Facile nucleophilic fluorination reactions using tert-alcohols as a reaction medium: Significantly enhanced reactivity of alkali metal fluorides and improved selectivity

Article abstract of DOI:10.1021/jo7021229

(Chemical Equation Presented) Although protic solvents are generally not preferred for nucleophilic displacement reactions because of their partial positive charge and hydrogen-bonding capacity that solvate the nucleophile and reduce its reactivity, we recently reported a remarkably beneficial effect of using tertiary alcohols as a reaction media for nucleophilic fluorination with alkali metal fluorides, as well as fluorine-18 radiolabeling with [ ¹⁸F]fluoride ion for the preparation of PET radiopharmaceuticals. In this work, we investigate further the influence of the tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluorides by studying various interactions among tert-alcohols, the alkali metal fluoride (CsF), and the sulfonyloxy substrate. Factors such as hydrogen bonding between CsF and the tert-alcohol solvent, the formation of a tert-alcohol solvated fluoride, and hydrogen bonding between the sulfonate leaving group and the tert-alcohol appear to contribute to the dramatic increase in the rate of the nucleophilic fluorination reaction in the absence of any kind of catalyst. We found that fluorination of 1-(2-mesyloxyethyl)naphthalene (5) and N-5-bromopentanoyl-3,4- dimethoxyaniline (8) with Bu₄N⁺F^- in a tert-alcohol afforded the corresponding fluoro products in much higher yield than obtained by the conventional methods using dipolar aprotic solvents. The protic medium also suppresses formation of byproducts, such as alkenes, ethers, and cyclic adducts.

Full text of DOI:10.1021/jo7021229

Facile Nucleophilic Fluorination Reactions Using tert-Alcohols as a
Reaction Medium: Significantly Enhanced Reactivity of Alkali
Metal Fluorides and Improved Selectivity
Dong Wook Kim,*,† Hwan-Jeong Jeong,† Seok Tae Lim,† Myung-Hee Sohn,†
John A. Katzenellenbogen,‡ and Dae Yoon Chi*,§
Department of Nuclear Medicine, Research Institute of Clinical Medicine, Chonbuk National UniVersity
School of Medicine, Jeonju, Jeonbuk 561-712, Korea, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801, and Department of Chemistry, Inha UniVersity, 253 Yonghyundong Namgu,
Inchon 402-751, Korea
kimdw@chonbuk.ac.kr; dychi@inha.ac.kr
ReceiVed October 4, 2007
Although protic solvents are generally not preferred for nucleophilic displacement reactions because of
their partial positive charge and hydrogen-bonding capacity that solvate the nucleophile and reduce its
reactivity, we recently reported a remarkably beneficial effect of using tertiary alcohols as a reaction
media for nucleophilic fluorination with alkali metal fluorides, as well as fluorine-18 radiolabeling with
[18F]fluoride ion for the preparation of PET radiopharmaceuticals. In this work, we investigate further
the influence of the tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluorides
by studying various interactions among tert-alcohols, the alkali metal fluoride (CsF), and the sulfonyloxy
substrate. Factors such as hydrogen bonding between CsF and the tert-alcohol solvent, the formation of
a tert-alcohol solvated fluoride, and hydrogen bonding between the sulfonate leaving group and the tert-
alcohol appear to contribute to the dramatic increase in the rate of the nucleophilic fluorination reaction
in the absence of any kind of catalyst. We found that fluorination of 1-(2-mesyloxyethyl)naphthalene (5)
and N-5-bromopentanoyl-3,4-dimethoxyaniline (8) with Bu4N+F- in a tert-alcohol afforded the corre-
sponding fluoro products in much higher yield than obtained by the conventional methods using dipolar
aprotic solvents. The protic medium also suppresses formation of byproducts, such as alkenes, ethers,
and cyclic adducts.
1. Introduction
generally favorable pharmaceutical properties of many fluorine-
containing organic compounds.1 This is especially true for
radiopharmaceuticals labeled with fluorine-18 that are used as
in vivo probes for the noninvasive imaging of molecular and
biological processes in living subjects using positron emission
tomography (PET). For this application, in particular, fluorine-
18 has many desirable characteristics: small steric size, stable
Methods for introducing a fluorine atom at a specific
molecular site have received much attention because of the
* To whom correspondence should be addressed. (D.W.K.) Tel: +82-63-
250-2396. Fax: +82-63-255-1172. (D.Y.C.) Tel: +82-32-860-7686. Fax: +82-
32-867-5604.
† Chonbuk National University School of Medicine.
‡ University of Illinois.
bonding to carbon, suitable decay rate and properties (t1/2
)
§ Inha University.
110 min), low positron energy, and ease of production.2
10.1021/jo7021229 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/01/2008
J. Org. Chem. 2008, 73, 957-962
957

Kim et al.
