Synthesis of amino-functionalized 2,2′-bipyridines

Article abstract of DOI:10.1055/s-2007-983824

Amino-functionalized 2,2′-bipyridines are versatile building blocks for the synthesis of sophisticated chelating ligands with the 2,2′-bipyridine core. The 4-, 5-, and 6-substituted 2-chloro-and 2-bromopyridine building blocks were prepared and coupled to symmetrically and non-symmetrically diamino-functionalized compounds by homo- and cross-coupling procedures. Further transformations were carried out to demonstrate the synthetic versatility of these compounds and the employed procedures. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983824

PAPER
2711
Synthesis of Amino-Functionalized 2,2¢-Bipyridines
S
ynthesis of
Diamino-
a
¢
-bipyrid
r
ines from
k
2-Bromo-
o
H
nes apke,b Holger Staats,a Ivonne Wallmann,a Arne Lützen*a
a
b
Received 25 May 2007
cal examples, involving conventional multistep proce-
dures and metal-catalyzed reactions.6 Recently, we
presented a new homo-coupling approach to 5,5¢-diami-
no-substituted 2,2¢-bipyridine, an interesting building
Abstract: Amino-functionalized 2,2¢-bipyridines are versatile
building blocks for the synthesis of sophisticated chelating ligands
with the 2,2¢-bipyridine core. The 4-, 5-, and 6-substituted 2-chloro-
and 2-bromopyridine building blocks were prepared and coupled to
symmetrically and non-symmetrically diamino-functionalized block for the construction of helicates.7 The expansion of
compounds by homo- and cross-coupling procedures. Further trans-
formations were carried out to demonstrate the synthetic versatility
of these compounds and the employed procedures.
this concept to the 4,4¢- and 6,6¢-isomers will be presented
in this paper. The 4,5¢-, 4,6¢- and 5,6¢-substituted conge-
ners, however, are still missing comparable efficient syn-
Key words: cross-coupling reactions, bipyridine, palladium, pro-
tecting group, amines
thetic entries and have not been previously synthesized. In
all cases the choice of the protecting group is crucial for
the coupling step and subsequent transformations. Previ-
ously we utilized the easily installed and deprotected pyr-
Bipyridines, especially 2,2¢-bipyridines, are one of the
most widely applied classes of ligands for the construction
of metal complexes and they have found broad applica-
tion, notably in supramolecular chemistry, photochemis-
try, and catalysis.1 Nature also uses this building block in
a number of naturally occurring substances.2 Newkome
and Schubert et al. have extensively reviewed the numer-
ous methods for the synthesis of symmetrically as well as
non-symmetrically substituted 2,2¢-bipyridines that have
emerged in recent years;3 non-symmetrically substituted
ligand systems could give access to more advanced appli-
cations and may lead to novel ideas for their use in future
applications. In particular, cross-coupling reactions have
become established in recent years as an efficient tool for
the construction of a number of different bipyridine cores,
replacing previous, frequently multistep, procedures. Re-
cently, we described a convenient access to the bipyridine
framework via modified Negishi cross-coupling reactions
to a series of mono- and variously disubstituted bipy-
role group as an efficient tool for the protection of the
amino groups in Negishi cross-coupling reactions.4 The
complete series of 4-, 5-, and 6-pyrrole-substituted 2-ha-
lopyridines as chloro and bromo derivatives can be effi-
ciently prepared, generally in excellent yields, by the
known reaction of the free amine with hexane-2,5-dione
in toluene (Figure 1).4
N
N
N
N
X
N
X
N
X
1a X = Cl
1b X = Br
2a X = Cl
2b X = Br
3a X = Cl
3b X = Br
Figure 1 Protected amino-substituted halopyridines as building
blocks for the synthesis of diamino-2,2¢-bipyridines
ridines with a broad spectra of functional groups, explor- In our original homo-coupling protocol the nickel com-
ing the synthetic depth of this approach.4 Herein, we plex, dibromobis(triphenylphosphine)nickel(II) [NiBr2
would like to report on the extension of this methodology (PPh3)2] was used together with zinc powder and tetraeth-
to the synthesis of novel amino-functionalized 2,2¢-bipy- ylammonium iodide.7 This catalyst system gave the pro-
ridines with subsequent transformations to other function- tected 5,5¢-diamino-2,2¢-bipyridine (8) from 2a in 85%
alities.
yield.
