Deoxyfluorination of α-N-phthaloyl cycloalkanones with bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor)

Article abstract of DOI:10.1016/j.jfluchem.2015.12.001

The deoxyfluorination of α-N-phthaloyl cyclobutanone with bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) produced a gem-difluoride product together with a vic-difluoride bearing a cyclopropane ring. In contrast, the deoxyfluorination of the corr

Full text of DOI:10.1016/j.jfluchem.2015.12.001

Accepted Manuscript
Title: Deoxyfluorination of ␣–N-phthaloyl cycloalkanones
with bis(2-methoxyethyl)aminosulfur trifluoride
(Deoxo-Fluor)
Author: Satoe Ishii Yasutaka Niwa Soichiro Watanabe
PII:
S0022-1139(15)30014-2
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.12.001
FLUOR 8698
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
29-9-2015
3-12-2015
12-12-2015
Please cite this article as: S. Ishii, Y. Niwa, S. Watanabe, Deoxyfluorination of
rmalphandashN-phthaloyl cycloalkanones with bis(2-methoxyethyl)aminosulfur
trifluoride
(Deoxo-Fluor),
Journal
of
Fluorine
Chemistry
(2015),
http://dx.doi.org/10.1016/j.jfluchem.2015.12.001
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*Graphical Abstract - Pictogram
Page 1 of 27

*Graphical Abstract - Synopsis
Graphical Abstract Synopsis
The deoxyfluorination of -N-phthaloyl cyclobutanone with Deoxo-Fluor produced a
gem-difluoride product together with a vic-difluoride bearing a cyclopropane ring. The
deoxyfluorination of the corresponding -N-phthaloyl cyclohexanone produced an
intramolecular cyclization product with two fluorine atoms, which provided the starting
material after workup.
1
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*Highlights (for review)
Highlights





Deoxo-Fluor has been investigated for the deoxyfluorination of -N-protected
cycloalkanones.
The deoxyfluorination of an -N-phthaloyl cyclobutanone gave the gem- and
vic-difluorides.
The deoxyfluorination of an -N-benzoyl cyclobutanone gave an oxazole
derivative.
These reactions involved the formation of a cationic species as intermediates
through neighboring group participation.
The presence or absence of a hydrogen atom on the protected amine was critical to
determining the outcome of the reaction.
1
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*Manuscript
Click here to view linked References
Deoxyfluorination of –N-phthaloyl cycloalkanones with
bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor)
Satoe Ishiia , Yasutaka Niwa a and Soichiro Watanabea,b*
a Department of Biomolecular Science, Faculty of Science, Toho University,
Miyama 2-2-1, Funabashi, Chiba, 274-8510 Japan
b Research Center for Materials with Integrated Properties, Toho University,
Miyama 2-2-1, Funabashi, Chiba, 274-8510 Japan
*
Corresponding author. Tel.: +81 47 472 1298; fax: +81 47 472 1298. E-mail address:
soichiro@biomol.sci.toho-u.ac.jp (S. Watanabe)
1
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Abstract
The deoxyfluorination of -N-phthaloyl cyclobutanone with
bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) produced a gem-difluoride
product together with a vic-difluoride bearing a cyclopropane ring. In contrast, the
deoxyfluorination of the corresponding -N-phthaloyl cyclopentanone produced the
gem-difluoride only. Furthermore, the deoxyfluorination of the corresponding
-N-phthaloyl cyclohexanone produced an intramolecular cyclization product with two
fluorine atoms as the main product, which provided the starting material after workup.
Cationic species formed through neighboring group participation are most likely the key
intermediates in these reactions. Control experiments using N-benzoyl congeners
produced oxazole or oxazoline derivatives, indicating that the presence or absence of a
hydrogen atom on the protected amine moiety was critical to determining the reaction
path.
Keywords
Deoxyfluorination; Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor);
Cycloalkanone; Neighboring group participation; gem-Difluoride; vic-Difluoride
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1. Introduction
Fluorine has several unique properties, including the highest electronegativity of all the
known elements, as well as a small atomic radius. Organofluorine compounds have
been the subject of increasing attention, especially from researchers working in material
science [1] and medicinal chemistry [2]. Therapeutic agents containing a fluorine atom
can exhibit enhanced physicochemical properties as well as improved drug metabolism
pharmacokinetic (DMPK) profiles compared with their non-fluorinated analogs. Around
20% of the pharmaceuticals currently on the market are estimated to contain fluorine
[3].