FIGURE 1. Various fluoride sources. (A) Phase-transfer-type proto-
cols: “naked” (free) fluoride from TBAF or MF/crown etherssstrong
nucleophiles as well as strong bases. (B) Hydrated fluoride in water:
“inert” (isolated) fluoridesneither nucleophilic nor basic.
FIGURE 2. Four proposed reactivity-enhancing effects of a tert-
alcohol medium on nucleophilic aliphatic fluorination reactions.
The nucleophilic displacement of various sulfonates and
halides by fluoride ion is the method typically used for the
introduction of a single fluorine atom at a specific aliphatic
molecular site.3 While alkali metal fluorides are the reagents
traditionally used for this purpose, their limited solubility in
organic solvents and their generally low nucleophilicity means
that vigorous reaction conditions are required for this sort of
substitution. Curiously, in their desolvated state, fluoride ions
are, in fact, potent nucleophiles,3 but in water they are tightly
hydrated and become chemically inert (“inert” fluoride, Figure
1B). Perhaps the sole exception of this is enzymatic fluorination
in water catalyzed by a fluorinase enzyme, but here, specific
hydrogen bonding of the enzyme with the fluoride and the
substrate appears to facilitate formation of C-F bonds.4
To facilitate nucleophilic aliphatic fluorinations, various
“naked” fluoride ion systems have been developed. Fluoride
ion solubility and nucleophilicity are improved by the use of
bulky countercations, often generated by phase-transfer type
protocols,5 such as tetrabutylammonium fluoride (TBAF), or
by alkali metal fluoride/crown ether complexation (Figure 1A).
While the enhanced nucleophilicity of these naked fluoride ions
generally accelerates the rate of nucleophilic fluorination,6 these
systems are generally strongly basic, which restricts their
synthetic utility because it engenders various side reactions, such
as eliminations of alkyl halides or sulfonates to form alkenes.7
In addition, because it is difficult to get naked fluoride that is
completely anhydrous, naked hydroxide typically completes with
fluoride in nucleophilic substitutions, leading to hydroxylations
that form alcohols.7
It is well-known that protic solvents do not provide the proper
medium for most nucleophilic displacement reactions. Despite
of their good solvating ability for salts, protic solvents reduce
the nucleophilicity of the anion by extensive hydrogen bonding
and interaction with the partial positive charge of these solvents.
Consequently, dipolar aprotic solvents, such as N,N-dimethyl-
formamide (DMF), dimethyl sulfoxide (DMSO), and acetoni-
trile, have been widely used as a medium for these substitution
reactions. Anions in this latter medium usually show enhanced
nucleophilicity that results from the selective solvation of their
counter cations by the negative end of the dipolar aprotic solvent
dipole and the lack of a proton for hydrogen bonding, which
leave the anions free or “naked”. In dipolar aprotic solvents,
the halide ions are all of comparable nucleophilicity, whereas
their nucleophilicity in protic solvents is much different,
following the order I- > Br- > Cl- > F-, the progressive
reduction in reactivity reflecting the increasing solvation of the
smaller anions by the protic solvent.8
Recently, we reported a highly efficient aliphatic nucleophilic
fluorination method with alkali metal fluorides using nonpolar
protic tert-alcohols as a reaction medium. In this method, the
tert-alcohol media not only greatly enhanced the reactivity of
alkali metal fluorides, it also reduced the formation of typical
byproducts (namely, alkenes, alcohols, or ethers) compared to
those obtained with conventional dipolar aprotic solvents.3,7,9
The attributes of this novel fluorination method were particularly
important for the efficient preparation of [18F]fluorine-substituted
radiopharmaceuticals for PET imaging studies. Since our
findings are in marked contrast with the expectations from the
conventional SN2 mechanism, we wanted to elucidate further
the mechanism of the SN2 fluorination reaction in tert-alcohol
solvent. In the present work, we have examined the influence
of the tert-alcohol medium on SN2 fluorination reactions with
cesium fluoride and other fluorides through a variety of
experiments.10
(1) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 1320-1367.
(b) Filler, R. In Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R., Ed.; Studies in Organic Chemistry 48;
Elservier; New York 1993; pp 1-23.
(2) (a) Phelps, M. E. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 9226-
9233. (b) Marx, V. Chem. Eng. News 2005, 83, 25.
(3) For reviews on nucleophilic fluorination, see: (a) Gerstenberger, M.
R. C.; Haas, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 647-667. (b)
Mascaretti, O. A. Aldrichim. Acta 1993, 26, 47-58. (c) Dmowski, W.
Replacement of Oxygen by Fluorine. 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
199-262.
