Modular Construction of Fluoroarenes from a New Difluorinated Building Block by Cross-Coupling/Electrocyclisation/Dehydrofluorination Reactions

Article abstract of DOI:10.1002/chem.201601584

Palladium-catalysed coupling reactions based on a novel and easy-to-synthesise difluorinated organotrifluoroborate were used to assemble precursors to 6π-electrocyclisations of three different types. Electrocyclisations took place at temperatures between 90 and 240 °C, depending on the central component of the π-system; nonaromatic trienes were most reactive, but even systems that required the temporary dearomatisation of two arenyl subunits underwent electrocyclisation, albeit at elevated temperatures. Photochemical conditions were effective for these more demanding reactions. The package of methods delivered a structurally diverse set of fluorinated arenes, spanning a 20 kcal mol^?1range of reactivity, by a flexible route.

Full text of DOI:10.1002/chem.201601584

DOI: 10.1002/chem.201601584
Full Paper
&
Palladium
Modular Construction of Fluoroarenes from a New Difluorinated
Building Block by Cross-Coupling/Electrocyclisation/
Dehydrofluorination Reactions
Jonathan M. Percy,*[a] Helena Emerson,[a] James W. B. Fyfe,[a] Alan R. Kennedy,[a]
Sergej Maciuk,[a] David Orr,[a] Lucie Rathouskꢀ,[a] Joanna M. Redmond,[b] and Peter G. Wilson[a]
Abstract: Palladium-catalysed coupling reactions based on
a novel and easy-to-synthesise difluorinated organotrifluoro-
borate were used to assemble precursors to 6p-electrocycli-
sations of three different types. Electrocyclisations took
place at temperatures between 90 and 2408C, depending
on the central component of the p-system; nonaromatic tri-
enes were most reactive, but even systems that required the
temporary dearomatisation of two arenyl subunits under-
went electrocyclisation, albeit at elevated temperatures. Pho-
tochemical conditions were effective for these more de-
manding reactions. The package of methods delivered
a structurally diverse set of fluorinated arenes, spanning
a 20 kcalmolÀ1 range of reactivity, by a flexible route.
and very effectively, from difluoroalkenes[14] by electrophilic
cyclisation or Ni-catalysed [2+2+2]-cycloaddition. Acetal 1 and
carbamate 2 (Figure 1), which are readily-prepared from tri-
fluoroethanol,[15] can be converted to organozinc halides 3 and
4, which can be deployed in Negishi coupling reactions[16] with
aryl halides. Iodides 5 and 6 underwent Suzuki–Miyaura cou-
plings with a wide range of Molander borates,[17] while Katz
and co-workers[18] have shown how acetal 1 can be converted
to Molander borate 7.
Introduction
Fluoroarenes are of considerable interest and utility in the
fields of agrochemical and pharmaceutical discovery and de-
velopment chemistry;[1] advances in positron emission tomog-
raphy (PET)[2] have added to this level of interest. While tradi-
tional methods like direct fluorination, the Balz–Schiemann re-
action, and the Halex reaction have been used extensively,[3]
and new functional-group transformations have been devel-
oped,[4] metal-catalysed transformations are gaining in impact
and popularity.[5] Copper-,[6] iron-,[7] nickel-,[8] palladium-[9] and
silver-based[10] methods are all known. These novel metal-
based and catalytic methods complement the older (and usu-
ally harsher) methods well; all involve assembly of the arene or
heteroarene scaffold, complete with the appropriate precursor
functionality, before fluorination takes place. For simple arenes,
these novel methods are hard to beat; however, not all precur-
sor types are readily available. A strategically different ap-
proach to fluoroarene synthesis could start from nonfluorinat-
ed species like indanones by carbene transfer and rearrange-
ment,[11] or from readily available fluorinated building blocks
like fluoroenynes,[12] fluorinated dienophiles[13] or most recently,
Figure 1. Fluorinated building blocks derived from trifluoroethanol from the
literature (1–7) and proposed in this work (8).
It follows that a range of methods that allow sp2–sp2 cou-
plings involving difluoroalkenol units are available. While the
preparation of building block 7 requires a low-temperature re-
action, it can be stored and deployed under conditions that
are less expensive to achieve and maintain, which would make
unknown 8 an attractive species.
The route proposed in this manuscript (Scheme 1) sought to
exploit the 6p-disrotatory thermal electrocyclic interconversion
between hexatriene 9 and cyclohexadiene 10. Dehydrofluori-
nation of the difluorinated cyclohexadiene product would be
assisted by the development of aromaticity in 11, and would
therefore be expected to be facile.[19] Tandem electrocyclisa-
[a] Prof. Dr. J. M. Percy, H. Emerson, J. W. B. Fyfe, Dr. A. R. Kennedy, S. Maciuk,
D. Orr, L. Rathouskꢀ, Dr. P. G. Wilson
WestCHEM Department of Pure and Applied Chemistry
University of Strathclyde, Thomas Graham Building
295 Cathedral Street, Glasgow G1 1XL (UK)
E-mail: jonathan.percy@strath.ac.uk
[b] Dr. J. M. Redmond
Allergic Inflammation DPU, GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road, Stevenage, SG1 2NY (UK)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/chem.201601584.
Chem. Eur. J. 2016, 22, 1 – 11
1
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Results and Discussion
Computational triage
Before carrying out any synthetic chemistry, we surveyed the
range of methods used to study the hexatriene/cyclohexadiene
electrocyclisation reaction through electronic structure calcula-
tions. While the early work by Houk and co-workers used the
MP2/6-31G*//RHF/3-21G* level of theory,[27] Rodriguez–Otero
recommended the energies obtained using the B3LYP func-
tional and the 6-31G** basis as reasonably accurate[28] when
compared to more computationally expensive methods.[29]
More recently, Fu, Liu, and co-workers used a two-layer ONIOM
method ((QCISD-(T)/6-31+G(d,p))/B3LYP/6-311+G(2df,2p))) to
study captodative effects on the electrocyclisation of 15
(Scheme 3) and predict accurate free energies of activation.[30]
We wished to anticipate the feasibility of the electrocyclisation
of larger systems so the cost of the calculations needed to be
kept to a minimum. The level of accuracy sought was only
around Æ2 kcalmolÀ1; we were interested in a level of accura-
cy that would predict rate changes of approximately tenfold
(we are considering a default DG° of 30 kcalmolÀ1 at 1008C).
We investigated the level of agreement between Rodriguez-
Otero’s low-cost method and the ONIOM method by optimis-
ing transition structures and hexatriene ground states for a set
of 1-substituted, 2-substituted, and 1,2-disubstituted hexa-
trienes using Spartan’08.[31]
Scheme 1. The relationship between 1,1-difluorinated hexa-1,3Z,5-triene 9
and fluorobenzene 11 through tandem electrocyclisation/dehydrofluorina-
tion.
tion/oxidation strategies are well known and effective.[20] How-
ever, while sigmatropic rearrangements have been used exten-
sively for the synthesis of selectively fluorinated molecules,[21]
the hexatriene/cyclohexadiene electrocyclisation reaction has
been used very lightly.[22] Dolbier and co-workers[23] reported
an interesting attempted electrocyclisation of 12 (Scheme 2);
free radical chemistry intervened and fluorinated cyclopentene
products 14a–c predominated, rather than the anticipated 13.
Dolbier also showed that terminal difluorination diverted the
related Cope rearrangement through a boat transition state;[24]
the electrocyclisation transition state has a similar geometry, in
which two hydrogen atoms approach quite closely at opposite
ends of the ring-closing bond (vide infra).
Scheme 3. Electrocyclisation systems studied using the ONIOM ((QCISD-(T)/
6-31+G(d,p))/ B3LYP/6-311+G(2df,2p)) and B3LYP/6-31G** methods.
