Synthesis of 5,5'-disubstituted 2,2'-bipyridines for modular chemistry

Article abstract of DOI:10.1055/s-1999-3445

A 0.5-11 g scale synthesis of the 5,5'-disubstituted 2,2'-bipyridines 8 is described. The pyridine units are connected to one another by Pd-catalyzed cross-coupling reactions. This method allows one to introduce bromo functions and flexible chains at the

Full text of DOI:10.1055/s-1999-3445

3$3(5
ꢀꢁꢂ
6\QWKHVLVꢃRIꢃꢄꢅꢄ¶ꢆ'LVXEVWLWXWHGꢃꢇꢅꢇ¶ꢆ%LS\ULGLQHVꢃIRUꢃ0RGXODUꢃ&KHPLVWU\
Oliver Henze, Uwe Lehmann, A. Dieter Schlüter*
Freie Universität Berlin, Institut für Organische Chemie, Takustr. 3, D-14195 Berlin, Germany
Fax +49(30)8383357; E-mail: adschlue@chemie.fu-berlin.de
5HFHLYHGꢀꢁꢀ2FWREHUꢀꢂꢃꢃꢄꢀ
growth reactions once the bipyridines is formed, and fi-
nally, a flexible substituent which not only increases the
solubility but is also designed as a protected anchor group
for manifold purposes. An important prerequisite for the
$EVWUDFW: A 0.5–11 g scale synthesis of the 5,5’-disubstituted 2,2’-
bipyridines ꢁ is described. The pyridine units are connected to one
another by Pd-catalyzed cross-coupling reactions. This method al-
lows one to introduce bromo functions and flexible chains at the ter-
minal phenyls which optimizes this class of bidentate ligands for feasibility of this strategy was the high selectivity of the
supra- and macromolecular applications.
Stille coupling between ꢀ and ꢈ towards coupling at pyri-
dine C-2.12
.H\ꢃ :RUGV: Stille cross-coupling, bipyridines, supramolecular
chemistry, modular chemistry
We have recently reported on repetitive syntheses of oli-
gophenylene rods and hexagons using a construction kit
of orthogonally protected building blocks.1,2 These build-
ing blocks can be variably connected to one another by
transition-metal mediated cross-coupling chemistry and
allow to prepare a variety of monodisperse products with
a reasonable quantity/effort ratio. We are presently devel-
oping a related methodology for the synthesis of shape-
persistent macrocycles with integral 2,2’:2:6"-terpyridine
donor moieties for the subsequent transition-metal com-
plexation and supramolecular assembly.3 The goal of the
present contribution is to expand this project to bipy-
ridines. It describes a multigram scale synthesis of sym-
metrical bipyridines ꢁ in which pyridines, already
containing all the substituents later required for achieving
compatibility with the existing modules, are connected in
the last step to bipyridines by the Stille reaction.
Bipyridines are one of the the most important ligands in
supramolecular chemistry4 and many syntheses have been
reported.5 One synthetic way to 5,5’-disubstituted bipy-
ridines uses 5,5’-dibromobipyridines as starting material.6
In a recent elegant example this compound was used to in-
troduce acetylene units at these positions via transion met-
al-catalyzed coupling reactions.7 The route most often
used to 5,5’-dibromobipyridines involves direct bromina-
tion of bipyridines under harsh conditions.7 With com-
monly available pressure equipments this reaction only
gives a few grams of pure product. Additionally, workup
is somewhat inconvenient. Some 2,2’-bipyridines8,9 in-
cluding the parent compound10 have also been prepared
by connecting two pyridine precursors at C-2 with the
help of transition metal complexes.
Intrigued by this work and given our experience with Su-
zuki and Stille cross-coupling reactions3,11 a route to the
symmetrical target bipyridines ꢁ was devised based on the
coupling of properly substituted pyridines (Scheme). Py-
ridine ꢈ was selected as the key compound, because it
contains the Stille functionalities, a trimethyltin (TMSn)
group at C-2, an aryl bromide substituent for further
Synthesis 1999, No. 4, 683 – 687 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢁꢉ
O. Henze et al.
3$3(5
ture was added carefully to a 20% K2CO3 solution (1 L) at 0 °C and
the phases were separated. The aqueous phase was extracted with
CH2Cl2 (200 mL) and the combined organic phases were washed
with H2O (300 mL). The organic phase was dried (MgSO4), the sol-
vent removed and the resulting oil chromatographed on silica gel
(EtOAc/hexane, 1:6) to give ꢊE as a colorless oil; yield: 45.2 g
(97%); Rf 0.53 (EtOAc/hexane, 1:6).
The reactions depicted in the Scheme were carried out
with three different R substituents [R = tetrahydropyranyl
(THP), methoxymethyl (MOM), and hexyl]. Compounds
ꢊ were prepared from the readily available corresponding
benzyl alcohol.13 Lithiation of ꢊ and subsequent stannyla-
tion allowed the selective incorporation of one tributyl-
stannyl (TBSn) group to give ꢇ which was quantitively
converted into the iodo analog ꢂ. The use of TBSn as
place holder in this iodination reaction is superior to the
more commonly used alternative trimethylsilyl because of
its lower, in fact, practically lack of interference with
THP.14 The commercially available pyridine ꢉ was selec-
tively stannylated at C-3 to give ꢄ8,15 and then coupled
with compounds ꢂ to give the key pyridines ꢀ on the 2 g
(R = THP), 32 g (MOM), and 25 g scale (R = C6H13) and
in 55–60% yields. The coupling between ꢂ and ꢄ proceeds
in fact regioselectively as shown in the Scheme. Com-
pound ꢄ does not undergo homopolymerization under the
applied conditions. The conversion of ꢀ into ꢈ was carried
out by the standard sequence of lithiation/stannylation.
