Convergent synthesis of 1,1′-biisoquinolines tethered to calamitic subunits

Article abstract of DOI:10.1055/s-2008-1067184

A convergent synthesis of a series of 4,4′-functionalized 1,1′-biisoquinolines via 1-chloro-4-hydroxyisoquinoline and substituted biphenyl- and phenylpyrimidine ethers as building blocks is described. The latter were prepared by Williamson etherification of the respective 4-hydroxybiphenyl and -phenylpyrimidine precursors with dibromoalkanes, allowing variation of the spacer lengths. 1-Chloro-4-hydroxyisoquinoline was obtained from N-phthalimidoglycine ethyl ester through a Gabriel-Colman reaction as a key step. Linkage of the building blocks by etherification in the presence of potassium carbonate gave the isoquinolines, which were submitted to a nickel(II) chloride mediated homocoupling to yield the ligand systems. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067184

PAPER
2551
Convergent Synthesis of 1,1¢-Biisoquinolines Tethered to Calamitic Subunits
S
ynthesis of 1,1
l
¢
-Biiso
i
quinoli
s
nes
T
ethe
a
re
d
to Cala
b
mitic
S
ubuni
e
ts th Kapatsina, Marie Lordon, Angelika Baro, Sabine Laschat*
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
E-mail: sabine.laschat@oc.uni-stuttgart.de
Received 22 April 2008; revised 6 May 2008
R
O
Abstract: A convergent synthesis of a series of 4,4¢-functionalized
1,1¢-biisoquinolines via 1-chloro-4-hydroxyisoquinoline and sub-
R
N
O
OH
Cl
stituted biphenyl- and phenylpyrimidine ethers as building blocks is
described. The latter were prepared by Williamson etherification of
N
the respective 4-hydroxybiphenyl and -phenylpyrimidine precur-
+ Br
R
N
sors with dibromoalkanes, allowing variation of the spacer lengths.
1-Chloro-4-hydroxyisoquinoline was obtained from N-phthalimi-
doglycine ethyl ester through a Gabriel–Colman reaction as a key
step. Linkage of the building blocks by etherification in the pres-
ence of potassium carbonate gave the isoquinolines, which were
submitted to a nickel(II) chloride mediated homocoupling to yield
the ligand systems.
N
R
coupling
etherification
Cl
2
3
X
X
O
X = CH, N
R1 = C8H17, CN
O
R1
–(CH )
R =
1
2 n
spacer
mesogenic unit
Key words: biisoquinolines, biphenyls, ligands, homocoupling,
Williamson etherification
Scheme 1
O
C7H15
C8H17
Metallomesogens, that is, metal-containing thermotropic
liquid crystals, have gained increasing interest because
they combine the unique properties of transition-metal
complexes (redox reactivity, luminescence and magne-
tism) with those of liquid crystals such as anisotropy of
physical properties, self-aggregation and orientation in
electric and magnetic fields.1 Pyridines, bipyridines and
phenanthrolines are widespread coordinating ligands in
such metallomesogens. The corresponding biisoquino-
lines,2 however, have only been rarely employed for this
purpose although they might offer access to helically
twisted metal complexes.1 We thus investigated ligands of
type 1 with a 1,1¢-biisoquinoline binding unit as potential
precursors for metallomesogens (Scheme 1). As me-
sogenic unit, we chose p-alkyl-1,1¢-biphenyl, 2-alkyl-5-
phenylpyrimidine and p-cyanobiphenyl,3 due to their ca-
pability to form nematic and smectic mesophases. In order
to allow easy modification of both tether lengths and ca-
lamitic moiety, a convergent synthetic approach was en-
visaged, in which the central aryl–aryl bond is formed in
the last step (Scheme 1). The details of the synthesis are
reported below.
LiAlH4, AlCl3
C7H15COCl
AlCl3, DCE
r.t., 8 h
47%
CH2Cl2, Et2O
reflux, 24 h
84%
OH
OH
OH
4
5
6
R
R
Br(CH2)nBr
8a 8b
10
9
6
n
6
K2CO3, acetone
reflux, 24 h
yield 73% 69% 41%
OH
O(CH2)nBr
6 R = C8H17
7 R = CN
8 R = C8H17
9 R = CN
Scheme 2
ium hydride and aluminium(III) chloride in dichloro-
methane/diethyl ether, under reflux following a procedure
by Gray,5 to give 4-hydroxy-4¢-octylbiphenyl (6) in 84%
yield. The latter was submitted to Williamson
etherification6 with the respective dibromoalkane in the
presence of potassium carbonate in acetone under reflux,
yielding the alkyl-substituted biphenylethers 8a and 8b in
73% and 69%, respectively. Analogously, the commer-
cially available 4-cyano-4-hydroxybiphenyl (7) was
etherified with 1,6-dibromohexane to provide derivative 9
in 41% yield.
As depicted in Scheme 2, the 4-alkyl-1,1¢-biphenyl moi-
ety 8 was prepared starting from 4-hydroxybiphenyl (4),
which was submitted to Friedel–Crafts acylation with oc-
tanoic chloride in dichloroethane at room temperature.4a
The obtained ketone 54b was reduced with lithium alumin-
SYNTHESIS 2008, No. 16, pp 2551–2560
Advanced online publication: 17.07.2008
DOI: 10.1055/s-2008-1067184; Art ID: Z09208SS
x
x.
x
x
.
2
0
0
8
Next, 2-octyl-5-phenylpyrimidine derivative 14 was pre-
pared (Scheme 3). According to a procedure by Liepa,7 4-
© Georg Thieme Verlag Stuttgart · New York

2552
E. Kapatsina et al.
PAPER
OH
O
NMe2
O
CO2Me
1) POCl3, DMF, 70 °C
2) NaBF4
CO2Et
NaOMe, MeOH
H
N
CO2H
NH
reflux, 24 h
91%
3) Na2CO3, EtOH–H2O
72%
O
HO
HO
O
10
11
15
16
NH
NaOH, MeOH, H2O
pyridine
70 °C, 5 h
54%
92%
OH
reflux, 5 h
C8H17
12
NH2
OH
Cl
POCl3, Et3N
N
C8H17
Br(CH2)6Br
N
C8H17
reflux, 5 h
69%
N
NH
N
N
K2CO3
40%
3
17
O
Br(H2C)6O
HO
14
13
8, 9 or 14
Ar
K2CO3, MeCN, reflux, 5 h
Scheme 3
Ar
O
n O
hydroxyphenylacetic acid (10) was treated with phospho-
rus oxychloride (POCl3) and N,N-dimethylformamide fol-
lowed by addition of sodium fluoroborate (NaBF4) and
subsequent hydrolysis with sodium carbonate in aqueous
ethanol to yield 3-dimethylamino-2-(hydroxyphenyl)pro-
penal (11) in 72% overall yield. This Vilsmeier procedure
was found to be more reliable in terms of product purifi-
cation than the method by Reichardt.8 Cyclocondensation
of 11 with the known amidine 129–11 in pyridine, follow-
ing a method by Sugita, yielded phenylpyrimidine 1312 in
54% yield. Subsequent Williamson etherification with
1,6-dibromohexane under the conditions described above
provided the ether 14 in 40% yield.
O
n O
N
NiCl2⋅6H2O
PPh3, Zn, DMF
70 °C, 3 h
N
N
2a–d Cl
yield (%)
2
O
O
1, 2
n
Ar
1
n
a
6
26 22
45 18
1a–d
Ar
C8H17
CN
b 10
c
d
6
6
77
4
3
N
C8H17 35
N
The synthesis of the desired biisoquinolines 1 commenced
with a Gabriel–Colman reaction13 of N-phthalimidogly-
cine ethylester (15) and sodium methoxide in refluxing
methanol, yielding isoquinolone ester 16 in 91% yield
(Scheme 4). Ester 16 was converted into 4-hydroxyiso-
quinolone (17) in 92% yield. Subsequent treatment with
POCl3 and triethylamine under reflux provided 1-chloro-
4-hydroxyisoquinoline (3). Etherification with the calam-
itic subunits 8, 9 and 14 gave the coupling precursors 2 in
moderate to good yields. Finally, the chlorides 2 were
coupled to the fully functionalized 1,1¢-biisoquinolines 1
in the presence of NiCl2·6H2O (1.1 equivalents), PPh3 (4.1
equivalents) and zinc (1.2 equivalents) in DMF at 70 °C,
analogously to a method by Bolm.14 However, the reac-
tion suffered from tedious chromatographic purification
of the biisoquinolines with two hydrophobic tails, giving
the desired products 1 in low yields (Scheme 4). When
NiBr2(PPh3)2 and zinc in the presence of tetraethylammo-
nium iodide (Et4NI)15 were used as catalyst, no conversion
at all was observed.
Scheme 4
position, nor the biisoquinoline moiety itself, are respon-
sible for the decreased yields in series 1. In order to study
whether an additional aryl moiety in the side chain influ-
ences the heteroaryl coupling, we synthesized a series of
biisoquinolines 22 (Scheme 5).
The bromides 18a–d were prepared in 67–77% yield by
etherification of 4-hexyl- and 4-octyloxyphenol with di-
bromobutane and dibromohexane, respectively. Reaction
with 3 gave the precursor isoquinolines 20, which were
coupled under the conditions described above to give bi-
isoquinolines 22. In contrast to the alkyloxy-substituted
biisoquinolines 21, the yields of derivatives 22 were much
lower, decreasing from 13% for compounds 22a and 22b
(with butyl spacer) to trace amounts of 3–4% for com-
pounds 22c and 22d (with hexyl spacer). Thus, the addi-
tional aryl moiety in the side chain seems to have a
deleterious effect on the nickel-mediated homocoupling.
In conclusion, a convergent synthetic route to 1,1¢-biiso-
quinolines 1 tethered to different calamitic units via a
Gabriel–Colman reaction and a nickel-mediated homo-
coupling as key steps was achieved. The latter coupling
reaction could also be successfully applied to the synthe-
sis of 4,4¢-bis(alkyloxy)-1,1¢-biisoquinolines 21 with
various alkyl chain lengths. However, when 4-alkyloxy-
phenyloxy units were attached, the yields of biisoquino-
lines 22 were significantly decreased. Further conversion
of these novel ligands into transition-metal complexes and
The presence of a strongly coordinating bipyridine sub-
unit in the target molecules 1 may cause catalyst deactiva-
tion due to irreversible binding, thus decreasing the yields.
To check this issue, a series of alkoxy-substituted biiso-
quinolines 21 with various alkyl chain lengths were pre-
pared from precursors 19 (Scheme 5). All compounds 21
were obtained in good yield regardless of the alkyl chain
lengths. Even 4,4¢-bis(octadecyloxy)-1,1¢-biisoquinoline
(21m) was isolated in 74% yield.16 These results indicate
that neither the electron-donating substituents in the 4,4¢-
Synthesis 2008, No. 16, 2551–2560 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,1¢-Biisoquinolines Tethered to Calamitic Subunits
2553
R1O
2.65 (m, 2 H, 4¢-CH2), 4.73 (s, 1 H, OH), 6.87–6.90 (m, 2 H, H-3,
H-5), 7.21–7.23 (m, 2 H, H-3¢, H-5¢), 7.43–7.48 (m, 4 H, H-2, H-6,
H-2¢, H-6¢).
