The synthesis of novel highly substituted benzene derivatives for use in palladium-catalysed cross-coupling reactions

Article abstract of DOI:10.1039/a804525i

A combination of conventional electrophilic aromatic substitution reactions and low-temperature ortho-directed lithiations has been used in the efficient synthesis of some novel highly substituted benzene derivatives containing alkoxy, alkyl, bromo, cyano

Full text of DOI:10.1039/a804525i

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The synthesis of novel highly substituted benzene derivatives for
use in palladium-catalysed cross-coupling reactions
Michael Hird, Robert A. Lewis, Kenneth J. Toyne, Jonathan J. West and Michael K. Wilson
Department of Chemistry, University of Hull, Hull, UK HU6 7RX
Received (in Cambridge) 15th June 1998, Accepted 4th September 1998
A combination of conventional electrophilic aromatic substitution reactions and low-temperature ortho-directed
lithiations has been used in the efficient synthesis of some novel highly substituted benzene derivatives containing
alkoxy, alkyl, bromo, cyano, fluoro and iodo functions. The use of such compounds is exemplified by selective
palladium-catalysed cross-coupling reactions to generate a series of liquid crystalline terphenyls with a lateral
fluoro substituent ortho to a lateral cyano group.
One aspect of our research on the synthesis of liquid crystals
Introduction
requires compounds (e.g. 27–30, 35 and 36) with a nitrile group
located next to a fluoro substituent to achieve a large lateral
dipole; such materials are expected to confer a high dielectric
biaxiality to ferroelectric mixtures.37,38 The preparation of these
liquid crystals required the synthesis of benzene intermediates
with four different substituents (compounds 19–24). Starting
materials 1–6 have been reported previously31,39 and have two
or three aromatic protons that are acidic. In each case the
presence of bromo and iodo substituents precludes the use of
butyllithium, which could undergo halogen–metal exchange
instead of hydrogen–metal exchange, whereas lithium diiso-
propylamide circumvents such problems and only gives
hydrogen–metal exchange.21 This paper explores the selectivity
of lithium diisopropylamide metallation in such compounds.
Palladium-catalysed cross-coupling reactions1–6 have revolu-
tionised the synthetic routes to aryl systems in many areas such
as liquid crystals,7–11 pharmaceuticals,12–15 natural products16
and polymers.17–20 The modern synthetic methodology often
requires apparently simple substituted benzene units in a
convergent synthetic strategy and yet, surprisingly, such units
have frequently not been reported. The difficulty in the syn-
thesis of highly substituted benzene units, arises because the
substituent(s) initially present may direct an electrophile to an
undesired position, or prevent a reaction through deactivation
and/or by steric hindrance. The methods and intermediates
reported here are useful generally in providing units suitable for
inclusion in pharmaceuticals, liquid crystals and oligomeric and
polymeric light-emitting systems. In addition to sites for select-
ive coupling, the benzene unit requires the presence of other
substituents to give the properties required of the final material.
In the work reported here, bromo and iodo leaving groups and
the boronic acid unit have been employed for the coupling
reactions, and alkoxy, alkyl, cyano and fluoro substituents
provide the desired properties in a selection of liquid crystals.
A discussion of the liquid crystal properties of the lateral
cyanofluoroterphenyls will be published later as part of a larger
programme of work.
One useful method for introducing functional units into an
aromatic ring, which complements electrophilic substitution
and may circumvent any limitations, is through hydrogen–metal
exchange reactions.7,21–29 Such metallation techniques are, of
course, only feasible where a proton is sufficiently acidic to be
removed by a convenient base such as butyllithium or lithium
diisopropylamide (LDA). Iodo and bromo substituents are
employed as the sites for palladium-catalysed cross-coupling
reactions and further substituents provide the required proper-
ties of the final materials. For example, a fluoro substituent
is often present to generate the required mesomorphic and
dielectric properties of liquid crystals for commercial display
devices,7,30–33 or to provide enhanced biological activity and
reduced side effects in pharmaceuticals,22,34–36 and alkyl and
alkoxy chains are essential features of viable liquid crystals,7
and they give greater processability to light-emitting
polymers.17–20 All of the halogeno units mentioned above are of
great significance because they can render the neighbouring
protons acidic, and hence enable the introduction of a wide
range of moieties either directly (e.g. aldehyde, carboxylic acid,
halogens, boronic acid) or through subsequent functional
group interconversions (e.g. amide, amine, nitrile, phenol, aryl,
alkyl).7,21–29
Results and discussion
All three aromatic protons of compound 1 are acidic, but
the proton between the reinforcing influences of the fluoro
substituent and the alkoxy chain proved, as expected, to be the
most acidic. Treatment of compound 1 with LDA (prepared in
situ from diisopropylamine and n-butyllithium)28,40 produced
an aryllithium salt which was quenched with carbon dioxide
to give carboxylic acid 7 on acidification (Scheme 1). In com-
pound 2, the reinforcing effects of the fluoro and bromo
substituents make the proton between the two units most acidic
and allowed the efficient preparation of the desired carboxylic
acid 8. There are similar acidity-reinforcing effects of two
substituents in compounds 4–6, which allowed the generation
of compounds 10–12 in good yields. The issue for compound 3
is less clear-cut because there is not a proton between two
acidity-promoting units and the pentyl chain could reduce the
tendency for proton abstraction next to the fluoro substituent
by its inductive effect and by steric hindrance. In fact, treatment
of compound 3 with LDA and subsequent quenching of the
lithium salt with solid carbon dioxide gave compound 9 as the
sole product, proving that the proton next to the fluoro
substituent is the more acidic position. In all cases shown in
Scheme 1, the lithiations with LDA were necessarily carried out
at low temperature (Ϫ78 ЊC) in order to prevent the form-
ation of a benzyne derivative through the elimination of
lithium halide.