Pyridine ꢈ was used as the crude material because it de-
composes rapidly on silica gel during chromatography
and in a Kugelrohr apparatus on attempted distillation.
The components ꢀ and ꢈ were subjected to a Stille cou-
pling using the standard conditions16 using 3 mol % of
Pd[(PPh3)4] as a catalyst. This coupling afforded the de-
sired bipyridines ꢁ on a 400 mg (R = THP), 7 g (R =
MOM) and 11 g scale (R = C6H13). The most convincing
structural proof for ꢁ is its 13C NMR spectrum which
shows exactly the 11 expected aromatic signals.
Anal. calcd for C9H10Br2O2 (310.0): C, 34.87; H, 3.25. Found C,
34.69; H, 3.16.
1H NMR (CDCl3/TMS, 250 MHz): d = 3.40 (s, 3 H, CH3), 4.50 (s,
2 H, CH2), 4.69 (s, 2 H, CH2), 7.42 (s, 2 H, phenyl-H), 7.58 (s, 1 H,
phenyl-H).
13C NMR (CDCl3/TMS): d = 55.41, 67.39, 95.77, 122.81, 129.05,
132.99, 141.92.
MS (EI, 70 eV): P/] (%) = 308 (1.0), 310 (2.0), 312 (1.0), 250 (100).
ꢊꢅꢂꢆ'LEURPRꢆꢄꢆKH[\OR[\PHWK\OEHQ]HQHꢃꢋꢊFꢌ
To a stirred solution of NaH (4.3 g, 180.0 mmol) in THF (250 mL)
under N2 was added dropwise a solution of 3,5-dibromobenzyl al-
cohol (40 g, 150.0 mmol) in THF (50 mL). After stirring for 1 h,
hexyl bromide (39.6 g, 240 mmol) was added and the mixture re-
fluxed for 24 h. After cooling to 20 °C, H2O was added until all salts
had dissolved and the mixture diluted with Et2O (100 mL). The
phases were separated, the aqueous phase was extracted with Et2O
(2 î 100 mL) and the combined organic phases were washed with
brine (100 mL). The organic phase was dried (MgSO4), the solvent
removed, and the resulting oil was distilled to afford ꢊF as a color-
less oil; yield: 44.1 g (84%); bp 127 °C/0.02 mbar; Rf 0.81 (EtOAc/
hexane, 1:6).
Anal. calcd for C13H18Br2O (350.1): C, 44.60; H, 5.18. Found C,
44.63; H, 4.98.
1H NMR (CDCl3/TMS, 250 MHz): d = 0.90 (t, 3 H, - = 7 Hz, CH3),
1.21–1.43 (m, 6 H, g-, d-, e-CH2), 1.53–1.67 (m, 2 H, b-CH2), 3.47
(t, 2 H, - = 7 Hz, a-CH2), 4.42 (s, 2 H, benzyl-CH2), 7.42 (s, 2 H,
phenyl-H), 7.56 (s, 1 H, phenyl-H).
All chemicals were purchased from Aldrich and Acros Chimica and
used without further purification. Solvents: anhyd Et2O, THF and
toluene were distilled from sodium/benzophenone. The mass spec-
tra were recorded in the electron impact (EI) mode.
13C NMR (CDCl3/TMS, 63 MHz): d = 14.03, 22.59, 25.79, 29.60,
31.62, 70.98, 71.20, 122.86, 128.96, 132.90, 142.84.
MS (EI, 80 eV): P/] (%) = 348 (0.9), 350 (1.7), 352 (0.8), 250 (100).
ꢇꢆꢋꢂꢅꢄꢆ'LEURPREHQ]\OR[\ꢌWHWUDK\GURS\UDQꢃꢋꢊDꢌ
To a stirred solution of 3,5-dibromobenzyl alcohol (5.0 g, 18.8
mmol) and dihydropyran (4.0 g, 47.6 mmol) in CH2Cl2 (40 mL) was
added TsOH·H2O at 20 °C. After stirring for 12 h, an aq 20%
NaHCO3 solution (20 mL) was added, the phases were separated,
the aqueous phase was extracted with CH2Cl2 (20 mL) and the com-
bined organic phases were washed with H2O (50 mL). The organic
phase was dried (MgSO4), the solvent removed and the resulting oil
chromatographed on silica gel (EtOAc/hexane, 1:6) to give ꢊD as a
colorless oil; yield: 6.04 g (92%); Rf 0.54 (EtOAc/hexane, 1:6).
7ULEXW\OWLQꢃ'HULYDWLYHVꢃꢇꢍꢃ*HQHUDOꢃ3URFHGXUH
To a stirred suspension of the respective ꢊ (14.1 mmol) in Et2O (50
mL) at –78 °C was added dropwise a solution of 1.6 M of BuLi in
hexane (9.7 mL, 15.5 mmol). After 2 h, Bu3SnCl (5.53 g, 17.0
mmol) was added and the mixture was allowed to warm to 20°C.
