Fluorination of pyrrole derivatives by Selectfluor

Article abstract of DOI:10.1016/j.tet.2016.03.067

Fluorination of a range of pyrrole substrates bearing various electron donating and withdrawing substituents at the 1-, 2- and 3-positons using Selectfluor has been assessed in order to develop effective methodology for the synthesis of corresponding fluo

Full text of DOI:10.1016/j.tet.2016.03.067

Tetrahedron xxx (2016) 1e8
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Fluorination of pyrrole derivatives by SelectfluorÔ
*
Darren Heeran, Graham Sandford
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Fluorination of a range of pyrrole substrates bearing various electron donating and withdrawing sub-
stituents at the 1-, 2- and 3-positons using SelectfluorÔ has been assessed in order to develop effective
methodology for the synthesis of corresponding fluoropyrrole derivatives. The synthesis of some novel
fluorinated pyrrole derivatives were achieved in reasonable quantities although many pyrrole substrates
were oxidatively polymerised by the fluorinating reagent, reducing the scope of a selective fluorination
approach for the preparation of fluoropyrrole products.
Received 1 February 2016
Received in revised form 10 March 2016
Accepted 21 March 2016
Available online xxx
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Fluoroheterocycle
Selective fluorination
Fluoropyrrole
Electrophilic fluorination
SelectfluorÔ
1. Introduction
the synthesis of, for example, appropriate fluoropyrrole derivatives
both for medicinal chemistry programmes and large scale
Since the discovery of the bioactivity of 9
a
-fluorocortisoid de-
synthesis.
rivatives by Fried and Sabo in 1954,1 fluorine and fluorinated
groups have been used extensively in drug design for many reasons
including changing lipophilicity, enhancing metabolic stability and
controlling pH profiles.2e6 Consequently, fluorine-containing drugs
are now prevalent within the life science industries and a consid-
erable number of blockbuster pharmaceuticals and agrochemicals
now contain at least one fluorine atom.7e9
In particular, fluorinated azaheterocycles are very important
subunits within life science products and a growing number of
pharmaceuticals that contain fluoroheteroaromatic motifs such as
Voriconazole (antifungal, Pfizer), Capecitabine (anticancer, Roche)
and Diclosulam (herbicide, Dow) have now reached the commer-
cial market10e12 with many others in clinical trials such as Abe-
maciclib (anticancer, Eli Lilly), Riociguat (heart failure, Bayer) and
Verubecestat (Alzheimers, Merck).13 Notably, these pharmaceuti-
cals all contain a fluorinated six-membered azaheterocycle, such as
fluoro-pyridine or -pyrimidine structural subunit, and effective
synthetic procedures at both discovery and manufacturing scales
are well reported in the literature.14e21 In contrast, it is particularly
striking that pharmaceuticals bearing related five-membered aza-
heterocycles, such as fluorinated pyrroles, furans and thiophenes,
are very rarely found in life science products and this is, in part, due
to the lack of available, efficient and regioselective methodology for
Of relevance to this study, the few reported methods for the
synthesis of fluorinated pyrroles22 that have been published in-
volve the use of fluorinated building blocks in cyclisation reactions
such as the cyclocondensation of
compounds with ammonia23 and various primary amines,24 related
cyclisation reactions of -difluoro- -iodotrimethylsilyl ke-
a,a-difluoro-g-iododicarbonyl
a,
a
g
tones,25,26 rhodium catalysed intramolecular NeH insertion of 5-
amino-4,4-difluoro-2-diazo-3-ketoesters,27 silver catalysed ami-
nofluorination of activated allenes,28 1,3-dipolar cycloaddition of
DMAD with azomethine ylides formed by reaction of imines and
difluorocarbene,29,30 the reaction of gem-difluorocyclopropyl ke-
tones with nitriles in the presence of trifluoromethanesulfonic
acid31 and ring closing metathesis of fluoroamidoalkene derivatives
followed by alkylation-aromatisation.32 All cyclisation methods
provide access to fluoropyrrole products but the range of systems
possible are limited by the structural complexity of the fluorinated
building blocks and so corresponding synthesis of libraries of
functional fluoro-pyrroles for drug screening programs are there-
fore limited. Other approaches that require pre-functionalisation of
pyrrole derivatives and reaction with a suitable fluorinating agent
include a photochemical modification of the BalzeSchiemann re-
action,33 fluorodecarboxylation of highly substituted derivatives
using SelectfluorÔ,34 and also the reaction of Grignard35 or lithi-
ated36 intermediates with NFSI, formed from corresponding bro-
minated pyrrole precursors. These methods rely on multi-step
access to appropriately functionalised pyrroles which may be
* Corresponding author. E-mail address: graham.sandford@durham.ac.uk
(G. Sandford).
http://dx.doi.org/10.1016/j.tet.2016.03.067
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
D. Heeran, G. Sandford / Tetrahedron xxx (2016) 1e8
difficult to prepare efficiently and, consequently, have not been
developed to any great extent.
lower the oxidation potential of the pyrrole substrate in order to
limit competing oxidation reactions. Reaction of pyrrole-2-
carboxylate 1 was attempted using microwave irradiation which
resulted in the formation of a number of fluorinated products and
some insoluble polymeric material with an appreciable amount of
starting material remaining. From the crude product mixture,
however, it was possible to isolate monofluorinated pyrrole de-
rivative (2) in 23% yield (Scheme 3) by purification using column
chromatography.
The most direct method for the synthesis of fluoropyrroles is the
transformation of CeH to CeF bonds by reaction of the parent
pyrrole with an electrophilic fluorinating agent. Electrophilic bro-
mination and chlorination reactions of pyrroles are very well
established where NBS, NCS, Br2 or Cl2, give simple access to a va-
riety of halogenated pyrrole scaffolds.37 However, related fluori-
nation processes for the preparation of fluoropyrroles are very rare
with only two reports published in which electrophilic fluorinating
38,39
agents XeF2
and, for a limited number of ester derivatives,
SelectfluorÔ are employed.40 Similarly, fluorination of pyrrole
substrates utilising a nucleophilic source of fluorine is also very
limited with only one example in which Et3N$2HF is used in anodic
fluorination reactions but these generally result in low yields and
significant amounts of polyfluorinated by-products.41 This is de-
spite the obvious potential utility of late stage fluorination of pyr-
roles for incorporation into drug discovery programmes.
