Pd-catalyzed sp2-sp cross-coupling reactions involving C-F bond activation in highly fluorinated nitrobenzene systems

Article abstract of DOI:10.1016/j.tet.2012.11.031

Direct and regioselective alkynylation of highly fluorinated nitrobenzene derivatives by palladiumcatalyzed Sonogashira type processes is described, representing the first examples of metal-catalyzed sp²-sp cross-coupling reactions involving C-

Full text of DOI:10.1016/j.tet.2012.11.031

Tetrahedron 69 (2013) 512e516
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd-catalyzed sp2esp cross-coupling reactions involving CeF bond
activation in highly fluorinated nitrobenzene systems
,
b
b
Matthew R. Cargill a, Graham Sandford a , Pinar Kilickiran , Gabriele Nelles
*
a Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK
b SONY Deutschland GmbH, Stuttgart Technology Center, Hedelfinger Strasse 61, 70327 Stuttgart, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 August 2012
Received in revised form 15 October 2012
Accepted 7 November 2012
Available online 14 November 2012
Direct and regioselective alkynylation of highly fluorinated nitrobenzene derivatives by palladium-
catalyzed Sonogashira type processes is described, representing the first examples of metal-catalyzed
sp2esp cross-coupling reactions involving CeF bond activation.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
reported similar Suzuki cross-coupling reactions between octa-
fluorotoluene and decafluorobiphenyl and various electron rich
Metal-catalyzed cross-coupling reactions of aryl halides with
suitable organic or organometallic partners, such as boronic acids,
Grignard reagents and alkene derivatives, are used extensively in
organic synthesis as an important method for forming carbone
carbon bonds. Applications of cross-coupling processes to the
pharmaceutical industry, drug development programs and natural
product target synthesis are well documented and continue to
increase.1e3 Typically, aryl iodides and bromides are employed as
the aromatic electrophilic coupling partner in Pd-catalyzed cou-
pling reactions because of the relative ease of oxidative addition of
the metal catalyst into the carbonehalogen bond due to the rela-
tively low CeI and CeBr bond strengths. Aryl chlorides are used less
frequently whilst examples of metal-catalyzed CeF bond activation
reactions are relatively rare because the CeF bond is the strongest
single covalent bond to carbon4 and, consequently, activation of
CeF bonds by transition metal catalysts is a very challenging re-
search goal, particularly in reactions involving highly fluorinated
aromatic substrates.
Research into transition metal mediated CeF bond activation
has been growing over the past decade although most of the
available literature is concerned with the formation of stoichio-
metric metalefluoride complexes, which may act as catalysts, or
the functionalization of monofluoroaromatic systems to afford
non-fluorinated products.5,6 Braun has successfully carried out
nickel-catalyzed Stille7,8 and Suzuki9 coupling reactions of several
perfluoroheteroaromatic derivatives, pentafluoropyridine and
2,4,6-trifluoro-5-chloropyrimidine, respectively. Radius has also
aryl boronic acid derivatives in which the CeF bond para to the
trifluoromethyl or pentafluorophenyl group was activated and
fluorine displaced by an aryl group.10
Perfluoroaromatic systems such as octafluorotoluene and
decafluorobiphenyl are highly reactive towards nucleophilic attack,
due to the presence of the highly electron withdrawing ring fluorine
substituents and a large number of reactions between perfluoro and
highly fluorinated aromatic derivatives and a range of nucleophiles
by SNAr processes have been reported.11 In particular, reactions in-
volving Grignard or organolithium reagents can, in some cases, be
useful methods for direct CeC bond formation although low regio-
selectivity, competing polysubstitution and substrate degradation
can lead to very low yielding reactions in many cases.
In a recent publication,12 we reported the first examples of
palladium-catalyzed SuzukieMiyaura sp2esp2 cross-coupling re-
actions of a perfluorinated substrate, pentafluoronitrobenzene, us-
ing a conventional, readily available palladium catalyst, Pd(PPh3)4.
The nitro group attached to the aryl ring not only helps to activate
the system towards nucleophilic attack by the palladium catalyst,
but also ‘directs’ oxidative addition to the ortho site. Crucially, re-
action between the boronic acid derivative, base and penta-
fluoronitrobenzene does not occur in the absence of the palladium
catalyst, indicating that oxidative addition of the palladium into the
CeF bond is a key part of the reaction process. The mechanism of the
oxidative addition step has some characteristics of an SNAr-type
process, consistent with earlier observations by Kim and Yu13 and
Widdowson14 concerning palladium-catalyzed cross-coupling re-
actions involving monofluorinated aromatic systems.
