A Convergent Radical Based Route to Trifluoromethyl Ketones and to α,β-Unsaturated Trifluoromethyl Ketones

Article abstract of DOI:10.1021/acs.orglett.5b01344

A convergent synthesis of trifluoromethyl ketones and α,β-unsaturated trifluoromethyl ketones is described, starting with aliphatic iodides and dithiocarbonates (xanthates) and exploiting both the α- and β-fragmentations of a sulfonyl radical. The transfo

Full text of DOI:10.1021/acs.orglett.5b01344

Letter
pubs.acs.org/OrgLett
A Convergent Radical Based Route to Trifluoromethyl Ketones and
to α,β-Unsaturated Trifluoromethyl Ketones
Lucile Anthore and Samir Z. Zard*
̀
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, 91128 Palaiseau, Cedex, France
S
* Supporting Information
ABSTRACT: A convergent synthesis of trifluoromethyl
ketones and α,β-unsaturated trifluoromethyl ketones is
described, starting with aliphatic iodides and dithiocarbonates
(xanthates) and exploiting both the α- and β-fragmentations of
a sulfonyl radical. The transformation initially furnishes the
ketones in a masked enol carbonate form, from which they can
be easily regenerated.
ncorporating fluorine atoms into small molecules can
drastically change their physicochemical properties, meta-
alkylation−decarboxylation process, but their approach requires
a strong base and presents limitations in the substrate scope.17
Some time ago, we devised a simple procedure for converting
a primary or secondary aliphatic carboxylic into the
corresponding trifluoromethyl ketone through reaction with
TFAA and pyridine.18 This method was used to prepare the
two compounds in Figure 1. We also reported an approach
hinging on the intermolecular addition of a trifluoroacetonyl
radical to an alkene.19 This latter route exploits the properties
of the degenerative xanthate transfer, which has emerged as a
powerful enabling tool for C−C bond formation.20 We now
describe yet another strategy allowing access to both
trifluoromethyl ketones and α,β-unsaturated trifluoromethyl
ketones.
I
bolic stability, and binding affinities.1,2 As a subclass,
trifluoromethyl ketones3 and α,β-unsaturated trifluoromethyl
ketones4 have proven particularly useful as enzyme inhibitors5
and as probes in the study of hydrolytic enzymes.6 The hydrate
form of the ketone is stabilized by the strongly electron-
withdrawing CF3− group and acts as a mimic for the
tetrahedral intermediates involved in the hydrolysis of esters
and amides. For instance, trifluoromethyl ketone analog 1 of
arachidonic acid (or ATK for Arachidonyl Trifluoromethyl
Ketone) is a powerful reversible inhibitor of certain human
phospholipases,7 and trifluoromethyl ketone 2 is a potent
histone deacetylase inhibitor (Figure 1).8 Trifluoromethyl
We previously took advantage of both the α- and β-
fragmentations of aliphatic sulfonyl radicals to design a tin-free
allylation and vinylation of dithiocarbonates (xanthates) 3 and
iodides 4, an approach we have now been able to extend to the
formation of enol carbonates of trifluoromethyl ketones
(Scheme 1).21 This convergent route to protected trifluor-
omethyl ketones builds on earlier observations by Fuchs22 and
on a successful preliminary example in our group.23 Thus,
addition of a radical generated from dithiocarbonate 3 or iodide
4 on vinyl alkyl sulfones 3 is followed by β-fragmentation to
give the desired protected trifluoromethyl ketone 7 with
concomitant expulsion of sulfonyl radical 6. The latter evolves
Figure 1. Biologically active trifluoromethyl ketones.