The structures of the carboxylic acids 7–12 were easily and
1
convincingly assigned through H NMR spectroscopy on the
basis of the expected frequency and coupling constants of the
aromatic protons. The proton meta to the fluoro substituent
gave a double doublet due to a 3JHH coupling constant of 8 Hz
J. Chem. Soc., Perkin Trans. 1, 1998, 3479–3484
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generated through selective metallation permit the introduction
of a wide range of functional units, as mentioned previously
and exemplified here by the introduction of the carboxy group
as a precursor to a nitrile function. The utility of the inter-
mediate compounds in selective palladium-catalysed cross-
coupling reactions at the bromo and iodo sites has been
demonstrated by the efficient synthesis of a series of liquid
crystalline terphenyls.
F
HO2C
X
F
a
X
Y
Y
1: X = C8H17O, Y = Br
7: X = C8H17O, Y = Br (48%)
8: X = Br, Y = C8H17O (81%)
9: X = C5H11, Y = Br (46%)
10: X = Br, Y = C5H11 (91%)
11: X = Br, Y = I (38%)
2: X = Br, Y = C8H17
3: X = C5H11, Y = Br
4: X = Br, Y = C5H11
5: X = Br, Y = I
O
6: X = I, Y = Br
12: X = I, Y = Br (77%)
Experimental
Confirmation of the structures of intermediates and products
1
was obtained by H NMR spectroscopy (JEOL JNM-GX270
b
spectrometer), infrared spectroscopy (Perkin-Elmer 457 grating
spectrophotometer) and mass spectrometry (Finnigan-MAT
1020 GC-MS spectrometer). Elemental analysis (Fisions
EA1108 CHN) data were obtained for each of the following
compounds, 19–24, 27–30, 32, 33, 35 and 36. All the aromatic
3JHH coupling constants are approximately 8 Hz in each case,
and they are not reported unless coupling with a fluoro
substituent also occurs. The progress of reactions was fre-
quently monitored using a Chrompack 9001 capillary gas
chromatograph fitted with a CP-SIL 5 CB 10 m × 0.25 mm,
0.12 µm column (Cat. No. 7700). Melting points and transition
temperatures were measured using a Mettler FP5 hot-stage and
control unit in conjunction with an Olympus BH2 polarising
microscope and these were confirmed using differential scan-
ning calorimetry (Perkin-Elmer DSC-7 and IBM data station).
The purities of compounds 19–24, 27–30, 32, 33, 35 and 36
were checked by GLC analysis (see above) and HPLC analysis
(Merck-Hitachi with Merck RP 18 column, Cat. No. 16 051)
and were found to be >99.9% pure in each case. The prepar-
ation of compounds 1–6 has been described previously,39
and tetrakis(triphenylphosphine)palladium(0) was prepared as
described in the literature.41
O
NC
F
H2NC
F
c
X
Y
X
Y
19: X = C8H17O, Y = Br (68%)
20: X = Br, Y = C8H17O (65%)
21: X = C5H11, Y = Br (77%)
22: X = Br, Y = C5H11 (48%)
23: X = Br, Y = I (85%)
13: X = C8H17O, Y = Br (98%)
14: X = Br, Y = C8H17O (93%)
15: X = C5H11, Y = Br (99%)
16: X = Br, Y = C5H11 (99%)
17: X = Br, Y = I (67%)
24: X = I, Y = Br (55%)
18: X = I, Y = Br (70%)
Scheme 1 Reagents: a (i), LDA, THF; (ii), CO2, THF; (iii), HCl, H2O;
b (i), oxalyl chloride, DMF; (ii), 35% NH3, diglyme; c thionyl chloride,
DMF.
4
and a JHF coupling constant of 7 Hz. The proton para to the
fluoro substituent also gave a double doublet due to a JHH
coupling constant of 8 Hz and a JHF coupling constant of
1 Hz. If an alternative proton had been abstracted and hence
the carboxy group located differently, then the fluoro substitu-
ent in the product would have been ortho to a proton and the 1H
NMR spectrum would clearly have revealed a signal with a
large coupling constant (3JHF = 12 Hz).
3
5
3-Bromo-2-fluoro-6-octyloxybenzoic acid 7
Standard functional group interconversions on acids 7–12
gave the desired cyano-substituted compounds (19–24) through
the intermediate amides (13–18); these nitriles represent final
materials before coupling reactions and so the structures were
further characterised by elemental combustion analyses.
Palladium-catalysed cross-coupling reactions with arylbor-
onic acids were used to construct liquid crystalline materials
27–30, 35 and 36. In the case of nitriles 19–22, the bromo
substituent is the only viable coupling site, and reaction in each
case with an appropriate biphenylboronic acid (25 or 26)
gave good yields of four isomeric liquid crystalline terphenyls
with a fluoro substituent and a cyano group inherently fixed on
the same side of the molecule to provide a high lateral dipole
(Scheme 2).
As shown in Scheme 3, selective couplings are particularly
useful in the construction of unsymmetrical multi-aryl liquid
crystals. Nitriles 23 and 24 each possess bromo and iodo leaving
groups, and the first coupling reaction with the alkoxy-
substituted arylboronic acid 31 occurs preferentially at the iodo
site in each case to generate biphenyls 32 and 33 respectively in
reasonably good yields. The subsequent exploitation of the less
reactive bromo substituent of biphenyls 32 and 33 in a second
coupling reaction, this time with the alkyl-substituted aryl-
boronic acid 34, generated unsymmetrical liquid crystalline
terphenyls 35 and 36 respectively.
