Electrophilic and nucleophilic side chain fluorination of para-substituted acetophenones

Article abstract of DOI:10.1016/j.tet.2008.05.060

para-Substituted α-fluoroacetophenones have been synthesised by three different routes. Electrophilic fluorination of trimethylsilyl enol ethers of acetophenones using Selectfluor (F-TEDA-BF₄, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate)) gave high to moderate yield depending on the electronic properties of the substituents. F-TEDA-BF₄ mediated fluorination of acetophenones in methanol resulted in a mixture of α-fluoroacetophenones and the corresponding 2-fluoro-1,1-dimethyl acetals. The dimethyl acetals were hydrolysed using trifluoroacetic acid in water to maximise the yield of the product. Nucleophilic fluorination of α-bromoacetophenones using tetrabutylammonium hydrogen bifluoride (TBABF) led to moderate yield when having electron-donating substituents, whereas low yields were experienced when more electron-withdrawing substituents were introduced.

Full text of DOI:10.1016/j.tet.2008.05.060

Tetrahedron 64 (2008) 7318–7323
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Electrophilic and nucleophilic side chain fluorination of para-substituted
acetophenones
*
Erik Fuglseth, Thor Håkon Krane Thvedt, Maria Førde Møll, Bård Helge Hoff
Department of Chemistry, Norwegian University of Science and Technology, Hogskoleringen 5, NO-7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
para-Substituted a-fluoroacetophenones have been synthesised by three different routes. Electrophilic
Received 19 February 2008
Received in revised form 29 April 2008
Accepted 15 May 2008
fluorination of trimethylsilyl enol ethers of acetophenones using Selectfluor (F–TEDA–BF4, 1-chloro-
methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate)) gave high to moderate yield
depending on the electronic properties of the substituents. F–TEDA–BF4 mediated fluorination of
Available online 18 May 2008
acetophenones in methanol resulted in a mixture of
fluoro-1,1-dimethyl acetals. The dimethyl acetals were hydrolysed using trifluoroacetic acid in water to
maximise the yield of the product. Nucleophilic fluorination of -bromoacetophenones using tetrabu-
a-fluoroacetophenones and the corresponding 2-
Keywords:
a
Electrophilic fluorination
1-Chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis-
(tetrafluoroborate)
tylammonium hydrogen bifluoride (TBABF) led to moderate yield when having electron-donating
substituents, whereas low yields were experienced when more electron-withdrawing substituents were
introduced.
Ó 2008 Elsevier Ltd. All rights reserved.
Tetrabutylammonium hydrogen bifluoride
a
-Fluoroacetophenone
1. Introduction
preparation of eight different para-substituted
a-fluoro-
acetophenones. Targeting nonhazardous procedures, Selectfluor
(F–TEDA–BF4) and tetrabutylammonium hydrogen bifluoride
(TBABF) were selected as fluorination reagents. F–TEDA–BF4 is
a stable crystalline solid with low hydroscopicity and toxicity,
suited for safe fluorination.27 TBABF is a nucleophilic fluorine
source, claimed to be noncorrosive, possessing good solubility
properties, and having a high thermal stability.12
The importance of fluorinated compounds in pharmaceuticals,
agrochemicals and material sciences has been thoroughly recog-
nised.1–5 As a consequence fluorinated building blocks are required.
a
-Fluoroacetophenones can give access to a number of interesting
molecules by reaction at the keto-group, the -carbon or the aro-
matic ring. Examples include synthesis of fluorinated tetralones,6
pyrozoles7 and thiadiazoles.8
-Fluoroacetophenones are also
a
a
suitable starting materials for fluorochemicals such as 1,1,2-tri-
fluoroethyl aryl ethers,9 1,2-difluoroethylaryls10 and 1,1,2-
trifluoroethylaryls.11
2. Results and discussion
Various methods can be used for synthesis of
a-fluo-
2.1. Comparison of the routes
roacetophenones, including nucleophilic displacement,11–16 elec-
trophilic fluorination,7,17–21 Friedel–Crafts chemistry,22,23 coupling
chemistry24 and reaction via diazo ketones.25,26 Some of these
methods have drawbacks due to the use of hazardous and toxic
chemicals.
The three routes investigated for the synthesis of
roacetophenones, 1a–h, are shown in Scheme 1.
a
-fluo-
Being in need of a series of a-fluoroacetophenones, it was rec-
Route B
ognised that the literature mainly covers reactions towards the
parent compound 2-fluoro-1-phenylethanone, and no systematic
study on the effect of substrate structure on yield had been per-
formed. Therefore, the aim of the work was to compare the use-
fulness of two electrophilic and one nucleophilic strategies for the
O
O
O
Br
F
Route A
Route C
R
R
R
2a-h
1a-h
3a-h
* Corresponding author. Tel.: þ47 73593973; fax: þ47 73550877.
E-mail address: bhoff@chem.ntnu.no (B.H. Hoff).
Scheme 1. Route A: (1) Base/TMSCl, (2) F–TEDA–BF4. Route B: (1) F–TEDA–BF4, (2) TFA.
Route C: TBABF. R¼OMe (a), OBn (b), H (c), F (d), Br (e), CF3 (f), CN (g) and NO2 (h).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.060

E. Fuglseth et al. / Tetrahedron 64 (2008) 7318–7323
7319
In route A, acetophenones were converted to the corresponding
trimethylsilyl enol ethers, and reacted with F–TEDA–BF4. The
fluorination was performed in acetonitrile at room temperature. In
route B,7,17 electrophilic fluorination of the acetophenones, 2a–h,
was performed using 2 equiv of F–TEDA–BF4 in refluxing methanol.
The reaction yielded the fluorinated ketones 1a–h and their cor-
responding 2-fluoro-1,1-dimethyl acetals. Hydrolysis under acidic
tested, only fluorination of 4h failed to reach full conversion after
additional F–TEDA–BF4 had been added. The highest conversion
obtained for 1h via route A was 91%.
2.3. Electrophilic fluorination in methanol (route B)
Treating the acetophenones, 2a–h, with 2 equiv of F–TEDA–BF4
in refluxing methanol7 gave the products 1a–h and the corre-
sponding 2-fluoro-1,1-dimethyl acetals, 6a–h, Scheme 3. For sub-
strates bearing electron-donating substituents, the ring fluorinated
ketones, 5a–b, and their 2-fluoro-1,1-dimethyl acetals, 7a–b, were
also formed. The chemoselectivity (aliphatic/aromatic) was found
to be dependent on the degree of conversion, with higher conver-
sion leading to increased levels of 5a–b and 7a–b.
conditions was required to convert the acetals to the
roacetophenones, 1a–h. For the nucleophilic approach (route C),
the -bromoacetophenones, 3a–h, were reacted with 2 equiv of
a-fluo-
a
TBABF in refluxing THF. The isolated yields for the three strategies
are summarised in Table 1.
