Synthesis of trifluoromethyl cyclohexyl, cyclohexenyl and aryl compounds via stepwise Robinson annulation

Article abstract of DOI:10.1039/c0ob00518e

The diketone 2-fluoro-2-(trifluoromethyl)-1-phenylhexane-1,5-dione 3 was synthesized by a Mukaiyama Michael type reaction from the corresponding tetrafluoroenol silyl ether prepared from pentafluoropropiophenone. This diketone was treated under basic cond

Full text of DOI:10.1039/c0ob00518e

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PAPER
Synthesis of trifluoromethyl cyclohexyl, cyclohexenyl and aryl compounds via
stepwise Robinson annulation†‡
Fabien Massicot,a Alex Mor Iriarte,a Thierry Brigaud,b Aure´lien Lebruna and Charles Portella*a
Received 30th July 2010, Accepted 22nd September 2010
DOI: 10.1039/c0ob00518e
The diketone 2-fluoro-2-(trifluoromethyl)-1-phenylhexane-1,5-dione 3 was synthesized by a
Mukaiyama Michael type reaction from the corresponding tetrafluoroenol silyl ether prepared from
pentafluoropropiophenone. This diketone was treated under basic conditions and was converted,
depending on the stoichiometry of the base, into the surprisingly stable ketol 4-fluoro-4-
(trifluoromethyl)-3-hydroxy-3-phenylcyclohexanone 4 as a single diastereomer (catalytic KOH) or to
the biphenylol 6-(trifluoromethyl)biphenyl-3-ol (excess KOH, THF) 5. Solvolysis of the trifluoromethyl
group (anionic activation) occurred using excess KOH in alcohol. The corresponding cyclohexenone
derivative 7, the usual product of Robinson annulation, might be prepared in good yield via mesylation
of the ketol. Thus various unprecedented fluorinated cyclohexane and aromatic derivatives were
achieved in a few steps from the commercially available pentafluoropropiophenone.
trifluoromethyl(trimethyl)silane;2 basic treatment of the interme-
Introduction
diate 1,5-diketone yielded either of the cyclic products depending
Several years ago we reported the regioselective synthesis of
on the base concentration. Another feature of that work was
fluorocyclohexenones and fluorophenols by a process beginning
the control of the regioselectivity, in case of aliphatic derivatives,
by Mukaiyama Michael reaction from difluoroenol silyl ether
by the effect of fluorine which activate enolate formation in its
(Scheme 1).1 The latter was generated in situ from acylsilane and
vicinity.1 We considered that a similar methodology could apply
to the trifluoromethyl (TFM) series, and would lead to substituted
trifluoromethyl phenols as final products. To the best of our
knowledge, 1,5-diketones have not been used so far as possible
building blocks for their preparation.3 TFM phenols and their
derivatives are compounds of interest both as bioactive species and
as synthetic intermediates. The emblematic compound containing
a TFM phenoxy moiety is the well known antidepressant drug
R
fluoxetine (Prozacꢀ).4 On the other hand, a TFM group in ortho
or para position of phenols allows carboxylic functionalization
through quinone methides, according to the anionically activation
methodology.5
Scheme
1
Reported procedure for the synthesis of difluorocyclo-
hexenones and fluorophenols.1
Results and discussion
Our attempt to prepare the requisite tetrafluoroenol silyl ether
2 from benzoylsilane and C2F5TMS, according to our method,2
failed. Then we have applied the Mg-promoted reductive
defluorinative-silylation of pentafluoropropiophenone 1 proposed
by Uneyama.6 Perfluoroalkyl phenones may be prepared using
condensation of an organometallic reagent on a perfluorocar-
boxylic acid derivative.7 The condensation of pentafluoroethyl
lithium with an alkyl benzoate8 was also reported to prepare
phenone 1. Inspired by the method consisting of addition of
CF3TMS onto an ester to prepare TFM ketones proposed by
Prakash then Shreeve,9 we have adapted the latter to prepare
aUniversite´ de Reims-Champagne-Ardenne, Institut de Chimie Mole´culaire
de Reims, UMR CNRS 6229, UFR Sciences, BP 1039, 51687, Reims cedex
2, France. E-mail: charles.portella@univ-reims.fr; Fax: +33 326 913166;
Tel: +33 326 913234
bCurrent address: Universite´ de Cergy-Pontoise, Laboratoire “Synthe`se
Organique Se´lective et Chimie bioOrganique “(SOSCO), 5 Mail Gay-
Lussac - Neuville sur Oise, 95031, Cergy-Pontoise cedex, France
† This publication is part of the web themed issue on fluorine chemistry.
