Site-selective Sonogashira reactions of 1,2-dibromo-3,5-difluorobenzene

Article abstract of DOI:10.1016/j.catcom.2012.03.022

A variety of mono- and diethynyl substituted fluorinated benzene derivatives was prepared by Sonogashira cross coupling reactions of 1,2-dibromo-3,5-difluorobenzene. The reactions proceed with very good site-selectivity in favor of position 1, due to elec

Full text of DOI:10.1016/j.catcom.2012.03.022

Catalysis Communications 25 (2012) 142–147
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Catalysis Communications
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Short Communication
Site-selective Sonogashira reactions of 1,2-dibromo-3,5-difluorobenzene
Sebastian Reimann a,b, Peter Ehlers a,b, Muhammad Sharif a,b, Kai Wittler c, Anke Spannenberg b,
Ralf Ludwig b,c, Peter Langer a,b,
⁎
a
Department of Chemistry, University of Rostock, Albert-Einstein-Str. 3a, D-18059 Rostock, Germany
Leibniz Institute for Catalysis e.V. at the University of Rostock (LIKAT), Albert-Einstein-Str. 3a, D-18059 Rostock, Germany
Department of Chemistry, Physical and Theoretical Chemistry, University of Rostock, Dr.-Lorenz-Weg 1, D-18059 Rostock, Germany
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of mono- and diethynyl substituted fluorinated benzene derivatives was prepared by Sonogashira
cross coupling reactions of 1,2-dibromo-3,5-difluorobenzene. The reactions proceed with very good site-
selectivity in favor of position 1, due to electronic and steric reasons.
Received 11 November 2011
Received in revised form 29 February 2012
Accepted 15 March 2012
© 2012 Elsevier B.V. All rights reserved.
Available online 28 March 2012
Keywords:
Catalysis
Palladium
Sonogashira reaction
Regioselectivity
Fluorine compounds
1. Introduction
and of other polyhalogenated heterocycles have also been studied
[10]. Site-selective Sonogashira reactions of dibromides, diiodides or
The unique properties of fluorine-containing arenes and hetarenes
are of considerable importance in organic, medicinal and agricultural
chemistry and play an important role as lead compounds [1]. The
fluorine atom combines high electronegativity with a small size.
Hereby, the replacement of hydrogen by fluorine in organic molecules
has often led to dramatic changes in their physico-chemical and bio-
logical properties [2]. This has a drastic effect on the overall electronic
distribution within the molecule thereby affecting dipole moments
and the acidity, basicity or activity of neighboring groups; any of
which can affect molecular interactions with receptors or other inter-
acting molecules [3]. Moreover, fluorinated arenes- and hetarenes are
useful substrates in transition metal-catalyzed cross-coupling reac-
tions [4]. Aryl fluorides are used as ligands [5] in catalytic reactions
and as organocatalysts [6].
In recent years, a number of site-selective palladium(0)-catalyzed
cross coupling reactions of polyhalogenated heterocycles have been de-
veloped. The site-selectivity of these reactions is generally influenced by
electronic and steric parameters [7,8]. For example, our group has
reported site-selective palladium(0)-catalyzed cross-coupling reactions
of tetrachloropyrimidine, N-methyltetrabromo-pyrrole and tetrabro-
moselenophene [9]. Site-selective Suzuki–Miyaura reactions of 2,3,5-
tribromoinden-1-one, tribromopyrazoles, tetrabrominated thiophene
bis(triflates) of fluorinated arenes have, to the best of our knowledge,
not been reported to date. Herein, we report the results of our study re-
lated to site-selective Sonogashira reactions of 1,2-dibromo-3,5-difluor-
obenzene. These reactions provide a convenient approach to various
fluorinated mono- and dialkynylbenzenes which have, to the best of
our knowledge, not been previously prepared.
2. Results and discussion
The Sonogashira reaction of commercially available 1,2-dibromo-3,5-
difluorobenzene 1 with different substituted acetylenes 2a-q (1.0 equiv.)
afforded the corresponding 1-alkynyl-substituted 2-bromo-3,5-difluoro-
benzene derivates 3a-q in moderate to good yields (Scheme 1, Table 1).
