Regioselective nucleophilic 1,4-trifluoromethylation of 2-polyfluoroalkylchromones with (trifluoromethyl)trimethylsilane. Synthesis of fluorinated analogs of natural 2,2-dimethylchroman-4-ones and 2,2-dimethylchromenes

Article abstract of DOI:10.1021/jo034591y

Reactions of 2-polyfluoroalkylchromones with (perfluoroalkyl)trimethylsilanes proceed as a 1,4-nucleophilic perfluoroalkylation to give 2,2-bis(polyfluoroalkyl)chroman-4-ones with high regioselectivity and good yields after acid hydrolysis. Oxidation of 6-methyl-2,2-bis(trifluoromethyl)chroman-4-one with a mixture of K ₂S₂O₈ and CuSO₄ in aqueous acetonitrile leads to fluorinated analogues of natural lactarochromal and the corresponding acid. Reduction of substituted 2,2-bis-(trifluoromethyl)chroman-4-one with sodium borohydride in methanol and subsequent dehydration of chromanols in refluxing xylene in the presence of p-toluene sulfonic acid gives 2,2-bis-(trifluoromethyl)chromenes, which are fluorinated analogues of natural precocenes.

Full text of DOI:10.1021/jo034591y

Regioselective Nu cleop h ilic 1,4-Tr iflu or om eth yla tion of
2-P olyflu or oa lk ylch r om on es w ith
(Tr iflu or om eth yl)tr im eth ylsila n e. Syn th esis of F lu or in a ted
An a logs of Na tu r a l 2,2-Dim eth ylch r om a n -4-on es a n d
2,2-Dim eth ylch r om en es
Vyacheslav Ya. Sosnovskikh,*,† Boris I. Usachev,† Dmitri V. Sevenard,‡ and
Gerd-Volker Ro¨schenthaler‡
Department of Chemistry, Ural State University, Lenina 51, 620083 Ekaterinburg, Russia, and
Institute of Inorganic and Physical Chemistry, University of Bremen, 28334 Bremen, Germany
vyacheslav.sosnovskikh@usu.ru
Received May 6, 2003
Reactions of 2-polyfluoroalkylchromones with (perfluoroalkyl)trimethylsilanes proceed as a 1,4-
nucleophilic perfluoroalkylation to give 2,2-bis(polyfluoroalkyl)chroman-4-ones with high regiose-
lectivity and good yields after acid hydrolysis. Oxidation of 6-methyl-2,2-bis(trifluoromethyl)-
chroman-4-one with a mixture of K2S2O8 and CuSO4 in aqueous acetonitrile leads to fluorinated
analogues of natural lactarochromal and the corresponding acid. Reduction of substituted 2,2-bis-
(trifluoromethyl)chroman-4-one with sodium borohydride in methanol and subsequent dehydration
of chromanols in refluxing xylene in the presence of p-toluene sulfonic acid gives 2,2-bis-
(trifluoromethyl)chromenes, which are fluorinated analogues of natural precocenes.
In tr od u ction
reactions of aldehydes, ketones, diketones, R-keto amides,
esters, and N-protected amino esters with CF3SiMe3 in
the presence of a catalytic amount of tetrabutylammo-
nium fluoride or cesium fluoride proceed as a nucleophilic
1,2-addition of the CF3 group at the carbonyl carbon atom
to give trifluoromethylated alcohols or trifluoromethyl
ketones in excellent yields following acid hydrolysis.5
However, little effort has been devoted to R,â-unsaturated
systems especially with respect to nucleophilic 1,4-
trifluoromethylation. To the best of our knowledge, there
are no methods for preparative addition of a CF3 group
The polyfluoroalkyl groups, especially the CF3 group,
are highly important substituents in the field of organic
chemistry. The introduction of these groups into organic
molecules can bring about some remarkable changes in
the physical properties, chemical reactivity, and biological
activity of the derived fluorinated compounds.1 In par-
ticular, due to the powerful electron-withdrawing ability
of RF groups the insertion of polyfluoroalkyl substituents
into the 2-position of chromones activates these molecules
and dramatic differences in the reactivity of 2-alkyl- and
2-polyfluoroalkylchromones with respect to nucleophilic
reagents are observed.2
Regioselective perfluoroalkylation of organic com-
pounds with various fluorinating agents is a well-
established methodology for the synthesis of partially
fluorinated materials applicable for agrochemistry and
the pharmaceutical industry.3 The unique properties of
(trifluoromethyl)trimethylsilane (Ruppert’s reagent) as
a nucleophilic trifluoromethylating agent are well-
known.4 This reagent is presently the most popular tool
in applications where perfluoroalkylation is involved. The
(3) (a) Organic Chemistry in Medicinal Chemistry and Biomedical
Applications; Filler, R., Ed.; Elsevier: Amsterdam, The Netherlands,
1993. (b) Welch, J . T.; Eswaraksrishnan, S. Fluorine in Bioorganic
Chemistry; J ohn Wiley and Sons: New York, 1991. (c) Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications;
Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsevier: Amster-
dam, The Netherlands, 1993.
(4) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757-
786. (b) Singh, R. P.; Shreeve, J . M. Tetrahedron 2000, 56, 7613-7632.
(c) Prakash, G. K. S.; Mandal, M. J . Fluorine Chem. 2001, 112, 123-
131. (d) Langlois, B. R.; Billard, T. Synthesis 2003, 185-194.
(5) (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J . Am. Chem.
Soc. 1989, 111, 393-395. (b) Krishnamurti, R.; Bellew, D. R.; Prakash,
G. K. S. J . Org. Chem. 1991, 56, 984-989. (c) Prakash, G. K. S.; Tongco,
E. C.; Mathew, T.; Vankar, Y. D.; Olah, G. A. J . Fluorine Chem. 2000,
101, 199-202. (d) Wiedemann, J .; Heiner, T.; Mloston, G.; Prakash,
G. K. S.; Olah, G. A. Angew. Chem. 1998, 110, 880-881. (e) Kotun, S.
P.; Anderson, J . D. O.; DesMarteau, D. D. J . Org. Chem. 1992, 57,
1124-1131. (f) Singh, R. P.; Kirchmeier, R. L.; Shreeve, J . M. Org.
Lett. 1999, 1, 1047-1049. (g) Singh, R. P.; Kirchmeier, R. L.; Shreeve,
J . M. J . Org. Chem. 1999, 64, 2579-2581. (h) Singh, R. P.; Cao, G.;
Kirchmeier, R. L.; Shreeve, J . M. J . Org. Chem. 1999, 64, 2873-2876.
(i) Singh, R. P.; Shreeve, J . M. J . Org. Chem. 2000, 65, 3241-3243. (j)
Singh, R. P.; Leitch, J . M.; Twamley, B.; Shreeve, J . M. J . Org. Chem.
2001, 66, 1436-1440. (k) Watanabe, S.; Fujita, T.; Sakamoto, M.; Mino,
Y.; Kitazume, T. J . Fluorine Chem. 1995, 73, 21-26. (l) Allen, A. D.;
Fujio, M.; Mohammed, N.; Tidwell, T. T.; Tsuji, Y. J . Org. Chem. 1997,
62, 246-252.
* To whom corresponding should be addressed. Phone: (3432) 61-
68-24. Fax: (3432) 61-59-78.
† Ural State University.
‡ University of Bremen.
(1) (a) Welch, J . T. Tetrahedron 1987, 43, 3123-3197. (b) Organof-
luorine Chemistry: Principles and Commercial Applications; Banks,
R. E., Smart, B. E., Tatlow, J . C., Eds.; Plenum Press: New York, 1994.
(2) (a) Sosnovskikh, V. Ya.; Kutsenko, V. A.; Yachevskii, D. S.
Mendeleev Commun. 1999, 204-205. (b) Sosnovskikh, V. Ya.; Usachev,
B. I. Russ. Chem. Bull. 2001, 50, 453-455. (c) Sosnovskikh, V. Ya.;
Usachev, B. I. Russ. Chem. Bull. 2001, 50, 1426-1429.