18a–d
n Br
H3C
Br
3
O
n
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.7, 29.3, 29.4, 29.5,
31.9 (CH2), 31.5 (4¢-CH2CH2), 35.6 (4¢-CH2), 115.6 (C-3, C-5),
126.5, 128.2 (C-2, C-6, C-2¢, C-6¢), 128.6 (C-3¢, C-5¢), 134.1, 138.1
(C-1, C-1¢), 141.5 (C-4¢), 154.8 (C-4).
HRMS (ESI, +): m/z [M + H+] calcd for C20H27O: 283.2056; found:
283.2046.
OR1
K2CO3, MeCN, reflux
O
n CH3
O
n O
18 n R1
a
b
c
d
4
4
6
6
C6H13
C8H17
C6H13
C8H17
N
N
Anal. Calcd for C20H26O: C, 85.06; H, 9.28. Found: C, 85.16; H,
9.16.
20
19 Cl
Cl
O
OR1
NiCl2⋅6H2O, PPh3, Zn, DMF, 70 °C
CH3
(Bromoalkyloxy)biphenyl Derivatives 8a, 9 and 14; General
Procedure
19
21
a
yield (%)
19 21
n O
20
n
n
O
K2CO3 (3 equiv) and dibromohexane (2.4 equiv) were added to a so-
lution of 6, 7 or 13 in acetone (50 mL) under an N2 atmosphere, and
the reaction mixture was heated under reflux for 24 h. After cooling
to r.t., the solvent was removed under vacuum and the residue was
dissolved in CH2Cl2–H2O (2:1, 75 mL). The aqueous layer was ex-
tracted with CH2Cl2 (2 × 15 mL) and the combined organic layers
were washed with H2O (2 × 25 mL) and dried (Na2SO4). The sol-
vent was removed under reduced pressure and the crude product
was purified by chromatography on SiO2 (PE–EtOAc, 50:1→5:1)
in the case of 9, or by recrystallization from EtOH for 8a and 14.
1
2
3
4
5
6
7
8
9
55 64
85 81
84 65
68 62
91 64
76 80
76 67
61 65
43 72
b
c
d
e
f
yield (%)
22
n
20 22
56 12
56 13
N
N
N
a
b
c
d
4
4
6
6
97
98
3
4
N
g
h
i
j
10 54 70
11 94 60
13 70 59
O
O
k
l
O
n
n
m 17 88 74
22a,c R1 = C6H15
22b,d R1 = C8H17
OR1
CH3
21
4-[(6-Bromohexyl)oxy]-4¢-octyl-1,1¢-biphenyl (8a)
Mp 67 °C (EtOH); Rf = 0.56 (PE–EtOAc, 20:1).
Scheme 5
FT-IR (ATR): 2917 (m), 2848 (m), 1606 (m), 1500 (m), 1465 (m),
investigation of their mesomorphic properties are under 1274 (m), 1243 (s), 1213 (m), 1033 (s), 996 (s), 842 (m), 813 (s),
784 cm–1 (m).
investigation and will be reported elsewhere.
1H NMR (500 MHz, CDCl3): d = 0.88 (t, J = 7.0 Hz, 3 H, CH3),
1.23–1.36 (m, 10 H, CH2), 1.51–1.56 (m, 4 H, OCH2CH2CH2CH2),
Melting points were measured on a Mettler–Toledo DSC822e
1.60–1.66 (m, 2 H, 4¢-CH2CH2), 1.79–1.85 (m, 2 H, CH2CH2Br),
calorimeter and are uncorrected. IR spectra were recorded on a
1.88–1.94 (m, 2 H, OCH2CH2), 2.61–2.64 (m, 2 H, 4¢-CH2), 3.43 (t,
Bruker Vector 22 FT-IR spectrometer. H and 13C NMR spectra
J = 6.8 Hz, 2 H, CH2Br), 4.00 (t, J = 6.4 Hz, 2 H, OCH2), 6.94–6.96
were recorded on a Bruker Avance 300 or a Bruker Avance 500
(m, 2 H, H-3, H-5), 7.21–7.23 (m, 2 H, H-3¢, H-5¢), 7.45–7.50 (m,
spectrometer with TMS as an internal standard. Mass spectra were
4 H, H-2, H-6, H-2¢, H-6¢).
1
obtained using a Finnigan MAT 95 or a Varian MAT 711 spec-
trometer. Flash chromatography was performed using Kieselgel 60,
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 25.3, 27.9, 29.1,
29.3, 29.4, 31.9, 32.7 (CH2), 31.6 (4¢-CH2CH2), 32.7 (CH2CH2Br),
33.8 (CH2Br), 35.6 (4¢-CH2), 67.8 (OCH2), 114.7 (C-3, C-5), 126.6,
127.9 (C-2, C-6, C-2¢, C-6¢), 128.8 (C-3¢, C-5¢), 133.7, 138.2 (C-1,
C-1¢), 141.4 (C-4¢), 158.4 (C-4).
MS (EI, +): m/z (%) = 444.2 (100) [M+], 364.2 (2), 345.0 (7), 282.2
(36) [M + H – (CH2)6Br]+, 209.1 (3), 196.1 (5), 183.1 (70), 154.1
(4), 83.1 (3), 55.0 (4), 43.0 (3) [C3H7]+.
40–63 mm (Fluka). All solvents were dried, and reactions were per-
formed in dried glassware. Petroleum ether (PE), where used, had a
boiling range of 30–75 °C. Compound 10 was purchased from
Fluka, and compounds 5,4a 117 and 1211 were prepared according to
literature procedures.
4¢-Octyl-1,1¢-biphenyl-4-ol (6)
A solution of AlCl3 (15.6 g, 117 mmol) in Et2O (60 mL) followed
by a solution of 5 (6 g, 20.2 mmol) in anhydrous CH2Cl2 (150 mL)
was added slowly to a suspension of LiAlH4 (2.76 g, 72.7 mmol) in
anhydrous Et2O (60 mL), and the reaction mixture was heated under
reflux for 24 h. The cooled mixture was poured very carefully into
H2O and the precipitate of aluminium hydroxide was dissolved in
2 N HCl (~600 mL). After separation of the layers, the aqueous lay-
er was extracted with EtOAc (4 × 200 mL) and the combined organ-
ic layers were washed with H2O (2 × 50 mL) and dried (Na2SO4).
The solvent was removed under vacuum and the residue was puri-
fied by chromatography on SiO2 (PE–EtOAc, 5:1) to give 6.
HRMS (EI, +): m/z [M+] calcd for C26H37BrO: 444.2028; found:
444.2038.
4¢-[(6-Bromohexyl)oxy]-1,1¢-biphenyl-4-carbonitrile (9)
Mp 62 °C; Rf = 0.23 (PE–EtOAc, 50:1).
FT-IR (ATR): 2935 (m), 2921 (m), 2226 (m), 1600 (m), 1493 (m),
1468 (m), 1286 (m), 1267 (m), 1240 (m), 1215 (m), 1199 (m), 1181
(m), 1076 (m), 980 (m), 854 (m), 814 (s), 727 (m), 710 (m), 659 (m),
644 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.48–1.55 (m, 4 H, CH2), 1.77–
1.98 (m, 4 H, CH2), 3.43 (t, J = 6.6 Hz, 2 H, CH2Br), 4.02 (t, J = 6.3
Hz, 2 H, OCH2), 6.95–7.02 (m, 2 H, H-3¢, H-5¢), 7.49–7.56 (m, 2 H,
H-3, H-5), 7.61–7.72 (m, 4 H, H-2, H-6, H-2¢, H-6¢).
13C NMR (125 MHz, CDCl3): d = 25.3, 27.9, 29.0, 32.7 (CH2), 33.8
(CH2Br), 67.9 (OCH2), 110.1 (C-4), 115.1 (C-3¢, C-5¢), 119.1 (CN),
127.1, 128.4 (C-2, C-6, C-2¢, C-6¢), 131.4 (C-1¢), 132.6 (C-3, C-5),
145.3 (C-1), 159.7 (C-4¢).
Yield: 4.20 g (70%); colorless crystals; mp 140 °C; Rf = 0.46 (PE–
EtOAc, 5:1).
FT-IR (ATR): 3414 (m, br), 2955 (m), 2917 (s), 2847 (m), 1609
(m), 1597 (m), 1498 (s), 1464 (m), 1375 (m), 1263 (s), 1242 (m),
1205 (m), 1179 (m), 1137 (m), 1002 (m), 840 (m), 813 (s), 784 (s),
721 (m), 682 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.4 Hz, 3 H, CH3),
1.27–1.32 (m, 10 H, CH2), 1.57–1.69 (m, 2 H, 4¢-CH2CH2), 2.60–
MS (ESI, +): m/z = 380.1 [M + Na]+, 360.1, 301.1, 149.0.
Synthesis 2008, No. 16, 2551–2560 © Thieme Stuttgart · New York

2554
E. Kapatsina et al.
PAPER
HRMS (ESI, +): m/z [M + Na+] calcd for C19H20BrNNaO:
380.0620; found: 380.0606.
and evaporated. The crude product was purified either by chroma-
tography on SiO2 and/or by recrystallization from EtOAc.
5-{4-[(6-Bromohexyl)oxy]phenyl}-2-octylpyrimidine (14)
Mp 115 °C (EtOH); Rf = 0.86 (PE–EtOAc, 1:1).
1-Chloro-4-({6-[(4¢-octyl-1,1¢-biphenyl-4-yl)oxy]hexyl}oxy)iso-
quinoline (2a)
Purified by recrystallization from EtOAc.
FT-IR (ATR): 2916 (m), 2848 (m), 1586 (m), 1536 (m), 1515 (m),
1445 (s), 1247 (s), 1180 (m), 1116 (m), 1011 (m), 994 (m), 838 (s),
651 (m), 608 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.9 Hz, 3 H, CH3),
1.21–1.45 (m, 10 H, CH2), 1.49–1.58 (m, 4 H, CH2), 1.79–1.98 (m,
6 H, CH2), 2.96–3.01 (m, 2 H, 2-CH2), 3.44 (t, J = 6.6 Hz, 2 H,
CH2Br), 4.02 (t, J = 6.4 Hz, 2 H, OCH2), 6.99–7.03 (m, 2 H, H-3,
H-5), 7.46–7.50 (m, 2 H, H-2, H-6), 8.83 (s, 2 H, H-4, H-6).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 25.3, 27.9, 28.9,
29.0, 29.2, 29.4, 31.9, 32.7 (CH2), 33.8 (CH2Br), 39.2 (2-CH2), 67.9
(OCH2), 115.2 (C-3¢, C-5¢), 128.0 (C-2¢, C-6¢), 126.7, 130.8 (C-1,
C-5), 154.8 (C-4, C-6), 159.9 (C-4), 169.5 (C-2).