Scheme 2. Negishi coupling affords an electrocyclisation precursor but free
radical chemistry accounts for the bulk of the reaction mixture.
Figure 2 plots the data and shows an acceptable level of
agreement between the two sets of values with the largest dif-
ferences around 1.5 kcalmolÀ1, and most points falling within
the Æ1 kcalmolÀ1 error bars of the line.
When the atoms at one of the termini are fluorines, addi-
tional steric repulsion will arise, raising the reaction barrier.
However, an sp2 carbon bearing two fluorine atoms is rehy-
bridising to sp3 during the course of the reaction, which will
help to lower the barrier; the effect is well-known in rearrange-
ment chemistry, having been observed in Claisen[25] and oxy-
Cope[26] rearrangements inter alia. If the two effects are at or
close to balance, the electrocyclisations of the fluorinated sys-
tems should not be significantly disadvantaged relative to
their desfluoro counterparts, and dehydrofluorination to a fluo-
roarene will provide a strong overall driving force. We there-
fore sought to develop a route to fluoroarenes based on as
short a sequence of reactions as possible and using electronic
structure calculations to guide us towards successful transfor-
mations and avoid nugatory synthetic effort.
The prototypical electrocyclisation system is represented by
the transition state from 16a (16aTS, optimised at the B3LYP/
6-31G** level of theory), the H···H interatomic distance mea-
sured from the transition structure is 1.86 ꢂ, which is short
compared to the sum of the van der Waals radii at 2.4 ꢂ
(Figure 3). In the fluorinated system 16bTS, the H···F interatom-
ic distance is 1.93 ꢂ, which is proportionally shorter still com-
pared to the sum of the van der Waals radii at 2.71 ꢂ, but the
calculated barrier heights (DG°) are very similar (31.0 and
31.7 kcalmolÀ1, respectively), with the former comparing well
with the experimental value (Ea =29.9 kcalmolÀ1).
We concluded that a single difluorinated terminus would
have only a very small negative or possibly no effect on the
rate of electrocyclisation, and that the electrocyclisation could
probably be carried out at convenient temperatures.
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
2
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
could be cyclised at slightly higher cost (DG° =37.7 kcalmolÀ1),
with a similar barrier obtainined for the related pyridyl system
18 (38.6 kcalmolÀ1). The barrier rose sharply (to 49.2 kcalmolÀ1
)
for the biaryl system 19a (lowered to 44.3 kcalmolÀ1 by the in-
clusion of two fluorine atoms in 19b), while the inclusion of an
heteroaryl ring in 20a and 20b instead of the phenyl, lowered
the barrier by approximately 5 kcalmolÀ1, consistent with the
lower aromaticity of the thiophene and furan cores.[32] These
findings suggested that quite a wide range of structures could
be taken through the electrocyclisation, leading not only to
substituted benzenes but also to fused-ring arenes and hetero-
arenes.[33] Synthetic chemistry was initiated to assemble precur-
sors to electrocyclisation and to verify these predictions.
Figure 2. Correlation between DG° calculated using the ONIOM method
((QCISD-(T)/6-31+G(d,p))/B3LYP/6-311+G(2df,2p)) and lower cost DFT
method (B3LYP/6-31G** (298 K, gas phase)). Error bars are set at 1 kcalmolÀ1
(B3LYP values) and 1 kcalmolÀ1 (ONIOM values).
Synthetic chemistry
We sought to secure a proof-of-concept using precursors as-
sembled from 8. If successful, the reactions would produce HF,
so we anticipated that enol acetal precursors made from 7
would not survive the electrocyclisation reaction conditions.
Aryloxycarbamates are useful species in directed metallation
reactions,[34] and as electrophilic partners in Ni-catalysed cou-
pling[35] and amination[36] reactions, so products elaborated
from 8 and containing the N,N-diethylcarbamoyloxy (ÀODEC)
group looked potentially valuable. We chose the Suzuki–
Miyaura approach because our Negishi couplings were im-
paired by the presence of ortho-substituents on the aryl halide,
whereas the couplings reported for 7 by Katz were tolerant of
one or two methyl groups at the ortho-position. The ordering
of the events was chosen so that the fluorinated material was
taken through the smallest number of steps possible.
Figure 3. Optimised transition structures (B3LYP/6-31G**) for electrocyclisa-
tion from a) prototype hexa-1,3Z,5-triene 16a and b) 1,1-difluoro-hexa-
1,3Z,5-triene 16b.
Borate 8 was prepared as a free-flowing crystalline solid in
approximately 10 g quantities (57% yield) by intercepting the
organolithium reagent derived from 2[15b] with trimethylborate,
followed by a fluoride workup, based on methodology de-
scribed by GenÞt and co-workers (Scheme 4).[37]
The system also accommodated the N,N-dimethylcarbamoy-
loxy group (ÀODMC) without any energetic penalty. Table 1
lists the calculated free energies of activation for three proto-
typical electrocyclisation systems. Divinylbenzene system 17a
Table 1. Calculated (kcalmolÀ1, B3LYP/6-31G**, 298 K) free energies of activation for electrocyclisation reactions of prototypical systems.
Substrate
DG°
Substrate
DG°
16a
16b
16c
16d
31.0
17c
34.4
31.7
29.5
29.3
17d
36.5
18
38.6
19a (X=H), 19b (X=F)
49.2, 44.3
17a
17b
37.7
35.7
20a
20b
46.3
44.7
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
3
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
out in this work, the use of less hindered alcohol solvents lead
to nucleophilic additions to the coupling products. We were
able to use Pd(OAc)2 as the precatalyst, a modest excess of 8,
a slightly lower loading of ligand than in the Katz procedure,
short reaction times, and vessels open to air in some cases
while achieving full conversion of starting halide. Couplings
proceeded more slowly under the conditions we reported for
iodide 6 ((Ph3P)2PdCl2, Cs2CO3, tBuOH/water, 908C), returning
alkene 21 as a significant side product. Use of the mono(Ru-
Phos)Pd0 complex in Suzuki–Miyaura reactions would usually
be expected to result in faster reactions than when the bis(tri-
phenylphosphino)Pd0 catalyst was used, though recent rigor-
ous examinations of the role of dispersive interactions have
questioned this simple dictum.[40] Commercial 2-bromobiphen-
yl 22a was used to prepare the first substrate 23a which was
isolated in 87% yield by this method. Furyl and thiophenyl
bromides 22b and 22c were prepared by Mioskowski’s
method[41] and coupled to afford 23b and 23c in good yields
(66 and 57%, respectively, Scheme 5).
Scheme 4. Preparation of difluorinated building block 8 (showing side prod-
uct 21). LDA=lithium diisopropylamide.
Examination of crude reaction solutions revealed the pres-
ence of 8 alone, with only trace amounts of alkene 21 as the
sole side product. Single crystals were grown for analysis by X-
ray crystallography (Figure 4), revealing an interesting structure
based on a corrugated 2D coordination polymer (see the Sup-
porting Information for a fuller description).
Scheme 5. Preparation and electrocyclisation/dehydrofluorination of first
generation species; photochemical yields are shown in parentheses (%).
Slow reactions took place when the three species were
heated at 2408C in degassed Ph2O; complete consumption of
23a required 11 days and phenanthrene 24a was isolated in
moderate (56%) yield from a tarry mixture. Any reaction that
produces HF clearly requires care; the electrocyclisation was
carried out in a crimp-sealed microwave vial that was heated
conventionally. At the end of the reaction, the vial cap was pe-
netrated by a syringe needle fitted with a barrel containing KF
and CaCO3. Any volatile HF produced would then vent through
a chemical scrub. The headspace was then blown out with ni-
trogen and aqueous KF solution was added to the vial before
it was opened and worked up conventionally. We observed
moderate levels of etching of the inside of reaction vessels; mi-
crowave vials used in this way were not reused for strongly
heated reactions. With a calculated free energy of activation of
nearly 50 kcalmolÀ1, this reaction is the most demanding of
those attempted in the manuscript; all of the systems pre-
pared subsequently were significantly more reactive. Furyl spe-
cies 23b and thiophenyl analogue 23c electrocyclised to 24b
(39%) and 24c (63%) respectively, after shorter reaction times
(6 days), consistent with the lower degrees of aromaticity in
the heteroarenes (and the lower calculated barriers).