10.1021/jo034591y CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/10/2003
J . Org. Chem. 2003, 68, 7747-7754
7747

Sosnovskikh et al.
SCHEME 1
to the CdC bond of conjugated enones. In the case of
2-cyclohexen-1-one and CF3SiMe3/Bu4NF, 1,2-addition
predominates (>90%).5a-c Furthermore, nucleophilic tri-
fluoromethylation of chalcone and (dibenzylidene)acetone
with trifluoromethane and silicon-containing bases ex-
clusively results in 1,2-addition.6a The adduct of trifluo-
romethane and N-formylmorpholine behaves the same
way in the reaction with chalcone.6b The only example
known to us, where a 1,4-addition takes place to a certain
extent, is observed in the reaction of trans-1-benzoyl-2-
(dimethylamino)ethylene with CF3H/N(SiMe3)3/DMF/Me4-
NF. However, in this reaction the 1,4-trifluoromethyla-
tion was followed by the elimination of dimethylamine6a
and the initial product of 1,4-addition (36% from the 19F
NMR spectrum) could not be isolated. Thus, this reaction
proceeding as an AN-E process could not be strongly
considered a successful nucleophilic 1,4-trifluoromethyl-
ation.
Resu lts a n d Discu ssion
The biological activity of many of the naturally occur-
ring compounds which incorporate a chroman ring sys-
tem has resulted in several applications of substituted
chroman-4-ones in synthesis.7 Despite advances in the
area, methods for preparing these valuable intermedi-
ates, especially 2-RF-chroman-4-ones, remain limited.8 In
contrast, chromones are readily prepared by a variety of
methods,9 and could in principle provide chroman-4-ones
via the conjugate addition sequence.8 We undertook a
study of 2-substituted chromones of differing electrophi-
licity and steric bulk to determine which of these sub-
strates preferentially undergo 1,4-addition rather than
1,2-addition during fluoride-initiated trifluoromethyla-
tion using Ruppert’s reagents (preliminary communica-
tion, see ref 10).
Here, we wish to report that (trifluoromethyl)- and
(perfluoroethyl)trimethylsilanes can be employed to gen-
erate compounds with the gem-bis(perfluoroalkyl) group
by 1,4-nucleophilic perfluoroalkylation of 2-RF-chromones
1 (RF ) CF2H, CF3, C2F5). In our initial studies, we
optimized the reaction conditions by using 2-trifluorom-
ethylchromone 1a and RFSiMe3 (RF ) CF3, C2F5) and
monitored the reaction progress by 19F NMR. To subse-
quently design a preparative procedure and determine
the scope of the reaction, products were not isolated but
were observed by 19F NMR spectroscopy. When chromone
1a was treated with 1.4 equiv of RFSiMe3 in dry THF in
the presence of a catalytic amount of anhydrous Me4NF
(3-4 mol %) as a nucleophilic initiator for several hours
(4-24 h) at different temperatures (from 25 to -30 °C),
19F NMR analysis of the reaction mixture showed almost
quantitative formation of the trimethylsilyl ethers 2 and
3 with high regioselectivity (Scheme 1). Anhydrous
tetramethylammonium fluoride11 proved to be the best
source of fluoride ion. Surprisingly, no trifluoromethy-
lation was observed in the case of CF3SiMe3/Bu4NF. The
use of tBuOK to initiate 1,4-trifluoromethylation was also
not satisfactory: in the presence of this catalyst the ratio
of the 1,2- and 1,4-adducts in the reaction between
chromone 1 (RF ) CF3, R ) MeO) and CF3SiMe3 was 53:
47, respectively.
As expected, regioselectivity of the nucleophilic attack
by RFSiMe3 on the pyrone ring will depend on the steric
effects of the C(2) fluorinated group. In fact, upon
increasing the length of the perfluoroalkyl chain in
Ruppert’s reagent to C2F5 the regioselectivity drops, most
likely due to steric repulsion between RF moieties. When
the temperature was decreased from 25 to -30 °C,
regioselectivity increased by 5% and 10% for RF ) CF3
and C2F5, respectively. Similarly, the reaction of 2-per-
fluoroethylchromone with CF3SiMe3 leads to a mixture
of the 1,4- and 1,2-addition products in the molar 2:3 ratio
80:20 at -30 °C and 73:27 at 0 °C. Note that steric
hindrance in the carbonyl compounds is also a limiting
factor in the reactions of RFSiMe3.5b The reaction was
markedly favored in regioselectivity when carried out
with chromone bearing the CF2H group at C(2). However,
in the case of 2-(1,1,2,2-tetrafluoroethyl)- and 6-methoxy-
2-(1,1,2,2-tetrafluoroethyl)chromones, the reaction mix-
ture almost immediately becomes dark-red and resinifies
under the same conditions. This can be explained by the
abstraction of the terminal hydrogen atom of the (CF2)2H
group with Ruppert’s reagent, which inhibits a nucleo-
philic addition of the CF3 group.
(6) (a) Large, S.; Roques, N.; Langlois, B. R. J . Org. Chem. 2000,
65, 8848-8856. (b) Billard, T.; Bruns, S.; Langlois, B. R. Org. Lett.
2000, 2, 2101-2103.
(7) (a) Kabbe, H. J .; Heitzer, H. Synthesis 1978, 888-889. (b)
Saengchantara, S. T.; Wallace, T. W. Tetrahedron 1990, 46, 3029-
3036.
(8) (a) Wallace, T. W. Tetrahedron Lett. 1984, 25, 4299-4302. (b)
Clarke, P. D.; Fitton, A. O.; Suschitzky, H.; Wallace, T. W.; Dowlat-
shahi, H. A.; Suschitzky, J . L. Tetrahedron Lett. 1986, 27, 91-94. (c)
Sosnovskikh, V. Ya.; Usachev, B. I. Synthesis 2002, 2341-2343.
(9) (a) Ellis, G. P. Chromenes, Chromanones, and Chromones. In
The Chemistry of Heterocyclic Compounds; Wiley: New York, 1977;
Vol. 31.
The formation of trimethylsilyl ethers 2 clearly indi-
cates that the 2-polyfluoroalkylchromones 1 easily un-
dergo 1,4-trifluoromethylation due to the presence of the
fluorinated group at the C(2) atom of the chromone
(11) (a) Christe, K. O.; Wilson, W. W.; Wilson, R. D.; Bau, R.; Feng,
J . J . Am. Chem. Soc. 1990, 112, 7619-7625. (b) Kolomeitsev, A. A.;
Seifert, F. U.; Ro¨schenthaler, G.-V. J . Fluorine Chem. 1995, 71, 47-
49.
(10) Sosnovskikh, V. Ya.; Sevenard, D. V.; Usachev, B. I.; Ro¨schentha-
ler, G.-V. Tetrahedron Lett. 2003, 44, 2097-2099.
7748 J . Org. Chem., Vol. 68, No. 20, 2003

Nucleophilic 1,4-Trifluoromethylation
SCHEME 2
SCHEME 3
reactions of chromones 1c-f with CF3SiMe3 were carried
out at -30 °C for 24 h and crystalline chromanones 4c-f
were isolated in 50-76% yields. No side products were
observed. This reaction is the first example of successful
preparative regioselective 1,4-trifluoromethylation of a
conjugated enone system that proceeds as an AN process
(Scheme 3).
The introduction of fluorine in place of hydrogen has
become a common practice by medicinal chemists in
attempts to improve the biological activity of organic
compounds.3 In our opinion, the approach described here
represents the best overall route to fluorinated analogues
of natural chromanones, chromanes, and chromenes with
gem-dimethyl groups at the C(2) atom.9 Thus, 4-oxo-2,2-
bis(trifluoromethyl)chroman-6-carbaldehyde 5a , the ana-
logue of natural lactarochromal, a metabolite of the
fungus Lactarius deliciosus14 in which both methyl
groups are replaced by the trifluoromethyl groups, was
synthesized by the oxidation of the 6-Me group of
chromanone 4b with a mixture of K2S2O8 and CuSO4 in
aqueous acetonitrile15 in 17% yield (the reaction condi-
tions are not optimized). In addition to hexafluorolac-
tarochromal 5a , this reaction gives the corresponding
hexafluoro acid 5b (yield 35%), which is also a fluorinated
analogue of the natural acid isolated from Chrysotham-
nus viscidiflorus16 (Scheme 4).
