A new, practical and efficient sulfone-mediated synthesis of trifluoromethyl ketones from alkyl and alkenyl bromides

Article abstract of DOI:10.1016/j.tetlet.2005.03.106

We report herein a new and efficient method to prepare trifluoromethyl ketones from the corresponding bromides through sulfones in good yields.

Full text of DOI:10.1016/j.tetlet.2005.03.106

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3311–3313
A new, practical and efficient sulfone-mediated synthesis of
trifluoromethyl ketones from alkyl and alkenyl bromides
Lourdes Mun˜oz, Esmeralda Rosa, Ma Pilar Bosch and Angel Guerrero*
Department of Biological Organic Chemistry, IIQAB (CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
Received 16 February2005; revised 15 March 2005; accepted 16 March 2005
Available online 5 April 2005
Abstract—We report herein a new and efficient method to prepare trifluoromethyl ketones from the corresponding bromides
through sulfones in good yields.
Ó 2005 Elsevier Ltd. All rights reserved.
Trifluoromethyl ketones (TFMKs) are an important
familyof compounds, which have been shown as potent
inhibitors of a varietyof esterases and proteases.
pyridine and trifluoroacetic anhydride,12 or bymetalla-
tion of alkyl iodides followed by reaction with a fluoro-
acylating agent.13
1
TFMKs act as transition state analogues of the enzyme
and the inhibition arises byformation of an adduct of
tetrahedral geometrybetween the serine residue at the
active site of the enzyme with the highly electrophilic
carbonyl moiety.2 The inhibition studies carried out
with these fluorinated derivatives maybe therapeutically
significant in different areas, for instance arachidonoyl
ethanolamide (anandamide) hydrolysis inhibitors in
processes involving analgesia, mood, nausea, memory,
etc.,3 and renin or angiotensin-converting enzyme inhibi-
tors in hypertension phenomena.4 Therefore, the devel-
opment of new methodologies for introduction of
trifluoromethylated building blocks for the synthesis of
fluorinated bioactive molecules is highlydesirable.
In the context of our project aimed at developing new
inhibitors of the antennal esterases of insects,14 we re-
port herein a practical and efficient procedure to prepare
long chain saturated and unsaturated trifluoromethyl
ketones through the corresponding sulfones (Scheme
1). Onlyone example has been found in the literature
using a similar approach,15 but in this report an over
reduction of the trifluorinated ketone to the mono-
and difluoro analogue was noticed, which makes the
approach impractical for preparative purposes.
In our case, a varietyof sulfones ( 2a–l) were prepared as
possible substrates for the trifluoroacylation reaction.
The sulfones were easilyobtained byreaction of the
corresponding bromides16 with sodium phenyl sulfinate
in anhydrous DMF17 in good to excellent yields (Table
1).
Synthesis of TFMKs has been accomplished by a num-
ber of methods,5 the most recent approaches involving
catalytic aerobic oxidative decarboxylation of a-trifluo-
romethyl-a-hydroxy acids,6 conversion of trifluoroethyl
7
amines byNBS/DBU treatment, Pd-catalyzed cross-
coupling reaction of aryl trifluoroacetates with organo-
boron compounds,8 Ru(II)-catalytic oxidation of
It should be noted that for several unsaturated sub-
strates some isomerization of the double bond was
detected, as has been noticed previouslyin the
preparation of similar substrates even under verymild
conditions.18 Isomerization was minimized (up to 5%
for sulfone 2d, entry4) byrunning the reaction at room
temperature, although longer reaction times (48 h) were
generallyrequired except for alllyic sulfones (0.5–3 h
reaction). In the presence of a phase transfer catalyst
(TEBA) in benzene–water–acetone19 inversion of the
stereochemistryof sulfone 2g was noticed (Z/E 17/83)
(not shown in Table 1), perhaps because the reaction
trifluoromethyl carbinols,9 nucleophilic trifluoromethyl-
10
ation of esters with TMSCF3
or Et3GeNa/
C6H5SCF3,11 reaction of carboxylic acid chlorides with
Keywords: Trifluoromethyl ketones; Sulfones; Fluorinated compounds.
*
Corresponding author. Tel.: +34 93 4006120; fax: +34 93 2045904;
e-mail: agpqob@iiqab.csic.es
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.106