Then H2O (30 mL) was added, the phases were separated, the aque-
ous phase extracted with Et2O (2 î 50 mL) and the combined organ-
ic phases were washed with H2O (100 mL). The organic phase was
dried (MgSO4), the solvent removed and the resulting oil chromato-
graphed on silica gel (EtOAc/hexane, 1:10) to give ꢇ as a colorless
oil.
Anal. calcd for C12H14Br2O2 (350.0): C, 41.18; H, 4.03. Found C,
40.81; H, 3.82.
1H NMR (CDCl3/TMS, 250 MHz): d = 1.45–1.95 (m, 6 H, THP),
3.49–3.61 (m, 1 H, THP), 3.80–3.94 (m, 1 H, THP), 4.41 (d, 1 H, -
= 13 Hz, benzyl-H), 4.64–4.72 (m, 2 H, benzyl-H, THP), 7.44 (s, 2
H, phenyl-H), 7.59 (s, 1 H, phenyl-H).
Amounts of ꢊ used and yields for ꢇ: ꢊD: 4.95 g, product ꢇD: 6.75 g
(85%); Rf 0.55 (EtOAc/hexane, 1:10). ꢊE: 4.40 g, product ꢇE: 6.45
g (87%); Rf 0.60 (EtOAc/hexane, 1:10). ꢊF: 4.74 g, product ꢇF: 6.77
g (89%); Rf 0.56 (EtOAc/hexane, 1:20).
13C NMR (CDCl3,/TMS, 63 MHz): d = 18.96, 25.15, 30.15, 61.74,
ꢇꢆꢋꢂꢆ%URPRꢆꢄꢆWULEXW\OVWDQQ\OEHQ]\OR[\ꢌWHWUDK\GURS\UDQꢃꢋꢇDꢌ
Anal. calcd for C24H41BrO2Sn (560.2): C, 51.46; H, 7.38. Found C,
51.28; H, 7.11.
1H NMR (CDCl3/TMS, 250 MHz): d = 0.81–0.92 (m, 9 H, CH3),
1.01–1.10 (m, 6 H, CH2), 1.25–1.40 (m, 6 H, CH2)ꢅ 1.45–1.96 (m,
12 H, CH2, THP), 3.49–3.61 (m, 1 H, THP), 3.82–3.96 (m, 1 H,
THP), 4.44 (d, 1 H, benzyl-H, 2- = 13 Hz), 4.66–4,78 (m, 2 H, ben-
zyl-H, THP), 7.32 (s, 1 H, phenyl-H), 7.47 (s, 2 H, phenyl-H).
66.87, 97.63, 122.60, 128.83, 132.62, 142.23.
MS (EI, 60 eV): P/] (%) = 348 (0.2), 350 (0.5), 352 (0.3).
ꢊꢅꢂꢆ'LEURPRꢆꢄꢆꢋPHWKR[\PHWKR[\PHWK\OꢌEHQ]HQHꢃꢋꢊEꢌ
To a vigorously stirred suspension of P2O5 (120 g) in CCl4 (300 mL)
was added a solution of 3,5-dibromobenzyl alcohol (40.0 g, 150.4
mmol) in dimethoxymethane (480 g, 6.4 mol). After 10 h this mix-
Synthesis 1999, No. 4, 683 – 687 ISSN 0039-7881 © Thieme Stuttgart · New York

3$3(5
Synthesis of 5,5’-Disubstituted 2,2’-Bipyridines for Modular Chemistry
ꢀꢁꢄ
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 9.69, 13.60, 19.24, 25.41,
27.27, 28.94, 30.46, 62.03, 68.05, 97.72, 123.12, 130.17, 133.79,
137.60, 139.84, 145.03.
ꢊꢆ%URPRꢆꢂꢆLRGRꢆꢄꢆꢋPHWKR[\PHWKR[\PHWK\OꢌEHQ]HQHꢃꢋꢂEꢌ
Anal. calcd for C9H10BrIO2 (357.0): C, 30.28; H, 2.82. Found C,
30.21; H, 2.72.
MS (EI, 60 eV): P/] (%) = 557 (0.4), 559 (0.7), 661 (0.4), 503 (100).
1H NMR (CDCl3/TMS, 250 MHz): d = 3.39 (s, 3 H, CH3), 4.48 (s,
2 H, CH2), 4.66 (s, 2 H, CH2), 4.44 (s, 1 H, phenyl-H) 7.60 (s, 1 H,
phenyl-H), 7.72 (s, 1 H, phenyl-H).
13C NMR (CDCl3/TMS, 63 MHz): d = 55.35, 67.16, 94.33, 95.68,
122.76, 129.66, 134.84, 138.47, 141.91.
ꢊꢆ%URPRꢆꢄꢆWULEXW\OVWDQQ\OꢆꢂꢆꢋPHWKR[\PHWKR[\PHWK\OꢌEHQꢆ
]HQHꢃꢋꢇEꢌ
Anal. calcd for C21H37BrO2Sn (520.1): C, 48.50; H, 7.17. Found C,
48.36; H, 6.88.