(4) (a) Zechel, D. L.; Reid, S. P.; Nashiru, O.; Mayer, C.; Stoll, D.;
Jakeman, D. L.; Warren, P. A. J.; Withers, S. G. J. Am. Chem. Soc. 2001,
123, 4350-4351. (b) O’ Hagan, D.; Schaffrath, C.; Cobb, S. L.; Hamilton,
J. T. G.; Murphy, C. D. Nature 2002, 416, 279. (c) Dong, C.; Huang, F.;
Deng, H.; Schffrath, C.; Spencer, J. B.; O’ Hagan, D.; Naismith, J. H. Nature
2004, 427, 561-565.
(5) (a) Forche, D. In Methoden der Organischen Chemie; Mueller, E.,
Ed.; Thieme-Verlag: Stuttgart 1962; Vol. 5/3. (b) CRC Handbook of
Chemistry and Physics, 71st ed.; CRC Press: Boston, 1990-1991.
(6) (a) Gokel, G. W. In Crown Ethers and Cryptands; Royal Society of
Chemistry: Cambridge 1991. (b) Dehmlow, E. V.; Dehmlow, S. S. In Phase
Transfer Catalysis, 3rd ed.; VCH: New York, 1993.
As shown Figure 2, we imagined that the tert-alcohol solvent
system might have four influences on the mechanism of this
(8) Smith, M. D.; March, J. AdVanced Organic Chemistry, 5th ed.; Wiley-
Interscience: New York, 2001; pp 462-674.
(9) (a) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002,
124, 10278-10279. (b) Kim, D. W.; Chi, D. Y. Angew. Chem., Int. Ed.
2004, 43, 483-485. (c) Kim, D. W.; Hong, D. J.; Jang, K. S.; Song, C. E.;
Chi, D. Y. AdV. Synth. Catal. 2006, 348, 1719-1727.
(10) Kim, D. W.; Ahn, D. -S.; Oh, Y. -H.; Lee, S.; Oh, S. J.; Lee, S. J.;
Kim, J. S.; Ryu, J. -S.; Moon, D. H.; Chi, D. Y. J. Am. Chem. Soc. 2006,
128, 16394-16397.
(7) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc. 1995,
117, 5166-5167.
(11) See the Supporting Information of ref 9a.
958 J. Org. Chem., Vol. 73, No. 3, 2008

Nucleophilic Fluorination in Protic Media
and CsI, in the reaction of alkyl mesylate 1 to the corresponding
alkyl halides (2a, 3, and 4, respectively) in acetonitrile. In this
representative dipolar aprotic solvent at 80 °C, the reaction rate
is inversely dependent on the strength of their ionic bonding:
the weaker the ionic bonding of the cesium halide, the higher
the reactivity. Thus, in acetonitrile, the order of reactivity is
CsI > CsBr > CsF. By contrast, at 80 °C with t-BuOH, a
nonpolar protic solvent, the reactivity of CsF, which can form
the strongest hydrogen bonding, shows a greatly enhanced rate
of substitution with 2-(3-fluoroproproxy)naphthalene (2a) (Fig-
ure 3B), with the other cesium halides following the reverse
order of reactivity: CsF . CsI > CsBr. These results suggest
that effective hydrogen bonding can occur between the tert-
alcohol solvent and fluoride ion in the CsF lattice that weakens
the ionic bonding of the salt, and that by selectivesand
presumably moderatessolvation of the fluoride ion, it makes
it a potent nucleophile. We believe that this effect (part A in
Figure 2) may be the most important factor in the reactivity-
enhancing effect of tert-alcohols on this reaction pathway.
2. B. Formation of “Flexible” Fluoride as a Good Nu-
cleophile. Table 1 presents the results of the same fluorination
reaction using CsF or TBAF, using different solvents. We
carried out the reaction of mesylate 1 with CsF to fluoroalkane
2a at 80 °C for 6 h in MeOH, EtOH, n-PrOH, t-BuOH, tert-
amyl alcohol, and 3-methyl-3-pentanol to examine the influence
of steric hindrance of the alcohol solvent on the reaction rate
and product purity (entries 1-7, Table 1). The rate of fluorina-
tion increased with increasing bulk of the alcohol (reaction rates
follow the order tert-alcohol > i-PrOH > EtOH > MeOH);
the selectivity against formation of the ether byproduct 2d also
increased. Comparison with entries 8 and 9 in Table 1 shows
that “naked” fluoride from TBAF in t-BuOH shows similar
(slightly lower) nucleophilicity than TBAF in CH3CN, while
water-solvated fluoride (fluoride ion has a high hydration energy,
117 kcal/mol) is not reactive, regardless of whether CsF or
TBAF is used (entries 10 and 11).
