Site-selective sonogashira reactions of 1,4-dibromo-2-fluorobenzene - Synthesis and properties of fluorinated alkynylbenzenes

Article abstract of DOI:10.1002/ejoc.201100394

A variety of alkynyl-substituted fluorinated benzene derivatives have been prepared by Sonogashira cross-coupling reactions of 1,4-dibromo-2-fluorobenzene. The reactions proceed with very good site-selectivity in favor of the 4-position because of electro

Full text of DOI:10.1002/ejoc.201100394

FULL PAPER
DOI: 10.1002/ejoc.201100394
Site-Selective Sonogashira Reactions of 1,4-Dibromo-2-fluorobenzene –
Synthesis and Properties of Fluorinated Alkynylbenzenes
Sebastian Reimann,[a,b] Muhammad Sharif,[a,b] Martin Hein,[a] Alexander Villinger,[a]
Kai Wittler,[c] Ralf Ludwig,[b,c] and Peter Langer*[a,b]
Keywords: Synthetic methods / Regioselectivity / Homogeneous catalysis / Palladium / Fluorine / Alkynes / Organofluorine
compounds / Liquid crystals / Luminescence
A variety of alkynyl-substituted fluorinated benzene deriva-
tives have been prepared by Sonogashira cross-coupling re-
actions of 1,4-dibromo-2-fluorobenzene. The reactions pro-
ceed with very good site-selectivity in favor of the 4-position
because of electronic and steric reasons. The regioselectivity
is explained by the results of DFT calculations. The absorp-
tion and emission (fluorescence) properties of the products,
mono- and dialkynylated fluorobenzenes, have been studied.
In addition, the mesomorphic properties of the products have
been investigated by polarization microscopy and differential
scanning calorimetry. 1,4-Dialkynyl-2-fluorobenzenes show
nematic liquid-crystalline properties over
range.
a long phase
rials,[8–10] show excellent properties for materials to be used
in active matrix LCDs.[11,12,13] Because of the degree of flu-
orination of many liquid crystals, a special methodology for
the synthesis of fluorinated arenes has been developed.[2]
Generally, the synthesis starts from aromatic building
blocks that already have the required fluorination pattern.
These building blocks can be functionalized by their com-
mercially-available brominated derivatives. This includes,
C–C coupling reactions such as Suzuki and Heck cou-
pling[14] and the Wittig reaction.[15]
Among transition-metal-catalyzed coupling reactions,
the Sonogashira coupling of aryl halides with terminal
acetylenes provides an efficient method for C–C bond for-
mation and has become a useful method to prepare arylated
alkynes and conjugated enynes, which are relevant for the
synthesis of important substructures of liquid crystals.[16,17]
Referring to this, a number of site-selective Sonogashira re-
actions of polyhalogenated arenes and hetarenes have been
developed in recent years. The site selectivity of these reac-
tions is generally influenced by electronic and steric param-
eters.[18] Site-selective Sonogashira reactions of dibromides,
diiodides, or bis(triflates) of fluorinated arenes have, to the
best of our knowledge, not been reported. Herein, we report
the results of our study of the site-selective Sonogashira re-
actions of 1,4-dibromo-2-fluorobenzene. These reactions
provide a convenient approach to new fluorinated mono-
and dialkynylbenzenes.[19] The products show interesting
absorption and fluorescence properties. In addition, they
exhibit long-range nematic liquid-crystal properties, which
have been confirmed by polarization microscopy (POM)
and differential scanning calorimetry (DSC).
Introduction
The unique properties of fluorine-containing carba- and
heterocycles have led to their remarkable record in medici-
nal and agricultural chemistry, and they play an important
role as lead compounds.[1,2] The solubility and bioavail-
ability of fluorinated compounds are often enhanced com-
pared to those of their nonfluorinated analogues.[3,4] More-
over, fluorinated arenes and hetarenes are useful substrates
in transition-metal-catalyzed cross-coupling reactions.[5]
Aryl fluorides are used as ligands[6] in catalytic reactions
and as organocatalysts.[7] Since the early 1980s, a large
number of liquid crystals with fluorine substituents have
been synthesized. In recent years, liquid crystal displays
(LCD) have become an important part of our daily life.[2]
Initial interest in such materials was aroused by the greater
nematic phase range, often dramatically increased, of lat-
erally fluorinated liquid crystals compared to their nonfluo-
rinated analogues. Later, it was found that liquid crystals
that derive their molecular dipole moment from fluorine
rather than cyano groups, so-called superfluorinated mate-
[a] Department of Chemistry, University of Rostock,
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
E-mail: peter.langer@uni-rostock.de
[b] Leibniz Institute for Catalysis e.V. at the University of Rostock
(LIKAT),
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
[c] Department of Chemistry, Physical and Theoretical Chemistry,
University of Rostock,
Dr.-Lorenz-Weg 1, 18059 Rostock, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100394.
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Site-Selective Sonogashira Reactions
Table 2). The best yields were obtained using 2.1 equiv. of
alkyne, Pd(PPh3)4 (3 mol-%) as the catalyst, CuI (3 mol-%),
and Et3N (2.5 equiv.) as the base in THF at 50 °C for 6 h.
Results and Discussion
Synthesis
The Sonogashira reaction of commercially available 1,4-
dibromo-2-fluorobenzene (1) with different substituted
acetylenes 2a–i (1.0 equiv.) afforded the corresponding alk-
ynyl-substituted 4-bromo-3-fluorobenzene derivatives 3a–i
in moderate to good yields (Scheme 1, Table 1). The best
yields were obtained using 1.0 equiv. of alkyne, Pd(PPh3)4
(3 mol-%) as the catalyst, and Et3N (2.0 equiv.) as the base
in tetrahydrofuran (THF) at 50 °C for 5 h. In some cases,
the formation of a small amount of the other regioisomer
was observed by GC–MS and 19F NMR spectroscopy,
which could not be separated preparatively by flash
chromatography.
Scheme 2. Synthesis of 4a–i. (i) 1 (1.0 equiv.), 2 (2.1 equiv.), Et3N
(2.5 equiv.), Pd(PPh3)4 (3 mol-%), CuI (3 mol-%), THF, 50 °C, 6 h.
Table 2. Synthesis of 4a–i.
Scheme 1. Synthesis of 3a–i. (i) 1 (1.0 equiv.), 2a–i (1.0 equiv.),
Et3N (2.0 equiv.), Pd(PPh3)4 (3 mol-%), CuI (3 mol-%), THF,
50 °C, 5 h.
Table 1. Synthesis of 3a–i.
[a] Yield of isolated product.
The synthesis of unsymmetrical para-substituted ethynyl-
fluorobenzenes was studied next. The Sonogashira reaction
of selected ethynyl-substituted 4-bromo-3-fluorobenzenes 3
with 1.1 equiv. of different substituted acetylenes 2 yielded
para-substituted ethynylfluorobenzenes 5a–e, which bear
different ethynyl moieties (Scheme 3, Table 3).
The structures of all products were confirmed by spectro-
scopic methods. In addition, high resolution 13C NMR
spectroscopy confirmed the site-selectivity of these reac-
tions. C-2 of the alkyne moiety showed long-range coupling
[a] Yield of isolated product.
with the fluorine atom over four bonds with a coupling con-
4
The Sonogashira reaction of 1 with 2.0 equiv. of alkyne stant of JC–F = 3.0 Hz. No coupling was observed for C-
afforded the symmetrical para-substituted ethynyl-fluoro- 1. In case of the opposite regioisomer, long-range coupling
benzenes 4a–i in moderate to good yields (Scheme 2, over three bonds for C-2 of around 8.0 Hz and for C-1 of
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The structures of 3b and 4d were independently con-
firmed by X-ray crystal structure analysis, which unambigu-
ously proved their constituents (Figures 1 and 2).[20] Com-
pound 3b shows a planar structure, whereas 4d and 5d have
a slight twist of the phenyl moieties along the alkyne bonds.
Scheme 3. Synthesis of 5a–e. (i) 3 (1.0 equiv.), 2 (1.1 equiv.), Et3N
(2.0 equiv.), Pd(PPh3)4 (3 mol-%), CuI (3 mol-%), THF, 50 °C, 6 h.
Table 3. Synthesis of 5a–e.
Figure 1. ORTEP plot of 3b.
The site-selective formation of 3a–i and 5a–e can be ex-
plained by steric and electronic factors. The first attack of
palladium(0)-catalyzed cross-coupling reactions generally
occurs at the more electron deficient and sterically less hin-
dered position.[18,21] The 1-position in 1 is sterically less hin-
dered because it is located next to two hydrogen atoms,
whereas the 2-position is located next to a fluorine atom
(Scheme 5). In addition, the 1-position (meta to the fluorine
atom) is more electron deficient than the 2-position (ortho
to the fluorine atom) because of π donation from the fluor-
ine atom. The same observations were made in the synthesis
of fluorinated terphenyls by site-selective Suzuki–Miyaura
reactions of halogenated fluorobenzenes.[22,23]
[a] Yield of isolated product.
around 3.0 Hz should be observed. C-3 showed a coupling
3
constant of JC–F = 8.0 Hz (124.0 ppm). C-6 (C–Br) reso-
nated as a doublet at around 110.0 ppm and showed a typi-
cal coupling to the fluorine atom with a coupling constant
2
of JC–F = 21.0 Hz (Scheme 4).
Scheme 5. Possible explanation for the site-selectivity of cross-cou-
pling reactions of 1.
This assumption was confirmed by DFT calculations at
the B3LYP level of theory using a 6-31G* basis set. In 1,
the C-1–Br bond is lengthened by about 1 pm compared to
the C-1–Br bond with the neighboring fluorine atom
(190.7 vs. 189.7 pm). Of course, the weaker C-1–Br bond
Scheme 4. Numbering of 3 (left) and opposite regioisomer (not ob-
served, right).
Figure 2. ORTEP plot of 4d.
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Site-Selective Sonogashira Reactions
will be preferentially attacked. The calculated natural Table 4. Transition temperatures of fluorinated dialkynylbenzenes
4a–i and 5a–e.[a]
charges from natural bond orbital analysis (NBO) support
this view. The NBO charges at the reactive centers in 1 indi-
cate that C-1 carries only half of the charge of C-2 (C-1:
–0.107 a.u. vs. C-2: –0.192 a.u., see Scheme 5 for number-
ing). It is well known that the most electron-deficient posi-
tion, which is C-2 in 1, will be attacked preferentially.