Figure 4. a) Contents of the asymmetric unit of 8 with non-H atoms drawn
with 50% probability ellipsoids; b) packing diagram of 8 viewed along the
crystallographic a direction.
Katz and co-workers used a combination of PdCl2 pre-cata-
lyst and the bulky and electron-rich RuPhos ligand (with trie-
thylamine in n-propanol) to couple 7 to a range of aryl bro-
mides. Molander and co-workers used a closely related set of
conditions for cross-coupling between heteroaryl trifluorobo-
rates, and aryl and heteroaryl halides.[38] The transmetallation
step is usually thought to be rate-determining in Suzuki–
Miyaura coupling, with trifluoroborate hydrolysis to RBFn(OH)3–n
an important determinant of the effectiveness of that part of
the cycle.[39] While Katz found that Cs2CO3 was not an effective
base, it performed much better in our hands in the tBuOH/
water mixture that we had found effective for the Suzuki–
Miyaura couplings of iodide 6. In some of the reactions carried
While we had secured a valuable proof-of-concept, the reac-
tion times and conditions were far from attractive so we made
a preliminary exploration of photochemical reaction condi-
tions. Exposure of acetonitrile solutions of 23a–c to a 254 nm/
9 W source resulted in rapid (within 4 h) and full consumption
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
4
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
of the precursors, and conversion to 24a–c, respectively. These
reactions were carried out on small scales (0.06–0.08 mmole) in
quartz NMR tubes or cuvettes placed close to the light source.
The small-scale reactions (NMR tubes) afforded moderate to
good yields of 24a (50%), 24b (59%) and 24c (73%) after
four hours. Photochemical electrocyclisations of 1,2-diaryle-
thenes are known and are usually reversible;[42] the irreversible
elimination of HF from our photoproducts commits the reac-
tions. Seeberger and co-workers recently reported a (Mallory)
photocycloaddition that was rendered irreversible by dehydro-
bromination of the photocycloadduct.[43]
Figure 5. Indanone 28, tetralone 29 and potential enol intermediate 30.
Unambiguous assignment of protons Ha and Hb from the
HMBC spectrum (the carbonyl carbon is a useful starting point)
allows the assignment of critical cross peaks correlating Cb/Hb
with the methine proton and carbon, and not with the methyl-
ene protons or carbon.
Bromostyrenes 25a–c were easy to make. The first system
studied (25a) was prepared from ortho-bromobenzaldehyde
by a Wittig methylenation following the method of Hibino.[44]
The same aldehyde was taken through a Knoevenagel reac-
tion,[45] then esterification[46] afforded alkenoate 25b. The al-
koxycarbonyl group was moved to the internal position in
25c, prepared from the commercial phenylacetic acid that was
esterified (99%)[47] and then condensed with formaldehyde
(58%).[48] Suzuki–Miyaura couplings between 8 and 25a–
c using procedure A, delivered electrocyclisation precursors in
moderate to good yields (Scheme 6).
3
In 28, a cross peak between Hb and Cc represents a JCÀH
4
coupling; in 29, that cross peak would represent a JCÀH cou-
pling, which is much less likely. The HMBC spectrum recorded
is therefore much more consistent with indanone 28 than with
tetralone 29. Further confidence in the structural assignment
1
was built by calculation of the 13C and H NMR chemical shifts
for 28 and 29 by using the EDF2/6-31G* method implemented
in Spartan’08.[31] Much better correlations were obtained be-
1
tween calculated and experimental 13C and H NMR chemical
shifts for 28 (R2 =0.9963 and 0.9940, respectively) than for 29
(R2 =0.9873 and 0.9393, respectively; see the Supporting Infor-
mation for more details). Reactions at 200 and 2208C resulted
in complete consumption of 26b and formed 27b and 28 in
a 1:1 ratio at both temperatures. The indanone could arise
from direct 5-exo conjugate addition of an enol on the alke-
noate. It is also possible that the enol carbamate could cleave
to enol 30, though this would require an equivalent of acid;
however, HF becomes available once electrocyclisation has
begun.
Scheme 6. Preparation and electrocyclisation/dehydrofluorination of second-
generation species.
A most surprising outcome occurred when 26b was ex-
posed to the photochemical conditions. Neither 27b nor 28
was the major product; instead, we isolated a novel difluori-
nated compound assigned bridged tricyclic structure 31 (35%;
Scheme 7) on the basis of 2D NMR spectra, limited literature
precedents[50] and calculated NMR chemical shifts (see the Sup-
porting Information for full details of the assignment).
For example, 26b coupled reproducibly in good yield (76%)
on 0.2–10 mmol scales; the coupling could even be carried out
open to the air (though we routinely worked under nitrogen).
As the calculated free-energy barrier to electrocyclisation of
26a was 26.5 kcalmolÀ1 and the effects of p-acceptor groups
at the terminal (+1 kcalmolÀ1 for a cyano group) and internal
position (À5 kcalmolÀ1 for a cyano group) of the parent hexa-
triene system were relatively small, we anticipated that all
three substrates could be electrocyclised under roughly similar
conditions. Precursor 26a was not consumed completely after
overnight heating at 130–1708C; however, raising the temper-
ature to 1808C for 24 hours resulted in complete consumption
of 26a and the formation of naphthalene 27a in 84% yield.
Heating 26b at 1808C (in diphenyl ether) overnight resulted in
full consumption of 26b and the isolation of electrocyclisation
product 27b and indanone 28 (products that were only sepa-
rable by preparative HPLC) in a 3:2 ratio (by 19F NMR, ca. 40%
overall). The indanone structure was established by correlation
spectroscopy, by calculation of the NMR chemical shifts and by
comparison of the measured 19F NMR chemical shift with the
limited number of related literature compounds.[49] We initially
assumed that the structure of this product was tetralone 29
(Figure 5), which had failed to undergo dehydrofluorination.
The benzobicyclo[2.1.1]hexane or methanoindene structure
was first prepared by Pomerantz from the reaction of benzyne
and bicyclobutane. Photolysis of divinylbenzene 32a, studied
independently by Pomerantz[51] and Meinwald and Mazzoc-
chi[52] produces a different molecular core 33a (after vinylcyclo-
Scheme 7. Novel photocycloadduct 31, isomeric structure 34 and divinyl-
benzene photochemistry.
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
5
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
propane rearrangement of the initial photoadduct); the corre-
sponding product from our system would be 34. However, the
inclusion of a phenyl[53] or heteroaryl[33b] group as in 32b re-
sults in the formation of the bicyclo[2.1.1] skeleton 33b. Given
the unexpected complexity of these outcomes, and more posi-
tive results under thermal conditions, we pursued the latter ex-
clusively for the rest of the study.
Though the yields for these reactions were disappointingly
low, enough material was secured to test the key aromatisa-
tion step. We noted that while 37b was isolated as a 10:1 mix-
ture of alkene Z (major) and E (minor) diastereoisomers, 38b
was isolated as a 1:5 mixture of alkene Z (minor) and E (major)
diastereoisomers on the basis of the (3J) alkene proton cou-
1
plings in the H NMR spectrum. Because the yield for this step
Suzuki–Miyaura reaction between 8 and 25c afforded 26c
(45–60%); electrocyclisation/dehydrofluorination followed
(1808C, 24 h, Ph2O) to afford 27c in good (78%) yield. The
competing conjugate addition in this case would be much less
favourable than 5-endo cyclisation, so the electrocyclisation
would be expected to win the competition. We had also at-
tempted to prepare 25a by selective monocoupling of ortho-
iodobromobenzene with potassium vinyltrifluoroborate (36a
from Scheme 8). While a good conversion of the aryl dihalide
could be achieved, the reaction was capricious with significant
run-to-run variation in the levels of inseparable side products.
