Anti-Markovnikov stereoselective addition of bis(trimethylsilyl)octadiene to ketal obtained by unprecedented retro-Claisen condensation of 3-hydroxy-2,4-pentanedione bis-ketal

Article abstract of DOI:10.1016/j.crci.2014.08.003

In the course of the Lewis acid-mediated cycloaddition of 1,8-bis(trimethylsilyl)-2,6-octadiene to bis-ketals, we have observed an unprecedented retro-Claisen condensation from the ketalisation of a 3-hydroxy-2,4-pentadione giving rise to a substituted 2,

Full text of DOI:10.1016/j.crci.2014.08.003

C. R. Chimie 17 (2014) 1165–1168
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Preliminary communication/Communication
Anti-Markovnikov stereoselective addition of
bis(trimethylsilyl)octadiene to ketal obtained by
unprecedented retro-Claisen condensation of
3-hydroxy-2,4-pentanedione bis-ketal
´ ´
´
Addition stereoselective et anti-Markovnikov du
`
´
bis(trimethylsilyl)octadiene sur un cetal obtenu par une condensation
´
inattendue de type retro-Claisen du 3-hydroxy-2,4-pentanedione
´
bis-cetal
*
´
Delphine Moraleda, Nicolas Galy, Paul Bremond, Maurice Santelli
Aix-Marseille Universite´, CNRS, ICR UMR 7273, avenue Escadrille-Normandie-Niemen, 13397 Marseille cedex 20, France
A R T I C L E I N F O
A B S T R A C T
Article history:
In the course of the Lewis acid-mediated cycloaddition of 1,8-bis(trimethylsilyl)-2,6-
octadiene to bis-ketals, we have observed an unprecedented retro-Claisen condensation
from the ketalisation of a 3-hydroxy-2,4-pentadione giving rise to a substituted 2,2,3-
trimethoxybutane and an anti-Markovnikov stereoselective cycloaddition of the 1,8-
bis(trimethylsilyl)-2,6-octadiene to this latter ketal.
Received 10 July 2014
Accepted after revision 18 August 2014
Available online 14 October 2014
Keywords:
´
ß 2014 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Allyl silane
Retro-Claisen condensation
Ketalization
Anti-Markovnikov addition
Cyclization
´
´
R E S U M E
´
Mots cles :
´
´
Au cours de la cycloaddition catalysee par un acide de Lewis du 1,8-bis(trimethylsilyl)-2,6-
Allylsilane
`
´
´
´
octadiene sur un bis-cetal, nous avons observe une condensation inattendue de type retro-
Condensation de re´tro-Claisen
Ce´talisation
´
Claisen au cours de la cetalisation de la 3-hydroxy-2,4-pentadione conduisant au 2,2,3-
trime´thoxybutane et une addition ste´re´ose´lective et anti-Markovnikoff du bis(trime´thyl-
Addition anti-Markovnikoff
Re´actions de cyclisation
`
´
silyl)octadiene sur ce dernier cetal.
´
´
´
´
ß 2014 Academie des sciences. Publie par Elsevier Masson SAS. Tous droits reserves.
*
Corresponding author.
E-mail address: m.santelli@univ-amu.fr (M. Santelli).
http://dx.doi.org/10.1016/j.crci.2014.08.003
1631-0748/ß 2014 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.

1166
D. Moraleda et al. / C. R. Chimie 17 (2014) 1165–1168
Me Me
OH OMe
1. Introduction
MeO
MeO
H(+)
HC(OMe)3
OMe
The addition of the 1,8-bis(trimethylsilyl)-2,6-octa-
diene (Bistro) 1 to various ketals afforded a large variety of
1,1-disubstituted-2,5-divinylcyclopentanes.[1] Some of
them proved to be valuable building blocks for the
synthesis of unnatural steroids[2] or vitamin D derivatives
[3]. Scheme 1 shows a good example of this strategy [4].