The amino group, in general, is one of the central func- The modification of this protocol by the supplementary
tional groups and can act as a chemical all-rounder; in par- addition of lithium chloride resulted in an improved per-
ticular, it can act as a precursor for other functional groups formance of the homo-coupling reaction, exemplified for
such as halides, imines, amides, etc. Thus, amination re- the synthesis of 5 (85% yield without vs. 94% yield with
actions have attracted much interest over the last decade.5 LiCl as additive).8 Therefore, using the pyrrole-protected
The synthesis of diamino-substituted 2,2¢-bipyridines, chloropyridines 1a or 2a the products 4 and 5 were isolat-
however, has thus far only been established for symmetri- ed in very high to quantitative yields (Scheme 1). Howev-
er, 3a was somewhat less stable than the other chlorides,
thus, we used the respective bromide 3b instead; Iyoda et
al. were able to demonstrate that bromides are equally
well suited to homo-coupling reactions under similar con-
SYNTHESIS 2007, No. 17, pp 2711–2719
Advanced online publication: 30.07.2007
DOI: 10.1055/s-2007-983824; Art ID: Z13107SS
x
x.
x
x
.
2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

2712
M. Hapke et al.
PAPER
N
N
H2N
a)
N
N
N
Br
N
N
N
N
N
N
a)
b)
2
10 (70%)
3b
N
N
N
X
b)
1a (4-pyrrolo)
2a (5-pyrrolo)
3b (6-pyrrolo)
NH2
7 (4,4'-diamino, 94%)
8 (5,5'-diamino, 77%)
9 (6,6'-diamino, 46%)
N
4 (4,4'-subst., 99%)
5 (5,5'-subst., 94%)
6 (6,6'-subst., 91%)
N
H2N
NH2
11 (84%)
Scheme 1 Synthesis of symmetrical diamino-2,2¢-bipyridines by
homo-coupling reactions. Reagents and conditions: (a) NiBr2(PPh3)2,
Zn powder, LiCl, n-Bu4NI, heat; (b) NH2OH·HCl, Et3N, EtOH, H2O,
heat.
Scheme 2 Synthesis of non-symmetrically substituted diamino-
2,2¢-bipyridines via the Negishi cross-coupling reaction, exemplified
for the preparation of 10 and 11. Reagents and conditions: (a) t-BuLi,
THF, –78 °C then ZnCl2, r.t. then 1a, Pd(Pt-Bu3)2, THF, heat; (b)
NH2OH·HCl, Et3N, EtOH, H2O, heat.
ditions.9 In fact, using 3b in this reaction gave the desired
protected bipyridine 6 also in very good yield.
appropriate chloro derivative 1a, 2a, or 3a was then added
together with the palladium catalyst and the resulting so-
lution was heated in tetrahydrofuran to yield the bipyri-
dine product after workup, which was then deprotected
following the usual protocol (Scheme 2).
The protected bipyridines 4, 5, and 6 can easily be depro-
tected by a standard procedure to yield the free diamines
in good to excellent yields.7 This approach conveniently
delivers diaminobipyridine building blocks, which can be
imagined to have a wide variety of areas of application,
especially in supramolecular chemistry.10
In order to identify the most favorable combination of
starting materials, we examined the reactions using both
the chloride and the bromide of the coupling partners with
their appropriate counterparts (Table 1).
For the synthesis of non-symmetrically substituted diami-
no-2,2¢-bipyridines, we employed our established cross-
coupling approach. As already reported the pyrrole group
easily allows the preparation of the corresponding 2-orga- These results clearly demonstrate that 3a is not really suit-
nozinc reagents from 2-bromopyridines.4b The starting ed for these purposes because it is the by far least reactive
compounds 1b, 2b, or 3b were lithiated using tert-butyl- and least stable compound of this series (Table 1, entries
lithium for lithiation and zinc chloride for the transmeta- 2 and 6). In fact 3a only gave the desired coupling product
lation, giving the respective organozinc species. The 15 when reacted with the most reactive bromo compound
Table 1 Synthesis of the Protected and Unprotected Diamino-2,2¢-bipyridines by Negishi Cross-Coupling Reactions and Subsequent Depro-
tection
Entry Chloropyridine Bromopyridine Cross-coupling product
Yield (%) Diaminobipyridine
Yield (%)
84
1
2
1a
3a
3b
1b
70
0a
N
N
N
N
N
N
H2N
H2N
NH2
11
10
3
4
1a
2a
2b
1b
75
61
30b
N
N
N
N
N
NH2
13
12
N
N
5
6
2a
3a
3b
2b
68
38
61
N
N
NH2
N
N
H2N
15
N
14
a Only dehalogenated 4-pyrrolopyridine derived from 1b was isolated.
b Low yield due to isolation problems during the purification process.