Recently we have shown that the reaction of N-benzyl-
2-trifluoromethylchromen-4-imines with malonic acid is
a convenient method for the synthesis of 2-methyl-2-
trifluoromethylchroman-4-ones. Using this method, an
analogue of lactarochromal in which one of the methyl
groups in the gem-dimethyl moiety is replaced by the CF3
group was described.8c
Substituted 2,2-dimethylchromans of various levels of
saturation and oxidation are common natural products
which are widely distributed among many plants.9 Fur-
thermore, they have considerable biological importance,
especially as potentially useful modern pesticides17 and
drug candidates in the field of potassium channel open-
ers.18 Because of their ease of preparation, reactivity, and
relative stability, 2,2-dimethylchromenes have an im-
system. In regards to this, it is worth noting that in our
hands neither the chromone nor the 2-methylchromone
react with CF3SiMe3. In the latter case, the only product
was the 1,2-adduct (12 h, ∼20 °C, 13% from the 19F NMR
spectrum, singlet at -82.07). The reaction of indenone
with CF3SiMe3 in the presence of KF gives the corre-
sponding trifluoromethylated alcohol after acid hydrolysis.4l
In attempting to ascertain if related systems can par-
ticipate in this reaction, we found that 2-trichlorometh-
ylchromone12 and N-benzyl-2-trifluoromethylchromen-
4H-imine8 fail to react under the above experimental
conditions and only the starting materials were recovered
with small amounts of decomposition products. In addi-
tion, 6-methyl-4-trifluoromethylcoumarin13 gives a com-
plex reaction mixture containing about 40% of the 1,2-
adduct with other unidentifiable products. The fact that
1,4-adducts were not observed in these reactions suggests
an important electronic effect of the RF group at the C(2)
atom in compounds 1 on the course of the reaction with
RFSiMe3. Clearly the electron-withdrawing RF group
enhances the electrophilicity of the substrate and encour-
ages conjugate addition.
The nucleophilic reaction mechanism for the 1,4-
trifluoromethylation of 2-RF-chromones with CF3SiMe3
should be the same as that reported for carbonyl
compounds.4b,c The reaction involves fluoride ion initia-
tion to form the trifluoromethylated enolate anion A,
which then via hypervalent silicon intermediate B cata-
lyzes the subsequent reaction (Scheme 2).
Our optimum conditions for the fluoride-induced 1,4-
trifluoromethylation were applied to the preparative
synthesis of chromanones 4a -f. When chromones 1a ,b
are treated in THF with CF3SiMe3/Me4NF for 4 h at -10
°C followed by acid hydrolysis at room temperature, 2,2-
bis(trifluoromethyl)chroman-4-ones 4a ,b were obtained
as colorless oils after vacuum distillation in 86% and 61%
isolated yields, respectively. Each product contained as
an admixture ∼10% trimethylsilyl ethers 3, which are
more stable than ethers 2 at the acid hydrolysis. The
(14) Ayer, W. A.; Trifonov, L. S. J . Nat. Prod. 1994, 57, 839-841.
(15) (a) Kamat, V. P.; Asolkar, R. N.; Kirtany, J . K. J . Chem. Res.
(S) 2001, 41. (b) Ohshima, E.; Otaki, S.; Sato, H.; Kumazawa, T.; Obase,
H.; Ishii, A.; Ishii, H.; Ohmori, K.; Hirayama, N. J . Med. Chem. 1992,
35, 2074-2084.
(16) Le-Van, N.; Pham, T. V. C. Phytochemistry 1981, 20, 485-487.
(17) Bowers, W. S. In Comprehensive Insect Physiology, Biochemistry
and Pharmacology; Gilbert, L. I., Kerkut, G. A. Eds.; Pergamon
Press: Oxford, UK, 1985; Vol. 8, p 551.
(12) Sosnovskikh, V. Ya.; Usachev, B. I. Synthesis 2002, 1007-1009.
(13) Whalley, W. B. J . Chem. Soc. 1951, 3235-3238.
(18) Weston, A. H.; Edwards, G. Biochem. Pharmacol. 1992, 43, 47-
54.
J . Org. Chem, Vol. 68, No. 20, 2003 7749

Sosnovskikh et al.
SCHEME 4
SCHEME 5
CHART 1
SCHEME 6
portant role and are valuable intermediates for synthetic
purposes in 2,2-dimethylchroman chemistry. For ex-
ample, precocene I (6a ) and precocene II (6b) are anti-
juvenile hormones which have been isolated from the
plant Ageratum houstonianum. Although precocenes are
nature-friendly in the general sense, they cause preco-
cious metamorphosis, sterility and other pronounced
biological effects in various insects.19
The central position of the 2H-chromene ring system
in large and diverse classes of naturally occurring and
biologically active heterocycles has led to the development
of a number of methods for their preparation,20 and
properties of these compounds were investigated.21 How-
ever, published data on the synthesis of partially fluori-
nated 2,2-dimethylchromenes are lacking. In view of the
unique biological properties displayed by precocenes 619
on one hand and by many CF3-containing heterocycles1,3
on the other hand, it was of interest to obtain fluorine-
containing precocenes by using our approach with (trif-
luoromethyl)trimethylsilane. Synthesis of these com-
pounds was achieved by reduction of chromanones 4c-f
with sodium borohydride in methanol and subsequent
dehydration of chromanols 7c-f in refluxing xylene for
2 h in the presence of p-toluene sulfonic acid as a catalyst.
Reduction of 4f exhibits relatively high stereoselectivity
and the diastereomer ratio was 79:21. Expectedly, these
reactions proceeded smoothly for all substrates and 2,2-
bis(trifluoromethyl)chroman-4-ols 7c-f and 2,2-bis(trif-
luoromethyl)chromenes 8c-f, fluorinated analogues of
natural precocenes 6, were isolated as crystalline prod-
ucts (except for 8f) in 76-89% yields for 7c-f and 51-
72% yields for 8c-f. The structures of these compounds
were confirmed by 1H, 19F NMR, and IR spectroscopy and
mass spectrometry. In the 19F NMR spectra the bis-
(trifluoromethyl) moiety of 4a ,c-e and 8c-e manifests
itself as a singlet ranging between -76 and -78 ppm;
CF3 groups of the trifluoromethylated chromanols 7c-e
appeared as quartets at about -76 and -77 ppm with
4J F,F ) 10.3 Hz due to the chiral center in their molecules,
and the signal for the CF3 group of compounds 4f and 8f
appeared as a doublet of doublets at about -79 ppm (4J F,F
) 5.1-6.1 H and 10.6-11.1 Hz). Two sets of signals in
1
the 19F and H NMR spectra of 7f showed the presence
of two diastereomers. The 1H NMR spectra of chromenes
8c-f showed signals for the aromatic protons and a
characteristic AX-system ranging between 5.4-5.7 and
6.8-7.2 ppm for the CHdCH moiety; the coupling
constant was J AX ) 10.1 Hz (Scheme 5).
Recently22 the condensation of khellinone with CF3CO2-
Et allowed us to obtain 7-trifluoromethylnorkhellin 9,
viz., the fluorinated analogue of natural furochromone
khellin, which is an efficient medicinal substance23 and
present in plant Ammi visnaga L known by its thera-
peutic properties.24 The replacement of Me by the CF3
group in khellin affects the electron density distribution
in the khellin system and makes trifluorokhellin 9 a
promising substrate for the preparation of potentially
bioactive compounds.25 Using the above method we were
able to synthesize three new khellin derivatives 10-12.
Trifluorokhellin 9 reacted easily and cleanly with CF3-
SiMe3 at -30 °C for 24 h to afford the desired furochro-
manone 10 in 70% isolated yields without any formation
of 1,2-adduct (monitoring by 19F NMR). Treatment of 10
with NaBH4 in methanol at room temperature for 10 min
gave furochromanol 11 (70%), which was easily converted
into furochromene 12 (73%) by refluxing in xylene for 2
h with a catalytic amount of p-toluene sulfonic acid
(Scheme 6).