Then, we have intended to synthesize 11-dimethyla-
minophenyl steroids analogous of Mifepristone1 (RU 486)
[5], and other similar antiprogestative steroids [6]. For this
8
MeOH
H2SO4
9
O2N
Me
Me Me
OH
Me
OMe
MeO
MeO
OMe
HO
(+)
(+)OMe
OMe
OMe
+
H
10
+ MeOH
O2N
O2N
Me
OMe
Me
OMe
MeO
MeO
O
MeO
MeO
OMe
OMe
TiCl4
Me3Si
SiMe3
+
MeC(OMe)3
+
H(+)
2
1
(Bistro)
O2N
O2N
O
O
11
12
, 68% yield
O
MeO2C
H
Scheme 4. Preparation of 1-(4-nitrophenyl)-2,2,3-trimethoxybutane
R1
R2
12 from 8.
R1 = OMe, R2 = H
R1 = H, R2 = OMe
H
H
3, 55%
4
purpose, it was necessary to synthesize the 1-(4-nitro-
phenyl)butane-2,3-dione diketal 6 from the 1-(4-nitro-
phenyl)butane-2,3-dione 5 (Scheme 2).
Scheme 1. (Color online) Synthesis of unnatural steroids from Bistro
1 and bis-ketal 2.
2. Synthesis of
a-diketone 5
Me2N
O
OH
Only few methods are known to synthesize
a-
diketones [7]. Among them, we chose the ozonolysis
H
"Bistro" strategy
NO2
NO2
H
H
O
TiCl4
Mifepristone♦ (RU-486)
12
or HCl
Cl Ti
..
H
4
.
(+)
..
.
.
.
.
.
MeO
Me
OMe
.
.
Me
O2N
MeO
O2N
MeO
OMe
O
Ketalization
NO2
14
MeO OMe
MeO OMe
MeSi
O
5
6
H
(+)
.
.
.
.
..
Scheme 2. Planned synthesis of
a
-bis-ketal 6.
Me
MeO
OMe
1 (Bistro)
Me3Si
14
NO2
H
NO2
H
Br
O
O
K2CO3
KI
O
O
H(+)
Me3Si
Cl(
Me3Si
+
)
H
H
acetone
70% yield
(+)
OMe
Me
OMe
Me
Me3Si
O2N
O2N
MeO
MeO
15
7
O2N
O
O
O2N
1. K2CO3 - TBAI
CH2Cl2 / acetone
/ H2O
1. MeONa
EtOH
OH
7
H
H
)
Cl(
H
H
2. O3
3. Me2S
2. Oxone®
75% yield
S*
OMe
Me
OMe
Me
O2N
8
Me3Si
R*
(+)
OMe
OMe
51% yield
H
H
16
13
Scheme 3. Synthesis of 3-hydroxy-3-(4-nitrobenzyl)pentane-2,4-dione
8 from acetylacetone.
Scheme 5. Synthesis of diether 13 from 12 and Bistro 1.

D. Moraleda et al. / C. R. Chimie 17 (2014) 1165–1168
1167
Fig. 1. (Color online) ORTEP diagram of compound 13 [22]. The atomic displacement parameters are drawn at the 50% probability level.
of the corresponding
b
-diketone enolates as it appears
induced by the addition of a chloride anion to the second
to be straightforward. In our case, the suitable 3-(4-
nitrobenzyl)pentane-2,4-dione 7 was obtained by alky-
lation of acetylacetone with p-nitrobenzyl bromide [8]
in 70% yield [9]. Surprisingly, ozonolysis of 7 in basic
medium followed by the treatment with dimethylsul-
fide afforded 3-hydroxy-3-(4-nitrobenzyl)pentane-2,4-
silicon atom and only the regioselective delivery of this
proton to the internal carbon atom of the vinyl group (anti-
Markovnikov addition) [19] can explain the stereoselective
formation of 13 (Scheme 5). In 16, the protonated methoxy
group induces a polarization of the vinyl group, thus
increasing the electrophilic properties of the terminal
methylene group and stimulating the anti-Markovnikov
nucleophilic attack from the second allylsilane moiety.
Because of this proximal effect, the primary nascent
carbocation may be promptly captured by the nucleophilic
double bond of the second allylsilane moiety [20].
In previous works, we have reported that the addition
of Bistro 1 to 2,4-pentanedione mono-ethylene ketal
or 2-acetylcyclohexanone mono-ethylene ketal [1b], or
2-methyl-1,3-cyclohexanedione mono-catechol ketal [21],
gave rise to bi- or tricyclic alcohols following a similar
mechanism, but with a regular Markovnikov electrophilic
addition of the carbonyl group to the vinyl group.
dione 8 in 51% yield and not the expected
a-diketone 5
[10]. To confirm the structure of 8, we also prepared it by
treatment of 7 by Oxone1 in basic medium (75% yield)
(Scheme 3) [11,12].
