Electrophilic fluorinating reagent mediated synthesis of fluorinated α-keto ethers, benzil, and 6,6′-dialkoxy-2,2′-bipyridines

Article abstract of DOI:10.1021/jo0258554

Interactions of various fluorinated and nonfluorinated alcohols with trans-stilbene in the presence of electrophilic reagents were studied. Under neat conditions, reactions of trans-stilbene (1) with fluorinated alcohols, R_fOH (R_f = CF₃CH₂-, CFH₂CH₂-, CF₃CF₂CH₂-, CF₂H(CF₂)₃CH₂-, (CF₃)₂CH-, (CF₃)₃C-(2a-f) in the presence of an electrophilic reagent, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) or N,N-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) (MEC-31), gave α-keto ethers (3a-f) and benzil (4) in good to moderate yields. α-Keto ether and benzil formation was very much dependent on the reaction time, the degree of fluorination of the alcohols, and whether a solvent such as CH₃CN, DMF or DMA was utilized. In solution, α-keto ethers and benzil did not form. Interestingly, under neat conditions, nonfluorinated alcohols, ROH (R = CH₃-, CH₃CH₂-, CH₃CH₂CH₂-, CH₃CH₂CH₂CH₂-, CH₃CH₂CH ₂CH₂CH₂CH₂-) (5g-k) did not react with trans-stilbene in the presence of MEC-31 but gave 6,6′-dialkoxy-2,2′-bipyridines (6g-k), regioselectively, in excellent isolated yields. On the other hand, fluorinated alcohols did not react with MEC-31. Reaction of MEC-31 with an excess of diethylene glycol (7) gave the bipyridine derivative (8) in 88% isolated yield. Reaction of 8 either with diethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) readily produced the corresponding difluoro derivative (9) in 85% isolated yield. All new compounds have been characterized by spectroscopic and elemental analysis.

Full text of DOI:10.1021/jo0258554

Electr op h ilic F lu or in a tin g Rea gen t Med ia ted Syn th esis of
F lu or in a ted r-Keto Eth er s, Ben zil, a n d
6,6′-Dia lk oxy-2,2′-bip yr id in es
Sudha Manandhar, Rajendra P. Singh, Gary V. Eggers, and J ean’ne M. Shreeve*
Department of Chemistry, University of Idaho, Moscow, Idaho 83844-2343
jshreeve@uidaho.edu
Received April 25, 2002
Interactions of various fluorinated and nonfluorinated alcohols with trans-stilbene in the presence
of electrophilic reagents were studied. Under neat conditions, reactions of trans-stilbene (1) with
fluorinated alcohols, RfOH (Rf ) CF3CH2-, CFH2CH2-, CF3CF2CH2-, CF2H(CF2)3CH2-, (CF3)2CH-,
(CF3)3C- (2a-f) in the presence of an electrophilic reagent, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) or N,N-difluoro-2,2′-bipyridinium bis(tetrafluo-
roborate) (MEC-31), gave R-keto ethers (3a -f) and benzil (4) in good to moderate yields. R-Keto
ether and benzil formation was very much dependent on the reaction time, the degree of fluorination
of the alcohols, and whether a solvent such as CH3CN, DMF or DMA was utilized. In solution,
R-keto ethers and benzil did not form. Interestingly, under neat conditions, nonfluorinated alcohols,
ROH (R ) CH3-, CH3CH2-, CH3CH2CH2-, CH3CH2CH2CH2-, CH3CH2CH2CH2CH2CH2-) (5g-k ) did
not react with trans-stilbene in the presence of MEC-31 but gave 6,6′-dialkoxy-2,2′-bipyridines (6g-
k ), regioselectively, in excellent isolated yields. On the other hand, fluorinated alcohols did not
react with MEC-31. Reaction of MEC-31 with an excess of diethylene glycol (7) gave the bipyridine
derivative (8) in 88% isolated yield. Reaction of 8 either with diethylaminosulfur trifluoride (DAST)
or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) readily produced the corresponding
difluoro derivative (9) in 85% isolated yield. All new compounds have been characterized by
spectroscopic and elemental analysis.
In tr od u ction
the preparation of useful organic compounds mediated
by electrophilic reagents.6 We have found new applica-
tions of Selectfluor and of MEC-31 in the preparation of
Synthetic and structural aspects of organofluorine
compounds derived directly from nonfluorinated precur-
sors by using fluorinating agents have been the focal
points of vigorous research as evidenced by the appear-
ance of a large number of publications.1 Because fluorine
is the element with highest electronegativity and its van
der Waals radius is close to that of hydrogen, the
incorporation of a fluorine atom or a fluorine-containing
group into organic molecules alters their physical, chemi-
cal, and biological properties dramatically, making them
suitable for diverse applications in material sciences and
agrochemistry as well as in the pharmaceutical indus-
try.2-5 The biological activity and numerous commercial
applications of organofluorine compounds have encour-
aged interest in developing synthetic methods for selec-
tive and efficient incorporation of fluorine or fluorinated
groups into organic compounds under mild reaction
conditions. Recently, there have been several reports for
(3) For the use of organofluorine compounds in medicinal and
biomedical chemistry, see: (a) Biomedical Frontiers of Fluorine
Chemistry; Ojima, I.; McCarthy, J . R.; Welch, J . T., Eds.; ACS
Symposium Series 639; American Chemical Society: Washington, DC,
1996. (b) Organic Chemistry in Medicinal Chemistry and Biomedical
Applications; Filler, R., Ed.; Elsevier: Amsterdam, 1993. (c) Welch, J .