Once oxidative addition has occurred, the arylepalladium oxi-
dative addition complex is, in principle, reactive towards a range of
substrates such as, for example, organo-stannane and organo-zinc
* Corresponding author. E-mail address: graham.sandford@durham.ac.uk
(G. Sandford).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.031

M.R. Cargill et al. / Tetrahedron 69 (2013) 512e516
513
reagents, alkynes and alkenes in Stille, Negishi, Sonogashira and
Heck type processes, respectively. However, the highly nucleophilic
nature of aryl tin and aryl zinc reagents may render these nucleo-
philic species incompatible for use with highly electrophilic fluo-
rinated aromatic systems. Consequently, we envisaged that alkyne
derivatives may be suitable coupling partners with which to further
develop perfluoroaromatic CeF bond activation coupling
chemistry.
coupling constants (21e22 Hz) consistent with the structure pro-
posed. No cross-coupling reaction was observed in the absence of
Pd(PPh3)4, confirming the catalytic nature of this process and the
requirement of palladium insertion into the CeF bond as a pre-
liminary step.
Despite the high efficiency of the coupling procedure, the iso-
lated yield of 2 was lower than expected due to difficulties with
product purification and subsequent decomposition of the product
upon isolation. We postulate that that the reactivity of 2 as a Mi-
chael acceptor towards water in work up processes may be a pos-
sible decomposition pathway.
In this paper, we describe sp2esp Sonogashira type cross-cou-
pling reactions involving carbonefluorine bond activation. Whilst
a limited number of SuzukieMiyaura and Stille type processes of
a suitable electrophilic fluoroaryl partner have been reported as
outlined above, no spesp2 cross-coupling reactions involving CeF
activation have been described previously.
The spesp2 alkynylearyl coupling process was found to be
highly selective and afforded the alkynylated product arising from
exclusive substitution of a fluorine atom ortho to the nitro group
and is similar to the regioselectivity observed for corresponding
Suzuki cross-coupling reactions of pentafluoronitrobenzene. A re-
action mechanism is suggested in which oxidative addition of the
palladium catalyst into the CeF bond ortho to the nitro group of 1
occurs initially by an SNAr-type process, as previously reported in
related SuzukieMiyaura coupling processes,12 followed by co-
ordination of the alkyne fragment to the palladium centre and the
expulsion of the metal-bound fluoride ion (Fig. 1).
2. Results and discussion
In initial experiments, reaction of phenyl acetylene with pen-
tafluoronitrobenzene 1 under similar conditions to those that we
utilized for corresponding SuzukieMiyaura cross-coupling pro-
cesses was unsuccessful, affording tarry material from which no
alkynylated product could be identified by 19F NMR spectroscopic
analysis of the product mixture (Scheme 1).
Pd0(PPh3)4
F
F
R
F
F
F
F
F
(4-n)PPh3
Pd0(PPh3)n
O
N
O
O2N
F
2
F
1
reductive
elimination
'nucleophilic
attack'
R
F
F
F
(PPh3)n Pd
O
Scheme 1. Attempted cross-coupling reaction of pentafluoronitrobenzene
phenyl acetylene.
1 with
F
(Ph3P)nPdII
F
F
O
N
O
N
O
F
F
Fluoride ion was selected as the base because, in our previous
investigations, conventional carbonate and amine bases were
found to be unsuitable due to their tendency to undergo competing
SNAr processes with highly electrophilic polyfluoronitrobenzene
systems. However, although SuzukieMiyaura processes require
a base to activate the boronic acid, in corresponding Sonogashira
reactions the base is believed to assist with the abstraction of
a proton from the alkyne derivative and in the neutralization of any
acidic byproduct, in this case hydrogen fluoride.
As the oxidative addition of the palladium catalyst into penta-
fluoronitrobenzene does not involve the base, and that the fluoride
ion displaced by this process can potentially assist with proton
abstraction from the alkyne fragment, the CeF activation process
was carried out in the absence of base (Scheme 2).
F
1a
HF
F
F
F
(Ph3P)nPdII
oxidative
addition
F
F
R
H
O
N
O
Alkyne coordination-
proton abstraction
1b
Fig. 1. Proposed reaction mechanism.
Interestingly, alkyne derivative 2 has been synthesized previously
in low yield by an SNAr process involving reaction of highly nucleo-
philic sodium phenyl acetylide with pentafluoronitrobenzene in
diethylether.15 Inthiscase, strongelectronicinteractionsbetween the
nitro group and the approaching nucleophile induce exclusive sub-
stitution ortho to the nitro group, although increasing the polarity of
the solvent upon the addition of small quantities of THF was found to
lead to preferential substitution to the para position. However, re-
actions involving highly fluorinated aromatic systems and phenyl
acetylide derivatives can be difficult to control and, in several cases,
dialkynylated products are observed, even when using a large excess
of perfluoroaromatic substrate.15,16
Scheme 2. Successful cross-coupling reaction of pentafluoronitrobenzene
phenyl acetylene.
