Synthesis of difluorinated β- And γ-amino acids: Investigation of a challenging deoxyfluorination reaction

Article abstract of DOI:10.1016/j.jfluchem.2012.06.016

Backbone-homologated amino acids containing the vicinal difluoride motif have been synthesised in a highly stereoselective manner. The key synthetic transformation is the DeoxoFluor-mediated fluorination of a vicinal fluorohydrin. The synthetic route is amenable to the production of all possible stereoisomers of α,β-difluoro-γ-aminobutyric acid. In addition, a novel difluoromethyl-substituted β-amino acid is accessed via an unexpected rearrangement process.

Full text of DOI:10.1016/j.jfluchem.2012.06.016

Journal of Fluorine Chemistry 143 (2012) 143–147
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of difluorinated
b- and g-amino acids: Investigation of a challenging
deoxyfluorination reaction
*
Zhiyong Wang, Luke Hunter
School of Chemistry, The University of New South Wales, Sydney 2052, Australia
A R T I C L E I N F O
A B S T R A C T
Article history:
Backbone-homologated amino acids containing the vicinal difluoride motif have been synthesised in a
highly stereoselective manner. The key synthetic transformation is the DeoxoFluor1-mediated
fluorination of a vicinal fluorohydrin. The synthetic route is amenable to the production of all possible
Received 4 April 2012
Received in revised form 6 June 2012
Accepted 14 June 2012
Available online 5 July 2012
stereoisomers of
a,b-difluoro-g-aminobutyric acid. In addition, a novel difluoromethyl-substituted b-
amino acid is accessed via an unexpected rearrangement process.
ß 2012 Elsevier B.V. All rights reserved.
This work is dedicated to Professor David
O’Hagan in honour of his 2012 ACS Award
for Creative Work in Fluorine Chemistry.
Keywords:
b-Amino acids
g-Amino acids
Difluoromethyl group
Gauche effect
XtalFluor-E1
1. Introduction
analogues [7], difluorosuccinates amenable for incorporation into
pseudopeptides [8], and difluoropyrrolidine-containing peptidase
inhibitors [9]. In each case the vicinal difluoride motif exerts a
degree of conformational control due to the fluorine gauche effect
[10], with important knock-on effects upon the properties of the
various functional molecules containing this motif.
Building upon these previous discoveries, we recently became
interested in exploring the vicinal difluoride motif within the
context of backbone-homologated amino acids. Specifically, we
Selective fluorination chemistry is an important strategy for
modulating the properties of bioactive molecules [1]. It is widely
recognised that judicious incorporation of fluorine atoms can lead
to desirable effects on the pharmacokinetic properties of drug
candidates, including higher stability to metabolism, greater
hydrophobicity, and the possibility of increased receptor binding
affinity through polar intermolecular interactions [2]. In addition
however, there is another impact of fluorine substitution that has
been less widely appreciated in the pharmaceuticals arena: fluorine
atoms affect molecular conformation [3]. The highly polarised C–F
bond can participate in a variety of stereoelectronic interactions
with neighbouring functional groups, and these can favour certain
molecular conformations over others [3]. Therefore, knowledge of
such effects affords the possibility of rationally ‘‘programming’’
molecules to adopt desired conformations through selective
fluorination chemistry.
targeted the novel molecular framework of
a,b-difluoro-g-amino
acids (e.g. 3 and 6, Scheme 1) [11]. We envisaged that such
molecules could be valuable as conformationally restricted
building blocks for the creation of shape-controlled peptides
[12]. The key steps in our planned syntheses of 3 and 6 were to be
the deoxyfluorination reactions [13] of vicinal fluorohydrins 1 and
4 (Scheme 1). Herein we provide full details of the outcomes of
these deoxyfluorination attempts, including some challenges and
unexpected discoveries that arose during the course of our
synthetic efforts [11].
Within this context, the vicinal difluoride motif has attracted
considerable interest [4]. A variety of molecules containing this
motif have been created, including surface-active fatty acid
derivatives [5], organic liquid crystals [6], antiretroviral nucleotide
2. Results and discussion
The syn-difluoro diastereoisomeric series was targeted initially.
We first investigated a two-step approach involving activation of
the fluorohydrin 1 as the triflate 7, followed by attempted
substitution with fluoride (Scheme 2) [14]. The triflate 7 was
* Corresponding author. Tel.: +61 293854474; fax: +61 293856141.