Mp 74 °C (EtOAc); Rf = 0.64 (PE–EtOAc, 1:5).
FT-IR (ATR): 2920 (m), 2850 (m), 1578 (m), 1562 (m), 1499 (m),
1453 (m), 1383 (m), 1311 (s), 1271 (s), 1247 (vs), 1177 (m), 1099
(s), 997 (m), 952 (m), 818 (m), 763 (s), 726 (s), 659 (s), 611 (m),
593 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 3 H, CH3),
1.21–1.40 (m, 10 H, CH2), 1.60–1.71 (m, 6 H, CH2), 1.83–2.09 (m,
4 H, CH2), 2.59–2.65 (m, 2 H, C6H4CH2), 4.03 (t, J = 6.5 Hz, 2 H,
C6H4OCH2), 4.22 (t, J = 6.3 Hz, 2 H, 4-OCH2), 6.92–6.98 (m, 2 H,
H-3¢, H-5¢), 7.19–7.25 (m, 2 H, H-3¢¢, H-5¢¢), 7.43–7.53 (m, 4 H,
H-2¢, H-6¢, H-2¢¢, H-6¢¢), 7.65–7.76 (m, 2 H, H-6, H-7), 7.80 (s, 1 H,
H-3), 8.21–8.28 (m, 2 H, H-5, H-8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 25.9, 26.0, 29.2,
29.3, 29.4, 29.5, 31.6 (CH2), 31.9 (C6H4CH2CH2), 35.6 (C6H4CH2),
67.8, 68.8 (OCH2), 114.7 (C-3¢, C-5¢), 121.9, 126.0, 128.7, 130.3
(C-5, C-8, C-6, C-7, C-3), 126.5, 128.0 (C-2¢, C-6¢, C-2¢¢, C-6¢¢),
127.0, 130.5 (C-4a, C-8a), 128.8 (C-3¢¢, C-5¢¢), 133.7, 138.2, 141.5
(C-1¢, C-1¢¢, C-4¢¢), 142.4, 150.0 (C-1, C-4), 158.4 (C-4¢).
MS (EI, +): m/z (%) = 446.1 (100) [M+], 361.0 (20) [M+ – C6H13],
348.0 (78) [M+ – C7H15 + H], 199.0 (10), 186.0 (28).
HRMS (ESI, +): m/z [M + H+] calcd for C24H36BrN2O: 447.2006;
found: 447.1984.
4-[(10-Bromodecyl)oxy]-4¢-octyl-1,1¢-biphenyl (8b)
NaOH (67 mg, 1.68 mmol) in H2O (0.5 mL) was added dropwise to
a solution of 6 (500 mg, 1.77 mmol) and 1,10-dibromodecane (669
mg, 2.23 mmol) in H2O (5 mL) under an N2 atmosphere, and the re-
action mixture was heated under reflux for 7 h. After cooling,
CH2Cl2 (10 mL) and H2O (5 mL) were added and the layers sepa-
rated. The aqueous layer was extracted with CH2Cl2 (2 × 10 mL)
and the combined organic layers were washed with H2O (2 × 5 mL)
and dried (Na2SO4). The solvent was removed under reduced pres-
sure and the residue was purified by recrystallization from EtOAc
to give 8b.
MS (EI, +): m/z = 543.2 (100) [M+].
HRMS (ESI, +): m/z [M + H+] calcd for C35H43ClNO2: 544.2977;
found: 544.2952.
1-Chloro-4-({10-[(4¢-octyl-1,1¢-biphenyl-4-yl)oxy]decyl}oxy)iso-
quinoline (2b)
Purified by chromatography (PE–EtOAc, 5:1) and recrystallization
from EtOAc.
Mp 78 °C (EtOAc); Rf = 0.42 (PE–EtOAc, 5:1).
Yield: 400 mg (45%); colorless solid; mp 71 °C (EtOH); Rf = 0.33
FT-IR (ATR): 2918 (vs), 2851 (s), 1608 (m), 1500 (s), 1486 (m),
1451 (m), 1385 (m), 1312 (m), 1274 (s), 1248 (vs), 1177 (m), 1099
(s), 1045 (m), 1003 (m), 981 (m), 951 (m), 845 (m), 813 (s), 780
(m), 764 (vs), 720 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 3 H, CH3),
1.18–1.51 (m, 22 H, CH2), 1.61–1.71 (m, 2 H, CH2), 1.75–1.87 (m,
2 H, CH2), 1.88–2.01 (m, 2 H, CH2), 2.57–2.70 (m, 2 H, C6H4CH2),
3.99 (t, J = 6.5 Hz, 2 H, C6H4OCH2), 4.19 (t, J = 6.4 Hz, 2 H, 4-
OCH2), 6.92–6.99 (m, 2 H, H-3¢, H-5¢), 7.20–7.23 (m, 2 H, H-3¢¢,
H-5¢¢), 7.41–7.55 (m, 4 H, H-2¢, H-6¢, H-2¢¢, H-6¢¢), 7.66–7.76 (m,
2 H, H-6, H-7), 7.79 (s, 1 H, H-3), 8.23–8.27 (m, 2 H, H-5, H-8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.1, 29.2, 29.3,
29.4, 29.5, 31.6 (CH2), 31.9 (C6H4CH2CH2), 35.6 (C6H4CH2), 68.0,
69.0 (OCH2), 114.7 (C-3¢, C-5¢), 121.9, 126.0, 128.7, 130.3 (C-
5, C-8, C-6, C-7, C-3), 126.5, 128.0 (C-2¢, C-6¢, C-2¢¢, C-6¢¢), 127.0,
130.5 (C-4a, C-8a), 128.8 (C-3¢¢, C-5¢¢), 133.6, 138.2, 141.5 (C-1¢,
C-1¢¢, C-4¢¢), 142.3, 150.0 (C-1, C-4), 158.5 (C-4¢).
(PE–EtOAc, 100:1).
FT-IR (ATR): 2917 (vs), 2849 (s), 1607 (m), 1500 (s), 1473 (m),
1464 (m), 1274 (m), 1253 (s), 1214 (m), 1180 (m), 1037 (m), 1009
(m), 811 (s), 784 (m), 720 (m), 645 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 3 H, CH3),
1.19–1.55 (m, 22 H, CH2), 1.60–1.71 (m, 2 H, CH2), 1.74–1.93 (m,
4 H, CH2), 2.59–2.68 (m, 2 H, C6H4CH2), 3.41 (t, J = 6.8 Hz, 2 H,
CH2Br), 3.99 (t, J = 6.5 Hz, 2 H, OCH2), 6.91–6.98 (m, 2 H, H-3,
H-5), 7.21–7.23 (m, 2 H, H-3¢, H-5¢), 7.42–7.53 (m, 4 H, H-2, H-6,
H-2¢, H-6¢).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.1, 28.2, 28.8,
29.3, 29.4, 29.5, 31.9, 32.8 (CH2), 31.6 (4¢-CH2CH2), 34.1 (CH2Br),
35.6 (4¢-CH2), 68.0 (OCH2), 114.7 (C-3, C-5), 126.5, 127.9 (C-
2, C-6, C-2¢, C-6¢), 128.8 (C-3¢, C-5¢), 133.6, 138.2 (C-1, C-1¢),
141.4 (C-4¢), 158.5 (C-4).
MS (ESI, +): m/z = 523.3 [M + Na]+, 461.3, 399.2.
HRMS (ESI, +): m/z [M + Na+] calcd for C30H45BrNaO: 523.2546;
MS (ESI, +): m/z = 600.3 [M + H+], 318.2, 180.0.
found: 523.2546.
HRMS (ESI, +): m/z [M + H+] calcd for C39H51ClNO2: 600.3603;
found: 600.3593.
Alkylation of 1-Chloro-4-hydroxyisoquinoline (3) to Products 2,
19, 20; General Procedure
4¢-({6-[(1-Chloroisoquinolin-4-yl)oxy]hexyl}oxy)-1,1¢-biphenyl-
4-carbonitrile (2c)
Purified by chromatography (PE–EtOAc, 5:1).
K2CO3 (3 equiv) and the respective alkylbromide 8, 9, 14 or 18 (1.1
equiv) were added to a solution of 3 (1 equiv) in MeCN (30 mL) un-
der an N2 atmosphere, and the reaction mixture was heated under re-
flux for 5 h. After cooling to r.t., the solvent was removed under
reduced pressure and the residue was partitioned between CH2Cl2
(50 mL) and H2O (25 mL). The layers were separated and the aque-
ous layer was extracted with CH2Cl2 (2 × 15 mL). The combined or-
ganic layers were washed with H2O (2 × 25 mL), dried (Na2SO4)
Mp 121 °C; Rf = 0.24 (PE–EtOAc, 5:1).
FT-IR (ATR): 2943 (m), 2867 (m), 2222 (m), 1600 (m), 1576 (m),
1493 (m), 1477 (m), 1450 (m), 1384 (m), 1312 (m), 1270 (s), 1248
(s), 1173 (m), 1163 (m), 1098 (s), 1035 (m), 1026 (m), 1008 (m),
Synthesis 2008, No. 16, 2551–2560 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,1¢-Biisoquinolines Tethered to Calamitic Subunits
2555
999 (m), 983 (m), 947 (m), 852 (m), 823 (s), 802 (m), 759 (m), 728
(m), 657 cm–1 (m).
1-Chloro-4-(octyloxy)isoquinoline (19g)
Purified by chromatography (PE–EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): d = 1.61–1.74 (m, 4 H, CH2), 1.83–
1.94 (m, 2 H, CH2), 1.95–2.05 (m, 2 H, CH2), 4.05 (t, J = 6.4 Hz,
2 H, 4¢-OCH2), 4.22 (t, J = 6.4 Hz, 2 H, 4-OCH2), 6.95–7.02 (m,
2 H, H-3¢, H-5¢), 7.49–7.55 (m, 2 H, H-3¢¢, H-5¢¢), 7.60–7.77 (m,
6 H, H-6, H-7, H-2¢, H-6¢, H-2¢¢, H-6¢¢), 7.80 (s, 1 H, H-3), 8.21–
8.28 (m, 2 H, H-5, H-8).
13C NMR (125 MHz, CDCl3): d = 25.8, 25.9, 29.1, 29.2 (CH2), 67.9,
68.7 (OCH2), 110.2 (C-4¢¢), 115.0 (C-3¢, C-5¢), 119.2 (CN), 121.8,
121.9, 126.0 (C-5, C-8, C-3), 127.1, 128.4 (C-2¢, C-6¢, C-2¢¢, C-6¢¢),
127.0, 130.4 (C-4a, C-8a), 132.6 (C-3¢¢, C-5¢¢), 131.4, 142.5, 145.3,
150.0 (C-1¢, C-1¢¢, C-1, C-4, C-4¢).
Mp 67 °C; Rf = 0.52 (PE–EtOAc, 10:1).