The Wittig-based methodology was significantly more reprodu-
cible and was therefore preferred (vide supra). Beaudry and co-
workers[54] have recently reported on selective monocouplings
of this type, suggesting that a vinyl group lowers the reactivity
of an ortho CÀBr bond towards oxidative addition by h2-coor-
dination to palladium, assisting selective monocoupling.
was 45%, Z/E isomerisation must have taken place during the
coupling reaction. The electrocyclisations were carried out at
2408C to afford the quinolines 39a–c. While these represent
relatively preliminary results (the couplings to 38a–c clearly re-
quire optimisation), they do demonstrate proof-of-concept for
the electrocyclisation/dehydrofluorination on the pyridine tem-
plate, and the availability of monofluorinated quinolines by
this route.
The electrocyclisations of all the substrates examined up to
this point require temporary dearomatisation which adds to
the activation energy; a triene without an aromatic core
should react at significantly lower energetic cost (ca. 6 kcal
molÀ1 from the calculations) and therefore at much lower tem-
peratures. Cyclohexanone was formylated under Vilsmeier con-
ditions from the literature to afford enal 40b,[58] followed by
Wittig reaction to afford bromodiene 41b, to test this idea.[59]
Suzuki–Miyaura reaction (procedure B) with 8 at 508C afforded
precursor 42b (32%) and traces of arene 43b (Scheme 9). The
low yield arose from the isolation and purification of 42b;
a more efficient protocol was subsequently discovered.
Scheme 8. Proof-of-concept quinoline construction through sequential
Suzuki–Miyaura coupling.
However, the selective monocoupling approach was more
successful from 2-iodo-3-bromopyridine 35, which was pre-
pared from commercial 2,3-dibromopyridine under literature
conditions.[55] Selective couplings at C-2 of 2,3-disubstituted
pyridines are known[56] and the preparation of the 2-iodo spe-
cies was intended to accentuate the higher reactivity of this
position. We used this approach to attempt to secure a proof-
of-concept for quinoline construction. However, Langer and
co-workers[57] had reported that two-fold Heck reaction/electro-
cyclisations based on 2,3-dihalopyridines were unsuccessful, so
the precedent was discouraging. If our electrocyclisation/dehy-
drofluorination was successful, the possibility of dialing-in dif-
ferent alkenyl components through the Suzuki–Miyaura reac-
tion made this an interesting system. The bis(triphenylphosphi-
no)Pd0 (procedure B) conditions were used to secure 37a–
c from 35 and the commercial trifluoroborates 36a–c in poor
to excellent (unoptimised) yields (Scheme 8). Couplings with 8
were carried out under the same conditions to afford 38a–c.
Scheme 9. Fluoroarene construction from wholly nonaromatic precursors.
In these alkenyl halide cases, we found that the RuPhos
ligand could be omitted without any reduction in reaction
yields. Running the coupling of 41b at 908C for a longer
period (18 h) secured 43b in one-pot in 45% yield (for the two
steps). Lower and higher homologues 43a (39%) and 43c
(48%) were also secured by this route directly from the dienyl
bromides; the triene precursors were not isolated for the ho-
mologues, but cyclised in situ at 908C under coupling condi-
tions to afford the arenes directly. The cycloalkene component
is additionally beneficial because it locks the triene in a produc-
tive arrangement; without the ring, the triene would be ex-
pected to be prone to isomerisation into an unproductive E-
linked species competitively with electrocyclisation. Unfortu-
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
6
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
nately, we were unable to take either pyranone 44a or piperi-
done 44b through the Vilsmeier chemistry successfully; formy-
lated products could not be identified.
Potassium 2,2-difluoro-1-(N,N-diethylcarbamoyloxy)ethenyl
trifluoroborate (8)
A solution of LDA (99 mL of a 1.91m solution in THF/heptanes/
ethyl benzene, 0.18 mol) was taken up in dry THF (75 mL) under N2
and cooled to À788C. Carbamate 2 (16.85 mL, 95 mmol) was
added dropwise over 20 min. The reaction mixture was stirred at
À788C for 1.5 h. Trimethylborate (15.6 mL, 0.143 mol) was then
added by syringe in one portion and stirring was continued at
À788C for 1 h further. The colour of the reaction was light brown/
dark orange over this time. The reaction mixture was allowed to
warm to room temperature with stirring over 2 h, during which
time the reaction colour continued to lighten to pale orange/dark
yellow. The reaction mixture was then cooled to 08C and aqueous
potassium hydrogen difluoride (44.3 g, 0.57 mol in water (164 mL))
was added in three roughly equal portions. The reaction mixture
was stirred at room temperature overnight appearing as a lemon-
coloured suspension the next morning. The solvent was removed
as rigorously as possible under reduced pressure to reveal a mix-
ture of fine white solid and viscous orange syrup. The syrup was
then extracted with an acetone/methanol (4:1) mixture (3ꢃ
100 mL). The extracts were then concentrated as rigorously as pos-
sible under reduced pressure until a small amount of precipitate
was apparent; fuller precipitation was achieved by adding diethyl
ether (30 mL), and swirling and scratching vigorously to afford
free-flowing finely crystalline 8 (15.4 g, 57%). M.p. 152–1548C (ace-
tone); 1H NMR (400 MHz, [D6]DMSO): d=3.23 (q, J=7.1 Hz, 4H),
1.05 ppm (t, J=7.1 Hz, 6H); 13C NMR (100 MHz, [D6]DMSO): d=
Conclusions
These sequences represent very concise proof-of-concept elab-
orations of commercial, or easy-to-synthesise and storable ma-
terials (8) into a structurally wide range of fluoroarenes. The
overall yields over several steps are good in some cases and
the temperatures required to carry out the key electrocyclisa-
tions are acceptable for laboratory applications. These findings
show that this de novo strategy is practical, even when the
precursor is a simple ortho-disubstituted benzene; rapid, clean
and high-yielding photochemical conditions can be used to
secure products in these cases. This methodology represents
a significant expansion of the repertoire applicable to the syn-
thesis of selectively fluorinated aromatic molecules, particularly
fused-ring aromatic systems.
Experimental Section
1
General
157.7 (dd, JC-F =298.3, 277.0 Hz), 153.8, 115.8 (brs), 41.2, 13.4 ppm;
19F NMR (376 MHz, [D6]DMSO): d=À91.6 (d, 2J=63.8 Hz, 1F),
NMR spectra were recorded on a Bruker DPX-400, AV-500 and
Avance-II+ 600 spectrometers. 1H, 19F and 13C NMR spectra were
recorded using the deuterated solvent as the lock and the residual
solvent as the internal reference. The multiplicities of the spectro-
scopic data are presented in the following manner: s=singlet, d=
doublet, dd=double doublet, dt=doublet of triplets, dq=doublet
of quartets, t=triplet, q=quartet, m=multiplet and br.=broad.
2
4
À109.2 (dq, J=63.8, J=8.6 Hz, 1F), À140.9–À141.7 ppm (m, 3F);
IR (film): n˜ =2978, 1734, 1699, 1481, 1428, 1266, 1217, 1019, 983,
914 cmÀ1; LRMS (EI): m/z (%): 246 [MÀK]À; HRMS (NSI): calcd for
C7H10BF5NO2: 246.0725 [MÀK]À; found: 246.0724; Crystal data:
C7H10BF5KNO2, crystal size=0.30ꢃ0.22ꢃ0.02 mm3, M=285.07,
monoclinic, a=4.9950(2), b=31.7122(15), c=14.7918(7) ꢂ, a=90,
b=91.740(4), g=908, U=2341.98(18) ꢂ3, T=123(2) K, space
group=P21/c, Z=8, m(MoKa)=0.507 mmÀ1, 11580 reflections mea-
sured, 5500 [R(int)=0.0353], which were used in all calculations.