E-mail address: l.hunter@unsw.edu.au (L. Hunter).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.06.016

144
Z. Wang, L. Hunter / Journal of Fluorine Chemistry 143 (2012) 143–147
Scheme 1. Deoxyfluorination reactions (1 ! 2 and 4 ! 5) investigated in this study.
Table 1
Direct fluorination of 1 under a variety of conditions.
Entry
(a)
Ratioa
Isolated yield of 2
1:2:8:9:10
1
2
3
4
5
6
7
DeoxoFluor1 (1.1 Equiv.), CH2Cl2, r.t.
1:0:0:0:0
0:2:0:3:0
3:1:3b:0:0
1:0:0:0:0
1:0:0:0:0
3:0:0:2:3
0:0:0:1:3
0%
DeoxoFluor1 (10 Equiv.), 70 8C
21% [11]
n/dc
0%
DeoxoFluor1 (3 Equiv.), TMS-morpholine (3 Equiv.), CH2Cl2, reflux
PBSF (2 Equiv.), Et3Nꢀ3HF (2 Equiv.), Et3N (6 Equiv.), THF, r.t.
PBSF (3 Equiv.), Et3N.3HF (3 Equiv.), Et3N (9 Equiv.), CH3CN, 95 8C
XtalFluor-E1 (2 Equiv.), Et3Nꢀ3HF (2 Equiv.), Et3N (1 Equiv.), CH2Cl2, reflux
XtalFluor-E1 (2 Equiv.), Et3Nꢀ3HF (2 Equiv.), CH2Cl2, reflux
0%
0%
0%
a
Determined by NMR analysis of the crude product mixture.
b
c
Mixture of several elimination products including fluoroalkene 8.
Not determined.
successfully prepared by treatment of 1 with triflic anhydride; the
product was sufficiently stable to be purified by flash chromatog-
raphy, and was characterised by IR and NMR spectrometry
(notably, a long-range F–F coupling of 1.7 Hz was observed in
the 19F NMR spectrum of 7). However, the apparent stability of
triflate 7 proved to be a drawback in the subsequent fluorination
attempts: triflate 7 was found to be surprisingly resistant to
attempts at SN2 fluorination, and was recovered intact from all
reaction trials.
Having established that the stepwise approach (Scheme 2) was
unsuitable for the synthesis of 2, we next investigated the direct
conversion of 1 into 2 (Table 1). Treatment of 1 with a slight excess
of bis(2-methoxyethyl)aminosulfur trifluoride (DeoxoFluor1) [15]
in CH2Cl2 led only to recovery of starting material (entry 1). More
vigorous reaction conditions (entry 2) [16] led to successful
formation of the desired difluoroalkane 2, but also to a substantial
quantity of the undesired difluoromethyl-containing compound 9
which presumably arose through neighbouring group participa-
tion and migration of the phenyl group (vide infra). Interestingly
the desired difluoroalkane 2 was obtained as a single stereoisomer
(stereochemistry confirmed by X-ray crystallography, Fig. 1),
indicating that the direct fluorination proceeded with pure SN2
character and that the competing neighbouring group participa-
tion pathway resulted exclusively in rearrangement rather than
epimerisation. In an attempt to suppress this rearrangement
pathway, the reaction was repeated with the additive TMS-
morpholine (Table 1, entry 3), which has been shown to suppress
SN1-type dissociation of the activated intermediate in Deoxo-
Fluor1-mediated reactions [17]. In this case the presence of TMS-
morpholine completely suppressed the rearrangement pathway
(entry 3), but unfortunately did not lead to an increase in the yield
of 2 due to the formation of several elimination products including
3
8
(alkene geometry confirmed by JHF = 19.6 Hz [18]). The
alternative reagent perfluorobutanesulfonyl fluoride (PBSF) [19]
was next investigated (entries 4 and 5). However no reaction was
observed with this reagent even at elevated temperature, and the
starting material 1 was recovered intact in each case. Finally, we
investigated the new fluorinating reagent (diethylamino)difluor-
osulfonium tetrafluoroborate (XtalFluor-E1) (entries 6 and 7),
which has been shown to effect direct fluorination with minimal
elimination side-reactions in other systems [20]. However, when 1
was treated with XtalFluor-E1 under a variety of conditions,
rearrangement was once again the dominant pathway (entries 6
and 7): this time the aldehyde 10 was also formed in substantial
quantities, presumably arising through neighbouring group
participation of the phenyl group followed by quenching with
adventitious water (vide infra) [21]. Such an interpretation is
supported by our observation that the XtalFluor-E1 reagent
Scheme 2. First attempts to synthesise difluoroalkane 2. Reagents and conditions:
(a) Tf2O, pyridine, CH2Cl2; (b) Et3Nꢀ3HF (neat), 50 8C; (c) HFꢀpyridine, CH2Cl2, 0 8C.