Synthesis 2007, No. 17, 2711–2719 © Thieme Stuttgart · New York

PAPER
Synthesis of Diamino-2,2¢-bipyridines from 2-Bromo- and 2-Chloropyridines
2713
N
2b but did not yield any coupling product 11 when reacted
with 1b.
a)
b)
c)
N
However, employing the matching pairs 1a and 3b, 1a
and 2b, or 2a and 3b (Table 1, entries 1, 3, and 5) gave the
desired protected diamino-bipyridines 10, 12, and 14 in
68–75% yield, which were subsequently deprotected to
give the non-symmetrically substituted diamino-2,2¢-bi-
pyridines 11, 13, and 15.
I
I
17 (33%)
N
N
N
N
H2N
NH2
Br
Br
18 (49%)
11
For reasons of curiosity we also attempted the coupling
reaction of the 3-pyrrole-substituted chloropyridine 16
with a pyridinylzinc reagent, but it was not a surprise that
these attempts were unsuccessful and no coupling product
was isolated. It is reasonable to assume that in the 3-posi-
tion and ortho to the proposed new bond, high steric hin-
drance is exerted by the pyrrole group thus preventing
formation of the final bond. The starting chloropyridine
16 was isolated unchanged in nearly quantitative yield
(Scheme 3).
N
N
AcHN
NHAc
19 (69%)
Scheme 4 Synthesis of halogenated and acetylated derivatives of
diamino-2,2¢-bipyridine 11. Reagents and conditions: (a) NaNO2, 2
M H2SO4, –10 °C; then KI, H2O, 0 °C; (b) Br2, HBr (62%), NaNO2,
–10 °C; then 0 °C; (c) AcCl, pyridine.
pose we used a triazene protecting group in addition to the
pyrrole group. Triazenes are also versatile functionalities
and have been demonstrated to be stable under conditions
involving organometallic reagents and a number of cata-
lysts;12 they are also easy to install. Thus, for this purpose,
we prepared the diethyl- and the pyrrolidine-substituted
triazenes 20 and 21 from 2-chloro-4-aminopyridine in
high yields (Scheme 5).13
N
N
[Pd]
N
N
Cl
N
N
N
16
ZnCl
N
Scheme 3 Attempted synthesis of 3-pyrrole-substituted 2,2¢-bipyri-
dines
N
N
To demonstrate the versatility of the prepared diamino-
2,2¢-bipyridines for further transformations, we chose 11
for subsequent elaboration. Some of the most interesting
and important derivatives of the bipyridines are halides,
especially as precursor compounds for the construction of
more complex structures.
N
N
NH2
N
N3Et2
a)
b)
Cl
Cl
N
Cl
20 (89%)
21 (85%)
Bromination as well as iodination were evaluated as pos-
sible transformations (Scheme 4). At first glance, it would
appear that the yields could be improved, however, it must
be considered that these are dihalogenations, and, for ex-
ample, for the iodination each single step gave at least a
yield of around 60% to account for an overall yield for the
two-step process of 33% for the diiodide 17. The bromi-
nation of 11 gave even better results and the dibromide 18
was isolated with 49% yield, which would translate into a
yield of 70% for each of the bromination steps. The syn-
thesis of these sophisticated bipyridines bearing bromide
and iodide substituents in different positions at each ring
requires only four steps from commercially available
amines and gives access to highly interesting building
blocks for subsequent functionalizations. The last deriva-
tization reaction of diamine 11 was the acetylation with
acetyl chloride in pyridine, affording the diacetamide 19
in good yield (69%, Scheme 4).
Scheme 5 Synthesis of the triazene-protected pyridines 20 and 21
from 2-chloro-4-aminopyridine. Reagents and conditions: (a) 1 M
H2SO4, NaNO2, –5 °C; then pyrrolidine, K2CO3, 0 °C; (b) 1 M H2SO4,
NaNO2, –5 °C; then Et2NH, K2CO3, 0 °C.
