromatic ring characterizes the
13C NMR spectra of the obtained ketones. The 1H and 13C resonance
signals associated to the functionality present in the steroid frame-
work confirm its integrity.
Finally X-ray studies conducted in monocrystals of compounds
7a and 8a confirmed the obtained structures (see Fig. 2).
4. Conclusion
3. Results and discussion
In situ generation of mixed anhydrides derived from different
acetylated bile acids and pivalic anhydride, followed by treatment
with phenylboronic acid in the presence water, tris(p-metoxyphe-
nyl)-phosphine and Pd(CH3COO)2 as catalyst, produced moderate
to good yields of the corresponding 24-phenyl-24-oxo steroids.
Although the obtained yield are slightly lower than those reported
Reaction of the acetylated bile acids with pivalic anhydride fol-
lowed by palladium-catalyzed cross coupling with phenylboronic
acid in THF, in the presence of tris-(4-methoxyphenyl)-phospine
and water, afforded the corresponding 24-oxo-24-phenyl steroids

M.C. Mayorquín-Torres et al. / Steroids 78 (2013) 1092–1097
1097
for the previously reported acyl chloride-diphenylcadmium meth-
References
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and diphenylcadmium implied in the preceding protocol described
for the preparation of the title compounds.
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Appendix A. Supplementary data
[12] Crystallographic data form compounds have been deposited with the
Cambridge Crystallographic Data Center as supplementary material numbers
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charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. E-
mail:deposit@ccdc.cam.ac.uk.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.steroids.2013.07.
008.