A solution of compound 1 (11.00 g, 0.036 mol) in dry THF (40
ml) was added dropwise to a stirred, cooled (Ϫ78 ЊC) solution
of lithium diisopropylamide [prepared in the usual way from
dry diisopropylamine (4.15 g, 0.041 mol) and n-butyllithium
(15.2 ml, 2.5 M, 0.038 mol)]28,40 in dry THF (80 ml) under dry
nitrogen. The mixture was stirred at Ϫ78 ЊC for 1 h and poured
onto a slurry of solid carbon dioxide in dry THF. The mixture
was allowed to warm to room temperature, the solvent was
removed in vacuo and 10% aqueous potassium hydroxide was
added. The solution was washed with ether and the aqueous
layer was acidified with 36% hydrochloric acid (congo red).
The product was extracted into ether (twice) and the com-
bined ethereal extracts were washed with water, and dried
(MgSO4). The solvent was removed in vacuo and the crude
product was purified by column chromatography (silica gel–
dichloromethane) to yield a colourless crystalline solid.
Yield 6.02 g (48%); mp 50–51 ЊC; δH(270 MHz; CDCl3) 0.90
(3H, t), 1.35 (8H, m), 1.45 (2H, quintet), 1.85 (2H, quintet),
4.10 (2H, t), 6.69 (1H, dd; 3JHH = 8 Hz, 5JHF = 1 Hz), 7.58 (1H,
3
4
dd; JHH = 8 Hz, JHF = 7 Hz), 10.10 (1H, s); νmax(KBr)/cmϪ1
3100–2850, 1710, 1480, 1300, 1270, 1080; MS m/z 248 (Mϩ),
246 (Mϩ).
The following compounds were prepared using the exper-
imental procedure described for the preparation of compound 7.
6-Bromo-2-fluoro-3-octyloxybenzoic acid 8. Quantities: com-
pound 2 (8.70 g, 0.029 mol). Yield 8.20 g (81%); mp 54–56 ЊC;
δH(270 MHz; CDCl3) 0.90 (3H, t), 1.35 (8H, m), 1.45 (2H,
quintet), 1.85 (2H, quintet), 4.00 (2H, t), 6.92 (1H, dd, 3JHH = 8
Hz, 4JHF = 7 Hz), 7.31 (H, dd; 3JHH = 8 Hz, 5JHF = 1 Hz), 11.30
(1H, s); νmax(KBr)/cmϪ1 3100–2850, 1710, 1480, 1300, 1270,
1080; MS m/z 348 (Mϩ), 346 (Mϩ).
Summary
Selective ortho-directed metallation has enabled the efficient
synthesis of some novel, highly substituted benzenes with
iodo, bromo, fluoro, cyano, alkoxy and alkyl substituents
(compounds 7–24). Importantly, the intermediate carbanions
3480
J. Chem. Soc., Perkin Trans. 1, 1998, 3479–3484

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NC
F
NC
F
a
C8H17O
Br
C8H17O
C5H11
19
27 (67%)
C5H11
B(OH)2
F
CN
F
CN
25
C8H17O
Br
C8H17O
C5H11
a
20
28 (61%)
NC
F
NC
F
a
C5H11
Br
C5H11
OC8H17
21
29 (63%)
C8H17O
B(OH)2
F
CN
F
CN
26
C5H11
Br
C5H11
OC8H17
a
22
30 (58%)
Scheme 2 Reagents: a Pd(PPh3)4, DME, Na2CO3, H2O.
NC
F
F
CN
Br
I
Br
I
23
24
C8H17O
B(OH)2
a
a
31
F
CN
NC
F
C8H17O
Br
C8H17O
Br
32 (56%)
33 (65%)
a
C5H11
B(OH)2
a
34
F
CN
NC
F
C8H17O
C5H11
C8H17O
C5H11
35 (66%)
36 (57%)
Scheme 3 Reagents: a Pd(PPh3)4, DME, Na2CO3, H2O.
3-Bromo-2-fluoro-6-phenylbenzoic acid 9. Quantities: com-
pound 3 (7.00 g, 0.029 mol). Yield 3.85 g (46%); oil; δH(270
MHz; CDCl3) 0.90 (3H, t), 1.35 (4H, m), 1.65 (2H, quintet),
2.70 (2H, t), 6.96 (1H, dd; 3JHH = 8 Hz, 5JHF = 1 Hz), 7.56 (1H,
dd; 3JHH = 8 Hz, 4JHF = 7 Hz); νmax(KBr)/cmϪ1 3200–2860, 1710,
1300; MS m/z 290 (Mϩ), 288 (Mϩ).
(1H, s); νmax(KBr)/cmϪ1 3100–2700, 1700, 1450, 1395, 1300; MS
m/z 346 (Mϩ), 344 (Mϩ).
3-Bromo-2-fluoro-6-iodobenzoic acid 12. Quantities: com-
pound 6 (9.63 g, 0.032 mol). Yield 7.77 g (77%); mp 166–
3
168 ЊC; δH(270 MHz; CDCl3) 7.36 (1H, dd; JHH = 8 Hz,
3
5
4JHF = 7 Hz), 7.58 (1H, dd; JHH = 8 Hz, JHF = 1 Hz), 9.30
(1H, s); νmax(KBr)/cmϪ1 3100–2700, 1700, 1450, 1395, 1300; MS
m/z 346 (Mϩ), 344 (Mϩ).