Furthermore, the NBO analysis shows that the higher
charge at C-2 is related to the charge transfer from the
neighboring fluorine atom, which strongly donates charge
from its lone pairs into the C-2–C antibonding orbital. This
charge transfer weakens the C-2–C bond and strengthens
the neighboring C-2–Br bond, which leads to a shorter
bond length relative to that of the C-1–Br bond. Of course,
this effect is stronger for the fluorine atom located in the
ortho position (see Supporting Information). A crude esti-
mate of the C–Br bond strength can be obtained from the
calculated energy differences (isodesmic reaction) between
[a] C, N, and I represent crystal, nematic, and isotropic phases,
respectively. [b] Compounds 4a–c, e, h, and 5a–d do not show any
mesophases.
1-bromo-2-fluorobenzene and 1-bromo-3-fluorobenzene.
The latter compound is 5.4 kJmol–1 lower in energy, which
explains its higher reactivity empirically.
As seen from Table 4, 4d, f, g, i, and 5e, which contain a
para-alkoxy or n-alkyl substituent, showed a nematic phase,
whereas unsubstituted 4a, para-tert-butyl derivative 4e, and
Liquid-Crystalline Properties
The synthesized fluorinated ethynylbenzenes were inves- ortho-substituted 4c showed no mesophases. In addition,
tigated with regard to their liquid-crystalline properties. It 4d, f, g, i, and 5e showed a long nematic phase range. The
is known that fluorinated para-substituted arenes, e.g. fluo- greatest phase range was observed for 4f, which bears two
rinated terphenyls or fluorinated phenol esters, can enhance para-methoxyphenyl moieties. This observation is in line
the nematic phase range.[2] Characterization and determi- with the statement of Goto et al. and Tarumi et al. who
nation of the liquid-crystalline phase range was carried out point out that the phase range of laterally fluorinated liquid
with a POM equipped with a hot stage. In all cases the crystals is often dramatically increased compared to their
transition temperatures were investigated in heating and nonfluorinated analogues.[10,26] For 4f and 5e, it was only
cooling cycles. Although monosubstituted 3 showed no ad- possible to investigate the phase transitions during the heat-
ditional phases between the crystalline (solid) and isotropic ing run because they decomposed at high temperatures.
(liquid) state, several symmetrical and unsymmetrical di-
In addition, the liquid-crystalline properties of 4d and 4f
substituted 4 and 5 showed thermotropic nematic liquid- were investigated by DSC (Figures 4 and 5, respectively).
crystalline phases (Figure 3). The transition temperatures of The DSC curve for 4d exhibits two peaks each for the heat-
4 and 5 are given in Table 4. No smectic phases were ob- ing and cooling runs for the corresponding phase transi-
served in the textures of 4 and 5, which is consistent with tions (heating run: 147 and 215 °C; cooling run: 211 and
the work of Subramanya et al. and Gallardo et al. who 140 °C). The bottom curve (cooling) shows a slight dis-
concluded that the presence of lateral groups in liquid-crys- placement of the NI and NC transition, partially due to
talline compounds eliminates the smectic phase.[24,25]
supercooling and partially due to instrumental hysteresis,
Figure 3. Nematic liquid crystals (schlieren texture) viewed by POM and structures of 4d, 4f, and 5e (left to right).
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P. Langer et al.
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which is attributed to the temperature scan rate. The DSC
curve for 4f was measured during the heating run and
shows two endothermic peaks at 182 and 281 °C, which
correspond to a sudden phase transition from the crystal to
nematic (182 °C) and nematic to isotropic phases (281 °C).
Absorption and Fluorescence
The UV/Vis and fluorescence spectroscopic data of sev-
eral fluorinated ethynylbenzenes, measured in dichloro-
methane at 25 °C, are summarized in Tables 5 and 6. All
the compounds contain a diphenylacetylene core as the
chromophore. The absorption wavelengths of monosubsti-
tuted 3 are in the UV region (285–318 nm), and they exhibit
four conspicuous transitions (λabs1–4) (Figures 6 and 7) and
four shoulders, which are not considered in the following
discussion.[27] For the methoxy and tert-butyl derivatives,
the absorptions are slightly redshifted to higher wave-
lengths, which is due to the positive mesomeric and induc-
tive effect of these substituents, respectively. Surprisingly,
the electron-withdrawing effect of one fluorine atom in the
para position causes no significant shift to shorter wave-
lengths relative to unsubstituted 3a.
Figure 4. DSC plot with phase diagram of 4d.
The absorption spectra of 4 are similar to those of 3.
However, all transitions of 4 appear at longer wavelengths
compared to those of 3, which is because of the extension
of the π-electron system. In contrast to the spectra of 3,
no shoulders between the first and second transitions were
observed. The presence of substituents located at the para
position of the phenyl ring has the same effect on the spec-
tra of 3 and 4. Electron-donating groups, such as methoxy
and tert-butyl, cause a slight shift to higher wavelengths,
whereas the electron-withdrawing effect of the fluorine
atom has nearly no influence. This trend is also observed in
the emission spectra. Diethynylbenzenes, which contain two
substituted aryl groups, exhibit absorptions in the UV re-
gion of λ3max,abs = 321–331 nm and emissions in the range
of λ5max,em = 369–396 nm. Compound 4f showed an ab-
sorption of λ3max,abs = 331 nm and an emission of λ5max,em
Figure 5. DSC plot with phase diagram of 4f.
Table 5. Absorption spectroscopic data for 3a, e–g (CH2Cl2, c = 1ϫ10–5 molL–1). The numbers of the absorptions refer to Figure 6.
λ1abs
logε λ1abs
λ2abs
logε λ2abs
λ3abs
logε λ3abs
λ4abs
logε λ4abs
[nm]
[nm]
[nm]
[nm]
3a
3e
3f
226
228
228
228
4.289
4.882
4.952
4.129
285
293
286
285
4.583
5.232
5.163
4.506
298
302
301
297
4.513
5.180
5.301
4.430
307
312
318
307
4.577
5.242
5.295
4.486
3g
Table 6. Absorption and emission spectroscopic data of 4a, e–g (CH2Cl2, c = 1ϫ10–5 molL–1). The numbers of the absorptions refer to
Figure 7.
log ε
λ2abs
λ1abs
logε λ1abs λ2abs(sh)
λ3max,abs logε λ3abs
λ4abs
logε λ4abs λ5max,em
λ6em(sh) Stokes shift (λ5– λ3)
[nm]
[nm]
[nm]
[nm]
[nm]
[nm]
[nm]
4a
4e
4f
230
231
237
228
4.488
4.933
4.084
4.094
303
304
318
303
4.659
5.144
4.366
4.129
323
329
331
321
4.797
5.339
4.506
4.276
343
349
357
343
4.623
5.171
4.390
4.127
369
379
396
369
376
388
402
373
46
50
65
48
4g
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Site-Selective Sonogashira Reactions
can be explained by steric and electronic reasons. The meso-
morphic properties and optical textures of the products
were investigated by DSC and POM. The existence of ne-
matic phases (schlieren texture) was confirmed. Disubsti-
tuted ethynylbenzenes showed long-range nematic liquid-
crystalline properties. Monosubstituted fluorobenzenes
show absorptions in the range of λabs = 285–318 nm. Dieth-
ynylbenzenes exhibit absorptions and emissions (fluores-
cence) in the range of λabs,max = 321–331 nm and λem,max
=
369–396 nm. Diethynylbenzenes represent promising fluo-
rescence dyes and liquid crystals.
Experimental Section
General: All reactions were carried out in oven-dried pressure tubes
under an argon atmosphere. Tetrakis(triphenylphosphane)palla-
dium(0) was prepared according to the literature method.[29] 1,4-
Dibromo-2-fluorobenzene (TCI), copper iodide (Acros), and the
corresponding alkynes (Acros, AlfaAesar) were purchased from a
commercial source. THF was distilled and purged with argon be-
fore use. Triethylamine was purchased from a commercial source
(Acros) and purged with argon before use. TLC was performed
with Merck precoated aluminium plates (Si 60 F254). Column
chromatography was performed with Merck silica gel 60 (0.043–
0.06 mm). NMR spectra were recorded with Bruker ARX 300 and
Bruker ARX 400 spectrometers. 13C and 1H NMR spectra were
referenced to signals of the deuterated solvents. GC–MS was car-
ried out with an Agilent HP-5890 instrument with an Agilent HP-
5973 Mass Selective Detector (EI) and HP-5 capillary column using
helium carrier gas. HRMS (ESI) measurements were performed
with an Agilent 1969A TOF mass spectrometer. UV/Vis spectra
were recorded with a Lambda 5 (Perkin–Elmer) spectrophotometer
with a solution concentration of 1ϫ10–5 molL–1. Fluorescence
spectra were recorded with a Hitachi F-4010 fluorescence spectro-
photometer using similar solution concentrations. The solvent used
(dichloromethane) was distilled before use. The mesomorphic prop-
erties and optical textures were investigated by POM (LaborLux
12 Pol-5, Leica) and by DSC (Mettler Toledo/DSC 823e/2007).
Figure 6. Absorption spectrum of 3a (in CH2Cl2).
Figure 7. Absorption and emission spectra of 4e (in CH2Cl2).
Calculations: Geometry optimizations were carried out with the
Gaussian 03 programme package. We used the B3LYP method,
which included the Becke-3-parameter gradient corrected exchange
functional combined with the gradient-corrected correlation LYP
functional by Lee, Yang and Parr, to calculate the structures of the
compounds. No imaginary frequencies were found, which indicated
that all geometries represent at least local minima on the potential
energy surface. For all structures the calculations were performed
with the 6-31G* basis set implemented in Gaussian 03.[30] In ad-
dition, we calculated the natural atomic charges by applying the
= 396 nm with a large Stokes shift of 65 nm. In fact, a large
Stokes shift generally corresponds to better fluorescence
properties. The bathochromic shift in the spectra of 4f and
the large Stokes shift might be associated with the push–
pull substitution pattern of 4f, which contains two methoxy
groups as electron-donating substituents and the fluorine
atom as an electron-withdrawing substituent. In contrast, a
hypsochromic effect is observed for 4g, which contains a
fluorine atom instead of methoxy groups. Thus, the elec- NBO program as implemented in Gaussian 03. All calculations
were carried out on the HPPC-Cluster in Rostock.
tron-donating 4-methoxyphenyl group of 4f seems to be ad-
vantageous. This result is in agreement with our earlier
work related to alkynylated pyrimidines.[28]
General Procedure for the Synthesis of 3a–i: A suspension of 1,4-
dibromo-2-fluorobenzene (1), Pd(PPh3)4 (3 mol-%), and CuI
(3 mol-%) in THF (3 mL/mmol 1) in an oven-dried pressure tube
was degassed by bubbling argon through the solution for 10 min.