Final R indices [F2 >s(F2)] R1=0.0498, wR2=0.0762; R indices (all
data) R1=0.0819, wR2=0.0850. Crystals were grown from acetone
by slow evaporation.
3
Unless stated otherwise, all couplings refer to J homocouplings. IR
spectra were recorded on an ATR IR spectrometer. GCMS spectra
were obtained on an instrument fitted with a DB5-type column
(30 mꢃ0.25 mm) running a 40–3208C temperature program, ramp
rate 208CminÀ1 with helium carrier gas flow at 1 cm3 minÀ1. Chemi-
cal ionisation (CI; methane) mass spectra were recorded on an Agi-
lent Technologies 5975C mass spectrometer. HRMS measurements
were obtained from a Waters GCT Premier MS (CI), Finnigan Mat
95 XP (EIMS and/or APCI-MS), or Thermo Scientific LTQ Orbitrap XL
via Advion TriVersa NanoMate infusion (NSI-ES) spectrometers
(EPSRC National Mass Spectrometry Service Centre, Swansea). Thin
layer chromatography was performed on pre-coated aluminium-
backed silica gel plates (E. Merck AG, Darmstadt, Germany. Silica
gel 60 F254, thickness 0.2 mm). Visualisation was achieved using
potassium permanganate or UV detection at 254 nm. Column chro-
matography was performed on silica gel (Zeochem, Zeoprep 60
HYD, 40–63 mm) using a Bꢄchi Sepacore system. Hexane was dis-
tilled before chromatography. THF was dried using a PureSolv
system from Innovative Technology, Inc. tert-Butanol/water
(2.7:1 v/v mixture) and diphenyl ether were degassed by sparging
with nitrogen through a finely drawn out pipette for 30 min before
use. With the exception of 8, potassium trifluoroborate salts were
purchased from Sigma Aldrich and used as received. All other
chemicals were purchased from Sigma Aldrich, Apollo Scientific,
Alfa Aesar, or Fluorochem. 1-(N,N-Diethylcarbamoyloxy)-2,2,2-tri-
fluoroethane was prepared according to the method of Ho-
warth.[15b] Details of the electronic structure calculations are con-
tained in the Supporting Information.
2-(1’-N,N-Diethylcarbamoyloxy-2’-difluoroethenyl)biphenyl
(23a); Suzuki–Miyaura coupling procedure A
A three-necked round-bottomed flask (50 mL) fitted with a reflux
condenser and take-off head was charged with a mixture of tri-
fluoroborate 8 (0.942 g, 3.3 mmol), caesium carbonate (2.94 g,
9 mmol),
2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl
(0.141 g, 0.3 mmol) and palladium acetate (33 mg, 0.15 mmol)
through the wide centre neck. An oval-shaped stirrer bead
(15 mmꢃ0.8 mm) was added and the necks were sealed with light-
ly-greased glass stoppers and the atmosphere was purged with ni-
trogen several times. A degassed mixture of tBuOH and water
(17 mL of a 2.7:1 v/v mixture) was added by syringe, followed by 2-
bromobiphenyl (0.52 mL, 3.0 mmol) against a positive pressure of
nitrogen and heating and stirring were started immediately. The
palladium salt dissolved at ca. 608C and the solution took on
a warm golden colour which darkened to dark amber as it heated
to 908C, reaching that temperature within 10 min of the start of
heating. The mixture was heated overnight; TLC revealed the per-
sistence of aryl bromide. Extending the time further and adding
additional portions of 8 did not force the reaction to completion.
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Cessation of the stirring revealed a colourless aqueous phase
(which contained no chromophoric material) beneath a clear
brown organic layer. The cooled mixture was diluted with water
(30 mL) and dichloromethane (30 mL) and shaken vigorously. The
layers were separated through an hydrophobic frit and the aque-
ous phase was re-extracted with dichloromethane (30 mL) and sep-
arated through an hydrophobic frit. The combined organic layers
were concentrated under reduced pressure to afford a brown oil
(1.4 g). The mixture was washed through a pad of silica gel (15 g)
in a sinter funnel (40 mm diameter) with n-hexane (125 mL) to
elute unreacted bromide, followed by diethyl ether/n-hexane (1:3;
125 mL) to elute 23a (0.862 g, 87%) as a clear oil; Rf =0.27 diethyl
ether/n-hexane (1:4); 1H NMR (400 MHz, CDCl3): d=7.62–7.57 (m,
1H), 7.49–7.31 (env., 8H), 3.19 (q, J=7.1 Hz, 2H), 3.00 (q, J=7.1 Hz,
2H), 1.61 (t, J=7.1 Hz, 3H), 1.06 ppm (t, J=7.1 Hz, 3H); 13C NMR
(m.p. 122–1248C); Rf =0.27 diethyl ether/n-hexane (1:4); 1H NMR
(400 MHz, CDCl3): d=8.71–8.68 (m, 2H), 8.22–8.19 (m, 1H), 8.03–
8.01 (m, 1H), 7.72–7.66 (m, 4H), 3.69 (q, J=7.0 Hz, 2H), 3.52 (q, J=
7.0 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H), 1.32 ppm (t, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=153.2, 148.0 (d, 1JC-F =251.0 Hz),
130.0 (d, 2JC-F =12.0 Hz), 129.5 (d, JC-F =5.1 Hz), 128.1 (d, JC-F
=
2
4.3 Hz), 127.4, 127.1, 126.2, 124.3 (d, JC-F =16.4 Hz), 122.9, 122.7 (d,
J
C-F =2.9 Hz), 121.8 (d, JC-F =6.8 Hz), 121.2 (d, JC-F =6.5 Hz), 42.7,
42.3, 14.4, 13.5 ppm; 19F NMR (376 MHz, CDCl3): d=À135.9 ppm
(s); IR (film): n˜ =3070-2860, 1716, 1651, 1454, 1424, 1340, 1247,
1256, 1152, 949, 770, 726, 754 cmÀ1; UV/Vis (acetonitrile): lmax (e)=
250 (57000), 295 nm (14000 molÀ1 dm3 cmÀ1); m/z: 340 (5%)
[M+C2H5]+, 312 (20) [M+H]+, 100 (100) [CONEt2]+; GC (98%): tR:
17.10 min; elemental analysis calcd (%) for C19H18FNO2: C 73.30, H
5.83, N 4.50; found: C 73.02, H 5.63, N 4.33; Crystal data:
C19H18FNO2, crystal size=0.35ꢃ0.32ꢃ0.20 mm3, M=311.34, mono-
clinic, a=9.1329(4), b=13.4075(5), c=12.8569(5) ꢂ, a=90, b=
91.015(4), g=908, U=1574.07(11) ꢂ3, T=123(2) K, space group=
P21/n, Z=4, m(MoKa)=0.093 mmÀ1, 6702 reflections measured,
3339 [R(int)=0.0359] which were used in all calculations. Final R in-
dices [F2 >s(F2)] R1=0.0481, wR2=0.1078; R indices (all data): R1=
0.0795, wR2=0.1282.