Z. Wang, L. Hunter / Journal of Fluorine Chemistry 143 (2012) 143–147
145
Scheme 3. Synthesis of the diastereoisomeric difluoroalkane 5. The yield of 5 refers
to isolated material; the yields of 11 and ent-9 are estimated from the crude NMR.
Fig. 1. X-ray crystal structure of 2 (thermal ellipsoids drawn at the 50% probability
level) [11]. The observed geometry of 2 features gauche F–C–C–F and F–C–C–N
dihedral angles (71.58 and 64.98 respectively).
The different propensities for rearrangement in the fluorination
reactions of 1 (Table 1) and 4 (Scheme 3) may be rationalised by
considering the likely conformations of the activated intermedi-
ates. In the fluorination of 1, the rearrangement side-reaction is
favoured because the activated intermediate 12 can readily adopt a
conformation that is ideally set up for neighbouring group
participation (Fig. 2). Such a conformation of 12 would be
stabilised by a gauche F–C–C–O alignment [22]. In contrast,
rearrangement is less favoured in the fluorination of 4 because the
activated intermediate 13 may prefer a conformation that is not
ideally set up for neighbouring group participation (Fig. 2). Such a
conformation of 13 would however be susceptible to elimination,
and this may explain the appearance of fluoroalkene 11 as a new
side-product.
Scheme 4. Synthesis of
derivative 16.
g-amino acid derivatives 14 and 15, and the b-amino acid
appeared to be rather hygroscopic despite our attempts to limit its
exposure to air; the inclusion of molecular sieves also did not
alleviate the formation of side-product 10. Overall then, the
optimal yield of difluoroalkane 2 was a modest 21%, obtained with
neat DeoxoFluor1 at 70 8C (entry 2).
With difluoroalkanes 2 and 5 in hand, the final step to complete
the syntheses of the amino acid targets was to convert the phenyl
groups into the corresponding carboxylates (Scheme 4). This was
achieved under standard conditions [23] to smoothly afford the
Attention was next turned towards the alternative diastereo-
isomeric series (Scheme 3). For the fluorination of 4, we employed
the conditions that were previously optimised for the synthesis of
2 (i.e. neat DeoxoFluor1, 70 8C). When these conditions were
applied to substrate 4 (Scheme 3) we were gratified to obtain a
considerably higher yield of the desired difluoroalkane 5 (up to 51%
yield of 5 compared to 21% yield of 2). Rearrangement was a less
prominent side-reaction in the fluorination of 4 (Scheme 3);
instead the major by-product was the fluoroalkene 11 (alkene
difluoro
now ready for further development as shape-controlled GABA
receptor ligands [24] or for incorporation into bioactive -amino
acid-containing peptides [25]. The rearrangement product 9 was
also converted in similar manner to the difluoromethyl-
containing -amino acid derivative 16 (Scheme 4). This novel
molecule is a potentially valuable building block for the creation of
medicinally relevant entities, since the difluoromethyl group is
recognised as a useful isostere of carbonyl and hydroxyl groups
from a drug development perspective [26].
g-amino acids 14 and 15 in protected form [11], which are
g
a
b
3
geometry confirmed by JHF = 35.3 Hz [18]).
Fig. 2. In the fluorination reactions of 1 and 4 different side-products (9–11) are formed: rearrangement is favoured for 1 whereas elimination is favoured for 4. This difference
is explained by considering the conformations of the activated intermediates 12 and 13.

