The synthesis of chiral fluorinated 4-alkyl-4′-[(4-alkylphenyl) ethynyl]biphenyls

Article abstract of DOI:10.1016/j.tetlet.2013.04.118

We have designed, synthesized, and evaluated the physical properties of new fluorinated phenyltolane based chiral liquid crystal materials with 2-methylbutyl chains. This type of fluoro-substitution in chemical combination with a phenyltolane core brings a surprising improvement to the mesomorphic properties. The investigated compounds exhibit broad temperature ranges for the N* phase and very low melting points. All homologues exhibited Blue Phase. We have applied a Cu-catalyzed cross-coupling reaction between aryl Grignard reagents and alkyl bromides for the synthesis of the products.

Full text of DOI:10.1016/j.tetlet.2013.04.118

Tetrahedron Letters 54 (2013) 3621–3623
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Tetrahedron Letters
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The synthesis of chiral fluorinated 4-alkyl-40-[(4-alkylphenyl)ethynyl]biphenyls
⇑
Jakub Herman , Przemysław Kula
Institute of Chemistry, Department of Advanced Technologies and Chemistry, Military University of Technology, Kaliskiego 2, 00-908 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
We have designed, synthesized, and evaluated the physical properties of new fluorinated phenyltolane
based chiral liquid crystal materials with 2-methylbutyl chains. This type of fluoro-substitution in chem-
ical combination with a phenyltolane core brings a surprising improvement to the mesomorphic proper-
ties. The investigated compounds exhibit broad temperature ranges for the N⁄ phase and very low
melting points. All homologues exhibited Blue Phase. We have applied a Cu-catalyzed cross-coupling
reaction between aryl Grignard reagents and alkyl bromides for the synthesis of the products.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 25 February 2013
Revised 18 April 2013
Accepted 26 April 2013
Available online 10 May 2013
Keywords:
Coupling
Alkylation
Liquid crystal
Biaryls
Chirality
Significant attention has been focused on the search for new
cholesteric liquid crystals having strong helical twisting power,
wide mesogenic temperature ranges, and high chemical stability.
These materials demonstrate a very broad number of unique appli-
cations.1 In spite of their widespread specific applications they are
utilized also as dopants in blue phase systems2 and ferroelectric
mixtures.3 In this work we focused on the synthesis of a new class
of liquid crystal materials with a 4-(phenylethynyl)biphenyl core,
which imparts strong mesogenic stability and increased birefrin-
gence. Lateral fluoro-substitution, in particular a 2,6-difluoro-
phenyl acetylene unit, brings unique and valuable nematic
stability,4 leading to a strong future application potential.
For the synthesis of the liquid crystal compounds described
above we mainly utilized the Sonogashira–Hagihara cross-cou-
pling reaction between 4-alkylaryl iodides and 40-alkylbiphenyl
acetylenes. The preparation of the substrates was achieved by
introduction of an alkyl chain onto the aromatic system. The cop-
per catalyzed cross-coupling reaction between aryl Grignard re-
agents and alkyl bromides was used to form an sp3–sp2 C–C
bond (Scheme 1). Transition metal catalyzed cross-coupling reac-
tions have played an important role as carbon-carbon bond form-
ing reactions in organic synthesis for many years.5 Copper salts and
complexes exhibit high catalytic activity for a wide range of
substrates. Cu-catalyzed cross-coupling reactions between alkyl
halides and Grignard reagents were first reported by Kochi and
co-workers,6 with many further reports on improved methods
now available.7
Our approach is simply a modification of a known procedure,8
which gives greater yields, and besides, non-branched alkyl chains
can be easily used for chiral branched (2-methylbutyl)alkyl chain
incorporation. The method presented here is mild, proceeds in
one pot and requires cheap, easily accessible reagents. Further-
more it can be applied in large scale reactions. We used a tetrahy-
drofuran solution of Li2CuCl4 complex as the catalyst system.
Following this one-pot procedure, we obtained both alkyl fluorine
substituted benzene 1–4 and 4-alkylbiphenyl derivatives 5–6
(Table 1), which were the main starting materials for mesogen
synthesis, see Scheme 2. The alkyl fluorine substituted benzene
derivatives 1–4 were then iodinated following ortho-directed lith-
iation. In parallel, 4-alkylbiphenyl derivatives 5–6 were iodinated
in acetic acid. The formation of desired liquid crystals was subse-
quently accomplished by a copper catalyzed coupling of iodobi-
phenyl derivative 9 with 2-methyl-but-3-yn-2-ol followed by an
alkaline cleavage of acetone and a second analogous coupling with
compound 7 or 8. The synthesis of (S)-4-(2-methyl-1-butyl) biphe-
nyl 6 was also reported by Kaszynski and Jawdosiuk9 He utilized
Kumada cross-coupling,10 using [1,3-bis(diphenylphosphino)pro-
pane]nickel(II) chloride as catalyst system. Although the Kumada
MgBr
R
Li2CuCl4 (3 mol%)
THF, 70 oC, 72 h
X
X
R-Br
X = F or H
R = n-pentyl or S-2-methylbutyl
⇑
Corresponding author. Tel.: +48 (22) 683 98 73; fax: +48 (22) 683 95 82.
E-mail address: jherman@wat.edu.pl (J. Herman).
Scheme 1. Copper-catalyzed cross-coupling of aryl Grignard reagents with alkyl
bromides.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.118