1H NMR (CDCl3/TMS, 250 MHz): d = 0.85–0.95 (m, 9 H, CH3),
1.02–1.11 (m, 6 H, CH2), 1.26–1.41 (m, 6 H, CH2) 1.48–1.61 (m, 6
H, CH2), 3.44 (s, 3 H, CH3), 4.58 (s, 2 H, CH2)ꢅ 4.71 (s, 2 H, CH2),
7.33 (s, 1 H, phenyl-H), 7.46 (s, 1 H, phenyl-H), 7.49 (s, 1 H, phe-
nyl-H).
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 9.69, 13.59, 27.26, 28.93,
55.32, 68.45, 95.71, 123.15, 130.26, 133.85, 137.80, 139.41,
145.20.
MS (EI, 70 eV): P/] (%) = 356 (9.3), 358 (9.0), 296 (47.0), 298
(45.5).
ꢊꢆ%URPRꢆꢂꢆKH[\OR[\PHWK\OꢆꢄꢆLRGREHQ]HQHꢃꢋꢂFꢌ
Anal. calcd for C13H18BrIO (397.1): C, 39.32; H, 4.57. Found C,
39.53; H, 4.26.
1H NMR (CDCl3/TMS, 250 MHz): d = 0.89 (t, 3 H, - = 7 Hz, CH3),
1.21–1.45 (m, 6 H, g-, d-, e-CH2), 1.51–1.69 (m, 2 H, b-CH2), 3.46
(t, 2 H, - = 7 Hz, a-CH2), 4.40 (s, 2 H, benzyl-CH2), 7.42ꢃ(s, 1 H,
phenyl-H), 7.60 (s, 1 H, phenyl-H), 7.72 (s, 1 H, phenyl-H).
MS (EI, 70 eV): P/] (%) = 519 (0.6), 461 (36.7), 463 (52.8), 465
(33.8).
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 14.07, 22.60, 25.79, 29.59,
ꢊꢆ%URPRꢆꢂꢆKH[\OR[\PHWK\OꢆꢄꢆWULEXW\OVWDQQ\OEHQ]HQHꢃꢋꢇFꢌ
Anal. calcd for C25H45BrOSn (560.2): C, 53.60; H, 8.10. Found C,
53.69; H, 7.81.
31.62, 70.94, 71.02, 94.39, 122.90, 129.61, 134.78, 138.43, 142.89.
MS (EI, 70 eV): P/] (%) = 396 (4.8), 398 (4.7), 296 (100), 298 (98).
1H NMR (CDCl3/TMS, 250 MHz): d = 0.79–0.96 (m, 12 H, CH3),
1.03–1.12 (m, 6 H, butyl-CH2), 1.24–1.48 (m, 12 H, CH2), 1.48–
1.69 (m, 8 H, CH2), 3.48 (t, 2 H, - = 7 Hz, a-CH2), 4.47 (s, 2 H, -
= 7 Hz, benzyl-CH2), 7.33ꢃ(s, 1 H, phenyl-H), 7.42 (s, 1 H, phenyl-
H), 7.49 (s, 1 H, phenyl-H).
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 9.69, 13.60, 14.00, 22.60,
25.86, 27.28, 28.96, 29.70, 31.67, 70.62, 72.15, 123.13, 130.05,
133.58, 137.57, 140.27, 145.00.
ꢇꢆ%URPRꢆꢄꢆWULPHWK\OVWDQQ\OS\ULGLQHꢃꢋꢄꢌ
To a stirred suspension of ꢉ (25.0 g, 106 mmol) in Et2O (700 mL)
was added dropwise at –78 °C a solution 1.6 M of BuLi in hexane
(70.0 mL, 112 mmol). After 4 h, Me3SnCl (22,5 g, 112 mmol) was
added to the resulting red solution and the mixture was allowed to
warm to 20 °C. Then H2O (300 mL) was added, the phases were
separated, the aqueous phase was extracted with Et2O (2 î 100 mL)
and the combined organic phases were washed with H2O (2 î 300
mL). The organic phase was dried (MgSO4), the solvent removed
and the resulting oil chromatographed over silica gel (EtOAc/hex-
ane, 1:6) to give a colorless oil; yield: 29.1 g (86%); Rf 0.56
(EtOAc/hexane, 1:6); bp 86°C/0.03 mbar).
MS (EI, 70 eV): P/] (%)= 559 (1.8), 501 (79.5), 503 (100), 505
(73.2).
&RQYHUVLRQꢃRIꢃꢇꢃWRꢃ,RGRꢃ&RPSRXQGVꢃꢂꢍꢃ*HQHUDOꢃ3URFHGXUH
To a solution of the respective ꢇ (8.80 mmol) in CHCl3 (50 mL)
were added small portions of I2 (2.20 g, 8.80 mmol) at 20 °C and the
resulting mixture was stirred at this temperature for 30 min when an
aq sat. solution of KF (20 mL) was added. Then aq 2 N Na2CO3 so-
lution (25 mL) was added and the resulting mixture extracted with
CHCl3 (3 î 50 mL). The organic phase was washed with aq sat.
Na2S2O5 solution (50 mL), dried (MgSO4), and the solvent re-
moved. The resulting oil was chromatographed on silica gel
(EtOAc/hexane, 1:20) to give ꢂ as a colorless oil.