FIGURE 3. Solvent dependence of the reactivity of CsF, CsBr, and
CsI in a nucleophilic substitution reaction. All reactions were carried
out on a 0.12 mmol reaction scale of mesylate 1, using 3 equiv of
cesium halide in 0.5 mL of solvent at 80 °C; product yields were
1
determined by H NMR.
These results suggest that because of its bulk, the tert-alcohol
does not coordinate to fluoride too tightly and thus affords some
flexibility between the alcohol and fluoride. Thus, tert-alcohol-
solvated fluoride, which we have termed “flexible” fluoride,
generated from the cesium fluoride lattice by hydrogen bonding
with the tert-alcohol, can be a good nucleophile for nucleophilic
fluorination.
fluorination process, all of which we have studied. Part A: The
strength of the CsF ionic bond might be reduced by hydrogen
bonding of the tert-alcohol solvent with the fluoride in the CsF
lattice, resulting in selective solvation of the fluoride into tert-
alcohol reaction media. Part B: The limited solvation of fluoride
coordinated with bulky tert-alcohols, which we term a “flexible”
fluoride, might make the fluoride an especially good nucleophile
in this medium. Part C: Hydrogen bonding of the tert-alcohol
solvent with oxygen atoms of a sulfonate leaving group might
enhance leaving group ability. Part D: The protic environment
of the reaction medium, as well as hydrogen bonding between
the tert-alcohol and reactive heteroatoms in the substrate, might
reduce side reactions such as eliminations, hydroxylations and
intramolecular alkylations.
2. C. Leaving Group Ability in tert-Alcohol Solvents.
Mesylates, iodides, and bromides are widely used as leaving
groups in nucleophilic substitution reactions, and in most SN2
reactions, the order of leaving group ability is mesylates >
iodides > bromides.8 Figure 4 shows a comparison of the
leaving group ability of mesylate, bromide, and iodide in the
fluorination reaction as a function of solvent. The rate of
consumption of alkyl mesylate 1, bromoalkane 3, and iodoalkane
4 under the conventional fluorination reaction conditions using
TBAF in acetonitrile as a dipolar aprotic solvent at 60 °C, or
under the fluorination reaction conditions using CsF in tert-
amyl alcohol as a nonpolar protic solvent 90 °C, show
pronounced differences in reactivity. The rate of loss of mesylate
1 is slightly slower than that of halides 3 and 4 under
conventional fluorination conditions (Figure 4A), the leaving
group reactivity order being iodide g bromide g mesylate. By
contrast, the rate of loss mesylate 1 is enhanced dramatically
relative to that of the halides in the tert-alcohol medium (Figure
4B), the leaving group reactivity order being mesylate . iodide
2. Results and Discussion
2. A. Selective Solvation of Fluoride Ion by H-Bonding in
tert-Alcohol Solvents. Figure 3 illustrates the dependence of
the reactivity of three cesium halidessCsF, CsBr, and CsIson
two different solvent systems, nonpolar protic (t-BuOH) and
dipolar aprotic (acetonitrile), to elucidate the first proposed effect
of the tert-alcohol medium on a nucleophilic fluorination
reaction. For an SN2 reaction using metal salts to proceed, their
ion pairs need to be separated during the reaction. Figure 3A
shows that the reactivity of the three cesium salts, CsF, CsBr,
J. Org. Chem, Vol. 73, No. 3, 2008 959

Kim et al.
TABLE 1. Fluorinations of Mesylate 1 with CsF in Different Solventsa
yield of productb (%)
entry
solvent
MF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
reaction temp (°C)
reaction time (h)
1
2a
2b
2c
2d
1
2
3
MeOH
EtOH
n-PrOH
i-PrOH
t-BuOH
t-amyl alcohol
3-methyl-3-pentanol
CH3CN
t-BuOH
H2O/toluene (1:1)
H2O/CH3CN (1:1)
80
80
80
80
80
80
80
60
60
80
60
6
6
6
6
6
6
6
1.5
1.5
6
35
20
47
58
78
92
93
94
92
91
43
31
29
14
7
19
10c
6c
4
5d
6d
7
trace
5c
3c
8
9
10
11
TBAF
TBAF
CsF
5c
3c
trace
trace
96
95
trace
TBAF
1.5
a All reactions were carried out on a 1.0 mmol reaction scale of mesylate 1, using 3 mmol of metal fluoride in 4.0 mL of solvent. b Isolated yield. c NMR
determined yield. d Reference 10.