‡ Electronic supplementary information (ESI) available: 1H NMR, 13C
NMR and 19F NMR spectra of 3, 4, 5 and 7; HSQC 13C-1H, NOESY
1H-1H and HOESY 19F-1H NMR spectra of compound 4. See DOI:
10.1039/c0ob00518e
600 | Org. Biomol. Chem., 2011, 9, 600–603
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phenone 1. We have found that it was possible to get 1 with a
satisfactory overall yield from methyl benzoate and C2F5TMS
by a solvent free procedure (addition step) and using potassium
fluoride in methanol (desilylation step) (Scheme 2). In addition
phenone 1 is also commercially available.
Scheme 2 Preparation of pentafluoropropiophenone 1.
The procedure proposed by Uneyama gave quantitatively the
desired tetrafluoroenol silyl ether 2. Unfortunately the same
procedure applied to an alkyl(pentafluoroethyl)ketone failed to
give the corresponding enol silyl ether10 so that the study was
continued only with the phenone derivative.
Compound 2 was reacted with methyl(vinyl)ketone (MVK)
under electrophilic activation (Scheme 3). Several conditions were
tested, the results of which are reported in Table 1. Among the
various Lewis acids considered, BF3·OEt2 gave the diketone 3 with
a satisfactory yield as long as an excess was used. Ytterbium tri-
flate, which was a good catalyst for reaction with difuoroenol silyl
ether,1 gave poor results with the higher homologue. Trimethylsilyl
triflate proved to be the best choice, since the highest yield of 3
was achieved using a catalytic amount.
Scheme 4 Reaction of diketone 2 with base.
In contrast to the difluoroanalogue which under basic catalysis
was directly converted to the cyclohexene derivative, the diketone
3 was converted into the stable ketol 4. Several experiments were
attempted to have access to the cyclohexene derivative 7 from 4
(Scheme 5).
Scheme 3 Preparation of diketone 3.
The diketone 3 was then reacted with base in various conditions
(Scheme 4). Under catalytic conditions similar to the one applied
to the difluoroanalogue,1 3 was converted to the cyclic ketol
4, isolated as a stable product and as a single diastereomer
(vide infra). Potassium hydroxide (0.1 equiv.) in MeOH gave the
best results. Using an excess of potassium hydroxide, an aldol
condensation–elimination sequence led directly to an aromatic
compound, the nature of which depends strongly on solvent and
temperature. The trifluoromethyl biphenylol 5 was obtained in a
satisfactory yield in refluxing THF. In refluxing ethanol, 5 was
unstable and the reaction led to the ethyl ester 6, via anionic
activation.5,11
Scheme 5 Reaction of the aldol 3 under various conditions.
Not surprisingly, treatment of 4 with excess potassium hydroxide
in THF led to the phenol 5. Dehydration was attempted under
acidic conditions. Under catalytic conditions, the expected cyclo-
hexenone 7 was obtained in 49% yield along with the precursory
diketone 3 as a retroaldol product. Under stoichiometric condi-
tions, the yield of 7 was improved (59%) but the reaction was
difficult to stop at the cyclohexene stage. The best selectivity and
yield (76%) were achieved using mesylation–elimination.