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J. Herman, P. Kula / Tetrahedron Letters 54 (2013) 3621–3623
Table 1
Table 2
Results of the Li2CuCl4-catalyzed cross-coupling of aryl Grignard reagents with alkyl
Phase transition temperatures (°C) and enthalpies (J/mol) of the investigated liquid
crystals
bromidesa
Product
No.
Yieldb (%)
91
Product
Temperature (°C) and enthalpy [J/mol]of the phase transitions
11a
12a
13b
14b
15b
16b
Cr 103.2 (18,330) N⁄ 124.8 (13) BP⁄ (366) 126.6 Iso
Cr 56.5 (17,990) N⁄ 105.1 (10) BP⁄ 106.5 (330) Iso
Cr1 68.7 (5525) Cr2 89.2 (12,608) N⁄ 158.0 BP⁄ 158.2 Iso
Cr 30.9 (18,715) N⁄ 140.0 BP⁄ 140.2 Iso
1
Cr1 55.6 (5100) Cr2 75.2 (11,400) N⁄ 153.8 BP⁄ 153.9 Iso
Cr 27.4 (24,530) N⁄ 133.8 BP⁄ 134.0 Iso
2
3
4
53
83
48
The melting temperatures are determined from heating, while N⁄–BP and clearing
temperatures are derived from cooling.
a
Obtained from differential scanning calorimetry DSC.
Obtained from polarizing thermomicroscope.
b
protocol can bring higher yields in small to medium scale reac-
tions, it is our belief that the combination of a one-pot procedure
with an easily accessible and cheap catalyst like Li2CuCl4, brings
noticeable benefits for large scale procedures11. The characterized
liquid crystal compounds possess (S)-2-methylbutyl chain as a
source of chirality either at one or both terminals of the molecule.
In the case where only one branched chiral chain is present, the
other side of the molecule is terminated with an n-pentyl alkyl
chain. The temperatures and enthalpies of the phase transitions
of the products are listed in Table 2.
In summary we have designed and synthesized a new family of
cholesteric liquid crystals12. We show that the products are inter-
esting materials for applicable mixture formulation. They are char-
acterized by a broad range of chiral nematic phases. Liquid crystals
incorporating 2,6-difluorophenyl acetylene unit 12, 14, and 16
proved to be valuable components exhibiting a broad nematic
phase with very low melting temperatures, still maintaining high
clearing temperatures. In addition, they can also play the role of
blue phase sources, as all of homologues exhibit a narrow range
blue phase. The high stability of the chiral nematic mesophase
originates mainly from the rigid core which consists of previously
mentioned 2,6-difluorophenyl acetylene structural substructure. It
was proven that such a sequence of structural units was built into
the liquid crystal molecule which brings unusual properties with
very stable mesophases.4 In order to obtain the intended mesogens
we have modified and improved a copper-catalyzed coupling
method between alkyl bromides and aryl Grignards.
5
6
66
44
a
Reaction conditions: 1. aryl bromide (1.5 mol), Mg (1.5 mol), 2. alkyl bromide
(1.57 mol), Li2CuCl4 (45 mmol), 70 °C, N2 atmosphere, 72 h.
b
Isolated yields
Acknowledgment
This work was supported by the Military University of Technol-
ogy Grant 08-714.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.
118.
References and notes
1. (a) Lu, M. H. J. Appl. Phys. 1997, 81, 1063; (b) Kim, K. H.; Song, D. H.; Shen, Z. G.;
Park, B. W.; Park, K. H.; Lee, J. H.; Yoon, T. H. Opt. Expr. 2011, 19, 10174; (c)
Manabe, T.; Sonoyama, K.; Takanishi, Y.; Ishikawa, K.; Takezoe, H. J. Mater.
Chem. 2008, 18, 3040.
2. Chojnowska, O.; Dabrowski, R. Phot. Lett. Poland 2012, 4, 81.
3. Hird, M. Liq. Cryst. 2011, 38, 1467.
4. (a) Kula, P.; Aptacy, A.; Herman, J.; Wójciak, W.; Urban, S. Liq. Cryst. 2013, 40,
482; (b) Buchecker, R.; Marck, G.; Schadt, M. Mol. Cryst. Liq. Cryst. 1995, 260, 93;
(c) Seils, F.; Schadt, M. Mol. Cryst. Liq. Cryst. 1995, 260, 127.
5. (a) Ulmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34, 2174; (b) Ulmann, F.
Justus Liebigs An. Chem. 1904, 332, 38.
Scheme 2. General synthetic path to the investigated compounds.
6. Tamura, M.; Kochi, J. K. J. Organomet. Chem. 1972, 42, 205.