T.; Eswaraksrishnan, S. Fluorine in Bioorganic Chemistry; J ohn Wiley
and Sons: New York, 1991. (d) Filler, R.; Kirk, K. Biological Properties
of Fluorinated Compounds. In Chemistry of Organic Fluorine Com-
pounds II: A Critical Review; Hudlicky, M.; Pavlath, A. E.; Eds.; ACS
Monograph 187; American Chemical Society: Washington, DC, 1995;
pp 1011-1022. (e) Elliot, A. J . Fluorinated Pharmaceuticals. In
Chemistry of Organic Fluorine Compounds II: A Critical Review;
Hudlicky, M.; Pavlath, A. E.; Eds.; ACS Monograph 187; American
Chemical Society: Washington, DC, 1995; pp 1119-1125. (f) Sholo-
shonok, V. A., Ed. Enantiocontrolled Synthesis of Organo-Fluorine
Compounds: Stereochemical Challenge and Biomedical Targets; J ohn
Wiley and Sons: 1999.
(4) For the use of organofluorine compounds in agrosciences, see:
(a) Cartwright, D. Recent Developments in Fluorine-Containing Agro-
chemicals. In Organofluorine Chemistry: Principles and Commercial
Applications; Banks, R. E.; Smart, B. E.; Tatlow, J . C., Eds.; Plenum:
New York, 1994; pp 237-257. (b) Lang, R. W. Fluorinated Agrochemi-
cals. In Chemistry of Organic Fluorine Compounds II; Hudlicky, M.;
Pavlath, A. E., Eds.; ACS Monograph 187; American Chemical
Society: Washington, DC, 1995; pp 1143-1148.
* To whom correspondence should be addressed. Fax: 208-885-9146.
(1) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737-
1755. (b) Umemoto, T. Ibid. 1757-1777. (c) Prakash, G. K. S.; Yudin,
A. K. Chem. Rev. 1997, 97, 757-777. (d) Taylor, S. D.; Kotoris, C. C.;
Hum, G. 1999, Tetrahedron, 55, 12431-12477. (e) Singh, R. P.;
Shreeve, J . M. Tetrahedron 2000, 56, 7613-7632.
(2) For the general applications of organofluorine compounds, see:
Organofluorine Chemistry: Principles and Commercial Applications;
Banks, R. E.; Smart, B. E.; Tatlow, J . C., Eds.; Plenum: New York,
1994.
(5) The ability of fluorine to change the properties of organic
molecules has been discussed extensively elsewhere. For example,
see: Smart, B. E. Characteristics of C-F Systems. In Organofluorine
Chemistry: Principles and Commercial Applications; Banks, R. E.;
Smart, B. E.; Tatlow, J . C., Eds.; Plenum: New York, 1994; pp 57-
82.
10.1021/jo0258554 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/30/2002
J . Org. Chem. 2002, 67, 6415-6420
6415

Manandhar et al.
SCHEME 1
SCHEME 3
SCHEME 2
various fluorinated R-keto ether derivatives as well as
6,6′-dialkoxy-2,2′-bipyridines in good to excellent isolated
yields.
1, the reaction of Selectfluor with trans-stilbene in the
presence of excess methanol led to the formation of a
mixture erythro and threo isomers of the corresponding
methoxy fluorinated products in good yield.9 Under
similar reaction conditions, the reaction with ethanol also
produced erythro/threo mixtures in good yield. But when
we attempted to extend this chemistry to polyfluoro
alcohols under similar reaction conditions with Select-
fluor or with MEC-31 in the presence of trans-stilbene
in acetonitrile as a solvent, analogous fluorinated ethers
were not obtained. Solvent was then excluded. When the
reaction of trans-stilbene (1) was carried out with Se-
lectfluor in excess trifluoroethanol (2a ) at 25 °C, the
formation of R-keto ether (3a ) was observed as the major
product and benzil (4) as a minor product but both in
low yields (Table 1). Upon heating at 60 °C for 48 h, the
yield of 3a and 4 improved only slightly. When MEC-31
was used at 60 °C for 24 h, the yield of the R-keto ether
(3a ) was found to be higher.
The yields of the R-keto ether and benzil were found
to be a function of the extent of fluorination of the alcohol
used (Table 1). Under similar reaction conditions, various
fluorinated alcohols (2b-f) were converted into the
corresponding R-keto ethers (3b-f) in moderate to good
yields (Scheme 3, Table 1). Perfluoro-tert-butyl alcohol
produced mostly benzil in 90% yield and traces of R-keto
ether were detected by GC/MS.