ketones are also valuable precursors for the synthesis of CF3-
substituted heterocycles,9 olefins,10 medicinal substances,11 or
fluorinated analogs of natural products.12
Traditionally, the preparation of trifluoromethyl ketones has
relied on the Friedel−Crafts type addition of trifluoroacetic
anhydride (TFAA) onto electron-rich alkenes and (hetero)-
aromatic nuclei, the monoaddition of organometallic reagents
to ethyl trifluoroacetate, or the oxidation of the corresponding
trifluoromethyl alcohol.13 The synthesis of aliphatic trifluor-
omethyl ketones remains however a challenge. Thus, although
the synthesis of the trifluoromethyl carbinol precurors is well
covered by the addition of CF3TMS (the Ruppert−Prakash
reagent) to aldehydes,14 the oxidation step is slow and requires
either an excess of oxidizing agent15 or strong oxidants with
limited functional group compatibility.16 Qu and co-workers
recently reported the synthesis of trifluoromethyl ketones by an
Scheme 1. Radical Addition to Enol Sulfone 5
Received: May 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01344
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Organic Letters
Letter
by α-scission into one molecule of sulfur dioxide and a methyl
radical 8, which is able to propagate the radical chain (Scheme
1).
Scheme 3. Synthesis of Enol Carbonates 7
Access to vinyl sulfone 5 requires first the synthesis of
trifluoromethyl ketone 9 by treatment of dimethylsulfone with
ethyl trifluoroacetate under basic conditions (Scheme 2). After
Scheme 2. Synthesis of Vinyl Sulfone 5
deleterious effect and prevented the formation of enol
carbonate 7h. Gratifyingly, xanthates leading to the rather
unreactive benzylic radicals nevertheless reacted with reason-
able efficiency, as illustrated by examples 7e and 7f. In all cases,
the reactions gave rise to the enol carbonates as the Z-isomers
with high or complete stereoselectivity, as determined by NMR
spectroscopy.24a,c
The mildly nucleophilic α-acetoxy substituted radicals also
reacted well with the electrophilic vinylating reagent 5. The
requisite precursor xanthates 10 are readily obtained either
directly, by reaction of α-acetoxy chlorides [RCHCl(OAc)] by
potassium O-ethyl xanthate, or indirectly (and more interest-
ingly), by radical addition of a xanthate onto vinyl acetate.25
The underlying idea was to introduce a leaving group in the β-
position in order to later access α,β-unsaturated trifluoromethyl
ketones (see Scheme 7). The radical reaction was in most cases
indeed faster and more efficient than with the first set of
xanthates 3 (Scheme 4). Variously substituted enol carbonates
screening different bases such as n-butyllithium or potassium
tert-butoxide, NaH as a 60% dispersion in oil proved best for
gram-scale synthesis. Intermediate 9 could not be purified on
silica, as only the hydrate form was recovered after column
chromatography. The ketone was therefore directly protected
as its enol carbonate and purified by filtration over silica
previously deactivated by acetone, followed by recrystallization
from Et2O/pentane at −20 °C. These conditions were
optimized to afford 10 g of 5 in 73% overall yield. The
purification by recrystallization is particularly valuable since the
product seems to slowly decompose on silica.
Interestingly, vinyl carbonate 5 was obtained as a single
geometrical isomer. The coupling constant of 4 Hz between the
CF3 carbon and the vinylic hydrogen, measured in the
undecoupled 13C NMR, is characteristic of a Z configuration
(the one drawn in Scheme 2).24 If the reaction temperature is
allowed to rise above 5 °C, the second geometrical isomer starts
forming and can be detected in the crude reaction mixture.
In a preliminary example, the radical vinylation proceeded in
good yield, both in refluxing chlorobenzene and ethyl acetate
(Scheme 2). The reaction was much slower in the latter solvent
and required stoichiometric amounts of a radical initiator. In
refluxing ethyl acetate, the α-scission of sulfonyl radical 6
leading to the unstabilized methyl radical is sluggish and the
chain can thus no longer propagate normally. Also, the use of
di-tert-butyl peroxide (DTBP) over dilauroyl peroxide (DLP) is
more convenient since all its decomposition products are
volatile.