1 with
Analogous sp2esp coupling reactions of tetrafluorinated nitro-
aromatic systems 3e4 are shown in Table 1. These systems are, in
principle, too acidic for selective reaction with organometallic re-
agents because ring metallation is preferred, as observed in re-
actions of less acidic substrates such as pentafluorobenzene with
aryl lithium reagents. Indeed, we found that reaction of phenyl
acetylide with tetrafluoronitrobenzene 3 in diethyl ether afforded
a complex mixture of products and tarry material, which could
not be identified but, presumably, arose from deprotonation
In this case, complete conversion of pentafluoronitrobenzene 1
into alkynated derivative 2 was observed by 19F NMR spectroscopic
analysis of the crude reaction mixture, along with 1 equiv of fluo-
ride ion present (ꢀ150 ppm). The structure of 2 was confirmed by
the presence of four resonances of equal intensity at ꢀ132.0,
ꢀ145.6, ꢀ149.1 and ꢀ150.9 ppm in the 19F NMR spectrum of the
3
purified product, all of which exhibit appropriate mutual JFF

514
M.R. Cargill et al. / Tetrahedron 69 (2013) 512e516
Table 1
relatively acidic hydrogen atoms on the aromatic ring compared to
conventional nucleophilic substitution processes involving carbon
centred nucleophiles.
Palladium-catalyzed cross-coupling reactions of 2,3,4,5-tetrafluoronitrobenzene 3
and 2,3,4,6-tetrafluoronitrobenzene 4 with a range of alkyne derivatives
Reactions of tetrafluoronitrobenzene derivative 3 resulted in
preferential alkynylation of the CeF bond ortho to the nitro group.
The structure of 6 was confirmed by X-ray crystallography (Fig. 2)
and NMR spectroscopy was used to confirm the identities of 5 and 7
by comparison of their respective 19F NMR spectra with data ob-
tained for 6.
Electrophile
Nucleophile
Product, (yield/%)
Fig. 2. Molecular structure of 6.
For tetrafluoronitrobenzene derivative 4, there are two CeF
bonds located ortho to the nitro group at which directed oxidative
addition of the palladium catalyst may occur but only products
8e10, resulting from exclusive alkynylation at the 2-position, were
observed. The structure of 8 was confirmed by the observation of an
overlapping doublet of doublet of doublets at 7.1 ppm by 1H NMR
3
spectroscopy, which displays two characteristic JHF coupling con-
stants (9.2 Hz) and by the observation of two fluorine resonances at
ꢀ126 and ꢀ135 ppm, which were mutually split (3JFF¼21.4 Hz) due
to their respective ortho relationship. The structures of 9 and 10
were assigned accordingly.
These results are consistent with corresponding Suzu-
kieMiyaura processes reported previously12 and may be explained
by considering the relative activation of the two CeF bonds at the 2-
and 6-positions towards oxidative addition. Although the activation
of the CeF bond at the 6-position towards nucleophilic attack by
the palladium catalyst is increased by the electron withdrawing
ortho nitro group, the CeF bond at the 2-position is also further
activated by an additional fluorine substituent attached to C-3 and
oxidative addition occurs preferentially at this site. In earlier
studies we found that SuzukieMiyaura reactions involving similar
Pd-catalyzed CeF activation processes of trifluoronitrobenzene
substrates were very low yielding and, consequently, analogous
Sonagashira processes were not carried out here.
followed by elimination to benzyne intermediates and subsequent
decomposition.
Complete conversion of tetrafluoronitrobenzene derivatives 3
and 4 into the corresponding alkynylated systems 5e10 was ob-
served by 19F NMR spectroscopic analysis of the respective crude
reaction mixtures and, in each case, 1 equiv of fluoride ion was also
detected. Once again, the isolated yields of 5e10 were reduced due
to problems with product isolation and decomposition, although
the cross-coupling procedures themselves appear to be highly
efficient, as determined by 19F NMR spectroscopic analysis of the
crude reaction mixtures. However, the palladium-catalyzed pro-
cesses reported here are far more effective for arylation of sites
ortho to nitro groups in highly fluorinated systems bearing
3. Conclusion
In conclusion, we have reported the first examples of metal-
catalyzed cross-coupling sp2esp CeC bond forming reactions of
fluoroaromatic systems in Sonogashira type processes involving
CeF activation. The regioselectivity of alkynylation is consistent
with corresponding SuzukieMiyaura cross-coupling reactions, in
which the nitro group is responsible for directing the palladium
catalyst into the ortho CeF bond and, where there is a choice, to the
CeF bond site most activated towards nucleophilic substitution,
suggesting that an SNAr-type pathway is occurring.