Table 1 Optimization of the preparation of diketone 3
Lewis Acid
Equiva
Temperature
Reaction time
Yieldb
As mentionned above, the intramolecular aldol reaction was
totally stereoselective. The structure of the ketol was tentatively
deduced from NMR spectra analysis and correlation experiments
(see Supplementary Information). According to this study, the
reaction gave the diastereomer where the fluorine atom and
the phenyl group are in cis relationship (Scheme 6). Such a
stereochemistry is in accordance with a transition state where the
trifluoromethyl and the phenyl groups are in equatorial position,
minimizing the diaxial interactions. The unprecedented structure
of compound 4 deserves a more detailed study of both structural
BF3-Et2O
Yb(OTf)3
TiCl4
2
-35 ◦
rt
C
C
12 h
12 h
7 h
12 h
30 min
30 min
30 min
60 min
60%
—
29%
—
54%
71%
72%
61%
0.5
1.8
0.5
1
0.5
0.2
0.1
-78 ◦
rt
BiCl3
TMSOTf
TMSOTf
TMSOTf
TMSOTf
0 ◦
0 ◦
0 ◦
0 ◦
C
C
C
C
a Reactions realized with 2.5 mmol of 2 and 6 mmol of methylvinylketone
in CH2Cl2. b Isolated yields.
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(PE/EtOAc 95/5) afforded 3 (1.0 g, 72%) as pale yellow oil
(Found: C, 56.6; H, 4.4. Calc. for C13H12O2F4: C, 56.5; H, 4.4%);
dH (250 MHz; CDCl3; Me4Si) 2.1 (3 H, s, CH3), 2.35–2.8 (4 H,
m, 2 ¥ CH2), 7.5 (2 H, t, 3JHH 7.5, phenyl), 7.6 (1 H, t, 3JHH 7.25,
3
phenyl), 8.0 (2 H, d, JHH 7.75, phenyl); dF (235.3 MHz; CDCl3;
CFCl3) -76.9 (3 F, d, 3JFF 7, CF3), -174.2 (1 F, m, CF); dC (62.9
MHz; CDCl3; Me4Si) 25.2 (d, 2JCF 20.6, CH2), 28.7 (CH3), 35.0 (d,
3JCF 2.6, CH2), 98.1 (dq, 1JCF 203.6, 2JCF 29.7, CF), 120.8 (qd, 1JCF
286.1, 2JCF 28.5, CF3), 127.6 (CH phenyl), 128.8 (2 x CH phenyl),
2
128.95 (2 x CH phenyl), 133.2 (CIV phenyl), 192.4 (d, JCF 25.7,
CO), 204.3 (CO).
4-fluoro-4-(trifluoromethyl)-3-hydroxy-3-phenylcyclohexanone (4)
To a solution of 3 (828 mg, 3 mmol) in methanol (20 mL) was
added, under argon, potassium hydroxide (17 mg, 0.3 mmol,
0.1 equiv.). After 2 h at rt, the reaction was concentrated under
reduced pressure and the crude product was diluted in AcOEt.
Mixture was washed with a saturated aqueous solution of NH4Cl
and the combined aqueous layers extracted twice with AcOEt.
Combined organic layers were finally washed with brine, dried
(MgSO4) and concentrated under reduced pressure. Purification
by preparative centrifugal thin-layer chromatography (PE/EtOAc
94/6) and crystallization from AcOEt-PE afforded 4 (695 mg,
84%) as white crystals mp 110–111 ◦C (from EP/EtOAc); (Found:
C, 56.7; H, 4.7. Calc. for C13H12O2F4: C, 56.5; H, 4.4%); dH (250
MHz; CDCl3; Me4Si) 2.4–2.8 (5 H, m, CH2CH2C(O)CHaHb), 3.5
Scheme 6 Stereochemistry of ketol 4.
and conformational aspects, in connection with its interesting
NMR features (see ESI), which will be published shortly.