3312
L. Mun˜oz et al. / Tetrahedron Letters 46 (2005) 3311–3313
Al(Hg)
THF/H2O
1. n-BuLi
2. CF3CO2Et
PhSO2Na
F3COC
SO2Ph
R
COCF3
4a-4l
R
Br
R
SO2Ph
2a-2l
SmI2
DMF
1a-1l
R
3a-3l
THF-HMPA
Scheme 1.
Table 1. New synthesis of trifluoromethyl ketones from sulfones
EntryBromide (%) Sulfone (%) lated sAuclfyone (%)
TFMK
Methoda
Compound (%)
1
2
3
4
5
1a, Octyl (—)b
2a (86)
3a (80)
3b (75)
3c (78)
3d (70)
3e (72)
A
A
A
A
A
B
4a (62)
4b (60)
4c (75)
4d (68)
4e (54)
4e (58)
4f (60)
4g (68)
4g (73)
4h (70)
—
1b, Dodecyl (—)b
2b (85)
2c (72)
2d (78)c
2e (60)d
1c, 10-Undecenyl (90)
1d, (Z)-11-Hexadecenyl (97)c
1e, (Z)-3-Hexenyl (86)d
6
7
1f, (E)-5-Octenyl (77)e
1g, (Z)-5-Octenyl (84)f
2f (56)e
2g (69)f
3f (72)
3g (72)
A
A
B
8
1h, (Z)-4-Nonenyl (—)b,g
1i, (E,Z)-2,6-Nonadienyl (76)h
1j, Cinnamyl (—)b,i
2h (75)g
2i (90)h
2j (84)i
2k (96)
21 (73)
3h (70)
—
—
A
9
10
11
12
—
—
1k, 2-Decynyl (98)
1l, 3-Phenylpropyl (—)b
—
3l (77)
A
4l (68)
a Method A: aluminium amalgam in THF–H2O 9:1 at reflux. Method B: SmI2/THF–HMPA at À78 °C.
b The absence of yields means that the compounds were either commercially available or had been previously synthesized in our laboratory.
c Bromide 1d: Z > 99%. Sulfone 2d: Z/E 95/5.
d Bromide 1e: Z > 99%. Sulfone 2e: Z/E 70/30.
e Bromide 1f: Z/E 5/95. Sulfone 2f: Z/E 20/80.
f Bromide 1g: Z/E 95/5. Sulfone 2g: Z/E 90/10.
g Bromide 1h: Z > 99%. Sulfone 2h: Z/E 90/10.
h Bromide 1i: Z/E 90/10. Sulfone 2i: Z/E 90/10.
i Bromide 1j: E > 99%. Sulfone 2j: E > 99%.
system required heating at 80–85 °C for 24 h for com-
plete conversion.
vents have been recommended,22 in our case, however,
sodium amalgam in methanol23 afforded a mixture of
products. Bycontrast, aluminium amalgam in THF–
H2O 9:1 at reflux24 (method A) or SmI2/THF–HMPA25
at À78 °C (method B) were found reliable desulfonyl-
ation reagents to provide the required TFMKs in satis-
factory yields. Remarkably, the processes occurred
leaving the highlyelectrophilic trifluoroacyl group intact
and in no case phenyl sulfinic acid elimination to event-
uallyproduce a,b-unsaturated products was detected. In
addition, the stereomeric purityof the unsaturated
TFMKs 4d–h was identical to that of the corresponding
acyl precursors 3d–h.26 In contrast to KobayashiÕs work,
our procedure does not produce anyover reduction
product perhaps because the portionwise addition of
the aluminium amalgam prepared26 allowed us a better
control of the reaction process (4 h reaction time vs
30–45 min in KobayashiÕs work). In addition and as
Assays for the trifluoroacylation of sulfones were carried
out using compound 2a as model. The best conditions
implied the use of 1.4 equiv of n-BuLi at À78 °C fol-
lowed byimmediate addition of ethyl trifluoroacetate
(10 equiv).20 Lower amounts (5 equiv) of the trifluoro-
acylating agent led to somewhat lower yields. The reac-
tion mixture was allowed to react for 1 h more at
room temperature to furnish 3a in 80% yield. These con-
ditions provided good yields for long chain saturated
(3a,b,l, entries 1, 2, 12) and unsaturated sulfones (3c–h,
entries 3–8), although allylic (2i,j, entries 9, 10) and
propargylic sulfones (2k, entry11) did not react and
the starting material was recovered almost quantita-
tively( Table 1). In this context, other trials to obtain tri-
fluoroacyl sulfones 3i–k under different experimental
conditions (higher temperatures, longer reaction times)
and different solvents (THF, THF–HMPA 1:1) failed.
In addition, replacement of ethyl trifluoroacetate by tri-
fluoroacetic anhydride or (trifluoroacetyl)benzotriazole,
a particularlyefficient acylating agent for allylic sulf-
ones,21 resulted also futile in our hands.
cited, the desulfonylation process can alternatively be car-
26
ried out bySmI treatment with equallygood results.
2
In summary, we have developed an easy, efficient and
scalable procedure for the synthesis of trifluoromethyl
ketones. In contrast to other methods, the process does
not require special fluorination reagents nor anyexpen-
sive catalyst, and therefore it can advantageously be
added to other reported methods for the preparation
of this important class of chemicals.
Removal of the sulfone group is a keyreaction in sul-
fone-mediated chemical synthesis. Although in general,
amalgams with Group IA–IIIA metals in alcoholic sol-