In this paper, we describe our attempts to develop general se-
lective fluorination strategies for the synthesis of functionalised
fluoropyrrole derivatives for use in life-science discovery labora-
tories. For this purpose, SelectfluorÔ, a shelf stable, commercially
available fluorinating agent of the NeF class was used.42 We aimed
to assess a model range of pyrrole substrates, bearing electron-
donating and -withdrawing substituents and protecting groups
attached to the pyrrole ring nitrogen (Scheme 1), that could be
efficiently and regioselectively fluorinated using SelectfluorÔ, with
a view to establishing the regioselectivity of electrophilic fluori-
nation processes and providing access to a range of polyfunctional
fluoropyrroles for incorporation into pharmaceutical screening li-
braries (Scheme 1).
Scheme 3. Synthesis of ethyl 5-fluoropyrrole-2-carboxylate 2 and DFT predicted 19F
chemical shifts of fluoropyrrole isomers.
DFT computations46 were performed to predict the 19F chemical
shifts of the three possible fluorinated pyrrole isomers and, there-
fore, determine the regioselectivity of the fluorination reaction. The
calculations (Scheme 3) show that the predicted shift for fluorine
attached to the carbon atom adjacent to the ring nitrogen
(ꢀ130.6 ppm) is in excellent agreement with the measured value
(ꢀ130.73 ppm). In addition, the 19F chemical shifts of the three
possible difluorinated isomers were also calculated, confirming that
the 4,5-difluorinated derivative is the minor product formed.
Subsequently, N-methyl protected pyrrole-2-carboxylate de-
rivative (3) was employed as the substrate but, under the same
conditions as above, gave a much more complex mixture of fluo-
rinated products due to the increased nucleophilicity of the sub-
strate. Nevertheless, it was possible to isolate the monofluorinated
pyrrole derivative (4), in 16% yield (Scheme 4). The lower yield was
attributed to a combination of loss of material during solvent re-
moval due to the high volatility of the product and the greater
number of by-products observed by 19F NMR spectroscopy. The
reaction was also performed at room temperature and using con-
ventional heating in an attempt to decrease the formation of by-
products but, unfortunately, many fluorinated products were ob-
served at reasonable conversion.
Scheme 1. Proposed synthesis of fluoropyrrole derivatives.
2. Results and discussion
We began our investigations by attempting the fluorination of
pyrrole and N-methylpyrrole using SelectfluorÔ by reaction in
acetonitrile but all attempts utilising various conditions gave an
insoluble black solid which we attribute to the formation of ap-
propriate poly(pyrrole) derivatives. Pyrrole and related systems are
readily polymerised when in contact with oxidising systems such
as H2O2, mCPBA, O3, AgNO3, and FeCl3,43,44 and it appears that
SelectfluorÔ is sufficiently oxidising to allow the formation of
polymer products to occur. SelectfluorÔ has been reported to oxi-
dise benzyl alcohols to corresponding aldehydes,45 consistent with
these observations (Scheme 2).
Scheme 4. Synthesis of methyl 1-methyl-5-fluoropyrrole-2-carboxylate.
In attempts to improve the regioselectivity of these processes,
fluorination of pyrrole-2-carboxylate derivative (1) was screened
using a range of Lewis acid catalysts (Table 1). However, the addi-
tion of all Lewis acids screened lowered the observed yields of
fluoropyrrole product, when either SelectfluorÔ or related elec-
trophilic fluorinating agent N-fluoro-benzene sulfonimide (NFSI)47
were used.
Scheme 2. Attempted synthesis of fluoropyrrole derivatives using SelectfluorÔ.
In light of this, we switched our focus to the fluorination of
pyrrole derivatives bearing an electron withdrawing substituent to
Consequently, due to the highly nucleophilic nature of pyrrole
derivatives and the oxidising ability of SelectfluorÔ, we chose to
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D. Heeran, G. Sandford / Tetrahedron xxx (2016) 1e8
3
Table 1
Table 3
Reaction of 1 with electrophilic fluorinating agent in the presence of a Lewis acid
Reaction of 7 with SelectfluorÔ under microwave conditionsa
under microwave conditionsa
Entry
Temp/ꢁC
Time/min
Yield/%b
Entry
Fluorinating agent
Lewis acid
NMR Yield/%b
1
2
3
4
5
6
7
8
70
70
70
60
60
60
100
100
5
10
2
62 (30)
46
38
40
53
45
45
47
1
2
3
4
5
6
7
8
9
SelectfluorÔ
SelectfluorÔ
SelectfluorÔ
SelectfluorÔ
SelectfluorÔ
SelectfluorÔ
SelectfluorÔ
NFSI
d
21
8
2
10
6
9
12
4
<1
ZrCl4
AgNO3
Ga(OTf)3
BF3$Et2O
HfCl4
InCl3
5
10
15
2
5
d
a
Conditions: 7 (2e10 mmol), SelectfluorÔ (1 equiv), MeCN (15e25 mL).
NMR yield determined using an
NFSI
ZrCl4
b
a,a,a-trifluorotoluene reference, isolated yield
a
Conditions: 1 (1.5 mmol), ‘Fþ’ reagent (1 equiv), Lewis acid (0.5 equiv), MeCN
in parentheses.
(15 mL), 70 ꢁC, 5 min.
b
NMR yield determined using an a,a,a-trifluorotoluene reference.
assess fluorination reactions of pyrrole-2-carboxylates bearing
electron withdrawing protecting groups attached to ring nitrogen,
in an attempt to improve the regioselectivity and yield of fluo-
ropyrrole product. Therefore, the synthesis of 4-nitrobenzyl pro-
tected pyrrole derivative (5) was carried out by reaction of nitro-
benzyl bromide and pyrrole 1 and the product successfully iso-
lated in 51% yield. Fluorination of nitrobenzyl pyrrole 5 was
and in this case, conditions shown in entry 1 gave a much-
improved yield of 62%.
However, variations in the reaction time and temperature (en-
tries 2 and 3) resulted in reduced yields. The desired product (8)
could however, be purified by column chromatography and was
isolated in a 30% yield. Similarly, the 4-nitrobenzyl substituted
pyrrole-2-carbonitrile derivative was again synthesised but sub-
sequent related fluorination reactions gave no improvement in
yield.