(19) Bowers, W. S.; Ohta, T.; Cleere, J . S.; Marsella, P. A. Science
1976, 193, 542-547.
The method described in this paper was also applicable
to the 1,4-trifluoromethylation of 3-chloro-2-trifluorom-
ethylchromone (13)26 and 1-methyl-2-(trifluoromethyl)-
quinolin-4(1H)-one (14).27 Reactions of these compounds
(20) (a) Chauder, B. A.; Lopes, C. C.; Lopes, R. S. C.; da Silva, A. J .
M.; Snieckus, V. Synthesis 1998, 279-282. (b) Talley, J . J . Synthesis
1983, 845-847. (c) Tercio, J .; Ferreira, B.; Catani, V.; Comasseto, J .
V. Synthesis 1987, 149-153. (d) Pandey, G.; Krishna, A. J . Org. Chem.
1988, 53, 2364-2365. (e) Bongini, A.; Cardillo, G.; Orena, M.; Porzi,
G.; Sandri, S. Tetrahedron Lett. 1979, 2545-2548. (f) Banerji, A.;
Goomer, N. C. Indian J . Chem. 1984, 23B, 885-886. (g) Chauder, B.
A.; Kalinin, A. V.; Snieckus, V. Synthesis 2001, 140-141.
(22) Sosnovskikh, V. Ya.; Kutsenko, V. A. Mendeleev Commun. 2000,
238-239.
(21) (a) Hepworth, J . D.; Livingstone, R. J . Chem. Soc. (C) 1966,
2013-2016. (b) J ennings, R. C.; Ottridge, A. P. J . Chem. Soc., Perkin
Trans. 1 1984, 1733-1738. (c) Anastasis, P.; Brown, P. E. J . Chem.
Soc., Perkin Trans. 1 1982, 2013-2018. (d) Anastasis, P.; Brown, P.
E. J . Chem. Soc., Perkin Trans. 1 1983, 197-200. (e) Bujons, J .; Camps,
F.; Messeguer, A. Tetrahedron Lett. 1990, 31, 5235-5236. (f) Murugesh,
M. G.; Subburaj, K.; Trivedi, G. K. Tetrahedron 1996, 52, 2217-2228.
(23) Gammill, R. B.; Day, C. E.; Schurr, P. E. J . Med. Chem. 1983,
26, 1672-1674.
(24) Mashkovskii, M. D. Lekarstvennye sredstva (Drugs); Gamta:
Vilnyus, 1993; Vol. 1, p 396.
(25) (a) Sosnovskikh, V. Ya.; Usachev, B. I. Tetrahedron Lett. 2001,
42, 5121-5122. (b) Sosnovskikh, V. Ya.; Usachev, B. I.; Vorontsov, I.
I. Tetrahedron 2003, 59, 2549-2554.
7750 J . Org. Chem., Vol. 68, No. 20, 2003

Nucleophilic 1,4-Trifluoromethylation
SCHEME 7
SCHEME 9
SCHEME 8
SCHEME 10
with CF3SiMe3 in the presence of Me4NF led to the
formation of the corresponding trifluoromethylated silyl
ethers, which upon hydrolysis with 20% HCl afforded the
3-chloro-2,2-bis(trifluoromethyl)chroman-4-one (15) and
1-methyl-2,2-bis(trifluoromethyl)-2,3-dihydroquinolin-
4(1H)-one (16) as the only isolated products. Although
slightly lower yields (53-58%) were obtained, in these
cases no 1,2-addition products could be detected when
reaction was followed by 19F NMR spectroscopy. It is
noteworthy that 3-chlorochromone 13 is less reactive
than 2-RF-chromones 1 and reacted with CF3SiMe3 at
room temperature for 24 h, whereas quinolone 14 reacted
as rapidly as 2-RF-chromones 1. The successful reaction
with quinolone 14 shows that the method is rather
flexible and can be used in the preparation of previously
unknown 2,2-bis(trifluoromethyl) derivatives of hydro-
genated quinoline which are potentially medicinally
active (Scheme 7). Earlier tri- and difluoromethylated
tetra- and dihydroquinoline derivatives were obtained by
cationic polar cycloaddition of R-methoxylated amines
with nucleophilic unsaturated compounds in the presence
of a Lewis acid.28
and is consistent with Singh and Shreeve’s observation
that the trans R,â-enones, including 1,1,1-trifluoro-4-
phenyl-3-buten-2-one isomeric to 17, react cleanly with
CF3SiMe3 in the presence of a catalytic amount of CsF
to produce trimethylsilyl ether intermediates in es-
sentially quantitative yields.4b,5f
The fragmentation patterns in the mass spectra of
chromanones 4, 10, and 15 are exemplified in Scheme 8
for the parent compound 4c. The molecular ion (the base
peak) undergoes the expected retro-Diels-Alder reaction
to give the peak at m/z 150. A mode of breakdown of the
•
m/z 150 ion occurs through loss of CO, CH3, and C2H2.
These degradation pathways confirmed the structure of
4c and are characteristic of all of the 2,2-bis(trifluorom-
ethyl)chroman-4-ones, including the 3-chloro derivative
15 (Scheme 9).
As expected, the molecular ion of 2,2-bis(trifluorom-
ethyl)chromenes 8 loses one trifluoromethyl group to give
a stable pyrilium cation as the base peak (Scheme 10).
In summary, the reaction of readily available 2-trif-
luoromethylchromones with Ruppert’s reagent is a simple
and efficient method for the synthesis of 2,2-dimethyl-
chroman-4-ones in which the gem-dimethyl group is
replaced by the gem-bis(trifluoromethyl) moiety. This
approach is the first example of a preparative 1,4-
trifluoromethylation and can be used for synthesis of
fluorinated analogues of natural compounds.
Interestingly, when a similar experiment was carried
out with an acyclic analogue of 1a , (E)-4,4,4-trifluoro-1-
phenyl-2-buten-1-one (17),29 in which the heterocyclic
oxygen atom is missing, no evidence of 1,4-addition was
observed by NMR spectroscopy and reaction exclusively
proceeded via nucleophilic addition of the CF3 group to
the carbonyl group to form the trimethylsilyl ether 18a .
Exp er im en ta l Section
1
The H NMR spectrum of the crude product after 12 h
The starting 2-polyfluoroalkylchromones 1a -f, 9, and 13
were prepared by reaction of the appropriate 2-hydroxyac-
etophenones with RFCO2Et according to described proce-
dures.2a,22,26 1-Methyl-2-(trifluoromethyl)quinolin-4(1H)-one (14)
was obtained from 2-aminoacetophenone, CF3CO2Et, and MeI
in the presence of tBuOK.27 (E)-4,4,4-Trifluoro-1-phenyl-2-
buten-1-one (17) was prepared according to described proce-
dures.29
2,2-Bis(p olyflu or oa lk yl)ch r om a n -4-on es 4a -f, 10, a n d
15: Gen er al 1,4-Tr iflu or om eth ylation P r ocedu r e.Chromone
1 or 9 (5 mmol) and (trifluoromethyl)trimethylsilane (1.0 g, 7
mmol) were dissolved in dry THF (15 mL) and cooled to -25
to -30 °C, and a catalytic amount of anhydrous Me4NF (20
at -10 °C followed by acid hydrolysis showed a 92:8
mixture of ether 18a and allylic alcohol 18b, indicating
that partial hydrolysis of 18a had occurred (Scheme 8).
This example shows again the interplay of electronic and
steric factors on the course of the reaction with CF3SiMe3
(26) Sosnovskikh, V. Ya.; Usachev, B. I. Russ. Chem. Bull. 2000,
49, 2074-2076.
(27) Sosnovskikh, V. Ya.; Usachev, B. I.; Sizov, A. Yu. Russ. Chem.
Bull. 2002, 51, 2109-2115.
(28) Fuchigami, T.; Ichikawa, S. J . Org. Chem. 1994, 59, 607-615.