6-Bromo-2-fluoro-3-pentylbenzoic acid 10. Quantities: com-
pound 4 (7.90 g, 0.032 mol). Yield 8.37 g (91%); mp 70–71 ЊC;
δH(270 MHz; CDCl3) 0.90 (3H, t), 1.35 (4H, m), 1.60 (2H, quin-
3-Bromo-2-fluoro-6-octyloxybenzamide 13
3
4
tet), 2.65 (2H, t), 7.16 (1H, dd; JHH = 8 Hz, JHF = 7 Hz), 7.34
3
5
(1H, dd; JHH = 8 Hz, JHF = 1 Hz), 10.30 (1H, s); νmax(KBr)/
cmϪ1 3200–2860, 1700, 1450, 1390, 1280; MS m/z 290 (Mϩ), 288
(Mϩ).
A solution of oxalyl chloride (3.30 g, 0.026 mol) in dry benzene
(5 ml) was added dropwise to a stirred solution of compound 7
(4.50 g, 0.013 mol) and dry DMF (5 drops) in dry benzene (30
ml) at room temperature under dry nitrogen. The solution was
stirred at room temperature overnight and the benzene and
excess of oxalyl chloride were removed in vacuo. A solution of
the residue in dry diglyme (10 ml) was added to stirred 35%
aqueous ammonia (100 ml) at room temperature. The resulting
6-Bromo-2-fluoro-3-iodobenzoic acid 11. Quantities: com-
pound 5 (9.63 g, 0.032 mol). Yield 4.20 g (38%); mp 179–
3
181 ЊC; δH(270 MHz; CDCl3) 7.16 (1H, dd; JHH = 8 Hz,
3
4
5JHF = 1 Hz), 7.63 (1H, dd; JHH = 8 Hz, JHF = 7 Hz), 9.10
J. Chem. Soc., Perkin Trans. 1, 1998, 3479–3484
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precipitate was filtered off, washed with water and dried (P2O5)
in vacuo to give a colourless solid.
imental procedure described for the preparation of compound
19.
Yield 4.40 g (98%); mp 120–122 ЊC; δH(270 MHz; CDCl3)
0.90 (3H, t), 1.35 (8H, m), 1.45 (2H, quintet), 1.85 (2H, quin-
tet), 4.00 (2H, t), 6.00 (1H, s), 6.10 (1H, s), 6.64 (1H, dd;
6-Bromo-2-fluoro-3-octyloxybenzonitrile 20. Quantities:
compound 14 (7.70 g, 0.022 mol). Yield 4.66 g (65%); mp 50–
52 ЊC; δH(270 MHz; CDCl3) 0.90 (3H, t), 1.35 (8H, m), 1.45
(2H, quintet), 1.85 (2H, quintet), 4.05 (2H, t), 7.06 (1H, dd;
5
3
4
3JHH = 8 Hz, JHF = 1 Hz), 7.49 (1H, dd; JHH = 8 Hz, JHF = 7
Hz); νmax(KBr)/cmϪ1 3390, 3180, 2920, 1650, 1450, 1290, 800;
MS m/z 347 (Mϩ), 345 (Mϩ).
4
3
5
3JHH = 8 Hz, JHF = 7 Hz), 7.35 (1H, dd; JHH = 8 Hz, JHF = 1
Hz); νmax(KBr)/cmϪ1 2960, 2920, 2240, 1460, 1300, 1230, 1100,
820; MS m/z 329 (Mϩ), 327 (Mϩ); Found: C, 54.85; H, 5.81; N,
4.27; C15H19BrFNO requires C, 54.89; H, 5.83; N, 4.27%.
The following compounds were prepared using the experi-
mental procedure described for the preparation of compound
13.
3-Bromo-2-fluoro-6-pentylbenzonitrile 21. Quantities: com-
pound 15 (3.00 g, 0.010 mol). Yield 2.08 g (77%); mp 25–27 ЊC;
δH(270 MHz; CDCl3) 0.90 (3H, t), 1.35 (4H, m), 1.65 (2H, quin-
tet), 2.80 (2H, t), 7.02 (1H, dd; JHH = 8 Hz, JHF = 1 Hz), 7.68
(1H, dd; 3JHH = 8 Hz, 4JHF = 7 Hz); νmax(KBr)/cmϪ1 2980, 2960,
2860, 2240, 1450, 850; MS m/z 271 (Mϩ), 269 (Mϩ); Found: C,
53.50; H, 4.81; N, 5.15; C12H13BrFN requires C, 53.35; H, 4.85;
N, 5.18%.
6-Bromo-2-fluoro-3-octyloxybenzamide 14. Quantities: com-
pound 8 (8.20 g, 0.024 mol). Yield 7.70 g (93%); mp 82–84 ЊC;
δH(270 MHz; CDCl3) 0.90 (3H, t), 1.35 (8H, m), 1.45 (2H, quin-
tet), 1.85 (2H, quintet), 4.00 (2H, t), 5.56 (1H, s), 6.05 (1H, s),
6.87 (1H, dd; 3JHH = 8 Hz, 4JHF = 7 Hz), 7.28 (1H, dd; 3JHH = 8
Hz, 5JHF = 1 Hz); νmax(KBr)/cmϪ1 3390, 3180, 2920, 1650, 1460,
1260, 870; MS m/z 347 (Mϩ), 345 (Mϩ).