The acetylene 2 (1.0 equiv.) and triethylamine (2.0 equiv.) were
added by syringe. The mixture was heated at 50 °C for 5 h. The
cooled reaction mixture was filtered, and the residue was washed
with CH2Cl2. The filtrate was washed with a saturated solution of
ammonium chloride (2ϫ25 mL) and water (2ϫ25 mL). The com-
Conclusion
We have demonstrated an easy, applicable route for the
synthesis of mono- and disubstituted ethynylfluorobenzenes
by site-selective Sonogashira reactions of 1,4-dibromo-2-
fluorobenzene. The site-selectivity in favor of the 4-position bined organic layers were dried with anhydrous Na2SO4, filtered,
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and the solvent was removed in vacuo. The product was purified
by column chromatography (silica gel, EtOAc/heptanes).
NMR (282.4 MHz, CDCl ): δ = –106.6 (t, CF) ppm. IR (ATR): ν
˜
3
= 3023 (w), 2950 (m), 2207 (m), 1590 (m), 1554 (s), 1485 (s), 1470
(s), 1456 (m), 1241 (m), 1217 (m), 1198 (m), 1036 (m), 949 (m), 818
(s), 753 (s), 715 (s), 611 (s), 524 (m), 449 (s), 416 (m) cm–1. GC–
MS (EI, 70 eV): m/z (%) = 288 (100) [M]+, 287 (14), 210 (14), 209
(90), 208 (31), 207 (86), 189 (15), 183 (28), 144 (5), 104 (31), 94
(10), 92 (17), 63 (4). HRMS: calcd. for C15H10BrF [M]+ 287.99444;
found 287.99422. C15H10BrF (289.14): calcd. C 62.31, H 3.49;
found C 62.25, H 3.304.
1-Bromo-2-fluoro-4-(2-phenylethynyl)benzene (3a): Starting with 1
(253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI (5.7 mg,
3 mol-%), 2a (0.11 mL, 1.0 mmol), Et3N (0.28 mL, 2.0 mmol), and
THF (3.0 mL), 3a was isolated as a colorless solid (0.189 g, 69%);
m.p. 88–89 °C, RF = 0.51 (hexane/CH2Cl2 = 5:1). 1H NMR
3
4
5
(300 MHz, CDCl3): δ = 7.08 (ddd, JH–F = 8.4, JH–H = 1.8, JH–
H = 0.7 Hz, CH next to CF), 7.10 (dd, 3JH–H = 9.1, 4JH–H = 1.8 Hz,
CH), 7.14–7.19 (m, 3 H of Ph), 7.30–7.38 (m, 2 H of Ph, 1 H of 1-Bromo-2-fluoro-4-[(4-propylphenyl)ethynyl]benzene (3d):[19] Start-
Br–Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 87.4 (d, JC–F
=
ing with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI
(5.7 mg, 3 mol-%), 2d (0.16 mL, 1.0 mmol), Et3N (0.28 mL,
2.0 mmol), and THF (3.0 mL), 3d was isolated as a slight yellow
solid (0.212 g, 65%); m.p. 78–80 °C, RF = 0.48 (hexane/CH2Cl2 =
4
2
3.0 Hz, C of alkyne), 91.3 (C, alkyne), 109.5 (d, JC–F = 21.0 Hz,
C–Br), 119.3 (d, 2JC–F = 23.3 Hz, CH next to CF), 122.5 (C of Ph),
124.4 (d, 3JC–F = 8.3 Hz, C next to alkyne), 127.5 (CH of Ph), 127.5
3
3
(CH of Ph), 128.5 (CH of Ph), 128.7 (d, JC–F = 3.8 Hz, CH next
5:1). 1H NMR (300 MHz, CDCl3): δ = 0.95 (t, JH–H = 8.4 Hz,
3
to CBr),131.7 (CH of Ph), 131.7 (CH of Ph), 134.1 (CH), 158.8 (d, CH3), 1.65 (m, CH2), 2.61 (t, JH–H = 7.7 Hz, CH2), 7.17 (d,
1JC–F = 246.0 Hz, CF) ppm. 19F NMR (282.4 MHz, CDCl3): δ =
3JH–H = 8.2 Hz, 2 H of nPr–Ph), 7.18 (d, 3JH–F = 8.1 Hz, H of Br–
Ph), 7.26 (dd, 3JH–H = 9.2, 4JH–H = 1.7 Hz, H of Br–Ph), 7.41–7.46
–106.4 (t, CF) ppm. IR (ATR): ν = 3081 (w), 3053 (w), 2204 (m),
˜
3
4
1610 (w), 1593 (w), 1275 (w), 1094 (w), 1069 (w), 952 (w), 834 (w), (m, 2 H of nPr–Ph), 7.51 (dd, JH–H = 8.3, JH–F = 7.2 Hz, H of
820 (m), 786 (s), 683 (s), 543 (s), 524 (s), 431 (s), 379 (s) cm–1. GC– Br–Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3), 24.6
MS (EI, 70 eV): m/z (%) = 274 (98) [M]+, 195 (6), 194 (38), 175
(14), 138 (5), 137 (7), 98 (4). HRMS: calcd. for C14H8BrF [M]+
273.97879; found 273.97811.
(CH2), 38.0 (CH2), 86.8 (C, alkyne), 91.6 (C, alkyne), 109.2 (d,
2JC–F = 21.0 Hz, C–Br), 119.3 (d, 2JC–F = 24.0 Hz, CH next to CF),
3
119.7 (C, nPr–Ph next to alkyne), 124.6 (d, JC–F = 8.8 Hz, C next
3
to alkyne), 128.4 (d, JC–F = 3.8 Hz, CH next to CBr), 128.7 (CH,
1-Bromo-2-fluoro-4-(2-p-tolylethynyl)benzene (3b): Starting with 1
(253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI (5.7 mg,
3 mol-%), 2b (0.13 mL, 1.0 mmol), Et3N (0.28 mL, 2.0 mmol), and
THF (3.0 mL), 3b was isolated as a colorless solid (0.195 g, 68%);
m.p. 134–136 °C, RF = 0.52 (hexane/CH2Cl2 = 5:1). 1H NMR
(300 MHz, CDCl3): δ = 2.29 (s, CH3), 7.07–7.11 (m, 2 H of Me–
Ph and 1 H next to CF), 7.16–7.21 (m, H of Br–Ph), 7.32–7.45 (m,
2 H of Me–Ph and 1 H of Br–Ph) ppm. 13C NMR (75 MHz,
nPr–Ph), 128.7 (CH, nPr–Ph), 133.5 (CH, nPr–Ph), 133.5 (CH,
1
nPr–Ph), 133.5 (CH), 143.9 (C next to nPr), 158.7 (d, JC–F
=
246.0 Hz, CF) ppm. 19F NMR (282.4 MHz, CDCl3): δ = –106.6 (t,
CF) ppm. IR (ATR): ν = 2957 (m), 2924 (m), 2856 (m), 2210 (m),
˜
1893 (w), 1591 (m), 1556 (m), 1509 (s), 1471 (s), 1404 (s), 1216 (s),
1116 (m), 1036 (m), 950 (m), 814 (s), 766 (m), 609 (m), 531 (m),
425 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 316 (56) [M]+, 290
(16), 289 (99), 288 (17), 287 (100), 220 (4), 208 (17), 207 (47).
HRMS: calcd. for C17H14BrF [M]+ 316.02574; found 316.02569.
C17H14BrF (317.2): C, 64.37; H, 4.45; found C 64.13, H 4.47.
4
CDCl3): δ = 21.6 (CH3), 86.7 (C, alkyne), 91.5 (d, JC–F = 3.0 Hz,
2
2
C of alkyne), 109.2 (d, JC–F = 21.0 Hz, C–Br), 119.3 (d, JC–F
=
3
23.3 Hz, CH next to CF), 124.5 (d, JC–F = 8.3 Hz, C next to alk-
yne), 127.4 (C next to alkyne of Me–Ph), 128.4 (d, 3JC–F = 3.8 Hz,
CH next to CBr), 129.2 (CH of Me–Ph), 129.3 (CH of Me–Ph),
131.6 (CH of Me–Ph), 131.6 (CH of Me–Ph), 133.5 (CH), 139.1
4-[2-(4-tert-Butylphenyl)ethynyl]-1-bromo-2-fluorobenzene
(3e):
Starting with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%),
CuI (5.7 mg, 3 mol-%), 2e (0.16 mL, 1.0 mmol), Et3N (0.28 mL,
2.0 mmol), and THF (3.0 mL), 3e was isolated as a colorless solid
(C of Me–Ph), 158.7 (d, JC–F = 246.8 Hz, CF) ppm. 19F NMR
1
(282.4 MHz, CDCl ): δ = –106.9 (t, CF) ppm. IR (ATR): ν = 3024 (0.205 g, 62%); m.p. 77–79 °C, RF = 0.51 (hexane/CH2Cl2 = 5:1).
˜
3
(w), 2919 (m), 2852 (m), 2727 (w), 2550 (w), 2353 (w), 2209 (m), 1H NMR (300 MHz, CDCl3): δ = 1.31 (s, 9 H, tBu), 7.18 (ddd,
1906 (m), 1738 (m), 1591 (m), 1556 (m), 1472 (m), 1404 (s), 1321 3JH–F = 8.2, JH–H = 2.0, 5JH–H = 0.9 Hz, H next to CF), 7.25 (dd,
4
(w), 1215 (m), 1117 (m), 1036 (m), 950 (m), 809 (s), 751 (s), 526 3JH–H = 9.1, JH–H = 1.6 Hz, H of Br–Ph), 7.41–7.45 (m, 4 H of
4
(s), 455 (m), 419 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 288 (99) tBu–Ph), 7.51 (dd, 3JH–H = 8.2, JH–F = 7.2 Hz, H of Br–Ph) ppm.