FIGURE 5. (a) Picture of formation of a gel-like solid during the
fluorination reaction using CsF in t-BuOH: (vial A) 0.5 mmol reaction
scale of mesylate 1 using CsF in 2 mL of t-BuOH after 30 min at 90
°C; (vial B) the same reaction condition as that of vial A except for
the use of bromoalkane 3 instead of mesylate 1 after 6 h; (vial C) the
same reaction condition as that of vial A except for the use of CsBr
instead of CsF after 6 h. (b) The result of inverting the reaction vials:
(vial A) gel-like solid remains adhered to the vial bottom; (vials B and
C) gel-like solid does not form.
fluorination of mesylate 1 using CsF in t-BuOH at 90 °C (vial
A) starts to turn into a heterogeneous liquid phase that becomes
a gel-like solid after approximately 20 min. After the reaction
was complete, the reaction medium of the gel-like solid phase
again returned to a heterogeneous liquid phase.2 By contrast,
with bromoalkane 3 as a substrate instead of mesylate 1 in the
same reaction media (vial B) or using CsBr as a nucleophile
source instead of CsF in the same reaction media (vial C), no
change in the reaction medium was observed during the progess
of the reaction. This result suggests that the interaction between
the tert-alcohol solvent, CsF (“flexible fluoride”) and the
sulfonyloxy group of substrate as a leaving groupsby extensive
hydrogen bondingsresults in formation of a gel-like solid phase
FIGURE 4. Dependence of leaving-group reactivity of bromoalkane
3, iodoalkane 4, and mesylate 1 on the reaction medium. All reactions
were carried out on a 0.12 mmol reaction scale of starting material,
using 3 equiv of metal fluoride in 0.5 mL of solvent. The quantity of
in the reaction medium. This gel, in fact, might be contributing
to acceleration of the reaction rate.
2. D. Selective Fluorination in Protic Media. To investigate
the influence of the tert-alcohol solvent system on the selectivity
of fluorination reactions, we carried out the fluorination on two
model compounds that have some potential for side reactions
under the basic reaction conditions associated with “naked”
fluoride. Fuorination using TBAF in the tert-alcohol was
compared to the reaction under conventional conditions using
acetonitrile as a solvent (Scheme 1). It is known that fluorination
of haloethyl or alkanesulfonylethyl aromatic compounds using
“naked” fluoride is often compromised by competing â-elimina-
tion of these systems to the corresponding styrenes, a side
1
starting material remaining was determined by H NMR.
> bromide. This result suggests that effective hydrogen bonding
between the oxygen atoms in the mesylate substrate and the
tert-alcohol solvent may enhance its leaving group activity
compared to that of the halides which are less effective in
forming hydrogen bonds in alcohol media.
We could observe a unique phase change in the reaction
medium during the progress of the reaction. Parts a and b of
Figure 5a and b show that the reaction medium of the
960 J. Org. Chem., Vol. 73, No. 3, 2008

Nucleophilic Fluorination in Protic Media
SCHEME 1. Selectivity of Fluorination Using TBAF in
tert-Alcohol Medium vs Acetonitrile
nucleophilic substitution using tert-alcohol media are in progress
in our laboratories. Further applications of this tert-alcohol
medium fluorination method for the prepration of fluorine-18
labeled molecular imaging probes for PET studies are also under
investigation.
4. Experimental Section
1-(2-Methanesulfonylethyl)naphthalene (5). To 1-(2-hydroxy-
ethyl)naphthalene (4.6 g, 26.8 mmol) in methylene chloride (150
mL) were added triethylamine (4.5 mL, 32.2 mmol) and methane-
sulfonyl chloride (2.5 mL, 32.2 mmol) at 0 °C. The mixture was
stirred at 25 °C for 6 h and evaporated under reduced pressure to
remove methylene chloride. The residue was dissolved in water
(200 mL) and extracted from the aqueous phase with EtOAc (200
mL × 3). The organic layer was dried (sodium sulfate) and
evaporated under reduced pressure. The residue was purified by
flash column chromatography (30% EtOAc/hexane) to give 5.7 g
(22.8 mmol, 85%) of 5 as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 2.79 (s, 3H), 3.55 (t, J ) 7.2 Hz, 2H), 4.54 (t, J ) 7.2
Hz, 2H), 7.40-7.59 (m, 4H), 7.79-8.03 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 32.7, 37.2, 69.6, 123.0, 125.5, 125.8, 126.5, 127.5,
127.9, 128.9, 131.6, 132.0, 133.8; MS (EI) m/z 250 (M+); HRMS
(EI) m/z calcd for C13H14O3S (M+) 250.0664, found 250.0700.