M.R. Cargill et al. / Tetrahedron 69 (2013) 512e516
515
4. Experimental section
4.1. General
1.51 mmol) and 2,3,4,5-tetrafluoronitrobenzene (0.255 g, 1.31 mmol)
afforded 1,2,3-trifluoro-5-nitro-4-(phenylethynyl)benzene (0.176 g,
48%) as a yellow solid; mp 79e80 ꢁC; HRMS-ASAP (m/z): (Mꢀ) calcd
for C14H6F3NO2 277.0351; found 277.0355; Rf 0.25 (hexane/DCM, 1:9);
GCeMS m/z (% relative intensity, ion): 277 (7, Mþ), 260 (38), 230 (21),
Analysis: Proton, carbon and fluorine nuclear magnetic resonance
spectra (1H NMR, 13C NMR and 19F NMR) were recorded (1H NMR,
500 MHz; 13C NMR, 126 MHz; 19F NMR, 470 MHz or 1H NMR,
700 MHz; 13C NMR, 176 MHz; 19F NMR, 658 MHz) using solvent res-
onance as the internal standard (1H NMR, CHCl3 at 7.26 ppm; 13C
105 (100), 77 (62), 51 (6); 1H NMR (700 MHz; CDCl3):
d 7.39e7.46 (3H,
3
4
m, HeAr), 7.45e7.62 (2H, m, HeAr), 7.88 (1H, ddd, JHF 9.4, JHF 6.8,
5JHF 2.1, H-6); 13C NMR (126 MHz; CDCl3):
d 76.2e76.3 (m, eC^Ce),
104.5e104.6 (m, eC^Ce), 108.0 (dd, 2JCF 17.5, 3JCF 3.9, C-4), 110.2 (dd,
NMR, CDCl3 at 77.36 ppm; 19F NMR, CFCl3 at 0.00 ppm).1H,13C and 19
F
2JCF 22.7, 3JCF 3.6, C-6), 121.8 (s, CeAr), 128.8 (s, CeAr), 130.3 (s, CeAr),
1
2
2
spectroscopicdataarereportedasfollows:chemicalshift, integration,
multiplicity (s¼singlet, d¼doublet, t¼triplet, m¼multiplet), coupling
constants (Hz), and assignment. Crystallographic data were recorded
with a Rigaku R-Axis SPIDER IP diffractometer equipped with
Cryostream (Oxford Cryosystems) low-temperature device at 120 K
with graphite-monochromated Mo K
132.5 (s, CeAr), 143.8 (ddd, JCF 263, JCF 15.5, JCF 15.5, C-2),
1
2
3
144.4e144.5 (m, C-5), 149.5 (ddd, JCF 258, JCF 11.3, JCF 3.8, CeAr),
152.4 (ddd, JCF 258, JCF 11.2, JCF 3.5, CeAr); 19F NMR (658 MHz;
1
2
3
3
4
5
CDCl3/CFCl3):
d
ꢀ125.01 (1F, ddd, JFF 20.6, JFF 8.1, JFH 2.1, F-3),
ꢀ129.43 (1F, ddd, 3JFF 20.8, 3JFH 9.4, 5JFF 8.5, F-1), ꢀ149.39 (1F, ddd, 3JFF
20.8, 3JFF 20.6, 4JFH 6.8, F-2).
ꢀ
a
-radiation (
l
¼0.71073 A).
Melting points were measured at atmospheric pressure and are
uncorrected.
4.2.1.3. 1,1-Diphenyl-3-(2,3,4-trifluoro-6-nitrophenyl)prop-2-yn-
1-ol 6. Reaction of Pd(PPh3)4 (0.076 g, 0.07 mmol),1,1-diphenylprop-
2-yn-1-ol (0.294 g, 1.41 mmol) and 2,3,4,5-tetrafluoronitrobenzene
(0.254 g, 1.30 mmol) afforded 1,1-diphenyl-3-(2,3,4-trifluoro-6-
nitrophenyl)prop-2-yn-1-ol (0.202 g, 40%) as a yellow solid; mp
88e89 ꢁC. Anal. Calcd for C21H12F3NO3: C, 65.80; H, 3.16; N, 3.65.