Cycloalkyl amine derivatives are an important class of compounds and numerous
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl amine derivatives have been
reported to possess interesting biological activities [4]. Given that the introduction of
fluorine can lead to improvements in the biological and DMPK properties of a
compound, the syntheses of several bioactive fluorinated cycloalkyl amine derivatives
have been reported in the literature, including pharmaceuticals [5], nucleoside
analogues [6] and amino acid derivatives [7]. We recently developed an interest in
synthesizing bioactive cycloalkyl amines bearing fluorine atoms adjacent to their amino
group to explore new synthetic methods for the preparation of bioisosteres of -lactam
antibiotics. One of the most commonly used methods for the formation of
fluorine-carbon bonds is the deoxyfluorination of alcohols and ketones, which can be
used to provide easy access to the corresponding monofluoride and gem-difluoride
compounds. We imagined that the deoxyfluorination of -N-protected cycloalkanones
would allow for the easy construction of the corresponding cycloalkyl amine derivatives
bearing fluorine atoms adjacent to the amine. Notably, a review of the literature
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revealed that a strategy of this type had not yet been developed. The diethylaminosulfur
trifluoride (DAST)- and Deoxo-Fluor-mediated cyclization reactions of aliphatic
-acylaminoketones [8] and -acylaminoalcohols [9] have been reported in the
literature for the formation of oxazoline derivatives (Figure 1).
Figure 1. Schematic representations of the deoxyfluorination reactions of (A)
α-acylaminoketones; (B) β-acylaminoalcohols; and (C) current study
We assumed that the use of a phthalimide-protected amine would promote the
deoxyfluorination of the pendant carbonyl group rather than the cyclization reaction,
because N-phthaloyl groups do not possess an acidic NH proton capable of facilitating
the formation of an oxazoline ring. Herein, we report the reaction of a series of
-N-phthaloyl cycloalkanones with Deoxo-Fluor and the unique relationship observed
between the ring size of the starting material and the type of products formed from the
reaction.
2. Results and discussion
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Our initial work focused on the deoxyfluorination reaction of α-N-phthaloyl
cyclobutanone (3a), which was prepared from cyclobutanone (1) via the corresponding
α-bromo derivative 2 (Scheme 1).
Scheme 1. Preparation and deoxyfluorination of the α-N-phthaloyl cyclobutanone
derivative 3a.
The deoxyfluorination of compound 3a generated gem-difluoride 4a and vic-difluoride
5, which contained a cyclopropane ring (Scheme 1). It is noteworthy that this reaction
required additional Deoxo-Fluor to be added for the complete consumption of the
starting material. The amount of Deoxo-Fluor used in the reaction was subsequently
adjusted from 4 to 15 eq. to determine the optimal conditions for this transformation
(Table 1). When the amount of Deoxo-Fluor added to the reaction was less than 10 eq.
(r.t., 3 days), significant quantities of the starting material 3a were recovered from the
reaction. The results of these optimization experiments therefore revealed that the use of
15 eq. of Deoxo-Fluor was optimal for the complete consumption of the starting
material and this amount was used in all of the following reactions.
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Table 1. Deoxyfluorination of compound 3a.a
Product Yields
Entry
Deoxo-Fluor (eq.)
Recovery of 3a (%)
4a (%)
5
5 (%)
7
1
2
3
4
4
73
34
-
9
12
38
13
10
35
15
12
39
-
aSee deoxyfluorination step in Scheme 1. These reactions were performed in CH2Cl2 at room temperature over 3 days.
