Reactions of TFDA with ketones. Synthesis of difluoromethyl 2,2-difluorocyclopropyl ethers

Article abstract of DOI:10.1021/jo049570y

The sequential reaction of 2 equiv of difluorocarbene (generated from trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) by treatment with catalytic fluoride ion) with a series of electron-rich aromatic ketones and α,β-unsaturated ketones leads to the formation of difluoromethyl 2,2-difluorocyclopropyl ethers in good yield.

Full text of DOI:10.1021/jo049570y

Rea ction s of TF DA w ith Keton es. Syn th esis of Diflu or om eth yl
2,2-Diflu or ocyclop r op yl Eth er s
Xiaohong Cai, Yian Zhai, Ion Ghiviriga, Khalil A. Abboud, and William R. Dolbier, J r.*
Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200
wrd@chem.ufl.edu
Received March 16, 2004
The sequential reaction of 2 equiv of difluorocarbene (generated from trimethylsilyl fluorosulfo-
nyldifluoroacetate (TFDA) by treatment with catalytic fluoride ion) with a series of electron-rich
aromatic ketones and R,â-unsaturated ketones leads to the formation of difluoromethyl 2,2-
difluorocyclopropyl ethers in good yield.
In tr od u ction
Difluoromethyl 2,2-difluorocyclopropyl ethers, 1, have
in the past attracted some interest in the agrochemical
and pharmaceutical industries,1-3 which is somewhat
remarkable since there have been no straightforward,
efficient procedures available for their synthesis. Fried,
Popper, Crabbe, and their co-workers each reported the
isolation of small quantities of compounds with this
structure, as minor side products in their studies of the
reaction of difluorocarbene (generated via the thermolysis
of an excess of sodium chlorodifluoroacetate) with various
steroidal enones, enol ethers, or esters.4-7 For example,
in the highest yield process reported, Popper observed
the formation of 15% of a product (2) deriving from the
reaction of 3 equiv of difluorocarbene with the given
steroid precursor.6
Trimethylsilyl fluorosulfonyldifluoroacetate (TFDA)
has recently been suggested to be a highly versatile
source of difluorocarbene.8 Unlike its precursor, fluoro-
sulfonyldifluoroacetic acid, which has also been utilized
as a difluorocarbene source for conversions of acids to
their difluoromethyl esters9 and alcohols and phenols to
their difluoromethyl ethers,10 TFDA releases difluoro-
carbene in a controlled, acid-free environment that
appears to be essential for high yield additions of difluo-
rocarbene to alkenes. Indeed, TFDA been shown to be
useful for adding CF2: to a wide variety of alkenes and
alkynes, including very electron-deficient alkenes such
as R,â-unsaturated esters.8,11-13 However, in a very recent
paper Chen and Xu report that TFDA is surprisingly not
effective in the direct difluorocyclopropanation of R,â-
unsaturated aromatic aldehydes and ketones.14,15 Thus,
they describe an indirect approach to accomplish this
task, a process proceeding via the addition of difluoro-
carbene to the respective acetals or ketals.
We have also observed the lack of direct CF2: addition
to R,â-unsaturated aldehydes and ketones. However, in
examining the progress of such reactions, it was noticed
that the substrates disappear quickly upon addition of
TFDA, and multiple new fluorine signals appear in 19F
NMR spectra of the crude reactions mixtures, including
signals that can be attributed to difluorocyclopropanes.
The aldehydes and the ketones undergo very different
reactions, interestingly none of which involve the direct
addition of CF2: to the substrate double bond! In this
(1) Katsuda, S. J P 55081836, 1980.
(2) Billings, C. A.; O’Neill, G. J .; Simons, C. W.; Holdsworth, R. S.;
Grace, W. R. U.S. Patent 3,932,529, 1974.
(3) Billings, C. A.; O’Neill, G. J .; Simons, C. W.; Holdsworth, R. S.;
Grace, W. R. U.S. Patent 3,995,062, 1976.
(4) Beard, C.; Dyson, N. H.; Fried, J . H. Tetrahedron Lett. 1966,
28, 3281-3286.
(5) Beard, C.; Brekoz, B.; Dyson, N. H.; Harrison, I. T.; Hodge, P.;
Kirkham, L. H.; Lewis, G. S.; Giannini, D.; Lewis, B.; Edwards, J . A.;
Fried, J . H. Tetrahedron 1969, 13, 1219-1239.
(11) Dolbier, W. R., J r.; Duan, J .-X.; Tian, F.; Chen, Q.-Y. Org. Synth.