The best yields were obtained using 1.0 equivalent of the alkyne,
Pd(PPh3)4 (3 mol%) as the catalyst and Et3N (2.0 equiv) as the base
(THF, 60 °C, 6 h). The formation of the opposite isomer was not observed.
The yields depend on the type of acetylene 2 employed. No significant
changes in yields could be observed for para-substituted electron-
donating, electron-withdrawing, and ortho- and meta-substituted
alkynes. The yield of compound 3o decreased to 35% when hept-1-yne
2o was employed (Table 1). However, the successful use of a broad
range of different acetylenes in this kind of reaction was successfully
shown.
The Sonogashira reaction of 1 with 2.1 equiv. of alkynes 2a-f,j,l,r
afforded the symmetrical ortho-substituted ethynylated fluoroben-
zenes 4a-i (Scheme 2, Table 2). The best yields were obtained using
⁎
Corresponding author at: Department of Chemistry, University of Rostock, Albert-
Einstein-Str. 3a, D-18059 Rostock, Germany.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2012.03.022

S. Reimann et al. / Catalysis Communications 25 (2012) 142–147
143
Scheme 2. Synthesis of 4a-i. Conditions and reagents: (i): 1 (1.0 equiv), 2 (2.1 equiv),
Et3N (2.5 equiv), Pd(PPh3)4 (3 mol %), CuI (3 mol %), THF, 60 °C, 6 h.
Scheme 1. Synthesis of 3a-q. Conditions: (i): 1 (1.0 equiv), 2a-q (1.0 equiv), Et3N (2.0
equiv), Pd(PPh3)4 (3 mol %), CuI (3 mol %), THF, 60 °C, 6 h.
2.1 equiv. of the alkyne, Pd(PPh3)4 (3 mol %) as the catalyst, CuI
(3 mol %) and Et3N (2.5 equiv) as the base (THF, 60 °C, 6 h). The yields
of disubstituted ethynyl-fluorobenzenes 4 were not significantly
influenced by the para-substituent of the acetylene, while ortho-
and meta-substituents resulted in lower yields (Table 2).
The synthesis of unsymmetrical ortho-substituted ethynylated
fluorobenzenes was next studied. The Sonogashira reaction of selected
ethynyl-substituted 2-bromo-3,5-difluorobenzenes 3 with 1.1 equiv.
of different substituted acetylenes 2 yielded ortho-substituted ethynyl-
fluorobenzenes 5a-f bearing different ethynyl moieties (Scheme 3,
Table 3).
The opposite regioisomer with a long range coupling over three bonds
for carbon atom C-7 in the range of 8.0 Hz and for carbon atom C-8 in
the range of 3.0 Hz could not be detected. Carbon atom C-2 (C-Br) res-
onated as a doublet of doublet in the range of 128.0 ppm and showed
a typical coupling to the fluorine atom F2 with a coupling constant of
2JC-F=22.0 Hz and a coupling to the fluorine atom F1 with a coupling
4
constant of JC-F=4.0 Hz (Scheme 4).
The structure of 3a is independently confirmed by X-ray crystal
structure analysis which unambiguously proves the constitution of
the molecule (Fig. 1) and shows a planar constitution of the mono-
substituted ethynyl benzene [11].
The structures of all products were confirmed by spectroscopic
methods. In addition, high resolution 13C NMR spectroscopy confirmed
the site-selectivity of these reactions. Carbon atom C-7 of the alkyne
moiety showed a long range coupling with the fluorine atom (F1 and
F2) over four bonds with a coupling constant of 4JC-F=4.0 Hz which ap-
pear as two doublets. No coupling was observed for carbon atom C-8.
The site-selective formation of 3a-p and 5a-f can be explained by
electronic and steric reasons. The first attack of palladium (0)-catalyzed
cross-coupling reactions generally occurs at the more electronic defi-
cient and sterically less hindered position [12,13]. Position 1 of 1,2-
dibromo-3,5-difluorobenzene (1) is sterically less hindered because it
is located next to a hydrogen and bromine atom, while position 2 is
located next to a fluorine- and bromine atom (cf. Scheme 5). In addition,
position 1 (located meta to the fluorine atom) is more electron deficient
than position 2 (located ortho to the fluorine atom), due to the π-
donating effect of the fluorine atom. The same observations were
made for the synthesis of fluorinated terphenyls by site-selective
Suzuki–Miyaura reactions of halogenated fluorobenzenes [14,15].