Scheme 4. Synthesis of Enol Carbonates 11
Chlorobenzene was therefore used as the solvent, although
the reaction could also be run at a lower temperature with more
fragile substrates. Olefin 5 is somewhat volatile, and its
continuous addition in excess was sometimes necessary for
complete conversion. By circulating ice-cold water in the
refluxing condenser, only 3 equiv of olefin 5 were needed and
the excess reagent could be easily recovered.
As our olefin is electron-poor, we anticipated that electron-
rich radicals would react better because of polarity matching.
Indeed, xanthates leading radicals with nucleophilic character
reacted efficiently (Scheme 3). Radicals substituted by an
amide-type nitrogen atom are a moderately electron-rich
species and provide access to latent amino trifluoromethyl
ketones 7a−d. The masked 1,3- and 1,2-diamines 7c and 7d are
particularly interesting. In contrast, a trifluoromethyl group on
the radical center negated the electron-donating effect of the
nitrogen and blocked the desired transformation leading to
compound 7i. An electron-withdrawing ketone also had a
11 were thus readily obtained, again as the Z-isomer, even with
complex substrates such as corticosteroid 11i (DLP/refluxing
EtOAc was used in this case).
Iodides 4g and 4j reacted in comparably good yields under
the same conditions (Scheme 5), but the reactions were slightly
slower and less efficient than with dithiocarbonates 3 and,
unexpectedly, the reaction mixtures turned dark in color.
Nevertheless, iodides are interesting substrates since some
iodides are more readily accessible than the corresponding
xanthates. For example, precursor 4j is trivially obtained by a
classical iodolactonization from the unsaturated carboxylic acid.
B
DOI: 10.1021/acs.orglett.5b01344
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Letter
Scheme 5. Enol Carbonates 7 from Iodides
Table 1. Optimization of the Formation of α,β-Unsaturated
Trifluoromethyl Ketones
entry
conditions
time
1 h
yield
a
a
b
c
d
e
f
KI, AcOH, 0.2 M, 110 °C
KI, AcOH, 0.2 M, 150 °C
LiI, AcOH, 0.2 M, 150 °C
LiI, HCO2H, 0.25 M, 150 °C
LiI, TFA, 0.2 M, 110 °C
LiI, TFA, 0.2 M, 150 °C
LiI, AcOH, 0.5 M, 150 °C
−
b
1 h
23%
c
10 min
10 min
5 min
10 min
10 min
−
c
35%
With a convenient access to enol carbonates 7, our next task
was the regeneration of the free trifluoromethyl ketone under
conditions that do not require extensive purification on silica so
as to minimize losses though formation of the hydrate. We first
examined methods previously applied to ordinary enol
carbonates.26 However, enol carbonates 7 proved unusually
resistant to acidic treatment owing to the presence of the
strongly electron-withdrawing trifluoromethyl group. They
were thus not affected by neat formic or trifluoroacetic acid,
or even by aqueous sulfuric acid. Such harsh acidic conditions
would normally destroy ordinary enol carbonates almost
instantly. In contrast, exposure to ethylenediamine at rt cleaved
the enol carbonate and furnished the desired trifluoromethyl
ketones 12 cleanly and without chromatographic purification
(Scheme 6).
a
−
b
−
g
94%
a
b
c
Starting material only. Degradation. Presence of the product and of
a side product.
yield (Table 1, entry b). In the hope of accelerating the reaction
by taking advantage of the greater oxophilicity of lithium
cations, we replaced potassium iodide with lithium iodide. The
desired enone 13g was indeed formed, accompanied by another
more polar side product (Table 1, entry c). Other acid solvents,
such as TFA or formic acid, were also tried in parallel with no
improvement (Table 1, entries d−f). Surmising that the side
product was arising from the addition of adventitious water to
the reactive enone, we concentrated the reaction medium and
indeed found that enone 13g was produced cleanly in high
yield and without chromatographic purification (Table 1, entry
g).