(29) Norcross, B. E.; Klinedinst, P. E., J r.; Westheimer, F. H. J . Am.
Chem. Soc. 1962, 84, 797-802.
J . Org. Chem, Vol. 68, No. 20, 2003 7751

Sosnovskikh et al.
2
mg) was added (solution changed from colorless to yellow). The
reaction mixture was left to stand with stirring at that
temperature for 24 h, after which it was hydrolyzed at ∼20
°C by reacting with 20% HCl (1 mL) for 15 min. After the
removal of solvent under reduced pressure, the residue was
worked up with boiling hexane and purified by filtration
through a silica gel layer (d ) 10 mm, l ) 10 mm) and
recrystallization from the same solvent to afford the analytical
samples of the compounds 4e-f and 10. In the case of 13, the
reaction was carried out at ∼20 °C. The liquid products from
1a ,b (the reaction was carried out at 0 °C for 4 h) were
extracted with CHCl3 (20 mL), and the extract was dried over
anhydrous K2CO3, filtered, and distilled under reduced pres-
sure to give chromanones 4a ,b with an admixture (11-12%)
of trimethylsilyl ethers 3.
17.6 Hz, CHH), 3.81 (3H, s, MeO), 6.07 (1H, t, J H,F ) 54.2
o
o
Hz, CF2H), 7.00 (1H, d, J ) 9.1 Hz), 7.15 (1H, d, J ) 9.1 Hz,
mJ ) 3.2 Hz), 7.29 (1H, d, mJ ) 3.2 Hz); 19F NMR (376 MHz,
4
4
CDCl3, CFCl3) δ -78.42 (3F, dd, J F,F ) 11.1 Hz, J F,F ) 5.1
2
2
Hz, CF3), -130.12 (1F, ddq, J F,F ) 300.8 Hz, J F,H ) 53.8 Hz,
4J F,F ) 11.1 Hz, CFFH), -132.75 (1F, ddq, J F,F ) 300.8 Hz,
2
2J F,H ) 54.7 Hz, J F,F ) 5.1 Hz, CFFH). Anal. Calcd for
4
C12H9F5O3: C, 48.66; H, 3.06. Found: C, 48.63; H, 3.17.
4,9-Dim et h oxy-7,7-b is(t r iflu or om et h yl)-6,7-d ih yd r o-
5H-fu r o[3,2-g]ch r om en -5-on e (10): yield 70% as yellow
crystals; mp 146-147 °C; IR (KBr) 1694 (CdO), 1609, 1545,
1484, 1441 cm-1 1H NMR (200 MHz, CDCl3) δ 3.21 (2H, s,
;
CH2), 4.06 (3H, s, MeO), 4.11 (3H, s, MeO), 6.98 (1H, d, J )
2.5 Hz), 7.59 (1H, d, J ) 2.5 Hz); 19F NMR (188 MHz, CDCl3,
CFCl3) δ -76.44 (s, CF3); MS m/z (Irel (%)) 384 (M+, 100), 369
(38), 355 (18), 220 (9), 205 (72), 192 (6), 177 (62), 147 (8), 119
(10), 69 (15); HRMS calcd for C15H10F6O5 (M+) 384.0432, found
384.0429.
2,2-Bis(tr iflu or om eth yl)ch r om a n -4-on e (4a ): yield 86%
as a colorless liquid; bp 94-97 °C (15 mmHg); IR (neat) 1710
(CdO), 1670, 1615, 1590 cm-1; 1H NMR (400 MHz, CDCl3) 4a
o
(89%) δ 3.22 (2H, s, CH2), 7.13 (1H, dd, J ) 8.4 Hz, mJ ) 1.0
3-C h lo r o -2,2-b is (t r iflu o r o m e t h y l)c h r o m a n -4-o n e
o
Hz), 7.17 (1H, ddd, J ) 8.4, 7.3 Hz, mJ ) 1.0 Hz), 7.60 (1H,
(15): yield 58% as colorless needles; mp 49-50 °C; IR (KBr)
o
o
ddd, J ) 8.4, 7.3 Hz, mJ ) 1.8 Hz), 7.89 (1H, dd, J ) 7.8 Hz,
1708 (CdO), 1609, 1591, 1465 cm-1
;
1H NMR (400 MHz,
mJ ) 1.8 Hz); H NMR (400 MHz, CDCl3) 3a (11%) δ -0.03
(9H, s, SiMe3), 5.81 (1H, s, dCH), 7.18 (1H, dd, J ) 8.4 Hz,
1
4
o
CDCl3) δ 5.00 (1H, q, J H,F ) 0.7 Hz, CH), 7.17 (1H, d, J )
o
8.5 Hz), 7.24 (1H, ddd, J ) 7.8, 7.2 Hz, mJ ) 0.9 Hz), 7.66
o
mJ ) 1.1 Hz), 7.27 (1H, ddd, °J ) 8.4, 7.3 Hz, mJ ) 1.1 Hz),
7.44 (1H, ddd, oJ ) 8.4, 7.3 Hz, mJ ) 1.7 Hz), 7.72 (1H, d quint,
oJ ) 8.0 Hz, mJ ) 5J H,F ) 1.4 Hz); 19F NMR (188 MHz, CDCl3,
CFCl3) 4a δ -77.78 (s, CF3); 19F NMR (188 MHz, CDCl3, CFCl3)
3a δ -73.70 (s, C2-CF3), -81.98 (s, C4-CF3); 13C NMR (50 MHz,
CDCl3) 4a δ 34.7 (s, C3), 80.0 (sept, 2J C,F ) 30.9 Hz, C2), 117.5
(s, C8), 119.2 (s, C4a), 121.9 (q, 1J C,F ) 287.8 Hz, CF3), 123.4 (s,
C6), 126.5 (s, C5), 137.1 (s, C7), 157.2 (s, C8a), 184.5 (s, C4).
(1H, ddd, oJ ) 8.5, 7.2 Hz, mJ ) 1.7 Hz), 7.95 (1H, dd, oJ ) 7.8
Hz, mJ ) 1.7 Hz); 19F NMR (188 MHz, CDCl3, CFCl3) δ -68.28
(q, J F,F ) 9.2 Hz, CF3), -72.47 (q, J F,F ) 9.2 Hz, CF3); MS m/z
(Irel (%)) 318 (M+, 22), 249 (6), 120 (100), 92 (46), 69 (7); HRMS
calcd for C11H5ClF6O2 (M+) 317.9882, found 317.9881.
1-Meth yl-2,2-bis(tr iflu or om eth yl)-2,3-d ih yd r oqu in olin -
4(1H)-on e (16): yield 53% as colorless needles; mp 52-53 °C;
IR (Nujol) 1700 (CdO), 1610, 1580 cm-1; H NMR (400 MHz,
1
CDCl3) δ 3.16 (2H, s, CH2), 3.19 (3H, sept, 5J H,F ) 1.0 Hz, Me),
6-Me t h y l-2,2-b is (t r iflu o r o m e t h y l)c h r o m a n -4-o n e
(4b): yield 61% as a colorless liquid; bp 122-125 °C (27
mmHg); IR (neat) 1710 (CdO), 1670, 1620, 1590 cm-1; 1H NMR
(400 MHz, CDCl3) 4b (88%) δ 2.34 (3H, s, Me), 3.19 (2H, s,
6.90 (1H, d, J ) 8.7 Hz), 6.92 (1H, ddd, J ) 7.7, 7.2 Hz, mJ
o
o
) 0.9 Hz), 7.53 (1H, ddd, J ) 8.7, 7.2 Hz, mJ ) 1.8 Hz), 7.88
o
(1H, dd, oJ ) 7.7 Hz, mJ ) 1.8 Hz); 19F NMR (188 MHz, CDCl3,
CFCl3) δ -70.55 (s, CF3). Anal. Calcd for C12H9F6NO: C, 48.50;
H, 3.05; N, 4.71. Found: C, 48.23; H, 3.11; N, 4.69.