N-5-Bromopentanoyl-3,4-dimethoxyaniline (8). To a well-
stirred solution of 5-bromopentanoic acid (1.3 g, 7.18 mmol) in
anhydrous THF (50 mL) were added triethylamine (0.5 mL, 7.18
mmol), p-toluenesulfonyl chloride (1.37 g, 7.18 mmol), and
4-(dimethylamino)pyridine (880 mg, 7.18 mmol) at 25 °C. After
30 min at 25 °C, 3,4-dimethoxyaniline (1.0 g, 6.52 mmol) was
added to the reaction mixture at 25 °C. The mixture was stirred
for additional 12 h at 25 °C. The residue was dissolved in water
(100 mL) and extracted from the aqueous phase with EtOAc (100
mL × 3). The organic layer was dried (sodium sulfate) and
evaporated under reduced pressure. The residue was purified by
flash column chromatography (20% EtOAc/hexane) to give 1.43 g
(4.55 mmol, 70%) of 8 as a yellow oil: 1H NMR (600 MHz, CDCl3)
δ 1.89-1.95 (m, 4H), 2.38 (t, J ) 7.2 Hz, 2H), 3.44 (t, J ) 6.5
Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 6.79 (d, J ) 8.9 Hz, 1H), 6.85-
6.86 (m, 1H), 7.36 (s, 2H).; 13C NMR (150 MHz, CDCl3) δ 24.0,
32.0, 33.2, 36.3, 55.8, 56.0, 104.9, 111.2, 111.8, 131.4, 145.8, 148.9,
170.5; MS (EI) m/z 315 (M+), 317 (M+), 153 (100), 138; HRMS
(EI) m/z calcd for C13H18O3N79Br (M+) 315.0469, found 315.0470.
Typical Procedure of Fluorination in Table 1. CsF (456 mg,
3.0 mmol) was added to the mixture of 2-(3-methanesulfonylox-
ypropoxy)naphthalene (1, 280 mg, 1.0 mmol) in alcohol (4.0 mL).
The mixture was stirred over 6 h at 80 °C. The reaction mixture
was triturated with ethyl ether to remove most of ionic salts. The
filtrate was evaporated under reduced pressure. The residue was
purified by flash column chromatography (20% CH2Cl2/hexanes)
to obtain 41-192 mg (20-94%) of 2-(3-fluoropropoxy)naphthalene
(2a) as a colorless oil with ether byproduct (2d).
reaction that can become dominant. Nevertheless, fluorination
of 1-(2-mesylethyl)naphthalene (5) to 1-(2-fluoroethyl)naph-
thalene (6) using TBAF in t-BuOH proceeded efficiently and
provided the corresponding fluoride in 87% yield, with the
alkene byproduct 7 being formed in only 9% yield. By contrast,
the same reaction in acetonitrile provided alkene 7 as the major
product (61%), with the desired fluoroalkane substitution product
(6) being formed in only 33% yield. Similarly, nucleophilic
fluorination of N-5-bromopentanoyl-3,4-dimethoxyaniline (8)
to N-5-fluoropentanoyl-3,4-dimethoxyaniline (10) using TBAF
in acetonitrile at 80 °C gave only trace quantities of the desired
fluoro product 10, forming instead the intramolecular cyclization
product 1-(3,4-dimethoxyphenyl)piperidin-2-one (9) in 70%
yield. The same transformation in tert-amyl alcohol, however,
furnished the desired fluoroalkane (10) in 30% yield. Thus, the
protic environment of the tert-alcohol, which reduces the basicity
of the “naked” fluoride by forming “flexible” fluoride, also
appears to hydrogen bond with the reactive heteroatom in the
substrate, effectively inhibiting side reactions such as elimination
and intramolecular alkylation, and consequently enhancing the
selectivity of the fluorination reaction.
3. Conclusion
In summary, we present a mechanistic study of the effect of
the tert-alcohol medium in nucleophilic fluorination of some
halo- and alkanesulfonyloxy alkane systems to the corresponding
fluoroalkanes. According to our findings, the tert-alcohol
solvents appear to reduce the strength of the ionic bonding of
alkali metal fluorides by hydrogen bonding to the fluoride,
thereby generating a tert-alcohol solvated “flexible” fluoride ion
species that has very favorable properties as a strong nucleophile
yet moderate base, highly suitable for the synthesis of orga-
nofluorine compounds with minimal side reactions that are base
catalyzed. In addition, the tert-alcohols appear to form strong
hydrogen bonds with the leaving group of sulfonylated sub-
strates, and they accelerate the rate of substitution, making this
reaction more valuable in various fluoride ion synthetic and [18F]-
fluoride ion radiosynthetic applications.
1
2-(3-Fluoropropoxy)naphthalene (2a): H NMR (400 MHz,
CDCl3) δ 2.14-2.39 (m, 2H), 4.24 (t, J ) 6.2 Hz, 2H), 4.72 (dt,
J ) 46.8, 5.8 Hz, 2H), 7.16-7.22 (m, 2H), 7.34-7.53 (m, 2H),
7.76-7.83 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 30.4 (d, J )
20.1 Hz), 63.6 (d, J ) 5.3 Hz), 80.8 (d, J ) 163.9 Hz), 106.8,
118.8, 123.6, 126.4, 126.7, 127.6, 129.1, 129.4, 134.6, 156.7; MS
(EI) m/z 204 (M+); HRMS (EI) m/z calcd for C13H13FO (M+)
204.0950, found 204.0932.