Scheme 6. Deprotection of Enol Carbonates 7
These conditions were applied successfully to enol carbonate
11b, which afforded enone 13b in equally high yield (Scheme
7). Complexation by the lithium cation polarizes the carbonyl
group and encourages attack of the ethyl group by an iodide
anion to generate volatile ethyl iodide and the lithium enol
carbonate 14. Loss of carbon dioxide and lithium acetate finally
furnishes the desired enone (Scheme 7).
In summary, we have established a modular route to
trifluoromethyl enol carbonates starting with either xanthates
or iodides with high functional group tolerance. Depending on
the substrates, the products can then be converted into aliphatic
trifluoromethyl ketones or α,β-unsaturated trifluoromethyl
ketones. In the case of xanthates, the ability to perform first
an intermolecular addition to an alkene allows access to
complex structures quite tedious to attain otherwise. The
present synthesis complements useful previous approaches,
especially in the case of α,β-unsaturated trifluoromethyl ketones
where the number of synthetic routes is more limited.
Enol carbonates 11 containing an allylic acetoxy group were
less robust and degraded under strong acidic conditions.
Furthermore, deprotection of these adducts leads to reactive
α,β-unsaturated trifluoromethyl ketones (see Scheme 7) that
Scheme 7. Synthesis of α,β-Unsaturated Ketones 11
are incompatible with the presence of ethylenediamine. We
therefore had to devise an alternative to the aminolysis better
suited for this particular class. We first attempted a Krapcho-
type dealkylcarboxylation by heating compound 11g in DMSO
in the presence of NaCl.27 Unfortunately, to start detecting
product 13g we had to raise the temperature to above 130 °C
for over 4 h, which caused extensive decomposition.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, full spectroscopic data, and copies of
1H and 13C NMR for all new compounds. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01344.
■
S
This setback led us to examine conditions we previously used
in the synthesis of thiophenes.28 Unfortunately, heating
compound 11g for 1 h at 110 °C with potassium iodide in
acetic acid under microwave irradiation did not induce any
transformation and only the starting material was recovered
(Table 1, entry a). By increasing the temperature to 150 °C, the
desired product was obtained, albeit quite slowly and in modest
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: samir.zard@polytechnique.edu.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b01344
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
J. C.; Ma, S.; Narayanan, B. A.; Nummy, L. J.; Premasiri, A.;
Roschangar, F.; Sarvestani, M.; Shen, S.; Spinelli, E.; Sun, X.;
Varsolona, R. J.; Yee, N.; Brenner, M.; Senanayake, C. H. J. Org.
Chem. 2013, 78, 3616.
ACKNOWLEDGMENTS
We thank Dr. Gilles Ouvry (Galderma) for a preliminary
experiment and Ecole Polytechnique for a scholarship to L.A.
■
(12) Grellepois, F.; Chorki, F.; Crousse, B.; Ourev
Delpon, D.; Begue, J.-P. J. Org. Chem. 2002, 67, 1253.
(13) Creary, X. J. Org. Chem. 1987, 52, 5026.
(14) Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.; Olah,
G. A. Angew. Chem., Int. Ed. 1998, 37, 820.
́
itch, M.; Bonnet-
DEDICATION
́
́
■
This paper is dedicated with respect to the memory of
Professor Marcel Fet
́
izon (Ecole Polytechnique).
(15) Linderman, R. J.; Graves, D. M. J. Org. Chem. 1989, 54, 661.
(16) Kesavan, V.; Bonnet-Delpon, D.; Begue, J.-P.; Srikanth, A.;
́ ́
REFERENCES
■
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
̈
Chandrasekaran, S. Tetrahedron Lett. 2000, 41, 3327.
(17) Yang, D.; Zhou, Y.; Xue, N.; Qu, J. J. Org. Chem. 2013, 78, 4171.
(18) (a) Boivin, J.; Kaim, L. E.; Zard, S. Z. Tetrahedron Lett. 1992, 33,
1285. (b) Boivin, J.; Kaim, L. E.; Zard, S. Z. Tetrahedron 1995, 51,
2573. (c) Reeves, J. T.; Tan, Z.; Fandrick, D. R.; Song, J. J.; Yee, N. K.;
Senanayake, C. H. Org. Synth. 2012, 89, 210.