FT-IR (ATR): 2914 (m), 1580 (m), 1455 (m), 1307 (m), 1282 (s),
1096 (m), 983 (m), 948 (m), 867 (m), 762 (s), 728 (s), 660 (s), 610
cm–1 (s).
1H NMR (500 MHz, CDCl3): d = 0.89 (t, J = 6.8 Hz, 3 H, CH3),
1.25–1.45 (m, 8 H, CH2), 1.50–1.60 (m, 2 H, CH2), 1.88–1.97 (m,
2 H, CH2), 4.18 (t, J = 6.4 Hz, 2 H, OCH2), 7.67 (ddd, J = 8.3, 6.9,
1.3 Hz, 1 H, H-6 or H-7), 7.72 (ddd, J = 8.3, 6.9, 1.3 Hz, 1 H, H-6
or H-7), 7.78 (s, 1 H, H-3), 8.21–8.23, 8.24–8.25 (2 × m, 2 H, H-5,
H-8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.1, 29.2, 29.3,
29.4, 31.8 (CH2), 68.9 (OCH2), 121.9, 125.9 (C-3, C-5, C-8), 126.9,
130.4 (C-4a, C-8a), 128.6, 130.1 (C-6, C-7), 142.3, 150.0 (C-1,
C-4).
MS (ESI, +): m/z = 479.2 [M + Na]+, 457.2 [M + H]+.
HRMS (ESI, +): m/z [M + Na+] calcd for C28H25ClN2NaO2:
479.1497; found: 479.1480.
GC-MS (EI): m/z (%) = 291 (30) [M+], 179 (100) [M+ + H – C8H17].
1-Chloro-4-({6-[4-(2-octylpyrimidin-5-yl)phenoxy]hex-
yl}oxy)isoquinoline (2d)
Purified by recrystallization from EtOAc.
Anal. Calcd for C17H22ClNO: C, 69.97; H, 7.60; N, 4.80; Cl, 12.15.
Found: C, 69.86; H, 7.57; N, 4.71; Cl, 12.09.
Mp 142 °C (EtOAc); Rf = 0.83 (PE–EtOAc, 1:1).
1-Chloro-4-(nonyloxy)isoquinoline (19h)
FT-IR (ATR): 2942 (m), 2915 (m), 2848 (m), 1586 (m), 1536 (m),
1516 (m), 1445 (s), 1394 (m), 1289 (m), 1247 (s), 1179 (m), 1116
(m), 1025 (m), 1011 (m), 995 (m), 839 (s), 721 (m), 709 (m), 652
(m), 608 (m), 561 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.85–0.90 (m, 3 H, CH3), 1.23–
1.46 (m, 10 H, CH2), 1.57–1.71 (m, 4 H, CH2), 1.79–1.94 (m, 4 H,
CH2), 1.95–2.03 (m, 2 H, CH2), 2.94–3.03 (m, 2 H, 2¢¢-CH2), 4.03
(t, J = 6.4 Hz, 2 H, 4¢-OCH2), 4.23 (t, J = 6.2 Hz, 2 H, 4-OCH2),
6.98–7.03 (m, 2 H, H-3¢, H-5¢), 7.45–7.52 (m, 2 H, H-2¢, H-6¢),
7.64–7.78 (m, 2 H, H-6, H-7), 7.80 (s, 1 H, H-3), 8.20–8.31 (m, 2 H,
H-5, H-8), 8.82 (s, 2 H, H-4¢¢, H-6¢¢).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 25.9, 28.9, 29.2,
29.5, 31.9 (CH2), 39.2 (2-CH2), 68.0 (4¢-OCH2CH2), 68.7 (4-
OCH2), 115.4 (C-3¢, C-5¢), 121.9, 126.0 (C-3, C-5, C-8), 126.8,
130.8 (C-1¢, C-5¢¢), 127.9 (C-2¢, C-6¢), 128.7, 130.2 (C-6, C-7),
127.0, 130.8 (C-4a, C-8a), 143.2, 149.7, 154.6 (C-6¢¢, C-2¢¢), 159.6,
169.7 (C-1, C-4, C-4¢¢).
Purified by chromatography (PE–EtOAc, 10:1).
Mp 57 °C; Rf = 0.52 (PE–EtOAc, 10:1).
FT-IR (ATR): 1576 (m), 1313 (m), 1272 (m), 1166 (w), 1100 (m),
949 (m), 853 (m), 773 (s), 750 (m), 728 (s), 660 (s), 614 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 6.8 Hz, 3 H, CH3),
1.25–1.45 (m, 10 H, CH2), 1.50–1.60 (m, 2 H, CH2), 1.88–1.97 (m,
2 H, CH2), 4.18 (t, J = 6.4 Hz, 2 H, OCH2), 7.66–7.77 (m, 2 H, H-6,
H-7), 7.79 (s, 1 H, H-3), 8.22–8.24, 8.24–8.26 (2 × m, 2 H, H-5, H-
8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.1, 29.2, 29.3,
29.4, 29.5, 31.9 (CH2), 68.9 (OCH2), 121.9, 126.0 (C-3, C-5, C-8),
126.9, 130.4 (C-4a, C-8a), 128.7, 130.2 (C-6, C-7), 142.3, 150.0
(C-1, C-4).
GC-MS (EI): m/z (%) = 305 (20) [M+], 179 (100) [M+ + H – C9H19].
Anal. Calcd for C18H24ClNO: C, 70.69; H, 7.91; N, 4.58; Cl, 11.59.
Found: C, 70.55; H, 7.81; N, 4.51; Cl, 11.77.
MS (ESI, +): m/z = 568.3 [M + Na]+, 546.3 [M + H]+.
HRMS (ESI, +): m/z [M + H+] calcd for C33H41ClN3O2: 546.2882;
found: 546.2875.
1-Chloro-4-(octadecyloxy)isoquinoline (19m)
Purified by chromatography (PE–EtOAc, 15:1).
Mp 67 °C; Rf = 0.43 (PE–EtOAc, 15:1).
1-Chloro-4-propoxyisoquinoline (19b)
Purified by chromatography (PE–EtOAc, 10:1).
FT-IR (ATR): 2922 (s), 2848 (s), 1575 (m), 1464 (m), 1448 (m),
1308 (m), 1275 (s), 1099 (m), 948 (m), 848 (m), 771 (s), 726 (s),
659 (m), 613 cm–1 (m).
Mp 56 °C; Rf = 0.48 (PE–EtOAc, 10:1).
1H NMR (250 MHz, CDCl3): d = 0.88 (t, J = 6.3 Hz, 3 H, CH3),
1.26–1.47 (m, 28 H, CH2), 1.50–1.62, 1.88–1.99 (2 × m, 4 H, CH2),
4.19 (t, J = 6.4 Hz, 2 H, OCH2), 7.66–7.78 (m, 2 H, H-6, H-7), 7.79
(s, 1 H, H-3), 8.23–8.28 (m, 2 H, H-5, H-8).
FT-IR (ATR): 2971 (m), 2942 (m), 1580 (m), 1562 (m), 1454 (m),
1381 (m), 1313 (s), 1277 (s), 1256 (m), 1098 (m), 996 (s), 956 (s),
901 (m), 871 (s), 799 (m), 759 (s), 727 (s), 660 (s), 640 (m), 609
cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 1.13 (t, J = 7.5 Hz, 3 H, CH3), 1.96
(qt, J = 6.4, 7.5 Hz, 2 H, OCH2CH2CH3), 4.15 (t, J = 6.4 Hz, 2 H,
OCH2CH2CH3), 7.65–7.76 (m, 2 H, H-6, H-7), 7.78 (s, 1 H, H-3),
8.22–8.23, 8.25–8.26 (2 × m, 2 H, H-5, H-8).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.1, 29.2, 29.4,
29.6, 29.7, 31.9 (CH2), 69.0 (OCH2), 121.89, 121.90, 126.0 (C-3,
C-5, C-8), 128.7 and 130.2 (C-6, C-7), 127.0 and 130.4 (C-4a, C-8a),
142.3, 150.0 (C-1, C-4).
13C NMR (125 MHz, CDCl3):
d = 10.6 (CH3), 22.6
MS (EI, +): m/z (%) = 431.3 (16) [M+], 396.4 (100) [M+ – Cl], 179
(92) [M+ – C18H37 + H].
(OCH2CH2CH3), 70.4 (OCH2CH2CH3), 121.9, 126.0 (C-3, C-5,
C-8), 128.7, 130.2 (C-6, C-7), 127.0, 130.5 (C-4a, C-8a), 142.3,
150.0 (C-1, C-4).
Anal. Calcd for C27H42ClNO: C, 75.05; H, 9.80; N, 3.23; Cl, 8.21.
Found: C, 75.16; H, 9.71; N, 3.19; Cl, 8.37.
GC-MS (EI): m/z (%) = 221 (30) [M+], 179 (100) [M+ + H – C3H7].
1-Chloro-4-{4-[4-(hexyloxy)phenoxy]butoxy}isoquinoline (20a)
Purified by recrystallization from EtOAc.
Anal. Calcd for C12H12ClNO: C, 65.02; H, 5.46; N, 6.33; Cl, 15.99.
Found: C, 64.90; H, 5.47; N, 6.22; Cl, 16.24.
Mp 80 °C; Rf = 0.86 (PE–EtOAc, 1:1).
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E. Kapatsina et al.
PAPER
FT-IR (ATR): 1510 (m), 1448 (m), 1386 (m), 1310 (m), 1273 (m),
1221 (s), 1098 (m), 1033 (m), 987 (m), 947 (m), 830 (s), 760 (m),
728 (m), 658 (m), 613 cm–1 (m).
MS (ESI, +): m/z = 478.2 [M + Na+], 456.2 [M+].
HRMS (ESI, +): m/z [M + H+] calcd for C27H35ClNO3: 456.2305;
found: 456.2291.
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.0 Hz, 3 H, CH3),
1.29–1.51 (m, 6 H, CH2), 1.70–1.81 [m, 2 H, Ph(4¢)OCH2CH2],
1.99–2.19 [m, 4 H, Ph(1¢)OCH2CH2CH2], 3.90 (t, J = 6.6 Hz, 2 H,
PhOCH2), 4.04 (t, J = 6.0 Hz, 2 H, PhOCH2), 4.27 [t, J = 5.9 Hz,
2 H, isoquinoline(4)OCH2], 6.82–6.85 (m, 4 H, H-2¢, H-3¢, H-5¢,
H-6¢), 7.66–7.76 (m, 2 H, H-6, H-7), 7.76 (s, 1 H, H-3), 8.19–8.29
(m, 2 H, H-5, H-8).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.6, 25.7, 26.1, 26.2,
29.4, 31.6 (CH2), 67.9, 68.5 (PhOCH2), 68.6 [isoquino-
line(4)OCH2], 115.4 (C-2¢, C-3¢, C-5¢, C-6¢), 121.8, 121.9, 126.0
(C-3, C-5, C-8), 127.0, 130.4 (C-4a, C-8a), 128.7, 130.3 (C-6, C-7),
142.5, 149.9 (C-1, C-4), 152.9, 153.4 (C-1¢, C-4¢).