In addition, this assumption could be confirmed by Density Func-
tional Theory calculations (DFT) at the B3LYP level of theory using a
6–31 G* basis set. In compound 1 the C-1–Br bond is lengthened by
about 0.7 pm compared to the C-2―Br bond with the neighboured
fluorine atom (189.7 pm vs. 189.0 pm). Of course, the lengthening
indicates a weaker C-1―Br bond, which can be preferentially attacked
Table 1
Synthesis of 3a-q.
2,3
R
% (3)a
70
a
b
c
d
e
f
69
67
66
72
66
75
56
59
69
63
Table 2
Synthesis of 4a-i.
4
2
R
% (4)a
56
a
a
g
h
i
b
c
b
c
d
e
f
53
62
56
56
57
69
42
d
e
f
j
k
l
61
42
g
h
j
r
m
n
o
p
q
47
35
59
59
i
l
43
a
a
Yields of isolated products.
Yields of isolated products.

144
S. Reimann et al. / Catalysis Communications 25 (2012) 142–147
Scheme 3. Synthesis of 5a-f. Conditions and reagents: (i): 3 (1.0 equiv), 2 (1.1 equiv),
Et3N (2.0 equiv), Pd(PPh3)4 (3 mol %), CuI (3 mol %), THF, 60 °C, 6 h.
Scheme 4. Numbering of compound 3 (left) and of the opposite regioisomer (not ob-
served, right).
(cf. Fig. 2). Also the calculated natural charges from Natural Bond
Orbital analysis (NBO) support this view (Fig. 3). The NBO-charges at
the reactive centers in compound 1 indicate that carbon atom C-1
carries only half of the charge than the carbon atom C-2 (C-1=
−0.116 [a.u.] vs. C-2=−0.227 [a.u.] ). It is well known from literature
that the less electronegative position which is the C-1 carbon in com-
pound 1 will be attacked preferentially. Furthermore the NBO analysis
shows that the higher charge at carbon C-2 is related to the charge
transfer from the neighboured fluorine atom which strongly donates
charge from its lone-pairs into the C-2―C anti-bond orbital. The charge
transfer weakens the C-2―C bond but strengthens the neighboured
C-2―Br bond leading to shorter bond length relative to that of the
C-1―Br bond. Of course, this effect is stronger for the fluorine atoms
located in ortho/para position (cf. Fig. 3). A crude estimate of the
C―Br bond strength can be obtained from the calculated energy differ-
ences (isodesmic reaction) between 1-bromo-2,4-fluorobenzene and 1-
bromo-3,5-fluorobenzene. The latter compound has a 5.0 kJ mol−1
lower energy explaining its higher reactivity empirically.
calculations (NBO, isodesmic reaction). The application of the concept
outlined herein to other fluorinated arenes is currently studied in our
laboratories.
3. Experimental section
3.1. General
All reactions were carried out in oven-dried reaction pressure tubes
under Argon atmosphere. Tetrakis(triphenylphosphine)palladium(0)
was purchased from a commercial source (ABCR). 1,2-Dibromo-3,5-
difluorobenzene (TCI), copper iodide (Acros) and the corresponding
alkynes (Acros, AlfaAesar, TCI) were purchased from a commercial
source. Solvent (THF) was distilled and purged with argon before use.
Triethylamine (Et3N) was purchased from a commercial source (Acros)
and purged with argon before use. Thin layer chromatography (TLC)
was run on Merck precoated aluminium plates (Si 60F254). Column
chromatography was performed using Merck Silicagel 60 (0.043–
0.06 mm). NMR data were recorded on a Bruker ARX 300 and Bruker
ARX 400 spectrometers. 13C- and 1H-NMR spectra were referenced to
signals of deutero solvents, respectively. Gas chromatography-mass anal-
ysis was carried out on an Agilent HP-5890 instrument with an Agilent
HP-5973 Mass Selective Detector (EI) and HP-5 capillary column using
helium carrier gas. ESI HR-MS measurements were performed on an
Agilent 1969A TOF mass-spectrometer.