1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]-
octane bis(tetrafluoroborate) (Selectfluor) and N,N-di-
fluoro-2,2′-bipyridinium bis(tetrafluoroborate) (MEC-31)
are well-known electrophilic reagents that are effective
in introducing fluorine into an organic molecules.1a,7
Recently, we have reported8 a new application of Select-
fluor in the formation of nitrogen-fluorine bonds by
displacing nitrogen-hydrogen bonds. The chemistry of
nonfluorinated alcohols with trans-stilbene in the pres-
ence of Selectfluor was reported.9 trans-Stilbene was
reacted with Selectfluor in the presence of weak nucleo-
philic reagents (NuH, Nu ) OMe, OH, OAc) in acetoni-
trile produced erythro/ threo mixtures of monofluorinated
compounds (Scheme 1). We were interested in using
fluorinated alcohols in order to synthesize the corre-
sponding polyfluorinated ethers. Surprisingly, the reac-
tion did not proceed when fluorinated alcohols were used
under reaction conditions identical to those described in
Scheme 1 in the presence of solvent. At the end of the
reaction, amide formation was observed10 arising from
the reaction of Selectfluor and trans-stilbene with the
solvent acetonitrile, followed by hydrolysis with aqueous
workup (Scheme 2). However, when the reaction was
carried out in the absence of solvent, a completely new
chemistry was observed.
In our continuing efforts to introduce fluorine into
organic compounds nucleophilically as well as electro-
philically,11 we report a new route to fluorinated R-keto
ethers, benzil, and 6,6′-dialkoxy-2,2′-bipyridine com-
pounds mediated by electrophilic fluorinating reagents.
On the basis of the literature, the reaction mechanism
for the formation of R-keto ether is likely similar to that
reported by Rozen12 where aromatic alkenes were reacted
with alcohols in the presence of elemental fluorine to
produce R-keto ethers.
Rea ction of n on flu or in a ted a lcoh ols w ith MEC-
31. Reaction of nonfluorinated alcohols under similar
reaction conditions gave completely different products
Resu lts a n d Discu ssion
R ea ct ion of F lu or in a t ed Alcoh ols a n d tr a n s-
Stilben e with Selectflu or /MEC-31. As shown in Scheme
(6) Stavber, S.; J ereb, M.; Zupan, M. J . Chem. Soc., Chem. Commun.
2002, 488-489. (b) Stavber, S.; Kralj, P.; Zupan, M. Synlett 2001,
1152-1154.
(11) Singh, R. P.; Kirchmeier, R. L.; Shreeve, J . M. Org. Lett. 1999,
1, 1047-1049. (b) Singh, R. P.; Shreeve, J . M. J . Org. Chem. 2000, 65,
3241-3243. (c) Singh, R. P.; Kirchmeier, R. L.; Shreeve, J . M. J . Org.
Chem. 1999, 64, 2579-2581. (d) Singh, R. P.; Cao, G.; Kirchmeier, R.
L.; Shreeve, J . M. J . Org. Chem. 1999, 64, 2873-2876. (e) Singh, R.
P.; Vij, A.; Kirchmeier, R. L.; Shreeve, J . M. J . Fluorine Chem. 1999,
98, 127-132. (f) Singh, R. P.; Vij, A.; Kirchmeier, R. L;Shreeve, J . M.
Inorg. Chem. 2000, 39, 375-377. (g) Singh, R. P.; Leitch, J . M.;
Twamley, B.; Shreeve, J . M. J . Org. Chem. 2001, 66, 1436-1440. (h)
Singh, R. P.; Chakraborty, D.; Shreeve, J . M. J . Fluorine Chem. 2001,
111 (2), 153-160. (i) Singh, R. P.; Shreeve, J . M. Org. Lett. 2001, 3,
2713-2715. (j) Singh, R. P. Twamley, B.; Shreeve, J . M. J . Org. Chem.
2002, 67, 1918-1924.
(7) Baasner, B., Hagemann, X.; Tatlow, J . C. Introduction of Fluorine
by N-F Compounds. In Methods of Organic Chemistry (Houben-Weyl)
Organo-Fluorine Compounds; Furin, G. G., Ed.; Georg Thieme Ver-
lag: New York, 1999; pp 432-499.
(8) Singh, R. P.; Shreeve, J . M. J . Chem. Soc., Chem. Commun. 2001,
1196-1197.
(9) Lal, G. S. J . Org. Chem. 1993, 58, 2791-2796. (b) Stavber, S.;
Sitler-Pecan, T.; Zupan, M. Bull. Chem. Soc. J pn. 1996, 69, 169-175.
(c) Stavber, S.; Sitler-Pecan, T.; Zupan, M. Tetrahedron Lett. 1994, 35,
1105-1108.