2003, 80, 172-176.
(6) Popper, T. L.; Carlon, F. E.; Marigliano, H. M.; Yudis, M. D.
Chem. Commun. 1968, 277-278.
(12) Battiste, M. A.; Tian, F.; Baker, J . M.; Battista, O.; Villalobos,
J .; Dolbier, W. R., J r. J . Fluorine Chem. 2003, 119, 39-51.
(13) Dolbier, W. R., J r.; Tian, F.; Duan, J .-X.; Li, A.-R.; Ait-Mohand,
S.; Bautista, O.; Buathong, S.; Baker, J . M.; Crawford, J .; Anselme,
P.; Cai, X.-H.; Modzelewska, A.; Koroniak, H.; Battiste, M. A.; Chen,
Q.-Y. J . Fluorine Chem. 2004, 125, 459-469.
(7) Crabbe, P.; Cervantes, A.; Cruz, A.; Galeazzi, E.; Iriarte, J .;
Velaede, E. J . Am. Chem. Soc. 1973, 95, 6655-6665.
(8) Tian, F.; Kruger, V.; Bautista, O.; Duan, J .-X.; Li, A.-R.; Dolbier,
W. R., J r.; Chen, Q.-Y. Org. Lett. 2000, 2, 563-564.
(9) Chen, Q.-Y.; Wu, S.-W. J . Org. Chem. 1989, 54, 3023-3027.
(10) Chen, Q.-Y.; Wu, S.-W. J . Fluorine Chem. 1989, 44, 433-440.
(14) Xu, W.; Chen, Q.-Y. J . Org. Chem. 2002, 67, 9421-9427.
(15) Xu, W.; Chen, Q.-Y. Org. Biomol. Chem. 2003, 1, 1151-1156.
10.1021/jo049570y CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/20/2004
4210
J . Org. Chem. 2004, 69, 4210-4215

Reactions of TFDA with Ketones
SCHEME 1
paper, we will discuss the chemistry that is going on with
the R,â-unsaturated ketones and related electron-rich
ketones, chemistry that leads to the formation of difluo-
romethyl 2,2-difluorocyclopropyl ethers in fair to good
yield.
Resu lts a n d Discu ssion
Trimethylsilyl fluorosulfonyldifluoroacetate (TFDA)
can be readily prepared via the reaction of fluorosulfo-
nyldifluoroacetic acid with trimethylsilyl chloride.8,11,16
Through multiple redistillations of TFDA, one can elimi-
nate most of the residual acid in the reagent, but such
TFDA reagent will still contain small amounts (2-3%)
of fluorosulfonyldifluoroacetic acid. Even traces of this
strong acid can prove problematic in reactions of TFDA
with some acid-sensitive alkene substrates. Therefore a
procedure was developed to remove the last traces of
residual acid from the TFDA.13 This procedure involves
treatment of the distilled TFDA with a quantity of
triethylamine equivalent to the content of residual acid.
After filtering the precipitated salt, the acid-free TFDA
is generally used immediately.
presence of 6 mol % anhydrous sodium fluoride at 80 °C
for 6 h gave compound 4b in 87% yield, after recovering
starting material via column chromatography.
It was found that the rate of addition of the TFDA
strongly affected the yields of these reactions. TFDA was
usually added at the rate of 0.20-0.25 mL/h, using a
syringe pump with a Teflon needle. Varying the temper-
ature of the reactions indicated that 80 °C was optimal
for the reactions of TFDA with these two ketone sub-
strates. Various solvents (toluene, benzene, methyl ben-
zoate, 3-pentanone) were tried, and toluene or benzene
were found to be the best solvents for this reaction.
Mech a n ism . Although the reaction clearly involves
the sequential reaction of 2 equiv of difluorocarbene with
the substrates, the actual mechanism must still be
considered uncertain. Nevertheless, we propose the mech-
anism depicted in Scheme 1, mainly because the overall
results, including the relative reactivity of the various
substrates, can be readily rationalized by it. This mech-
anism suggests initial formation of an oxonium ylide
(intermediate A) formed from complexation of CF2: with
the carbonyl oxygen of 3a , which then undergoes an
intramolecular, orbital-symmetry-allowed, suprafacial
hydrogen shift to give enol ether intermediate B. Addition
of a second equivalent of difluorocarbene to B leads to
the observed products. The presence of the aromatic
substituent (which would of course stabilize the ylide)
appears to be essential for the success of this overall
reaction, since the compound where the phenyl has been
replaced by one or two methyls does not undergo a useful
reaction. In additional support of this mechanism, enol
ethers related to B have been detected as minor compo-
nents in a number of reactions of TFDA with ketones.