CH2), 7.02 (1H, d, oJ ) 8.5 Hz), 7.40 (1H, ddq, oJ ) 8.5 Hz, m
J
)
) 2.3 Hz, 4J H,Me ) 0.6 Hz), 7.67 (1H, dq, mJ ) 2.3 Hz, 4J H,Me
1
0.4 Hz); H NMR (400 MHz, CDCl3) 3b (12%) δ -0.03 (9H, s,
(E)-4,4,4-Tr iflu or o-1-p h en yl-1-(tr iflu or om eth yl)bu t-2-
en yl tr im eth ylsilyl eth er (18a ): yield 85% as dark yellow
oil after acid hydrolysis and evaporation of THF in vacuo; 1H
NMR (400 MHz, CDCl3) 18a (92%) δ 0.10 (9H, s, SiMe3), 6.12
o
SiMe3), 2.38 (3H, s, Me), 5.77 (1H, s, dCH), 7.07 (1H, d, J )
o
4
8.5 Hz), 7.23 (1H, ddq, J ) 8.5 Hz, mJ ) 2.2 Hz, J H,Me ) 0.6
Hz), 7.48 (1H, br s).
(1H, dq, 3J H,H ) 15.8 Hz, 3J H,F ) 6.2 Hz), 6.64 (1H, dq, 3J H,H
)
6-Me t h oxy-2,2-b is(t r iflu or om e t h yl)ch r om a n -4-on e
15.8 Hz, 4J H,F ) 1.9 Hz), 7.38-7.48 (5H, m, Ph); 1H NMR (400
MHz, CDCl3) 18b (8%) δ 6.26 (1H, dq, 3J H,H ) 15.8 Hz, 3J H,F
(4c): yield 76% as colorless needles; mp 91-92 °C; IR (KBr)
1705 (CdO), 1619, 1493, 1435 cm-1 1H NMR (400 MHz,
;
)
CDCl3) δ 3.20 (2H, s, CH2), 3.82 (3H, s, MeO), 7.06 (1H, dd, oJ
3
4
6.3 Hz), 6.85 (1H, dq, J H,H ) 15.8 Hz, J H,F ) 1.9 Hz), 7.38-
7.48 (5H, m, Ph); 19F NMR (376 MHz, CDCl3, CFCl3, in 2 weeks
after preparation) 18a (75%) δ -76.93 (s, CF3), -65.77 (dd, 3J
) 6.2 Hz, 4J ) 1.9 Hz, CF3); 19F NMR (376 MHz, CDCl3, CFCl3,
in 2 weeks after preparation) 18b (25%) δ -79.28 (s, CF3),
o
) 9.1 Hz), 7.18 (1H, dd, J ) 9.1 Hz, mJ ) 3.2 Hz), 7.30 (1H,
d, mJ ) 3.2 Hz); 19F NMR (188 MHz, CDCl3, CFCl3) δ -76.44
(s, CF3); MS m/z (Irel (%)) 314 (M+, 100), 150 (63), 135 (17),
122 (13), 107 (29), 79 (29), 53 (15), 51 (13); HRMS calcd for
12H8F6O3 (M+) 314.0378, found 314.0389.
3
4
C
-65.70 (dd, J ) 6.3 Hz, J ) 1.9 Hz, CF3).
7-Me t h oxy-2,2-b is(t r iflu or om e t h yl)ch r om a n -4-on e
4-Oxo-2,2-b is(t r iflu or om et h yl)ch r om a n -6-ca r b a ld e-
h yd e (5a ) a n d 4-oxo-2,2-bis(tr iflu or om eth yl)ch r om a n -6-
ca r boxylic a cid (5b). The title compounds were obtained by
(4d ): yield 67% as colorless needles; mp 88-89 °C; IR (KBr)
1688 (CdO), 1620, 1583, 1504, 1440 cm-1; 1H NMR (200 MHz,
CDCl3) δ 3.16 (2H, s, CH2), 3.88 (3H, s, MeO), 6.57 (1H, d, mJ
using a slight modification of a published procedure.11a
A
o
) 2.5 Hz), 6.70 (1H, dd, J ) 8.9 Hz, mJ ) 2.5 Hz), 7.83 (1H,
mixture of chromanone 4h (0.92 g, 2.6 mmol), K2S2O8 (1.80 g,
6.7 mmol), and CuSO4‚5H2O (0.19 g, 0.76 mmol) in acetonitrile
(22 mL) and H2O (15 mL) was boiled for 2 h. Then the reaction
mixture was diluted with 150 mL of H2O, and the product was
extracted with chloroform (3 × 30 mL). The combined extract
was treated with a saturated solution of NaHCO3 (50 mL), and
the aqueous layer was separated and acidified by concentrated
HCl (5 mL). The resulting precipitate was collected, washed
with H2O, and dried to give acid 5b as a colorless solid (0.30
g, 35%), mp 182-183 °C; IR (Nujol) 1740, 1715 (CdO), 1630,
o
d, J ) 8.9 Hz); 19F NMR (188 MHz, CDCl3, CFCl3) δ -76.59
(s, CF3); MS m/z (Irel (%)) 314 (M+, 81), 150 (100), 122 (36),
107 (17), 79 (5), 51 (4); HRMS calcd for C12H8F6O3 (M+)
314.0378, found 314.0383.
5,7-Dim e t h oxy-2,2-b is(t r iflu or om e t h yl)ch r om a n -4-
on e (4e): yield 64% as colorless crystals; mp 77-78 °C; IR
(KBr) 1687 (CdO), 1618, 1577, 1467, 1425 cm-1; 1H NMR (200
MHz, CDCl3) δ 3.12 (2H, s, CH2), 3.87 (3H, s, MeO), 3.90 (3H,
s, MeO), 6.18 (1H, d, mJ ) 1.9 Hz), 6.23 (1H, d, mJ ) 1.9 Hz);
19F NMR (188 MHz, CDCl3, CFCl3) δ -76.73 (s, CF3); MS m/z
(Irel (%)) 344 (M+, 100), 315 (47), 180 (82), 152 (62), 137 (72),
122 (19), 109 (15), 69 (73); HRMS calcd for C13H10F6O4 (M+)
344.0483, found 344.0483.
1600 cm-1 1H NMR (400 MHz, CDCl3) δ 3.29 (2H, s, CH2),
;
o o
7.26 (1H, d, J ) 8.7 Hz), 8.33 (1H, dd, J ) 8.7 Hz, mJ ) 2.2
Hz), 8.67 (1H, d, mJ ) 2.2 Hz). Anal. Calcd for C12H6F6O4: C,
43.92; H, 1.84. Found: C, 44.02; H, 1.85.
2-(Diflu or om eth yl)-6-m eth oxy-2-(tr iflu or om eth yl)ch r o-
The chloroform layer was dried over anhydrous K2CO3 and
filtered, chloroform was distilled off, and aldehyde 5a was
extracted from the residue with hot hexane (50 mL). The
hexane extract was passed through a silica gel layer (d ) 10
m a n -4-on e (4f): yield 50% as colorless crystals; mp 58-59 °C;
1
IR (Nujol) 1700 (CdO), 1615, 1595 cm-1; H NMR (400 MHz,
CDCl3) δ 3.08 (1H, d, J ) 17.6 Hz, CHH), 3.21 (1H, d, J )
7752 J . Org. Chem., Vol. 68, No. 20, 2003

Nucleophilic 1,4-Trifluoromethylation
mm, l ) 10 mm) and eluted with boiling hexane (15 mL).