MS (EI, +): m/z (%) = 427.2 (100) [M+], 356.1 (10) [M – C5H11]+,
249.2 (37), 234.1 (58) [M – OC6H13 – Ph – O]+, 192.0 (20) [M –
OC6H13 – Ph – OC3H6]+, 123.0 (38), 110.0 (30), 55.1 (20), 43.0 (33).
HRMS (ESI, +): m/z [M + Na+] calcd for C25H30ClNNaO3:
450.1812; found: 450.1805.
1-Chloro-4-({6-[4-(octyloxy)phenoxy]hexyl}oxy)isoquinoline
(20d)
Purified by chromatography (PE–EtOAc, 7:1)
Mp 73 °C; Rf = 0.92 (PE–EtOAc, 1:1).
FT-IR (ATR): 1508 (s), 1473 (m), 1310 (m), 1290 (m), 1274 (m),
1231 (s), 1099 (s), 1046 (m), 1033 (m), 951 (m), 823 (m), 813 (m),
766 (s), 730 (m), 661 (m), 612 (m), 524 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 3 H, CH3),
1.24–1.65 (m, 14 H, CH2), 1.71–2.03 (m, 6 H, CH2), 3.89 (t, J = 6.2
Hz, 2 H, PhOCH2), 3.94 (t, J = 6.3 Hz, 2 H, PhOCH2), 4.21 [t,
J = 6.4 Hz, 2 H, isoquinoline(4)OCH2], 6.78–6.83 (m, 4 H, H-2¢, H-
3¢, H-5¢, H-6¢), 7.66–7.77 (m, 2 H, H-6, H-7), 7.79 (s, 1 H, H-3),
8.20–8.28 (m, 2 H, H-5, H-8).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.7, 25.9, 26.0, 26.1,
29.1, 29.3, 31.9 (CH2), 29.4 [Ph(1¢)OCH2CH2, Ph(4¢)OCH2CH2,
isoquinoline(4)OCH2CH2], 68.4 [Ph(4¢)OCH2], 68.6 [Ph(1¢)OCH2],
68.8 [isoquinoline(4)OCH2], 115.4 (C-2¢, C-3¢, C-5¢, C-6¢), 121.8,
121.9, 126.0 (C-3, C-5, C-8), 126.9, 130.4 (C-4a, C-8a), 128.7,
130.3 (C-6, C-7), 142.3, 150.0 (C-1, C-4), 153.1, 153.3 (C-1¢, C-4¢).
1-Chloro-4-{4-[4-(octyloxy)phenoxy]butoxy}isoquinoline (20b)
Purified by recrystallization from EtOAc.
Mp 86 °C; Rf = 0.92 (EtOAc).
MS (ESI, +): m/z = 506.2 [M + Na+], 484.4 [M+], 449.4 [MH – Cl]+.
FT-IR (ATR): 1508 (s), 1475 (m), 1386 (m), 1310 (m), 1273 (m),
1231 (s), 1098 (m), 1048 (m), 1025 (m), 955 (m), 827 (s), 763 (s),
728 (m), 661 (m), 613 cm–1 (m).
HRMS (ESI, +): m/z [M + Na+] calcd for C29H38ClNO3: 506.2438;
found: 506.2437.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 6.9 Hz, 3 H, CH3),
1.21–1.51 (m, 10 H, CH2), 1.70–1.82 [m, 2 H, Ph(4¢)OCH2CH2],
1.99–2.21 [m, 4 H, Ph(1¢)OCH2CH2CH2], 3.92 (t, J = 6.6 Hz, 2 H,
PhOCH2), 4.04 (t, J = 5.9 Hz, 2 H, PhOCH2), 4.28 [t, J = 6.0 Hz,
2 H, isoquinoline(4)OCH2], 6.79–6.87 (m, 4 H, H-2¢, H-3¢, H-5¢, H-
6¢), 7.66–7.77 (m, 2 H, H-6, H-7), 7.81 (s, 1 H, H-3), 8.19–8.28 (m,
2 H, H-5, H-8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.1, 26.2, 29.3,
29.4, 31.8 (CH2), 68.0, 68.6 (PhOCH2), 68.7 [isoquino-
line(4)OCH2], 115.4 (C-2¢, C-3¢, C-5¢, C-6¢), 121.8, 121.9, 126.0
(C-3, C-5, C-8), 127.0, 130.4 (C-4a, C-8a), 128.7, 130.3 (C-6, C-7),
142.5, 149.9 (C-1, C-4), 152.9, 153.4 (C-1¢, C-4¢).
Coupling of Isoquinoline Derivatives 2, 19, 20 to Products 1, 21
and 22; General Procedure
A solution of NiCl2·6H2O (1.22 equiv) in degassed anhydrous DMF
(8 mL) was heated at 70 °C (bath temperature) and Ph3P (4.86
equiv) and Zn (1.31 equiv) were added. The mixture became brown
and was heated at 70 °C for 1 h, then a solution of 2a–d, 19 or 20 in
degassed anhydrous DMF (5 mL) was added. The reaction mixture
was stirred at 70 °C for 4 h (TLC monitoring). After cooling to r.t.,
the mixture was quenched with aq NH3 (5%, 21 mL), the layers
were separated and the aqueous layer was extracted with CH2Cl2–
Et2O (2:1, 3 × 25 mL). The combined organic layers were concen-
trated under vacuum and the residue was taken up in CH2Cl2 (15
mL), washed with H2O (4 × 8 mL) and brine (10 mL), dried
(Na2SO4) and concentrated under vacuum. The crude products were
purified by chromatography on SiO2 and/or by recrystallization
from EtOAc.
MS (ESI, +): m/z = 478.2 [M + Na+], 456.2 [M + H+].
HRMS (ESI, +): m/z [M + H+] calcd for C27H35ClNO3: 456.2305;
found: 456.2282.
4,4¢-Bis({6-[(4¢-octyl-1,1¢-biphenyl-4-yl)oxy]hexyl}oxy)-1,1¢-bi-
isoquinoline (1a)
Purified by chromatography (PE–EtOAc, 1:2) followed by recrys-
tallization from EtOAc.
1-Chloro-4-({6-[4-(hexyloxy)phenoxy]hexyl}oxy)isoquinoline
(20c)
Purified by recrystallization from EtOAc.
Mp 63 °C; Rf = 0.83 (EtOAc).
Mp 145 °C (EtOAc); Rf = 0.23 (PE–EtOAc, 1:2).
FT-IR (ATR): 2938 (m), 1508 (s), 1473 (m), 1453 (m), 1307 (m),
1287 (m), 1274 (m), 1224 (s), 1097 (m), 1033 (m), 999 (m), 949
(m), 825 (m), 768 (s), 729 (s), 660 (m), 613 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 6.8 Hz, 3 H, CH3),
1.27–1.54 (m, 6 H, CH2), 1.57–1.68 (m, 4 H, CH2), 1.69–1.88 (m,
4 H, CH2), 1.91–2.03 (m, 2 H, CH2), 3.90 (t, J = 6.1 Hz, 2 H,
PhOCH2), 3.94 (t, J = 5.8 Hz, 2 H, PhOCH2), 4.21 [t, J = 6.3 Hz,
2 H, isoquinoline(4)OCH2], 6.79–6.84 (m, 4 H, H-2¢, H-3¢, H-5¢,
H-6¢), 7.69–7.75 (m, 2 H, H-6, H-7), 7.79 (s, 1 H, H-3), 8.21–8.28
(m, 2 H, H-5, H-8).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.6, 25.7, 25.9, 26.0,
29.2, 29.3, 29.4, 31.6 (CH2), 68.4, 68.6 (PhOCH2), 68.8 [isoquino-
line(4)OCH2], 115.4 (C-2¢, C-3¢, C-5¢, C-6¢), 121.9, 122.0, 126.0
(C-3, C-5, C-8), 127.0, 130.4 (C-4a, C-8a), 128.7, 130.2 (C-6, C-7),
142.4, 149.9 (C-1, C-4), 153.1, 153.3 (C-1¢, C-4¢).
FT-IR (ATR): 2921 (m), 2852 (m), 1579 (m), 1498 (s), 1453 (m),
1374 (m), 1312 (m), 1273 (m), 1244 (s), 1174 (m), 1094 (m), 990
(m), 817 (m), 802 (m), 767 (m), 721 (m), 684 (m), 631 (m), 516
cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 6 H, CH3),
1.22–1.40 (m, 20 H, CH2), 1.57–1.79 (m, 12 H, CH2), 1.84–1.96 (m,
4 H, CH2), 1.99–2.11 (m, 4 H, CH2), 2.58–2.67 (m, 4 H, C6H4CH2),
4.03 (t, J = 6.5 Hz, 4 H, C6H4OCH2), 4.22 (t, J = 6.2 Hz, 4 H, 4-
OCH2), 6.95–6.99 (m, 4 H, H-3¢¢, H-5¢¢), 7.20–7.24 (m, 4 H, H-3¢¢¢,
H-5¢¢¢), 7.44–7.52 (m, 10 H, H-2¢¢, H-6¢¢, H-2¢¢¢, H-6¢¢¢, H-6 or H-7),
7.63–7.70 (m, 2 H, H-6 or H-7), 7.72–7.76 (m, 2 H, H-5 or H-8),
8.24 (s, 2 H, H-3), 8.31–8.35 (m, 2 H, H-5 or H-8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.0, 26.1, 29.3,
29.4, 29.5, 31.6 (CH2), 31.9 (C6H4CH2CH2), 35.6 (C6H4CH2), 67.9,
Synthesis 2008, No. 16, 2551–2560 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,1¢-Biisoquinolines Tethered to Calamitic Subunits
2557
68.7 (OCH2), 114.7 (C-3¢¢, C-5¢¢), 121.3, 126.9 (C-5, C-8), 122.6
(C-3), 126.5, 127.9 (C-2¢¢, C-6¢¢, C-2¢¢¢, C-6¢¢¢), 127.6, 129.3 (C-6,
C-7), 128.5, 129.1 (C-4a, C-8a), 128.8 (C-3¢¢¢, C-5¢¢¢), 133.6, 138.2,
141.4, 149.9, 150.6, 158.4 (C-1¢¢, C-1¢¢¢, C-4¢¢¢, C-1, C-4, C-4¢¢).
MS (ESI, +): m/z = 1017.7 [M + H+], 653.4, 567.3, 289.1.