Ketalization of 8 with methanol in the presence of
trimethyl orthoformate and a catalytic amount of sulfuric
acid did not lead to the corresponding bis-ketal 9 but to the
unexpected 1-(4-nitrophenyl)-2,2,3-trimethoxybutane 12
[13]. This compound resulted from a retro-Claisen like
condensation [14,15] in acidic medium. Indeed, after
formation of 9, its protonation allowed a fragmentation
reaction [16] with formation of enol 10 and then
ketalisation of the corresponding tautomeric
yketone 11 to give 12 (Scheme 4).
a-methox-
Acknowledgments
The retro-Claisen condensation is a well-known reac-
tion in basic medium and the usual reagents are metal
alkoxides and recently Lewis acid salts [17], but, to the best
of our knowledge, it was never previously reported in
protic medium.
´
`
D.M. is grateful to the French ‘‘Ministere de l’Education
nationale’’ for a grant, and N.G. is grateful to the CNRS and
´
ˆ
the Region Provence-Alpes-Cote d’Azur for a grant. This
work has been financially supported by the CNRS and the
ˆ
MEN. We thank Dr M. Giorgi (Spectropole, Aix-Marseille
3. Addition of bis(trimethylsilyl)octadiene (Bistro) to
ketal 12
Universite´) for X-ray structure determination of 13.
References and notes
The addition of Bistro 1 to ketal 12 led stereoselectively
to the unexpected product 13 (Scheme 5) [18]. The
structure of 13 was established by spectral data, and then
confirmed by a X-ray crystal structure determination
(Fig. 1) which revealed two stereogenic centers with the
relative configurations R* and S* and the presence of a
trans-disubstituted cyclohexane.
The unexpected formation of 13 could be rationalized
by the following mechanism. First, TiCl4, or adventitious
HCl, led to the stabilized methoxycarbenium ion 14, then, a
stereoselective attack of one allylsilane moiety from
1 afforded 15. Then, a protonation of the methoxy group
by adventitious HCl gave 16. Finally, a cascade reaction
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[12] 3-Hydroxy-3-(4-nitrobenzyl)pentane-2,4-dione (8). Method A: Ozono-
lysis: A 500-mL three-neck flask equipped with a stirring bar, was
charged with anhydrous ethanol (325 mL), sodium methylate (8.75 g,
162 mmol) and 3-(4-nitrobenzyl)pentane-2,4-dione 7 (CAS number:
56699-21-9) (19.1 g, 81.2 mmol). The stirred mixture was cooled to–
60 8C and ozone in oxygen was bubbled through the stirred solution for
4 h. Then the mixture was flushed with argon and dimethylsulfide
(11 mL, 0.15 mol) was added. After stirring at room temperature for 1 h,
tartaric acid (20 g. 0.13 mol) was added and the suspension was stirred
for 1 h, and then filtered and washed with CH2Cl2 and concentrated
under vacuo to give red oil. The crude product was purified by flash-
chromatography on silica gel (petroleum ether/diethyl ether, 70:30) to
give alcohol 8 (10.4 g, 41.4 mmol, 51%). Method B: Enolate oxidation. To
[18] (2R*,3S*)-2,3-Dimethoxy-1-(4-nitrophenyl)-2-(trans-4-vinylcyclohex-
yl)butane (13). In a 100-mL two-neck flask equipped with a magnetic
bar and an outlet of argon, was added anhydrous nitromethane
(1.62 mL, 29.7 mmol) and anhydrous CH2Cl2 (34 mL). The solution
was cooled to–70 8C and TiCl4 (4.20 mL, 37.2 mmol) was added. Then
12 (2.00 g, 7.43 mmol) diluted in anhydrous CH2Cl2 (5 mL) was slowly
added in 0.5 h. The solution was cooled to–90 8C and Bistro 1 (3.80 g,