HRMS: P/] calcd for C8H12BrNSn 320.91745, found 320.91738.
1H NMR (CDCl3/TMS, 270 MHz): d = 0.31 [s, 9 H, Sn(CH)3], 7.40
(d, 1 H, pyrid-H, 3- = 8 Hz), 7.58 (dd, 1 H, pyrid-H, 3- = 8 Hz, 4- =
2 Hz ), 8.31 (d, 1 H, pyrid-H, 4- = 2 Hz).
13C NMR (CDCl3, 63 MHz): d = –9.6, 127.7, 135.8, 142.7, 145.4,
156.6.
MS (EI, 70 eV): P/] (%) = 319 (7.1), 321 (10.6), 323 (6.6), 304
(68.9), 306 (100), 308 (64.5), 276 (23.0).
Amounts of ꢇ used and yields for ꢂꢎ ꢇD: 4.90 g, product ꢂD: 3.22 g
(92%); Rf 0.40 (EtOAc/hexane, 1:20). ꢇE: 3.50 g, product ꢂE: 2.21
g (91%); Rf 0.36 (EtOAc/hexane, 1:20). ꢇF: 3.36 g, product ꢂF: 2.17
g (92%); Rf 0.67 (EtOAc/hexane, 1:20).
&RXSOLQJꢃRIꢃ,RGLGHVꢃꢂꢃZLWKꢃꢇꢆ%URPRꢆꢄꢆWULPHWK\OVWDQQ\OS\ULꢆ
GLQHꢃꢋꢄꢌꢍꢃ*HQHUDOꢃ3URFHGXUH
To a solution of the respective ꢂ (6.90 mmol) and ꢄ (7.60 mmol) in
toluene (15 mL) was added (Ph3P)4Pd(240 mg, 0.20 mmol) and the
mixture refluxed for 24 h. After cooling to 20 °C, first an aq sat. KF
solution (15 mL) and then aq 2 N Na2CO3 solution (25 mL) were
added. After removal of the solids formed, the phases were separat-
ed, the aqueous phase was extracted with toluene, the combined or-
ganic phases were washed with H2O (2 î 50 mL) and dried
(MgSO4). After removal of the solvent, the residual oil was chro-
matographed on silica gel (EtOAc/hexane, 1:10) to give ꢀ as a col-
orless oil which slowly crystallized.
The conversions of ꢊ into ꢂ were also carried out at larger scales
without isolating the intermediate ꢇ. ꢊE: 38.5 g (124.2 mmol); yield
of ꢂE: 36.8 g (83%). ꢊF: 37.0 g (105.7 mmol); yield of ꢂF: 36.1 g
(85%). In this larger scale, ꢂF was isolated by distillation; bp
140 °C/0.008 mbar; without addition of KF solution.
ꢇꢆꢋꢂꢆ%URPRꢆꢄꢆLRGREHQ]\OR[\ꢌWHWUDK\GURS\UDQꢃꢋꢂDꢌ
Anal. calcd for C12H14BrIO2 (397.0): C, 36.30; H, 3.55. Found C,
36.26; H, 3.41.
1H NMR (CDCl3/TMS, 250 MHz): d = 1.43–1.90 (m, 6 H, THP),
3.47–3.59 (m, 1 H, THP), 3.79–3.90 (m, 1 H, THP)ꢅ 4.40 (d, 1 H,
benzyl-H, 2- = 13 Hz), 4.62–4.71 (m, 2 H, benzyl-H, THP), 7.46 (s,
1 H, phenyl-H), 7.61 (s, 1 H, phenyl-H), 7.72 (s, 1 H, phenyl-H).
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 19.08, 25.24, 30.26, 61.94,
66.89, 94.29, 97.79, 122.76, 129.71, 134.88, 138.35, 142.37.
Amounts of ꢂ and ꢄ used and yields for ꢀ: ꢂD: 2.70 g (6.90 mmol),
ꢄ: 2.40 g (7.60 mmol), product ꢀD: 2.17 g (59%); mp 90 °C; Rf 0.16
(EtOAc/hexane, 1:10). ꢂE: 54.70 g (153.2 mmol), ꢄ: 51.60 g (160.8
mmol), product ꢀE: 32.70 g (55%); mp 67 °C; Rf 0.13 (EtOAc/hex-
ane, 1:10). ꢂF: 40.00 g (100.7 mmol), ꢄ: 35.54 g (110.7 mmol),
product ꢀF: 24.7 g (58%); mp 39 °C; Rf 0.28 (EtOAc/hexane, 1:20).
MS (EI, 60 eV): P/] (%) = 398 (1.3), 396 (1.2), 295 (100), 297 (91).
Synthesis 1999, No. 4, 683 – 687 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢁꢀ
O. Henze et al.
3$3(5
ꢇꢆ%URPRꢆꢄꢆ>ꢂꢆEURPRꢆꢄꢆꢋWHWUDK\GURS\UDQꢆꢇꢆ\OR[\PHWK\OꢌSKHꢆ
Q\O@S\ULGLQHꢃꢋꢀDꢌ
ꢄꢅꢄ¶ꢆ%LVꢆ>ꢂꢆEURPRꢆꢄꢆꢋWHWUDK\GURS\UDQꢆꢇꢆ\OR[\PHWK\OꢌSKHQ\O@ꢆ
ꢇꢅꢇ¶ꢆELS\ULG\OꢃꢋꢁDꢌ
Anal. calcd for C34H34Br2N2O2 (694.5): C, 58.80; H, 4.94; N, 4.03.