HRMS (ESI, +): m/z [M + H+] calcd for C70H85N2O4: 1017.6504;
FT-IR (ATR): 2921 (m), 2851 (m), 1607 (m), 1577 (m), 1539 (m),
1517 (m), 1503 (m), 1441 (s), 1417 (m), 1392 (m), 1377 (m), 1294
(s), 1246 (s), 1181 (m), 1159 (m), 1094 (s), 1059 (m), 1027 (m), 995
(m), 934 (m), 872 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 0.87 (t, J = 6.7 Hz, 6 H, CH3),
1.20–1.48 (m, 20 H, CH2), 1.61–1.78 (m, 8 H, CH2), 1.77–1.99 (m,
8 H, CH2), 1.99–2.13 (m, 4 H, CH2), 2.93–3.04 (m, 4 H, 2¢¢¢-CH2),
4.07 (t, J = 6.7 Hz, 4 H, 4¢¢-OCH2), 4.35 (t, J = 6.2 Hz, 4 H, 4-
OCH2), 6.99–7.09 (m, 4 H, H-3¢¢, H-5¢¢), 7.43–7.52 (m, 6 H, H-2¢¢,
H-6 or H-7), 7.63–7.71 (m, 2 H, H-6 or H-7), 7.71–7.78 (m, 2 H, H-
5 or H-8), 8.24 (s, 2 H, H-3), 8.29–8.36 (m, 2 H, H-5 or H-8), 8.83
(s, 4 H, H-4¢¢¢, H-6¢¢¢).
found: 1017.6496.
4,4¢-Bis({10-[(4¢-octyl-1,1¢-biphenyl-4-yl)oxy]decyl}oxy)-1,1¢-bi-
isoquinoline (1b)
Purified by chromatography (PE–EtOAc, 5:1) followed by recrys-
tallization from EtOAc.
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 28.8, 29.2, 29.4,
31.9 (CH2), 39.0 (2¢¢¢-CH2), 67.8, 68.7 (OCH2), 115.4 (C-3¢¢, C-5¢¢),
121.5, 126.9 (C-5, C-8), 122.7 (C-3), 126.8, 130.8 (C-1¢¢, C-5¢¢¢),
127.9 (C-2¢¢, C-6¢¢), 127.5, 129.5 (C-6, C-7), 128.5, 129.1 (C-4a,
C-8a), 143.2, 149.7, 159.8, 169.7 (C-1, C-4, C-2¢¢¢, C-4¢¢), 154.4
(C-4¢¢¢, C-6¢¢¢).
Mp 127 °C (EtOAc); Rf = 0.46 (PE–EtOAc, 5:1).
FT-IR (ATR): 2923 (m), 2852 (m), 1578 (m), 1500 (m), 1454 (m),
1300 (m), 1247 (m), 1176 (m), 1097 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.9 Hz, 6 H, CH3),
1.23–1.71 (m, 48 H, CH2), 1.75–1.87 (m, 4 H, CH2), 1.94–2.06 (m,
4 H, CH2), 2.57–2.66 (m, 4 H, C6H4CH2), 4.00 (t, J = 6.5 Hz, 4 H,
C6H4OCH2), 4.33 (t, J = 6.3 Hz, 4 H, 4-OCH2), 6.92–6.98 (m, 4 H,
H-3¢¢, H-5¢¢), 7.19–7.24 (m, 4 H, H-3¢¢¢, H-5¢¢¢), 7.43–7.52 (m, 10 H,
H-2¢¢, H-6¢¢, H-2¢¢¢, H-6¢¢¢, H-6 or H-7), 7.66–7.75 (m, 4 H, H-5 or
H-8, H-6 or H-7), 8.25 (s, 2 H, H-3), 8.33–8.38 (m, 2 H, H-5 or H-
8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.1, 26.2, 29.2,
29.3, 29.4, 29.5, 29.7, 31.6 (CH2), 31.9 (C6H4CH2CH2), 35.6
(C6H4CH2), 68.1, 68.8 (OCH2), 114.7 (C-3¢¢, C-5¢¢), 121.4, 126.9
(C-5, C-8), 122.6 (C-3), 126.5, 127.9 (C-2¢¢, C-6¢¢, C-2¢¢¢, C-6¢¢¢),
127.6, 129.3 (C-6, C-7), 128.5, 129.1 (C-4a, C-8a), 128.8 (C-3¢¢¢,
C-5¢¢¢), 133.5, 138.2, 141.4, 150.0, 150.6, 158.5 (C-1¢¢, C-1¢¢¢, C-4¢¢¢,
C-1, C-4, C-4¢¢).
HRMS (ESI, +): m/z [M + H+] calcd for C66H81N6O4: 1021.6314;
found: 1021.6317.
Anal. Calcd for C66H80N6O4: C, 77.61; H, 7.89; N, 8.23. Found: C,
77.58; H, 8.00; N, 8.15.
4,4¢-Bis(propyloxy)-1,1¢-biisoquinoline (21b)
Purified by chromatography (PE–EtOAc, 1:1).
Mp 164 °C; Rf = 0.30 (PE–EtOAc, 1:1).
FT-IR (ATR): 2968 (m), 2934 (m), 1576 (m), 1502 (m), 1450 (m),
1369 (m), 1295 (s), 1276 (s), 1246 (s), 1159 (m), 1094 (s), 1057 (m),
1020 (m), 961 (m), 903 (m), 893 (m), 852 (m), 766 (s), 722 cm–1
(m).
MS (ESI, +): m/z = 1151.8 [M + Na+], 1129.8 [M + H+].
HRMS (ESI, +): m/z [M + H+] calcd for C78H101N2O4: 1129.7756;
1H NMR (300 MHz, CDCl3): d = 1.19 (t, J = 7.4 Hz, 6 H, CH3),
1.97–2.08 (m, 4 H, CH2), 4.29 (t, J = 6.4 Hz, 4 H, OCH2), 7.47 (ddd,
J = 8.4, 7.0, 1.2 Hz, 2 H, H-6 or H-7), 7.68 (ddd, J = 8.4, 7.0, 1.2
Hz, 2 H, H-6 or H-7), 7.74 (ddd, J = 8.4, 1.2, 0.8 Hz, 2 H, H-5 or
H-8), 8.24 (s, 2 H, H-3), 8.35 (ddd, J = 8.4, 1.2, 0.8 Hz, 2 H, H-5 or
H-8).
13C NMR (75 MHz, CDCl3): d = 10.7 (CH3), 22.7 (CH2), 70.3
(OCH2), 121.3, 126.9 (C-5, C-8), 122.8 (C-3), 127.6, 129.1 (C-6,
C-7), 128.5, 129.2 (C-4a, C-8a), 149.8, 150.7 (C-1, C-4).
found: 1129.7744.
4¢-[(6-{[4¢-({6-[(4¢-cyano-1,1¢-biphenyl-4-yl)oxy]hexyl}oxy)-1,1¢-
biisoquinolin-4-yl]oxy}hexyl)oxy]-1,1¢-biphenyl-4-carbonitrile
(1c)
Purified by chromatography (PE–EtOAc, 5:1).
Mp 186 °C; Rf = 0.22 (PE–EtOAc, 5:1).
MS (ESI, +): m/z = 395.2 [M + Na+], 373.2 [M + H+].
FT-IR (ATR): 2922 (m), 2223 (m), 1580 (m), 1470 (m), 1379 (m),
1268 (s), 1245 (s), 1168 (m), 1094 (s), 1024 (m), 950 (m), 830
cm–1 (m).
Anal. Calcd for C24H24N2O2: C, 77.39; H, 6.49; N, 7.52. Found: C,
77.19; H, 6.48; N, 7.49.
1H NMR (300 MHz, CDCl3): d = 1.60–1.75 (m, 10 H, CH2), 1.83–
1.95 (m, 6 H, CH2), 4.10 (t, J = 6.4 Hz, 4 H, 4¢¢-OCH2), 4.35 (t,
J = 6.4 Hz, 4 H, 4-OCH2), 6.90–6.99 (m, 4 H, H-3¢¢, H-5¢¢), 7.52–
7.59 (m, 4 H, H-3¢¢¢, H-5¢¢¢), 7.66–7.82 (m, 12 H, H-6, H-7, H-2¢¢, H-
6¢¢, H-2¢¢¢, H-6¢¢¢), 7.86 (s, 2 H, H-3), 8.26 (s, 2 H, H-3), 8.24–8.38
(m, 2 H, H-5 or H-8).
13C NMR (125 MHz, CDCl3): d = 25.8, 29.1, 29.2 (CH2), 67.9, 68.7
(OCH2), 110.3 (C-4¢¢¢), 115.0 (C-3¢¢, C-5¢¢), 119.2 (CN), 121.3,
126.9 (C-5, C-8), 122.8 (C-3), 127.1, 128.4 (C-2¢¢, C-6¢¢, C-2¢¢¢, C-
3¢¢¢), 128.6, 129.2 (C-4a, C-8a), 132.6 (C-3¢¢¢, C-5¢¢¢), 131.4, 145.3,
150.0, 159.7 (C-1, C-4, C-1¢¢, C-1¢¢¢, C-4¢¢).
4,4¢-Bis(octyloxy)-1,1¢-biisoquinoline (21g)
Purified by chromatography (PE–EtOAc, 5:1).
Mp 105 °C; Rf = 0.24 (PE–EtOAc, 5:1).
FT-IR (ATR): 2922 (m), 2853 (m), 1576 (m), 1502 (m), 1453 (m),
1296 (s), 1244 (m), 1173 (m), 1159 (m), 1096 (s), 1023 (m), 956
(m), 849 (m), 766 (s), 665 (m), 625 cm–1 (s).
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 7.3 Hz, 6 H, CH3),
1.31–1.47 (m, 16 H, CH2), 1.58–1.64 (m, 4 H, CH2), 1.97–2.02 (m,
4 H, CH2), 4.32 (t, J = 6.5 Hz, 4 H, OCH2), 7.47 (ddd, J = 8.4, 6.9,
1.2 Hz, 2 H, H-6 or H-7), 7.67 (ddd, J = 8.4, 6.9, 1.2 Hz, 2 H, H-6
or H-7), 7.73–7.75 (m, 2 H, H-5 or H-8), 8.23 (s, 2 H, H-3), 8.33–
8.35 (m, 2 H, H-5 or H-8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.2, 29.3, 29.4,
31.8 (CH2), 68.8 (OCH2), 121.3, 126.9 (C-5, C-8), 122.8 (C-3),
127.6, 129.2 (C-6, C-7), 128.5, 129.1 (C-4a, C-8a), 149.8, 150.6 (C-
1, C-4).
MS (ESI, +): m/z = 865.4 [M + Na+], 843.4 [M + H+].
HRMS (ESI, +): m/z [M + H+] calcd for C56H51N4O4: 843.3905;
found: 843.3900.
4,4¢-Bis({6-[4-(2-octylpyrimidin-5-yl)phenoxy]hexyl}oxy)-1,1¢-
biisoquinoline (1d)
Purified by recrystallization from EtOAc.
HRMS (ESI, +): m/z [M + H+] calcd for C34H44N2O2: 513.3481;
Mp 147 °C; Rf = 0.19 (PE–EtOAc, 1:1).
found: 513.3471.
Synthesis 2008, No. 16, 2551–2560 © Thieme Stuttgart · New York

2558
E. Kapatsina et al.
PAPER
Anal. Calcd for C34H44N2O2: C, 79.65; H, 8.65; N, 5.46. Found:
C, 79.41; H, 8.62; N, 5.35.
HRMS (ESI, +): m/z [M + H+] calcd for C50H61N2O6: 785.5430;
found: 785.4504.