The two different difluoride compounds obtained from this reaction could be readily
distinguished by 19F NMR spectroscopy. For example, the proton decoupled 19F NMR
spectra of compounds 4a and 5 showed two doublets with coupling constants of 193
and 10 Hz, respectively. These coupling constants were consistent with the expected
2JFF and 3JFF values [10]. Although the structure of the gem-difluoride compound was
unambiguously determined to be 4a by NMR spectroscopy, further analysis was needed
to determine the structure of vic-difluoride 5. The non-decoupled 19F NMR spectrum of
5 contained two signals, including a doublet of doublets and a multiplet, which
indicated that the proton responsible for the former of these two signals was coupled to
only one other proton (Figure 2). The 1H NMR spectrum of 5 contained a doublet of
doublets at 6.6 ppm, which appeared as a singlet in 19F decoupled 1H NMR spectrum.
This result indicated that this proton was coupled to only two fluorine atoms.
Considering that a vic-difluoride with a cyclobutane ring cannot show such a coupling
pattern, we determined the structure of this compound to be a cyclopropane derivative
with two vicinal fluorine atoms. Taken together with the 13C NMR spectrum of 5
(supplementary data), these data were consistent with the structure depicted in Scheme
1 for compound 5. This is the first example of vic-difluoride formation with ring
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contraction from a cyclobutanone derivative, whilst several similar rearrangements of
cycloalkanols including cyclobutanol derivatives as well as carbohydrates with
cycloalkanone moiety in deoxyfluorination have been reported in the literature [11].
Figure 2. (A) Non-decoupled and (B) 1H decoupled 19F NMR spectra of 5.
It is well known that cyclobutyl cations can be readily converted to the corresponding
cyclopropylmethyl cations via a rearrangement reaction. This process was believed to
be responsible for the formation of the cyclopropane derivative 5 in the current study. A
plausible mechanism for this reaction is shown in Scheme 2.
The first step in this reaction involved the activation of the carbonyl group by
Deoxo-Fluor [8], followed by a neighboring group participation process to form
cationic intermediate 6. The requirement for a large excess of Deoxo-Fluor suggested
that the activation step was in equilibrium. Beyond this point, there are two possibilities,
including (1) substitution by the fluoride anion formed in the first step to afford fluoride
7 (path a in Scheme 2); and (2) rearrangement to form another cationic species 8 with a
three membered ring (path b in Scheme 2). In compound 7, the carbonyl group of the
phthalimido moiety would attack the C–O of the cyclobutane ring in an intramolecular
manner to afford cationic intermediate 9. The two products 4a and 5 would be obtained
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from 9 in a similar manner to that explained for the reaction of intermediate 6. In
contrast, cation 8 would be trapped by a fluoride anion to afford fluoride 10, which
would be converted to difluoride 5 via the cationic species 11.
Scheme 2. Plausible reaction mechanism for the deoxyfluorination of the -N-phthaloyl
cyclobutanone derivative 3a.
To extend our findings to other cycloalkanone systems, we applied these reaction
conditions to α-N-phthaloyl cyclopentanone (3b) and α-N-phthaloyl cyclohexanone (3c).
Interestingly, the products obtained from these reactions were not only different from
those obtained from the cyclobutanone derivative, but were also different from each
other (Scheme 3). Although cyclopentanone derivative 3b produced gem-difluoride 4b
as its main product, cyclohexanone derivative 3c produced a new difluoride 12c as its
8
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main product, together with the gem-difluoride 4c and the elimination products 13c and
14c. These reactions proceeded slowly and the starting materials were recovered (34
and 33% for 3b and 3c, respectively). Purifying these reaction mixtures was very
difficult because of the similarities in the structures of the products. For this reason, the
yields for the reaction of 3c were determined based on the ratio of the 19F NMR
integrals. Although compounds 12c, 13c and 14c were successfully isolated after
repeated purifications, it was not possible to isolate difluoride 4c in a pure form. The
structure of compound 4c was therefore determined by comparing its 1H and 19F NMR
spectra with those of compounds 4a, 4b and 5 (supplementary data). Among these
compounds, difluoride 12c had a very unique ring structure and, interestingly,
underwent a gradual conversion to the starting material 3c after workup.
Scheme 3. Deoxyfluorination of the α-N-phthaloyl cycloalkanone derivatives 3b and 3c.
The structure of compound 12c was determined by 1H, 13C and 19F NMR spectroscopy.