(b) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071. (c) Fujiwara, T.;
O’Hagan, D. J. Fluorine Chem. 2014, 167, 16. (d) Zhu, W.; Wang, J.;
Wang, S.; Gu, Z.; Acena, J. L.; Izawa, K.; Liu, H.; Soloshonok, V. A. J.
Fluorine Chem. 2014, 167, 37.
(2) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320.
(3) (a) Begue, J.-P.; Bonnet-Delpon, D. Tetrahedron 1991, 47, 3207.
́ ́
(b) Kelly, C. B.; Mercadante, M. A.; Leadbeater, N. E. Chem. Commun.
2013, 49, 11133.
(4) (a) Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G.
Tetrahedron 2007, 63, 7753. (b) Nenajdenko, V.; Sanin, A.; Balenkova,
E. Molecules 1997, 2, 186.
(5) (a) Veale, C. A.; Damewood, J. R., Jr.; Steelman, G. B.; Bryant,
C.; Gomes, B.; Williams, J. J. Med. Chem. 1995, 38, 86. (b) Gelb, M.
H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985, 24, 1813. (c) Shao,
Y.-M.; Yang, W.-B.; Kuo, T.-H.; Tsai, K.-C.; Lin, C.-H.; Yang, A.-S.;
Liang, P.-H.; Wong, C.-H. Bioorg. Med. Chem. 2008, 16, 4652.
(d) Garrett, G. S.; McPhail, S. J.; Tornheim, K.; Correa, P. E.; McIver,
J. M. Bioorg. Med. Chem. Lett. 1999, 9, 301. (e) Frey, R. R.; Wada, C.
K.; Garland, R. B.; Curtin, M. L.; Michaelides, M. R.; Li, J.; Pease, L. J.;
Glaser, K. B.; Marcotte, P. A.; Bouska, J. J.; Murphy, S. S.; Davidsen, S.
K. Bioorg. Med. Chem. Lett. 2002, 12, 3443. (f) Madsen, A. S.;
Kristensen, H. M. E.; Lanz, G.; Olsen, C. A. ChemMedChem. 2014, 9,
614.
(6) (a) Abdel-Aal, Y.; Hammock, B. Science 1986, 233, 1073.
(b) Liang, T. C.; Abeles, R. H. Biochemistry 1987, 26, 7603.
(7) Trimble, L. A.; Street, I. P.; Perrier, H.; Tremblay, N. M.; Weech,
P. K.; Bernstein, M. A. Biochemistry 1993, 32, 12560.
(8) Jose, B.; Oniki, Y.; Kato, T.; Nishino, N.; Sumida, Y.; Yoshida, M.
Bioorg. Med. Chem. Lett. 2004, 14, 5343.
̃
(19) Denieul, M.-P.; Quiclet-Sire, B.; Zard, S. Z. Chem. Commun.
1996, 2511.
(20) For general reviews, see: (a) Quiclet-Sire, B.; Zard, S. Z. Pure
Appl. Chem. 2011, 83, 519. (b) Quiclet-Sire, B.; Zard, S. Z. Top Curr.
Chem. 2006, 264, 201. (c) Quiclet-Sire, B.; Zard, S. Z. Chem.Eur. J.
2006, 12, 6002.
(21) (a) Bertrand, F.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem., Int.
Ed. 1999, 38, 1943. (b) Bertrand, F.; Le Guyader, F.; Liguori, L.;
Ouvry, G.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. C. R. Acad. Sci., Ser.
IIC: Chem. 2001, 4, 547.
(22) (a) Xiang, J.; Jiang, W.; Gong, J.; Fuchs, P. L. J. Am. Chem. Soc.
1997, 119, 4123. (b) Xiang, J.; Fuchs, P. L. J. Am. Chem. Soc. 1996,
118, 11986.