Table 1
Isolated yields for the routes A–C
R
Product
Isolated yield (%)
Route A
O
O
O
F-TEDA-BF4
MeOH
F
F
F
Route B
Route C
OMe
OBn
H
F
Br
CF3
CN
NO2
1a
1b
1c
1d
1e
1f
91
89
76
74
69
69
55
44
67
58
66
25
77
73
64
70
48
51
42
36
33
26
20
20
R
R
R
2a-h
1a-h
5a-b
1g
1h
MeO OMe
MeO OMe
F
Electrophilic fluorination via the trimethylsilyl enol ethers
(route A) provided on average the highest yield. The process was
especially suited for substrates bearing electron-donating sub-
stituents. A decrease in yield was observed as more electron-
withdrawing groups were introduced, and only a moderate 44%
yield was obtained for the 4-nitro derivative, 1h.
F
R
R
F
7a-b
6a-h
Scheme 3. Products formed in fluorination of acetophenones using F–TEDA–BF4 in
methanol.
Fluorination of acetophenones in methanol (route B) gave yields
in the range of 25–77%. Fluorination of 2a–b also led to ring fluo-
rinated by-products, which complicated the purification step. Of
the methods tested, route B gave the highest yields of 1e–h.
Nucleophilic fluorination of 3a–h using TBABF (route C) gave
moderate to low yield, depending on substrate structure. The best
Table 2 summarises the reaction time, degree of conversion and
product distribution for the reactions prior to acetal cleavage. The
reaction time varied from 48 h for 2a to 11 days for 2h.
The ketone to dimethyl acetal product ratio depended on
substrate structure, the dimethyl acetal form being favoured by
electron-withdrawing groups. This is in agreement with ketone–
dimethyl acetal equilibrium constants found for acetophenones.28
yields for route C were obtained when reacting
a-bromoaceto-
phenones having electron-donating substituents, whereas for
substrates bearing electron-withdrawing substituents low yields
were experienced.
1H NMR spectroscopy also indicated trace amounts of
a,a-
difluoroacetophenones and a-chloroacetophenones being present
at high conversions. The formation of the latter is most likely due to
electrophilic chlorine impurities in the commercial reagent.
Treating the ketone/dimethyl acetal mixture under acidic con-
2.2. Electrophilic fluorination via trimethylsilyl enol ethers
(route A)
ditions, converted 6a–h and 7a–b to the corresponding
a-fluo-
In the first step, the acetophenones (2a–h) were converted to
the trimethylsilyl enol ethers 4a–h, Scheme 2. For preparation of
4a–g, lithium hexamethyldisilazane (LiHMDS) and trimethylsilyl
chloride (TMSCl) were used, giving a conversion of >98%. Com-
pound 4h proved to be more difficult to prepare in decent purity by
this method. Changing the base to DBU improved the synthesis, and
a conversion of 95% could be obtained.
roacetophenones,1a–h and 5a–b. The yield of 1a–h varied between
25 and 77%. The low yield in the case of 1d is explained by the
volatility of the intermediate 2-fluoro-1,1-dimethyl acetal, 6d. A
test distillation performed at atmospheric pressure, revealed that
both 6d and 1d co-distilled with methanol at 66–67 ꢀC.
The hydrolytic stability of the dimethyl acetals was also de-
pendent on the aromatic substituents. Electron-withdrawing
Table 2
O
O
OSiMe3
Reaction time, conversion and product distribution (1H NMR spectroscopy) for
fluorination of acetophenones, 2a–h, using F–TEDA–BF4 in methanol
F
TMSCl
Base
F-TEDA-BF4
Acetonitrile
Substrate
Reaction time (h)
Conv. (%)
Product distribution (%)
R
R
R
1
5
6
7
2a-h
4a-h
1a-h
2a
2b
2c
2d
2e
2f
48
72
96
98
96
98
99
98
99
99
99
67
57
36
38
26
7
13
6
0
0
0
0
0
0
11
24
62
61
72
92
86
92
7
9
0
0
0
0
0
0
Scheme 2. Synthesis of 1a–h via the trimethylsilyl enol ethers, 4a–h, using F–TEDA–BF4.
The crude trimethylsilyl enol ethers, 4a–h, were treated with F–
TEDA–BF4 at room temperature in acetonitrile. The reaction prog-
ress was monitored by 1H NMR spectroscopy. Some reactions failed
to go to completion, but addition of 0.1–0.3 additional equivalents
of F–TEDA–BF4 allowed for full conversion (>98%). Of the substrates
96
125
144
192
261
2g
2h
13
7

7320
E. Fuglseth et al. / Tetrahedron 64 (2008) 7318–7323
Ar
O
O
O
O
F
TBAHF2
THF
Br
+
O
Ar
Br
O
O
+
H
Ar
R
R
Ar
8a-h
Ar
3a-h
Scheme 4. Synthesis of
1a-h
9a-h
a
-fluoroketones, 1a–h, via a-bromoketones 3a–h, using TBABF.
groups increased the stability. Compound 6h proved to be particu-
larly stable and could not be cleaved by several protocols.29–31
However, refluxing with 10% aqueous hydrochloric acid in THF, or
trifluoroacetic acid/water/chloroform,32 provided full conversion
within 20 h. The use of HCl had the drawback of formation of small
experimentally simple, and the yields were independent of the
electronic properties of the aromatic substituents. The protocol
suffers from low chemoselectivity for substrates bearing electron-
donating groups, prolonged reaction times and the requirement of
2 equiv of F–TEDA–BF4. However, the method gave the highest yields
amounts of the corresponding
a
-chloroacetophenone. The mecha-
for compounds 1e–h. Nucleophilic displacement of a-bromoaceto-
nistic rational behind this transformation has not been investigated.
phenones containing electron-donating substituents gave moderate
yields. For substrates bearing electron-withdrawing groups, con-
densation reactions led to complex mixtures and low yields. Com-
pared to the electrophilic fluorinations, this method is of less value.
2.4. Nucleophilic displacement (route C)
The yield of the nucleophilic displacement reaction using TBABF
depended on the aromatic ring substituents. Moderate outcome
was observed for substrates having electron-donating groups,
whereas only 20% isolated yield was obtained for 1g–h. The de-
crease in reaction yield through the series parallels the increasing
electron-withdrawing property and acidity of the acetophenones.33
The main by-products in these reactions were trans-1,2,3-tri-
(benzoyl)cyclopropanes, 8a–h, Scheme 4.
4. Experimental
4.1. General
The acetophenones 2a, 2c and 2f–h, the a-bromoacetophenones
3a and 3c and tetrabutylammonium hydrogen bifluoride (50% so-
lution) were purchased from Fluka. LiHMDS, Selectfluor (F–TEDA–
BF4) and trimethylsilyl chloride were purchased from Aldrich.