However, recognizing that TFDA is a potentially good
TMS transfer agent and lacking direct evidence for the
ylide intermediate, a mechanism involving trimethylsilyl
enol ethers (C) as intermediates, such as that depicted
in Scheme 2, must be considered a viable alternative.
R ea ct ion s of TF DA w it h Ar yl Met h yl Ket on es.
Considering the proposed reaction mechanism, it does not
appear that the double bond in compound 3a should be
essential for the reaction. Indeed, when the reaction was
carried out using aryl ketones in the place of unsaturated
ketones, analogous reactions were observed to occur
Rea ction s of TF DA w ith r,â-Un sa tu r a ted Ke-
ton es. The reactions of TFDA with unsaturated ketones
were investigated, initially using 4-phenylbut-3-ene-2-
one 3a as a model substrate for the purpose of optimiza-
tion. Its reaction with acid-free TFDA (2.5 equiv) in
benzene in the presence of 6 mol % anhydrous sodium
fluoride at 80 °C for 7 h did not give simple adduct 5a
but, instead, gave compound 4a in 20% yield after
purification by column chromatography. Examination of
the crude reaction mixture by 19F NMR indicated that
4a was the only cyclopropane-containing product that
was formed in the reaction. It was characterized by peaks
1
in the H NMR at 1.90 ppm (m, 1H) and 2.07 ppm (m,
1H) for the cyclopropane hydrogens and a doublet of
doublets at 6.35 ppm (J ) 71.5 Hz, J ) 75.4 Hz, 1H) due
to the difluoromethoxy group. There were corresponding
signals in its 19FNMR spectrum at -80.8 ppm (m, 2F)
for the difluoromethoxy group, and at -135.8 ppm (dm,
J (F-F) ) 161.7 Hz, 1F) and -139.6 ppm (dm, J (F-F) ) 161.7
Hz, 1F) for the classic AB cyclopropyl CF2 group. The
molecular weight of the product was confirmed by HRMS.
Use of a larger excess of TFDA (4.5 equiv) allowed the
yield of compound 4a to be improved to 51%, with
additional TFDA not further increasing the yield.
The analogous reaction of benzofuran-2-yl methyl
ketone with acid-free TFDA (4.0 equiv) in benzene in the
(16) Terjeson, R. J .; Mohtasham, J .; Peyton, D. H.; Gard, G. L. J .
Fluorine Chem. 1989, 42, 187-200.
J . Org. Chem, Vol. 69, No. 12, 2004 4211

Cai et al.
SCHEME 2
TABLE 1. Rea ction of TF DA w ith Ar yl Keton es
entry ketone
R
temp (°C)a TFDA (equiv) yield of 4
3h and i gave compounds 4h and 4i in good yields (54-
59%).
1
2
3
4
5
3c
3d
3e
3f
H
4-Me
4-MeO
4-NO2
3,4-diMeO
120
115
115
120
120
4.0
4.5
4.5
4.5
5.0
27
68
70
22
71
3g
a
Oil bath temperature.
(Table 1). Use of different substituents on the aryl groups
indicated that the reaction works best for electron-rich
aryl methyl ketones. Higher temperatures also proved
advantageous for the reactions with aryl methyl ketones.
Thus, whereas treatment of acetophenone with TFDA
(4.0 equiv) in benzene in the presence of 10 mol %
anhydrous sodium fluoride at 80 °C for 5 h gave only a
trace of desired compound 4c, recovering mostly the
acetophenone starting material, carrying the reaction out
in refluxing toluene (at 110 °C) led to a 27% yield of
product 4c (Table 1, entry 1). A significant increase in
yields of difluoromethyl 2,2-difluorocyclopropyl ethers
4d ,e, f (68-71%) was observed when electron-donating
groups (4-Me, 4-MeO, 3,4-diMeO) were present in the
starting aryl ketones. In contrast, the reaction of TFDA
with an acetophenone bearing an electron-withdrawing
substituent (R ) 4-NO2) led to a significantly lower yield
(22%) of product 4f under similar reaction conditions
(Table 1, entry 4).
It was also found that placement of an electron-
donating group, such as alkoxy, in the para position of
propiophenone apparently provides sufficient stabiliza-
tion of the oxonium ylide to allow conformation A′ to
become kinetically available for the H-transfer process,
perhaps via facilitation of the interconversion of syn and
anti oxonium ylides, A and D, as depicted in Scheme 3.