(10) Stavber, S.; Pecan, T. S.; Papez, M.; Zupan, M. J . Chem. Soc.,
Chem. Commun. 1996, 2247-2248.
(12) Rozen, S.; Mishani, E.; Kol. M. J . Am. Chem. Soc. 1992, 114,
7643-7645.
6416 J . Org. Chem., Vol. 67, No. 18, 2002

Synthesis of Fluorinated R-Keto Ethers
TABLE 1. Rea ction of Va r iou s F lu or in a ted Alcoh ols With tr a n s-Stilben e in th e P r esen ce of Electr op h ilic Rea gen ts
than those obtained with fluorinated alcohols. Reaction
of trans-stilbene (1) with anhydrous methanol (5g) in the
presence of MEC-31 at 60 °C for 24 h did not produce
either R-keto ether or benzil. Unreacted trans-stilbene
was recovered quantitatively along with the formation
of 6,6′dimethoxy-2,2′-bipyridine (6g) in 95% yield. Com-
pound 6g was also obtained in 95% yield in a separate
reaction where trans-stilbene was not used in the reac-
tion. The synthesis of bipyridine derivatives continues
to attract attention because of their importance as
industrial and medicinal compounds, as analytical re-
agents, and as ligands for the preparation of metal
complexes with catalytic activities.13 The classical Ull-
mann reactions requires drastic experimental conditions
and in most cases gives low yields of the desired bi-
pyridines. Bipyridines can be also obtained from pyrid-
ylphosphine oxides, but the synthesis required several
steps. The synthesis of 6g was reported in the literature
by in situ generation of the Ni(0) complex, Ni[P(C6H5)3]4,
directly from nickel dichloride, triphenylphosphine and
coupling reaction of 2-methoxy-6-halo pyridine.14 Syn-
thesis of 6g in the present reaction was found to be
excellent in comparison to any reported methods. Under
similar reaction conditions, 5h -k were reacted with
MEC-31 to obtain the 6,6′-dialkoxy-2,2-bipyridines (6h -
k ) in >90% isolated yields (Scheme 4, Table 2). These
(13) Newkome, G. R.; Puckeff, W. E.; Kiefer, G. E.; Gupta, V. K.;
Xia, Yuanjiao, Coreil, M.; Hackney, A. J . Org. Chem. 1982, 47, 7. 4116-
4120. (b) Whitchurch, C.; Andrews, A. R. J . Anal. Chim. Acta 2002,
454, 45-51. (c) Schubert, U. S.; Heller, M. Chem.-Eur. J . 2001, 7,
5252-5259. (d) Bin, L.; Wang-Lin; Pei, J .; Liu, S.-J .; Lai, Y.-H. Haung,
W. Macromolecules 2001, 34, 7932-7940. (e) Zassinovich, G.; Mestroni,
G.; Camus, A. J . Organomet. Chem. 1979, 168, C37-C38.
(14) Tiecco, M.; Testaferri, L.; Cianell, D.; Montanucci, M. Synthesis
1984, 736-738.
J . Org. Chem, Vol. 67, No. 18, 2002 6417

Manandhar et al.
SCHEME 4
SCHEME 5
TABLE 2. Rea ction of Mec-31 With Va r iou s Alcoh ols (60
°C, 24 h )
It was also found that secondary and tertiary alcohols
did not react with MEC-31 even when attempted at 60
°C for several days. One of the impediments may be the
steric hindrance of the alcohols. Also fluorinated alcohols,
for example, trifluoroethanol did not react with MEC-31
under conditions similar to those used for nonfluorinated
primary alcohols. This is expected due to the lower
nucleophilicity of the trifluoroethoxy group. MEC-31
reacted smoothly with excess of diethylene glycol (7) to
produce 8 in 88% isolated yield. Reaction of 7 with MEC-
31 in 1:1 ratio produced only the disubstituted ether (8)
with none of the bridged species being formed. Reaction
of 8 with 2.5 equiv of diethylaminosulfur trifluoride
(DAST) or bis(2-methoxyethyl)aminosulfur trifluoride
(Deoxofluor) at room temperature led to the formation
of the corresponding fluorinated product (9) in 85%
isolated yield (Scheme 5).
Con clu sion
In summary, new applications of Selectfluor and MEC-
31 to produce R-keto ethers and benzil and MEC-31 to
form 6,6′-dialkoxy-2,2′-bipyridines are reported. Reac-
tions of trans-stilbene with fluorinated alcohols in the
presence of Selectfluor or MEC-31 led to the formation
of R-keto perfluoroalkylated ethers in good yields. Flu-
orinated alcohols were found to be unreactive with MEC-
31 in the absence of trans-stilbene. On the other hand,
the reaction of nonfluorinated alcohols with MEC-31 led
to the formation of 6,6′′-dialkoxy-2,2′-bipyridines in excel-
lent isolated yields. Diethylene glycol also reacted with
MEC-31 to produce corresponding 6,6′-disubstituted 2,2′-
bipyridine which reacted with DAST or Deoxofluor to give
the corresponding fluorinated analogue in good yield.
reactions show excellent regioselectivity and no other
isomers were identified by NMR. Currently, the exact
reaction mechanism of the formation of dialkoxy bipyri-
dine regioselectively is unclear but definitely there is a
role of [F] in this chemistry. A very similar chemistry of
MEC-31 with water has been reported by Umemoto et
al.15 Simple bipyridine was found to be unreactive with
methanol under similar reaction conditions.