The coupling reaction of 20 with the pyridylzinc reagent
derived from 2-bromo-6-methoxypyridine under our stan-
dard coupling conditions was smooth and gave the pyrro-
lidine triazene-substituted 2,2¢-bipyridine 22 in 73% yield
(Scheme 6). Nearly the same yield (74%) was obtained
when reacting 21 with the organozinc species derived
from 3b. These experiments again proved the versatility
of our coupling procedure, which allows for the transfor-
mation of substrates with very different amino or amino/
hydroxy protecting groups to be used.
A complete reaction sequence, which also contains a fur-
ther transformation of the cross-coupling product, is
shown in Scheme 7. The diethyl-substituted triazene 21
reacted with the organozinc reagent derived from 3b to
give the 2,2¢-bipyridine 24 in 70% yield. After selective
and nearly quantitative deprotection of the pyrrole group
Finally, we investigated the synthetic flexibility of our ap-
proach, studying the possibility of selective transforma-
tions at only one of the two amino groups, using
orthogonal protecting group methodology.11 For this pur-
Synthesis 2007, No. 17, 2711–2719 © Thieme Stuttgart · New York

2714
M. Hapke et al.
PAPER
All coupling reactions were performed under an argon atmosphere
using standard Schlenk techniques and oven-dried glassware prior
to use. TLC was performed on aluminum TLC plates silica gel 60
F254 from Merck; detection: UV light (254 and 366 nm). Products
were purified by column chromatography on silica gel 60 (70–230
N
N
N
1
mesh) from Merck. H and 13C NMR spectra were recorded on a
Bruker DRX 500 spectrometer or a Bruker DMX 500 spectrometer
at 300 K at 500.1 and 125.8 MHz, or a Bruker AM 400 at 298 K at
400.1 MHz and 100.6 MHz, respectively. 1H NMR chemical shifts
are reported relative to residual undeuterated solvent as internal
standard. 13C NMR chemical shifts are reported relative to deuterat-
ed solvent or a small amount of acetone in D2O as internal standard.
Signals were assigned on the basis of 1H, 13C, H,H-COSY, HMQC,
and HMBC NMR experiments. MS spectra were taken on a Finni-
gan MAT 212 with data system MMS–ICIS (EI, CI, Me3CH, NH3),
a Finnigan MAT 95 with data system DEC-Station 5000 (CI,
Me3CH or NH3; HiRes-CI, Me3CH or NH3; FD), or an A.E.I. MS-
50 (EI; HiRes-EI). Melting points were measured with a hot-stage
microscope SM-Lux from Leitz or a SMP-20 from Büchi and are
not corrected. Elemental analyses were carried out with a Fisons In-
strument EA1108 or a Heraeus Vario EL.
N
Cl
a)
b)
20
N
N
N
N
N
N
MeO
N
N
N
N
N
23 (74%)
22 (73%)
Scheme 6 Cross-coupling reactions starting from pyrrolidinyltri-
azene-protected 20: Reagents and conditions: (a) 6-methoxypyridin-
2-ylzinc chloride (prepared from 2-bromo-6-methoxypyridine),
Pd(Pt-Bu3)2, THF, heat; (b) 6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-
2-ylzinc chloride (prepared from 3b), Pd(Pt-Bu3)2, THF, heat.
Most solvents were dried, distilled and stored under argon accord-
ing to standard procedures. t-BuLi solns were purchased from Ald-
rich and were titrated prior to use against N-pivaloyl-o-toluidine.14
All chemicals were used as received from commercial sources.
15
16
Pd(Pt-Bu3)2 and NiBr2(PPh3)2 were prepared after published
procedures. Pyrrole-protected pyridines 2b, 3b, 1a, and 2a were
prepared according to a published procedure.4 In general, pyrrole-
protected pyridines should be stored in dark vials to avoid photo-
degradation upon exposure to sunlight. The synthesis of 5,5¢-diami-
no-2,2¢-bipyridine (8) has recently been published.7
N
N3Et2
N
N
Br
N
a)
3b
+
N
N3Et2
All products were fully characterized; the numbering used in NMR
spectral interpretation is given in Figure 2.