2-(3-Methoxypropoxy)naphthalene (2d in entry 1): 1H NMR
(600 MHz, CDCl3) δ 2.08-2.13 (m, 2H), 3.36 (s, 3H), 3.59 (t, J
) 6.2 Hz, 2H), 4.16 (t, J ) 6.2 Hz, 2H), 7.13-7.14 (m, 2H), 7.30-
7.32 (m, 1H), 7.41-7.42 (m, 1H), 7.71-7.74 (m, 3H).; 13C NMR
(150 MHz, CDCl3) δ 29.6, 58.7, 64.8, 69.3, 106.6, 118.9, 123.5,
126.3, 126.7, 127.6, 128.9, 129.3, 134.5, 156.9; MS (EI) m/z 204
(M+), 144 (100); HRMS (EI) m/z calcd for C14H16O2 (M+)
216.1150, found 216.1148.
Further studies on the development of even more efficient
protocols (greater selectivity, shorter reaction time, etc.) for
J. Org. Chem, Vol. 73, No. 3, 2008 961

Kim et al.
1
2-(3-Ethoxypropoxy)naphthalene (2d in entry 2): H NMR
1-Vinylnaphthalene (7). Compound 7 (14 mg, 9%) as a
byproduct above reaction was obtained as a colorless oil: 1H NMR
(600 MHz, CDCl3) δ 5.47 (dd, J ) 10.7, 1.7 Hz, 1H), 5.79 (dd, J
) 17.5, 8.8 Hz, 1H), 7.43-7.52 (m, 4H), 7.61-7.62 (m, 1H), 7.77-
7.85 (m, 2H), 8.10-8.12 (m, 1H); 13C NMR (150 MHz, CDCl3) δ
117.1, 123.6, 123.7, 125.6, 125.7, 126.0, 128.1, 128.5, 131.1, 133.6,
134.4, 135.6; MS (EI) m/z 154 (M+), 153 (100), 76; HRMS (EI)
m/z calcd for C12H10 (M+) 154.0783, found 154.0784. CAS Registry
No. provided by the author: 826-74-4.
N-5-Fluoropentanoyl-3,4-dimethoxyaniline (10). According to
the typical procedure for fluorination with 8 (315 mg, 1.0 mmol)
and TBAF (783 mg, 3.0 mmol) in tert-amyl alcohol, 10 (76 mg,
30%) was obtained as a yellow oil: 1H NMR (600 MHz, CDCl3)
δ 1.74-1.88 (m, 4H), 2.40 (t, J ) 7.2 Hz, 2H), 3.85 (s, 6H), 4.49
(dt, J ) 47.2, 5.8 Hz, 2H), 6.79 (d, J ) 8.2 Hz, 1H), 6.86 (dd, J
) 8.6, 2.4 Hz, 1H), 7.36 (d, J ) 2.7 Hz, 1H), 7.45 (s, 1H); 13C
NMR (150 MHz, CDCl3) δ 21.5 (d, J ) 5.7 Hz), 29.7 (d, J ) 18.6
Hz), 36.8, 55.8, 56.0, 83.9 (d, J ) 163.8 Hz), 104.8, 111.2, 111.7,
131.5, 145.7, 148.9, 170.7; MS (EI) m/z 255 (M+), 153 (100), 138;
HRMS (EI) m/z calcd for C13H18O3NF (M+) 255.1271, found
255.1270.
1-(3,4-Dimethoxyphenyl)piperidin-2-one (9). Compound 9 (76
mg, 32%) as a byproduct above reaction was obtained as a colorless
oil: 1H NMR (600 MHz, CDCl3) δ 1.92-1.95 (m, 4H), 2.55 (t, J
) 6.2 Hz, 2H), 3.61 (t, J ) 5.5 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H),
6.77-6.78 (m, 2H), 6.86-6.88 (m, 1H); 13C NMR (150 MHz,
CDCl3) δ 21.3, 23.4, 32.7, 52.0, 55.7, 55.8, 110.0, 111.2, 118.0,
136.4, 147.6, 149.0, 170.0; MS (EI) m/z 235 (M+, 100), 220, 166;
HRMS (EI) m/z calcd for C13H17O3N (M+) 235.1208, found
235.1208.