SCHEME 3
It should be mentioned that attempts to use simple
aliphatic methyl ketones, such as 2-hexanone, as sub-
strates in this reaction were unsuccessful.
Thus, the reaction of 4-benzyloxypropiophenone with
TFDA under the usual conditions gave compound 4j as
a mixture of isomers in a total yield of 35%. The trans/
cis isomeric ratio was 1:0.7, with the structures of the
trans and cis diastereomers being confirmed by NMR.
Rea ction s of Ar yl Alk yl Keton es. Somewhat sur-
prisingly, no reaction was observed when propiophenone
or isobutyrophenone were used as substrates in this
reaction, despite numerous attempts at various temper-
atures with various solvents. This lack of reactivity was
attributed to the unfavorable steric strain of required syn-
oxonium ylide intermediate A′ relative to both the
alternative syn-ylide conformation A′′ and the anti-ylide
isomer, D, which may be preferentially formed.
To test this steric hypothesis, reactions of TFDA with
1-tetralones were carried out, with the expectation that,
because of the geometrical constraints of the system,
tetralones should exhibit no reluctance to undergo the
desired sequence of reactions. This expectation was
realized when the reactions of TFDA with 1-tetralones
Representative 1H, 13C, and 19F chemical shifts are
1
given in Figure 1. Long range H-13C couplings seen in
the GHMBC spectrum confirmed the structural identity
of both compounds, e.g., for the case of trans-4j: 6.10-
67.4, 1.34-67.4, 1.34-111.3.
4212 J . Org. Chem., Vol. 69, No. 12, 2004

Reactions of TFDA with Ketones
F IGURE 1. 1H, 13C, and 19F NMR data for trans- and cis-4j.
TABLE 2. Cyclop r op a n e Bon d Len gth s [Å] in
Com p ou n d 4k
A large coupling with the cyclopropyl proton (15.8 Hz
in trans-4j and 17.5 Hz in cis-4j) identified the fluorine
cis to it. The trans coupling was 3.5 Hz in trans-4j and
2.3 Hz in cis-4j. The methyl group displays 2.5 Hz
couplings with both cyclopropyl fluorines in both com-
pounds.
distal
C14-C16
C14-C15
C15-C16
1.614
1.568
1.259
C14-C16′
C14-C15′
C15′-C16′
1.719
1.731
1.413
proximal
proximal
Only one of the cyclopropyl fluorines displayed an NOE
with aromatic protons in the HOESY spectrum, namely,
the one trans to the methyl in trans-4j and the one cis to
the methyl in cis-4j; therefore the methyl and the
aromatic substituent are trans in trans-4j and cis in cis-
4j. The other cyclopropyl fluorine coupled with the
fluorines in the difluoromethoxy group, J -151.26,-83.86 ) 5.9
Hz and J -151.26,-81.94 ) 2.1 Hz in trans-4j and J -137.60,-82.89
) 7.2 Hz and J -137.60,-83.60 ) 4.7 Hz in cis-4j. These are
through-space couplings that confirm the stereochemistry
given in Figure 1.
X-r a y cr ysta l str u ctu r e. We considered it of interest
to obtain a crystalline difluoromethyl 2,2-difluorocyclo-
propyl ether for single-crystal X-ray analysis in order to
ascertain the impact of the difluoromethoxy functionality
on the difluorocyclopropane structure. To accomplish this,
the reaction of TFDA (4.0 equiv) with 2-acetylfluorene,
3k , was carried out to give 4k in 53% isolated yield.
Product 4k was recrystallized from toluene, and its
detailed structure was obtained by single-crystal X-ray
analysis (Figure 2).
F IGURE 2. ORTEP drawing of compound 4k (one of two
observed conformations).
C14-C15 bond (proximal to the CF2 group) are substan-
tially lengthened, and the C15-C16 bond is substantially
shortened in comparison to the “normal” 1.553 and 1.464
Å observed for the distal and proximal C-C bonds,
respectively, of unsubstituted or alkyl-substituted 1,1-
difluorocyclopropanes.17,18 The remaining proximal bond,
in contrast, is significantly shortened.
Con clu sion s
In summary we have developed a new and useful
procedure for the preparation of difluoromethyl 2,2-
difluorocyclopropyl ethers in fair to good yield from the
sequential addition of 2 equiv of difluorocarbene to a
The most notable aspect of the X-ray structure of 4k
is the impact of the difluoromethyl ether function on the
cyclopropane bond lengths. As can be seen below Table
2, the C14-C16 bond (distal to the CF2 group) and the
(17) Perretta, A. T.; Laurie, V. W. J . Chem. Phys. 1975, 62, 2469-
2473.