4
[M]+, 287 (14), 209 (12), 208 (17), 207 (48), 189 (10), 183 (10), 145
13C NMR (75 MHz, CDCl3): δ = 31.2 (CH3), 31.2 (CH3), 31.2
4
(5), 123 (4), 105 (7), 104 (8), 63 (4). HRMS: calcd. for C15H10BrF (CH3), 34.9 (C of tBu), 86.7 (d, JC–F = 3.0 Hz, C of alkyne), 91.5
[M]+ 287.99444; found 287.99497. C15H10BrF (289.14): calcd. C
62.31, H 3.49; found C 62.27, H, 3.55.
(C, alkyne), 109.2 (d, JC–F = 21.0 Hz, C–Br), 119.3 (d, JC–F
24.0 Hz, CH next to CF), 119.5 (C of tBu–Ph), 124.6 (d, JC–F
=
=
2
2
3
9.0 Hz, C next to alkyne), 125.5 (CH of tBu–Ph), 125.5 (CH of
tBu–Ph), 128.4 (d, JC–F = 3.8 Hz, CH next to C–Br), 131.5 (CH
1-Bromo-2-fluoro-4-(2-o-tolylethynyl)benzene (3c): Starting with 1
(253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI (5.7 mg,
3 mol-%), 2c (0.13 mL, 1.00 mmol), Et3N (0.28 mL, 2.0 mmol), and
THF (3.00 mL), 3c was isolated as a colorless oil (0.161 g, 56%).
3
of tBu–Ph), 131.5 (CH of tBu–Ph), 133.5 (CH), 152.2 (C of tBu–
1
Ph), 158.7 (d, JC–F = 246.0 Hz, CF) ppm. 19F NMR (282.4 MHz,
CDCl ): δ = –106.6 (t, CF) ppm. IR (ATR): ν = 3086 (w), 2959
˜
3
1
RF = 0.45 (hexane/CH2Cl2 = 5:1). H NMR (300 MHz, CDCl3): δ
(m), 2924 (m), 2864 (m), 2212 (m), 1910 (w), 1590 (w), 1555 (w),
1405 (w), 1362 (m), 1243 (m), 1220 (m), 1099 (m), 951 (m), 872 (s),
830 (s), 817 (s), 711 (m), 556 (m), 448 (w), 432 (w) cm–1. GC–MS
(EI, 70 eV): m/z (%) = 330 (49) [M]+, 318 (17), 317 (100), 316 (19),
315 (100), 289 (15), 287 (15), 236 (10), 221 (13), 220 (18), 207 (10),
196 (10), 144 (17), 143 (17). HRMS: calcd. for C18H16BrF [M]+
330.04139; found 330.040588. C18H16BrF (331.22): calcd. C 65.27,
H 4.87; found C 65.01, H 5.23.
= 2.42 (s, CH3), 7.08–7.13 (m, H next to CF and H of 2-Me–Ph
next to Me), 7.15–7.24 (m, 2 H of 2-Me–Ph and 1 H of Br–Ph),
7.39–7.58 (m, 1 H of 2-Me–Ph and 1 H of Br–Ph) ppm. 13C NMR
4
(75 MHz, CDCl3): δ = 20.7 (CH3), 90.3 (C, alkyne), 91.2 (d, JC–F
2
= 3.0 Hz, 1 C, alkyne), 109.3 (d, JC–F = 21.0 Hz, C–Br), 119.2 (d,
2JC–F = 23.3 Hz, CH next to CF), 122.3 (C next to alkyne of Me–
Ph), 124.6 (d, 3JC–F = 8.3 Hz, C next to alkyne), 125.7 (CH of Me–
Ph), 127.5 (d, 3JC–F = 3.8 Hz, CH next to CBr), 128.4 (CH of Me–
Ph), 129.6 (CH of Me–Ph), 132.0 (CH of Me–Ph), 133.5 (CH),
1-Bromo-2-fluoro-4-[2-(4-methoxyphenyl)ethynyl]benzene
(3f):
1
140.4 (C of Me–Ph), 158.8 (d, JC–F = 246.8 Hz, CF) ppm. 19F
Starting with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%),
610
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 604–615

Site-Selective Sonogashira Reactions
CuI (5.7 mg, 3 mol-%), 2f (0.12 mL, 1.0 mmol), Et3N (0.28 mL,
2.0 mmol), and THF (3.0 mL), 3f was isolated as a colorless solid
1558 (w), 1486 (s), 1476 (s), 1404 (s), 1178 (s), 1043 (m), 868 (s),
814 (s), 614 (s), 456 (w) cm–1. GC–MS (EI, 70 eV): m/z (%) = 254
(39) [M]+, 241 (28), 239 (31), 213 (47), 200 (21), 198 (17), 175 (10),
(0.215 g, 71%); m.p. 93–95 °C, RF = 0.65 (hexane/ethyl acetate =
1
4:1). H NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H, MeO), 6.86– 161 (11), 160 (100), 159 (30), 147 (48), 146 (84), 145 (10), 134 (21),
3
4
6.90 (m, 2 H, MeO–Ph), 7.16 (ddd, JH–F = 8.1, JH–H = 1.9,
133 (45), 132 (35), 131 (24), 105 (15), 81 (7), 41 (10). HRMS: calcd.
5JH–H = 0.8 Hz, H next to CF), 7.25 (dd, JH–H = 9.1, JH–H
=
for C12H12BrF [M]+ 254.01009; found 254.01034.
3
4
1.7 Hz, H of Br–Ph), 7.43–7.52 (m, 2 H of MeO–Ph and 1 H of
1-Bromo-2-fluoro-4-[(trimethylsilyl)ethynyl]benzene (3i): Starting
with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI
(5.7 mg, 3 mol-%), 2i (0.10 mL, 1.0 mmol), Et3N (0.28 mL,
2.0 mmol), and THF (3.0 mL), 3i was isolated as a colorless oil
(0.166 g, 61%). RF = 0.70 (hexane/CH2Cl2 = 5:1). 1H NMR
Br–Ph) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.3 (OCH3), 86.2 (C,
4
2
alkyne), 91.4 (d, JC–F = 3.0 Hz, C of alkyne), 109.0 (d, JC–F
=
21.0 Hz, C–Br), 114.1 (CH of MeO–Ph), 114.1 (CH of MeO–Ph),
2
114.6 (C, MeO–Ph next to alkyne), 119.1 (d, JC–F = 24.3 Hz, CH
3
next to CF), 124.6 (d, JC–F = 8.3 Hz, C next to alkyne), 128.3 (d,
3
(300 MHz, CDCl3): δ = 0.93 (t, JH–H = 7.3 Hz, CH3), 1.41–1.59
3JC–F = 3.8 Hz, CH next to C–Br), 133.4 (CH), 133.2 (CH of MeO–
3
3
(m, 4 H, 2 CH2), 2.37 (t, JH–H = 7.3 Hz, CH2), 7.02 (ddd, JH–F
1
Ph), 133.2 (CH of MeO–Ph), 158.6 (d, JC–F = 246.8 Hz, CF),
4
5
= 8.4, JH–H = 1.8, JH–H = 0.7 Hz, H next to CF), 7.09–7.30 (m,
160.1 (C–OMe) ppm. 19F NMR (282.4 MHz, CDCl3): δ = –106.7
3
4
H of Br–Ph), 7.42 (dd, JH–H = 8.1, JH–F = 7.2 Hz, H of Br–Ph)
(t, CF) ppm. IR (ATR): ν = 2964 (m), 2933 (w), 2841 (w), 2205
˜
ppm. 13C NMR (75 MHz, CDCl3): δ = 0.1 (CH3; TMS), 96.9 (C,
(w), 1602 (m), 1509 (m), 1403 (m), 1288 (m), 1217 (w), 1108 (m),
1025 (m), 951 (m), 821 (s), 721 (m), 695 (m), 612 (m), 537 (m), 471
(w), 401 (w) cm–1. GC–MS (EI, 70 eV): m/z (%) = 304 (100) [M]+,
291 (37), 289 (37), 263 (14), 261 (15), 194 (5), 182 (29), 181 (45),
155 (6). HRMS: calcd. for C15H10OBrF [M]+ 303.98936; found
303.99005. C15H10OBrF (305.1): calcd. C 59.04, H 3.30; found C
59.12, H 3.44.
4
2
alkyne), 102.9 (d, JC–F = 3.0 Hz, 1 C, alkyne), 110.0 (d, JC–F
=
2
21.0 Hz, C–Br), 119.9 (d, JC–F = 23.2 Hz, CH, next to CF), 124.4
3
3
(d, JC–F = 8.3 Hz, C next to alkyne), 129.0 (d, JC–F = 3.8 Hz, C
1
next to C–Br), 133.6 (CH), 158.8 (d, JC–F = 246.0 Hz, CF) ppm.
19F NMR (282.4 MHz, CDCl3): δ = –106.6 (t, 4JF-H = 5.6, JF-H
=
3
11.3 Hz, CF) ppm. IR (ATR): ν = 2960 (m), 2899 (w), 2160 (s),
˜
2114 (w), 1559 (m), 1474 (s), 1401 (s), 1250 (s), 1159 (s), 1042 (m),
958 (m), 837 (s), 757 (s), 689 (m), 657 (s), 615 (s), 514 (m) cm–1.
GC–MS (EI, 70 eV): m/z (%) = 270 (19) [M]+, 258 (16), 257 (100),
256 (16), 255 (99), 146 (4), 128 (4), 127 (3). HRMS: calcd. for
C11H12BrFSi [M]+ 269.98702; found 269.98671.
1-Bromo-2-fluoro-4-[2-(4-fluorophenyl)ethynyl]benzene (3g): Start-
ing with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI
(5.7 mg, 3 mol-%), 2g (0.114 mL, 1.0 mmol), Et3N (0.28 mL,
2.0 mmol), and THF (3.0 mL), 3g was isolated as a colorless solid
(0.199 g, 66%); m.p. 88–89 °C, RF = 0.51 (hexane/CH2Cl2 = 4:1).