Due to the limited success observed when employing the 4-
nitrobenzyl group, the tosyl group was selected as ring nitrogen
protecting group due to its strong electron-withdrawing ability,
stability to oxidising conditions and ease of introduction and re-
Table 2
Reaction of 5 with SelectfluorÔ under microwave conditionsa
Table 4
Reaction of 9 with SelectfluorÔ under microwave conditionsa
Entry
Temp/ꢁC
Time/min
Yield/%b
1
2
3
4
5
6
7
8
9
10
70
70
70
5
10
15
2
27 (15)
21
20
23
22
20
20
20
25
70
100
100
100
60
60
60
5
10
15
5
10
15
Entry
R
Temp/ꢁC
Time/min
Yield/%b
1
2
3
4
5
6
7
8
CO2Et
CO2Et
CO2Et
CN
CN
CN
70
70
100
70
100
150
100
100
5
60
60
5
15
15
60
180
<1
2
5
25
a
Conditions: 5 (0.5e0.6 mmol), SelectfluorÔ (1 equiv), MeCN (15 mL).
NMR yield determined using an
0
b
a,a,a-trifluorotoluene reference, isolated yield
<1
11
6
in parentheses.
CN
CN
10
assessed and a range of reaction conditions were screened (Table
2). From the initial starting point (entry 1), the time of reaction
was increased but no improvement in yield was observed despite
significant quantities of starting material remaining. Hence, the
reaction time was lowered (entry 4) but, again, no improvement in
yield was observed. The reaction temperature was varied but nei-
ther an increase or decrease in temperature, over a range of re-
action times, gave increased yields of fluoropyrrole product and, in
all cases, the yield of 5-fluoropyrrole product remained low
(w20%). Despite this, the desired product (6) could be isolated by
column chromatography in 15% yield.
We next studied reaction of a pyrrole derivative bearing a ni-
trile substituent which could be transformed to a number of
substrates of synthetic versatility post fluorination. Initially, the
unprotected pyrrole-2-carbonitrile derivative (7) was used as
substrate for a similar screen of fluorination conditions (Table 3)
a
Conditions: 9 or 10 (1 mmol), SelectfluorÔ (1 equiv), MeCN (15 mL).
NMR yield determined using an a,a,a-trifluorotoluene reference.
b
moval. Both tosyl protected pyrroles 9 and 10 were synthesised and
subsequent fluorination conditions were screened (Table 4).
Initial fluorination reactions of 9 and 10 demonstrated the
ability of the tosyl substituent to reduce the nucleophilicity of the
pyrrole ring compared to substrates attempted previously but, in
these cases, negligible conversion to fluorinated products was ob-
served (entries 1 and 4). Unfortunately, upon increasing the re-
action time and temperature of the fluorination reactions, the
major product observed was an unwanted fluorosulfonyl derivative
(12) (Fig. 1), which was identified by 19F NMR and GCeMS of the
crude reaction mixture. The formation of this species presumably
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4
D. Heeran, G. Sandford / Tetrahedron xxx (2016) 1e8
Table 6
Reaction of 15 with SelectfluorÔ under microwave conditionsa
Entry
Temp/ꢁC
Time/min
Yield/%c
Fig. 1. Possible reaction mechanism resulting in the formation of fluorinated by-
product 12.
1
2
3
4
70
70
70
5
10
20
2
10
9
8
70
9
5
100
70
2
5
9
d
occurs via nucleophilic attack of fluoride at the sulfur atom of the
tosyl group and we suspect that the fluoride ion originates from the
tetrafluoroborate counterion of the SelectfluorÔ reagent, due to
prolonged exposure to high temperatures under microwave
conditions.
6b
a
Conditions: 15 (2 mmol), SelectfluorÔ (1 equiv), MeCN (15 mL).
Selectfluor (2 equiv).
NMR yield determined using an a,a,a-trifluorotoluene reference.
b
c
An additional substituent present on the pyrrole ring will pre-
vent the formation of any 4,5-difluorinated by-product which can
be difficult to separate and could provide useful functionality for
subsequent synthetic transformations. Consequently, the synthesis
of 13 was carried out, as a bromine substituent allows a range of
possible synthetic transformations, particularly palladium cata-
lysed cross coupling chemistry. 4-Bromopyrrole-2-carboxaldehyde
(13) was obtained in good yield48 and optimised fluorination con-
ditions (Table 5) provided the desired product in 29% yield. Fur-
thermore, the structure of 14 was confirmed by X-ray
crystallography (Fig. 2) and the regiochemistry of the fluorination
reaction was consistent with DFT predicted 19F NMR data.
The reactivity of 3-substituted pyrrole derivatives bearing an
electron withdrawing substituent, such as methyl pyrrole-3-
carboxylate (15), was also investigated (Table 6). Based on steric
and electronic factors, the major product predicted was the 5-
fluoro product 16 and the initial conditions applied gave
a promising yield of around 10% as measured by 19F NMR spec-
troscopy since the other major component in the crude reaction
mixture was unreacted starting material. However, upon in-
creasing the reaction time, a larger quantity of insoluble polymer
product was observed alongside
a slight decrease in yield.
Therefore, a shorter reaction time was employed both with the
temperature unchanged and at an elevated temperature of 100 ꢁC
but, in both cases, comparable yields were obtained. Finally, two
equivalents of SelectfluorÔ were used in an attempt to increase
conversion but a large amount of polymeric product was obtained
and a negligible yield of the 5-fluorinated product observed by
NMR.
Finally, the reactivity of a 2,5-disubstituted pyrrole derivative
was assessed as it was envisaged that two electron withdrawing
substituents would help to prevent competing oxidation reactions.
Methyl 5-formylpyrrole-2-carboxylate (17) was employed and
early investigations of reactions conducted at 70 ꢁC (Table 7) did
not give rise to any polymeric product. However, even after a period
of 2.5 h at this temperature (entry 3), the yield of fluorinated
product was disappointingly low and hence the reaction temper-
ature was increased. The results obtained at a reaction temperature
of 100 ꢁC were somewhat similar to that seen at lower tempera-
tures and again a low yield of 17% was obtained even after 2.5 h
although a large proportion of starting material still remained.
Further increases in reaction temperature, however, showed no
significant benefit in terms of obtained yield, but appreciable
amounts of polymer by-product began to form.
Table 5
Reaction of 13 with SelectfluorÔ under microwave conditionsa
Entry
Time/min
Yield/%b
1
2
3
4
5
10
15
7.5
29
31
12
34 (29)
Table 7
a
Conditions: 5 (1e6 mmol), SelectfluorÔ (1 equiv), MeCN (15e25 mL).