Hexane excess was distilled off, and aldehyde 5a was crystal-
lized from the remaining solution (∼20 mL) upon cooling to
-10 °C and stirring. The resulting precipitate was collected,
washed with cold hexane, and recrystallized from hexane to
give aldehyde 5a as colorless needles (0.14 g, 17%), mp 85 °C;
MHz, CDCl3, CFCl3) major diastereomer (79%) δ -79.31 (3F,
4 4
dd, J F,F ) 10.8 Hz, J F,F ) 4.6 Hz, CF3), -130.37 (1F, ddq,
2
4
2J F,F ) 297.8 Hz, J F,H ) 54.4 Hz, J F,F ) 10.8 Hz, CFFH),
2
2
4
-134.30 (1F, ddqd, J F,F ) 297.8 Hz, J F,H ) 55.1 Hz, J F,F
)
4.6 Hz, J F,H ) 1.3 Hz, CFFH); 19F NMR (376 MHz, CDCl3,
4
CFCl3) minor diastereomer (21%) δ -77.46 (3F, dd, 4J F,F ) 11.5
1
4
2
IR (Nujol) 1710 (CdO), 1615, 1590 cm-1; H NMR (400 MHz,
Hz, J F,F ) 5.7 Hz, CF3), -131.67 (1F, ddqd, J F,F ) 293.0 Hz,
4 4
CDCl3) δ 3.30 (2H, s, CH2), 7.31 (1H, d, oJ ) 8.6 Hz), 8.17 (1H,
2J F,H ) 54.4 Hz, J F,F ) 11.5 Hz, J F,H ) 2.0 Hz, CFFH),
2 2 4
o
dd, J ) 8.6 Hz, mJ ) 2.1 Hz), 8.40 (1H, d, mJ ) 2.1 Hz), 9.99
-134.66 (1F, ddq, J F,F ) 293.0 Hz, J F,H ) 54.6 Hz, J F,F )
(1H, s, CHO). Anal. Calcd for C12H6F6O3: C, 46.17; H, 1.94.
Found: C, 46.14; H, 1.87.
5.7 Hz, CFFH). Anal. Calcd for C12H11F5O3: C, 48.33; H, 3.72.
Found: C, 48.42; H, 3.75.
4,9-Dim et h oxy-7,7-b is(t r iflu or om et h yl)-6,7-d ih yd r o-
5H-fu r o[3,2-g]ch r om a n -5-ol (11): yield 70% as a yellow
powder; mp 91-92 °C; IR (KBr) 3543 (OH), 1628, 1554, 1492,
2,2-Bis(tr iflu or om eth yl)ch r om a n -4-ols 7c-f a n d 11:
Gen er a l P r oced u r e. To a solution of chroman-4-one 4 or 10
(2.5 mmol) in methanol (5 mL) was added powdered sodium
borohydride (0.47 g, 12.4 mmol) slowly (5 min) at room
temperature, and the mixture was stirred for 10 min. After
dilution with water (25 mL), the residue was filtered off,
washed with water, dried, and purified by recrystallization
from hexane or by SiO2 flash chromatography to give the
compounds 7c-f and 11.
1
1451 cm-1; H NMR (200 MHz, CDCl3) δ 2.50 (1H, dd, 2J )
3
2
3
14.6 Hz, J ) 7.0 Hz, CHH), 2.72 (1H, dd, J ) 14.6 Hz, J )
6.4 Hz, CHH), 3.89 (1H, s, OH), 4.01 (3H, s, MeO), 4.16 (3H,
s, MeO), 5.28 (1H, t, J ) 6.7 Hz, CH), 6.89 (1H, d, J ) 2.5 Hz),
7.55 (1H, d, J ) 2.5 Hz); 19F NMR (188 MHz, CDCl3, CFCl3) δ
-75.51 (q, J F,F ) 10.3 Hz, CF3), -76.22 (q, J F,F ) 10.3 Hz, CF3);
MS m/z (Irel (%)) 386 (M+, 100), 371 (24), 343 (13), 222 (13),
207 (57), 192 (10), 69 (11); HRMS calcd for C15H12F6O5 (M+)
386.0589, found 386.0594.
6-Me t h o x y -2,2-b is (t r iflu o r o m e t h y l)c h r o m a n -4-o l
(7c): yield 89% as colorless crystals; mp 76-77 °C; IR (KBr)
1
3370 (OH), 1617, 1499, 1468, 1429 cm-1; H NMR (400 MHz,
CDCl3) δ 2.06 (1H, d, J ) 7.9 Hz, OH), 2.19 (1H, ddq, 2J )
2,2-Bis(tr iflu or om eth yl)-2H-ch r om en es 8c-f a n d 12:
Gen er a l P r oced u r e. A mixture of chroman-4-ol 7 or 11 (1.5
mmol) and a catalytic amount of p-toluene sulfonic acid (∼10
mg) in xylene (2 mL) was heated at reflux for 2 h. After the
removal of solvent under reduced pressure, the residue was
worked up with boiling hexane and purified by filtration
through a silica gel layer (d ) 10 mm, l ) 10 mm) and
recrystallization from the same solvent (except for 8f) to afford
the compounds 8c-f and 12.
3
4
2
14.2 Hz, J ) 10.4 Hz, J H,F ) 1.5 Hz, CHH), 2.77 (1H, dd, J
) 14.2 Hz, 3J ) 5.9 Hz, CHH), 3.79 (3H, s, MeO), 4.97 (1H,
dt, J ≈ 10.0 Hz, J ≈ 7.0 Hz), 6.82 (1H, ddd, J ) 8.9 Hz, mJ )
o
3.0 Hz, J ) 0.7 Hz), 6.95 (1H, d, oJ ) 8.9 Hz), 7.03 (1H, dd, m
J
) 3.0 Hz, J ) 0.9 Hz); 19F NMR (188 MHz, CDCl3, CFCl3) δ
-76.25 (q, J F,F ) 10.3 Hz, CF3), -77.83 (q, J F,F ) 10.3 Hz, CF3);
MS m/z (Irel (%)) 316 (M+, 100), 315 (2), 299 (5), 152 (72), 151
(15), 137 (48), 109 (8), 69 (6); HRMS calcd for C12H10F6O3 (M+)
316.0534, found 316.0545.
6-Me t h o x y -2,2-b is (t r iflu o r o m e t h y l)-2H -c h r o m e n e
(8c): yield 72% as colorless crystals; mp 34-35 °C; IR (KBr)
1652, 1625, 1587 (CdC), 1495, 1469, 1457, 1438 cm-1; 1H NMR
(400 MHz, CDCl3) δ 3.77 (3H, s, MeO), 5.68 (1H, d, J ) 10.1
7-Me t h o x y -2,2-b is (t r iflu o r o m e t h y l)c h r o m a n -4-o l
(7d ): yield 83% as colorless crystals; mp 74-75 °C; IR (KBr)
1
3259 (OH), 1631, 1591, 1512, 1442 cm-1; H NMR (200 MHz,
o
Hz), 6.62 (1H, d, mJ ) 3.0 Hz), 6.79 (1H, dd, J ) 8.9 Hz, mJ
2
3
CDCl3) δ 2.0 (1H, br s, OH), 2.24 (1H, dd, J ) 14.4 Hz, J )
10.4 Hz, CHH), 2.76 (1H, dd, 2J ) 14.4 Hz, 3J ) 6.0 Hz, CHH),
3.81 (3H, s, MeO), 4.97 (1H, m), 6.57 (1H, d, mJ ) 2.5 Hz),
) 3.0 Hz), 6.85 (1H, d, J ) 10.1 Hz), 6.89 (1H, d, oJ ) 8.9 Hz);
19F NMR (188 MHz, CDCl3, CFCl3) δ -78.15 (s, CF3); MS m/z
(Irel (%)) 298 (M+, 27), 229 (100), 69 (4); HRMS calcd for
o
o
6.68 (1H, dd, J ) 8.9 Hz, mJ ) 2.5 Hz), 7.40 (1H, d, J ) 8.9
12H8F6O2 (M+) 298.0429, found 298.0431.
Hz); 19F NMR (188 MHz, CDCl3, CFCl3) δ -76.02 (q, J F,F
)
C
7-Me t h o x y -2,2-b is (t r iflu o r o m e t h y l)-2H -c h r o m e n e
10.3 Hz, CF3), -77.47 (q, J F,F ) 10.3 Hz, CF3); MS m/z (Irel
(%)) 316 (M+, 85), 315 (29), 299 (41), 152 (58), 151 (100), 69
(23), 28 (94); HRMS calcd for C12H10F6O3 (M+) 316.0534, found
316.0552.