Column chromatography was performed using silica gel 60A from
Inthecaseof3c–e, ca. 20%of thesubstrates wereconsumedinthis
side reaction. Compounds 8c–e were isolated and characterised. The
stereochemistryof8c–ewasevidentfromthe 1HNMR spectra, which
contained a one proton triplet at ca. 4.2 ppm and a two proton dou-
blet at ca. 3.7 ppm, both with a coupling constant of ca. 5.6 Hz. These
compounds are most likely formed via the trans-1,2-dibenzoyl-
ethylenes, by a cycloaddition reaction of ionic character.34,35 1H NMR
spectroscopy also indicated compounds 9a–h, products of Darzen-
type condensations,36–38 to be formed under these conditions.
Pyridine and triethylamine have previously been used in fluori-
Fluka, pore size 40–63 mm. 1-(4-Benzyloxyphenyl)ethanone (2b)
was prepared from 4-hydroxyacetophenone using benzyl chloride
and potassium carbonate in N,N-dimethylformamide as solvent. 1-
(4-Fluorophenyl)ethanone (2d) was prepared as described by Olah
et al.40 The
a-bromoacetophenones 3b and 3d–h were prepared by
bromination of the corresponding acetophenones using molecular
bromine. NMR spectra and high resolution mass spectra were in
accordance with proposed structures. Compounds 6b, 6e–h and 7b
were isolated by column chromatography after synthesis according
to route B (4.41 mmol scale), omitting the hydrolytic step.
nations ofa
-bromoacetophenonesusing TBABF.15,39 Themethodwas
tested in fluorination of 3b using both pyridine and triethylamine,
and in reaction of 3c using pyridine. However, this led to further loss
in yield due to formation of compounds 10b, 11b and 10c, Scheme 5.
4.2. Analyses
NMR spectra were recorded with Bruker Avance DPX 400
operating at 400 MHz for 1H, 375 MHz for 19F and 100 MHz for 13C.
For 1H and 13C NMR chemical shifts are in parts per million relative
to TMS, while for 19F NMR the shift values are relative to hexa-
fluorobenzene. Coupling constants are in hertz. NMR resonance
assignment was aided by the HMBC technique.41 MS (EI/70 eV):
Finnigan MAT 95 XL, MS (ESI): Waters QTOF II and MS (CI): Waters
Prospec Q. FTIR spectra were recorded on a Thermo Nicolet Avatar
330 infrared spectrophotometer. All melting points are uncorrected
and measured by a Bu¨chi melting point instrument.
CH3
O
O
N+ CH3
Br-
N+
Br-
CH3
R
R
10b-c
11b
Scheme 5. By-products caused by pyridine or triethylamine.
3. Conclusion
Using three different methods, eight
a
-fluoroacetophenones
4.3. Electrophilic fluorination via trimethylsilyl enol ethers
(route A)
have been prepared. Three of these have previously not been char-
acterised (1b,1f and 1g). In general, electrophilic fluorination via the
trimethylsilyl enol ethers, 4a–h, using F–TEDA–BF4, gave higher
yields than that for the other methods tested. The yield depended on
the aromatic ring substituents, with substrates bearing electron-
donatinggroupsgivinghigher yield. Incontrastto molecularfluorine
and trifluoromethyl hypofluorite,18,20 the use of F–TEDA–BF4 enables
the fluorination to take place at room temperature in conventional
media. Fluorinationof acetophenoneswithF–TEDA–BF4 in methanol
The trimethylsilyl enol ethers, 4a–g, were prepared as described
by Wiles et al.42 starting with 20 mmol of the acetophenones.
Compound 4h was prepared according to Schumacher and Reis-
sig.43 1H NMR spectra were in accordance with that reported pre-
viously: 4a,44 4b,44 4c,45 4d,18 4f,43 4g46 and 4h.43 Compound 4e:
1H NMR (CDCl3)
d
: 0.26 (s, 9H), 4.44 (d, J¼1.9 Hz, 1H), 4.89 (d,
J¼1.9 Hz, 1H) and 7.44 (m, 4H).
gave the
a
-fluoroacetophenones, 1a–h, and the corresponding 2-
fluoro-1,1-dimethyl acetals, 6a–h. The dimethyl acetals were
hydrolysed to 1a–h using trifluoroacetic acid. The method is
The crude trimethylsilyl enol ether 4 (20 mmol) dissolved in dry
acetonitrile (50 mL) was added to a suspension of F–TEDA–BF4
(20 mmol) in dry acetonitrile (150 mL). The reaction mixture was

E. Fuglseth et al. / Tetrahedron 64 (2008) 7318–7323
7321
stirred at room temperature and monitored by 1H NMR spectros-
copy until complete consumption of the trimethylsilyl enol ether.
Additional F–TEDA–BF4 (0.1–0.2 equiv) was added in cases where
complete conversion was not obtained. A solvent switch from
acetonitrile to EtOAc (100 mL) was performed. The organic phase
was washed with water (2ꢁ100 mL) and brine (100 mL), and dried
over Na2SO4 before the solvent was evaporated under reduced
pressure. The crude products were purified as follows: 1a, silica gel
chromatography (pentane/EtOAc, 5:2); 1b, crystallisation (i-PrOH);
1c, bulb to bulb distillation (94–96 ꢀC at 1.5ꢁ10ꢂ2 mbar); 1d, silica
gel chromatography (cyclohexane/acetone, 5:1); 1e, silica gel
chromatography (pentane/acetone, 10:1); 1f, bulb to bulb distilla-
tion (83–85 ꢀC at 7.5ꢁ10ꢂ2 mbar); 1g, crystallisation (EtOH) and 1h,
silica gel chromatography (CHCl3).
J¼47.0 Hz). IR (KBr, cmꢂ1): 2940, 1700, 1599, 1242, 1174, 1082, 1007,
975, 834 and 755. MS (EI, m/z, %): 244 (Mþ, 3), 91 (100) and 65 (7).
HRMS (EI): 244.0895 (calcd 244.0990).
4.6.3. 2-Fluoro-1-phenylethanone (1c)14
Clear oil, which solidified upon storage, mp 25–26 ꢀC (26 ꢀC).49
NMR14,50 and IR-spectra21 were in accordance with that reported
previously. MS (EI, m/z, %): 138 (Mþ, 9), 105 (100) and 77 (64).
HRMS (EI): 138.0483 (calcd 138.0481).
4.6.4. 2-Fluoro-1-(4-fluorophenyl)ethanone (1d)19
White solid, mp 49–51 ꢀC (48–50 ꢀC).19 1H NMR (CDCl3)
d: 5.49
(d, J¼46.9 Hz, 2H), 7.15–7.21 (m, 2H) and 7.83–7.98 (m, 2H). 13C
NMR (CDCl3)
d
: 83.5 (d, J¼186.7 Hz), 116.1 (d, J¼22.0 Hz, 2C), 130.2
(dd, J¼4.2 and 1.1 Hz), 130.7 (dd, J¼12.1 and 3.1 Hz, 2C), 166.2 (d,
4.4. Electrophilic fluorination in methanol (route B)
J¼255.0 Hz) and 192.0 (d, J¼15.8 Hz). 19F NMR (CDCl3)
: ꢂ103.3
d
(m) and ꢂ230.0 (t, J¼47.0 Hz). IR (KBr, cmꢂ1): 2951, 1686, 1600,
1236, 1161, 1083, 976 and 835. MS (EI, m/z, %): 156 (Mþ, 1), 123 (42),
95 (27) and 75 (10). HRMS (EI): 156.0379 (calcd 156.0387).