(23) (a) Ouvry, G. PhD Thesis, Ecole Polytechnique, 2002. (b) Zard,
S. Z. Org. Biomol. Chem. 2007, 5, 205.
(24) (a) Vogeli, U.; von Philipsborn, W. Org. Magn. Reson. 1975, 7,
617. (b) Chambers, R. D.; Roche, A. J. J. Fluorine Chem. 1996, 79, 139.
(c) Beg
́ ́ ́
ue, J.-P.; Bonnet-Delpon, D.; Mesureur, D.; Ourevitch, M.
Magn. Reson. Chem. 1991, 29, 675.
(25) Bagal, S. K.; Tournier, L.; Zard, S. Z. Synlett 2006, 2006, 1485.
(26) Teranishi, K.; Nakao, H.; Komoda, A.; Hisamatsu, M.; Yamada,
T. Synthesis 1995, 1995, 176.
(27) Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 14, 957.
(28) Jullien, H.; Quiclet-Sire, B.; Tet
2014, 16, 302.
́
art, T.; Zard, S. Z. Org. Lett.
(9) (a) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432.
(b) Zanatta, N.; Schneider, J. M. F. M.; Schneider, P. H.; Wouters, A.
D.; Bonacorso, H. G.; Martins, M. A. P.; Wessjohann, L. A. J. Org.
Chem. 2006, 71, 6996. (c) Kiss, L. E.; Ferreira, H. S.; Learmonth, D. A.
Org. Lett. 2008, 10, 1835. (d) Fan, H.; Wang, X.; Zhao, J.; Li, X.; Gao,
J.; Zhu, S. J. Fluorine Chem. 2013, 146, 1. (e) Bazhin, D. N.; Chizhov,
D. L.; Roschenthaler, G.-V.; Kudyakova, Y. S.; Burgart, Y. V.;
̈
Slepukhin, P. A.; Saloutin, V. I.; Charushin, V. N. Tetrahedron Lett.
2014, 55, 5714. (f) Zanatta, N.; Amaral, S. S.; dos Santos, J. M.; da
Silva, A. M. P. W.; Schneider, J. M. F. M.; Fernandes, L. d. S.;
Bonacorso, H. G.; Martins, M. A. P. Tetrahedron Lett. 2013, 54, 4076.
(g) El Kharrat, S.; Laurent, P.; Blancou, H. Tetrahedron 2014, 70,
1252.
(10) (a) Lebel, H.; Paquet, V. Org. Lett. 2002, 4, 1671. (b) Nader, B.
S.; Cordova, J. A.; Reese, K. E.; Powell, C. L. J. Org. Chem. 1994, 59,
2898. (c) Hamlin, T. A.; Kelly, C. B.; Cywar, R. M.; Leadbeater, N. E.
J. Org. Chem. 2014, 79, 1145.
(11) (a) Pierce, M. E.; Parsons, R. L.; Radesca, L. A.; Lo, Y. S.;
Silverman, S.; Moore, J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M.
D.; Nguyen, D.; Luo, C.; Morgan, S. J.; Davis, W. P.; Confalone, P. N.;
Chen, C.-Y.; Tillyer, R. D.; Frey, L.; Tan, L.; Xu, F.; Zhao, D.;
Thompson, A. S.; Corley, E. G.; Grabowski, E. J. J.; Reamer, R.;
Reider, P. J. J. Org. Chem. 1998, 63, 8536. (b) Nicolaou, K. C.;
́
Krasovskiy, A.; Majumder, U.; Trepanier, V. E.; Chen, D. Y. K. J. Am.
́
Chem. Soc. 2009, 131, 3690. (c) Reeves, J. T.; Fandrick, D. R.; Tan, Z.;
Song, J. J.; Rodriguez, S.; Qu, B.; Kim, S.; Niemeier, O.; Li, Z.; Byrne,
D.; Campbell, S.; Chitroda, A.; DeCroos, P.; Fachinger, T.; Fuchs, V.;
Gonnella, N. C.; Grinberg, N.; Haddad, N.; Jager, B.; Lee, H.; Lorenz,
̈
D
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