L. Mun˜oz et al. / Tetrahedron Letters 46 (2005) 3311–3313
3313
added and the mixture was allowed to react at rt for an
additional hour. The solvent was evaporated off and the
residue extracted with ether. The combined organic phases
were washed with brine, dried, and the residue chromato-
graphed on silica gel eluting with hexane–ether (95:5) to
give the acylated sulfone 3c (78% yield). 1H NMR
(300 MHz, CDCl3): d 7.81 (dm, J = 8.7 Hz, 2H), 7.74 (tt,
J1 = 7.5 Hz, J2 = 1.2 Hz, 1H), 7.60 (tm, J = 7.2 Hz, 2H);
5.79 (ddt, J1 = 17.1 Hz, J2 = 10.2 Hz, J3 = 6.6 Hz, 1H),
5.01–4.90 (m, 2H), 4.60 (dd, J1 = 10.8 Hz, J2 = 4.2 Hz,
1H), 1.97 (m, 4H), 1.21 (m, 12H) ppm. 13C NMR
(75 MHz, CDCl3): d 185.47 (q, J = 38.3 Hz, COCF3),
139.03, 136.22, 134.93, 129.56, 129.37, 114.62 (q,
J = 291.9 Hz, COCF3), 114.18, 69.90, 33.69, 29.09, 28.93,
28.88, 28.86, 28.75, 28.54, 26.53 ppm. 19F NMR
Acknowledgements
We gratefullyacknowledge CICYT (AGL2003-06599-
C02-01, PTR 1995-0656-OP) and Generalitat de Catalu-
nya (2001SGR-00342) for financial support.
References and notes
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obtained byimmersing Al foil (200 mg, 8.6 g matoms/
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THF/H2O (9:1) (18 mL). The reaction mixture was heated
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yield). 1H NMR (300 MHz, CDCl3):
d 5.80 (ddt,
J1 = 17.1 Hz, J2 = 10.2 Hz, J3 = 6.6 Hz, 1H), 5.02–4.90
(m, 2H), 2.70 (t, J = 7.8 Hz, 2H), 2.03 (m, 2H), 1.65 (m,
2H), 1.28 (m, 12H) ppm. 13C NMR (75 MHz, CDCl3): d
191.58 (q, J = 34.7 Hz, COCF3), 139.12, 115.56 (q,
J = 290.4 Hz, COCF3), 114.09, 36.32, 33.76, 29.33, 29.26,
29.13, 29.04, 28.87, 28.69, 22.33 ppm. 19F NMR
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MS (EI), m/z (%): 250 (M+, 0.96).
Desulfonylation of sulfone 3g. Representative procedure
(method B). Under Ar 0.16 g (0.46 mmol) of acylated
sulfone 3g was dissolved in 23 mL of a 0.1 M solution of
SmI2 in THF (2.3 mmol). The solution was cooled to
À20 °C and then anhydrous HMPA (1.8 mL) was slowly
added. The mixture was stirred for 1 h, left to warm to rt
and the reaction poured into NH4Cl satd solution. The
solvent was removed and the residue extracted with ether.
Conventional work up led to a residue, which was
chromatographed on silica gel to afford pure 4g (70 mg,
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20. Acylation of sulfone 2c: Representative procedure. To a
stirred solution of sulfone 2c (3.93 mmol) dissolved in
5 mL of anhydrous THF was added, under Ar at À78 °C,
3.9 mL of a 1.4 M solution of n-butyllithium in hexane
(5.50 mmol). Then ethyl trifluoroacetate (39.30 mmol) was
1
73%). H NMR (300 MHz, CDCl3): d 5.33 (m, 2H), 2.70
(t, J = 7.5 Hz, 2H), 2.02 (m, 4H), 1.68 (m, 2H), 1.39 (m,
2H), 0.95 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 191.50 (q, J = 34.6 Hz, COCF3), 132.45, 128.00, 115.56
(q, J = 290.7 Hz, COCF3), 36.23, 28.73, 26.57, 21.94,
20.51, 14.28. 19F NMR (282 MHz, CDCl3): d À79.89 (s).
IR (film)
t . Exact mass: calculated for
1765 cmÀ1
C10H15F3O: 208.107500. Found: 208.106787.