The acetophenone (8.84 mmol) and F–TEDA–BF4 (2 equiv) were
mixed in methanol (64 mL) and stirred at reflux for 2–11 days. The
reaction mixture was cooled to room temperature, and the meth-
anol was removed under reduced pressure. The residue was diluted
with dichloromethane (150 mL). The organic fraction was washed
with water (2ꢁ30 mL) and brine (30 mL), dried over Na2SO4 and
concentrated under reduced pressure. The crude product was
mixed with chloroform (15 mL), trifluoroacetic acid (3 mL) and
water (3 mL). The acetals 6a–e were cleaved at room temperature,
whereas compounds 6f–h were hydrolysed by refluxing for 20 h.
Trifluoroacetic acid was neutralised by addition of saturated
aqueous NaHCO3. The mixture was extracted with chloroform
(3ꢁ25 mL), dried over Na2SO4 and concentrated under reduced
pressure. Compounds were purified as follows 1a: silica gel chro-
matography (pentane/EtOAc, 5:2), 1b: crystallisation (i-PrOH), 1c:
silica gel chromatography (CH2Cl2), 1d: silica gel chromatography
(cyclohexane/acetone, 5:1), 1e: silica gel chromatography (pen-
tane/acetone, 10:1), 1f: silica gel chromatography (CH2Cl2), 1g:
crystallisation (EtOH), 1h: crystallisation (i-PrOH).
4.6.5. 1-(4-Bromophenyl)-2-fluoroethanone (1e)25
White solid, mp 72–73 ꢀC (71–72 ꢀC).25 1H NMR was in agree-
ment with Ying et al.51 13C and 19F NMR corresponded with that
reported by Bridge et al.25 IR was in accordance with Barkakaty
et al.47 MS (EI, m/z, %): 216/218 (Mþ, 7), 183/185 (100), 155/157 (50)
and 104 (40). HRMS (EI): 215.9585 (calcd 215.9586).
4.6.6. 2-Fluoro-1-(4-trifluoromethylphenyl)ethanone (1f)
White solid, mp 35–36 ꢀC. 1H NMR (CDCl3)
d
: 5.52 (d, J¼46.8 Hz,
2H), 7.76–7.79 (m, 2H) and 8.02–8.04 (m, 2H). 13C NMR (CDCl3)
d
:
83.8 (d, J¼184.3 Hz), 123.4 (q, J¼273 Hz), 126.0 (q, J¼3.8 Hz, 2C),
128.6 (d, J¼3.1 Hz, 2C), 135.4 (q, J¼32.9 Hz), 136.5 (m) and 192.9 (d,
J¼16.4 Hz). 19F NMR (CDCl3)
d
: ꢂ63.9 (s, 3F) and ꢂ230.2 (t,
J¼47.0 Hz). IR (KBr, cmꢂ1): 2937, 1707, 1418, 1330, 1175, 1066, 976
and 836. MS (EI, m/z, %): 206 (Mþ, 0.1), 173 (35), 145 (100), 125 (29),
95 (17) and 75 (9). HRMS (EI): 206.0360 (calcd 206.0355).
4.5. Nucleophilic displacement (route C)
4.6.7. 1-(4-Cyanophenyl)-2-fluoroethanone (1g)
White solid, mp 104–105 ꢀC. 1H NMR (CDCl3)
d: 5.51 (d,
Tetrabutylammonium hydrogen bifluoride (10 mmol in aceto-
nitrile) was treated under a stream of nitrogen gas to remove
acetonitrile prior to dilution with freshly distilled THF (25 mL). The
J¼46.8 Hz, 2H), 7.81 (m. 2H) and 8.02 (m, 2H). 13C NMR (CHCl3)
d:
83.8 (d, J¼183.5 Hz), 117.4, 117.6, 128.6 (d, J¼3.3 Hz, 2C), 132.7 (2C),
136.7 (d, J¼1.1 Hz) and 192.7 (d, J¼16.9 Hz). 19F NMR (CDCl3)
d:
a
-bromoacetophenone (5 mmol) was dissolved in THF (25 mL) and
ꢂ229.6 (t, J¼47.0 Hz). IR (KBr, cmꢂ1): 3095, 2932, 2231, 1709, 1437,
1232, 1083, 979 and 839. MS (EI, m/z, %): 163 (Mþ, 2), 130 (100), 102
(56), 76 (11) and 75 (17). HRMS (EI): 163.0437 (calcd 163.0433).
added drop wise to the TBABF solution under a nitrogen atmo-
sphere. The mixture was refluxed until TLC analysis indicated
complete conversion. The reaction mixture was then diluted with
diethyl ether (50 mL) and washed with dilute HCl (0.1 M, 3ꢁ20 mL)
and water (2ꢁ30 mL). The water phase was back extracted twice
with diethyl ether. The combined organic fractions were dried over
MgSO4, concentrated, and then subjected to purification by silica
gel column chromatography (CH2Cl2/MeOH, 100:1).
4.6.8. 2-Fluoro-1-(4-nitrophenyl)ethanone (1h)25
Off-white solid, mp 96–97 ꢀC (90–92 ꢀC).25 1H, 13C and 19F NMR
corresponds with that of Bridge et al.,25 except the C–F coupling
constant for the carbonyl: 192.8 (d, J¼17.0 Hz). IR (KBr, cmꢂ1): 3119,
2934, 1709, 1607, 1526, 1346, 1227, 1091, 973, 857 and 799. MS (EI,
m/z, %): 183 (Mþ, 1), 150 (100), 104 (33), 92 (15) and 76 (20). HRMS
(EI): 183.0339 (calcd 183.0332).
4.6. Analytical data for a-fluoroacetophenones
4.6.1. 2-Fluoro-1-(4-methoxyphenyl)ethanone (1a)47
4.7. Analytical data for impurities and intermediates
White solid, mp 79–80 ꢀC (78–79 ꢀC).7 1H, 13C and 19F NMR were
in accordance with that reported by Funabiki et al.48 IR was in ac-
cordance with Barkakaty et al.47 MS (EI, m/z, %): 168 (Mþ, 6),127 (8),
71 (6) and 43 (100). HRMS (EI): 168.0580 (calcd 168.0587).