2.1. Conclusions
In conclusion, we demonstrated an easy and applicable route for the
versatile synthesis of mono- and disubstituted ethynyl-fluorobenzenes
by site-selective Sonogashira reactions of 1,2-dibromo-3,5-difluoroben-
zene. The site-selectivity in favor of position 1 can be explained by elec-
tronic and steric reasons and was confirmed by X-ray structure analysis,
high resolution 13C NMR spectroscopy and Density Functional Theory
Table 3
Synthesis of 5a-f.
5
3
2
R1
R2
% (5)a
60
a
a
b
b
c
d
e
f
a
b
b
c
f
61
55
62
55
58
a
c
a
b
c
a
Yields of isolated products.

S. Reimann et al. / Catalysis Communications 25 (2012) 142–147
145
Fig. 2. B3LYP/ 6–31G* calculated structures. The bond lengths are given in ppm.
3.3. General procedure for the synthesis of 3a-q
A suspension of 1,2-dibromo-3,5-difluorobenzene 1, Pd(PPh3)4
(3 mol %), CuI ( 3 mol %) in THF (3 mL/mmol 1) was degassed by bub-
bling argon through the solution for 10 minutes in a oven dried pressure
tube. The acetylene 2 (1.0 equiv.) and finally triethylamine (2.0 equiv.)
were added by syringe. The mixture was heated at 60 °C for 6 h. After
cooling to room temperature the organic and aqueous layer were sepa-
rated and the latter was extracted with CH2Cl2 (3×25 mL). The com-
bined organic layers were dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo. The product was purified by column chromatog-
raphy (silica gel, EtOAc/heptane).
Fig. 1. ORTEP drawing of 3a. Displacement ellipsoids are drawn at the 30% probability
level.
X-ray crystal structure analysis of 3a: Data were collected on a STOE
IPDS II diffractometer using graphite-monochromated Mo Kα radiation.
The structure was solved by direct methods and refined by full-matrix
least-squares procedures on F2 with the SHELXTL software package
(G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112–122.). XP (Bruker
AXS) was used for graphical representation. crystal data: C14H7BrF2,
ꢀ
M=293.11, triclinic, space group P1, a=6.8718(4), b=7.3507(5),
3.4. 2-bromo-3,5-difluorophenyl-1-ethynylbenzene (3a)
c=12.0591(8) Å, α=80.181(5), β=79.038(5), γ=74.648(5)°,
V=572.02(6) Å3, T=150(2) K, Z=2, μ=3.59 mm−1, 9493 reflections
measured, 2633 independent reflections (Rint=0.0347), final R values
(I>2σ(I)): R1=0.028, wR2=0.0562, final R values (all data): R1=
0.0398, wR2=0.0588, 154 refined parameters. CCDC−… contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Starting with
1 (271.9 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg,
3 mol%), CuI (5.7 mg, 3 mol%), ethynylbenzene 2a (0.11 mL,
1.0 mmol), Et3N (0.28 mL, 2.0 mmol) and THF (3.0 mL), 3a was isolat-
ed by column chromatography (heptane) as a colorless solid (0.203 g,
70%); mp=71–72 °C. 1H NMR (300 MHz, CDCl3): δ=7.78 (dt, 3J=
8.4 Hz, 4 J=2.8 Hz, 1H, CH), 7.63–7.68 (ddd, J=1.5 Hz, JH-H
=
4
3
5
2.9 Hz, JH-F =8.6 Hz, JH-F =1.5 Hz, 1H, CH), 7.25–7.33 (m, 3H,
CHPh), 7.46–7.52 (m, 2H, CHPh). 13C NMR (75 MHz, CDCl3): δ=86.2
4
3
3.2. Calculations
(dd, JC-F =4.0 Hz, Calkyne), 96.1 (Calkyne), 105.0 (t, JC-F =26.0 Hz,
CH), 107.9 (dd, 2J=22.0 Hz, JC-F =4.0 Hz, C-Br) 115.6 (dd, JC-F
=
4
3
5
4
Geometry optimizations have been carried out using the Gaussian
03 programme package. We used the B3LYP method including 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 indicating that all geometries represent at
least local minimum structures on the potential energy surface. For
all structures the calculations have been performed with 6–31 G*
basis set implemented in Gaussian 03 [16]. Additionally we calculated
the natural atomic charges by applying the NBO program as imple-
mented in Gaussian 03. All calculations have been carried out on
the HPPC-Cluster in Rostock.