24 (70%)
N
21
Cl
9
b)
3
4
6'
4'
10'
8'
9
8
4
N
3'
N
N
5
2
3
2
8
5
6
5'
N
HO
N3Et2
H2N
N3Et2
10
2'
N
9'
10
N
N
6
c)
N
X
N
N
Figure 2 Numbering of the pyridine and bipyridine core
26 (85%)
25 (96%)
Scheme 7 Synthesis of the differently amino-protected 2,2¢-bipyri-
dine 24, selective deprotection (to 25), and hydroxylation (to 26).
Reagents and conditions: (a) t-BuLi, THF, –78 °C; then ZnCl2, r.t.;
then Pd(Pt-Bu3)2, heat; (b) NH2OH·HCl, Et3N, EtOH, H2O, heat; (c)
NaNO2, 2 M H2SO4, H2O, 0 °C; then r.t. and 80 °C.
2-Bromo-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (1b)
4-Amino-2-bromopyridine (2.50 g, 14.50 mmol), hexane-2,5-dione
(2.0 mL, 16.80 mmol, 1.2 equiv), and PTSA (24 mg, 0.14 mmol, 1
mol%) were dissolved in toluene (10 mL) and heated in a Dean–
Stark apparatus for 2 h. After cooling, the dark brown mixture was
washed with sat. aq NaHCO3 (20 mL), H2O (5 × 20 mL), and brine
(20 mL). After drying (MgSO4) the solvent was removed in vacuo.
The dark residue was subjected to column chromatography (silica
gel, n-hexane–EtOAc, 2:1, with 5% Et3N, Rf = 0.7) to give the prod-
uct as a pale yellow solid; yield: 3.13 g (86%); mp 122 °C.
1H NMR (500.1 MHz, CDCl3): d = 2.09 (s, 6 H, H10), 5.93 (s, 2 H,
H8), 7.13 (dd, 3J = 5.5 Hz, 4J = 1.7 Hz, 1 H, H5), 7.37 (d, 4J = 1.7
Hz, 1 H, H3), 8.46 (d, 3J = 5.5 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 13.1 (C10), 108.1 (C7), 121.9
(C5), 126.9 (C6), 128.3 (C8), 142.6 (C2), 148.3 (C4), 150.7 (C3).
under standard conditions the resulting monoprotected bi-
pyridine 25 was subjected to hydroxylation. This final
step gave the protected amino-substituted hydroxybipyri-
dine 26 in an excellent 85% yield, giving an overall yield
of 57% for the whole sequence.
In summary, we have presented a novel and convenient
homo- and cross-coupling approach to symmetrical and
non-symmetrical diamino-2,2¢-bipyridines. These com-
pounds are excellent and versatile building blocks and
starting materials for a wealth of further transformations,
some of which have been demonstrated in this paper. Fi-
nally, we demonstrated the application of orthogonal pro-
tecting group methodology for the preparation of
variously substituted diamino-2,2¢-bipyridines.
MS (EI): m/z (%) = 252.0 ([C11H1181BrN2]+, 100), 250.0
([C11H1179BrN2]+, 99), 251.0 ([C11H1081BrN2]+, 86), 249.0
([C11H1079BrN2]+, 77).
HRMS (EI): m/z [M – H]+ calcd for [C11H1079BrN2]+: 249.0022;
found: 249.0023.
Anal. Calcd for C11H11BrN2: C, 52.62; H, 4.42; N, 11.16. Found: C,
52.78; H, 4.42; N, 11.23.
Synthesis 2007, No. 17, 2711–2719 © Thieme Stuttgart · New York

PAPER
Synthesis of Diamino-2,2¢-bipyridines from 2-Bromo- and 2-Chloropyridines
2715
2-Chloro-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (3a)
1H NMR (400.1 MHz, CDCl3): d = 2.23 (s, 12 H, H10), 5.96 (s, 4
3
4
2-Amino-6-chloropyridine (1.80 g, 10.40 mmol), hexane-2,5-dione
(2.0 mL, 16.80 mmol, 1.2 equiv), and PTSA (24 mg, 0.14 mmol, 1
mol%) were dissolved in toluene (10 mL)) and heated in a Dean–
Stark apparatus for 2 h. After cooling, the dark brown mixture was
washed with sat. aq NaHCO3 (20 mL), H2O (5 × 20 mL), and brine
(20 mL). After drying (MgSO4) the solvent was removed in vacuo.