Reaction of 17 with SelectfluorÔ under microwave conditionsa
b
NMR yield determined using an
a,a,a-trifluorotoluene reference, isolated yield
in parentheses.
Entry
Temp/ꢁC
Time/min
Yield/%b
1
2
3
4
5
6
7
8
9
10
70
70
70
100
100
100
125
125
125
150
5
30
150
10
60
150
10
30
60
10
4
11
16
5
16
17
11
17
15
18
a
Conditions: 17 (1 mmol), SelectfluorÔ (1 equiv), MeCN (15 mL).
NMR yield determined using an a,a,a-trifluorotoluene reference.
b
Fig. 2. Molecular structure of 14.
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D. Heeran, G. Sandford / Tetrahedron xxx (2016) 1e8
5
3. Conclusions
was removed in vacuo; analysis by 19F NMR relative to an
a,a,a-
trifluorotoluene reference gave the yield of 5-fluorinated product.
In conclusion, the effect of various substituents on the fluori-
nation of pyrrole substrates using SelectfluorÔ has been assessed
but, unfortunately, general methodology for the ready synthesis of
fluoropyrroles could not be achieved despite assessment of a range
of pyrrole derivatives in electrophilic fluorination reactions. In
general, competing oxidation and subsequent polymerisation of
the pyrrole substrates by SelectfluorÔ, which is established as
a reasonably strong oxidising agent as well as a fluorinating agent,
was a recurring problem for all substrates encountered. However,
the synthesis of fluorinated pyrrole derivatives (2, 4, 6, 8 and 14),
which possess suitable functionality for further synthetic trans-
formations to produce structures relevant for application in the life
science industries, was achieved in synthetically useful reactions.
4.2.3. Reaction of pyrrole-2-carbonitrile (7) with SelectfluorÔ under
microwave conditions (Table 3). A solution of 7 (0.18 g, 2 mmol) and
SelectfluorÔ (0.71 g, 2 mmol) in MeCN (15 mL) was heated with
microwave irradiation. The reaction was quenched by the addition
of H2O (30 mL) and CHCl3 (30 mL) was subsequently added. The
layers were separated and the aqueous phase extracted with CHCl3
(3ꢂ30 mL) before the solvent was removed in vacuo; analysis by 19
F
NMR relative to an a,a,a-trifluorotoluene reference gave the yield of
5-fluorinated product.
4.2.4. Reaction of ethyl N-tosyl-pyrrole-2-carboxylate (9) with
SelectfluorÔ under microwave conditions (Table 4). A solution 9 or
10 (1 mmol) and SelectfluorÔ (0.35 g, 1 mmol) in MeCN (15 mL)
was heated with microwave irradiation. The reaction was quenched
by the addition of H2O (30 mL) and CHCl3 (30 mL) was subsequently
added. The layers were separated and the aqueous phase extracted
with CHCl3 (3ꢂ30 mL) before the solvent was removed in vacuo;
4. Experimental
4.1. General
analysis by 19F NMR relative to an
a,a,a-trifluorotoluene reference
Chemicals were purchased from Alfa Aesar, Apollo Scientific,
Fluorochem or Sigma Aldrich and, unless otherwise stated, were
used without any further purification. Dry solvents were obtained
using an Innovative Technology Inc. Solvent Purification System. All
column chromatography was carried out using Silicagel LC60A
(40e63 micron) purchased from Fluorochem. Microwave reactions
were performed in a Biotage Initiator microwave synthesiser
(0e400 W) in a sealed vessel. Proton, carbon and fluorine nuclear
magnetic resonance spectra (1H NMR, 13C NMR and 19F NMR) were
recorded on a Bruker 400 Ultrashield (1H NMR at 400 MHz; 13C
NMR at 101 MHz; 19F NMR at 376 MHz) spectrometer or a Varian
VNMRS-700 (1H NMR at 700 MHz; 13C NMR at 176 MHz) with re-
sidual solvent peaks as the internal standard. 1H, 13C and 19F
spectroscopic data are reported as follows: chemical shift (ppm),
integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet), coupling constant (Hz). Accurate mass
analysis was achieved with a QtoF Premier mass spectrometer
(Waters Ltd., UK) or an LCT Premier XE mass spectrometer (Waters
Ltd., UK) equipped with an accurate solids analysis probe (ASAP).
Infra-red (IR) spectra were recorded on a Perkin Elmer FTIR Spec-
trum TwoÔ fitted with an ATR probe. Melting points were mea-
sured with a Gallenkamp apparatus at atmospheric pressure and
are uncorrected.
gave the yield of 5-fluorinated product. The presence of fluorinated
by-product 12 was confirmed by a combination of 19F NMR and
GCeMS analysis. 19F NMR (376 MHz, Chloroform-d)
SF). GCeMS (EI) m/z 174.0.
d 66.31 (1 F, s,
4.2.5. Reaction of 4-bromopyrrole-2-carboxaldehyde (13) with
SelectfluorÔ under microwave conditions (Table 5). A solution of 13
(0.17 g, 1 mmol) and SelectfluorÔ (0.35 g, 1 mmol) in MeCN (15 mL)
was heated with microwave irradiation at 70 ꢁC. The reaction was
quenched by the addition of H2O (30 mL) and CHCl3 (30 mL) was
subsequently added. The layers were separated and the aqueous
phase extracted with CHCl3 (3ꢂ30 mL) before the solvent was re-
moved in vacuo; analysis by 19F NMR relative to an
a,a,a-tri-
fluorotoluene reference gave the yield of 5-fluorinated product.
4.2.6. Reaction of methyl pyrrole-3-carboxylate (15) with
SelectfluorÔ under microwave conditions (Table 6). A solution of 15
(0.25 g, 2 mmol) and SelectfluorÔ (0.71 g, 2 mmol) in MeCN
(15 mL) was heated with microwave irradiation. The reaction was
quenched by the addition of H2O (30 mL) and CHCl3 (30 mL) was
subsequently added. The layers were separated and the aqueous
phase extracted with CHCl3 (3ꢂ30 mL) before the solvent was re-
moved in vacuo; analysis by 19F NMR relative to an
a,a,a-tri-
fluorotoluene reference gave the yield of 5-fluorinated product.