J. Herman, P. Kula / Tetrahedron Letters 54 (2013) 3621–3623
3623
7. (a) Hamze, A.; Brion, J. D.; Alami, M. Org. Lett. 2012, 14, 2782; (b) Cahiez, G.;
Gager, O.; Buendia, J. Angew. Chem., Int. Ed. 2010, 49, 1278; (c) Cahiez, G.; Gager,
O.; Buendia, J. Synlett 2010, 299; (d) Erdik, E.; Eroglu, F. Synth. React. Inorg. Met.
2000, 30, 955.
8. Cahiez, G.; Chaboche, C.; Jezequel, M. Tetrahedron 2000, 56, 2733.
9. Kaszynski, P.; Jawdosiuk, M. Mol. Cryst. Liq. Cryst. 1989, 174, 21.
product was distilled under reduced pressure: bp 98–100 °C (28 mmHg), yield
205 g (83%), ½a 2D5
ꢁ
9:5 (c, 5.1; CHCl3). MS(EI) m/z: 166 (M+), 133, 110, 96. 1H NMR
(CDCl3), d 7.65–7.60 (m, 1H), 7.53 (t, J = 2.2, 3.1 Hz, 1H), 6.82–6.75 (m, 2H), 2.50
(d, J = 8.8 Hz, 2H), 1.60–1.58 (m, 1H), 1.35–1.25 (m, 2H), 0.93 (t, J = 12.2 Hz,
3H), 0.86 (t, J = 11.4 Hz, 3H). 13C NMR (CDCl3) d 11.65, 19.0, 29.4, 36.6, 42.3,
109.0, 115.5, 121.7, 124.9, 126.4, 128.9, 145.0, 161.4.
10. Kiso, Y.; Yamamoto, K.; Tamao, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374.
11. Representative procedure for the one pot coupling of alkyl bromides with aryl
Grignards: (S)-1-Fluoro-3-(2-methyl-1-butyl)benzene 3: A solution of (262.5 g,
1.5 mol) 1-bromo-3-fluorobenzene in anhydrous THF (1 L) was added
dropwise to Mg chips (36.5 g, 1.5 mol) with vigorous stirring under N2
atmosphere. The mixture was refluxed for 1 h, then a 1 mol/dm3 solution of
catalyst Li2CuCl4 in anhydrous THF (45 mL, 3 mol %) was added. Next, (S)-1-
bromo-2-methylbutane (214.2 g, 1.58 mol) was added dropwise to the mixture
which was stirred under reflux for 2 days. When the reaction was completed
the mixture was poured into 1500 mL of H2O and 100 mL of 10% HCl. The crude
product was extracted with pentane. The organic layer was washed with H2O
(2 ꢀ 300 mL), separated, dried over MgSO4, and the solvent evaporated. The
12. 4S,40S-[2-Fluoro-4-(2-methyl-1-butyl)phenyl]ethynyl-40-(2-methyl-1-
butyl)biphenyl (11): Compounds 11–16 were obtained via Sonogashira
reactions. The products were purified using silica gel and hexane as eluent,
and then recrystallized from EtOH. Mp.103.2 °C, MS(EI): 412 (M+); 299. 1H
NMR (CDCl3), d 7.62–7.58 (m, 4H), 7.55 (d, J = 7.9 Hz, 2H), 7.44–7.40 (m, 1H),
7.25–7.22 (d, J = 7.3 Hz, 2H), 6.95–6.9 (m, 2H), 2.65–2.60 (m, 2H), 2.45–2.40
(m, 2H), 1.65–1.60 (m, 2H), 1.45–1.40 (m, 2H), 1.25–1.20 (m, 4H), 0.95–0.90
(m, 6H). 13C NMR (CDCl3) d 11.65, 19.0, 27.8, 29.4, 33.9, 36.6, 42.3, 83.3, 93.8,
109.0, 115.5, 121.7, 124.9, 126.4, 128.9, 132.2, 133.2, 137.7, 142.8, 145.0, 161.4,
163.5. Anal. Calcd for C30H33F: C, 87.33; H, 8.06; F, 4.61. Found: C, 87.87; H
8.15; F, 4.56.