Found: C, 65.90; H, 3.21; N, 3.69; Rf 0.3 (hexane/DCM, 1:9); GCeMS
m/z (% relative intensity, ion): 383 (0.5, Mþ), 350 (10), 182 (9), 105
Chemicals and solvents: Unless otherwise stated, commercially
available reagents were used without purification. MeCN, DMF, THF
and toluene were dried by colorimetric titration whilst anhydrous
DMSO and 1,4-dioxane were purchased from SigmaeAldrich.
Hexane and DCM were purchased from Fischer and used without
further purification. All microwave-irradiated reactions were car-
ried out in a Biotage InitiatorÔ Sixty microwave system (0e400 W
at 2.45 GHz). Flash column chromatography was carried out using
(100), 77 (30), 51 (3); 1H NMR (700 MHz; CDCl3):
d 3.01 (1H, s, eOH),
Fluorochem Silicagel LC60A (40e63
m
).
7.30 (2H, t, 3JHH 7.3, HeAr), 7.37 (4H, dd, 3JHH 7.3, 3JHH 7.3, HeAr), 7.61
(4H, d, 3JHH 7.3, HeAr), 7.86e7.91 (1H, m, H-5); 13C NMR (126 MHz;
4.2. Coupling reactions of polyfluoronitrobenzene derivatives
CDCl3): d 74.1e74.2 (m, eC^Ce), 75.5 (s, CeOH), 106.9e107.1 (m, C-
1), 107.1e107.2 (m, eC^Ce), 110.1 (dd, 2JCF 22.6, 3JCF 3.5, C-5), 126.3
2
4.2.1. General procedure. Pd(PPh3)4 (0.05 equiv) was charged to
a 0.5e2.0 ml microwave vial, which was sealed and purged with
argon to create an inert atmosphere. Dry, degassed DMSO (1.9 ml),
phenyl acetylene (1.1 equiv) and pentafluoronitrobenzene
(1.0 equiv) were added in sequence to the vial, which was then
heated to 120 ꢁC for 20 min under microwave irradiation. The re-
action mixture was cooled and filtered through an alumina plug
with DCM as the eluent to remove inorganic and particulate ma-
terial. The organic washings were concentrated in vacuo, poured
onto water (100 ml) and extracted with DCM (3ꢂ100 ml). The or-
ganic fractions were combined, washed with water (100 ml) and
dried (MgSO4). Volatiles were removed in vacuo and the desired
product was purified by either column chromatography using silica
gel using a mixture of hexane and DCM (1:9) as the eluent or by
Kugelrohr distillation.
(s, CeAr), 128.4 (s, CeAr), 128.8 (s, CeAr), 143.8 (ddd, 1JCF 264, JCF
15.3, 2JCF 15.3, C-3), 143.9 (s, CeAr),144.2e144.4 (m, C-6), 149.9 (ddd,
1JCF 258, 2JCF 11.2, 3JCF 3.8, CeF), 152.9 (ddd, 1JCF 258, 2JCF 10.5, 3JCF 3.2,
CeF); 19F NMR (658 MHz; CDCl3; CFCl3):
d
ꢀ124.27 (1F, dd, 3JFF 20.7,
4JFF 8.6, F-2), ꢀ128.21 (1F, ddd, 3JFF 20.7, 3JFH 8.5, 4JFF 8.6, F-4), ꢀ148.78
(1F, ddd, 3JFF 20.7, 3JFF 20.7, 4JFH 6.7, F-3).
Crystal data for 6: C21H12F3NO3, M¼383.32, monoclinic, space
ꢀ
group P21/n, a¼14.4535(11), b¼6.2011(5), c¼19.5369(14) A,
3
ꢀ3
,
ꢁ
ꢀ
b
¼106.78(1) , U¼1676.5(2) A , F(000)¼784, Z¼4, Dc¼1.519 mg m
ꢀ
m
¼0.124 mmꢀ1 (Mo
K
a,
l
¼0.71073 A), T¼120(1) K. 13,464
Reflections (2.07ꢃ
q
ꢃ27.5ꢁ) were collected on a Bruker SMART-CCD
6K diffractometer
(u
-scan, 0.3ꢁ/frame) yielding 3846 unique
data (Rmerg¼0.0671). The structure was solved by direct method
and refined by full-matrix least squares on F2 for all data using
SHELXL17 and OLEX218 software. All non-hydrogen atoms were
refined with anisotropic displacement parameters, H-atoms
were located on the difference map and refined isotropically.