4.2. Fluorination of pyrroles. General procedures
4.2.7. Reaction of methyl 5-formylpyrrole-2-carboxylate (17) with
SelectfluorÔ under microwave conditions (Table 7). A solution of 17
(0.15 g, 1 mmol) and SelectfluorÔ (0.35 g, 1 mmol) in MeCN (15 mL)
was heated with microwave irradiation. The reaction was quenched
by the addition of H2O (30 mL) and CHCl3 (30 mL) was subsequently
added. The layers were separated and the aqueous phase extracted
with CHCl3 (3ꢂ30 mL) before the solvent was removed in vacuo;
4.2.1. Reaction of ethyl pyrrole-2-carboxylate (1) with electrophilic
fluorinating agent in the presence of a Lewis acid under microwave
conditions (Table 1). To a solution of 1 (0.21 g, 1.5 mmol) and
SelectfluorÔ (0.53 g, 1.5 mmol) in dry MeCN (15 mL) was added
Lewis acid (50 mol %) before heating with microwave irradiation at
70 ꢁC for 5 min. The reaction was quenched by the addition of H2O
(30 mL) and CHCl3 (30 mL) was subsequently added. The layers
were separated and the aqueous phase extracted with CHCl3
analysis by 19F NMR relative to an
a,a,a-trifluorotoluene reference
gave the yield of 5-fluorinated product.
(3ꢂ30 mL) before the solvent was removed in vacuo; analysis by 19
F
NMR relative to an
a
,
a,
a-trifluorotoluene reference gave the yield of
4.3. Synthesis of pyrrole substrates
5-fluorinated product.
4.3.1. Ethyl N-(4-nitrobenzyl)-pyrrole-2-carboxylate (5). To a solu-
tion of ethyl pyrrole-2-carboxylate 1 (2.09 g, 15 mmol) in dry DMF
(25 mL) at 0 ꢁC, sodium hydride (0.54 g, 23 mmol) was added. The
reaction mixture was stirred for 20 min, before the dropwise ad-
dition of 4-nitrobenzyl bromide (4.80 g, 23 mmol) in dry DMF
(10 mL). After a further 25 min, any excess hydride was decom-
posed by the addition of ethanol (15 mL) and the reaction mixture
poured into distilled water (50 mL). The aqueous solution was
4.2.2. Reaction of ethyl N-(4-nitrobenzyl)-pyrrole-2-carboxylate (5)
with SelectfluorÔ under microwave conditions (Table 2). A solution
of 5 (0.15 g, 0.55 mmol) and SelectfluorÔ (0.20 g, 0.55 mmol) in
MeCN (15 mL) was heated with microwave irradiation. The reaction
was quenched by the addition of H2O (30 mL) and CHCl3 (30 mL)
was subsequently added. The layers were separated and the
aqueous phase extracted with CHCl3 (3ꢂ30 mL) before the solvent
Please cite this article in press as: Heeran, D.; Sandford, G., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.067

6
D. Heeran, G. Sandford / Tetrahedron xxx (2016) 1e8
3
4
extracted with DCM (4ꢂ50 mL) and washed with distilled water
(9ꢂ100 mL) and brine (100 mL) before being dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a gradient of hexane/ethyl ac-
etate (0e20% ethyl acetate) as the eluent to give ethyl N-(4-
nitrobenzyl)-pyrrole-2-carboxylate 5 (2.10 g, 51%) as a yellow solid;
C20H), 7.47 (1 H, dd, JHH 3.2, JHH 1.6, C5H), 7.40e7.34 (2 H, m,
3
4
3
C30H), 6.95 (1 H, dd, JHH 3.7, JHH 1.6, C3H), 6.32 (1 H, t, JHH 3.5,
C4H), 2.44 (3 H, s, ArCH3). 13C NMR (176 MHz, Chloroform-d)
d
146.7 (s, C40), 134.3 (s, C10), 130.5 (s, C30), 128.0 (s, C20), 126.7 (s,
C5), 126.7 (s, C3), 112.4 (s, C4), 111.8 (s, CN), 103.9 (s, C2), 21.9 (s,
ArCH3). HRMS (ESI) m/z calcd for [MþH]þ C12H11N2O2S 247.0541;
found 247.0547.
Mp 92e94 ꢁC. 1H NMR (400 MHz, Chloroform-d)
d 8.21e8.11 (2 H,
3
4
m, C30H), 7.21e7.13 (2 H, m, C20H), 7.05 (1 H, dd, JHH 4.0, JHH 1.8,
3
4
3
C5H), 6.93 (1 H, dd, JHH 2.6, JHH 1.8, C3H), 6.25 (1 H, dd, JHH 4.0,
4.3.5. 4-Bromopyrrole-2-carboxaldehyde (13). A solution of pyr-
role-2-carboxaldehyde 12 (3.80 g, 40 mmol) in dry THF (40 mL) was
cooled to 0 ꢁC under Argon. NBS (7.12 g, 40 mmol) was added and
the reaction mixture stirred for 15 min before the solvent was re-
moved in vacuo. The crude product was dried under high vacuum
for 30 min before the addition of distilled water (20 mL) and the
resulting suspension filtered. The resulting solid was dissolved in
a minimum amount of hot ethanol/water solution (9:1) before the
addition of activated charcoal and filtration through a Celite plug.
Upon cooling, the product recrystallised to give 4-bromopyrrole-2-
carboxaldehyde 13 (3.54 g, 51%) as an off white solid; Mp
119e122 ꢁC. IR (neat, cmꢀ1) 3204, 3108, 3982, 2861, 1653, 1378,
3
3JHH 2.6, C4H), 5.65 (2 H, s, ArCH2), 4.19 (2 H, q, JHH 7.1, CH2CH3),
1.28 (3 H, t, JHH 7.1, CH2CH3). 13C NMR (176 MHz, Chloroform-d)
3
d
161.1 (s, C]O), 147.4 (s, C40), 146.1 (s, C10), 129.2 (s, C3), 127.2 (s,
C20), 124.0 (s, C30), 122.4 (s, C2), 118.9 (s, C5), 109.2 (s, C4), 60.2 (s,
CH2CH3), 51.8 (s, ArCH2), 14.5 (s, CH2CH3). HRMS (ESI) m/z calcd for
[MþH]þ C14H15N2O4 275.1032; found 275.1043.