146
Z. Wang, L. Hunter / Journal of Fluorine Chemistry 143 (2012) 143–147
3. Conclusions
7.89–7.83 (m, 2H), 7.78–7.71 (m, 2H), 7.49–7.38 (m, 5H), 5.87 (dd,
J = 46.1, 2.9 Hz, 1H), 5.55 (dddd, J = 18.6, 9.2, 2.9, 2.9 Hz, 1H), 4.25
(dd, J = 14.9, 9.2 Hz, 1H), 3.87 (dd, J = 14.9, 2.9 Hz, 1H); 13C {1H}
The investigation of a challenging deoxyfluorination reaction
has been described. DeoxoFluor1 was found to be the reagent of
choice for stereoselectively incorporating vicinal difluoride motifs
within the densely-functionalised molecular systems 2 and 5.
NMR (50 MHz, CDCl3)
d 167.8 (C), 134.7 (CH), 133.3 (d, J = 20.4 Hz,
C), 131.9 (CH), 130.0 (C), 129.3 (CH), 125.9 (d, J = 7.9 Hz, CH), 123.9
(CH), 92.2 (d, J = 183.7 Hz, CH), 85.9 (d, J = 24.2 Hz, CH), 36.7 (d,
This work has enabled the synthesis of novel difluorinated
b
- and
J = 7.4 Hz, CH2); 19F NMR (282 MHz, CDCl3)
d
ꢂ75.3 (d, J = 1.7 Hz,
g
-amino acids (14–16) that have a variety of potential applications
3F), ꢂ195.3 (ddq, J = 46.1, 18.6, 1.7 Hz, 1F); 19F {1H} NMR
in biotechnology and medicine.
(282 MHz, CDCl3)
d
ꢂ75.3 (d, J = 1.7 Hz, 3F), ꢂ195.3 (q,
J = 1.7 Hz, 1F); MS data for 7 could not be obtained due to product
4. Experimental
decomposition.
4.1. General methods
4.4. Procedure for fluorination using DeoxoFluor1 + TMS-
morpholine: synthesis of (E)-2-(3-fluoro-3-phenylallyl)isoindoline-
1,3-dione (8)
Tetrahydrofuran, acetonitrile, dichloromethane and N,N-
dimethylformamide were purified by passage through activated
alumina. Triethylamine was stored over potassium hydroxide
pellets. Purified water was obtained from a Millipore Milli-Q plus
system. All other reagents and solvents were purchased in the
highest available quality and used as supplied. Reactions were
conducted in oven-dried glassware, with magnetic stirring, under a
positive pressure of nitrogen. Analytical thin layer chromatogra-
phy was performed with Merck aluminium-backed TLC plates
precoated with silica gel 60 F254 (0.2 mm), and visualisation was
achieved by inspection under short-wave UV light followed by
staining with phosphomolybdic acid or potassium permanganate
dip. Flash chromatography was performed using Davisil 40–63
mesh silica gel; eluting solvents are quoted as volume/volume
mixtures. Nuclear magnetic resonance spectra were recorded at
TMS-morpholine (61
m
L, 0.35 mmol) was added dropwise to a
L, 0.35 mmol) in CH2Cl2 (1 mL) at
solution of DeoxoFluor1 (64
m
0 8C. The mixture was stirred at room temperature for 10 min then
transferred via cannula to a flask containing fluorohydrin 1 (34 mg,
0.12 mmol). The resulting mixture was heated at reflux for 16 h,
then cooled, diluted with CDCl3, and directly analysed by NMR.
Data for the crude fluoroalkene 8: 1H NMR (300 MHz, CDCl3)
7.89–7.44 (m, 9H), 5.53 (dt, J = 19.6, 7.5 Hz, 1H), 4.47 (dd, J = 7.5,
1.5 Hz, 2H); 19F NMR (282 MHz, CDCl3)
ꢂ94.9 (d, J = 19.6 Hz, 1F);
19F {1H} NMR (282 MHz, CDCl3)
ꢂ94.9 (s, 1F).
d
d
d
4.5. Procedure for fluorination using XtalFluor-E1: synthesis of (R)-3-
(1,3-dioxoisoindolin-2-yl)-2-phenylpropanal (10)
300 K using
a Bruker Avance DPX400, DPX300 or DPX200
instrument; where necessary, resonances were assigned using
COSY or HSQC experiments. Infrared spectra were recorded as neat
thin films using a Bruker Alpha-E instrument. Mass spectra were
recorded on a Finnigan MAT 900XL instrument using electrospray
ionisation operating in either the positive or negative ion mode;
signal intensities are quoted as a percentage of the base peak.