The 1H NMR spectrum of 12c contained four different aromatic protons, which
indicated that the phthalimide group was not symmetrical. The proton decoupled 19F
9
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NMR spectrum of 12c showed two doublets with a coupling constant of 18 Hz. The 13C
NMR spectrum contained only one carbonyl carbon signal and two quaternary carbon
signals that were coupled to fluorine with coupling constants of 235 and 231 Hz. These
results indicated that compound 12c contained two quaternary carbon atoms that were
directly attached to fluorine, and that one of the carbonyl carbons from the N-phthaloyl
group in compound 3c had been converted to an sp3 carbon. Taken together with the
results of several other NMR experiments, these data were consistent with the proposed
structure of 12c.
The formation of compound 12c can be understood in terms of a similar mechanism to
that shown in Scheme 2. The attack of a second fluoride anion on the cationic
intermediate 15 (corresponding to intermediate 9 in the reaction of the cyclobutanone
derivative 3a) could lead to one of two different reaction pathways: paths a and b
(Scheme 4). Path a would lead to the gem-difluoride 4c, whilst path b would result in
the formation of compound 12c. Given that compound 12c generated starting material
3c following a workup procedure, it seems likely that there was an equilibrium process
between compounds 15 and 12c. The nucleophilic attack of water on intermediate 15
instead of a fluoride anion would afford starting material 3c.
The main products from the deoxyfluorination reactions of 3a and 3c were the
rearrangement product 5 and the intramolecular cyclization product 12c, respectively.
This difference in product type can be explained in terms of the stability of the
associated cationic intermediates. The positive charges in cationic intermediates 9 and
15 would be delocalized across the carbon atoms derived from the carbonyl and imide
carbons in the starting materials. In the case of the cyclobutanone derivative 3a, the
cyclobutyl cation would be particularly unstable and would consequently undergo a
10
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rapid intramolecular rearrangement process to give 5. In contrast, cationic intermediate
15 would be much more stable than 9 and would exist for a long enough time to react
with the fluoride anion and generate 12c.
Scheme 4. The key steps in the deoxyfluorination of -N-phthaloyl cyclohexanone (3c).
The oxazoline derivatives were not formed in the reactions described above because
none of the substrates had a hydrogen atom on their imido nitrogen. We wanted to
confirm the importance of having a hydrogen atom on the nitrogen atom next to the
carbonyl group to facilitate the formation of oxazoline derivatives. Thus, we conducted
the same reaction using a benzoyl protecting instead of a phthalimide. The reactions of
-N-benzoyl cyclobutanone (16) and cyclopentanone (18) afforded the oxazole and
oxazoline derivatives 17 and 19, respectively, as their main products (Scheme 5). These
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results were therefore consistent with the previously reported products described in the
Introduction [8].
Scheme 5. Deoxyfluorination reactions of the -N-benzoyl cycloalkanone derivatives
16 and 18.
During the reaction of the cyclobutanone derivative 16 with Deoxo-Fluor, the
cyclobutyl ring was cleaved to produce derivative 17, bearing a 2-fluoroethyl side chain
at the 5-position of the oxazole ring. The structure of the compound 17 was determined
based on a comparison of its NMR data with those of similar compounds reported in the
literature (see supplementary data). The cleavage of the cyclobutyl ring in 16 was
attributed to the nucleophilic attack of the fluoride anion on the strained cationic
cyclobutyl ring (Scheme 6).
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Scheme 6. Plausible reaction mechanism for the formation of the oxazole derivative 17.
3. Conclusions
We have prepared several -N-phthaloyl protected cycloalkenones, including
cyclobutanone 3a, cyclopentanone 3b and cyclohexanone 3c, and investigated their
reactions with Deoxo-Fluor. The products of these reactions varied depending upon the
size of the ring in the starting materials. For example, the cyclobutanone derivative 3a
produced the N-protected cyclopropylmethyl amine 5 bearing two fluorine atoms at its
vicinal position, whilst the cyclohexanone derivative 3c generated the difluoride 12c,
which was slowly converted back to the starting material following its workup. These
products possessed unique structural features and were obtained via cationic
intermediates, which were stabilized by neighboring group participation from the
adjacent phthalimide group. Control experiments using the N-benzoyl congeners gave
the corresponding oxazole and oxazoline derivatives, indicating that the presence or
absence of a hydrogen atom on the protected amine moiety was critical to determining
the outcome of the reaction. In terms of the synthesis of organofluorine compounds, it is
noteworthy that this approach could be used to provide access to different fluorinated
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compounds from the same -amino cycloalkanone substrate by varying the nature of
the protecting group. For the cyclobutanone derivatives, in particular, unique
cyclopropane and oxazole derivatives were formed when the nitrogen was protected as
a phthalimide or benzamide, respectively. Studies based on deprotecting the
phthalimide group and derivatizing the resulting cyclic fluorides are currently underway
in our laboratory.