4.7.1. 2-Fluoro-1-(3-fluoro-4-methoxyphenyl)ethanone (5a)7
Synthesis according to route B. Compound 5a was isolated by
silica gel chromatography (pentane/EtOAc, 5:2) as a white solid mp
84–85 ꢀC (82–84 ꢀC).7 1H NMR was in accordance with that
4.6.2. 1-(4-Benzyloxyphenyl)-2-fluoroethanone (1b)
reported previously.7 13C NMR (CDCl3)
d
: 56.5, 83.8 (dd, J¼182.9 and
White solid, mp 110–111 ꢀC. 1H NMR (CDCl3)
d
: 5.14 (s, 2H), 5.46
(d, J¼47.0 Hz, 2H), 7.02–4.04 (m, 2H), 7.36–7.43 (m, 5H) and 7.87–
7.89 (m, 2H). 13C NMR (CDCl3)
: 70.2, 83.5 (d, J¼181.1 Hz), 115.0
0.7 Hz), 112.8 (d, J¼2.0 Hz), 115.9 (dd, J¼19.3 and 3.2 Hz), 125.7 (t,
J¼3.5 Hz), 127.1 (dd, J¼5.3 and 1.2 Hz), 152.3 (dd, J¼249.0 and
d
0.5 Hz), 153.0 (d, J¼10.8 Hz) and 191.5 (dd, J¼16.0 and 2.0 Hz). 19
F
(2C), 127.0, 127.5 (2C), 128.4, 128.8 (2C), 130.3 (d, J¼2.9 Hz, 2C),
NMR (CDCl3)
d
: ꢂ133.3 (m) and ꢂ230.0 (t, J¼46.9 Hz). IR (KBr,
135.9, 163.4 and 191.9 (d, J¼15.5 Hz). 19F NMR (CDCl3)
d: ꢂ230.4 (t,
cmꢂ1): 2925, 2852, 1697, 1612, 1519, 1280, 1084, 1012 and 995. MS

7322
E. Fuglseth et al. / Tetrahedron 64 (2008) 7318–7323
(EI, m/z, %): 186 (Mþ, 45), 153 (100), 125 (37), 110 (48), 95 (63) and
4.7.7. 4-(2-Fluoro-1,1-dimethoxyethyl)benzonitrile (6g)
82 (47). HRMS (EI): 186.0497 (calcd 186.0492).
The dimethyl acetal 6g was purified by silica gel chromatography
(CHCl3) yielding colourless oil. 1H NMR (CDCl3): 3.27 (s, 6H), 4.48 (d,
4.7.2. 1-(4-(Benzyloxy)-3-fluorophenyl)-2-fluoroethanone (5b)
Synthesis according to route B. The mother liquor after crys-
tallisation of 1b was concentrated, and compound 5b was isolated
by silica gel chromatography (CH2Cl2) yielding a white solid, mp
J¼47.0 Hz, 2H) and 7.67 (m, 4H).13C NMR (CDCl3)
d: 49.4 (2C), 82.6 (d,
J¼178.2 Hz),100.2 (d, J¼19.8 Hz),112.6,118.8,128.4 (d, J¼1.0 Hz, 2C),
132.2 (2C) and 143.7. 19F NMR (CDCl3)
d: ꢂ230.7 (t, J¼46.9 Hz). IR
(KBr, cmꢂ1): 2943, 2843, 2232, 1610, 1294, 1067 and 1034. MS (EI,
m/z, %): 209 (Mþ, 6),179 (43),178 (95),177(76),176 (100),146 (8),130
(64) and 104 (5). HRMS (EI): 209.0855 (calcd 209.0852).
90–92 ꢀC. 1H NMR (CDCl3)
d
: 5.22 (s, 2H), 5.42 (d, J¼47.0 Hz, 2H),
7.05 (m, 1H), 7.33–7.44 (m, 5H), 7.64 (m, 1H) and 7.68 (dd, J¼11.5
and 2.1 Hz, 1H). 13C NMR (CDCl3)
d
: 71.4, 83.7 (dd, J¼183.0 and
0.7 Hz), 114.6 (d, J¼1.9 Hz), 116.2 (dd, J¼19.5 and 3.2 Hz), 125.6 (t,
J¼3.4 Hz), 127.6 (2C), 128.7, 129.0 (2C), 130.5 (d, J¼5.2 Hz), 135.6,
152.0 (d, J¼10.8 Hz), 152.6 (dd, J¼249.4 and 0.5 Hz) and 191.5 (dd,
4.7.8. 1-(Fluoro-1,1-dimethoxyethyl)-4-nitrobenzene (6h)
The dimethyl acetal 6h was purified by silica gel chromatogra-
phy (CHCl3), yielding a with solid, mp 45–46 ꢀC. 1H NMR (CDCl3)
d:
J¼16.0 and 2.0 Hz). 19F NMR (CDCl3)
d
: ꢂ132.7 (m) and ꢂ230.0 (t,
3.29 (s, 6H), 4.50 (d, J¼47.0 Hz, 2H), 7.72 (m, 2H) and 8.24 (m, 2H).
J¼46.9 Hz). IR (KBr, cmꢂ1): 2933, 1707, 1687, 1608, 1517, 1275, 1081
and 994. MS (EI, m/z, %): 262 (Mþ, 2), 139 (7), 91 (100) and 65 (8).
HRMS (EI): 262.0804 (calcd 262.0805).
13C NMR (CDCl3)
d
: 49.4, 82.6 (d, J¼178.1 Hz), 100.2 (d, J¼20.8 Hz),
123.5 (2C), 128.7 (2C), 145.6 (d, J¼3.5 Hz) and 148.2. 19F NMR
(CDCl3)
d
: ꢂ230.8 (t, J¼46.9 Hz). IR (KBr, cmꢂ1): 3001, 2941, 1609,
1522, 1354, 1288, 1090 and 1071. MS (CI, CH4–Cl, m/z, %): 231
(Mþþ2, 11) and 230 (Mþþ1, 100). HRMS (CI, CH4–Cl): 230.0821
(calcd for C10H13FNOþ4 230.0823).