Optical rotations were measured with a Perkin Elmer model 341
polarimeter at 589 nm with a path length of 1 dm; solution
concentrations are reported as grams per 100 mL. Melting points
were determined using a Stanford Research Systems Optimelt
instrument.
Triethylamine trihydrofluoride (52 mg, 0.43 mmol) was added
to a solution of Xtalfluor-E1 (262 mg, 1.14 mmol) in CH2Cl2
(0.5 mL). A solution of fluorohydrin 1 (35 mg, 0.12 mmol) in CH2Cl2
(0.5 mL) was added via cannula, and the mixture was heated to
reflux overnight. The mixture was cooled and quenched by
addition of 5% aqueous sodium bicarbonate solution (5 mL). The
mixture was extracted with CH2Cl2 (2 ꢃ 5 mL) and the organic
layers were dried (MgSO4) and concentrated onto silica. The crude
product was subjected to flash chromatography eluting with 9:1
hexane/ethyl acetate.
Data for aldehyde 10: [
(cmꢂ1) 1773, 1713, 1397 1359; 1H NMR (300 MHz, CDCl3)
J = 0.7 Hz, 1H), 7.78 (m, 2H), 7.68 (m, 2H), 7.38–7.22 (m, 5H), 4.33–
4.12 (m, 3H); 13C {1H} NMR (75 MHz, CDCl3)
198.6 (C), 168.1 (C),
a
]D–2 (c 0.100, EtOH); IR (neat) vmax
d
9.75 (d,
4.2. Procedure for fluorination using neat DeoxoFluor1: synthesis of
2-((2R,3R)-2,3-difluoro-3-phenylpropyl)isoindoline-1,3-dione (2)
and (R)-2-(3,3-difluoro-2-phenylpropyl)isoindoline-1,3-dione (9)
d
134.1 (CH), 132.9 (C), 131.9 (C), 129.4 (CH), 129.2 (CH), 128.5 (CH),
+
123.4 (CH), 56.9 (CH), 38.1 (CH2); HRMS (ESI, +ve) C17H14NO3
A mixture of fluorohydrin 1 (1.03 g, 3.44 mmol) and neat
DeoxoFluor1 (6.35 mL, 34.4 mmol) was stirred at 70 8C in a plastic
reaction vessel overnight. The mixture was cooled to 0 8C, diluted
with dichloromethane, and concentrated onto silica. The crude
product was subjected to flash chromatography eluting with
9:1 ! 1:1 hexane/ethyl acetate to give the two isolated products 2
and 9 (2:3 ratio, combined yield 54%). Characterisation data for 2
and 9 are reported elsewhere [11].
[MH+] requires m/z 280.0968, found 280.0964; C17H13NO3Na+
[MNa+] requires m/z 302.0788, found 302.0783.
4.6. Procedure for fluorination using neat DeoxoFluor1: synthesis of
2-((2S,3R)-2,3-difluoro-3-phenylpropyl)isoindoline-1,3-dione (5),
(S)-2-(3,3-difluoro-2-phenylpropyl)isoindoline-1,3-dione (ent-9) and
(Z)-2-(3-fluoro-3-phenylallyl)isoindoline-1,3-dione (11)
A mixture of fluorohydrin 2 (97 mg, 0.32 mmol) and neat
DeoxoFluor1 (0.71 g, 3.2 mmol) was stirred at 70 8C in a plastic
reaction vessel overnight. The mixture was cooled to 0 8C, diluted
with dichloromethane, and concentrated onto silica. The crude
product was subjected to flash chromatography eluting with
9:1 ! 1:1 hexane/ethyl acetate to give the isolated product 5
(40 mg, 41%) along with an inseparable mixture of the side-
products ent-9 (18 mg, 17%) and 11 (20 mg, 21%). Characterisation
4.3. (1R,2S)-3-(1,3-dioxoisoindolin-2-yl)-1-fluoro-1-phenylpropan-
2-yl trifluoromethanesulfonate (7)
Trifluoromethanesulfonic anhydride (114
mL, 0.685 mmol) was
added to a solution of fluorohydrin 1 (41.0 mg, 0.137 mmol) in dry
CH2Cl2 (0.5 mL) at 0 8C, and the resulting mixture was stirred at
0 8C for 3 h. The mixture was diluted with 9:1 hexane/EtOAc
(ꢁ2 mL), then directly subjected to flash chromatography eluting
with 9:1 ! 3:2 hexane/EtOAc to afford the triflate 7 as a clear oil
data for 5 are reported elsewhere [11]. Data for ent-9: [a]D–60
(c 0.45, CHCl3) [value calculated from a mixture of 5, ent-9 and 11
of known composition]; NMR data of ent-9 identical to that of 9
[11]. Data for 11: 1H NMR (300 MHz, CDCl3)
d 7.91–7.87 (m, 2H),
(15.5 mg, 26%); [a]D–13 (c 0.41, CHCl3); IR (neat) v
max (cmꢂ1) 1744,
1720, 1420, 1396, 1242, 1211, 1142; 1H NMR (300 MHz, CDCl3)
d

Z. Wang, L. Hunter / Journal of Fluorine Chemistry 143 (2012) 143–147
147
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7.77–7.73 (m, 2H), 5.62 (dt, J = 35.3, 7.1 Hz, 1H), 4.62 (dd, J = 7.1,
1.7 Hz, 2H); 19F NMR (282 MHz, CDCl3)
d
ꢂ116.4 (d, J = 35.3 Hz,
1F); HRMS (ESI, +ve) C17H13FNO2Na+ [MNa+] requires m/z
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282.0925, found 282.0920.