Conclusions
In summary, the three successive products of annulation
may be prepared selectively from 2-fluoro-2-(trifluoromethyl)-
1-phenylhexane-1,5-dione, applying well adapted reaction con-
ditions. The very starting material of these transformations is
pentafluoropropiophenone, converted quantitatively to the cor-
responding enol silyl ether. Thus fluorinated ketol 4, bearing an
uncommon geminal fluorine/trifluoromethyl motif, cyclo-
hexenone 7 or the trifluoromethyl biphenylol 5 are prepared con-
veniently in a few steps from 1,1,1,2,2-pentafluoropropiophenone.
2
4
(1 H, dd, JHH 14.8, JHF 3.6, C(O)CHaHb), 3.7 (1 H, br s, OH),
7.3–7.4 (3 H, m, phenyl), 7.5–7.55 (2 H, m, phenyl); dF (235.3
MHz; CDCl3; CFCl3) -74.3 (3 F, d, 3JFF 7, CF3), -177.6 (1 F, dm,
3JHF 42.6, CF); dC (62.9 MHz; CDCl3; Me4Si) 26.6 (dq, 2JCF 20.2,
3
3
3JCF 1.4, CFCH2), 34.8 (d, JCF 2.4, COCH2), 51.9 (d, JCF 2.2,
Experimental
C(OH)CH2), 77.9 (d, 2JCF 24.4, C(OH)), 94.5 (dq, 1JCF 190.5, 2JCF
28.9, CF), 123.0 (qd, JCF 286.6, JCF 28.9, CF3), 125.3 (2 x CH
phenyl), 125.4 (2 x CH phenyl), 128.3 (CH phenyl), 140.2 (CIV
phenyl), 207.9 (CO).
1
2
1,1,1,2,2-Pentafluoropropiophenone (1)
To methyl benzoate (10 g, 73 mmol) were added under argon
pentafluoroethyl trimethylsilane (14.4 g, 80.3 mmol, 1.1 equiv.)
then caesium fluoride (661 mg, 4.38 mmol, 0.06 equiv.). After 12 h
at rt, MeOH (50 mL) and potassium fluoride (8.47 g, 146 mmol,
2 equiv.) were added and the reaction mixture was stirred again
during 4 h. The reaction was then concentrated under reduced
pressure and the crude product was diluted in Et2O. Mixture was
washed with water and the combined aqueous layers extracted
twice with Et2O. Combined organic layers were finally washed with
brine, dried (MgSO4) and concentrated under reduced pressure.
Purification by distillation (85 ◦C, 95 mBar) afforded 1 (8.2 g,
6-(trifluoromethyl)biphenyl-3-ol (5)
Method A. To a solution of 4 (276 mg, 1 mmol) in THF
(10 mL) was added potassium hydroxyde (280 mg, 5 mmol,
5 equiv.). After 5 h at reflux, the reaction was quenched with
a saturated aqueous solution of NH4Cl and extracted twice
with AcOEt. The combined organic layers were washed with
brine, dried (MgSO4) and concentrated under reduced pressure.
Purification by preparative centrifugal thin-layer chromatography
(PE/EtOAc 90/10) afforded 5 (140 mg, 59%) as a pale yellow oil.
1
50%) as pale yellow oil which H and 13C NMR spectra were in
agreement with litterature data.8 dF (235.3 MHz; CDCl3; C(F)Cl3)
82.0 (3 F, s, CF3), 115.9 (1 F, s, CF).
Method B. To a solution of 3 (276 mg, 1 mmol) in THF
(10 mL) was added potassium hydroxyde (168 mg, 3 mmol,
3 equiv.). After 12 h at reflux, the reaction was quenched with
a saturated aqueous solution of NH4Cl and extracted twice
with AcOEt. The combined organic layers were washed with
brine, dried (MgSO4) and concentrated under reduced pressure.