4.3.2. N-(4-Nitrobenzyl)-pyrrole-2-carbonitrile. The same pro-
cedure as for the synthesis of 5 was employed with pyrrole-2-
carbonitrile 7 (0.36 g, 4 mmol), sodium hydride (0.14 g, 6 mmol)
and 4-nitrobenzyl bromide (1.28 g, 6 mmol). The crude product
obtained was purified by column chromatography on silica gel
using a gradient of hexane/ethyl acetate (0e10% ethyl acetate) as
the eluent to yield N-(4-Nitrobenzyl)-pyrrole-2-carbonitrile (0.22 g,
24%) as a yellow solid; Mp 97e99 ꢁC. IR (neat, cmꢀ1) 3142, 3127,
3077, 2212,1507, 1340, 1072, 734. 1H NMR (700 MHz, Chloroform-d)
1354, 918, 769. 1H NMR (400 MHz, Acetone-d6)
9.52 (1 H, d, 4JHH 1.0, CHO), 7.34e7.31 (1 H, m, C5H), 7.09e7.05 (1 H,
m, C3H). 13C NMR (101 MHz, Acetone-d6)
179.4 (s, C]O), 134.3 (s,
d 11.39 (1 H, s, NH),
d
C2), 126.8 (s, C5), 121.5 (s, C3), 98.4 (s, C4). HRMS (ESI) m/z calcd for
[MþH]þ C5H4BrNO 173.9554; found 173.9553.
d
8.22e8.19 (2 H, m, C30H), 7.30e7.27 (2 H, m, C20H), 6.91 (1 H, dd,
4
3
4
3JHH 2.7, JHH 1.6, C5H), 6.88 (1 H, dd, JHH 4.0, JHH 1.6, C3H), 6.28
4.4. Preparative scale fluorination of pyrrole derivatives
(1 H, dd, JHH 4.0, JHH 2.7, C4H), 5.33 (2 H, s, ArCH2). 13C NMR
3
3
(176 MHz, Chloroform-d)
d
148.0 (s, C10), 143.2 (s, C40), 127.9 (s, C20),
4.4.1. Ethyl 5-fluoropyrrole-2-carboxylate (2). A solution of ethyl
pyrrole-2-carboxylate 1 (0.56 g, 4 mmol) and SelectfluorÔ (1.42 g,
4 mmol) in MeCN (25 mL) was heated by microwave irradiation at
70 ꢁC for 5 min. The reaction was quenched by the addition of H2O
(50 mL) and CHCl3 (50 mL) was subsequently added. The layers
were separated and the aqueous phase extracted with CHCl3
(3ꢂ25 mL). The combined organic phases were dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using hexane/diethyl ether (5:1) as
the eluent to give ethyl 5-fluoropyrrole-2-carboxylate 2 (0.15 g, 23%)
as a yellow solid; Rf (3:1, hexane:Et2O) 0.40. IR (neat, cmꢀ1) 3218,
127.1 (s, C5), 124.4 (s, C30), 121.1 (s, C3), 113.5 (s, CN), 110.8 (s, C4),
104.5 (s, C2), 51.7 (s, ArCH2). HRMS (ASAP) m/z calcd for [M]þ
C12H9N3O2 227.0693; found 227.0695.
4.3.3. Ethyl N-tosyl-pyrrole-2-carboxylate (9). Sodium hydride
(0.43 g, 18 mmol) was suspended in anhydrous DMF (10 mL) and
cooled to 0 ꢁC before a solution of ethyl pyrrole-2-carboxylate 1
(2.09 g, 15 mmol) in anhydrous DMF (15 mL) was added over
a period of 20 min. The reaction mixture was then allowed to return
to room temperature and stirred for 1 h before the addition of tosyl
chloride (3.43 g, 18 mmol) in anhydrous DMF (10 mL). After 17 h the
reaction mixture was poured into distilled water (100 mL) and the
aqueous solution extracted with ethyl acetate (3ꢂ50 mL). The
combined organic extracts were washed with distilled water
(4ꢂ100 mL) and brine (100 mL) before being dried (Na2SO4) and
concentrated in vacuo. The crude product was filtered through
a silica plug using ethyl acetate as the eluent and the solvent re-
moved in vacuo to yield 9 (3.27 g, 88%) as a pale yellow solid; Mp
43e45 ꢁC. IR (neat, cmꢀ1) 2993, 2980, 1725, 1705, 1681, 1543, 1359,
2984, 1676, 1586, 1237. 1H NMR (400 MHz, Chloroform-d)
d 9.85
(1 H, s, NH), 6.75 (1 H, ddd, 4JHF 4.7, 3JHH 4.0, 4JHH 2.9, C3H), 5.58 (1 H,
ddd, 3JHF 4.0, 3JHH 4.0, 4JHH 2.7, C4H), 4.31 (2 H, q, 3JHH 7.1, CH2CH3),
1.34 (3 H, t, JHH 7.2, CH2CH3). 19F NMR (376 MHz, Chloroform-d)
3
4
3
3
d
ꢀ130.64 (1 F, ddd, JHF 4.7, JHF 4.0, JHF 2.5). 13C NMR (176 MHz,
Chloroform-d) d
161.0 (s, C]O), 149.4 (d, 1JCF 267.4, CF), 115.2 (s, C3),
114.2 (s, C2), 89.2 (d, 2JCF 11.4, C4), 60.6 (s, CH2CH3), 14.6 (s, CH2CH3).
HRMS (ESI) m/z calcd for [MþH]þ C7H9FNO2 158.0617; found
158.0598.
1258, 1171. 1H NMR (700 MHz, Chloroform-d)
d 7.90e7.84 (2 H, m,
C20H), 7.70 (1 H, dd, 3JHH 3.2, 4JHH 1.9, C5H), 7.35e7.28 (2 H, m, C30H),
4.4.2. Methyl 1-methyl-5-fluoropyrrole-2-carboxylate (4). A solu-
tion of methyl 1-methyl-pyrrole-2-carboxylate 3 (0.56 g, 4 mmol)
and SelectfluorÔ (1.42 g, 4 mmol) in MeCN (25 mL) was heated by
microwave irradiation at 70 ꢁC for 5 min. The reaction was
quenched by the addition of H2O (50 mL) and CHCl3 (50 mL) was
subsequently added. The layers were separated and the aqueous
phase extracted with CHCl3 (3ꢂ25 mL). The combined organic
phases were dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel using
hexane/diethyl ether (5:1) as the eluent to yield methyl 1-methyl-5-
fluoropyrrole-2-carboxylate 4 (0.10 g, 16%) as a colourless oil; Rf (3:1,
hexane:Et2O) 0.42. IR (neat, cmꢀ1) 2955, 1704, 1565, 1472, 1252,
7.04 (1 H, dd, 3JHH 3.7, 4JHH 1.9, C3H), 6.30 (1 H, t, 3JHH 3.4, C4H), 4.19
3
3
(2 H, q, JHH 7.1, CH2CH3), 2.42 (3 H, s, ArCH3), 1.26 (3 H, t, JHH 7.1,
CH2CH3). 13C NMR (176 MHz, Chloroform-d)
158.9 (s, C]O), 145.0
d
(s, C40), 136.1 (s, C10), 129.6 (s, C30), 129.2 (s, C5), 128.3 (s, C20), 125.4
(s, C2), 123.2 (s, C3), 110.4 (s, C4), 60.9 (s, CH2CH3), 21.8 (s, ArCH3),
14.3 (s, CH2CH3). HRMS (ESI) m/z calcd for [MeH]ꢀ C14H14NO4S
292.0644; found 292.0640.