1
(100 MHz, CDCl3): d=154.8 (dd, JC-F =291.0, 284.1 Hz), 153.2, 141.7
(br. d, 3JC-F =3.1 Hz), 141.4, 130.10, 130.06, 129.7, 128.8, 128.4,
127.6, 127.4, 111.8 (dd, 2JC-F =44.0, 19.6 Hz), 41.6, 40.8, 13.3,
2
12.7 ppm; 19F NMR (376 MHz, CDCl3): d=À96.5 (d, J=51.6 Hz, 1F),
2
À106.6 ppm (d, J=51.6 Hz, 1F); (film): n˜ =2978, 1724, 1422, 1267,
1141, 983, 744, 703 cmÀ1
; UV/Vis (acetonitrile): lmax (e)=206
(34260), 229 nm (18900 molÀ1 dm3 cmÀ1); LRMS (CI): m/z: 360.1 (8)
[M+C2H5]+, 332.1 (30) [M+H]+, 215.0 (75) [MÀOCONEt2]+, 100.0
(100) [CONEt2]+; HRMS (NSI): m/z: calcd for C19H20F2NO2+: 332.1457
[M+H]+; found: 332.1456; GC (98%); tR =14.70 minutes.
9-N,N-Diethylcarbamoyloxy-10-fluorophenanthrene 24a;
small scale photochemical procedure
Electrocyclisation precursor 23a (21 mg, 0.06 mmol) was taken up
in [D3]acetonitrile (0.5 mL) and exposed to UV-C radiation (254 nm,
9W) in a quartz NMR tube for 4 h. Full conversion of 23a was con-
firmed by 19F NMR. KF (2 mL of 1.0m aqueous solution) was added
to the tube via syringe and the tube contents were emptied. The
organic solvent was removed from the quenched reaction mixture
under reduced pressure, then the mixture was extracted with di-
chloromethane (3ꢃ5 mL). The organic extracts were combined and
the phases were separated by passing through a hydrophobic frit.
The solvent was removed under reduced pressure and the residue
was taken up in methanol (3 mL). Silica (ca. 500 mg) was added
and the solvent was removed under reduced pressure. The silica
was loaded onto the top of a silica column and the purified prod-
uct was obtained by flash column chromatography (10% diethyl
ether in n-hexane) to afford phenanthrene 24a (10 mg, 0.03 mmol,
50%) as a colourless solid.
2-(1’-N,N-Diethylcarbamoyloxy-2’-difluoroethenyl)biphenyl
(23a): Suzuki–Miyaura coupling procedure B
A mixture of trifluoroborate 8 (332 mg, 1.16 mmol), 2-bromobi-
phenyl 22a (232 mg, 1.0 mmol), caesium carbonate (978 mg,
3.0 mmol), and bis(triphenylphosphino)palladium dichloride
(14 mg, 0.02 mmol) was taken up in a degassed mixture (6.5 mL) of
tert-butanol and H2O (2.7:1 v/v) in a Schlenk tube. The reaction
mixture was stirred at 908C for 18 h, then cooled to room temper-
ature and partitioned between dichloromethane (30 mL) and H2O
(30 mL). The organic phase was separated and dried by passing
through a hydrophobic frit. The aqueous phase was extracted with
dichloromethane (30 mL) and the extract was dried by passing
through a hydrophobic frit. The organic phases were combined
and the solvent was removed under reduced pressure. The
19F NMR spectrum revealed a mixture of 21 and 23a (1:5) which
was not purified further.
1-N,N-Diethylcarbamoyloxy-2-fluoro-5,6,7,8-tetrahydronaph-
thalene 43b; one-pot bisphosphino coupling/electrocyclisa-
tion)
Phenanthrene 24a; general electrocyclisation/dehydrofluori-
nation procedure
Electrocyclisation precursor 23a (0.397 g, 1.2 mmol) was taken up
in degassed diphenyl ether (12 mL); the solution was divided
equally between four microwave vials. Each vial was sealed and
heated with stirring for 264 h. The reaction solution was cooled to
room temperature and each vial cap was pierced with a syringe
needle attached to a syringe barrel containing a dry scrub (KF and
CaCO3). A stream of nitrogen was then passed through the head-
space of each vial for 20 minutes, then KF (2 mL of a saturated
aqueous solution) was added via syringe. The quenched reaction
mixture was stirred for 10 min then each vial was opened and the
solution extracted with dichloromethane (2ꢃ3 mL). The organic ex-
tracts were combined and passed through a hydrophobic frit and
the solvent removed under reduced pressure to reveal a solution
of crude product in diphenyl ether. The crude solution was purified
by flash column chromatography on silica (100% n-hexane, then
20% diethyl ether in n-hexane) to afford fluoroarene 24a (0.209 g,
56%), which crystallised from pentane/dichloromethane) as blocks
A mixture of trifluoroborate 8 (168 mg, 0.59 mmol), diene 41b
(100 mg, 0.54 mmol), caesium carbonate (528 mg, 1.6 mmol) and
bis(triphenylphosphino)palladium dichloride (8 mg, 0.01 mmol) was
taken up in a degassed mixture (3.5 mL) of tert-butanol and H2O
(2.7:1 v/v) in a Schlenk tube. The reaction mixture was stirred at
908C for 18 h, then cooled to room temperature and partitioned
between dichloromethane (15 mL) and H2O (15 mL). The organic
phase was separated and dried by passing through a hydrophobic
frit. The aqueous phase was extracted with dichloromethane
(15 mL) and the extract was dried by passing through a hydropho-
bic frit. The organic phases were combined and the solvent was re-
moved under reduced pressure. The residue was purified by flash
column chromatography (20% diethyl ether in n-hexane) to afford
fluoroarene 43b (64 mg, 45%) as a colourless oil; Rf =0.10 (20% di-
1
ethyl ether in hexane); H NMR (400 MHz, CDCl3): d=6.90–6.86 (m,
2H), 3.51–3.35 (m, 4H), 2.78–2.62 (m, 4H), 1.82–1.73 (m, 4H), 1.34–
1.18 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=152.7 (d, JC-F
=
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
8
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
[12] a) J. J. Xu, Y. Wang, D. J. Burton, Org. Lett. 2006, 8, 2555; b) Y. Wang, J. J.
Xu, D. J. Burton, J. Org. Chem. 2006, 71, 7780; c) Y. Wang, D. J. Burton,
Tetrahedron Lett. 2006, 47, 9279.
[13] T. Pundt, M. Lau, I. Hussain, M. A. Yawer, H. Reinke, P. Langer, Tetrahe-
dron Lett. 2007, 48, 2745.
[14] a) K. Fuchibe, H. Jyono, M. Fujiwara, T. Kudo, M. Yokota, J. Ichikawa,
Chem. Eur. J. 2011, 17, 12175; b) K. Fuchibe, Y. Mayumi, M. Yokota, H.
Aihara, J. Ichikawa, Bull. Chem. Soc. Jpn. 2014, 87, 942; c) K. Fuchibe, T.
Morikawa, K. Shigeno, T. Fujita, J. Ichikawa, Org. Lett. 2015, 17, 1126;
d) T. Fujita, Y. Watabe, T. Ichitsuka, J. Ichikawa, Chem. Eur. J. 2015, 21,
13225.
244.9 Hz), 153.0, 136.8 (d, JC-F =12.4), 135.4 (d, JC-F =3.7 Hz), 132.2,
126.2 (d, JC-F =7.1 Hz), 112.9 (d, JC-F =18.6 Hz), 42.4, 42.0, 28.8, 23.3
(d, JC-F =2.0 Hz), 22.5, 22.1, 14.1, 13.3 ppm; 19F NMR (376 MHz,
CDCl3): d=À134.5 ppm (t, JF-H
,
4JF-H =7.5 Hz); IR (film): n˜ =2933,
2325, 1719, 1493, 1415, 1264, 1205, 1151, 1067, 937, 799, 755 cmÀ1
;
LRMS (CI): m/z: 266 (100) [M+H]+; HRMS (ESI): calcd for C15H21FNO2
266.1551 [M+H]+; found: 266.1559; GC (97%) tR =14.62 min.
Acknowledgements
[15] a) S. T. Patel, J. M. Percy, R. D. Wilkes, Tetrahedron 1995, 51, 9201; b) J. A.
Howarth, W. M. Owton, J. M. Percy, M. H. Rock, Tetrahedron 1995, 51,
10289.