4.7.3. 1-(2-Fluoro-1,1-dimethoxyethyl)-4-methoxybenzene (6a)
Compound 6a was synthesised from 1a according to Ranu
et al.30 Compound hydrolysed during work-up yielding only 4 mg
(5%) after silica gel chromatography (hexane/EtOAc, 7:3). 1H NMR
4.7.9. 1-(Benzyloxy)-2-fluoro-4-(2-fluoro-1,1-
dimethoxyethyl)benzene (7b)
(CDCl3)
d
: 3.27 (s, 6H), 3.82 (s, 3H), 4.48 (d, J¼47.2 Hz, 2H), 6.91
(m, 2H) and 7.45 (m, 2H). 13C NMR (CDCl3)
d
: 49.1 (2C), 55.3, 83.5
Compound 7b was isolated by silica gel chromatography (pen-
(d, J¼178.1 Hz), 100.4 (d, J¼20.1 Hz), 113.6 (2C), 128.5 (d, J¼0.9 Hz,
tane/EtOAc, 9:1) yielding a yellowish oil. 1H NMR (CDCl3)
d
: 3.29 (s,
6H), 4.47 (d, J¼47.4 Hz, 2H), 5.16 (s, 2H), 7.20 (m,1H), 7.29 (dd, J¼12.5
and 2.0 Hz, 1H) and 7.32–7.49 (m, 6H). 13C NMR (CDCl3)
: 49.4 (2C),
2C), 130.2 (d, J¼0.9 Hz) and 159.7. 19F NMR (CDCl3)
: ꢂ228.7 (t,
d
J¼47.4 Hz). IR (KBr, cmꢂ1): 2942, 2837, 1612, 1513, 1250, 1071 and
1038. MS (EI, m/z, %): 214 (Mþ, 6), 183 (62), 181 (100), 149 (40),
135 (88), 121 (25) and 107 (41). HRMS (EI): 214.1000 (calcd
214.1005).
d
71.5, 83.3 (d, J¼178.2 Hz), 100.1 (dd, J¼20.8 and 1.7 Hz), 115.2 (d,
J¼2.0 Hz), 115.8 (d, J¼20.4 Hz), 123.3 (d, J¼2.9 Hz), 127.6 (2C), 128.4,
128.9 (2C),132.0 (d, J¼5.4 Hz),136.7,147.0 (d, J¼10.8 Hz) and 152.8 (d,
J¼245.9 Hz).19FNMR(CDCl3)
:ꢂ134.3(m)andꢂ229.3(t, J¼46.9 Hz).
d
4.7.4. 1-(Benzyloxy)-4-(2-fluoro-1,1-dimethoxyethyl)benzene (6b)
Compound 6b was purified by silica gel chromatography (pen-
tane/EtOAc, 9:1) yielding a white sold, mp 64.5–66.5 ꢀC. 1H NMR
IR (KBr, cmꢂ1): 2943, 2836, 1601, 1515, 1276, 1072 and 1036. MS (EI,
m/z, %): 308 (Mþ, 31), 277 (58), 276 (53), 275 (88), 257 (53), 186 (27),
183 (18) and 91 (100). HRMS (EI): 308.1218 (calcd 308.1224).
(CDCl3)
2H), 7.36 (m, 2H) and 7.40–7.42 (m, 5H). 13C NMR (CDCl3)
(2C), 70.2, 83.7 (d, J¼178.2 Hz), 100.6 (d, J¼20.0 Hz), 114.6 (2C),
d
: 3.30 (s, 6H), 4.51 (d, J¼47.3 Hz, 2H), 5.10 (s, 2H), 7.02 (m,
d
: 49.3
4.7.10. trans-1,2,3-Tribenzoylcyclopropane (8c)35
Compound 8c was isolated after synthesis according to route C
by silica gel chromatography (CH2Cl2/MeOH, 100:1) and re-crys-
tallised from EtOAc yielding a white solid, mp 216–217 ꢀC (216–
127.7 (2C), 128.2, 128.8 (2C), 128.8 (2C), 130.6, 137.1 and 159.1. 19
F
NMR (CDCl3)
d
: ꢂ228.7 (t, J¼46.9 Hz). IR (KBr, cmꢂ1): 2935, 2830,
1610, 1514, 1454, 1247, 1098 and 1038. MS (EI, m/z, %): 291 (Mþþ1,
4), 260 (24), 259 (50), 258 (73),169 (5),167 (5), 92 (34), 91 (100) and
65 (26). HRMS (EI): 290.1305 (calcd 290.1318).
217 ꢀC).52 1H NMR corresponds with that of Fuhrmann et al.36 13
C
NMR (CDCl3) d: 30.4, 36.4 (2C), 128.5 (4C), 128.7 (4C), 128.8 (2C),
128.9 (2C), 133.6 (2C), 134.0, 136.5 (3C), 193.0 (2C) and 196.0. IR
(KBr, cmꢂ1): 3066, 3042, 2999, 1685, 1672, 1596, 1447, 1330, 1220
and 715. MS (EI, m/z, %): 354 (Mþ, 1), 249 (32), 233 (9), 105 (100)
and 77 (38). HRMS (EI): 354.1262 (calcd 354.1256).
4.7.5. 1-Bromo-4-(2-fluoro-1,1-dimethoxyethyl)benzene (6e)
The dimethyl acetal 6e was purified by silica gel chromatogra-
phy (CH2Cl2) yielding a colourless oil. 1H NMR (CDCl3)
d: 3.27 (s,
6H), 4.47 (d, J¼47.1 Hz, 2H), 7.40 (m, 2H) and 7.52 (m, 2H). 13C NMR
4.7.11. trans-1,2,3-Tri(4-fluorobenzoyl)cyclopropane (8d)
(CDCl3)
d
: 49.3 (2C), 83.2 (d, J¼178.2 Hz),100.4 (d, J¼20.4 Hz),123.0,
trans-1,2,3-Tri(4-fluorobenzoyl)cyclopropane (8d) was isolated
after synthesis according to route C by silica gel chromatography
129.3 (d, J¼0.9 Hz, 2C), 131.6 (2C) and 137.5 (d, J¼0.5 Hz). 19F NMR
(CDCl3)
d
: ꢂ229.8 (t, J¼46.9 Hz). IR (KBr, cmꢂ1): 2944, 2836, 1592,
(CH2Cl2). White solid, mp 200–202 ꢀC. 1H NMR (CDCl3)
d
: 3.69 (d,
J¼5.6 Hz, 2H), 4.15 (t, J¼5.6 Hz, 1H), 7.09–7.13 (m, 4H), 7.18–7.22 (m,
2H), 8.01–8.03 (m, 4H) and 8.21–8.24 (m, 2H). 13C NMR (CDCl3)
1485, 1394, 1290, 1071, 826 and 743. MS (EI, m/z, %): 264 (35), 262
(36), 245 (36), 243 (32), 234 (64), 233 (86), 232 (82), 231 (100), 230
(78), 229 (93), 216 (31), 201 (7), 199 (9), 105 (10) and 91 (17). HRMS
(EI): 262.0006 (calcd 262.0005).
d
:
30.3, 36.0 (2C), 116.0 (d, J¼22.0 Hz, 4C), 116.1 (d, J¼22 Hz, 2C), 131.4
(d, J¼9.5 Hz, 4C), 131.5 (d, J¼9.6 Hz, 2C), 132.8 (d, J¼2.7 Hz, 2C),
132.8 (d, J¼2.7 Hz), 166.1 (d, J¼256.1 Hz, 2C), 166.4 (d, J¼256.8 Hz),
191.3 (2C) and 194.1. IR (KBr, cmꢂ1): 3068, 3018, 1684, 1665, 1597,
1506, 1227, 1156 and 849. MS (EI, m/z, %): 408 (Mþ, 7), 409 (2), 286
(55), 285 (92), 269 (57), 124 (65), 123 (100) and 95 (90). HRMS (EI):
408.0977 (calcd 408.0973).