1H NMR (300 MHz, CDCl3): δ = 7.02–7.08 (m, 2 H), 7.15–7.19
(m, H of Br–Ph), 7.24–7.29 (m, H of Br–Ph), 7.48–7.55 (m, 2 H of
F–Ph and 1 H of Br–Ph) ppm. 13C NMR (75 MHz, CDCl3): δ =
87.0 (C alkyne), 90.1 (C, alkyne), 109.6 (d, 2JC–F = 21.0 Hz, C–Br),
General Procedure for the Synthesis of 4a–i: A suspension of 1,
Pd(PPh3)4 (3 mol-%), and CuI (3 mol-%) in THF (4 mL/mmol 1)
in an oven-dried pressure tube was degassed by bubbling argon
through the solution for 10 min. The acetylene 2 (2.1 equiv.) and
triethylamine (2.5 equiv.) were added by syringe. The mixture was
heated at 50 °C for 6 h. The cooled reaction mixture was filtered,
and the residue was washed with CH2Cl2. The filtrate was washed
with a saturated solution of ammonium chloride (2ϫ25 mL) and
water (2ϫ25 mL). The combined organic layers were dried with
anhydrous Na2SO4, filtered, and the solvent was removed in vacuo.
The product was purified by column chromatography (silica gel,
EtOAc/heptanes).
2
2
115.7 (d, JC–F = 21.8 Hz CH, F–Ph), 115.9 (d, JC–F = 21.8 Hz
CH, F–Ph), 118.6 (d, 4JC–F = 3.0 Hz, C F–Ph next to alkyne), 119.3
(d, JC–F = 24.0 Hz, CH next to CF), 124.2 (d, JC–F = 8.3 Hz, C
2
3
3
next to alkyne), 127.3 (d, JC–F = 3.8 Hz, CH next to CBr), 133.3
(CH), 133.7 (d, 3JC–F = 8.3 Hz CH, F–Ph), 133.7 (d, 3JC–F = 8.3 Hz
1
1
CH, F–Ph), 158.7 (d, JC–F = 246.8 Hz, CF), 162.8 (d, JC–F
=
249.0 Hz, CF of F–Ph) ppm. 19F NMR (282.4 MHz, CDCl3): δ =
–106.4 (t, CF of Br–Ph), –109.5 (m, CF of F–Ph) ppm. IR (ATR):
ν = 3070 (m), 2921 (w), 2210 (w), 1900 (w), 1557 (m), 1508 (s),
˜
2-Fluoro-1,4-bis(phenylethynyl)benzene (4a):[19] Starting with
1
(253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI (5.7 mg,
3 mol-%), 2a (0.23 mL, 2.1 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (4.0 mL), 4a was isolated as a colorless solid (0.219 g, 74%);
m.p. 170–171 °C, RF = 0.44 (hexane/CH2Cl2 = 5:1). 1H NMR
(300 MHz, CDCl3): δ = 7.17–7.20 (m, 2 H), 7.26–7.31 (m, 6 H),
7.40–7.50 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 82.6 (C
of alkyne), 88.1 (d, 3JC–F = 4.5 Hz, C of alkyne), 92.1 (C of alkyne),
1471 (m), 1403 (m), 1321 (m), 1213 (s), 1152 (s), 827 (s), 757 (m),
670 (m), 611 (m), 530 (m), 499 (m), 611 (w), 424 (m), 405 (m) cm–1.
GC–MS (EI, 70 eV): m/z (%) = 292 (39) [M]+, 212 (32), 193 (17),
192 (9), 168 (4), 167 (3), 147 (7), 96 (5). HRMS: calcd. for
C14H7BrF2 [M]+ 291.96937; found 291.96989. C14H7BrF2 (293.1):
calcd. C 57.37, H 2.41; found C 57.53, H 2.341.
1-Bromo-2-fluoro-4-(hex-1-ynyl)benzene (3h): Starting with
1
4
2
96.1 (d, JC–F = 3.0 Hz, C of alkyne), 112.1 (d, JC–F = 15.8 Hz, C
(253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI (5.7 mg,
3 mol-%), 2h (0.12 mL, 1.0 mmol), Et3N (0.28 mL, 2.0 mmol), and
THF (3.0 mL), 3h was isolated as a colorless oil (0.118 g, 50%). RF
2
next to CF), 118.5 (d, JC–F = 23.3 Hz, CH next to CF), 122.7 (d,
3JC–F = 9.0 Hz, C next to alkyne), 124.9 (C of Ph), 125.0 (C of Ph),
127.4 (d, 3JC–F = 3.8 Hz, CH), 128.5 (2 CH of Ph), 128.8 (4 CH of
1
= 0.61 (hexane/CH2Cl2 = 5:1). H NMR (300 MHz, CDCl3): δ =
4
Ph), 133.3 (4 CH of Ph), 133.3 (d, JC–F = 2.3 Hz, CH), 162.2 (d,
3
0.93 (t, JH–H = 7.3 Hz, CH3), 1.41–1.59 (m, 4 H, 2 CH2), 2.37 (t,
1JC–F = 250.5 Hz, CF) ppm. 19F NMR (282.4 MHz, CDCl3): δ =
3
4
5
3JH–H = 7.3 Hz, CH2), 7.02 (ddd, JH–F = 8.4, JH–H = 1.8, JH–H
–109.5 (t, CF) ppm. IR (ATR): ν = 3053 (m), 2204 (w), 1610 (w),
˜
= 0.7 Hz, H next to CF), 7.09–7.30 (m, H of Br–Ph), 7.42 (dd,
1511 (m), 1412 (m), 1328 (w), 1275 (w), 1204 (w), 1157 (w), 1094
(w), 1025 (w), 952 (w), 834 (w), 820 (m), 751 (s), 683 (s), 524 (m),
494 (m), 470 (m), 431 (m), 379 (m) cm–1. GC–MS (EI, 70 eV): m/z
(%) = 296 (100) [M]+, 294 (19), 292 (7), 148 (17), 122 (3). HRMS:
calcd. for C22H13F [M]+ 296.09958; found 296.10000. C16H21F
(296.33): calcd. C 89.17, H 4.42; found C 89.51, H 4.384.
4
3JH–H = 8.1, JH–F = 7.2 Hz, H of Br–Ph) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.6 (CH3), 19.1, 22.1, 30.6 (CH2), 78.8 (d,
2
4JC–F = 3.0 Hz, C alkyne), 92.7 (C, alkyne), 108.5 (d, JC–F
=
2
21.0 Hz, C–Br), 119.4 (d, JC–F = 23.3 Hz, CH next to CF), 127.2
(d, 3JC–F = 8.3 Hz, C next to alkyne), 128.5 (d, 3JC–F = 3.8 Hz, CH
1
next to CBr), 133.2 (CH), 158.6 (d, JC–F = 246.0 Hz, CF) ppm.
19F NMR (282.4 MHz, CDCl3): δ = –107.0 (t, CF of Br–Ph) ppm. 2-Fluoro-1,4-bis(2-p-tolylethynyl)benzene (4b): Starting with
1
IR (ATR): ν = 2957 (m), 2930 (m), 2872 (m), 2233 (w), 1598 (w),
(253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI (5.7 mg,
˜
Eur. J. Org. Chem. 2012, 604–615
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
611

P. Langer et al.
= 2.1 Hz, CH), 162.4 (d, JC–F = 253.7 Hz, CF) ppm. 19F NMR
FULL PAPER
3 mol-%), 2b (0.26 mL, 2.1 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (4.0 mL), 4b was isolated as a colorless solid (0.226 g, 70%);
m.p. 200–202 °C, RF = 0.41 (hexane/CH2Cl2 = 5:1). 1H NMR
1
(282.4 MHz, CDCl ): δ = –109.8 (t, CF) ppm. IR (ATR): ν = 3029
˜
3
(w), 2955 (m), 2927 (m), 2867 (m), 2215 (w), 1914 (w), 1603 (m),
(300 MHz, CDCl3): δ = 2.37 (s, 6 H, CH3), 7.17 (d, 3JH–H = 7.9 Hz, 1515 (m), 1412 (s), 1211 (s), 1093 (s), 954 (s), 865 (s), 816 (s), 621
4 H of Me–Ph), 7.41–7.52 (m, 5 H), 7.63–7.71 (m, 2 H) ppm. 13C
(s), 538 (s), 461 (w) cm–1. GC–MS (EI, 70 eV): m/z (%) = 380 (100)
NMR (75 MHz, CDCl3): δ = 20.7 (CH3), 20.7 (CH3), 86.4 (C of [M]+, 352 (18), 351 (66), 322 (30), 161 (23). HRMS: calcd. for
alkyne), 90.9 (C of alkyne), 91.9 (C of alkyne), 95.2 (C of alkyne),
112.2 (d, 2JC–F = 15.7 Hz, C next to CF), 118.4 (d, 2JC–F = 22.0 Hz,
CH next to CF), 122.3 (C of 2-Me–Ph), 122.5 (C of 2-Me–Ph),
C28H25F [M]+ 380.19348; found 380.19424. C28H25F (380.50):
calcd. C 88.38, H 6.62; found C 88.14, H 6.21.
1,4-Bis[2-(4-tert-butylphenyl)ethynyl]-2-fluorobenzene (4e): Starting
with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI
(5.7 mg, 3 mol-%), 2e (0.331 g, 2.1 mmol), Et3N (0.35 mL,
2.5 mmol), and THF (4.0 mL), 4e was isolated as a colorless solid
(0.256 g, 63%); m.p. 235–237 °C, RF = 0.29 (hexane/CH2Cl2 = 5:1).