14.9 mmol) diluted in anhydrous CH2Cl2 (5 mL) was added. The solu-
tion was stirred at–90 8C for 2 h and then overnights at–60 8C. Then, the
solution was poured onto aqueous saturated NH4Cl solution and
extracted with CH2Cl2. The extract was washed until neutrality and
possibly filtrated on Celite1. The solution was dried over MgSO4, and
concentrated under vacuo. The residue was purified by flash chroma-
tography on silica gel, eluting with a gradient of petroleum ether-
diethyl ether (100:0 to 50:50) to give 13 as a yellow solid (1.34 g,
3.86 mmol, 52%). 1H NMR (CDCl3, 300 MHz) 8.07 (d, J = 8.8 Hz, 2H), 7.46
(d, J = 8.8 Hz, 2H), 5.70 (ddd, J = 17.1, 10.4, 6.2 Hz, 1H), 4.91 (br. d,
J = 17.1 Hz, 1H), 4.84 (br. d, J = 10.4 Hz, 1H), 3.40 (q, J = 6.4 Hz, 1H), 3.31
(s, 3H), 3.26 (s, 3H), 3.14 (½AB, J = 14.1 Hz, 1H), 2.88 (½AB, J = 14.1 Hz,
1H), 1.84–1.72 (m, 5H), 1.58-1.48 (m, 2H), 1.15-0.97 (m, 3H), 0.96 (d,
J = 6.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 148.2 (s), 146.3 (s), 144.3 (d),
131.9 (d) (2 C), 122.8 (d) (2 C), 112.0 (t), 82.3 (s), 80.8 (d), 56.4 (q), 51.1
(q), 44.6 (d), 42.0 (d), 36.0 (t), 33.2 (t), 33.1 (t), 27.9 (t), 27.7 (t), 13.9 (q).
a
solution of 7 (4.70 g, 20.0 mmol), K2CO3 (27.6 g, 0.20 mol), and
tetrabutylammonium iodide (1.48 g, 4.0 mmol) in CH2Cl2, acetone,
and water (1/1/1, 600 mL) stirred at 0 8C was added Oxone1 (74 g,
0.12 mol) in water (600 mL) over 30 min. After stirring at 0 8C for 3 h,
the mixture was extracted with CH2Cl2. The organic phase was dried
over MgSO4, filtrated, and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (petroleum ether/diethyl
ether, 50:50) to give 8 (3.76 g, 15.0 mmol, 75%). 1H NMR (CDCl3,
300 MHz) 8.07 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 4.76 (s, 1H),
3.32 (s, 2H), 2.18 (s, 6H); 13C NMR (CDCl3, 75 MHz) d 206.1 (s)(2 C),
147.3 (s), 142.4 (s), 131.2 (d)(2 C), 123.4 (d)(2 C), 90.7 (s), 41.3 (t), 25.5
(q)(2 C). C12H13NO5 (251.24): C 57.37, H 5.22; found C 57.42, H 5.28.
[13] 1-(4-Nitrophenyl)-2,2,3-trimethoxybutane (12). A 250-mL round-bot-
tomed flask equipped with a stirring bar, was charged with anhydrous
C20H29NO4 (347.45): C 69.14, H 8.41; found C 69.08, H 8.38.
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& Sons, New York, 2013, p. 874.
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Jouannetaud, S. Thibaudeau, Chem. Commun (2012) 5877–5879;
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(2005) 2505–2508 [For an anti-Markovnikov addition products involv-
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mentary crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.htm-
l.[or from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: internat +44 1223 336 033; or e mail:
deposit@ccdc cam ac uk].
methanol (42 mL), trimethyl orthoformate (84 mL),
8 (4.40 g,
17.5 mmol) and conc. sulfuric acid (0.40 mL, 7.5 mmol). The mixture
was stirred at reflux for 10 h. Then, a saturated aqueous solution of
NaHCO3 was added and after usual work-up, the mixture was concen-
trated under vacuo and the crude product was purified by flash chro-
matography on silica gel (petroleum ether-diethyl ether, 70:30) to give
12 (3.22 g, 12.0 mmol, 68%). 1H NMR (CDCl3, 300 MHz) 8.07 (d,
J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 3.32 (q, J = 6.5 Hz, 1H), 3.27 (s,
3H), 3.25 (s, 3H), 3.24 (s, 3H), 3.14 (½AB, J = 14.2 Hz, 1H), 3.0 (½AB,