HRMS: P/] calcd for C17H17Br2NO2 424.96260, found 424.96423.
Found C, 58.81; H, 4.89 3.64.
1H NMR (CDCl3/TMS, 250 MHz): d = 1.35–1.83 (m, 6 H, THP),
3.39–3.49 (m, 1 H, THP), 3.71–3.84 (m, 1 H, THP)ꢅ 4.39 (d, 1 H,
benzyl-H, 2- = 13 Hz), 4.62 (dd, 1 H, THP), 4.68 (d, 1 H, benzyl-H,
2- = 13 Hz), 7.32 (s, 1 H, phenyl-H), 7.36–7.44 (m, 3 H, 2 phenyl-
H, 1 pyrid-H), 7.56 (d, 1 H, pyrid-H, 3- = 8 Hz, 4- = 2 Hz), 8.39 (d,
1 H, pyrid-H, 4- = 2 Hz).
13C NMR (CDCl3/TMS, 63 MHz): d = 18.95, 25.00, 30.07, 61.78,
67.30, 97.66, 122.84, 124.26, 127.68, 128.38, 129.97, 133.93,
136.46, 137.92, 141.13, 141.33, 147.86.
1H NMR (CDCl3/TMS, 250 MHz): d = 1.41–1.90 (m, 12 H, THP),
3.44–3.59 (m, 2 H, THP), 3.77–3.91 (m, 2 H, THP)ꢅ 4.46 (d, 2 H,
benzyl-H, 2- = 13 Hz), 4.68 (dd, 2 H, THP), 4.77 (d, 2 H, benzyl-H,
2- = 13 Hz), 7.50 (s, 4 H, phenyl-H), 7.61 (s, 2 H, phenyl-H), 7.90
(dd, 2 H, pyrid-H, 3- = 8 Hz, 4- = 2 Hz), 8.43 (d, 2 H, pyrid-H, 3- =
8 Hz), 8.80 (d, 2 H, pyrid-H, 4- = 2 Hz).
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 19.22, 25.31, 30.40, 62.12,
67.78, 97.98, 120.92, 123.12, 124.71, 128.91, 130.08, 134.93,
135.10, 139.50, 141.46, 147.50, 154.88.
MS (EI, 60 eV): P/] (%) = 425 (1.3), 427 (2.3), 429 (1.2), 327 (100).
MS (EI, 60 eV): P/] = 692 (10.3), 694 (20.2), 696 (11.8), 594 (100).
ꢇꢆ%URPRꢆꢄꢆ>ꢂꢆEURPRꢆꢄꢆPHWKR[\PHWKR[\PHWK\OꢌSKHQ\O@ꢃS\ULꢆ
GLQHꢃꢋꢀEꢌ
Anal. calcd for C14H13Br2NO2 (387.1): C, 43.44; H, 3.38; N, 3.61.
ꢄꢅꢄµꢆ%LVꢆ>ꢂꢆEURPRꢆꢄꢆꢋPHWKR[\PHWKR[\PHWK\OꢌSKHQ\O@ꢆꢇꢅꢇ¶ꢆELꢆ
S\ULG\OꢃꢋꢁEꢌ
Anal. calcd for C28H26Br2N2O4 (614.3): C, 54.74; H, 4.27; N, 4.56.
Found C, 43.33; H, 3.33; N, 3.47.
Found C, 54.85; H, 4.31; N, 4.40.
1H NMR (CDCl3/TMS, 250 MHz): d = 3.38 (s, 3 H, CH3), 4.59 (s,
2 H, CH2), 4.69 (s, 2 H, CH2)ꢅ 7.40 (s, 1 H, phenyl-H), 7.46–7.54
(m, 3 H, 2 phenyl- H, 1 pyrid- H), 7.64 (dd, 1 H, pyrid-H, 3- = 8 Hz,
4- = 2 Hz), 8.49 (d, 1H, pyrid-H, 4-= 2 Hz).
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 55.36, 67.88, 95.79, 123.12,
124.52, 127.93, 128.85, 130.25, 134.20, 136.68, 138.34, 141.17,
141.42, 148.13.
1H NMR (CDCl3/TMS, 250 MHz): d = 3.44 (s, 6 H, CH3), 4.65 (s,
4 H, CH2), 4.75 (s, 4 H, CH2)ꢅ 7.57 (s, 4 H, phenyl-H), 7.70 (s, 2 H,
phenyl- H), 7.99 (dd, 2 H, pyrid-H, 3- = 8 Hz, 4- = 2 Hz), 8.50 (d, 2
H, pyrid-H, 3- = 8 Hz), 8.89 (d, 2 H, pyrid-H, 4- = 2 Hz).
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 55.49, 68.15, 95.92, 121.00,
123.21, 124.78, 129.14, 130.15, 134.95, 135.19, 139.65, 141.08,
147.53, 154.94.
MS (EI, 70 eV): P/] (%) = 385 (7.5), 387 (14.2), 389 (7.2), 327
(100).
MS (EI, 70 eV): P/] = 612 (53.4), 614 (100), 616 (55.4).