24.0 Hz, JC-F =4.0 Hz, CH), 122.0 (CPh), 128.0 (dd, JCF =12.0 Hz,
4JC-F =12.0 Hz, C) 128.5, 129.3, 131.9 (CHPh), 159.5 (dd, 1 J=
247.0 Hz, 4 J=12.0 Hz, C-F), 161.3 (dd, 1 J=248.0 Hz, 4 J=13.0 Hz,
C-F). 19 F NMR (282.4 MHz, CDCl3): δ=−99.19 (F-2), -110.78 (F-1).
IR (ATR, cm-1): = 3084 (w), 3020 (w), 2918 (w), 2849 (w), 2209
(w), 1578 (s), 1489 (w), 1461 (w), 1440 (s), 1416 (s), 1356 (m), 1275
(w), 1228 (w), 1170 (w), 1122 (s), 996 (m), 980 (w), 913 (w), 857
(m), 835 (m), 750 (s), 685 (s), 599 (s), 566 (w), 524 (s). MS (EI,
70 eV): m/z (%)=292 (M+, 100), 212 (38), 193 (21), 173 (4), 106
(7), 96 (3). HRMS (EI, 70 eV): calcd. for C14H7BrF2 291.96937, found
291.969201. Anal. calcd. for C14H7BrF2 (293.11): C, 57.37; H, 2.41.
Found: C, 57.34; H, 2.654.
Scheme 5. Possible explanation for the site-selectivity of cross-coupling reactions of 1.