1H NMR (300 MHz, CDCl3): δ = 1.25 (s, 18 H, CH3), 7.15–7.21
(m, 2 H), 7.28–7.32 (m, 4 H), 7.36–7.44 (m, 5 H) ppm. 13C NMR
3
124.9 (d, JC–F = 8.8 Hz, C next to alkyne), 125.6 (CH of 2 Me–
3
Ph), 125.7 (CH of 2 Me–Ph), 127.2 (d, JC–F = 3.8 Hz, CH), 128.8
(CH of 2 Me–Ph), 128.8 (CH of 2 Me–Ph), 129.5 (CH of 2 Me–
Ph), 129.6 (CH of 2 Me–Ph), 131.9 (CH of 2 Me–Ph), 132.0 (CH
4
of 2 Me–Ph), 133.0 (d, JC–F = 2.3 Hz, CH), 140.4 (CH3 of 2-Me–
1
Ph), 140.5 (CH3 of 2-Me–Ph), 162.1 (d, JC–F = 250.5 Hz, CF)
ppm. 19F NMR (282.4 MHz, CDCl3): δ = –109.7 (t, CF) ppm. IR
(75 MHz, CDCl3): δ = 31.2 (6 CH3), 34.9 (2 C of tBu), 82.0 (C of
(ATR): ν = 3022 (w), 2918 (m), 2851 (m), 2213 (m), 1901 (w), 1723
˜
3
alkyne), 87.6 (C of alkyne), 92.2 (C of alkyne), 96.3 (d, JC–F
=
(w), 1603 (w), 1538 (s), 1518 (s), 1436 (s), 1413 (s), 1181 (m), 1019
(w), 954 (m), 838 (w), 809 (s), 749 (s), 719 (s), 693 (m), 612 (m),
538 (s), 504 (s), 471 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 324
(100) [M]+, 323 (11), 162 (7), 161 (5). HRMS: calcd. for C24H17F
[M]+ 324.13088; found 324.13098.
2
3.8 Hz, C of alkyne), 112.1 (d, JC–F = 16.0 Hz, C next to CF),
2
3
118.4 (d, JC–F = 22.5 Hz, CH next to CF), 119.7 (d, JC–F
=
9.0 Hz, C next to alkyne), 124.9 (C of tBu–Ph), 125.0 (C of tBu–
Ph), 127.3 (2 CH of tBu–Ph), 127.3 (2 CH of tBu–Ph), 127.4 (d,
3JC–F = 3.8 Hz, CH), 131.5 (2 CH of tBu–Ph), 131.5 (2 CH of tBu–
4
2-Fluoro-1,4-bis[(2-methylphenyl)ethynyl]benzene (4c): Starting with
1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI (5.7 mg,
3 mol-%), 2c (0.26 mL, 2.1 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (4.0 mL), 4c was isolated as a colorless solid (0.221 g, 68%);
m.p. 103–104 °C, RF = 0.27 (hexane/CH2Cl2 = 5:1). 1H NMR
(300 MHz, CDCl3): δ = 2.58 (s, 3 H, CH3), 2.59 (s, 3 H, CH3),
7.21–7.27 (m, 2 H), 7.29–7.37 (m, 6 H), 7.51–7.59 (m, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 20.7 (CH3), 20.8 (CH3), 86.5 (C
of alkyne), 91.1 (C of alkyne), 92.0 (C of alkyne), 95.2 (C of al-
Ph), 133.2 (d, JC–F = 1.5 Hz, CH), 152.2 (2C next to tBu), 162.1
1
(d, JC–F = 250.5 Hz, CF) ppm. 19F NMR (282.4 MHz, CDCl3): δ
= –109.7 (t, CF) ppm. IR (ATR): ν = 2957 (m), 2865 (m), 2216
˜
(w), 1914 (m), 1667 (m), 1611 (m), 1514 (m), 1488 (m), 1413 (s),
1362 (m), 1264 (s), 1212 (m), 1101 (m), 955 (m), 870 (m), 833 (s),
697 (m), 561 (s), 431 (w) cm–1. GC–MS (EI, 70 eV): m/z (%) = 408
(100) [M]+, 394 (29), 393 (88), 335 (5), 309 (5), 189 (21), 161 (14).
HRMS: calcd. for C30H30F [M]+ 409.2326; found 409.2322.
C30H29F (408.55): calcd. C 88.20, H 7.15; found C 88.43, H 7.075.
2
2
kyne), 112.3 (d, JC–F = 16.8 Hz, C next to CF), 118.3 (d, JC–F
=
2-Fluoro-1,4-bis[(4-methoxyphenyl)ethynyl]benzene (4f): Starting
with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.65 mg, 3 mol-%), CuI
(5.7 mg, 3 mol-%), 2f (0.25 mL, 2.1 mmol), Et3N (0.35 mL,
2.5 mmol), and THF (4.0 mL), 4f was isolated as a colorless solid
(0.244 g, 69%); m.p. 182–184 °C, RF = 0.33 (hexane/CH2Cl2 = 5:1).
1H NMR (300 MHz, CDCl3): δ = 3.76 (s, MeO), 6.79–6.84 (m, 4
H), 7.34–7.44 (m, 2 H), 7.34–7.44 (m, 5 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.3 (CH3 of MeO), 81.4 (C of alkyne), 87.0
(C of alkyne), 92.0 (C of alkyne), 96.1 (C of alkyne), 112.1 (d, 2JC–
22.5 Hz, CH next to CF), 122.4 (C of 2-Me–Ph), 122.6 (C of 2-
Me–Ph), 125.0 (d, 3JC–F = 9.0 Hz, C next to alkyne), 125.7 (CH of
2 Me–Ph), 125.7 (CH of 2 Me–Ph), 127.3 (d, 3JC–F = 3.8 Hz, CH),
128.9 (CH of 2 Me–Ph), 128.9 (CH of 2 Me–Ph), 129.6 (CH of 2
Me–Ph), 129.6 (CH of 2 Me–Ph), 132.0 (CH of 2 Me–Ph), 132.0
4
(CH of 2 Me–Ph), 133.0 (d, JC–F = 2.3 Hz, CH), 140.5 (CH3 of
1
Me–Ph), 140.6 (CH3 of Me–Ph), 162.1 (d, JC–F = 250.5 Hz, CF)
ppm. 19F NMR (282.4 MHz, CDCl3): δ = –109.4 (t, CF) ppm. IR
(ATR): ν = 3017 (m), 1901 (w), 1598 (m), 1536 (m), 1507 (m), 1414
˜
= 16.5 Hz, C next to CF), 114.1 (2 CH of MeO–Ph), 114.1 (2
F
(m), 1212 (m), 1083 (m), 1037 (m), 954 (m), 935 (m), 862 (m), 817
(m), 755 (s), 710 (m), 616 (m), 551 (m), 444 (s), 396 (w) cm–1. GC–
MS (EI, 70 eV): m/z (%) = 324 (100) [M]+, 323 (16), 320 (8), 307
(12), 162 (8), 147 (3), 115 (5). HRMS: calcd. for C24H17F [M]+
324.13088; found 324.13091. C24H17F (408.55): calcd. C 88.86, H
5.28; found C 89.00, H 5.24.
CH of MeO–Ph), 114.7 (C of Me–Ph), 114.9 (C of Me–Ph), 118.2
2
3
(d, JC–F = 22.5 Hz, CH next to CF), 124.9 (d, JC–F = 9.0 Hz, C
3
next to alkyne), 127.2 (d, JC–F = 3.0 Hz, CH), 133.2 (2 CH of
MeO–Ph), 133.3 (2 CH of MeO–Ph), 133.2 (d, JC–F = 2.0 Hz,
4
1
CH), 160.0 (2 C of MeO–Ph), 161.9 (d, JC–F = 249.8 Hz, CF)
ppm. 19F NMR (282.4 MHz, CDCl3): δ = –110.0 (t, CF) ppm. IR
2-Fluoro-1,4-bis[2-(4-propylphenyl)ethynyl]benzene (4d):[19] Starting
with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI
(5.7 mg, 3 mol-%), 2b (0.33 mL, 2.1 mmol), Et3N (0.35 mL,
2.5 mmol), and THF (4.0 mL), 4b was isolated as a colorless solid
(0.267 g, 70%); m.p. 147–149 °C, RF = 0.31 (hexane/CH2Cl2 = 5:1).
(ATR): ν = 2933 (w), 2836 (w), 2210 (m), 1603 (m), 1540 (m), 1517
˜
(s), 1458 (m), 1414 (m), 1289 (m), 1242 (s), 1168 (s), 1028 (s), 954
(m), 839 (s), 826 (s), 798 (s), 585 (m), 529 (m), 465 (s), 424 (w)
cm–1. GC–MS (EI, 70 eV): m/z (%) = 356 (100) [M]+, 341 (32), 313
(4), 270 (7), 178 (11), 122 (4). HRMS: calcd. for C24H17O2F [M]+
356.12071; found 356.12046. C16H21F (296.33): calcd. C 89.17, H
4.42; found C 89.51, H 4.38.
3
1H NMR (300 MHz, CDCl3): δ = 0.95 (t, JH–H = 8.6 Hz, 6 H,
CH3), 1.59–1.71 (m, 4 H, CH2), 2.61 (t, 3JH–H = 7.7 Hz, 4 H, CH2),
7.17 (d, 3JH–H = 8.5 Hz, 4 H of nPr–Ph), 7.23–7.29 (m, 2 H), 7.42–
7.49 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1 (CH3),
24.6 (CH2), 38.3 (CH2), 82.3 (C of alkyne), 87.8 (d, 3JC–F = 4.5 Hz,
2-Fluoro-1,4-bis[2-(4-fluorophenyl)ethynyl]benzene (4g): Starting
with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI
(5.7 mg, 3 mol-%), 2g (0.24 mL, 2.1 mmol), Et3N (0.35 mL,
4
C of alkyne), 92.6 (C of alkyne), 96.6 (d, JC–F = 3.0 Hz, C of
2
2
alkyne), 112.5 (d, JC–F = 16.7 Hz, C next to CF), 118.5 (d, JC–F 2.5 mmol), and THF (4.0 mL), 4g was isolated as a colorless solid
2
= 23.4 Hz, C next to alkyne), 120.2 (d, JC–F = 13.3 Hz, CH next
(0.226 g, 68%); m.p. 154–155 °C, RF = 0.28 (hexane/CH2Cl2 = 5:1).
to CF), 125.2 (d, 3JC–F = 10.2 Hz, C next to alkyne), 127.5 (d, 3JC–
1H NMR (300 MHz, CDCl3): δ = 7.02–7.11 (m, 4 H), 7.22–7.28
= 4.1 Hz, CH), 128.9 (2CH of nPr–Ph), 128.9 (2CH of nPr–Ph), (m, 2 H), 7.43-7.59 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
F
4
131.9 (2CH of nPr–Ph), 131.9 (2 CH of nPr–Ph), 133.4 (d, JC–F
δ = 82.3 (C of alkyne), 87.7 (C of alkyne), 91.0 (C of alkyne), 95.0
612
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 604–615

Site-Selective Sonogashira Reactions
3
2
(d, JC–F = 5.5 Hz, C of alkyne), 112.0 (d, JC–F = 18.4 Hz, C next
mmol 3) in an oven-dried pressure tube was degassed by bubbling
argon through the solution for 10 min. The acetylene 2 (1.1 equiv.)