3
5
3-Bromo-2-fluoro-6-pentylbenzamide 15. Quantities: com-
pound 9 (3.10 g, 0.011 mol). Yield 3.13 g (99%); mp 88–90 ЊC;
δH(270 MHz; CDCl3) 0.90 (3H, t), 1.35 (4H, m), 1.65 (2H, quin-
tet), 2.70 (2H, t), 5.85 (1H, s), 6.15 (1H, s), 6.94 (1H, dd;
6-Bromo-2-fluoro-3-pentylbenzonitrile 22. Quantities: com-
pound 16 (7.10 g, 0.025 mol). Yield 3.25 g (48%); mp 32–34 ЊC;
δH(270 MHz; CDCl3) 0.90 (3H, t), 1.35 (4H, m), 1.65 (2H, quin-
tet), 2.65 (2H, t), 7.31 (1H, dd; JHH = 8 Hz, JHF = 7 Hz), 7.40
(1H, dd; 3JHH = 8 Hz, 5JHF = 1 Hz); νmax(KBr)/cmϪ1 2950, 2240,
1600, 1450, 1220, 870, 820; MS m/z 271 (Mϩ), 269 (Mϩ); Found:
C, 53.34; H, 4.84; N, 5.18; C12H13BrFN requires C, 53.35; H,
4.85; N, 5.18%.
3
4
5
3
4
3JHH = 8 Hz, JHF = 1 Hz), 7.48 (1H, dd; JHH = 8 Hz, JHF = 7
Hz); νmax(KBr)/cmϪ1 3400, 3200, 2980, 2880, 1660, 1400; MS
m/z 289 (Mϩ), 287 (Mϩ).
6-Bromo-2-fluoro-3-pentylbenzamide 16. Quantities: com-
pound 10 (8.25 g, 0.029 mol). Yield 8.30 g (99%); mp 118–
120 ЊC; δH(270 MHz; CDCl3) 0.90 (3H, t), 1.30 (4H, m), 1.70
(2H, quintet), 2.60 (2H, t), 5.85 (1H, s), 6.10 (1H, s), 7.10 (1H,
6-Bromo-2-fluoro-3-iodobenzonitrile 23. Quantities: com-
pound 17 (2.60 g, 7.56 mmol). Yield 2.10 g (85%); mp 112–
114 ЊC; δH(270 MHz; CDCl3) 7.27 (1H, dd; 3JHH = 8 Hz, 5JHF = 1
3
4
3
dd; JHH = 8 Hz, JHF = 7 Hz), 7.30 (1H, dd; JHH = 8 Hz,
5JHF = 1 Hz); νmax(KBr)/cmϪ1 3390, 3200, 2920, 1650, 1460,
1380, 870; MS m/z 289 (Mϩ), 287 (Mϩ).
3
4
Hz), 7.84 (1H, dd; JHH = 8 Hz, JHF = 7 Hz); νmax(KBr)/cmϪ1
2240, 1620, 1500, 1420, 1150, 890, 820; MS m/z 327 (Mϩ), 325
(Mϩ); Found: C, 25.76; H, 0.60; N, 4.25; C7H2BrFIN requires
C, 25.80; H, 0.62; N, 4.30%.
6-Bromo-2-fluoro-3-iodobenzamide 17. Quantities: compound
11 (4.00 g, 0.012 mol). Yield 2.66 g (67%); mp 219–221 ЊC;
3
5
3-Bromo-2-fluoro-6-iodobenzonitrile 24. Quantities: com-
pound 18 (5.00 g, 0.015 mol). Yield 2.71 g (55%); mp 108–
δH(270 MHz; CDCl3) 7.30 (1H, dd; JHH = 8 Hz, JHF = 1 Hz),
7.77 (1H, dd; 3JHH = 8 Hz, 4JHF = 7 Hz), 7.85 (1H, s), 8.10 (1H,
s); νmax(KBr)/cmϪ1 3390, 3200, 2920, 1650, 1460, 1380, 870; MS
m/z 345 (Mϩ), 343 (Mϩ).
3
110 ЊC; δH(270 MHz; CDCl3) 7.50 (1H, dd; JHH = 8 Hz,
3
5
4JHF = 7 Hz), 7.60 (1H, dd; JHH = 8 Hz, JHF = 1 Hz);
νmax(KBr)/cmϪ1 2240, 1600, 1500, 1420, 1150, 900, 820; MS m/z
327 (Mϩ), 325 (Mϩ); Found: C, 25.78; H, 0.60; N, 4.27;
C7H2BrFIN requires C, 25.80; H, 0.62; N, 4.30%.
3-Bromo-2-fluoro-6-iodobenzamide 18. Quantities: compound
12 (7.50 g, 0.022 mol). Yield 5.30 g (70%); mp 188–190 ЊC;
3
4
δH(270 MHz; CDCl3) 7.23 (1H, dd; JHH = 8 Hz, JHF = 7 Hz),
7.32 (1H, s), 7.46 (1H, dd; 3JHH = 8 Hz, 5JHF = 1 Hz), 7.80 (1H,
s); νmax(KBr)/cmϪ1 3390, 3200, 2920, 1650, 1460, 1380, 870; MS
m/z 345 (Mϩ), 343 (Mϩ).
3-Cyano-2-fluoro-4-octyloxy-4Љ-pentyl-1,1Ј:4Ј,1Љ-terphenyl 27
Compound 25 (1.00 g, 3.73 mmol) was added to a stirred
mixture of compound 19 (1.00 g, 3.05 mmol), tetrakis-
(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) and
sodium carbonate (3.50 g) in DME (35 ml) and water (35 ml) at
room temperature under nitrogen. The stirred mixture was
heated under reflux for 4 h (GLC analysis revealed a complete
reaction) and the cooled mixture was added to water (100 ml).
The product was extracted into ether (twice) and the combined
ethereal extracts were washed with brine and dried (MgSO4).