Purification by preparative centrifugal thin-layer chromatography
(PE/EtOAc 90/10) afforded 5 (142 mg, 60%) as a pale yellow
oil. dH (250 MHz; CDCl3; Me4Si) 5.6 (1 H, br s, OH), 6.75 (1 H,
m, phenyl), 6.85–6.9 (1 H, m, phenyl), 7.3–7.4 (2 H, m, phenyl),
7.6 (1 H, m, phenyl); dF (235.3 MHz; CDCl3; CFCl3) -56.0 (3
F, s, CF3); dC (62.9 MHz; CDCl3; Me4Si) 113.9 (CH phenyl),
2-fluoro-2-(trifluoromethyl)-1-phenylhexane-1,5-dione (3)
To a solution of 26 (1.39 g, 5 mmol) in CH2Cl2 (10 mL) was added,
at 0 ◦C under argon, methylvinylketone (1 mL, 12 mmol, 2.4 equiv.)
then trimethylsilyl trifluoromethanesulfonate (0.18 mL, 1 mmol,
0.2 equiv.). After 30 min. stirring, the reaction was quenched with
a saturated aqueous solution of NaHCO3 and extracted twice
with CH2Cl2. The combined organic layers were washed with
brine, dried (MgSO4) and concentrated under reduced pressure.
Purification by preparative centrifugal thin-layer chromatography
602 | Org. Biomol. Chem., 2011, 9, 600–603
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2
1
118.8 (CH phenyl), 121.25 (q, JCF 30, CCF3), 124.4 (q, JCF
272, CF3), 127.6 (CH phenyl), 127.8 (CH phenyl), 128.2 (q, 3JCF
5.4, C(CF3)CH), 128.8 (CH phenyl), 139.5 (CIV phenyl), 143.6 (q,
3JCF 1.6, C(Ph)C(CF3)), 157.5 (C(OH)); HRMS (ESI-) Calcd for
[C13H9F3O - H]-: 237.0527; found: 237.0535.
Acknowledgements
We are grateful to CNRS, Universite´ de Reims Champagne-
Ardenne and Erasmus programme (AMI) for supporting this re-
search. We also thank Dominique Harakat for Mass Spectrometry
analysis and Sylvie Lanthony for elemental analyses.
4-fluoro-4-(trifluoromethyl)-3-phenylcyclohex-2-enone (7)
Method A. To a solution of 4 (276 mg, 1 mmol) in THF
(10 mL) was added, at 0 ◦C under argon triethylamine (1.01 g,
10 mmol, 10 equiv.) then methanesulfonyl chloride (572 mg,
5 mmol, 5 equiv.). After 12 h the reaction was quenched with
a saturated aqueous solution of NH4Cl and extracted twice
with AcOEt. The combined organic layers were washed with
brine, dried (MgSO4) and concentrated under reduced pressure.
Purification by preparative centrifugal thin-layer chromatography
(PE/EtOAc 95/5) afforded 7 (196 mg, 76%) as a pale yellow oil.
Notes and references
1 O. Lefebvre, T. Brigaud and C. Portella, Tetrahedron, 1998, 54, 5939–
5948.
2 T. Brigaud, P. Doussot and C. Portella, J. Chem. Soc., Chem. Commun.,
1994, 2117–2118.
3 S. Bu¨ttner, A. Riahi, I. Hussain, M. A. Yawer, M. Lubbe, A. Villinger,
H. Reinke, C. Fischer and P. Langer, Tetrahedron, 2009, 65, 2124–
2135references therein.
4 D. T. Wrong, F. P. Bymaster and E. A. Engleman, Life Sci., 1995, 57,
411–441.
5 (a) A. S. Kiselyov, Mini-Rev. Org. Chem., 2007, 4, 183–189; (b) Gavin
O’Mahony and Andrew K. Pitts, Org. Lett., 2010, 12, 2024–
2027.
6 Y. Nakamura, Y. Ozeki and K. Uneyama, J. Fluorine Chem., 2008, 129,
274–279.