4.3.4. N-Tosyl-pyrrole-2-carbonitrile (10). The same procedure as
for the synthesis of 9 was employed with pyrrole-2-carbonitrile 7
(1.38 g, 15 mmol), sodium hydride (0.43 g, 18 mmol) and tosyl
chloride (3.43 g, 18 mmol). The crude product was recrystallized
from hexane/ethyl acetate to give N-tosyl-pyrrole-2-carbonitrile 10
1103. 1H NMR (400 MHz, chloroform-d) 6.81 (1 H, dd, 4JHF 6.3, 3JHH
d
4.3, C3H), 5.56 (1 H, dd, 3JHH 4.3, 3JHF 4.3, C4H), 3.79 (3 H, s, CO2CH3),
4
(3.02 g, 82%) as
114e1150 ꢁC49). IR (neat, cmꢀ1) 2989, 1726, 1705, 1681, 1582, 1354,
1283, 1134. 1H NMR (400 MHz, Chloroform-d)
8.01e7.85 (2 H, m,
a
pale yellow solid; Mp 110e112 ꢁC (lit.
3.76 (3 H, d, JHF 1.2, NCH3). 19F NMR (376 MHz, Chloroform-d)
4
3
4
d
ꢀ131.89 (1 F, ddq, JHF 6.3, JHF 4.2, JHF 1.2). 13C NMR (101 MHz,
4
1
d
Chloroform-d) d 161.4 (d, JCF 2.2, C]O), 150.5 (d, JCF 267.1, CF),
Please cite this article in press as: Heeran, D.; Sandford, G., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.067

D. Heeran, G. Sandford / Tetrahedron xxx (2016) 1e8
7
3
2
116.0 (d, JCF 4.3, C3), 114.5 (s, C2), 87.6 (d, JCF 12.2, C4), 51.1 (s,
[MþH]þ C5H4BrNOF 191.9460; found 191.9463. Crystals suitable for
OCH3), 30.6 (d, JCF 2.8, NCH3). HRMS (ESI) m/z calcd for [MþH]þ
X-ray diffraction were grown by slow evaporation from acetone.
3
C7H9FNO2 158.0617; found 158.0615.
Crystal data for 14: C5H3BrFNO, M¼191.99, orthorhombic, space
ꢀ
group
P
bca, a¼7.1484(3), b¼8.5392(4), c¼19.5396(9) A,
3
ꢀ
4.4.3. Ethyl N-(4-nitrobenzyl)-5-fluoropyrrole-2-carboxylate (6). A
solution of ethyl N-(4-nitrobenzyl)-pyrrole-2-carboxylate 5 (0.15 g,
0.55 mmol) and SelectfluorÔ (0.20 g, 0.55 mmol) in MeCN (15 mL)
was heated with microwave irradiation at 70 ꢁC for 5 min. The
reaction was quenched by the addition of H2O (30 mL) and CHCl3
(30 mL) was subsequently added. The layers were separated and
the aqueous phase extracted with CHCl3 (3ꢂ30 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo.
The crude product was purified by column chromatography on
silica gel using a gradient of hexane/diethyl ether (0e10% diethyl
ether) as the eluent to give ethyl N-(4-nitrobenzyl)-5-fluoropyrrole-
2-carboxylate 6 (25 mg, 15%) as a pale yellow solid; Mp 52e54 ꢁC. Rf
(3:1, hexane:Et2O) 0.26. IR (neat, cmꢀ1) 3217, 2932,1751, 1667,1523,
U¼1192.73(9) A , F(000)¼736.0, Z¼8, Dc¼2.138 mg mꢀ3
,
ꢀ
m
¼6.817 mmꢀ1 (Mo-K
a
,
l
¼0.71073 A), T¼120(1) K. 15,683 re-
flections were collected on a Bruker D8 Venture diffractometer
(Photon100 CMOS detector, ImS-microsource, focussing mirrors)
yielding 1582 unique data (Rmerg¼0.0669). The structure was
solved by direct method and refined by full-matrix least squares on
F2 for all data using SHELXTL and OLEX2 software. All non-
hydrogen atoms were refined with anisotropic displacement pa-
rameters, H-atoms were placed in calcd positions and refined in
riding mode. Final wR2(F2)¼0.0934 for all data (82 refined param-
eters), conventional R1 (F)¼0.0399 for 1201 reflections with Iꢃ2
s,
GOF¼1.111. Crystallographic data for the structure have been de-
posited with the Cambridge Crystallographic Data Centre as sup-
plementary publication CCDC-14449050.
1344, 1256. 1H NMR (400 MHz, Chloroform-d)
d 8.21e8.12 (2 H, m,
C30H), 7.31e7.27 (2 H, m, C20H), 6.93 (1 H, dd, 4JHF 6.2, 3JHH 4.2, C3H),
5.69 (1 H, dd, 3JHH 4.2, 3JHF 4.2, C4H), 5.59 (2 H, s, ArCH2), 4.21 (2 H,
Acknowledgements
q, JHH 7.1, CH2CH3), 1.29 (3 H, t, JHH 7.1, CH2CH3). 19F NMR
3
3
4
4
(376 MHz, Chloroform-d)
d
ꢀ131.65 (1 F, dd, JHF 6.2, JHF 4.2). 13
C
We thank EPSRC (Durham University DTA) for a studentship to
D.H., Dr. D. S. Yufit for X-ray crystallographic analysis and Dr. M. A.
Fox for DFT calculations.