The solvent was removed in vacuo and the crude product was
purified by column chromatography [silica gel–light petroleum
(bp 40–60 ЊC) with the gradual introduction of dichloro-
methane] to give a colourless solid which was recrystallised
from ethanol to yield fine colourless crystals.
3-Bromo-2-fluoro-6-octyloxybenzonitrile 19
A solution of thionyl chloride (7.70 g, 0.065 mol) in dry DMF
(10 ml) was added dropwise to a stirred solution of compound
13 (4.20 g, 0.013 mol) in dry DMF (25 ml) at room temperature.
The stirred mixture was heated at 120 ЊC for 3 h and poured
into ice–water. The product was extracted into ether (twice) and
the combined ethereal extracts were washed with water, satur-
ated sodium hydrogen carbonate solution, water, and dried
(MgSO4). The solvent was removed in vacuo and the residue
was purified by column chromatography [silica gel–light petrol-
eum (bp 40–60 ЊC) with the gradual introduction of dichloro-
methane] to yield a colourless solid.
Yield 2.88 g (68%); mp 51–53 ЊC; δH(270 MHz; CDCl3) 0.90
(3H, t), 1.35 (8H, m), 1.45 (2H, quintet), 1.85 (2H, quintet),
4.10 (2H, t), 6.67 (1H, dd; 3JHH = 8 Hz, 5JHF = 1 Hz), 7.65 (1H,
dd; 3JHH = 8 Hz, 4JHF = 7 Hz); νmax(KBr)/cmϪ1 2960, 2920, 2240,
1460, 1300, 1220, 1080, 820; MS m/z 329 (Mϩ), 327 (Mϩ);
Found: C, 54.83; H, 5.77; N, 4.26; C15H19BrFNO requires C,
54.89; H, 5.83; N, 4.27%.
Yield 0.96 g (67%); transitions (ЊC) C 100.0 SA 163.5 I; δH(270
MHz; CDCl3) 0.90 (6H, 2 × t), 1.35 (12H, m), 1.45 (2H, quin-
tet), 1.65 (2H, quintet), 1.85 (2H, quintet), 2.65 (2H, t), 4.10
3
5
(2H, t), 6.83 (1H, dd; JHH = 8 Hz, JHF = 1 Hz), 7.27 (2H, d),
7.53 (2H, dd; 3JHH = 8 Hz, 5JHF = 1 Hz), 7.55 (2H, d), 7.62 (1H,
3
4
dd; JHH = 8 Hz, JHF = 7 Hz), 7.67 (2H, d); νmax(KBr)/cmϪ1
2980, 2960, 2860, 2240, 1610, 1490, 1250, 810; MS m/z 471
(Mϩ); Found: C, 81.48; H, 8.10; N, 2.95; C32H38FNO requires
C, 81.49; H, 8.12; N, 2.97%.
The following compounds were prepared using the exper-
3482
J. Chem. Soc., Perkin Trans. 1, 1998, 3479–3484

View Article Online
The following compounds were prepared using the exper-
2Ј-Cyano-3Ј-fluoro-4-octyloxy-4Љ-pentyl-1,1Ј:4Ј,1Љ-terphenyl
imental procedure described for the preparation of compound
27.
36. Quantities: compound 33 (1.00 g, 2.50 mmol), compound
34 (0.60 g, 3.13 mmol). Yield 0.67 g (57%); transitions (ЊC) C
96.5 N 90.0 I; δH(270 MHz; CDCl3) 0.90 (6H, 2 × t), 1.35 (12H,
m), 1.45 (2H, quintet), 1.65 (2H, quintet), 1.85 (2H, quintet),
2.65 (2H, t), 4.10 (2H, t), 7.02 (2H, d), 7.25 (2H, d), 7.30 (1H,
2-Cyano-3-fluoro-4-octyloxy-4Љ-pentyl-1,1Ј:4Ј,1Љ-terphenyl 28.
Quantities: compound 20 (1.50 g, 4.57 mmol), compound 25
(1.50 g, 5.60 mmol). Yield 1.32 g (61%); transitions (ЊC) C 116.5
I; δH(270 MHz; CDCl3) 0.90 (6H, 2 × t), 1.35 (12H, m), 1.45
(2H, quintet), 1.65 (2H, quintet), 1.85 (2H, quintet), 2.65 (2H,
t), 4.10 (2H, t), 7.25 (4H, m), 7.54 (2H, d), 7.58 (2H, d), 7.68
(2H, d); νmax(KBr)/cmϪ1 2980, 2960, 2860, 2240, 1610, 1490,
1250, 810; MS m/z 471 (Mϩ); Found: C, 81.45; H, 8.11; N, 2.95;
C32H38FNO requires C, 81.49; H, 8.12; N, 2.97%.
3
5
dd; JHH = 8 Hz, JHF = 1 Hz), 7.41 (2H, d), 7.50 (2H, dd;
5
3
4
3JHH = 8 Hz, JHF = 1 Hz), 7.68 (1H, dd; JHH = 8 Hz, JHF = 7
Hz); νmax(KBr)/cmϪ1 2980, 2960, 2860, 2240, 1610, 1490, 1250,
810; MS m/z 471 (Mϩ); Found: C, 81.45; H, 8.10; N, 2.97;
C32H38FNO requires C, 81.49; H, 8.12; N, 2.97%.
Acknowledgements
3-Cyano-2-fluoro-4Љ-octyloxy-4-pentyl-1,1Ј:4Ј,1Љ-terphenyl 29.