Exp er im en ta l Section
Gen er a l. All the reactions were performed in 25 mL Pyrex
glass Schlenk vessels under dry nitrogen and in a moisture
free atmosphere. Selectfluor, MEC-31, fluorinated alcohols,
(15) Umemoto, T,; Nagayoshi, M.; Adachi, K.; Tomizawa, G. J . Org.
Chem. 1998, 63, 3379-3385.
6418 J . Org. Chem., Vol. 67, No. 18, 2002

Synthesis of Fluorinated R-Keto Ethers
trans-stilbene, DAST, Deoxofluor, and nonfluorinated alcohols
were used as received. 1H, 19F, and 13C NMR spectra were
recorded in CDCl3 on a spectrometer operating at 300, 282,
and 75 MHz, respectively. Chemical shifts are reported in ppm
relative to the appropriate standard, CFCl3 for 19F and TMS
for 1H and 13C NMR spectra. IR spectra were recorded using
NaCl plates for neat liquids and KBr pellets for solids. Mass
spectra were measured on an electron impact 70 eV spectrom-
eter. Elemental analyses were performed by Desert Analytics
Laboratory, Tucson, AZ.
Gen er a l P r oced u r e for th e P r ep a r a tion of r-Keto
Eth er s. In a typical reaction, trans-stilbene (2 mmol) and
MEC-31 (2.5 mmol) were mixed with the alcohol (5 mL) and
heated at 60 °C for 24 h. At the end of the reaction the excess
alcohol was recovered by trapping at -195 °C under reduced
pressure. To the crude reaction mixture was added methylene
chloride, and the solution was washed twice with water. The
methylene chloride layer was separated and dried over anhy-
drous magnesium sulfate. After filtration, the solvent was
removed under reduced pressure, and product was purified
by thin-layer chromatography.
NMR (CDCl3) δ 68.2 (septet, J C-C-F ) 35 Hz, CH(CF3)2, 68.5,
119.1 (quartet, J C-F ) 284 Hz, CH(CF3)2, 127.3, 128.53, 129.0,
134.2, 135.6, 137.5, 168.2; MS (EI) m/z (species, rel int): 362
(M+, 1), 324 (M+- 2F, 1), 322 (M+ - 2HF, 13), 303 [M+ - (2HF
+ F), 10], 254 [M+ - (CF3 + HF + F), 4], 253 [M+ - (CF3
+
2HF), 27], 105 (C6H5CO+, 1), 69 (CF3+, 3). Anal. Calcd for
C
17F6H12O2: C, 56.40; H, 3.30. Found: C, 56.69; H, 3.13.
2-Ter tiar y P er flu or obu toxy-2-ph en ylacetoph en on e (3f).
Product was difficult to separate from benzil by using silica
gel thin-layer chromatography. It was characterized along with
benzil. Yield: 10% (based on GC); 19F NMR (CDCl3). -74.27
(s, 9F); MS (EI) m/z (species, rel int): 341 [M+ - (CF3 + HF),
1], 235 [OC(CF3)3+, 1].
Ben zil (4). In all the reactions, benzil was characterized
by comparing melting point, MS, 1H and 13C NMR spectra with
an authentic samples.
General procedure for the preparation of 6,6′-dialkoxy-2,2′-
bipyridine derivatives: In a typical reaction, MEC-31 (2 mmol)
was mixed with the appropriate nonfluorinated alcohol (5 mL)
and heated at 60 °C for 24 h. At the end of the reaction the
excess alcohol was recovered by trapping at liquid nitrogen
temperature under reduced pressure. In the crude reaction
mixture, methylene chloride was added and was washed with
water two times. The methylene chloride layer was separated
and dried over anhydrous magnesium sulfate. After filtration,
the solvent was removed under reduced pressure, and the
product was purified by flash chromatography.