(600 MHz, CDCl3) δ 1.21 (t, J ) 6.9 Hz, 3H), 2.09-2.13 (m, 2H),
3.51 (q, J ) 6.9 Hz, 2H), 3.63 (t, J ) 6.2 Hz, 2H), 4.18 (t, J ) 6.5
Hz, 2H), 7.12-7.18 (m, 2H), 7.31-7.32 (m, 1H), 7.41-7.43 (m,
1H), 7.71-7.76 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 15.2,
29.7, 64.9, 66.3, 67.1, 106.6, 118.9, 123.5, 126.3, 126.7, 127.6,
128.9, 129.3, 134.6, 156.9; MS (EI) m/z 230 (M+), 144 (100);
HRMS (EI) m/z calcd for C15H18O2 (M+) 230.1307, found 230.1312.
2-(3-n-Propoxypropoxy)naphthalene (2d in entry 3): 1H NMR
(600 MHz, CDCl3) δ 0.92 (t, J ) 7.5 Hz, 3H), 1.57-1.63 (m, 2H),
2.09-2.13 (m, 2H), 3.41 (t, J ) 6.8 Hz, 2H), 3.63 (t, J ) 6.3 Hz,
2H), 4.18 (t, J ) 6.3 Hz, 2H), 7.13-7.15 (m, 2H), 7.30-7.33 (m,
1H), 7.41-7.44 (m, 1H), 7.71-7.76 (m, 3H); 13C NMR (150 MHz,
CDCl3) δ 10.6, 22.9, 29.7, 64.9, 67.2, 72.7, 106.6, 118.9, 123.5,
126.3, 126.7, 127.6, 128.9, 129.3, 134.6, 157.0; MS (EI) m/z 244
(M+), 144 (100); HRMS (EI) m/z calcd for C16H20O2 (M+)
244.1463, found 244.1463.
2-(3-Isopropoxypropoxy)naphthalene (2d in entry 4): 1H
NMR (600 MHz, CDCl3) δ 1.16 (d, J ) 6.2 Hz, 6H), 2.07-2.11
(m, 2H), 3.57-3.59 (m, 1H), 3.63 (t, J ) 6.3 Hz, 2H), 4.18 (t, J )
6.2 Hz, 2H), 7.14-7.15 (m, 2H), 7.30-7.33 (m, 1H), 7.41-7.44
(m, 1H), 7.71-7.76 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 22.1,
30.0, 64.5, 64.9, 71.6, 106.6, 118.9, 123.5, 126.3, 126.7, 127.6,
128.8, 129.3, 134.6, 157.0; MS (EI) m/z 244 (M+), 144 (100);
HRMS (EI) m/z calcd for C16H20O2 (M+) 244.1463, found 244.1465.
1
2-(3-t-Butoxypropoxy)naphthalene (2d in entry 5). H NMR
(400 MHz, CDCl3) δ 1.21 (s, 9H), 2.04-2.11 (m, 2H), 3.60 (t, J
) 6.0 Hz, 2H), 4.19 (t, J ) 6.0 Hz, 2H), 7.15-7.18 (m, 2H), 7.31-
7.46 (m, 2H), 7.73-7.78 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
27.5, 30.4, 58.0, 64.8, 72.8, 106.6, 119.0, 123.4, 126.24, 127.7,
127.6, 128.8, 129.2, 134.6, 157.0; MS (EI) m/z 258 (M+), 210,
144 (100); HRMS (EI) m/z calcd for C17H22O2 (M+) 258.1620
Found 258.1624
1-(2-Fluoroethyl)naphthalene (6). According to the typical
procedure for fluorination with 5 (250 mg, 1.0 mmol) and TBAF
(783 mg, 3.0 mmol) in t-BuOH, 6 (151 mg, 87%) was obtained as
a colorless oil: 1H NMR (600 MHz, CDCl3) δ 3.49 (dt, J ) 13.7,
6.9 Hz, 2H), 4.75 (dt, J ) 47.4, 6.9 Hz, 2H), 7.37-7.54 (m, 4H),
7.75-8.02 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 33.8 (d, J )
20.1 Hz), 83.5 (d, J ) 168.0 Hz), 123.3, 125.5, 125.6, 126.2, 127.1,
127.5, 128.9, 132.0, 132.8 (d, J ) 8.5 Hz), 133.8; MS (EI) m/z
174 (M+), 141 (100). Anal. Calcd: C, 82.73; H, 6.36. Found: C,
82.63; H, 6.34. CAS Registry No. provided by the author: 693785-
25-0.
Acknowledgment. This work was supported by grants from
the Atomic Energy Technology and Development Program of
KOSEF (106403001 to D.W.K.), Research Funds of Chonbuk
National University in 2006 (to D.W.K.), and the National
Institutes of Health (PHS 5R01 CA25836 to J.A.K.).
Supporting Information Available: 1H and 13C NMR spectra
of 1, 2a, 2d, and 3-10. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO7021229
962 J. Org. Chem., Vol. 73, No. 3, 2008