Experimental
4. 1. General methods
Melting points were determined on a Yanaco micro melting point apparatus. All
melting points were uncorrected. Preparative gel permeation chromatography was
performed by LC-9201 (Japan Analytical Industry) with JAIGEL 1H+2H columns with
CHCl3 as solvent. 1H, 13C, and 19F NMR spectra were measured in CDCl3 with a Bruker
Avance 300 or 400 spectrometers using tetramethylsilane as an internal standard. High
resolution mass spectra were recorded on a Thermo Fisher Exactive at Center for
Analytical Instrumentation, Chiba University. Elemental analyses were performed by
the Instrument Analysis Center in Faculty of Sciences, Toho University.
4. 2. Experimental procedure
4. 2. 1. 2-(2-Oxocyclobutyl)isoindoline-1, 3-dion (3a)
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To a solution of cyclobutanone (0.75 ml, 10 mmol) in chloroform (45 ml) was slowly
added bromine (0.56 ml, 11 mmol) in chloroform (2 ml) at room temperature and the
mixture was stirred for 1 hr. The reaction mixture was washed with aqueous sodium
hydrogen sulfite solution, saturated aqueous sodium hydrogen carbonate, then brine.
The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent
was removed under reduced pressure to give a crude containing 2-bromocyclobutanone
2. This crude product and potassium phthalate (1.57 g, 8.47 mmol) was dissolved in
DMF (170 ml), and the solution was stirred under reflux for 1 d. After the solvent was
removed under reduced pressure, the residue was separated by column chromatography
(SiO2/CH2Cl2) to give compound 3a (0.449 g, 2.08 mmol, 19%). 3a: white solid; mp
146.0-147.0 ˚C; 1H NMR (300 MHz, CDCl3):  7.85-7.81 (2H, m), 7.76-7.73 (2H, m),
5.47 (1H, t, J=9.5 Hz), 3.28-3.04 (2H, m), 2.73-2.44 (2H, m); 13C NMR (75 MHz,
CDCl3 ):  203.6 (s), 166.8 (s), 134.4 (d), 131.7 (s), 123.6 (d), 60.8 (d), 43.0 (t), 17.9
(t).; Anal. Calcd for C12H9NO3: C, 66.97; H, 4.22; N, 6.51. Found: C, 66.69; H, 4.32; N,
6.47.
4. 2. 2. Deoxyfluorination of 3a
To a solution of compound 3a (0.196 g, 0.911 mmol) in dichloromethane (13.5 ml) was
added Deoxo-Fluor (2.4 ml, 14 mmol) under argon atmosphere and the reaction mixture
was stirred at room temperature for 3 days. Saturated aqueous solution of sodium
hydrogen carbonate was added to the reaction mixture and the solution was stirred for 1
hour. The organic layer was washed with saturated aqueous solution of sodium
hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, filtered, and
15
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the solvent was removed under reduced pressure. The residue was separated by column
chromatography (SiO2/Hexane:Ethyl acetate = 3:1) to give 2-(2,
2-difluorocyclobutyl)isoindoline-1, 3-dion (4a: 0.027 g, 0.11 mmol, 12%) and
2-(2-cyclopropyl-1, 2-difluoro)isoindoline-1, 3-dion (5: 0.082 g, 0.35 mmol, 39%).