2-Tr iflu or oet h oxy-2-p h en yla cet op h en on e (3a ). Yield:
62%; colorless viscous liquid; IR (NaCl film): 3031, 1758, 1494,
1452, 1408, 1276, 1170, 1135, 1049, 977, 752 cm-1
;
19F NMR
1
(CDCl3) δ -74.01 (t, 3F, J ) 8.5 Hz); H NMR (CDCl3) δ 4.48
(q, 2H, J ) 8.5 Hz), 5.09 (s, 1H), 7.19-7.34 (m., 10H), 13C NMR
(CDCl3) δ 56.50, 60.70 (q, J C-C-F ) 36.70 Hz, CH2CF3), 122.86
(q, J C-F ) 277 Hz, CH2CF3),) 127.63, 128.53, 128.77, 137.67,
6,6′-Dim eth oxy-2,2′-bip yr id in e (6g).14 Yield: 95%; color-
less solid, mp ) 118 °C; IR (KBr film): 2951, 1579, 1463, 1300,
1265, 1071, 1020, 907, 793, 732 cm-1; 1H NMR (CDCl3) δ 3.97
(s, 6H), 6.69 (d, 2H, J ) 8.3 Hz), 7.60 (t. 2H, J ) 8.1 Hz), 7.95
(d, 2H, J ) 7.5 Hz). 13C NMR (CDCl3) δ 53.6, 111.3, 114.2,
171.04; MS (EI) m/z (species, rel int) 294 (M+, 14), 275 (M+
-
F, 1), 189 (M+ - PhCO, 1), 167 [M+ - (PhCO + HF + 2H),
100], 152 (PhCHOCH2CF+ + H, 17), 105 (PhCO+, 1.3). Anal.
Calcd for C16F3H13O2: C, 65.29; H, 4.46. Found: C, 65.17; H,
4.53.
139.6, 153.9, 163.8; MS (EI) m/z (species, rel int): 217 (M+
+
2-Flu or oeth oxy-2-ph en ylacetoph en on e (3b). Yield: 72%;
H, 100), 216 (M+, 62), 201 (M+ - CH3, 2), 186 (M+ - 2CH3, 8),
colorless viscous liquid; IR (NaCl film): 3063, 2954, 1691, 1595,
185 (M+ - OCH3, 7), 155 (M+ - 2OCH3 + H, 2), 108 (M+
-
C5H3NOCH3, 2).
1492, 1449, 1219, 1124, 1051, 972, 880, 757, 697 cm-1
;
19F
NMR (CDCl3) δ -223.03 (m, 1F); 1H NMR (CDCl3) δ 3.69 (m,
1H), 3.80 (m, 1H), 4.48 (t, 1H, J ) 4.2 Hz), 4.64 (t, 1H, J ) 4.2
Hz), 5.68 (s, 1H), 7.19-7.44 (m. 8H), 7.91-7.95 (m, 2H). 13C
NMR (CDCl3) δ 68.8 (d, J C-C-F ) 19.84 Hz, CH2CFH2), 83.16
(d, J C-F ) 169.5 Hz, CH2CFH2), 82.49, 85.48, 127.7, 128.54,
128.69, 128.69, 128.94, 129.18, 133.35, 134.97, 135.94, 196.86.
6,6′-Dieth oxy-2,2′-bip yr id in e (6h ). Yield: 92%; colorless
solid, mp ) 69-70 °C; IR (KBr film): 2978, 2895, 1573, 1432,
1384, 1298, 1259, 1145, 1074, 1031, 981, 923, 823, 796 cm-1
;
1H NMR (CDCl3) δ 1.32 (t, 6H, J ) 7.1), 4.45 (q, 4H, J ) 7.02),
6.69 (d, 2H, J ) 8.18), 7.63 (t, 2H, J ) 8.1), 7.94 (d, 2H, J )
7.7); 13C NMR (CDCl3) δ 15.1, 61.9, 111.4, 113.9, 139.6, 153.9,
163.6; MS (EI) m/z (species, rel int) 245 (M+ + H, 100), 244
(M+, 28), 229 (M+ - CH3, 8), 214 (M+ - 2CH3, 3). Anal. Calcd
for C14H16N2O2: C, 68.83; H, 6.60. Found: C, 68.93; H, 6.67.
6,6′-Dip r op oxy-2,2′-bip yr id in e (6i). Yield: 92%; colorless
solid, mp ) 60 °C; IR (KBr film): 2964, 2879, 1573, 1435, 1379,
MS (EI) m/z (species, rel int) 259 (M+ + H, 25), 195 (M+
-
OCH2CFH2, 75), 153 (M+ - PhCO+, 100), 105 (C6H5CO+, 48),
77 (C6H5+, 35), 47 (CH2CFH2, 10). Anal. Calcd for C16FH15O2:
C, 74.39; H, 5.86. Found: C, 74.09; H, 6.29.
2-P en t a flu or op r op oxy-2-p h en yla cet op h en on e (3c).
1297, 1263, 1147, 1072, 1006, 982, 908, 848, 796, 732 cm-1
;
Yield: 56%; colorless viscous liquid, IR (NaCl film): 3066,
1693, 1597, 1449, 1201, 1130, 1101, 1010, 960, 757, 697 cm-1
;
1H NMR (CDCl3) δ 1.02 (t, 6H, J ) 6 Hz), 1.81 (m, 4H, J )
7.05 Hz), 4.33 (t. 4H, J ) 6.6 Hz), 6.67 (d, 2H, J ) 8.13 Hz),
7.60 (t, 2H, J ) 7.83 Hz), 7.92 (d, 2H, J ) 7.38 Hz). 13C NMR
(CDCl3) δ 11.1, 22.8, 67.7, 111.4, 113.8, 139.5, 154.0, 163.8;
MS (EI) m/z (species, rel int) 273 (M+ + H, 100), 272 (M+, 15),
257 (M+ - CH3, 1), 243 (M+ - CH2CH3+, 7), 230 (M+ - CHCH2-
CH3+, 4), 43 (CH3CH2CH2+, 7). Anal. Calcd for C16H20N2O2:
C, 70.56; H, 7.40. Found: C, 70.63; H, 7.33.