Quantities: compound 21 (1.20 g, 4.44 mmol), compound 26
(1.75 g, 5.37 mmol). Yield 1.32 g (63%); transitions (ЊC) C 61.5
SC 84.5 SA 160.5 I; δH(270 MHz; CDCl3) 0.90 (6H, 2 × t), 1.35
(12H, m), 1.45 (2H, quintet), 1.75 (2H, quintet), 1.85 (2H, quin-
tet), 2.85 (2H, t), 4.05 (2H, t), 6.99 (2H, d), 7.18 (1H, dd;
We express our thanks to our collaborators at DERA
(Malvern), and we thank Dr D. F. Ewing, Mrs B. Worthington,
Mr R. Knight, Mr A. D. Roberts and Mr A. T. Rendell for
various spectroscopic measurements.
5
3
References
3JHH = 8 Hz, JHF = 1 Hz), 7.57 (4H, d), 7.62 (1H, dd; JHH = 8
4
Hz, JHF = 7 Hz), 7.66 (2H, d); νmax(KBr)/cmϪ1 2980, 2960,
1 N. Miyaura, T. Yanagi and A. Suzuki, Synth. Commun., 1981, 11,
513.
2 A. O. King, E. Negishi, F. J. Villani and A. Silveira, J. Org. Chem.,
1978, 43, 358.
3 A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc., 1987, 109,
5478.
2860, 2240, 1610, 1490, 1250, 810; MS m/z 471 (Mϩ); Found: C,
81.46; H, 8.09; N, 2.92; C32H38FNO requires C, 81.49; H, 8.12;
N, 2.97%.
2-Cyano-3-fluoro-4Љ-octyloxy-4-pentyl-1,1Ј:4Ј,1Љ-terphenyl 30.
Quantities: compound 22 (1.20 g, 4.44 mmol), compound 26
(1.80 g, 5.52 mmol). Yield 1.52 g (58%); transitions (ЊC) C 89.0
N 100.0 I; δH(270 MHz; CDCl3) 0.90 (6H, 2 × t), 1.35 (12H, m),
1.45 (2H, quintet), 1.65 (2H, quintet), 1.85 (2H, quintet), 2.70
4 M. J. Sharp and V. Snieckus, Tetrahedron Lett., 1985, 26,
5997.
5 W. J. Scott and J. K. Stille, J. Am. Chem. Soc., 1986, 108,
3033.
6 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
7 G. W. Gray, M. Hird, D. Lacey and K. J. Toyne, J. Chem. Soc.,
Perkin Trans. 2, 1989, 2041.
8 U. H. Lauk, P. Skrabal and H. Zollinger, Helv. Chim. Acta, 1985, 68,
1406.
9 M. Hird, G. W. Gray and K. J. Toyne, Mol. Cryst. Liq. Cryst., 1991,
206, 187.
10 M. Hird, K. J. Toyne and G. W. Gray, Liq. Cryst., 1993, 14,
741.
3
(2H, t), 4.00 (2H, t), 6.99 (2H, d), 7.27 (1H, dd; JHH = 8 Hz,
5JHF = 1 Hz), 7.47 (1H, dd; 3JHH = 8 Hz, 4JHF = 7 Hz), 7.56 (2H,
d), 7.60 (2H, d), 7.68 (2H, d); νmax(KBr)/cmϪ1 2980, 2960, 2860,
2240, 1610, 1490, 1250, 810; MS m/z 471 (Mϩ); Found: C,
81.48; H, 8.12; N, 2.96; C32H38FNO requires C, 81.49; H, 8.12;
N, 2.97%.
11 J. W. Goodby, M. Hird, K. J. Toyne and T. Watson, J. Chem. Soc.,
Chem. Commun., 1994, 1701.
4-Bromo-3-cyano-2-fluoro-4Ј-octyloxybiphenyl 32. Quantities:
compound 23 (1.84 g, 5.64 mmol), compound 31 (1.63 g, 6.48
mmol). Yield 1.28 g (56%); mp 59–61 ЊC; δH(270 MHz; CDCl3)
0.90 (3H, t), 1.35 (8H, m), 1.45 (2H, quintet), 1.85 (2H, quin-
12 G. A. Potter and R. J. McCague, J. Org. Chem., 1990, 55,
6184.
13 J. W. Goodby, M. Hird, R. A. Lewis and K. J. Toyne, Chem.
Commun., 1996, 2719.
3
tet), 4.10 (2H, t), 6.99 (2H, d), 7.35 (1H, dd; JHH = 8 Hz,
14 D. B. Reitz, J. J. Li, M. B. Norton, E. J. Reinhard, J. T. Collins, G. D.
Anderson, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert
and P. C. Isakson, J. Med. Chem., 1994, 37, 3878.
15 J. L. Li, M. B. Norton, E. J. Reinhard, G. D. Anderson, S. A.
Gregory, P. C. Isakson, C. M. Koboldt, J. L. Masferrer, W. E.
Perkins, K. Seibert, Y. Zhang, B. S. Zweifel and D. B. Reitz, J. Med.
Chem., 1996, 39, 1846.
3
5
4JHF = 7 Hz), 7.42 (2H, d), 7.52 (2H, dd; JHH = 8 Hz, JHF = 1
Hz), 7.67 (1H, dd; JHH = 8 Hz, JHF = 1 Hz); νmax(KBr)/cmϪ1
2920, 2240, 1610, 1500, 1250, 1120, 820; MS m/z 405 (Mϩ), 403
(Mϩ); Found: C, 62.36; H, 5.73; N, 3.43; C21H23BrFNO requires
C, 62.38; H, 5.73; N, 3.46%.