4a: white solid; mp 136.0-138.0 ˚C, 1H {19F} NMR (300 MHz, CDCl3):  7.90-7.86 (2H,
m), 7.75-7.73 (2H, m), 5.05 (1H, t, J=8.8 Hz), 3.14-3.00 (1H, m), 2.89-2.72 (1H, m),
2.60-2.40 (1H, m), 2.30-2.17 (1H, m); 13C {19F} NMR (75 MHz, CDCl3):  166.3 (s),
134.8 (d), 131.6 (s), 124.0 (d), 121.3 (s), 52.8 (d), 31.4 (t), 14.6 (t); 19F {1H} NMR (283
MHz, CDCl3):  -84.1 (1F, d, J=204 Hz), -108.8 (1F, d, J=204 Hz); HRMS(ESI), m/z:
+
calcd for C12H10F2NO2 238.0674 [M+H]+; found 238.0676.
5: white solid; mp 71.1-72.1 ˚C, 1H {19F} NMR (300 MHz, CDCl3):  7.96-7.92 (2H,
m), 7.82-7.78 (2H, m), 6.56 (1H, s), 1.52-1.45 (1H, m), 1.42-1.28 (1H, m), 1.23-1.14
(1H, m), 1.07-1.00 (1H, m); 13C {19F} NMR (75 MHz, CDCl3):  166.3 (s), 134.8 (d),
131.6 (s), 124.0 (d), 86.3 (d), 75.6 (s), 10.0 (t), 8.5 (t); 19F {1H} NMR (283 MHz,
CDCl3):  -166.0 (1F, d, J=12 Hz), -196.3 (1F, d, J=12 Hz).; HRMS(ESI), m/z: calcd
for C12H9F2NO2Na+ 260.0494 [M+Na]+; found 260.0486.
4. 2. 3. Deoxyfluorination of 2-(2-Oxocyclopentyl)isoindoline-1, 3-dion (3b)
The same procedure for the deoxyfluorination of 3 was used, but using 3b[12] (100 mg,
0.44 mmol) and Deoxo-Fluor (1.2 ml, 6.5 mmol). The crude mixture was separated by
column chromatography (SiO2/CH2Cl2) to give 2-(2,
2-difluorocyclopentyl)isoindoline-1, 3-dion (4b: 25 mg, 0.1 mmol, 23%) with a
recovery of 3b (3.6 mg, 0.15 mmol, 34%). 4b: white solid; mp 84.0-86.0 ˚C; 1H {19F}
16
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NMR (300 MHz, CDCl3):  7.88-7.84 (2H, m), 7.76-7.72 (2H, m), 4.79 (1H, t, J=9.3
Hz), 2.77-2.59 (1H, m), 2.48-2.37 (1H, m), 2.29-2.04 (3H, m), 1.84-1.68 (1H, m); 13C
{19F} NMR (75 MHz, CDCl3):  167.8 (s), 134.2 (d), 132.1 (s), 128.9 (s), 123.4 (d),
54.7 (d), 35.0 (t), 26.21 (t), 20.2 (t); 19F {1H} NMR (283 MHz, CDCl3):  -91.6 (1F, d,
+
J=232 Hz), -103.5 (1F, d, J=232 Hz); HRMS(ESI), m/z: calcd for C13H12F2NO2
252.0831 [M+H]+; found 252.0833.
4. 2. 4. Deoxyfluorination of 2-(2-Oxocyclohexyl)isoindoline-1, 3-dion (3c)
The same procedure for the deoxyfluorination of 3a was used, but using 3c[13] (85.3
mg, 0.351 mmol) and Deoxo-Fluor (0.94 ml, 5.3 mmol). The separation of crude
mixture 71.0 mg) was very difficult and the yields of products were determined by the
ratio of 19F NMR integral (nondecoupling). Yields: 2-(2,
2-difluorocyclohexyl)isoindoline-1, 3-dion 4c: 7%,
4b,5a-difluoro-5a,6,7,8,9,9a-hexahydrobenzo[4,5]oxazolo[2,3-a]isoindol-11(4bH)-one
12c: 26%, 2-(2-fluoro-2-cyclohexenyl)isoindoline-1, 3-dion 13c: 7%,
2-(2-fluoro-1-cyclohexenyl)isoindoline-1, 3-dion 14c: 5%. Recovery of 3c: 33%.