(18) Dolbier, W. R., J r.; Odaniec, M.; Gomulka, E.; J askolski, M.;
Koroniak, H. Tetrahedron 1984, 40, 3945-3948.
J . Org. Chem, Vol. 69, No. 12, 2004 4213

Cai et al.
same temperature for 4 h. After removing the solvent under
reduced pressure, the residue was purified by column chro-
matography on silica gel (hexanes/AcOEt, 20/1) to give the
desired products, 4c-k .
variety of R,â-unsaturated ketones, aromatic ketones, and
1-tetralones using acid-free TFDA as the difluorocarbene
precursor.
2,2-Diflu or o-1-d iflu or om e t h oxy-1-p h e n ylcyclop r o-
p a n e, 4c: yellow oil, yield 27%; 1H NMR (CDCl3) δ 2.02-2.21
(m, 2H), 6.16 (dd, J ) 72.0 and 76.1 Hz, 1H) 7.41-7.51 (m,
Exp er im en ta l Section
P r oced u r e for Rem ova l of Tr a ce Acid fr om TF DA. To
a 5-mL, one-necked, round-bottomed flask equipped with a
magnetic stirrer and a nitrogen (N2) inlet was added 1.0 g of
TFDA that, according to its 19F NMR spectrum, contained 2.2%
2-fluorosulfonyl-2,2-difluoroacetic acid. Triethylamine (12.2 µL,
0.088 mmol) (1.0 equiv relative to residual acid) was added
dropwise at room temperature using a syringe. The mixture
was stirred for 5 min, and then the solid was filtered by a pipet
with some cotton to obtain a colorless liquid. No residual
5H); 13C NMR δ 21.9 (t, J ) 10.1 Hz), 98.2, 109.5 (t, J (F-C)
)
291.8 Hz), 116.8 (t, J (F-C) ) 258.6 Hz), 128.8, 129.0, 129.8,
131.1; 19F NMR δ -83.1 (m, 2F), -134.9 (dm, J (F-F) ) 158.7
Hz, 1F), -140.8 (dm, J (F-F) ) 158.7 Hz, 1F); HRMS (EI) calcd
for C10H8F4O, M+, 220.0511, found 220.0513.
2,2-Diflu or o-1-d iflu or om eth oxy-1-(4′-m eth ylp h en yl)cy-
clop r op a n e, 4d : yellow oil, yield 68%; 1H NMR (CDCl3) δ
1.98-2.18 (m, 2H), 2.39 (s, 3H), 6.16 (dd, J ) 72.0 and 76.4
Hz, 1H) 7.25 (d, J ) 8.1 Hz, 1H), 7.37 (d, J ) 8.1 Hz, 1H); 13
C
2-fluorosulfonyl-2,2-difluoroacetic acid could be observed by 19
NMR after this treatment.
F
NMR δ 21.2, 21.9 (t, J ) 10.6 Hz), 63.6, 98.2, 109.7 (dd, J (F-C)
) 289.1 and 294.6 Hz), 116.8 (dd, J (F-C) ) 259.8, and 256.4
Hz), 128.0, 128.8, 129.7, 140.0; 19F NMR δ -83.2 (m, 2F),
-134.8 (dm, J (F-F) ) 158.7 Hz, 1F), -141.0 (dm, J (F-F) ) 158.7
Hz, 1F); HRMS (EI) calcd for C11H10F4O, M+, 234.0668, found
234.0671.