146
S. Reimann et al. / Catalysis Communications 25 (2012) 142–147
1.1 mmol), Et3N (0.28 mL, 2.0 mmol) and THF (3.0 mL), 5a was isolated
by column chromatography (heptane) as a slightly yellowish oil (0.210 g,
3
61%). 1H NMR (300 MHz, CDCl3): δ=2.28 (s, 3H, CH3), 6.76 (dt, JHF
=
8.9 Hz, 4 J=2.4 Hz, 1H, CH), 6.99 (ddd, JH-F=8.9 Hz, JH-H=2.4 Hz,
5JH-F=1.3 Hz, 1H, CH), 7.07 (d, 3J=8.1 Hz, 7.05–7.11 (m, 2H, CH),
7.25–7.31 (m, 3H, CH) 7.38 (d, 3J=8.1 Hz, 2H, CH), 7.45–7.50. 13C
NMR (75 MHz, CDCl3): δ=21.6 (CH3), 80.2 (d, 5J=1.7 Hz, Calkyne),
86.4 (t, 4J=4.5 Hz, Calkyne), 95.5 (Calkyne), 98.6 (Calkyne), 104.5 (d,
3
4
2
4
2JCF=25.7 Hz, CH), 114.5 (dd, JC-F=23.2 Hz, JC-F=3.8 Hz, CH),
119.8, 122.4 (C), 128.5, 129.0, 129.1, 131.6, 131.8 (CH), 132.4, 139.0
(C), 161.5 (dd, 1J=250.8 Hz, 3J=13.3 Hz, C-F), 162.8 (dd, 1J=
252.8 Hz, 3J=13.9 Hz, C-F). 19F NMR (282.4 MHz, CDCl3): δ=
−104.03 (F-2), -107.85 (F-1). IR (ATR, cm-1):=3082 (w), 3059 (w),
3028 (w), 2916 (w), 2854 (w), 2206 (m), 1608 (m), 1572 (s), 1511
(s), 1468 (m), 1430 (m), 1360 (m), 1283 (m), 1229 (s), 1168 (s),
1132 (w), 1114 (s), 1071 (w), 1007 (m), 930 (m), 857 (m), 830 (m),
818 (s), 756 (s), 729 (m), 690 (s), 603 (m), 568 (m), 531 (m), 461
(m). MS (EI, 70 eV): m/z (%)=328 (M+, 100), 327 (25), 326 (11),
325 (27), 312 (22). HRMS (EI, 70 eV): calcd. for C23H14F2 328.35407,
found 328.353998. Anal. calcd. for C23H14F2 (328.35): C, 84.13; H,
4.30. Found: C, 84.19; H, 4.488.
Fig. 3. NBO Natural Charges calculated on the B3LYP/6-31 G* optimized structures. The
charges are given in units of e (elementary charge).
3.5. General procedure for the synthesis of 4a-i
A suspension of 1,2-dibromo-3,5-difluorobenzene 1, Pd(PPh3)4
(3 mol%), CuI ( 3 mol%) in THF (3 mL/mmol 1) was degassed by bub-
bling argon through the solution for 10 minutes in a oven dried pressure
tube. The acetylene 2 (2.1 equiv.) and finally triethylamine (2.5 equiv.)
were added by syringe. The mixture was heated at 60 °C for 6 h. After
cooling to room temperature the organic and aqueous layer were sepa-
rated and the latter was extracted with CH2Cl2 (3×25 mL). The com-
bined organic layers were dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo. The product was purified by column chromatog-
raphy (silica gel, EtOAc/heptane).
Acknowledgements
S. Reimann would like to acknowledge gratefully the University of
Rostock (scholarship of the interdisciplinary faculty of the University
of Rostock/Dept. LLM) and the state of Mecklenburg-Vorpommern for
financial support. P. Ehlers would like to acknowledge the state of
Mecklenburg-Vorpommern for financial support.
3.6. 3,5-difluoro-1,2-(phenylethynyl)benzene (4a)
Starting with 1 (271.9 mg, 1.0 mmol), Pd(PPh3)4 (34.6 mg, 3 mol-%),
CuI (5.7 mg, 3 mol-%), ethynylbenzene 2a (0.23 mL, 2.1 mmol), Et3N
(0.35 mL, 2.5 mmol) and THF (3.0 mL), 3a was isolated by column chro-
matography (heptane) as a slightly yellowish oil (0.176 g, 56%). 1H NMR
(300 MHz, CDCl3): δ=6.77 (dt, 3J=8.9 Hz, 4J=2.6 Hz, 1H, CH),
References
3
4
5
7.63–7.68 (ddd, J=1.5 Hz, JH-H =8.8 Hz, JH-F =2.5 Hz, JH-F =1.3 Hz,
1H, CH), 7.21–7.32 (m, 6H, CHPh), 7.43–7.52 (m, 4H, CHPh). 13C NMR
(75 MHz, CDCl3): δ=80.8 (d, 5 J=1.5 Hz, Calkyne), 86.3 (t, 4J=4.0 Hz,
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2
4
2
4
(dd, JC-F =21.2 Hz, JC-F =3.8 Hz, C), 114.0 (dd, JC-F =24.1 Hz, JC-F
=
3.5 Hz, CH), 122.4 (C), 122.8 (C), 128.4 (CH), 128.7 (C),128.5, 128.8,
129.6, 131.7, 131.8 (CH-Ar), 161.5 (dd, 1J=250.9 Hz, 3 J=13.4 Hz, C-F),
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CDCl3): δ=−103.87 (F-2), -107.45 (F-1). IR (ATR, cm−1): = 3084 (w),
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599 (s), 566 (m), 523 (m). MS (EI, 70 eV): m/z (%)=314 (M+, 100),
294 (10), 288 (5), 273 (2), 236 (2), 156 (8). HRMS (EI, 70 eV): calcd.
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A suspension of substituted ethynyl-fluorobenzenes 3 (1.0 equiv.),
Pd(PPh3)4 (3 mol %), CuI ( 3 mol %) in THF (3 mL/mmol 3) was
degassed by bubbling argon through the solution for 10 min in an
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the following address: Cambridge Crystallographic Data Centre, 12 Union Road, GB-
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