The structures of these products were determined as follows.
Repeated purification procedure afforded small amount of compounds 13c and 14c.
4c: 19F {1H} NMR (283 MHz, CDCl3):  -99.1 (1F, d, JFF=234 Hz), -111.9 (1F, d,
+
JFF=234 Hz); HRMS(ESI), m/z: calcd for C14H14F2NO2 266.0987 [M+H]+; found:
266.0983.
12c: white solid; 1H {19F} NMR (300 MHz, CDCl3):  7.82(d, J=8.6 Hz, 1H),
7.72-7.68(m, 2H), 7.64-7.61(m, 1H), 4.27(dd, J=11.6, 7.4 Hz, 1H), 2.45-2.32(m, 2H),
17
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1.88-1.72(m, 4H), 1.58-1.52(m, 1H), 1.42-1.30(m, 1H); 13C {19F} NMR (75 MHz,
CDCl3):  171.0(s), 140.9(s), 134.2(d), 131.7(d), 130.7(s), 124.5(d), 123.9 (s), 122.5(d),
121.8 (s), 59.9(d), 31.8(t), 29.8(t), 22.7 (t), 21.8 (t); 19F {1H} NMR (283 MHz, CDCl3):
 -85.4 (1F, d, J=19 Hz), -89.4 (1F, d, J=19 Hz).
13c: white solid; mp 115.0-116.0 ˚C; 1H {19F} NMR (300 MHz, CDCl3):  7.86-7.82
(2H, m), 7.75-7.71 (2H, m), 5.54-5.52 (1H, m), 5.05-5.01 (1H, m), 2.41-2.28 (1H, m),
2.27-2.21 (1H, m), 2.19-2.16 (1H, m), 2.12-2.01 (1H, m), 1.94-1.89 (1H, m), 1.74-1.63
(1H, m); 13C {19F} NMR (75 MHz, CDCl3):  167.9 (s), 154.2 (s), 134.0 (d), 132.0 (s),
123.3 (d), 106.4 (d), 46.2 (d), 28.3 (t), 22.7 (t), 21.2 (t); 19F {1H} NMR (283 MHz,
+
CDCl3):  -116.5 (1F, s); HRMS(ESI), m/z: calcd for C14H13FNO2 246.0925 [M+H]+;
found 246.0920.
14c: white solid; mp 169.0-171.0 ˚C; 1H {19F} NMR (300 MHz, CDCl3):  7.90-7.87
(2H, m), 7.75-7.72 (2H, m), 2.43-2.39 (2H, m), 2.36-2.32 (2H, m), 1.88-1.79 (4H, m);
13C {19F} NMR (75 MHz, CDCl3):  166.7 (s), 157.3 (s), 134.2 (d), 132.1 (s), 123.5 (d),
106.9 (s), 26.2 (t), 25.9 (t), 22.7 (t), 22.1 (t); 19F {1H} NMR (283 MHz, CDCl3): 
+
-103.8 (1F, s); HRMS(ESI), m/z: calcd for C14H13FNO2 246.0925 [M+H]+; found
246.0923.
Compound 4c could not be isolated in pure form. The 19F NMR spectra of the crude
mixture and partially separated fractions were compared to those of compounds 4a, 4b,
and 5. Compound 4c has two doublets with coupling constant of 234 Hz (1H complete
decoupling) that has similar chemical shift with 4a and 4b, but not 5. Compound 12c
was gradually converted to 3c during workup process. Although we could measure 1H,
18
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13C, and 19F NMR spectra, melting point, elemental analysis, and high resolution MS
analysis could not be conducted.