P r oced u r e for P r ep a r a tion of 2,2-Diflu or o-1-d iflu o-
r om eth oxy-1-[(E)-2-p h en yleth en yl]cyclop r op a n e, 4a . A
15-mL three-necked, round-bottomed flask was equipped with
a magnetic stirrer, an addition funnel, and a water-cooled
condenser bearing a nitrogen (N2) inlet. Dry benzene (2.4 mL),
sodium fluoride (5.1 mg, 0.12 mmol, 0.06 equiv) and 4-phe-
nylbut-3-ene-2-one (292 mg, 2.0 mmol) (3a ) were added to this
flask. The solution was then heated to reflux, and slow N2
bubbling was initiated for 1 h, after which TFDA (1.50 g, 6.0
mmol, 3.0 equiv) (free of acid according to 19F NMR) was added
slowly using a syringe pump via a Teflon needle at the rate of
0.25 mL/h. After 4 h, an additional amount of TFDA (1.0 g,
4.0 mmol, 2.0 equiv) was similarly added. When the addition
was complete, the mixture refluxed for 3 h. After the solvent
was removed under reduced pressure, the residue was purified
by column chromatography on silica gel (hexanes/AcOEt: 20/
1) to provide 110 mg (51%) of the yellow product, 2,2-difluoro-
1-difluoromethoxy-1-[(E)-2-phenylethenyl]cyclopropane, 4a: 1H
NMR(CDCl3) δ 1.87-1.94 (m, 1H), 2.02-2.12 (m, 1H), 6.13 (d,
J ) 16.1 Hz, 1H), 6.35 (dd, J ) 71.5 and 75.4 Hz, 1H), 6.80 (d,
J ) 16.1 Hz, 1H), 7.28-7.44 (m, 5H); 13C NMR δ 23.3, 63.0,
110.4 (dd, J ) 291.1 and 198.1 Hz), 117.4 (dd, J ) 256.3 and
259.3 Hz), 119.8, 126.7, 128.7, 128.8, 134.0, 135.2; 19F NMR δ
-80.8 (m, 2F), -135.8 (dm, J (F-F) ) 161.7 Hz, 1F), -139.6 (dm,
J (F-F) ) 161.7 Hz, 1F); HRMS (EI) calcd for C12H10F4O, M+,
246.0668, found 246.0650.
P r oced u r e for P r ep a r a tion of 1-(Ben zofu r a n -2-yl)-2,2-
d iflu or o-1-d iflu or om eth oxycyclop r op a n e, 4b. Precisely as
described above, dry benzene (1.2 mL), sodium fluoride (2.6
mg, 0.06 mmol, 0.06 equiv), and benzofuran-2-yl-methyl ketone
(160 mg, 1.0 mmol) (3b) were allowed to react with two batches
of acid-free TFDA (0.51 g, 2.0 mmol, 2.0 equiv) and then 0.51
g (2.0 mmol, 2.0 equiv). After analogous purification by column
chromatography 96 mg (87%) of the yellow oil product,
1-(benzofuran-2-yl)-2,2-difluoro-1-difluoromethoxycyclopro-
pane, 4b, was obtained: 1H NMR (CDCl3) δ 2.21-2.36 (m, 2H),
6.42 (dd, J ) 71.7 and 74.6 Hz, 1H), 6.94 (s, 1H), 7.24-7.32
(m, 1H), 7.33-7.40 (m, 1H), 7.50-7.54 (m, 1H), 7.58-7.63 (m,
1H); 13C NMR δ 22.8, 58.0, 108.4, 109.0 (dd, J (F-C)) 292.0 and
293.6 Hz), 111.6, 117.1 (dd, J ) 259.9 and 263.9 Hz), 121.7,
123.4, 125.7, 127.3, 147.3, 155.2; 19F NMR δ -82.6 (m, 2F),
-134.7 (dm, J (F-F) ) 158.7 Hz, 1F), -140.1 (dm, J (F-F) ) 158.7
Hz, 1F); HRMS (EI) calcd for C12H8F4O2, M+, 260.0460, found
260.0457.
2,2-Diflu or o-1-d iflu or om eth oxy-1′-(4′-m eth oxyp h en yl)-
cyclop r op a n e, 4e: yellow oil, yield 70%; 1H NMR (CDCl3) δ
1.94-2.18 (m, 2H), 3.83 (s, 3H), 6.15 (dd, J ) 72.5 and 76.6
Hz, 1H) 6.95 (dm, J ) 8.7 Hz, 1H), 7.41 (dm, J ) 8.7 Hz, 1H);
13C NMR δ 22.1 (t, J ) 10.1 Hz), 55.3, 63.3, 109.7 (dd, J )
288.8 and 294.1 Hz), 114.3, 116.8 (t, J (F-C) ) 258.4 Hz), 122.9,
130.6, 160.6; 19F NMR δ -83.4(m, 2F), -134.4 (dm, J (F-F)
)
158.7 Hz, 1F), -141.1 (dm, J (F-F) ) 158.7 Hz, 1F); HRMS (EI)
calcd for C11H10F4O2, M+, 250.0617, found 250.0621.