4,4¢-Bis(nonyloxy)-1,1¢-biisoquinoline (21h)
Purified by chromatography (PE–EtOAc, 4:1).
4,4¢-Bis{4-[4-(octyloxy)phenoxy]butoxy}-1,1¢-biisoquinoline
(22b)
Purified by chromatography (PE–EtOAc, 1:1) and recrystallization
from EtOAc.
Mp 110 °C; Rf = 0.31 (PE–EtOAc, 4:1).
FT-IR (ATR): 2925 (m), 1454 (m), 1297 (s), 1096 (m), 766 (s), 686
(m), 624 cm–1 (s).
Mp 138 °C; Rf = 0.31 (PE–EtOAc, 1:1).
FT-IR (ATR): 2923 (m), 2854 (m), 1505 (s), 1468 (m), 1383 (w),
1301 (m), 1223 (s), 1094 (m), 1036 (m), 824 (m), 772 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 6.7 Hz, 6 H, CH3),
1.26–1.50 (m, 20 H, CH2), 1.56–1.66 (m, 4 H, CH2), 1.95–2.04 (m,
4 H, CH2), 4.32 (t, J = 6.4 Hz, 4 H, OCH2), 7.44 (ddd, J = 8.4, 7.1,
1.2 Hz, 2 H, H-6 or H-7), 7.68 (ddd, J = 8.4, 7.1, 1.2 Hz, 2 H, H-6
or H-7), 7.74 (ddd, J = 8.4, 1.2, 0.8 Hz, 2 H, H-5 or H-8), 8.23 (s,
2 H, H-3), 8.34 (ddd, J = 8.4, 1.2, 0.8 Hz, 2 H, H-5 or H-8).
13C NMR (63 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.2, 29.3, 29.4,
29.6, 31.9 (CH2), 68.9 (OCH2), 121.4, 126.9 (C-5, C-8), 122.8
(C-3), 127.6, 129.2 (C-6, C-7), 128.6, 129.1 (C-4a, C-8a), 149.9,
150.7 (C-1, C-4).
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 6.8 Hz, 6 H, CH3),
1.22–1.42 (m, 20 H, CH2), 1.70–1.82 [m, 4 H, Ph(4¢)OCH2CH2],
2.05–2.27 [m, 8 H, Ph(1¢)OCH2CH2CH2], 3.91 (t, J = 6.6 Hz, 4 H,
PhOCH2), 4.08 (t, J = 6.0 Hz, 4 H, PhOCH2), 4.40 [t, J = 5.9 Hz,
4 H, isoquinoline(4)OCH2], 6.80–6.91 (m, 8 H, H-2¢, H-3¢, H-5¢,
H-6¢), 7.47 (ddd, J = 8.4, 7.0, 1.3 Hz, 2 H, H-6 or H-7), 7.67 (ddd,
J = 8.4, 7.0, 1.3 Hz, 2 H, H-6 or H-7), 7.74 (ddd, J = 8.4, 1.3, 0.8
Hz, 2 H, H-5 or H-8), 8.24 (s, 2 H, H-3), 8.31 (ddd, J = 8.4, 1.3, 0.8
Hz, 2 H, H-5 or H-8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.1, 26.2, 26.3,
29.3, 29.4, 31.8 (CH2), 68.0, 68.4 (PhOCH2), 68.7 [isoquino-
line(4)OCH2], 115.4 (C-2¢, C-3¢, C-5¢, C-6¢), 121.3, 126.9 (C-5,
C-8), 122.7 (C-3), 127.6, 129.3 (C-6, C-7), 128.5, 129.0 (C-4a,
C-8a), 149.7, 150.8 (C-1, C-4), 153.1, 153.3 (C-1¢, C-4¢).
Anal. Calcd for C36H48N2O2: C, 79.96; H, 8.95; N, 5.18. Found: C,
79.70; H, 8.92; N, 5.04.
4,4¢-Bis(octadecyloxy)-1,1¢-biisoquinoline (21m)
Purified by chromatography (PE–EtOAc, 2:1).
Mp 99 °C; Rf = 0.40 (PE–EtOAc, 2:1).
MS (EI, +): m/z (%) = 840.5 (12) [M+], 741.3 (100) [M – C7H15]+,
287.0 (12), 277.2 (23), 222.1 (18), 123.0 (45), 110.0 (100), 55.0
(17).
FT-IR (ATR): 2914 (s), 2849 (s), 1471 (m), 1456 (m), 1297 (s),
1274 (m), 1102 (m), 759 (s), 715 (m), 689 (m), 624 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.7 Hz, 6 H, CH3),
1.21–1.50 (m, 56 H, CH2), 1.56–1.66 (m, 4 H, CH2), 1.95–2.04 (m,
4 H, CH2), 4.32 (t, J = 6.4 Hz, 4 H, OCH2), 7.48 (ddd, J = 8.4, 7.1,
1.2 Hz, 2 H, H-6 or H-7), 7.69 (ddd, J = 8.4, 7.1, 1.2 Hz, 2 H, H-6
or H-7), 7.74 (ddd, J = 8.4, 1.2, 0.8 Hz, 2 H, H-5 or H-8), 8.24 (s,
2 H, H-3), 8.34 (ddd, J = 8.4, 1.2, 0.8 Hz, 2 H, H-5 or H-8).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.7, 26.2, 29.1, 29.3,
29.4, 29.6, 29.7, 31.9 (CH2), 68.8 (OCH2), 121.4, 126.9 (C-5, C-8),
122.7 (C-3), 127.6, 129.2 (C-6, C-7), 128.3, 129.1 (C-4a, C-8a),
149.9, 150.6 (C-1, C-4).
HRMS (ESI, +): m/z [M + H+] calcd for C54H69N2O6: 841.5156;
found: 841.5143.
4,4¢-Bis({6-[4-(hexyloxy)phenoxy]hexyl}oxy)-1,1¢-biisoquino-
line (22c)
Purified by chromatography (PE–EtOAc, 1:1) and recrystallization
from EtOAc.
Mp 84 °C; Rf = 0.30 (PE–EtOAc, 1:1).
FT-IR (ATR): 2935 (m), 2864 (m), 1509 (s), 1474 (m), 1299 (m),
1229 (s), 1095 (m), 1038 cm–1 (m).
Anal. Calcd for C54H84N2O2: C, 81.76; H, 10.67; N, 3.53. Found: C,
81.49; H, 10.71; N, 3.43.
1H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 6.9 Hz, 6 H, CH3),
1.30–1.36 (m, 8 H, CH2), 1.41–1.48 (m, 4 H, CH2), 1.62–1.79 (m,
12 H, CH2), 1.82–1.89 (m, 4 H, CH2), 2.00–2.07 (m, 4 H, CH2),
3.90 (t, J = 6.6 Hz, 4 H, PhOCH2), 3.96 (t, J = 6.5 Hz, 4 H,
PhOCH2), 4.33 [t, J = 6.3 Hz, 4 H, isoquinoline(4)OCH2], 6.80–
6.85 (m, 8 H, H-2¢, H-3¢, H-5¢, H-6¢), 7.47 (ddd, J = 8.4, 7.0, 1.4 Hz,
2 H, H-6 or H-7), 7.66 (ddd, J = 8.4, 7.0, 1.4 Hz, 2 H, H-6 or H-7),
7.74 (ddd, J = 8.4, 1.3, 0.9 Hz, 2 H, H-5 or H-8), 8.23 (s, 2 H, H-3),
8.32 (ddd, J = 8.4, 1.3, 0.9 Hz, 2 H, H-5 or H-8).
13C NMR (125 MHz, CDCl3): d = 14.0 (CH3), 22.6, 25.7, 26.0, 29.3,
29.4, 31.6 (CH2), 68.5, 68.7 [PhOCH2, isoquinoline(4)OCH2],
115.4 (C-2¢, C-3¢, C-5¢, C-6¢), 121.3, 126.9 (C-5, C-8), 122.8 (C-3),
127.6, 129.3 (C-6, C-7), 128.5, 129.1 (C-4a, C-8a), 149.8, 150.7
(C-1, C-4), 153.1, 153.3 (C-1¢, C-4¢).
4,4¢-Bis{4-[4-(hexyloxy)phenoxy]butoxy}-1,1¢-biisoquinoline
(22a)
Purified by chromatography (PE–EtOAc, 1:1) and recrystallization
from EtOAc.
Mp 139 °C; Rf = 0.30 (PE–EtOAc, 1:1).
FT-IR (ATR): 1505 (s), 1469 (m), 1303 (m), 1225 (s), 1095 (m),
1035 (m), 831 (m), 818 (m), 771 (m), 750 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.1 Hz, 6 H, CH3),
1.27–1.51 (m, 12 H, CH2), 1.69–1.83 [m, 4 H, Ph(4¢)OCH2CH2],
2.03–2.27 [m, 8 H, Ph(1¢)OCH2CH2CH2], 3.91 (t, J = 6.6 Hz, 4 H,
PhOCH2), 4.08 (t, J = 6.1 Hz, 4 H, PhOCH2), 4.40 [t, J = 5.9 Hz,
4 H, isoquinoline(4)OCH2], 6.79–6.91 (m, 8 H, H-2¢, H-3¢, H-5¢,
H-6¢), 7.47 (ddd, J = 8.4, 6.9, 1.3 Hz, 2 H, H-6 or H-7), 7.66 (ddd,
J = 8.4, 6.9, 1.3 Hz, 2 H, H-6 or H-7), 7.74 (ddd, J = 8.4, 1.3, 0.8
Hz, 2 H, H-5 or H-8), 8.24 (s, 2 H, H-3), 8.31 (ddd, J = 8.4, 1.3, 0.8
Hz, 2 H, H-5 or H-8).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.6, 25.7, 26.2, 26.3,
29.4, 31.6 (CH2), 68.0, 68.4 (PhOCH2), 68.7 [isoquino-
line(4)OCH2], 115.4 (C-2¢, C-3¢, C-5¢, C-6¢), 121.3, 126.9 (C-5,
C-8), 122.7 (C-3), 127.6, 129.3 (C-6, C-7), 128.5, 129.0 (C-4a,
C-8a), 149.7, 150.8 (C-1, C-4), 153.0, 153.4 (C-1¢, C-4¢).
MS (ESI, +): m/z = 1683.0 [2 × MH+], 841.5 [M + H+].
HRMS (ESI, +): m/z [M + H+] calcd for C54H69N2O6: 841.5156;
found: 841.5160.
4,4¢-Bis({6-[4-(octyloxy)phenoxy]hexyl}oxy)-1,1¢-biisoquino-
line (22d)
Purified by chromatography (PE–EtOAc, 2:1).
Mp 94 °C; Rf = 0.32 (PE–EtOAc, 1:2).
FT-IR (ATR): 2929 (m), 2854 (m), 1507 (s), 1472 (m), 1299 (m),
1227 (s), 1173 (m), 1095 (m), 1035 (m), 822 (m), 769 (s), 627
cm–1 (m).