The dark residue was subjected to sublimation to give the desired
product as colorless needles; yield: 2.58 g (89%); mp 60–61 °C. The
compound is prone to degradation, becoming darkly colored, and
should therefore be stored in a freezer and sublimed prior to use.
H, H9), 7.24 (dd, J = 7.8 Hz, J = 0.9 Hz, 2 H, H5), 7.93 (dd,
3
3
4
3J = 7.8 Hz, J = 7.8 Hz, 2 H, H4), 8.46 (dd, J = 7.8 Hz, J = 0.9
Hz, 2 H, H3).
13C NMR (100.6 MHz, CDCl3): d = 13.5 (C10), 107.1 (C9), 119.5
(C3), 121.9 (C5), 128.7 (C8), 138.9 (C4), 151.4 (C6), 155.1 (C2).
MS (EI): m/z (%) = 342.1 ([C22H22N4]+, 100).
HRMS (EI): m/z [M]+ calcd for [C22H22N4]+: 342.1844; found:
342.1843.
1H NMR (500.1 MHz, CDCl3): d = 2.15 (s, 6 H, H10), 5.88 (s, 2 H,
H9), 7.13 (d, 3J = 7.7 Hz, 1 H, H5), 7.32 (d, 3J = 7.7 Hz, 1 H, H3),
7.77 (dd, 3J = 7.7 Hz, 3J = 7.7 Hz, 1 H, H4).
13C NMR (125.8 MHz, CDCl3): d = 13.2 (C10), 107.5 (C9), 120.0
(C5), 122.6 (C6), 128.7 (C8), 140.1 (C4), 150.4 (C3), 151.7 (C2).
MS (EI): m/z (%) = 206.0 ([C11H1135ClN2]+, 100), 205.0
([C11H1035ClN2]+, 82), 207.0 ([C11H1037ClN2]+, 40), 208.0
([C11H1137ClN2]+, 33).
HRMS (EI): m/z [M – H]+ calcd for [C11H1035ClN2]+: 205.0527;
found: 205.0535.
4,4¢-Diamino-2,2¢-bipyridine (7) (as the Dihydrochloride); Typ-
ical Procedure for Removal of the Pyrrole Protecting Group7
Deprotection of 4,4¢-bis(2,5-dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyri-
dine (4, 360 mg, 1.05 mmol) was achieved by treatment with
NH2OH·HCl (1.47 g, 21.0 mmol, 20 equiv) in a mixture of Et3N (0.5
mL), EtOH (10 mL), and H2O (2.5 mL). The resulting soln was re-
fluxed until TLC monitoring revealed complete consumption of the
starting material (usually after 20 h). After cooling to r.t. the reac-
tion was quenched by pouring into ice-cold 1 M HCl (10 mL). The
resulting soln was washed with i-Pr2O (15 mL) and the pH was ad-
justed to 9–10 by careful addition of 6 M NaOH. The resulting mix-
ture was extracted with CH2Cl2 (3 × 20 mL) and the combined
organic extracts were dried (Na2SO4). After removal of the solvent
in vacuo, the brown residue was subjected to column chromatogra-
phy (silica gel) to give the desired diamine. For further purification,
the diamine was dissolved in EtOH. Et2O (15 mL) was added and
the mixture was filtered. A 2 M soln of HCl in Et2O (1.05 mL, 2.10
mmol) was added to the filtrate and pure 7·2 HCl precipitated,
which was collected and dried in vacuo; yield: 254 mg (94%); mp
>250 °C.
Anal. Calcd for C11H11ClN2: C, 63.93; H, 5.36; N, 13.55. Found: C,
64.22, H, 5.42, N, 13.77.