2,2-Diflu or o-1-d iflu or om et h oxy-1-(4′-n it r op h en yl)cy-
clop r op a n e, 4f: yellow oil, yield 22%; 1H NMR (CDCl3) δ
2.15-2.38 (m, 2H), 6.25 (t, J ) 72.7 Hz, 1H) 7.65 (d, J ) 8.7
Hz, 1H), 8.29 (d, J ) 8.7 Hz, 1H); 13C NMR δ 22.5, 62.1, 116.8
(t, J (F-C) ) 259.8 Hz), 119.5 (t, J (F-C) ) 336.4 Hz), 124.0, 129.1,
139.0, 148.3; 19F NMR δ -82.1 (dd, J ) 9.1 and 73.2 Hz, 2F),
-135.5 (dm, J (F-F) ) 161.8 Hz, 1F), -139.8 (dm, J (F-F) ) 161.8
Hz, 1F); LRMS C10H7F4NO3, 265 (M+), 215 (M - CF2).
2,2-Diflu or o-1-diflu or om eth oxy-1-(3′,4′-dim eth oxyph en -
yl)cyclop r op a n e, 4g: yellow oil, yield 71%; 1H NMR (CDCl3)
δ 1.96-2.16 (m, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 6.15 (dd, J )
72.3 and 76.6 Hz, 1H) 6.88 (d, J ) 8.2 Hz, 1H), 6.97-7.02 (m,
2H); 13C NMR δ 22.1, 55.9, 56.0, 109.6 (d, J ) 6.0 Hz), 110.8,
111.8, 116.7 (dd, J ) 212.0 and 236.2 Hz), 117.7 (dd, J ) 182.8
and 204.5 Hz), 121.7, 123.1, 149.3, 150.2; 19F NMR δ -83.6
(m, 2F), -134.6 (dm, J (F-F) ) 158.7 Hz, 1F), -140.9 (dm, J (F-F)
) 158.7 Hz, 1F); HRMS (EI) calcd for C12H12F4O3, M+,
280.0723, found 280.0729.
1,1-Diflu or o-7b-d iflu or om eth oxy-1a ,2,3,7b-tetr a h yd r o-
1H-cyclop r op a [a ]n a p h th a len e, 4h : yellow oil, yield 59%.
1H NMR (CDCl3) δ 1.86-2.01 (m, 1H), 2.16-2.27 (m, 1H),
2.48-2.72 (m, 2H), 2.77-2.89 (m, 1H), 6.24 (dd, J 1 ) 70.8 Hz,
J 2 ) 77.2 Hz, 1H), 7.19 (d, J ) 6.7 Hz, 1H), 7.25-7.38 (m,
2H), 7.62-7.68 (m, 1H); 13CNMR δ 15.2, 26.1, 28.8 (t, J ) 11.6
Hz), 60.8, 111.0 (dd, J ) 298.6, 299.1 Hz), 117.2 (t, J ) 258.6
Hz), 126.5, 126.9, 127.4, 128.3, 128.9, 135.7; 19F NMR δ -81.6
(m, 2F), -130.9 (dd, J d(F-F) ) 158.7 Hz, J d(F-H) ) 12.2 Hz, 1F),
-143.9 (d, J d(F-F) ) 158.7 Hz, 1F); HRMS (EI) calcd for
C12H10F4O, M+, 246.0668, found 246.0667.
1,1-Diflu or o-7b-d iflu or om eth oxy-5-m eth oxy-1a ,2,3,7b-
Gen er a l P r oced u r e for P r ep a r a tion of Diflu or om eth yl
2,2-Diflu or o-1-su bstitu ted Cyclop r op yl Eth er s. A 15-mL
three-necked, round-bottomed flask was equipped with a
magnetic stirrer, an addition funnel, and a water-cooled
condenser bearing a nitrogen (N2) inlet. The flask was charged
with solvents, sodium fluoride (0.06 equiv) and appropriate
ketones 3c-k . The solution was heated to reflux, and slow N2
bubbling was initiated for 1 h. Acid-free TFDA (0.6 g, 2 mmol,
2.0 equiv) was added slowly using a syringe pump via a Teflon
needle at the rate of 0.25 mL/h. After 3 h, an additional amount
of TFDA was added. The reaction mixture was heated at the
tetr a h yd r o-1H-cyclop r op a [a ]n a p h th a len e, 4i: yellow oil,
1
yield 54%; H NMR (CDCl3) δ 1.91-2.07 (m, 1H), 2.09-2.20
(m, 1H), 2.40-2.67 (m, 2H), 2.73-2.84 (m, 1H), 3.81 (s, 3H),
6.21 (dd, J ) 70.8 and 77.7 Hz, 1H), 6.71 (s, 1H), 6.88 (dd, J
) 8.4 and 2.3 Hz, 1H), 7.53 (d, J ) 8.7 Hz, 1H); 13C NMR δ
16.0, 26.5, 28.2 (t, J ) 11.1 Hz), 55.2, 60.5, 110.9 (dd, J ) 299.6
and 297.2 Hz), 112.8, 113.9, 117.1 (t, J ) 258.7 Hz), 119.1,
128.2, 137.8, 159.6; 19F NMR δ -81.8 (m, 2F), -132.2 (dd, J
) 158.7 and 18.3 Hz, 1F), -144.5 (d, J (F-F) ) 158.7 Hz, 1F);
HRMS (EI) calcd for C13H12F4O2, M+, 276.0773, found 276.0778.