MS (ESI, +): m/z = 807.4 [M + Na+], 785.5 [M + H+], 579.2 [M + H
– OC6H13 – Ph – OCH2]+.
Synthesis 2008, No. 16, 2551–2560 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,1¢-Biisoquinolines Tethered to Calamitic Subunits
1-[(6-Bromohexyl)oxy]-4-(hexyloxy)benzene (18c)
2559
1H NMR (500 MHz, CDCl3): d = 0.88 (t, J = 6.9 Hz, 6 H, CH3),
1.23–1.48 (m, 20 H, CH2), 1.59–1.72 (m, 8 H, CH2), 1.73–1.79 (m,
4 H, CH2), 1.82–1.90 (m, 4 H, CH2), 2.00–2.07 (m, 4 H, CH2), 3.90
(t, J = 6.6 Hz, 4 H, PhOCH2), 3.96 (t, J = 6.5 Hz, 4 H, PhOCH2),
4.33 [t, J = 6.4 Hz, 4 H, isoquinoline(4)OCH2], 6.81–6.86 (m, 8 H,
H-2¢, H-3¢, H-5¢, H-6¢), 7.47 (ddd, J = 8.4, 7.0, 1.3 Hz, 2 H, H-6 or
H-7), 7.67 (ddd, J = 8.4, 7.0, 1.3 Hz, 2 H, H-6 or H-7), 7.74 (ddd,
J = 8.4, 1.3, 0.8 Hz, 2 H, H-5 or H-8), 8.23 (s, 2 H, H-3), 8.32 (ddd,
J = 8.4, 1.3, 0.8 Hz, 2 H, H-5 or H-8).
The general procedure described for 8, 9 and 14 was used with 4-
hexyloxyphenol (750 mg, 3.44 mmol) and 1,6-dibromohexane
(1.27 mL, 2.01 g, 8.26 mmol) to obtain 18c.
Yield: 824 mg (67%); colorless solid; mp 51 °C; Rf = 0.26 (PE–
EtOAc, 100:1).
FT-IR (ATR): 2935 (m), 1508 (s), 1474 (m), 1226 (s), 1031 (s), 825
(vs), 769 (s), 725 (m), 645 (m), 533 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 6.8 Hz, 3 H, CH3),
1.27–1.57 (m, 10 H, CH2), 1.69–1.82 (m, 4 H, CH2), 1.83–1.95 (m,
2 H, CH2), 3.42 (t, J = 6.8 Hz, 2 H, CH2Br), 3.90 (t, J = 6.6 Hz, 2 H,
OCH2), 3.91 (t, J = 6.5 Hz, 2 H, OCH2), 6.80–6.83 (m, 4 H, H-2,
H-3, H-5, H-6).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.6, 25.3, 25.7, 27.9,
29.2, 29.4, 31.6, 32.7, 33.8 (CH2), 68.3, 68.6 (OCH2), 115.4 (C-2,
C-3, C-5, C-6), 153.1, 153.3 (C-1, C-4).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH3), 22.7, 25.9, 26.0, 26.1,
29.3, 29.4, 31.8 (CH2), 68.5, 68.7 [PhOCH2, isoquinoline(4)OCH2],
115.4 (C-2¢, C-3¢, C-5¢, C-6¢), 121.3, 126.9 (C-5, C-8), 122.7 (C-3),
127.6, 129.3 (C-6, C-7), 128.5, 129.1 (C-4a, C-8a), 149.8, 150.7
(C-1, C-4), 153.1, 153.3 (C-1¢, C-4¢).
MS (ESI, +): m/z = 919.6 [M + Na+], 897.6 [M + H+].
HRMS (ESI, +): m/z [M + H+] calcd for C58H76N2O6: 897.5782;
found: 897.5771.
MS (EI, +): m/z (%) = 358.1 (72) [M + 81Br]+, 110.0 (100).
HRMS (ESI, +): m/z [M + Na+] calcd for C18H29BrNaO2: 379.1249;
found: 379.1230.
1-(4-Bromobutoxy)-4-(hexyloxy)benzene (18a)
The general procedure described for 8, 9 and 14, was used with 4-
hexyloxyphenol (750 mg, 3.44 mmol) and 1,4-dibromobutane (0.99
mL, 1.78 g, 8.26 mmol) to obtain 18a.
1-[(6-Bromohexyl)oxy]-4-(octyloxy)benzene (18d)
The general procedure described for 8, 9 and 14 was used with 4-
octyloxyphenol (250 mg, 1.12 mmol) and 1,6-dibromohexane (0.41
mL, 656 mg, 2.69 mmol) to obtain 18d.
Yield: 857 mg (76%); colorless solid; mp 45 °C; Rf = 0.18 (PE–
EtOAc, 100:1).
FT-IR (ATR): 2935 (m), 2871 (m), 1508 (s), 1473 (m), 1394 (m),
1277 (m), 1226 (s), 1114 (m), 1044 (m), 1029 (s), 827 (vs), 770 (s),
653 cm–1 (m).
Yield: 332 mg (77%); colorless solid; mp 57 °C; Rf = 0.34 (PE–
EtOAc, 100:1).
1H NMR (300 MHz, CDCl3): d = 0.91 (t, J = 7.0 Hz, 3 H, CH3),
1.32–1.42 (m, 6 H, CH2), 1.69–1.80 [m, 2 H, Ph(4)OCH2CH2],
1.86–1.97 (m, 2 H, H-2¢), 2.00–2.12 (m, 2 H, H-3¢), 3.49 (t, J = 6.6
Hz, 2 H, H-4¢), 3.90 [t, J = 6.2 Hz, 2 H, Ph(4)OCH2], 3.94 (t, J = 6.7
Hz, 2 H, H-1¢), 6.77–6.86 (m, 4 H, H-2, H-3, H-5, H-6).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.6, 25.7, 31.6 (CH2),
28.0 [Ph(4)OCH2CH2], 29.4 (C-2¢), 29.5 (C-3¢), 33.6 (C-4¢), 67.4
(C-1¢), 68.7 [Ph(4)OCH2], 115.4 (C-2, C-3, C-5, C-6), 152.9, 153.4
(C-1, C-4).
FT-IR (ATR): 2935 (m), 2857 (m), 1508 (s), 1474 (m), 1229 (s),
1030 (s), 1008 (m), 997 (m), 826 (s), 770 (m), 645 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.8 Hz, 3 H, CH3),
1.24–1.54 (m, 14 H, CH2), 1.69–1.82 (m, 4 H, CH2), 1.83–1.93 (m,
2 H, CH2), 3.42 (t, J = 6.8 Hz, 2 H, CH2Br), 3.89 (t, J = 6.4 Hz, 2 H,
OCH2), 3.90 (t, J = 6.4 Hz, 2 H, OCH2), 6.80–6.83 (m, 4 H, H-2, H-
3, H-5, H-6).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.7, 25.3, 26.1, 27.9,
29.2, 29.4, 31.8, 32.7, 33.8 (CH2), 68.3, 68.6 (OCH2), 115.4 (C-2,
C-3, C-5, C-6), 153.1, 153.3 (C-1, C-4).
GC-MS (EI): m/z (%) = 386 (56) [M + 81Br]+, 384 (100) [M+], 383
(12), 377 (16).
HRMS (ESI, +): m/z [M + Na+] calcd for C20H33BrNaO2: 407.1562;
+
MS (EI, +): m/z (%) = 328.1 (28) [M + 79Br]+, 135 (64) [BrC4H8 ],
110 (100), 55 (56), 43 (32).
HRMS (EI, +): m/z [M+] calcd for C16H25BrO2: 328.1038; found:
328.1025.
found: 407.1546.
1-(4-Bromobutoxy)-4-(octyloxy)benzene (18b)
The general procedure described for 8, 9 and 14 was used with 4-
octyloxyphenol (750 mg, 3.37 mmol) and 1,4-dibromobutane (0.97 Acknowledgment
mL, 1.75 g, 8.09 mmol) to obtain 18b.
We gratefully acknowledge the Deutsche Forschungsgemeinschaft,
Yield: 877 mg (73%); colorless solid; mp 52 °C; Rf = 0.16 (PE–
EtOAc, 100:1).
the Fonds der Chemischen Industrie, the Ministerium für Wissen-
schaft, Forschung und Kunst des Landes Baden-Württemberg
(Landesgraduierten fellowship for E.K.), and the European Union
(ERASMUS fellowship for M.L.) for generous financial support.
We would like to thank Lisa Steudle for skilful technical assistance.
FT-IR (ATR): 2920 (m), 1508 (s), 1473 (m), 1226 (s), 1044 (m),
1028 (s), 826 (vs), 769 (m), 653 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 0.88 (t, J = 7.1 Hz, 3 H, CH3),
1.23–1.48 (m, 10 H, CH2), 1.71–1.79 (m, 2 H, CH2), 1.88–1.95 (m,
2 H, CH2), 2.02–2.10 (m, 2 H, CH2), 3.48 (t, J = 6.6 Hz, 2 H,
CH2Br), 3.90 (t, J = 6.6 Hz, 2 H, OCH2), 3.94 (t, J = 6.1 Hz, 2 H,
OCH2), 6.78–6.85 (m, 4 H, H-2, H-3, H-5, H-6).
13C NMR (125 MHz, CDCl3): d = 4.1 (CH3), 22.7, 26.1, 28.0, 29.3,
29.4, 29.5, 31.8, 33.5 (CH2), 67.5, 68.7 (OCH2), 115.4 (C-2, C-3,
C-5, C-6), 152.9, 153.3 (C-1, C-4).
References
(1) For reviews, see: (a) Laschat, S.; Baro, A.; Steinke, N.;
Giesselmann, F.; Hägele, C.; Scalia, G.; Judele, R.;
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D. Chem. Commun. 2006, 3755. (c) Donnio, B.; Guillon,
D.; Deschenaux, R.; Bruce, D. W. In Comprehensive
MS (EI, +): m/z (%) = 356.1 (100) [M + 79Br]+, 135.0 (70)
[BrC4H8]+, 110.0 (78).
HRMS (ESI, +): m/z [M + H+] calcd for C18H30BrO2: 357.1429;
found: 357.1425.
Synthesis 2008, No. 16, 2551–2560 © Thieme Stuttgart · New York

2560
E. Kapatsina et al.
PAPER
(4) (a) Organikum, 21st ed.; Wiley-VCH: Weinheim, 2001,
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(16) Application of the catalyst system NiCl2·6H2O/Zn/PPh3 to
4-ethoxy-1-bromoisoquinoline yielded only 38% of the
desired 1,1¢-biisoquinoline 22a, whereas no product was
formed with NiBr2(PPh3)2/Zn/Et4NI. As the latter system
catalyzed the reaction with 4-ethoxy-1-chloroisoquinoline,
the experiments were carried out with chloroisoquinolines
20 in the presence of nickel chloride as the catalyst.
(2) For an excellent review on atropselective synthesis of biaryl
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Synthesis 2008, No. 16, 2551–2560 © Thieme Stuttgart · New York