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Chemistry 68 (2003) 5897–5908.
4.7. Procedure for phenyl oxidation: synthesis of (S)-2-((1,3-
dioxoisoindolin-2-yl)methyl)-3,3-difluoropropanoic acid (16)
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Ruthenium chloride hydrate (ꢁ1 mg) was added to a mixture of
difluoroalkane
9
(30.1 mg, 0.100 mmol), NaIO4 (0.348 g,
1.80 mmol), CH2Cl2 (0.75 mL), CH3CN (0.75 mL) and H2O
(0.94 mL), and the mixture was stirred at room temperature for
3 days. The mixture was filtered through celite (EtOAc wash) and
the filtrate was concentrated in vacuo. The crude product was
subjected to flash chromatography eluting with 49:49:2 hexane/
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EtOAc/AcOH ! 98:2 EtOAc/AcOH to afford the
a clear oil (18.3 mg, 68%); [ +6 (c 0.100, CHCl3:MeOH:
AcOH = 80:18:2); IR (neat) vmax (cmꢂ1) 1775, 1713, 1469, 1440,
1396, 1369; 1H NMR (300 MHz, CD3CN)
7.91–7.80 (m, 4H), 6.20
b-amino acid 16 as
a
]
D
d
(td, J = 54.9, 4.7 Hz, 1H), 6.03 (br s, 1H), 4.08 (dd, J = 14.4, 7.2 Hz,
1H), 4.00 (dd, J = 14.4, 6.6 Hz, 1H), 3.43 (m, 1H); 13C {1H} NMR
(75 MHz, CDCl3)
131.6 (C), 122.8 (CH), 115.1 (t, J = 240.4 Hz, CH), 47.3 (t, J = 21.7 Hz,
CH), 33.5 (t, J = 5.8 Hz, CH2); 19F NMR (282 MHz, CDCl3)
–122.1
(ddd, J = 287.2, 54.9, 11.8 Hz, 1F), ꢂ125.8 (ddd, J = 287.2, 55.0,
15.4 Hz, 1F); 19F {1H} NMR (282 MHz, CDCl3)
–122.1 (d,
d 168.1 (t, J = 5.7 Hz, C), 167.5 (C), 134.2 (CH),
d
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d
J = 287.2 Hz, 1F), ꢂ125.8 (d, J = 287.2 Hz, 1F); MS (ESI, +ve) m/z
292 (MNa+, 55%); HRMS (ESI, +ve) C12H9F2NO4Na+ requires m/z
292.0392, found 292.0394.
[17] (a) M.M. Bio, M. Waters, G. Javadi, Z.J. Song, F. Zhang, D. Thomas, Synthesis (2008)
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Acknowledgement
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[18] W.R. Dolbier, Guide to Fluorine NMR for Organic Chemists, Wiley, 2009.
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This work was funded by a University of Sydney Postdoctoral
Research Fellowship and a UNSW start-up grant awarded to LH.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2012.
06.016.
[21] Neighbouring group participation and subsequent rearrangement has been ob-
served in the reaction of XtalFluor-E1 with prolinol derivatives: see A. Cochi, D.G.
Pardo, J. Cossy, Organic Letters, 13 (2011) 4442–4445.
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