(8d ): yield 68% as colorless crystals; mp 49-50 °C; IR (KBr)
1651, 1626, 1575 (CdC), 1513, 1487, 1468, 1448 cm-1; 1H NMR
(400 MHz, CDCl3) δ 3.80 (3H, s, MeO), 5.51 (1H, d, J ) 10.1
o
Hz), 6.53 (2H, m), 6.83 (1H, d, J ) 10.1 Hz), 6.99 (1H, d, J )
5,7-Dim et h oxy-2,2-b is(t r iflu or om et h yl)ch r om a n -4-ol
9.0 Hz); 19F NMR (188 MHz, CDCl3, CFCl3) δ -78.28 (s, CF3);
MS m/z (Irel (%)) 298 (M+, 25), 229 (100), 69 (9), 28 (15); HRMS
calcd for C12H8F6O2 (M+) 298.0429, found 298.0414.
(7e): yield 76% as a yellow powder; mp 140-141 °C; IR (KBr)
1
3547 (OH), 1632, 1600, 1500, 1464, 1436 cm-1; H NMR (200
MHz, CDCl3) δ 2.43 (1H, dd, 2J ) 15.3 Hz, 3J ) 7.2 Hz, CHH),
2.67 (1H, dd, 2J ) 15.3 Hz, 3J ) 6.2 Hz, CHH), 3.65 (1H, s,
OH), 3.79 (3H, s, MeO), 3.87 (3H, s, MeO), 5.10 (1H, t, J ) 6.5
Hz), 6.19 (2H, s); 19F NMR (188 MHz, CDCl3, CFCl3) δ -75.54
(q, J F,F ) 10.3 Hz, CF3), -76.33 (q, J F,F ) 10.3 Hz, CF3); MS
m/z (Irel (%)) 346 (M+, 93), 345 (41), 329 (100), 182 (42), 181
(23), 164 (41), 136 (14), 69 (43), 28 (18); HRMS calcd for
5,7-Dim e t h oxy-2,2-b is(t r iflu or om e t h yl)-2H -ch r om -
en e (8e): yield 67% as colorless crystals; mp 86-87 °C; IR
(KBr) 1651, 1624, 1588 (CdC), 1504, 1467, 1437 cm-1; 1H NMR
(200 MHz, CDCl3) δ 3.80 (3H, s, MeO), 3.81 (3H, s, MeO), 5.42
(1H, d, J ) 10.1 Hz), 6.09 (1H, s), 6.17 (1H, s), 7.17 (1H, d, J
) 10.1 Hz); 19F NMR (188 MHz, CDCl3, CFCl3) δ -78.34 (s,
CF3); MS m/z (Irel (%)) 328 (M+, 18), 259 (100), 69 (13), 28 (2);
HRMS calcd for C13H10F6O3 (M+) 328.0534, found 328.0549.
2-(Diflu or om eth yl)-6-m eth oxy-2-(tr iflu or om eth yl)-2H-
ch r om en e (8f): yield 51% as a colorless oil; IR (neat) 1650,
1615, 1590 (CdC), 1500, 1475, 1445 cm-1; 1H NMR (400 MHz,
CDCl3) δ 3.76 (3H, s, MeO), 5.69 (1H, d, J ) 10.1 Hz), 5.94
C
13H12F6O4 (M+) 346.0640, found 346.0637.
2-(Diflu or om eth yl)-6-m eth oxy-2-(tr iflu or om eth yl)ch r o-
m a n -4-ol (7f): yield 88% as colorless crystals; mp 59-60 °C;
1
IR (Nujol) 3300 (OH), 1620, 1500 cm-1; H NMR (400 MHz,
CDCl3) major diastereomer (79%) δ 2.03 (1H, d, J ) 7.6 Hz,
OH), 2.08 (1H, dd, 2J ) 14.0 Hz, 3J ) 9.9 Hz, CHH), 2.76 (1H,
2
(1H, t, J H,F ) 54.7 Hz, CF2H), 6.61 (1H, d, mJ ) 3.0 Hz), 6.76
2
3
dd, J ) 14.0 Hz, J ) 5.8 Hz, CHH), 3.79 (3H, s, MeO), 5.00
o
(1H, dd, J ) 8.9 Hz, mJ ) 3.0 Hz), 6.82 (1H, d, J ) 10.1 Hz),
2
(1H, dt, J ) 9.7 Hz, J ) 6.7 Hz), 6.01 (1H, t, J H,F ) 54.8 Hz,
o
6.83 (1H, d, J ) 8.9 Hz); 19F NMR (376 MHz, CDCl3, CFCl3)
CF2H), 6.81 (1H, ddd, J ) 8.9 Hz, mJ ) 3.0 Hz, J ) 0.7 Hz),
o
δ -80.00 (3F, dd, 4J F,F ) 10.6 Hz, 4J F,F ) 6.1 Hz, CF3), -132.22
6.89 (1H, d, J ) 8.9 Hz), 7.02 (1H, dd, mJ ) 3.0 Hz, J ) 0.9
o
2
2
4
1
(1F, ddqd, J F,F ) 298.0 Hz, J F,H ) 54.3 Hz, J F,F ) 10.6 Hz,
Hz); H NMR (400 MHz, CDCl3) minor diastereomer (21%) δ
4J F,H ) 0.8 Hz, CFFH), -133.47 (1F, ddq, J F,F ) 298.0 Hz,
2
2
3
2.03 (1H, d, J ) 7.6 Hz, OH), 2.29 (1H, ddt, J ) 14.4 Hz, J
2J F,H ) 55.1 Hz, J F,F ) 6.1 Hz, CFFH). Anal. Calcd for
4
2
3
) 8.6 Hz, J ) 1.2 Hz, CHH), 2.57 (1H, ddd, J ) 14.4 Hz, J
) 5.5 Hz, J ) 2.1 Hz, CHH), 3.79 (3H, s, MeO), 4.94 (1H, q, J
C
12H9F5O2: C, 51.44; H, 3.24. Found: C, 51.53; H, 3.10.
2
) 7.1 Hz), 6.10 (1H, t, J H,F ) 54.6 Hz, CF2H), 6.82 (1H, ddd,
4,9-Dim eth oxy-7,7-bis(tr iflu or om eth yl)-7H-fu r o[3,2-g]-
oJ ) 8.9 Hz, mJ ) 3.0 Hz, J ) 0.6 Hz), 6.90 (1H, d, J ) 8.9
ch r om en e (12): yield 73% as yellow crystals; mp 75-76 °C;
o
1
Hz), 6.97 (1H, dd, mJ ) 3.0 Hz, J ) 0.8 Hz); 19F NMR (376
IR (KBr) 1647, 1607 (CdC), 1490 cm-1; H NMR (200 MHz,
J . Org. Chem, Vol. 68, No. 20, 2003 7753

Sosnovskikh et al.
CDCl3) δ 4.03 (3H, s, MeO), 4.06 (3H, s, MeO), 5.62 (1H, d, J
) 10.2 Hz), 6.87 (1H, d, J ) 2.5 Hz), 7.33 (1H, d, J ) 10.2 Hz),
7.53 (1H, d, J ) 2.5 Hz); 19F NMR (188 MHz, CDCl3, CFCl3) δ
-77.84 (s, CF3); MS m/z (Irel (%)) 368 (M+, 86), 353 (23), 338
(13), 325 (6), 299 (100), 269 (55), 69 (14), 28 (8); HRMS calcd
for C15H10F6O4 (M+) 368.0483, found 368.0494.
Organic Chemistry, University of Bremen (Germany),
for recording the mass spectra, and Dr. M. I. Kodess,
Institute of Organic Synthesis, Ural Branch, Russian
1
Academy of Sciences (Russia), for recording the H and
19F NMR spectra.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
Ack n ow led gm en t. Financial support by the Deut-
sche Forschungsgemeinschaft (436 RUS 17/105/02) is
gratefully acknowledged. We are very grateful to Dr.
A. Marhold, BAYER AG, Leverkusen (Germany) for the
generous gifts of RFSiMe3, Dr. T. Du¨lcks, Institute of
1
tal details and H and 19F NMR spectra for compounds 4f, 7f,
8f, and 18a . This material is available free of charge via the
Internet at http://pubs.acs.org.
J O034591Y
7754 J . Org. Chem., Vol. 68, No. 20, 2003