Final wR2(F2)¼0.1126 for all data (301 refined parameters), con-
4.2.1.1. 1,2,3,4-Tetrafluoro-5-nitro-6-(phenylethynyl)benzene
2. Reaction of Pd(PPh3)4 (0.102 g, 0.09 mmol), phenyl acetylene
(0.132 g, 1.29 mmol) and pentafluoronitrobenzene (0.250 g,
1.17 mmol) afforded 1,2,3,4-tetrafluoro-5-nitro-6-(phenylethynyl)
benzene (0.127 g, 37%) as a yellow solid; mp 111e112 ꢁC; HRMS-
ASAP (m/z): (Mꢀ) calcd for C14H6F4NO2 295.0256; found
295.0252; Rf 0.3 (hexane/DCM, 1:9); 1H NMR (700 MHz; CDCl3):
ventional R(F)¼0.0545 for 2229 reflections with Iꢄ2 , GOF¼1.003.
s
3
ꢀ
The largest peak on the residual map is 0.30 e/A . Crystallographic
data for the structure have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication CCDC-
895941.
d
7.38e7.41 (2H, m, HeAr), 7.43e7.46 (1H, m, HeAr), 7.55e7.58 (2H,
m, HeAr); 13C NMR (126 MHz; CDCl3):
d
73.9e74.0 (m, eC^Ce),
4.2.1.4. 2-Methyl-4-(2,3,4-trifluoro-6-nitrophenyl)but-3-yn-2-ol
7. Reaction of Pd(PPh3)4 (0.074 g, 0.06 mmol), 1,1-dimethylprop-2-
yn-1-ol (0.122 g, 1.46 mmol) and 2,3,4,5-tetrafluoronitrobenzene
(0.249 g, 1.28 mmol) afforded 2-methyl-4-(2,3,4-trifluoro-6-
nitrophenyl)but-3-yn-2-ol (0.246 g, 69%) as a yellow solid, which
decomposed upon heating. Anal. Calcd for C11H8F3NO3: C, 50.98; H,
3.11; N, 5.40. Found: C, 51.15; H, 3.15; N, 5.73; Rf 0.4 (hexane/DCM,
1:9); ESþ-MS m/z (% relative intensity, ion): 282 (100, [MþNa]þ),
104.4e104.5 (m, eC^Ce), 105.5 (dd, 2JCF 18.7, 3JCF 1.9, C-6), 121.1 (s,
CeAr), 129.0 (s, CeAr), 130.7 (s, CeAr), 132.5 (s, CeAr), 136.6e136.9
(m, C-5), 139.9e141.7 (m, CeF), 140.8e142.4 (m, CeF), 142.2e143.9
(m, CeF), 147.1e148.7 (m, CeF); 19F NMR (658 MHz; CDCl3/CFCl3):
3
4
5
d
ꢀ132.02 (1F, ddd, JFF 21.3, JFF 3.8, JFF 9.8, FeAr), ꢀ145.64 (1F,
ddd, 3JFF 21.5, 6JFF 6.2, 5JFF 9.8, FeAr), ꢀ149.10 (1F, ddd, 3JFF 21.3, 3JFF
4
3
3
4
21.0, JFF 6.2, FeAr), ꢀ150.85 (1F, ddd, JFF 21.5, JFF 21.0, JFF 3.8,
FeAr).
220 (30), 189 (18), 79 (34); 1H NMR (700 MHz; CDCl3):
d
1.65 (6H, s,
eCH3), 2.34 (1H, s, eOH), 7.80e7.85 (1H, m, HeAr); 13C NMR
(126 MHz; CDCl3): 31.1 (s, eCH3), 66.1 (s, CeOH), 69.2e69.3
(m, eC^Ce), 107.2 (dd, JCF 17.2, JCF 4.3, C-1), 109.2e109.3
4.2.1.2. 1,2,3-Trifluoro-5-nitro-4-(phenylethynyl)benzene 5. React-
ion of Pd(PPh3)4 (0.074 g, 0.06 mmol), phenyl acetylene (0.154 g,
d
2
3

516
M.R. Cargill et al. / Tetrahedron 69 (2013) 512e516
2
3
(m, eC^Ce), 110.2 (dd, JCF 22.6, JCF 3.5, C-5), 143.7 (dt, 1JCF 263,
4.2.1.7. 2-Methyl-4-(2,3,5-trifluoro-6-nitrophenyl)but-3-yn-2-ol
10. Reaction of Pd(PPh3)4 (0.078 g, 0.07 mmol), 1,1-dimethylprop-
2-yn-1-ol (0.115 g, 1.41 mmol) and 2,3,4,6-tetrafluoronitrobenzene
(0.254 g, 1.37 mmol) afforded 2-methyl-4-(2,3,5-trifluoro-6-
nitrophenyl)but-3-yn-2-ol (0.219 g, 58%) as a yellow solid, which
decomposed upon heating; HRMS-ASAP (m/z): (Mꢀ) calcd for
2JCF 15.4, C-3), 144.6e144.8 (m, C-6), 149.9 (ddd, 1JCF 258, JCF 11.1,
2
3JCF 3.8, CeF), 152.9 (ddd, 1JCF 258, 2JCF 11.3, 3JCF 3.6, CeF); 19F NMR
3
4
(658 MHz; CDCl3/CFCl3):
d
ꢀ125.05 (1F, dd, JFF 20.4, JFF 8.6, F-2),
ꢀ128.98 (1F, ddd, 3JFF 20.6, 3JFH 8.9, 4JFF 8.6, F-4), ꢀ149.31 (1F, ddd,
3JFF 20.6, 3JFF 20.4, JFH 6.7, F-3).