and triethylamine (2.0 equiv.) were added by syringe. The mixture
was heated at 50 °C for 6 h. The cooled reaction mixture was fil-
tered, and the residue was washed with CH2Cl2. The filtrate was
2
to CF), 115.8 (dd, JC–F = 21.9 Hz, 4 CH of F–Ph), 118.4 (d,
2JC–F = 23.4 Hz, CH next to CF), 118.7 (dd, JC–F = 3.0 Hz, 2 C
4
3
of F–Ph), 124.7 (d, JC–F = 10.0 Hz, C next to alkyne), 127.3 (d,
3JC–F = 4.0 Hz, CH), 133.2 (d, JC–F = 2.0 Hz, CH), 133.7 (dd,
4
3JC–F = 8.0 Hz, 4 CH of F–Ph), 162.3 (d, JC–F = 249.5 Hz, F–Ph,
washed with a saturated solution of ammonium chloride
1
CF), 162.6 (d, 1JC–F = 252.8 Hz, CF) ppm. 19F NMR (282.4 MHz, (2ϫ25 mL) and water (2ϫ25 mL). The combined organic layers
CDCl ): δ = –109.5 (m, 3 CF) ppm. IR (ATR): ν = 3062 (w), 2924
were dried with anhydrous Na2SO4, filtered, and the solvent was
˜
3
(w), 2215 (w), 1613 (w), 1599 (m), 1538 (m), 1599 (m), 1538 (m), removed in vacuo. The product was purified by column chromatog-
1515 (m), 1415 (m), 1231 (m), 1209 (m), 1154 (m), 1094 (m), 956 raphy (silica gel, EtOAc/heptanes).
(m), 838 (s), 812 (s), 785 (m), 739 (m), 526 (s), 386 (m) cm–1. GC–
2-Fluoro-1-[2-(4-fluorophenyl)ethynyl]-4-(2-phenylethynyl)benzene
(5a): Starting with 3a (275 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg,
3 mol-%), CuI (5.7 mg, 3 mol-%), 2g (0.125 mL, 1.1 mmol), Et3N
(0.28 mL, 2.0 mmol), and THF (2.0 mL), 5a was isolated as a col-
MS (EI, 70 eV): m/z (%) = 332 (100) [M]+, 330 (10), 310 (5), 166
(13). HRMS: calcd. for C22H11F3 [M]+ 332.08074; found
332.08099. C22H11F3 (332.32): calcd. C 79.51, H 3.34; found C
79.61, H 3.40.
2-Fluoro-1,4-bis[2-(trimethylsilyl)ethynyl]benzene (4h):[19] Starting
with 1 (253 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI
(5.7 mg, 3 mol-%), 2i (0.26 mL, 2.1 mmol), Et3N (0.35 mL,
2.5 mmol), and THF (4.0 mL), 4h was isolated as a colorless solid
(0.212 g, 73%); m.p. 94–95 °C, RF = 0.57 (hexane/ethyl acetate =
4:1). 1H NMR (300 MHz, CDCl3): δ = 0.24 (s, 9 H, TMS), 0.25 (s,
orless solid (0.212 g, 68%); m.p. 205–207 °C, RF = 0.34 (hexane/
1
CH2Cl2 = 5:1). H NMR (300 MHz, CDCl3): δ = 7.02–7.19 (m, 2
H), 7.23–7.31 (m, 2 H), 7.34–7.40 (m, 3 H), 7.45–7.58 (m, 5 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 82.3 (C of alkyne), 87.9
3
4
(d, JC–F = 5.8 Hz, C of alkyne), 92.1 (C of alkyne), 95.0 (d, JC–F
2
= 4.3 Hz, C of alkyne), 111.9 (d, JC–F = 16.4 Hz, C next to CF),
115.8 (d, JC–F = 21.0 Hz, 2 CH of F–Ph), 118.5 (d, JC–F
21.0 Hz, CH next to CF), 118.8 (d, JC–F = 2.8 Hz, C of F–Ph),
122.6 (C of Ph), 125.5 (d, JC–F = 10.0 Hz, 1 C), 127.4 (d, JC–F
2
2
=
3
4
9 H, TMS), 7.12–7.18 (m, 2 H), 7.36 (dd, JH–H = 8.2, JH–F
=
4
7.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 0.00 (6 CH3,
TMS), 97.7 (C of alkyne), 97.7 (C of alkyne), 102.3 (C of alkyne),
103.4 (C of alkyne), 112.3 (d, 2JC–F = 16.0 Hz, C next to CF), 118.8
3
3
=
3.4 Hz, CH), 128.5 (2 CH of Ph), 128.8 (CH of Ph), 131.7 (2CH
4
3
of Ph), 133.2 (d, JC–F = 2.0 Hz, CH), 133.7 (d, JC–F = 8.1 Hz, 2
2
3
(d, JC–F = 23.3 Hz, CH next to CF), 125.1 (d, JC–F = 8.0 Hz, C
1
1
CH of F–Ph), 162.0 (d, JC–F = 250.0 Hz, CF), 162.8 (d, JC–F
=
3
4
next to alkyne), 127.7 (d, JC–F = 3.0 Hz, CH), 133.8 (d, JC–F
255.0 Hz, CF of F–Ph) ppm. 19F NMR (282.4 MHz, CDCl3): δ =
= 2.3 Hz, CH), 162.6 (d, JC–F = 250.5 Hz, CF) ppm. 19F NMR
1
–109.5 (m, 2 CF) ppm. IR (ATR): ν = 3058 (w) 3046 (w), 2927 (w),
˜
(282.4 MHz, CDCl ): δ = –109.4 (t, CF) ppm. IR (ATR): ν = 2955
˜
3
1612 (w), 1595 (w), 1539 (w), 1512 (s), 1415 (s), 1210 (s), 1153 (m),
1095 (m), 955 (m), 866 (m), 833 (s), 752 (s), 685 (s), 597 (s), 525
(s), 478 (s), 395 (m) cm–1. GC–MS (EI, 70 eV): m/z (%) = 314 (100)
[M]+, 312 (20), 157 (20). HRMS: calcd. for C22H12F2 [M]+
314.09016; found 314.09072.
(w), 2897 (w), 2157 (m), 1608 (w), 1539 (w), 1488 (m), 1406 (m),
1246 (m), 961 (m), 836 (s), 753 (s), 696 (m), 626 (m), 534 (w), 461
(w), 420 (w), 398 (w) cm–1. GC–MS (EI, 70 eV): m/z (%) = 288 (45)
[M]+, 275 (10), 274 (27), 273 (100), 196 (8), 129 (19). HRMS: calcd.
for C16H21FSi2 [M]+ 288.11603; found 288.11609. C16H21FSi2
(288.51): calcd. C 66.61, H 7.34; found C 66.73, H 7.23.
2-Fluoro-4-(2-phenylethynyl)-1-[2-(2-tolyl)ethynyl]benzene (5b):
Starting with 3a (275 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-
%), CuI (5.7 mg, 3 mol-%), 2c (0.138 mL, 1.1 mmol), Et3N
(0.28 mL, 2.0 mmol), and THF (2.0 mL), 5b was isolated as a col-
orless solid (0.188 g, 61%); m.p. 117–119 °C, RF = 0.39 (hexane/
CH2Cl2 = 5:1). 1H NMR (300 MHz, CDCl3): δ = 2.46 (s, 3 H,
CH3), 7.10–7.14 (m, 6 H), 7.27–7.32 (m, 3 H), 7.38–7.51 (m, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 20.7 (CH3), 86.4 (C of
alkyne), 88.1 (C of alkyne), 92.0 (C of alkyne), 95.3 (C of alkyne),
112.5 (d, 2JC–F = 22.4 Hz, C next to CF), 118.3 (d, 2JC–F = 24.0 Hz,
CH next to CF), 122.5 (CH of 2 Me–Ph), 122.6 (C of 2 Me–Ph),
1-[2-{3-Fluoro-4-(2-{4-(pentyloxy)phenyl}ethynyl)phenyl}ethynyl]-4-
(pentyloxy)benzene (4i): Starting with
1 (253 mg, 1.0 mmol),
Pd(PPh3)4 (34.6 mg, 3 mol-%), CuI (5.7 mg, 3 mol-%), 2j (0.394 g,
2.1 mmol), Et3N (0.35 mL, 2.5 mmol), and THF (4.0 mL), 4i was
isolated as a colorless solid (0.321 g, 69%); m.p. 135–136 °C, RF
=
0.36 (hexane/CH2Cl2 = 5:1). 1H NMR (300 MHz, CDCl3): δ = 0.93
(t, 3JH–H = 7.7 Hz, 6 H, CH3), 1.35–1.47 (m, 8 H, CH2), 1.75–1.84
3
(m, 4 H, CH2), 3.97 (t, JH–H = 6.7 Hz, 4 H, OCH2), 6.85–6.89
(m, 4 H), 6.85–6.89 (m, 2 H), 7.41–7.50 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.0 (CH3), 22.5 (CH2), 28.2 (CH2), 28.9
(CH2), 68.1 (OCH2), 81.4 (C of alkyne), 86.9 (d, 3JC–F = 4.5 Hz, C
of alkyne), 92.2 (C of alkyne), 96.2 (d, 4JC–F = 3.0 Hz, C of alkyne),
3
124.7 (d, JC–F = 9.8 Hz, 1 C), 125.7 (CH of 2 Me–Ph), 127.4 (d,
3JC–F = 3.7 Hz, CH), 128.5 (CH of Ph), 128.5 (2 CH of Ph), 128.8
(CH of Ph), 128.8 (CH of Ph), 129.6 (CH of 2 Me–Ph), 131.7 (CH
2
112.1 (d, JC–F = 16.0 Hz, C next to CF), 114.5 (4 CH of PentO–
4
of 2 Me–Ph), 131.9 (CH of 2 Me–Ph), 133.0 (d, JC–F = 2.0 Hz,
Ph), 114.6 (C of PentO–Ph), 114.7 (C of PentO–Ph), 118.2 (d,
1
CH), 140.5 (C), 162.1 (d, JC–F = 250.0 Hz, CF) ppm. 19F NMR
2JC–F = 22.0 Hz, CH next to CF), 124.9 (d, 3JC–F = 9.0 Hz, C next
(282.4 MHz, CDCl3): δ = –109.5 (t, CF) ppm. IR (ATR): ν = 3053
˜
3
to alkyne), 127.2 (d, JC–F = 3.0 Hz, CH), 133.2 (2 CH of PentO–
(w), 3016 (w), 2922 (w), 2733 (w), 1609 (m), 1596 (m), 1509 (m),
1413 (m), 1206 (m), 1155 (m), 1088 (m), 952 (m), 818 (m), 791 (w),
751 (s), 684 (s), 612 (m), 526 (m), 453 (w) cm–1. GC–MS (EI,
70 eV): m/z (%) = 310 (100) [M]+, 309 (31), 308 (10), 307 (21), 289
(11). HRMS: calcd. for C22H12F2 [M]+ 310.11523; found
310.11527. C22H12F2 (310.364): calcd. C 89.01, H 4.87; found C
89.20, H 4.81.