3
5
16 W. Wang and V. Snieckus, J. Org. Chem., 1992, 57, 424.
17 Z. Bao, W. K. Chan and L. Yu, J. Am. Chem. Soc., 1995, 117,
12 426.
18 M. Rehahn, A.-D. Schluter, G. Wegner and W. J. Feast, Polymer,
1989, 30, 1060.
19 J. M. Tour, Chem. Rev., 1996, 96, 537.
20 F. E. Goodson, T. I. Wallow and B. M. Novak, Macromolecules,
1998, 31, 2047.
21 B. J. Wakefield, Organolithium Methods, Academic Press, London,
1988.
22 A. M. Roe, R. A. Burton, G. L. Willey, M. W. Baines and A. C.
Rasmussen, J. Med. Chem., 1968, 11, 814.
4-Bromo-2-cyano-3-fluoro-4Ј-octyloxybiphenyl 33. Quantities:
compound 24 (2.50 g, 7.67 mmol), compound 31 (2.21 g, 8.882
mmol). Yield 2.02 g (65%); mp 43–45 ЊC; δH(270 MHz; CDCl3)
0.90 (3H, t), 1.35 (8H, m), 1.45 (2H, quintet), 1.85 (2H, quin-
3
tet), 4.10 (2H, t), 7.00 (2H, d), 7.17 (1H, dd; JHH = 8 Hz,
3
4
5JHF = 1 Hz), 7.47 (2H, d), 7.77 (1H, dd; JHH = 8 Hz, JHF = 7
Hz); νmax(KBr)/cmϪ1 2920, 2240, 1610, 1470, 1250, 1180, 820;
MS m/z 405 (Mϩ), 403 (Mϩ); Found: C, 62.35; H, 5.71; N, 3.42;
C21H23BrFNO requires C, 62.38; H, 5.73; N, 3.46%.
23 C. Tamborski and E. J. Soloski, J. Org. Chem., 1966, 31, 746.
24 D. L. Ladd and J. Weinstock, J. Org. Chem., 1981, 46, 203.
25 A. J. Bridges, W. C. Patt and T. M. Stickney, J. Org. Chem., 1990, 55,
773.
26 V. Snieckus, Pure Appl. Chem., 1990, 62, 671.
27 A. J. Bridges, A. L. Emmanuel, E. C. Maduakor and C. E. Schwartz,
Tetrahedron Lett., 1992, 33, 7495.
28 P. L. Coe, A. J. Waring and T. D. Yarwood, J. Chem. Soc., Perkin
Trans. 1, 1995, 2729.
29 A. J. Bridges, A. Lee, E. C. Maduakor and C. E. Schwartz,
Tetrahedron Lett., 1992, 33, 7499.
2Ј-Cyano-3Ј-fluoro-4Љ-octyloxy-4-pentyl-1,1Ј:4Ј,1Љ-terphenyl
35. Quantities: compound 32 (1.20 g, 2.97 mmol), compound
34 (0.68 g, 3.54 mmol). Yield 0.92 g (66%); transitions (ЊC) C
90.0 SA 99.0 N 101.0 I; δH(270 MHz; CDCl3) 0.90 (6H, 2 × t),
1.35 (12H, m), 1.45 (2H, quintet), 1.65 (2H, quintet), 1.85 (2H,
quintet), 2.65 (2H, t), 4.00 (2H, t), 7.01 (2H, d), 7.31 (2H, d),
7.34 (1H, dd; 3JHH = 8 Hz, 5JHF = 1 Hz), 7.49 (2H, dd; 3JHH = 8
Hz, JHF = 1 Hz), 7.52 (2H, d), 7.67 (1H, dd; JHH = 8 Hz,
4JHF = 7 Hz); νmax(KBr)/cmϪ1 2980, 2960, 2860, 2240, 1610,
1490, 1250, 810; MS m/z 471 (Mϩ); Found: C, 81.45; H, 8.10; N,
2.97; C32H38FNO requires C, 81.49; H, 8.12; N, 2.97%.
5
3
30 P. Balkwill, D. Bishop, A. Pearson and I. Sage, Mol. Cryst. Liq.
Cryst., 1985, 123, 1.
J. Chem. Soc., Perkin Trans. 1, 1998, 3479–3484
3483

View Article Online
31 G. W. Gray, M. Hird and K. J. Toyne, Mol. Cryst. Liq. Cryst., 1991,
204, 43.
37 J. C. Jones, M. J. Towler and J. R. Hughes, Displays, 1993, 14,
86.
32 V. F. Petrov, Liq. Cryst., 1995, 19, 729.
38 A. J. Slaney, V. Minter and J. C. Jones, Ferroelectrics, 1996, 178,
33 K. J. Toyne, in Thermotropic Liquid Crystals, ed. G. W. Gray, Wiley,
Chichester, 1987.
65.
39 G. W. Gray, M. Hird and K. J. Toyne, Mol. Cryst. Liq. Cryst., 1991,
34 D. O’Hagan and H. S. Rzepa, Chem. Commun., 1997, 645.
35 D. Kim, H. Kim and Y. Chae, Bioorg. Med. Chem. Lett., 1994, 4,
1309.
36 A. J. Elliot, in Chemistry of Organic Fluorine Compounds II, ed.
M. Hudlicky and A. E. Pavlath, American Chemical Society,
Washington, DC, 1995, p. 1119.
195, 221.
40 K. F. Podraza and R. L. Bassfield, J. Org. Chem., 1988, 53,
2643.
41 D. R. Coulson, Inorg. Synth., 1972, 13, 121.
Paper 8/04525I
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J. Chem. Soc., Perkin Trans. 1, 1998, 3479–3484