[16] S. H. Kyne, J. M. Percy, R. D. C. Pullin, J. M. Redmond, P. G. Wilson, Org.
Biomol. Chem. 2011, 9, 8328.
We thank the EPSRC Pharma Synthesis Studentship Scheme In-
itiative and GSK (studentship to P.G.W.), James Sanderson (GSK
Stevenage) for preparing 23c, Adam McCarter for assistance
with preparation of the Supporting Information and the EPRSC
National Mass Spectrometry Service Centre, Swansea, for accu-
rate mass measurements.
[17] P. G. Wilson, J. M. Percy, J. M. Redmond, A. W. McCarter, J. Org. Chem.
2012, 77, 6384.
[18] J. D. Katz, B. T. Lapointe, C. J. Dinsmore, J. Org. Chem. 2009, 74, 8866.
[19] J. M. Hammann, T. A. Unzner, T. Magauer, Chem. Eur. J. 2014, 20, 6733.
[20] a) S.-M. T. Toguem, M. Hussain, I. Malik, A. Villinger, P. Langer, Tetrahe-
dron Lett. 2009, 50, 4962; b) G. A. Salman, A. Ali, M. Hussain, R. A. Khera,
P. Langer, Synthesis 2011, 2208; c) M. Hussain, S. T. Van, P. Langer, Synlett
2012, 2735.
Keywords: cross-coupling · density functional calculations ·
electrocyclic reactions · fluorine · palladium
[21] Y. H. Lam, S. J. Stanway, V. Gouverneur, Tetrahedron 2009, 65, 9905.
[22] a) W. R. Dolbier, K. Palmer, H. Koroniak, H. Q. Zhang, V. L. Goedkin, J. Am.
Chem. Soc. 1991, 113, 1059; b) W. R. Dolbier, K. W. Palmer, Tetrahedron
Lett. 1993, 34, 6201; c) L. Luo, M. D. Bartberger, W. R. Dolbier, J. Am.
Chem. Soc. 1997, 119, 12366.
[23] W. R. Dolbier, K. W. Palmer, J. Org. Chem. 1993, 58, 7064.
[24] W. R. Dolbier, K. W. Palmer, J. Am. Chem. Soc. 1993, 115, 9349.
[25] a) G. Dimartino, J. M. Percy, Chem. Commun. 2000, 2339; b) T. Anderl, C.
Audouard, A. Miah, J. M. Percy, G. Rinaudo, K. Singh, Org. Biomol. Chem.
2009, 7, 5200.
[26] G. DiMartino, M. B. Hursthouse, M. E. Light, J. M. Percy, N. S. Spencer, M.
Tolley, Org. Biomol. Chem. 2003, 1, 4423.
[27] K. N. Houk, Y. Li, J. D. Evanseck, Angew. Chem. Int. Ed. Engl. 1992, 31,
682; Angew. Chem. 1992, 104, 711.
[28] J. Rodrꢅguez-Otero, J. Org. Chem. 1999, 64, 6842.
[29] E. M. Cabaleiro-Lago, J. Rodriguez-Otero, A. Pena-Gallego, J. Mol. Struct.
THEOCHEM 2007, 811, 141.
[1] a) P. Jeschke, ChemBioChem 2004, 5, 570; b) K. Muller, C. Faeh, F. Dieder-
ich, Science 2007, 317, 1881; c) S. Purser, P. R. Moore, S. Swallow, V. Gou-
verneur, Chem. Soc. Rev. 2008, 37, 320; d) W. K. Hagmann, J. Med. Chem.
2008, 51, 4359; e) K. L. Kirk, Org. Process Res. Dev. 2008, 12, 305; f) P.
Jeschke, Pest Manage. Sci. 2010, 66, 10.
[2] S. M. Ametamey, M. Honer, P. A. Schubiger, Chem. Rev. 2008, 108, 1501.
[3] a) C. Ni, M. Hu, J. Hu, Chem. Rev. 2015, 115, 765; b) A. J. Cresswell, S. G.
Davies, P. M. Roberts, J. E. Thomson, Chem. Rev. 2015, 115, 566; c) M. G.
Campbell, T. Ritter, Chem. Rev. 2015, 115, 612.
[4] a) P. Tang, W. Wang, T. Ritter, J. Am. Chem. Soc. 2011, 133, 11482; b) F.
Sladojevich, S. I. Arlow, P. Tang, T. Ritter, J. Am. Chem. Soc. 2013, 135,
2470; c) T. Fujimoto, F. Becker, T. Ritter, Org. Process Res. Dev. 2014, 18,
1041; d) T. Fujimoto, T. Ritter, Org. Lett. 2015, 17, 544.
[5] a) M. G. Campbell, T. Ritter, Org. Process Res. Dev. 2014, 18, 474; b) C. N.
Neumann, T. Ritter, Angew. Chem. Int. Ed. 2015, 54, 3216; Angew. Chem.
2015, 127, 3261.
[6] a) P. S. Fier, J. F. Hartwig, J. Am. Chem. Soc. 2014, 136, 10139; b) P. S. Fier,
J. Luo, J. F. Hartwig, J. Am. Chem. Soc. 2013, 135, 2552; c) N. Ichiishi, A. J.
Canty, B. F. Yates, M. S. Sanford, Organometallics 2014, 33, 5525; d) Y. Ye,
M. S. Sanford, J. Am. Chem. Soc. 2013, 135, 4648; e) Y. Ye, S. D. Schimler,
P. S. Hanley, M. S. Sanford, J. Am. Chem. Soc. 2013, 135, 16292; f) M.
Tredwell, S. M. Preshlock, N. J. Taylor, S. Gruber, M. Huiban, J. Passchier,
J. Mercier, C. Genicot, V. Gouverneur, Angew. Chem. Int. Ed. 2014, 53,
7751; Angew. Chem. 2014, 126, 7885.
[7] S. R. Dubbaka, S. Gadde, V. R. Narreddula, Synthesis 2015, 47, 854.
[8] E. Lee, J. M. Hooker, T. Ritter, J. Am. Chem. Soc. 2012, 134, 17456.
[9] a) T. Furuya, H. M. Kaiser, T. Ritter, Angew. Chem. Int. Ed. 2008, 47, 5993;
Angew. Chem. 2008, 120, 6082; b) D. A. Watson, M. Su, G. Teverovskiy, Y.
Zhang, J. Garcia-Fortanet, T. Kinzel, S. L. Buchwald, Science 2009, 325,
1661; c) T. Furuya, D. Benitez, E. Tkatchouk, A. E. Strom, P. Tang, W. A.
Goddard III, T. Ritter, J. Am. Chem. Soc. 2010, 132, 3793; d) T. J. Maimone,
P. J. Milner, T. Kinzel, Y. Zhang, M. K. Takase, S. L. Buchwald, J. Am. Chem.
Soc. 2011, 133, 18106; e) E. Lee, A. S. Kamlet, D. C. Powers, C. N. Neu-
mann, G. B. Boursalian, T. Furuya, D. C. Choi, J. M. Hooker, T. Ritter, Sci-
ence 2011, 334, 639; f) A. R. Mazzotti, M. G. Campbell, P. Tang, J. M.
Murphy, T. Ritter, J. Am. Chem. Soc. 2013, 135, 14012; g) J. R. Brandt, E.
Lee, G. B. Boursalian, T. Ritter, Chem. Sci. 2014, 5, 169; h) H. G. Lee, P. J.
Milner, S. L. Buchwald, J. Am. Chem. Soc. 2014, 136, 3792.
[30] T. Q. Yu, Y. Fu, L. Liu, Q. X. Guo, J. Org. Chem. 2006, 71, 6157.
[31] Spartan’08, Wavefunction, Irvine, CA, 2008.
[32] K. E. Homer, P. B. Karadakov, J. Org. Chem. 2013, 78, 8037.