ꢄꢅꢄµꢆ%LVꢆꢋꢂꢆEURPRꢆꢄꢆKH[\OR[\PHWK\OSKHQ\Oꢌꢆꢇꢅꢇ¶ꢆELS\ULG\Oꢃ
ꢋꢁFꢌꢎ
Anal. calcd for C36H42Br2N2O2 (694.5): C, 62.23; H, 6.10; N, 4.03.
Found C, 62.22; H, 6.16; N, 3.88.
1H NMR (CDCl3/TMS, 250 MHz): d = 0.89 (t, 6 H, - = 7 HZ, CH3),
1.19–1.46 (m, 12 H, g-, d-, e-CH2), 1.55–1.70 (m, 4 H, b-CH2), 3.54
(t, 4 H, - = 7 Hz, a-CH2), 4.58 (s, 4 H, benzyl-CH2), 7.53ꢃ(s, 4 H,
phenyl-H), 7.68 (s, 2 H, phenyl-H), 7.99 (dd, 2 H, pyrid-H, 3- = 8
Hz, 4- = 2 Hz), 8.50 (d, 2 H , pyrid- H, 3- = 8 Hz), 8.88 (d, 2 H, pyrid-
H, 4- = 2 Hz).
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 13.98, 22.55, 25.81, 29.62,
31.60, 70.97, 71.78, 120.94, 123.15, 124.49, 128.88, 129.93,
134.95, 135.09, 139.53, 141.91, 147.50, 154.90.
ꢇꢆ%URPRꢆꢄꢆꢋꢂꢆEURPRꢆꢄꢆKH[\OR[\PHWK\OSKHQ\OꢌS\ULGLQHꢃꢋꢀFꢌ
Anal. calcd for C18H21Br2NO (427.2): C, 50.61; H, 4.96; N, 3.28.
Found C, 50.52; H, 4.92; N, 3.16.
1H NMR (CDCl3/TMS, 250 MHz): d = 0.89 (t, 3 H, - = 7 Hz, CH3),
1.20–1.46 (m, 6 H, g-, d-, e-CH2), 1.53–1.70 (m, 2 H, b-CH2)ꢅ 3.51
(t, 2 H, - = 7 Hz, a-CH2), 4.52 (s, 2 H, benzyl-CH2), 7.41ꢃ(s, 1 H,
phenyl-H), 7.50– 7.56 (m, 3 H, 2 phenyl-H, 1 pyrid.-H), 7.68 (dd, 1
H, pyrid.-H, 3- = 8 Hz, 4- = 2 Hz), 8.52 (d, 1 H , pyrid. H, 4- = 2 Hz).
13C NMRꢀ(CDCl3/TMS, 63 MHz): d = 13.96, 22.52, 25.77, 29.57,
31.56, 71.01, 71.64, 123.21, 124.42, 128.01, 128.80, 130.21,
134.45, 136.78, 138.41, 141.48, 142.11, 148.26.
MS (EI, 70 eV): P/] = 425 (5.0), 427 (9.4), 429 (4.8), 327 (100).
MS (EI, 70 eV): P/] (%) = 692 (43.3) 694 (82.0), 696 (48.7).
%LS\ULGLQHVꢃꢁꢍꢃ*HQHUDOꢃ3URFHGXUH
To a stirred solution of the respective ꢀ (1.80 mmol) in Et2O (20
mL) was added at –78 °C a 1.6 N solution of BuLi in hexane (1.2
mL, 1.9 mmol). After 2 h, to the resulting red solution was added a
solution of Me3SnCl (5% excess based on BuLi) in Et2O (10 mL).
The mixture was allowed to reach 20 °C and the solvent removed.
To the remaining brownish oil ꢈ was added a second portion of the
same ꢀ dissolved in toluene (10 mL). After the addition of
(Ph3P)4Pd (3 mol %), the mixture was refluxed for 24 h and then
cooled to 20 °C. Then, first an aq sat. KF solution (15 mL) was add-
ed followed by aq 2 N Na2CO3 solution (25 mL) before the organic
material was extracted with toluene (50 mL). The organic phase was
washed with H2O (100 mL) and dried (MgSO4). After removal of
the solvent, the residual oil was chromatographed on silica gel
(EtOAc/hexane, 1:3) to give a yellow oil which slowly crystallized.
$FNQRZOHGJHPHQW
Support of this work by the Deutsche Forschungsgemeinschaft (Sfb
448, Teilprojekt A1) and the Fonds der chemischen Industrie is gra-
tefully acknowledged. O. H. thanks the Graduiertenkolleg "Synthe-
tische, mechanistische und verfahrenstechnische Aspekte von
Metallkatalysatoren" for financial support. We thank M. Mujkic for
her competent help with some of the experiments.
5HIHUHQFHV
(1) Hensel, V.; Schlüter, A. D. /LHEꢅꢀ$QQꢅꢆꢀ5HFXHLO ꢊꢏꢏꢈ, 303.
Hensel, V.; Lützow, K.; Jacob, J.; Geßler, K.; Saenger, W.;
Schlüter, A. D. $QJHZꢅꢀ&KHPꢅ ꢊꢏꢏꢈ, ꢂꢇꢃ, 2768; $QJHZꢅꢀ
&KHPꢅꢀ,QWꢅꢀ(Gꢅꢀ(QJOꢅꢀꢊꢏꢏꢈ, ꢈꢁ, 2654. Hensel, V.; Schlüter, A.