4214 J . Org. Chem., Vol. 69, No. 12, 2004

Reactions of TFDA with Ketones
2,2-Diflu or o-1-d iflu or om eth oxy-(4′-ben zyloxyp h en yl)-
cyclop r op a n e, 4j: white solid, mp: 59-62 °C, yield 35%
(trans/cis ) 1:0.7); HRMS (EI) calcd for C18H16F4O2, M+,
340.1086, found 340.1087. trans-Isomer: 1H NMR (CDCl3) δ
1.34 (d, J ) 6.5 Hz, 3H), 1.96 (dqd, J ) 16.3, 6.6 and 3.5 Hz,
1H), 5.06 (s, 2H), 6.10 (dd, J ) 75.9 and 73.5 Hz, 1H), 7.00-
7.06 (m, 2H), 7.34-7.46 (m, 7H); 19F NMR δ -81.93 (dd, J )
168.1 and 75.9 Hz, 1F), -83.86 (dd, J ) 168.1 and 73.5 Hz,
1F), -130.31 (ddq, J ) 160.9, 15.8 and 2.6 Hz, 1F), -151.26
(dcv, J ) 160.9 and 3.1 Hz, 1F). cis-Isomer: 1H NMR (CDCl3)
δ 0.94 (ddt, J ) 6.9, 2.2 and 1.1 Hz, 3H), 2.15 (dqd, J ) 17.5,
6.7 and 2.3 Hz, 1H), 5.06 (s, 2H), 6.10 (t, J ) 74.3 Hz, 1H),
7.01 (d, J ) 8.8 Hz, 2H), 7.34-7.46 (m, 7H); 19F NMR δ -82.89
(ddd, J ) 168.9, 74.5 and 7.2 Hz, 1F), -82.89 (ddd, J ) 168.9,
74.2 and 4.7 Hz, 1F), -137.60 (ddddq, J ) 161.4, 17.0, 7.6,
4.7 and 2.3 Hz, 1F), -141.79 (d, J ) 161.4 Hz, 1F).
6.8 Hz, 2H); 13C NMR δ 22.1 (t, J ) 10.5 Hz), 36.2, 63.9, 109.7
(dd, J ) 289.0 and 296.2 Hz), 116.3 (t, J ) 257.3 Hz), 120.2,
120.3, 125.1, 125.7, 127.0, 127.5, 127.8, 129.1, 140.6, 143.4,
143.6, 143.9; 19F NMR δ -81.3 (m, 2F), -134.4 (dm, J (F-F)
)
158.7 Hz, 1F), -140.8 (dm, J (F-F) ) 158.7 Hz, 1F); HRMS (EI)
calcd for C17H12F4O, M+, 308.0824, found 308.0827.
Ack n ow led gm en t. The support of this work in part
by the National Science Foundation (CHE-9982587 and
CHE-0239884) is gratefully acknowledged. K.A.A. wishes
to acknowledge the National Science Foundation and
the University of Florida for funding of the purchase of
the X-ray equipment.
Su p p or tin g In for m a tion Ava ila ble: X-ray experimental
details, drawings, and tables; general experimental methods;
and 1H, 19F, and 13C NMR spectra of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
2,2-Diflu or o-1-d iflu or om eth oxy-1-(9H-flu or en -2-yl)cy-
clop r op a n e, 4k : yellow needles, mp 88-90 °C, yield 53%;
1H NMR (CDCl3) δ 2.07-2.23 (m, 1H), 3.94 (s, 3H), 6.21 (dd,
J 1 ) 72.3 and 76.4 Hz, 1H), 7.32-7.44 (m, 2H), 7.49 (d, J )
7.9 Hz, 1H), 7.57 (d, J ) 7.2 Hz, 1H), 7.66 (s, 1H), 7.82 (t, J )
J O049570Y
J . Org. Chem, Vol. 69, No. 12, 2004 4215