19F NMR (CDCl3) δ -83.88 (s, 3F), -123.54 (t, 2F, J H-F ) 11.3
1
Hz); H NMR (CDCl3) δ 3.96 (m, 2H), 5.75 (s, 1H), 7.20-7.90
(m, 10H). 13C NMR (CDCl3) δ 65.5 (t, J C-C-F ) 26.5 Hz, CH2-
CF2CF3), 85.6, 113.0 (triplet of quartets, J C-F ) 255 Hz, J C-C-F
,
36 Hz), 118.6 (quartet of triplets, J C-F ) 286 Hz, J C-C-F, 36
Hz), 127.8, 128.6, 129.0, 129.1, 129.1, 133.6, 134.4, 134.5,
195.4; MS (EI) m/z (species, rel int) 345 (M+ + H, 61), 239
(M+ - PhCO, 69), 195 (M+ - OCH2CF2CF3, 24),105 (PhCO+,
100), 77 (Ph+, 22). Anal. Calcd for C17F5H13O2: C, 59.29; H,
3.81. Found: C, 59.16; H, 3.78.
6,6′-Dibu toxy-2,2′-bip yr id in e (6j). Yield: 92%; colorless
solid, mp ) 70 °C; IR (KBr film): 3082, 2953, 2864, 1571, 1433,
1381, 1301, 1252, 1145, 1070, 1027, 985, 843, 799 cm-1 1H
;
2-Octaflu or open toxy-2-ph en ylacetoph en on e (3d). Prod-
uct was difficult to separate from benzil by using silica gel thin-
layer chromatography. It was characterized along with benzil.
Yield: 56% (based on GC); 19F NMR (CDCl3) δ -120.03 (m,
2F), -126.13 (m, 2F), -130.78 (m, 2F), -137.78 (m, 2F); MS
(EI) m/z (species, rel int) 426 (M+, 1), 321 (M+ - PhCO, 85),
195 ([M+ - OCH2(CF2)3CF2H, 2), 105 (C6H5CO+, 100), 77
(C6H5+, 28).
NMR (CDCl3) δ 0.93 (t, 6H, J ) 7.3 Hz), 1.47 (m, 4H), 1.75
(m, 4H), 4.36 (t, 4H, J ) 6.6 Hz), 6.66 (d, 2H, J ) 8.1 Hz),
7.60 (t, 2H, J ) 8.0 Hz), 7.89 (d, 2H, J ) 7.4 Hz); 13C NMR
(CDCl3) δ 14.4, 19.8, 31.6, 65.9, 111.4, 113.8, 139.5, 154.0,
163.8; MS (EI) m/z (species, rel int) 301 (M+ + H, 100), 300
(M+, 14), 270 (M+ - 2CH3, 3), 257 (M+ - CH2CH2CH3+, 4),
244 (M+ - CHCH2CH2CH3+, 1), 57 (C4H9+, 4). Anal. Calcd for
C
18H24N2O2: C, 71.97; H, 8.05. Found: C, 72.11; H, 7.97.
2-Hexa flu or oisop r op oxy-2-p h en yla cetop h en on e (3e).
6,6′-Dih exoxy-2,2′-bip yr id in e (6k ). Yield: 85%; colorless
Yield: 42%; IR (KBr film): 2965, 1724, 1583, 1424, 1385, 1244,
solid, mp ) 76 °C; IR (KBr film): 2947, 2918, 1575, 1435, 1303,
1195, 1107, 927, 780, 738, 689 cm-1
;
19F NMR (CDCl3) δ -
1261, 1126, 1074, 1016, 984, 850, 798, 728 cm-1 1H NMR
;
1
73.29 (d, 6F, J ) 6 Hz); H NMR (CDCl3) δ 5.26 (s, 1H), 6.68
(CDCl3) δ 0.85 (t, 6H, J ) 6.9 Hz), 1.27-1.44 (m, 12H), 1.71-
1.80 (m, 4H), 4.34 (t, 4H, J ) 6.72 Hz), 6.66 (d, 2H, J ) 8.16
(sept., 1H, J ) 6 Hz), 7.2-7.5 (m. 8H), 7.8-7.9 (m, 2H); 13C
J . Org. Chem, Vol. 67, No. 18, 2002 6419

Manandhar et al.