D. &KHPꢅꢀ(XUꢅꢀ-. ꢊꢏꢏꢁ, ꢉ, 421.
Hensel, V.; Schlüter, A. D. (XUꢅꢀ-ꢅꢀ2UJ. &KHP., in press.
(2) For a recent review on repetitive/iterative synthesis in organic
chemistry, see:
Amounts of ꢀ used and yields for ꢁ: ꢀDꢃfirst portion: 780 mg (1.80
mmol), second portion: 770 mg (1.80 mmol), product ꢁD: 420 mg
(34%); mp 144 °C; Rf 0.19 (EtOAc/hexane, 1:3). ꢀEꢃfirst portion:
14.0 g (36.2 mmol), second portion: 14.0 g (36.2 mmol), product
ꢁE: 7.3 g (33%); mp 143 °C; Rf 0.10 (EtOAc/hexane, 1:3). ꢀFꢃfirst
portion: 12.0 g (28.1 mmol), second portion: 12.0 g (28.1 mmol),
product ꢁF: 11.0 g (56%); mp 90 °C; Rf 0.19 (EtOAc/hexane, 1:6).
7RSꢅꢀ&XUUꢅꢀ&KHP., Vol. 197, Vögtle, F., Ed.; Springer: Berlin,
1998.
Synthesis 1999, No. 4, 683 – 687 ISSN 0039-7881 © Thieme Stuttgart · New York

3$3(5
Synthesis of 5,5’-Disubstituted 2,2’-Bipyridines for Modular Chemistry
ꢀꢁꢈ
(3) Lehmann, U.; Henze, O.; Schlüter, A. D. &KHPꢅꢀ(XUꢅꢀ-., in
press.
(9) For an oligopyridine synthesis, see:
Cardenas, D. J.; Sauvage, J.-P. 6\QOHWW ꢊꢏꢏꢀ, 916.
(4) For example, see:
(10) Yamamoto, Y.; Azuma, Y.; Mitoh, H. 6\QWKHVLV ꢊꢏꢁꢀ, 564.
(11) Schlüter, A. D.; Wegner, G. $FWDꢀ3RO\PHU. ꢊꢏꢏꢂ, ꢍꢍ, 59.
Frahn, J.; Karakaya, B.; Schäfer, A.; Schlüter, A. D.ꢀ
7HWUDKHGURQꢀꢊꢏꢏꢈ, ꢉꢈ, 15459.
(12) It is not clear whether the coupling ofꢃꢀ and ꢈ follows
exclusively a cross-coupling pattern.
Comprehensive Supramolecular Chemistry, Lehn, J.-M., Ed.;
Vol. 9, Pergamon: London, 1996.
(5) Spitzner, D. In +RXEHQꢊ:H\O, 4th ed., Vol. E 7b, Kreher, R.,
Ed.; Thieme: Stuttgart, 1992; p 304, 318, 322, 433, 437, 446,
530, 593, 614, 615, 628, 656.
(6) Romero, F. M.; Ziessel, R. 7HWUDKHGURQꢀ/HWW. ꢊꢏꢏꢄ, ꢈꢁ, 6471.
(7) Hissler, M.; El-ghayoury, A.; Harriman, A.; Ziessel, R.
$QJHZꢅꢀ&KHP. ꢊꢏꢏꢁ, ꢂꢂꢇ, 1804; $QJHZꢅꢀ&KHPꢅꢀ,QWꢅꢀ(Gꢅꢀ(QJO.
ꢊꢏꢏꢁ, ꢈꢋ, 1717.
Grosshenny, V.; Romero, F. M.; Ziessel, R. -ꢅꢀ2UJꢅꢀ&KHP.
ꢊꢏꢏꢈ,ꢀꢁꢌ, 1491, and references cited therein.
(8) For example, see: Bolm, C.; Ewald, M.; Felder, M.;
Schlinghoff, G. &KHPꢅꢀ%HUꢅ ꢊꢏꢏꢇ, ꢂꢌꢉ, 1169.
(13) Dickinson, R. P.; Dack, K. N.; Long, C. J.; Steele, J. -ꢅꢀ0HGꢅꢀ
&KHP. ꢊꢏꢏꢈ, ꢍꢇ, 3442.
(14) Stannyl instead of the more commonly used silyl group was
introduced because iododestannylation proceeds at milder
conditions than iododesilylation and, thus, leaves even the
sensitive THP group intact.
(15) Parham, W. E.; Piccirilli, R. M. -ꢅꢀ2UJꢅꢀ&KHP. ꢊꢏꢈꢈ, ꢍꢌ, 257.
(16) Stille, J. K.ꢀ$QJHZꢅꢀ&KHPꢅꢀꢊꢏꢁꢀꢆꢀꢃꢄꢆ 504ꢎꢀ$QJHZꢅꢀ&KHPꢅꢀ,QWꢅꢀ
(Gꢅꢀ(QJO.ꢃꢊꢏꢁꢀ, ꢌꢉ, 508.
Synthesis 1999, No. 4, 683 – 687 ISSN 0039-7881 © Thieme Stuttgart · New York