Method B. To methanol (20 mL) cooled down to 0 ◦C under
argon was added slowly acetyl chloride (80 mg, 1 mmol). The
mixture was warmed up to rt, 4 (276 mg, 1 mmol, 1 equiv.) in
methanol (5 mL) was added and the mixture was heated 12 h at
reflux. The reaction was then concentrated under reduced pressure
and the residue diluted in AcOEt. Mixture was washed with a
saturated aqueous solution of Na2CO3 and the combined aqueous
layers extracted twice with AcOEt. Combined organic layers
were finally washed with brine, dried (MgSO4) and concentrated
under reduced pressure. Purification of the residue by preparative
centrifugal thin-layer chromatography (PE/EtOAc 95/5) afford 7
(152 mg, 59%) and 5 (38 mg, 16%) as two pales yellow oils. dH (250
MHz; CDCl3; Me4Si) 2.55–2.7 (4 H, m, 2 ¥ CH2), 6.2 (1 H, s, CH),
7.3 (5 H, m, phenyl); dF (235.3 MHz; CDCl3; CFCl3) -76.5 (3 F, d,
3JFF 10, CF3), -163.8 (1 F, m, CF); dC (62.9 MHz; CDCl3; Me4Si)
7 (a) E. T. McBee, O. R. Pierce and D. D. Meyer, J. Am. Chem. Soc.,
1955, 77, 917–919; (b) K. T. Dishart and R. Levine, J. Am. Chem. Soc.,
1956, 78, 2268–2270; (c) T. Yamazaki, T. Terajima and T. Kawasaki-
Taskasuka, Tetrahedron, 2008, 64, 2419–2424; (d) T. F. McGrath and
R. Levine, J. Am. Chem. Soc., 1956, 78, 3656–3658; (e) L. S. Chen, G. J.
Chen and C. Tamborski, J. Fluorine Chem., 1981, 18, 117–129; (f) P. V.
Ramachandran, A. V. Teodorovic and H. C. Brown, Tetrahedron, 1993,
49, 1725–1738.
8 P. G. Gassman and N. J. O’Reilly, J. Org. Chem., 1987, 52, 2481–2490.
9 (a) J. Wiedemann, T. Heiner, G. Mloston, G. K. S. Prakash and G.
A. Olah, Angew. Chem., Int. Ed., 1998, 37, 820–821; (b) R. P. Singh,
G. Cao, R. L. Kirchmeier and J. M. Shreeve, J. Org. Chem., 1999, 64,
2873–2876.
10 Attempts to prepare the enol silyl ether derived from C11H23COC2F5
by reaction with Mg/TMSCl in various solvents (THF, dichloroethane,
dioxane) at rt or at reflux temperature failed. Using DMF, the hydrolysis
product (C11H23COCHFCF5) was isolated in 70% yield but it proved
difficult to isolate the intermediate silyl ether.
11 (a) D. C. Thompson, K. Perera and R. London, Chem. Biol. In-
teract., 2000, 126, 1–14; (b) K. Ramig, M. Englander, F. Kallashi,
L. Livchits and J. Zhou, Tetrahedron Lett., 2002, 43, 7731–
7734.
2
3
29.2 (d, JCF 22.5, CFCH2), 32.5 (d, JCF 9.1, CFCH2CH2), 91.4
1
2
1
2
(dq, JCF 188.6, JCF 31.8, CF), 122.9 (qd, JCF 286.8, JCF 31.0,
4
CF3), 128.3 (CH phenyl), 128.4 (d, JCF 3.0, CH phenyl), 129.7
(CH phenyl), 134.1 (d, JCF = 5.7 Hz, CH), 135.1 (CIV phenyl),
3
2
4
151.5 (d, JCF = 18.5 Hz, C(Ph)), 195.5 (d, JCF = 2.7 Hz, CO);
HRMS (EI+) Calcd for [C13H10F4O]+: 258.0668; found: 258.0652.
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The Royal Society of Chemistry 2011
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