4
NMR (176 MHz, Chloroform-d)
d
160.8 (d, JCF 2.1, C]O), 150.3 (d,
1JCF 268.7, CF),147.5 (s, C40),144.7 (s, C10), 127.7 (s, C20), 124.1 (s, C30),
3
2
117.0 (d, JCF 4.0, C3), 114.3 (s, C2), 88.3 (d, JCF 11.6, C4), 60.2 (s,
CH2CH3), 46.2 (d, 3JCF 2.0, ArCH2), 14.5 (s, CH2CH3). HRMS (ESI) m/z
calcd for [MþH]þ C14H14FN2O4 293.0938; found 293.0944.
References and notes
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320e330.
4.4.4. 5-Fluoropyrrole-2-carbonitrile (8). A solution of pyrrole-2-
carbonitrile
7 (0.90 g, 10 mmol) and SelectfluorÔ (3.55 g,
€
3. Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881e1886.
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7. O’Hagan, D. J. Fluor. Chem. 2010, 131, 1071e1081.
10 mmol) in MeCN (25 mL) was heated with microwave irradiation
at 70 ꢁC for 5 min. The reaction was quenched by the addition of
H2O (100 mL) and CHCl3 (50 mL) was subsequently added. The
layers were separated and the aqueous phase extracted with CHCl3
(3ꢂ30 mL). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a gradient of hexane/diethyl
ether (0e10% diethyl ether) as the eluent to give 5-fluoropyrrole-2-
carbonitrile 8 (0.33 g, 30%) as a white solid; Mp 55e57 ꢁC. Rf (3:1,
hexane:Et2O) 0.25. IR (neat, cmꢀ1) 3196, 3152, 2227, 1588, 1007. 1H
8. Jeschke, P. ChemBioChem 2004, 5, 570e589.
9. Jeschke, P. Pest Manag. Sci. 2010, 66, 10e27.
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drugsatfda/index.cfm?fuseaction¼Reports.ReportsMenu (accessed 15.12.15).
~
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Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422e518.
14. Shestopalov, A. M.; Shestopalov, A. A.; Rodinovskaya, L. A.; Gromova, A. V. In
Fluorinated Heterocyclic Compounds: Synthesis, Chemistry and Applications;
Petrov, V. A., Ed.; John Wiley & Sons,: 2009; pp 243e271.
15. Shestopalov, A.; Rodinovskaya, L.; Mortikov, V.; Fedorov, A. In Fluorine in Het-
erocyclic Chemistry Volume 2: 6-Membered Heterocycles; Nenajdenko, V., Ed.;
Springer International Publishing: 2014; pp 1e58.
16. Gakh, A. In Halogenated Heterocycles: Synthesis, Application and Environment;
Iskra, J., Ed.; Topics in Heterocyclic Chemistry; Springer Berlin Heidelberg:
2012; 27, pp 33e63.
17. Kosjek, T.; Heath, E. In Halogenated Heterocycles: Synthesis, Application and En-
vironment; Iskra, J., Ed.; Topics in Heterocyclic Chemistry; Springer Berlin Hei-
delberg: 2012; Vol. 27, pp 219e246.
18. Schuman, P. D.; Tarrant, P.; Warner, D. A.; Westmoreland, G. U.S. 3954758, 1976.
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NMR (400 MHz, Chloroform-d)
4JHF 4.5, 3JHH 4.3, 4JHH 3.0, C3H), 5.64 (1 H, ddd, 3JHH 4.1, 3JHF 3.6, 4JHH
2.7, C4H). 19F NMR (376 MHz, Chloroform-d)
ꢀ128.90 (1 F, ddd,
d 8.67 (1 H, s, NH), 6.72 (1 H, ddd,
d
4JHF 4.5, 3JHF 3.6, 3JHF 2.5). 13C NMR (176 MHz, Chloroform-d)
d 148.7
(d, 1JCF 268.1, CF), 120.7 (d, 3JCF 2.7, C3), 114.1 (s, CN), 92.8 (d, 3JCF 5.2,
2
C2), 89.3 (d, JCF 11.0, C4). HRMS (ESI) m/z calcd for [MꢀH]ꢀ
C5H2FN2 109.0202; found 109.0196.
4.4.5. 4-Bromo-5-fluoropyrrole-2-carboxaldehyde (14). A solution
of 4-bromopyrrole-2-carboxaldehyde 13 (1.04 g, 6 mmol) and
SelectfluorÔ (2.13 g, 6 mmol) in MeCN (25 mL) was heated with
microwave irradiation at 70 ꢁC for 7.5 min. The reaction was
quenched by the addition of H2O (50 mL) and CHCl3 (50 mL) was
subsequently added. The layers were separated and the aqueous
phase extracted with CHCl3 (3ꢂ30 mL). The combined organic ex-
tracts were dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel using
a gradient of hexane/diethyl ether (0e20% diethyl ether) as the
eluent to give 4-bromo-5-fluoropyrrole-2-carboxaldehyde 14 (0.33 g,
29%) as off white crystals. Mp 148e150 ꢁC (with degradation). Rf
(3:1, hexane:Et2O) 0.20. IR (neat, cmꢀ1) 3115, 2950, 2783, 2676,
2553, 1627, 1576, 1409, 1143, 668. 1H NMR (400 MHz, Acetone-d6)
27. Wang, Y.; Zhu, S. Org. Lett. 2003, 5, 745e748.
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1998, 90, 117e119.
30. Novikov, M. S.; Khlebnikov, A. F.; Sidorina, E. S.; Kostikov, R. R. J. Chem. Soc.,
4
4
d
9.40 (1 H, d, JHH 3.5, CHO), 7.05 (1 H, d, JHF 4.5, C3H). 19F NMR
Perkin Trans. 1 2000, 231e237.
(376 MHz, Acetone-d6)
d
ꢀ132.72 (1 F, m). 13C NMR (151 MHz, Ac-
31. Yang, T.-P.; Lin, J.-H.; Chen, Q.-Y.; Xiao, J.-C. Chem. Commun. 2013, 9833e9835.
32. Cogswell, T.; Donald, C.; Marquez, R. Org. Biomol. Chem. 2016, 14, 183e190.
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34. Wang, J.; Scott, A. I. J. Chem. Soc., Chem. Commun. 1995, 2399e2400.
etone-d6)
d
178.2 (d, 4JCF 2.7, C]O), 149.3 (d, 1JCF 268.0, CF), 124.3 (s,
2
C2), 120.9 (s, C3), 76.1 (d, JCF 15.1, C4). HRMS (ESI) m/z calcd for
Please cite this article in press as: Heeran, D.; Sandford, G., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.067

8
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Please cite this article in press as: Heeran, D.; Sandford, G., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.067