[33] a) I. Skoric, N. Basaric, Z. Marinic, A. Visnjevac, B. Kojic-Prodic, M. Sindler-
Kulyk, Chem. Eur. J. 2005, 11, 543; b) D. Vidakovic, I. Skoric, M. Horvat, Z.
Marinic, M. Sindler-Kulyk, Tetrahedron 2008, 64, 3928; c) D. Vuk, Z. Mar-
inic, K. Molcanov, D. Margetic, I. Skoric, Tetrahedron 2014, 70, 886.
[34] a) M. C. Whisler, S. MacNeil, V. Snieckus, P. Beak, Angew. Chem. Int. Ed.
2004, 43, 2206; Angew. Chem. 2004, 116, 2256; b) A. Antoft-Finch, T.
Blackburn, V. Snieckus, J. Am. Chem. Soc. 2009, 131, 17750.
[35] a) S. Sengupta, M. Leite, D. S. Raslan, C. Quesnelle, V. Snieckus, J. Org.
Chem. 1992, 57, 4066; b) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N.
Zhang, A. M. Resmerita, N. K. Garg, V. Percec, Chem. Rev. 2011, 111,
1346; c) K. W. Quasdorf, A. Antoft-Finch, P. Liu, A. L. Silberstein, A. Ko-
maromi, T. Blackburn, S. D. Ramgren, K. N. Houk, V. Snieckus, N. K. Garg,
J. Am. Chem. Soc. 2011, 133, 6352; d) T. Mesganaw, N. K. Garg, Org. Pro-
cess Res. Dev. 2013, 17, 29.
[36] a) T. Mesganaw, A. L. Silberstein, S. D. Ramgren, N. F. F. Nathel, X. Hong,
P. Liu, N. K. Garg, Chem. Sci. 2011, 2, 1766; b) L. Hie, S. D. Ramgren, T.
Mesganaw, N. K. Garg, Org. Lett. 2012, 14, 4182.
[37] a) S. Darses, G. Michaud, J. P. GenÞt, Tetrahedron Lett. 1998, 39, 5045;
b) S. Darses, J. P. GenÞt, J. L. Brayer, J. P. Demoute, Tetrahedron Lett.
1997, 38, 4393.
[38] G. A. Molander, B. Canturk, L. E. Kennedy, J. Org. Chem. 2009, 74, 973.
[39] A. J. J. Lennox, G. C. Lloyd-Jones, J. Am. Chem. Soc. 2012, 134, 7431.
[40] a) E. Lyngvi, I. A. Sanhueza, F. Schoenebeck, Organometallics 2015, 34,
805; b) C. L. McMullin, N. Fey, J. N. Harvey, Dalton Trans. 2014, 43,
13545; c) P. Vidossich, G. Ujaque, A. Lledos, Chem. Commun. 2014, 50,
661.
[10] a) T. Furuya, T. Ritter, Org. Lett. 2009, 11, 2860; b) T. Furuya, A. E. Strom,
T. Ritter, J. Am. Chem. Soc. 2009, 131, 1662; c) P. Tang, T. Furuya, T. Ritter,
J. Am. Chem. Soc. 2010, 132, 12150; d) P. Tang, T. Ritter, Tetrahedron
2011, 67, 4449; e) S. R. Dubbaka, V. R. Narreddula, S. Gadde, T. Mathew,
Tetrahedron 2014, 70, 9676.
[11] a) X. H. Cai, K. Wu, W. R. Dolbier, Jr., J. Fluorine Chem. 2005, 126, 477;
b) J. Chang, X. N. Song, W. Q. Huang, D. S. Zhu, M. Wang, Chem.
Commun. 2015, 51, 15362.
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
9
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
[41] J. M. Becht, S. Ngouela, A. Wagner, C. Mioskowski, Tetrahedron 2004, 60,
6853.
[49] a) P. E. Harrington, M. A. Tius, J. Org. Chem. 1999, 64, 4025; b) I. Pravst,
M. Zupan, S. Stavber, Synthesis 2005, 3140.
[42] a) K. A. Muszkat, M. Eisenstein, E. Fischer, A. Wagner, Y. Ittah, W. Luttke,
J. Am. Chem. Soc. 1997, 119, 9351; b) U. Mazzucato, A. Spalletti, J. Phys.
[50] a) A. B. Shtarev, E. Pinkhassik, M. D. Levin, I. Stibor, J. Michl, J. Am. Chem.
Soc. 2001, 123, 3484; b) P. W. Chia, D. Bello, A. M. Z. Slawin, D. O’Hagan,
Chem. Commun. 2013, 49, 2189.
Chem.
A 2009, 113, 14521; c) R. D. Richardson, M. G. J. Baud, C. E.
Weston, H. S. Rzepa, M. K. Kuimova, M. J. Fuchter, Chem. Sci. 2015, 6,
3853.
[51] M. Pomerantz, J. Am. Chem. Soc. 1967, 89, 694.
[52] J. Meinwald, P. H. Mazzocchi, J. Am. Chem. Soc. 1967, 89, 696.
ˇ
[43] a) D. T. McQuade, A. G. O’Brien, M. Dorr, R. Rajaratnam, U. Eisold, B. Mon-
nanda, T. Nobuta, H. G. Lohmannsroben, E. Meggers, P. H. Seeberger,
Chem. Sci. 2013, 4, 4067; b) Y. H. Su, N. J. W. Straathof, V. Hessel, T. Noel,
Chem. Eur. J. 2014, 20, 10562.
[53] M. Sindler-Kulyk, W. H. Laarhoven, J. Am. Chem. Soc. 1976, 98, 1052.
[54] P. Zhao, M. D. Young, C. M. Beaudry, Org. Biomol. Chem. 2015, 13, 6162.
[55] F. Cottet, M. Marull, O. Lefebvre, M. Schlosser, Eur. J. Org. Chem. 2003,
1559.
[44] a) S. Hibino, E. Sugino, Y. Adachi, K. Nomi, K. Sato, K. Fukumoto, Hetero-
cycles 1989, 28, 275; b) W.-Y. Qi, T.-S. Zhu, M.-H. Xu, Org. Lett. 2011, 13,
3410.
[56] S. Schrçter, C. Stock, T. Bach, Tetrahedron 2005, 61, 2245.
[57] A. Ali, M. Hussain, I. Malik, A. Villinger, C. Fischer, P. Langer, Helv. Chim.
Acta 2010, 93, 1764.
[45] D. R. Brittelli, J. Org. Chem. 1981, 46, 2514.
[46] A. A. Poeylaut-Palena, S. A. Testero, E. G. Mata, J. Org. Chem. 2008, 73,
2024.
[58] Z. Arnold, A. Holy, Collect. Czech. Chem. Commun. 1961, 26, 3059.
[59] S. V. Gagnier, R. C. Larock, J. Am. Chem. Soc. 2003, 125, 4804.
[47] J. Kim, Y. Ohk, S. H. Park, Y. Jung, S. Chang, Chem. Asian J. 2011, 6, 2040.
[48] X. Berzosa, X. Bellatriu, J. Teixido, J. I. Borrell, J. Org. Chem. 2010, 75,
487.
Received: April 11, 2016
Published online on && &&, 0000
&
&
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
10
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
Electrocyclic reactions: Thermal and
photochemical electrocyclisations com-
bine with Suzuki–Miyaura couplings of
a novel fluorinated building block to de-
liver a set of structurally diverse fluo-
roarenes, based on computational
triage by a low-cost DFT method (see
figure).
&
Palladium
J. M. Percy,* H. Emerson, J. W. B. Fyfe,
A. R. Kennedy, S. Maciuk, D. Orr,
L. Rathouskꢀ, J. M. Redmond, P. G. Wilson
&& – &&
Modular Construction of Fluoroarenes
from a New Difluorinated Building
Block by Cross-Coupling/
Electrocyclisation/Dehydrofluorination
Reactions
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
11
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