4
Ph), 133.3 (2 CH of PentO–Ph), 133.2 (d, JC–F = 2.0 Hz, CH),
159.7 (C, PentO), 162.0 (d, 1JC–F = 250.0 Hz, CF) ppm. 19F NMR
(282.4 MHz, CDCl ): δ = –110.1 (t, CF) ppm. IR (ATR): ν = 2955
˜
3
(w), 2929 (m), 2870 (m), 2216 (m), 1603 (m), 1566 (w), 1516 (m),
1467 (m), 1416 (m), 1285 (s), 1248 (s), 1211 (s), 1172 (s), 1049 (m),
983 (m), 955 (m), 866 (m), 828 (s), 621 (m), 534 (m), 418 (w) cm–1.
GC–MS (EI, 70 eV): m/z (%) = 468 (67) [M]+, 398 (17), 329 (22),
328 (100), 327 (16), 299 (13), 55 (14). HRMS: calcd. for C32H33O2F
[M]+ 468.24591; found 468.24541. C32H33O2F (468.602): calcd. C
82.02, H 7.10; found C 81.94, H 7.04.
1-[2-(4-tert-Butylphenyl)ethynyl]-2-fluoro-4-(2-phenylethynyl)benz-
ene (5c): Starting with 3a (275 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg,
3 mol-%), CuI (5.7 mg, 3 mol-%), 2e (0.174 g, 1.1 mmol), Et3N
(0.28 mL, 2.0 mmol), and THF (2.0 mL), 5c was isolated as a col-
orless solid (0.198 g, 56%); m.p. 144–146 °C, RF = 0.32 (hexane/
General Procedure for the Synthesis of 5a–e: A suspension of substi-
tuted 3, Pd(PPh3)4 (3 mol-%), and CuI (3 mol-%) in THF (3 mL/
Eur. J. Org. Chem. 2012, 604–615
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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613

P. Langer et al.
CH2Cl2 = 5:1). 1H NMR (300 MHz, CDCl3): δ = 1.24 (s, 9 H, (m), 1172 (s), 1031 (s), 810 (s), 524 (s), 457 (m), 393 (w) cm–1. GC–
FULL PAPER
tBu), 7.17–7.22 (m, 2 H), 7.26–7.32 (m, 6 H), 7.37–7.49 (m, 4 H)
MS (EI, 70 eV): m/z (%) = 340 (100) [M]+, 325 (28), 297 (11), 170
ppm. 13C NMR (100 MHz, CDCl3): δ = 31.5 (CH3, tBu), 35.3 (C (11.8). HRMS: calcd. for C24H17OF [M]+ 340.12579; found
of tBu), 82.4 (C of alkyne), 87.9 (C of alkyne), 92.6 (C of alkyne), 340.12593.
96.6 (C of alkyne), 112.5 (d, 2JC–F = 23.3 Hz, C next to CF), 118.8
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra, DFT-calculated structures.
2
(d, JC–F = 23.3 Hz, CH next to CF), 119.6 (C of tBu–Ph), 124.7
3
(d, JC–F = 8.7 Hz, 1 C), 125.8 (2 CH of tBu–Ph), 125.9 (3 CH of
3
Ph), 127.5 (d, JC–F = 4.1 Hz, CH), 131.8 (2CH of tBu–Ph), 131.9
4
(2CH of Ph), 133.5 (d, JC–F = 2.7 Hz, CH), 152.5 (2C of
Acknowledgments
tBu),162.6 (d, 1JC–F = 250.0 Hz, CF) ppm. 19F NMR (282.4 MHz,
CDCl ): δ = –109.6 (t, CF) ppm. IR (ATR): ν = 3055 (w), 2959
˜
The authors would like to thank PD Dr. R. Schumann (Depart-
ment of Biology, University of Rostock), A. Lehmann and L. R.
Knöpke (Leibniz Institute for Catalysis e.V. at the University of
Rostock) for the opportunity to measure absorption and emission
spectra and for scientific discussions. Furthermore we would like
to thank A. Weihs for measuring the DSC spectra. S. R. gratefully
acknowledges the University of Rostock (scholarship of the inter-
disciplinary faculty of the University of Rostock/Dept. LLM) and
the State of Mecklenburg-Vorpommern for financial support.
3
(w), 2901 (w), 2866 (w), 1612 (w), 1541 (w), 1415 (m), 1362 (m),
1330 (w), 1267 (m), 1107 (m), 1092 (m), 1015 (w), 864 (m), 833 (s),
751 (s), 685 (s), 670 (w), 560 (s), 526 (m), 430 (w) cm–1. GC–MS
(EI, 70 eV): m/z (%) = 352 (89) [M]+, 338 (27), 337 (100), 322 (10),
309 (14), 296 (11), 186 (14), 154 (30). HRMS: calcd. for C26H21F
[M]+ 352.16218; found 352.16211. C26H21F (352.443): calcd. C
88.60, H 6.01; found C 89.01, H 6.41.
1-[2-(4-tert-Butylphenyl)ethynyl]-2-fluoro-4-[2-(4-methylphenyl)eth-
ynyl]benzene (5d): Starting with 3b (287 mg, 1.0 mmol), Pd(PPh3)4
(34.6 mg, 3 mol-%), CuI (5.7 mg, 3 mol-%), 2e (0.174 g, 1.1 mmol),
Et3N (0.28 mL, 2.0 mmol), and THF (2.0 mL), 5d was isolated as a
colorless solid (0.194 g, 53%); m.p. 179–180 °C, RF = 0.31 (hexane/
CH2Cl2 = 4:1). 1H NMR (300 MHz, CDCl3): δ = 1.33 (s, 9 H,
tBu), 2.38 (s, 3 H, CH3), 7.17 (d, 3JH–H = 7.7 Hz, 2 H of 4 Me–Ph),
7.23–7.30 (m, 1 H), 7.36–7.51 (m, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.6 (CH3 of Me–Ph), 31.2 (CH3 of tBu), 34.9 (C of
tBu), 82.0 (C of alkyne), 87.5 (d, 3JC–F = 4.8 Hz, C of alkyne), 92.2
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2
(C of alkyne), 96.3 (d, JC–F = 3.0 Hz, C of alkyne), 112.1 (d, JC–
2
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3
=
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Ph), 131.4 (CH of Me–Ph), 131.4 (CH of Me–Ph), 131.6 (CH of
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1
139.0 (C of Me–Ph), 152.2 (C of tBu–Ph),162.6 (d, JC–F
=
249.8 Hz, CF) ppm. 19F NMR (282.4 MHz, CDCl3): δ = –109.8 (t,
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˜
1603 (w), 1515 (w), 1362 (m), 1267 (m), 1212 (m), 1106 (m), 956
(m), 1014 (m), 868 (m), 832 (s), 818 (s), 749 (s), 620 (m), 560 (m),
529 (w), 463 (w), 395 (w) cm–1. GC–MS (EI, 70 eV): m/z (%) = 366
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calcd. for C27H23F [M]+ 366.17783; found 366.17798. C27H23
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F
2-Fluoro-1-[2-(4-methoxyphenyl)ethynyl]-4-[2-(4-methylphenyl)eth-
ynyl]benzene (5e): Starting with 3b (287 mg, 1.0 mmol), Pd(PPh3)4
(34.6 mg, 3 mol-%), CuI (5.7 mg, 3 mol-%), 2f (0.129 g, 1.1 mmol),
Et3N (0.28 mL, 2.0 mmol), and THF (2.0 mL), 5e was isolated as
a colorless solid (0.233 g, 68%); m.p. 182 °C, RF = 0.56 (heptane/
ethyl acetate = 4:1). 1H NMR (300 MHz, CDCl3): δ = 2.38 (s, 3 H,
3
CH3), 3.84 (s, 3 H, OCH3), 6.89 (d, JH–H = 9.3 Hz, 2 H of 4
Me–Ph), 7.15–7.28 (m, 3 H), 7.40–7.53 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.6 (CH3), 55.4 (MeO), 81.4 (C of alkyne),
3
87.5 (d, JC–F = 4.9 Hz, C of alkyne), 92.2 (C of alkyne), 96.2 (d,
2
4JC–F = 2.8 Hz, C of alkyne), 112.2 (d, JC–F = 16.3 Hz, C next to
CF), 112.2 (CH of MeO–Ph), 112.3 (CH of MeO–Ph), 114.9 (C of
2
MeO–Ph), 118.4 (d, JC–F = 21.0 Hz, CH next to CF), 119.6 (C of
3
3
Me–Ph), 124.7 (d, JC–F = 8.1 Hz, C), 127.3 (d, JC–F = 4.0 Hz,
CH), 129.2 (2 CH of Me–Ph), 131.6 (2 CH of MeO–Ph), 133.1 (d,
4JC–F = 2.7 Hz, CH), 133.3 (2 CH of Me–Ph), 139.1 (C of Me–Ph),
160 (C of MeO–Ph) ppm. 19F NMR (282.4 MHz, CDCl3): δ =
–110.0 (t, CF) ppm. IR (ATR): ν = 3023 (w), 2919 (w), 2853 (w),
˜
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Received: March 22, 2011
Published Online: November 24, 2011
Eur. J. Org. Chem. 2012, 604–615
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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