4.7.6. 1-(2-Fluoro-1,1-dimethoxyethyl)-4-(trifluoromethyl)-
benzene (6f)
The dimethyl acetal 6f was purified by silica gel chromatography
(pentane/acetone, 7:1) yielding a clear oil. 1H NMR (CDCl3)
d
: 3.30 (s,
6H), 4.51 (d, J¼47.0 Hz, 2H) and 7.66 (m, 4H).13C NMR (CDCl3)
d
: 49.2
(2C), 82.9 (d, J¼178.2 Hz),100.2 (d, J¼20.6 Hz),124.1 (q, J¼272.3 Hz),
125.2 (q, J¼3.8 Hz, 2C), 127.8 (d, J¼0.9 Hz, 2C), 130.7 (q, J¼32.4 Hz)
4.7.12. trans-1,2,3-Tri(4-bromobenzoyl)cyclopropane (8e)53
trans-1,2,3-Tri(4-bromobenzoyl)cyclopropane (8e) was isolated
after synthesis according to route C by silica gel chromatography
(CH2Cl2/MeOH,100:1). White solid, mp 198–200 ꢀC. 1H NMR (CDCl3)
and142.3(m).19FNMR(CDCl3)
d
: ꢂ63.2(s) andꢂ230.3(t, J¼47.0 Hz).
IR (KBr, cmꢂ1): 2949, 2839, 1620, 1411, 1327, 1166 and 845. MS (EI,
m/z, %): Mþdmissing, 221 (32), 219 (100),173 (47),159 (17),145 (31)
and 109 (24). HRMS (EI): not obtained, molecular ion unstable.
d
:3.69(d, J¼5.6 Hz, 2H), 4.13(t, J¼5.6 Hz,1H), 7.59–7.61(m, 4H), 7.67–
7.70 (m, 2H), 7.85–7.87 (m, 4H) and 8.03–8.06 (m, 2H). 13C NMR

E. Fuglseth et al. / Tetrahedron 64 (2008) 7318–7323
7323
(CDCl3)
d
:30.3, 36.1 (2C),129.1 (2C),129.6,129.9 (4C),130.2(2C),132.1
References and notes
(4C),132.3 (2C),135.0 (3C),191.8 (2C) and 194.6. IR (KBr, cmꢂ1): 3052,
1693,1670,1397,1317,1296,1204,1072 and1008. MS(EI, m/z, %): 589/
591 (Mþ, 1), 406 (17), 185 (59), 183 (58), 157 (14), 155 (14) and 28
(100). HRMS (EI): 589.8529 (calcd for C24H15O739Br81Br2: 589.8551).
1. Souzy, R.; Ameduri, B. Prog. Polym. Sci. 2005, 30, 644–687.
2. Lee, Y. S. J. Fluorine Chem. 2007, 128, 392–403.
3. Begue, J. P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992–1012.
4. Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029.
5. Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827–856.
6. Heinrich, M. R. Tetrahedron Lett. 2007, 48, 3895–3900.
7. Katoch-Rouse, R.; Pavlova, O. A.; Caulder, T.; Hoffman, A. F.; Mukhin, A. G.; Horti,
A. G. J. Med. Chem. 2003, 46, 642–645.
4.7.13. (3-(Bromomethyl)-3-(4-fluorophenyl)oxiran-2-yl)(4-
fluorophenyl)methanone (9d)
8. Yoon, S. C.; Cho, J.; Kim, K. J. Chem. Soc., Perkin Trans. 1 1998, 109–116.
9. Zajc, B.; Zupan, M. J. Org. Chem. 1990, 55, 1099–1102.
10. Elke, F.-L. DE Patent 4328761, 1993.
11. Leroy, J. J. Org. Chem. 1981, 46, 206–209.
12. Bosch, P.; Camps, F.; Chamorro, E.; Gasol, V.; Guerrero, A. Tetrahedron Lett. 1987,
28, 4733–4736.
13. Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002, 124, 10278–10279.
14. Makosza, M.; Bujok, R. J. Fluorine Chem. 2005, 126, 209–216.
15. Moughamir, K.; Atmani, A.; Mestdagh, H.; Rolando, C.; Francesch, C. Tetrahedron
Lett. 1998, 39, 7305–7306.
Compound 9d was isolated after synthesis according to route C by
column chromatography (CH2Cl2) starting with 3d. 1H NMR (CDCl3)
d
: 3.67 (d, J¼11.1 Hz,1H), 3.80 (d, J¼11.1 Hz,1H), 4.38(s,1H), 7.11–7.23
(m, 4H), 7.55–7.60 (m, 2H) and 8.04–8.09 (m, 2H).13C NMR (CDCl3)
d:
31.4, 64.8, 116.0 (d, J¼21.8 Hz, 2C), 116.4 (d, J¼22.1 Hz, 2C), 128.3 (d,
J¼8.4 Hz, 2C), 131.4 (d, J¼9.6 Hz, 2C), 132.2 (d, J¼3.1 Hz), 132.4 (d,
J¼3.3 Hz), 163.1 (d, J¼248.8 Hz), 166.5 (d, J¼257.3 Hz) and 190.2.
16. Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, J. A. J. Org.
Chem. 1979, 44, 3872–3881.
4.7.14. 1-(2-(4-(Benzyloxy)phenyl)-2-oxoethyl)pyridinium
17. Stavber, S.; Jereb, M.; Zupan, M. Chem. Commun. 2000, 1323–1324.
18. Middleton, W. J. U.S. Patent 4,215,044, 1979.
19. Middleton, W. J.; Bingham, E. M. J. Am. Chem. Soc. 1980, 102, 4845–4846.
20. Purrington, S. T.; Lazaridis, N. V.; Bumgardner, C. L. Tetrahedron Lett. 1986, 27,
2715–2716.
21. Sato, S.; Yoshida, M.; Hara, S. Synthesis 2005, 2602–2605.
22. Ramachandran, P. V.; Teodorovic, A. V.; Gong, G.; Brown, H. C. Tetrahedron:
Asymmetry 1994, 5, 1075–1086.
23. Bergmann, F.; Kalmus, A.; Breuer, E. J. Am. Chem. Soc. 1957, 79, 4178–4181.
24. Kitazume, T.; Asai, M.; Lin, J. T.; Yamazaki, T. J. Fluorine Chem. 1987, 35, 477–
488.
25. Bridge, C. F.; O’Hagan, D. J. Fluorine Chem. 1997, 82, 21–24.
26. Knunyants, I. L.; Kisel, Y.; Bykhovskaya, E. G. Bull. Acad. Sci. U.S.S.R., Div. Chem.
Sci. (Engl. Trans.) 1956, 363–364.
27. Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C. H. Angew.