Hz), 7.60 (t, 2H, J ) 7.59 Hz), 7.89 (d, 2H, J ) 7.5 Hz); 13C
NMR (CDCl3) δ 14.4, 23.0, 26.3, 29.5, 32.1, 66.3, 111.4, 113.8,
removal of solvent afforded the product as a viscous liquid
which was purified by chromatography using pentane and
dichloromethane mixture (2:1). Yield: 85%; viscous liquid; IR
(NaCl film): 1574, 1431, 1298, 1259, 1134, 1048, 930, 798, 725
139.5, 154.0, 163.7; MS (EI) m/z (species, rel int) 357 (M+
+
H, 100), 356 (M+, 20), 341 (M+ - CH3, 7), 327 (M+ - C2H5, 3),
313 (M+ - C3H7, 1), 285 (M+ - C5H11, 4), 272 (M+ - C6H14, 5),
188 [M+ - (C12H26 + 2H), 4]. Anal. Calcd for C22H32N2O2: C,
74.12; H, 9.05. Found: C, 73.50; H, 9.27.
cm-1 19F NMR (CDCl3) δ -223.36 (m, 2F); 1H NMR (CDCl3) δ
;
3.61 (m, 8H), 4.45-4.64 (m, 8H), 6.69-6.75 (m, 2H), 7.57-
7.65 (m, 2H), 7.86-7.91 (m, 2H). 13C NMR (CDCl3): δ 64.88,
70.01, 70.50 (d, J ) 19.6 Hz), 83.24 (d, J ) 169 Hz), 111.39,
113.84, 139.36, 153.25, 162.38. MS (EI) m/z (species, rel int)
6,6′-B is {[2-(2-h y d r o x y )e t h o x y]e t h o xy }-2,2′-b ip y r i-
d in e (8). Compound 8 was prepared by the same procedure
as used for 6g-k . Yield: 88%; colorless solid; mp 94 °C; IR
(KBr film): 2953, 2887, 1577, 1444, 1300, 1263, 1135, 1063,
1032, 795 cm-1; 1H NMR (CDCl3) δ 1.54 (s, 2H), 3.62 (t, 4H, J
) 4 Hz), 3.71 (t, 4H, J ) 5.7 Hz), 3.86 (t, 4H, J ) 4.8 Hz), 4.55
(t, 4H, J ) 4.6 Hz), 6.72 (d, 2H, J ) 12.5 Hz), 7.61 (t, 2H, J )
7.7 Hz), 7.88 (d, 2H, J ) 12.3 Hz); 13C NMR (CDCl3) δ 62.1,
65.2, 70.0, 72.9, 111.7, 114.2, 139.7, 153.6, 163.2. MS (EI) m/z
(species, rel int) 365 (M+ + H, 1), 220 (M+ - C6H10NO3 , 100),
219 [M+ - (C6H10NO3 + H), 100], 205 [M+ - (C7H11NO3 + 2H),
40), 203 [M+ - (C6H10NO3 + OH), 56], 165 (C9H11NO2+, 56),
57 (CHCH2OCH2+, 78). Anal. Calcd for C18H24N2O6: C, 59.33;
H, 6.64. Found: C, 59.27; H, 6.70.
P r ep a r a tion of 6,6′-Bis[2-(2-flu or oeth oxy)eth oxy]-2,2′-
bip yr id in e (9). Compound 8 (1 mmol) was dissolved in
dichloromethane (5 mL), and DAST or Deoxofluor (2 mmol)
was added at 25 °C. The reaction was monitored by GCMS
and was complete in 15 h. Reaction was quenched by the slow
addition of aqueous sodium bicarbonate solution until ef-
fervescence had ceased. The dichloromethane layer was sepa-
rated and dried over anhydrous MgSO4, It was filtered, and
369 (M+ + H, 59), 305 (M+ - OCH2CH2F, 14), 278 [M+
-
(CHCH2OCH2CH2F), 12], 277 [M+ - CH2CH2OCH2CH2F, 3],
258 [M+ - (OCH2CH2F + CH2CH2F), 8], 215 (M+ - C6H11
-
O2F2+, 30), 132 (C6H9 F O2+, 12), 131 (C5H8O2F+, 16), 91 (CH2-
CH2OCH2CH2F+, 1), 77 (C5H3N+, 17), 47 (CH2CH2F+ , 69), 45
(C2H5O+, 100). Anal. Calcd for C18H22N2O4: C, 58.69; H, 6.02.
Found: C, 58.53; H, 5.99.
Ack n ow led gm en t . This work was supported by
the National Science Foundation (Grant No. CHE -
9720365) and by the Petroleum Research Fund, admin-
istered by ACS. We are particularly grateful to Dr.
Robert J . Syvret of Air Products and Chemical, Inc., for
the gift of Selectfluor and Dr. Kazuhiro Shimokawa of
Daikin Industries for MEC-31. We are also thankful to
Drs. G. Knerr and A. Blumenfeld for recording MS and
NMR, respectively.
J O0258554
6420 J . Org. Chem., Vol. 67, No. 18, 2002