4. 2. 5. Deoxyfluorination of N-(2-Oxocyclobutyl)benzamide (16)
To a solution of compound 16 [14] (0.201 g, 1.06 mmol) in dichloromethane (20 ml)
was added Deoxo-Fluor (0.97 ml, 5.3 mmol) under argon atmosphere and the reaction
mixture was stirred at room temperature for 3 days. Saturated aqueous solution of
sodium hydrogen carbonate was added to the reaction mixture and the solution was
stirred for 1 hour. The organic layer was washed with saturated aqueous solution of
sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, filtered,
and the solvent was removed under reduced pressure. The residue was separated by
column chromatography (SiO2/CH2Cl2) to give 5-(2-fluoroethyl) -2-phenyloxazole (17:
0.080 g, 0.42 mmol, 40%). 17: pale yellow oil; 1H NMR (300 MHz, CDCl3): 
8.03-7.99 (2H, m), 7.47-7.42 (2H, m), 6.99 (1H, s), 4.73 (2H, dt, J=46.7, 6.2 Hz), 3.16
(2H, ddt, J=23.1, 6.2, 1.0 Hz); 13C {19F} NMR (75 MHz, CDCl3):  161.3 (s), 148.1 (s),
130.2 (d), 128.7 (d), 127.5 (s), 126.1 (d), 125.3 (d), 80.9 (t), 27.3 (t); 19F {1H} NMR
(283 MHz, CDCl3):  -217.5 (1F, s); HRMS(APCI), m/z: calcd for C11H11FNO+
192.0819 [M+H]+; found 192.0813.
4. 2. 6. Deoxyfluorination of N-(2-Oxocyclopentyl)benzamide (18)
To a solution of compound 18 [15] (0.527 g, 2.59 mmol) in dichloromethane (50 ml)
was added Deoxo-Fluor (2.4 ml, 13 mmol) under argon atmosphere and the reaction
19
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mixture was stirred at room temperature for 4 days. Saturated aqueous solution of
sodium hydrogen carbonate was added to the reaction mixture and the solution was
stirred for 1 hour. The organic layer was washed with saturated aqueous solution of
sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, filtered,
and the solvent was removed under reduced pressure. The residue was separated by
column chromatography (SiO2/CH2Cl2) and preparative gel permeation chromatography
to give 3a,5,6,6a-tetrahydro-6a-fluoro-2-phenyl-4H-cyclopentoxazole (19: 0.139 g,
0.677 mmol, 26%) and N-(2, 2-difluorocyclopentyl)benzamide (20: 0.057 g, 0.25 mmol,
10%).
19: pale yellow solid; mp 102.5-104.0 ˚C; 1H NMR (300 MHz, CDCl3):  7.99-7.95
(2H, m), 7.54-7.48 (1H, m), 7.46-7.40 (2H, m), 4.52 (1H, ddd, J=19.4, 9.0, 2.7 Hz),
2.37-2.29 (1H, m), 2.26-2.11 (2H, m), 1.88-1.77 (2H, m), 1.69-1.59 (1H, m); 13C {19F}
NMR (75 MHz, CDCl3):  161.9 (s), 131.7 (d), 129.8 (s, CF), 128.4 (d), 128.3 (d),
126.8 (s), 74.7 (d), 35.9 (t), 32.1 (t), 23.0 (t); 19F NMR (283 MHz, CDCl3):  -109.2 (1F,
dd, J=19.4, 9.7 Hz). ; HRMS(ESI), m/z: calcd for C12H13FNO+ 206.0976 [M+H]+; found
206.0975.
20: pale yellow solid; mp 125.0-126.5 ˚C; 1H {19F} NMR (300 MHz, CDCl3):  7.98
(2H, d, J=7.3 Hz), 7.52 (2H, t, J=7.3 Hz), 7.45 (2H, t, J=7.3 Hz), 6.33 (1H, br s), 4.67
(1H, q, J=8.3 Hz), 2.38-2.33 (1H, m), 2.25-2.17 (1H, m), 1.89-1.81 (2H, m), 1.65-1.57
(1H, m); 13C {19F} NMR (75 MHz, CDCl3):  167.4 (s), 134.0 (d), 129.0 (s, CF2), 128.6
(d), 127.0 (d), 54.5 (d), 32.9 (t), 29.6 (t), 17.9 (t); 19F {1H} NMR (283 MHz, CDCl3): 
-105.3 (2F, ABq, J=229 Hz); HRMS(APCI), m/z: calcd for C12H14F2NO+ 226.1038
[M+H]+; found 226.1003.
20
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Acknowledgements
This work was supported by MEXT-Supported Program for the Strategic Research
Foundation at Private Universities, 2012-2016.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.jfluchem.2015.
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