Chem., Int. Ed. 2005, 44, 192–212.
bromide (10b)
1-(2-(4-(Benzyloxy)phenyl)-2-oxoethyl)pyridinium
bromide
precipitated from the reaction mixture upon fluorination of 3b using
TBABF in the presence of pyridine. It was also synthesised from 3b.
1-(4-Benzyloxyphenyl)-2-bromoethanone (3b) (1.5 g, 4.9 mmol)
dissolved inTHF (25 mL) was treated with pyridine (0.93 g,12 mmol)
and stirred at 45 ꢀC for 5 h. THF was removed and the residue was re-
crystallised from ethanol utilising diethyl ether as anti solvent,
yielding 1.2 g (64%) of a slight yellowish solid, mp 198–200 ꢀC. 1H
NMR (DMSO)
(m, 5H), 8.03–8.05 (m, 2H), 8.27 (t, 2H), 8.73 (t, 1H) and 8.99 (d, 2H).
13C NMR (CDCl3)
: 66.5, 70.3,115.9 (2C),127.1 (2C),128.4 (2C),128.7,
d: 5.29 (s, 2H), 6.44 (s, 2H), 7.26–7.28 (m, 2H), 7.36–7.50
d
129.1 (2C), 131.3 (2C), 136.8, 146.9 (2C), 163.9 and 189.5. IR (KBr,
cmꢂ1): 3028, 2939,1690,1670,1636,1599,1492,1240,1173, 990, 834,
752 and 686. HRMS (ESI): 304.1331 (calcd for C20H18NOþ2 : 304.1332).
28. Toullec, J.; El-Alaoui, M.; Kleffert, P. J. Org. Chem. 1983, 48, 4808–4816.
29. Creary, X.; Inocencio, P. A. J. Am. Chem. Soc. 1986, 108, 5979–5983.
30. Ranu, B. C.; Jana, R.; Samanta, S. Adv. Synth. Catal. 2004, 346, 446–450.
31. Bailey, A. D.; Cherney, S. M.; Anzalone, P. W.; Anderson, E. D.; Ernat, J. J.; Mohan,
R. S. Synlett 2006, 215–218.
32. Ellison, R. A.; Lukenbach, E. R.; Chiu, C. W. Tetrahedron Lett. 1975, 499–502.
33. Guthrie, J. P.; Cossar, J.; Klym, A. Can. J. Chem. 1987, 65, 2154–2159.
34. Saba, A. J. Chem. Res., Synop. 1990, 288–289.
4.7.15. 1-(2-Oxo-2-phenylethyl)pyridinium bromide (10c)54
Compound 10c was isolated as described for 10b. 1H and 13C
NMR were in accordance with Szwajca et al.54
35. Saba, A. Gazz. Chim. Ital. 1991, 121, 55–56.
36. Fuhrmann, J.; Haber, H.; Haupt, M.; Henning, H. G. J. Prakt. Chem. 1982, 324,
1055–1059.
37. Scott, J. H.; Smith, T. A.; Hutchinson, J. H. J. Heterocycl. Chem. 1984, 21, 903–
904.
4.7.16. 2-(4-(Benzyloxy)phenyl)-N,N,N-triethyl-2-
oxoethanaminium bromide (11b)
The identity of 11b was confirmed by synthesis of a reference
sample. 1-(4-Benzyloxyphenyl)-2-bromoethanone (3b) (1.5 g,
4.9 mmol) in THF (25 mL) was mixed with triethylamine (1.0 g,
10 mmol) and heated at 50 ꢀC. After 5 h the reaction mixture was
cooled to room temperature and diethyl ether (25 mL) was added.
The solid material obtained after filtration was re-crystallised from
isopropanol, yielding 1.51 g (75%) of a white solid, mp 162–164 ꢀC.
38. Toche, R. B.; Jachak, M. N.; Badgujar, N. S.; Avhale, A. B.; Kendre, D. B. Org. Prep.
Proced. Int. 2005, 37, 405–408.
39. Murata, T.; Shimada, M.; Kadono, H.; Sakakibara, S.; Yoshino, T.; Masuda, T.;
Shimazaki, M.; Shintani, T.; Fuchikami, K.; Bacon, K. B.; Ziegelbauer, K. B.;
Lowinger, T. B. Bioorg. Med. Chem. Lett. 2004, 14, 4013–4017.
40. Olah, G. A.; Yamato, T.; Hashimoto, T.; Shih, J. G.; Trivedi, N.; Singh, B. P.; Piteau,
M.; Olah, J. A. J. Am. Chem. Soc. 1987, 109, 3708–3713.
41. Bax, A.; Summers, M. F. J. Am. Chem. Soc. 1986, 108, 2093–2094.
42. Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Tetrahedron 2005, 61, 10757–
10773.
43. Schumacher, R.; Reissig, H. U. Liebigs Ann. Recl. 1997, 521–526.
44. Wang, Q.; Zhang, P. Hecheng Huaxue 1999, 7, 159–163.
45. Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J. Tetrahedron 1987,
43, 2075–2088.
46. Bajic, M.; Kumar, A.; Boykin, D. W. Heterocycl. Commun. 1996, 2, 135–140.
47. Barkakaty, B.; Takaguchi, Y.; Tsuboi, S. Tetrahedron 2006, 63, 970–976.
48. Funabiki, K.; Fukushima, Y.; Sugiyama, T.; Shibata, K.; Matsui, M. Synlett 2001,
1308–1310.
1H NMR (CDCl3)
(s, 2H), 5.45 (s, 2H), 7.05–7.07 (m, 2H), 7.35–7.40 (m, 5H) and 8.34–
8.36 (m, 2H). 13C NMR (CDCl3)
: 8.4 (3C), 54.6 (3C), 59.9, 70.2, 115.2
d
: 1.41 (t, J¼7.3 Hz, 9H), 3.87 (q, J¼7.3 Hz, 6H), 5.13
d
(2C), 126.7, 127.4 (2C), 128.2, 128.6 (2C), 131.6 (2C), 135.7, 164.2 and
189.5. IR (KBr, cmꢂ1): 2974, 2913, 1687, 1601, 1576, 1456, 1237, 1006,
833 and 755. HRMS (ESI): 326.2116 (calcd for C21H28NOþ2 326.2115).
49. Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1991, 56, 4925–4929.
50. Surya Prakash, G. K.; Hu, J.; Olah, G. A. J. Fluorine Chem. 2001, 112, 357–362.
51. Ying, W.; DesMarteau, D. D.; Gotoh, Y. Tetrahedron 1996, 52, 15–22.
52. Moritani, I.; Obata, N. Tetrahedron Lett. 1965, 2817–2823.
53. Ibata, T.; Kashiuchi, M. Bull. Chem. Soc. Jpn. 1986, 59, 929–930.
54. Szwajca, A.; Leska, B.; Schroeder, G.; Szafran, M. J. Mol. Struct. 2004, 708,
87–95.
Acknowledgements
Norwegian University of Science and Technology is acknowl-
edged for a Ph.D. grant.