4
C
11H8F3NO3 259.0456; found 259.0459; Rf 0.2 (hexane/DCM, 1:9);
1H NMR (700 MHz; CDCl3):
1.61 (6H, s, eCH3), 2.63 (1H, s, eOH),
7.12 (1H, ddd, 3JHF 9.2, 3JHF 9.2, 4JHF 6.4, HeAr); 13C NMR (126 MHz;
CDCl3): 30.9 (s, eCH3), 66.0 (s, CeOH), 68.4e68.5 (m, eC^Ce),
107.1 (dd, 2JCF 25.3, JCF 22.5, C-4), 109.5e109.6 (m, eC^Ce), 110.2
4.2.1.5. 1,2,5-Trifluoro-4-nitro-3-(phenylethynyl)benzene
8. Reaction of Pd(PPh3)4 (0.076 g, 0.07 mmol), phenyl acetylene
(0.127 g, 1.24 mmol) and 2,3,4,6-tetrafluoronitrobenzene (0.253 g,
1.29 mmol) afforded 1,2,5-trifluoro-4-nitro-3-(phenylethynyl)ben-
zene (0.151 g, 44%) as a yellow solid; mp 123e124 ꢁC; HRMS-ASAP
(m/z): (Mꢀ) calcd for C14H6F3NO2 277.0351; found 277.0345; Rf 0.2
(hexane/DCM, 1:9); GCeMS m/z (% relative intensity, ion): 277 (1,
Mþ), 260 (22), 230 (18), 105 (100), 77 (66), 51 (8); 1H NMR
d
d
2
2
3
3
(ddd, JCF 18.3, JCF 3.3, JCF 1.5, C-1), 136.9e137.2 (m, C-6), 147.6
(ddd, 1JCF 256, 2JCF 14.2, 4JCF 4.0, C-2), 150.2 (ddd, 1JCF 259, 3JCF 11.5,
4JCF 4.0, C-5), 151.8 (ddd, 1JCF 259, 2JCF 13.9, 3JCF 12.2, C-3); 19F NMR
3
4
5
(658 MHz; CDCl3/CFCl3):
d
ꢀ122.22 (1F, ddd, JFH 9.1, JFF 6.4, JFF
3
3
4
(700 MHz; CDCl3):
d
7.12 (1H, ddd, JHF 9.2, JHF 9.2, JHF 6.3, H-6),
13.1, F-5), ꢀ125.95 (1F, ddd, 3JFF 21.3, 3JFH 9.2, 4JFF 6.4, F-1), ꢀ134.69
3
4
7.38e7.42 (2H, m, HeAr), 7.43e7.46 (1H, m, HeAr), 7.57e7.59 (2H,
(1F, ddd, JFF 21.3, JFH 6.3, 5JFF 13.1, F-2).
m, HeAr); 13C NMR (126 MHz; CDCl3):
d 75.2e75.3 (m, eC^Ce),
104.8e104.9 (m, eC^Ce), 106.7 (dd, 2JCF 25.4, 2JCF 22.4, C-6), 111.0
Acknowledgements
2
(d, JCF 16.7, C-3), 121.1 (s, CeAr), 128.8 (s, CeAr), 130.5 (s, CeAr),
132.5 (s, CeAr), 136.7e137.0 (m, C-4), 147.5 (ddd, 1JCF 256, 2JCF 14.3,
4JCF 4.1, C-2), 150.3 (ddd, 1JCF 261, 3JCF 11.6, 4JCF 4.0, C-5), 151.7 (ddd,
1JCF 259, 2JCF 13.9, 3JCF 12.3, C-1); 19F NMR (658 MHz; CDCl3/CFCl3):
We thank SONYand Durham University DTA account for funding
and Dr. D.S. Yufit and Prof. J.A.K. Howard for X-ray crystallography.
d
ꢀ122.21 (1F, ddd, 3JFH 9.2, 4JFF 6.4, 5JFF 13.0, F-5), ꢀ126.13 (1F, ddd,
3
4
3
4
3JFF 21.4, JFH 9.2, JFF 6.4, F-1), ꢀ134.66 (1F, ddd, JFF 21.4, JFH 6.3,
References and notes
5JFF 13.0, F-2).
1. Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic Synthesis; Wi-
ley: New York, NY, 1995.
4.2.1.6. 1,1-Diphenyl-3-(2,3,5-trifluoro-6-nitrophenyl)prop-2-yn-
1-ol 9. Reaction of Pd(PPh3)4 (0.076 g, 0.06 mmol), 1,1-
diphenylprop-2-yn-1-ol (0.297 g, 1.43 mmol) and 2,3,4,6-
tetrafluoronitrobenzene (0.254 g, 1.30 mmol) afforded 1,1-
diphenyl-3-(2,3,5-trifluoro-6-nitrophenyl)prop-2-yn-1-ol (0.255 g,
50%) as a viscous yellow liquid; HRMS-ASAP (m/z): (Mꢀ) calcd for
2. Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-coupling Reactions; Wiley-VCH:
New York, NY, 1998.
3. Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44,
4442e4489.
4. O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308e319.
5. Amii, H.; Uneyama, K. Chem Rev. 2009, 109, 2119e2183.
6. Sun, A. D.; Love, J. A. Dalton Trans. 2010, 39, 10362e10374.
7. Braun, T.; Perutz, R. N.; Sladek, M. I. Chem. Commun. 2001, 2254e2255.
8. Braun, T.; Izundu, J.; Steffen, A.; Neumann, B.; Stammler, H. G. J. Chem. Soc.,
Dalton Trans. 2006, 5118e5123.
9. Steffen, A.; Sladek, M. I.; Braun, T.; Neumann, B.; Stammler, H. G. Organome-
tallics 2005, 24, 4057e4064.
10. Schaub, T.; Backes, M.; Radius, U. J. Am. Chem. Soc. 2006, 128, 15964e15965.
11. Brooke, G. M. J. Fluorine Chem. 1997, 86, 1e76.
12. Cargill, M. R.; Sandford, G.; Tadeusiak, A. J.; Yufit, D. S.; Howard, J. A. K.;
Kilickiran, P.; Nelles, G. J. Org. Chem. 2010, 75, 5860e5866.
13. Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2002, 125, 1696e1697.
14. Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003, 578e579.
15. Coe, P. L.; Tatlow, J. C.; Terrell, R. C. J. Chem. Soc. C 1967, 2626e2628.
16. Riera, J.; Stephens, R. Tetrahedron 1966, 22, 2555e2559.
17. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.
18. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. J.
Appl. Crystallogr. 2009, 42, 339e341.
C
21H12F3NO3 383.0753; found 383.0769; Rf 0.3 (hexane/DCM, 1:9);
3
1H NMR (700 MHz; CDCl3):
d 3.04 (1H, s, eOH), 7.13 (1H, ddd, JHF
9.2, 3JHF 9.2, 4JHF 6.4, HeAr), 7.29e7.32 (2H, m, HeAr), 7.35e7.38 (4H,
m, HeAr), 7.59e7.62 (4H, m, HeAr); 13C NMR (126 MHz; CDCl3):
d
73.0e73.1 (m, eC^Ce), 75.4 (s, CeOH), 107.4e107.5 (m, eC^Ce),
107.4 (dd, 2JCF 25.4, 2JCF 22.4, C-6),110.1 (ddd, 2JCF 18.2, 3JCF 3.1, 3JCF 1.1,
C-3),126.2 (s, CeAr),128.5 (s, CeAr),128.8 (s, CeAr),136.6e136.8 (m,
C-4), 143.6 (s, CeAr),147.9 (ddd, 1JCF 256, 2JCF 14.3, 4JCF 4.0, C-2), 150.4
(ddd, 1JCF 260, 3JCF 11.4, 4JCF 4.0, C-5), 151.9 (ddd, 1JCF 261, 2JCF 14.2, 3JCF
12.5, C-1); 19F NMR (658 MHz; CDCl3/CFCl3):
d
ꢀ121.54 (1F, ddd, 3JFH
9.2, 4JFF 6.6, 5JFF 13.1, 5-F), ꢀ125.38 (1F, ddd, 3JFF 21.4, 3JFH 9.2, 4JFF 6.6,
1-F), ꢀ133.84 (1F, ddd, 3JFF 21.4, 4JFH 6.4, 5JFF 13.1, 2-F).