4,4¢-Bis(2,5-dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine (4): Typi-
cal Procedure for the Homo-Coupling Reaction
To a suspension of NiBr2(PPh3)2 (0.72 g, 0.97 mmol, 25 mol%),
zinc powder (0.54 g, 8.23 mmol, 1.7 equiv), LiCl (0.35 g, 8.23
mmol, 1.7 equiv), and Et4NI (1.25 g, 4.84 mmol, 1 equiv) in anhyd
THF (20 mL) was added a soln of 1a (1 g, 4.84 mmol) in anhyd THF
(10 mL). The mixture was stirred under reflux for 20 h. After cool-
ing aq NH3 (20 mL), H2O (15 mL), and CH2Cl2 (60 mL) were added
and it was stirred at r.t. for 15 min. The mixture was extracted sev-
eral times with CH2Cl2. The combined organic extracts were dried
(Na2SO4) and the solvents were removed in vacuo. The pure prod-
uct was obtained after column chromatography (silica gel, n-hex-
ane–EtOAc, 5:1, with 5% Et3N, Rf = 0.6) as a yellow solid; yield:
819 mg (99%); mp 243–245 °C.
1H NMR (500.1 MHz, CDCl3): d = 2.15 (s, 12 H, H10), 5.97 (s, 4 H,
H9), 7.20 (d, 3J = 4.9 Hz, 4J = 1.6 Hz, 2 H, H5), 8.41 (d, 4J = 1.6 Hz,
2 H, H3), 8.75 (d, 3J = 4.9 Hz, 2 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 13.2 (C10), 107.5 (C9), 120.0
(C3), 123.0 (C5), 128.4 (C8), 147.7 (C4), 150.3 (C6), 156.9 (C2).
1H NMR (400.1 MHz, D2O, as dihydrochloride): d = 7.02 (dd,
4
3J = 7.1 Hz, J = 2.5 Hz, 1 H, H5), 7.22 (d, 4J = 2.5 Hz, 2 H, H3),
8.16 (d, 3J = 7.1 Hz, 1 H, H6).
13C NMR (100.6 MHz, D2O, as dihydrochloride): d = 111.8 (C3),
112.3 (C5), 143.4 (C6), 144.7 (C2), 162.7 (C4).
MS (EI): m/z (%) = 186.1 ([C10H10N4]+, 100).
HRMS (EI): m/z [M – H]+ calcd for [C10H9N4]+: 185.0822; found:
185.0828.
6,6¢-Diamino-2,2¢-bipyridine (9) (as the Dihydrochloride)
Following the typical procedure for 7 using 6 (550 mg, 1.61 mmol)
gave diamine 9. For further purification, the diamine was dissolved
in EtOH, Et2O (15 mL) was added and the mixture was filtered. A
2 M soln of HCl in Et2O (1.61 mL, 3.22 mmol) was added to the fil-
trate and pure 9·2 HCl precipitated, which was collected and dried
under vacuum; yield: 191 mg (46%); mp >250 °C.
MS (CI): m/z (%) = 342.8 ([MH]+, 100), 398.9 ([MH + Me3CH]+,
20).
HRMS (CI): m/z [MH]+ calcd for [C22H23N4]+: 343.1923; found:
343.1923.
1H NMR (400.1 MHz, D2O, as dihydrochloride): d = 7.09 (d,
3
3J = 8.9 Hz, 1 H, H5), 7.25 (d, J = 8.8 Hz, 2 H, H3), 7.94 (dd,
3J = 8.8 Hz, 3J = 8.9 Hz, 1 H, H4).
Anal. Calcd for C22H22N4·0.5 EtOAc: C, 74.58; H, 6.78; N, 14.50.
Found: C, 74.87; H, 6.68; N, 14.71.
13C NMR (100.6 MHz, D2O, as dihydrochloride): d = 115.1 (C3),
117.8 (C5), 141.1 (C2), 146.0 (C4), 157.6 (C6).
MS (EI): m/z (%) = 186.1 ([C10H10N4]+, 100).
HRMS (EI): m/z [M]+ calcd for [C10H10N4]+: 186.0905; found:
5,5¢-Bis(2,5-dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine (5)
Following the typical procedure for 4 using 2a and heating to reflux
for 24 h gave 5 as a yellow solid after column chromatography (sil-
ica gel, n-hexane–EtOAc, 5:1, with 5% Et3N, Rf = 0.8); yield: 782
mg (94%). The analytical data are in accordance with previously re-
ported data.8
186.0905.
Anal. Calcd for C10H12N4Cl2: C, 46.35; H, 4.67; N, 21.62. Found:
C, 46.94; H, 4.49; N; 20.07.
6,6¢-Bis(2,5-dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine (6)
Following the typical procedure for 4 using 3b and stirring under re-
flux for 24 h gave 6 as a yellow solid after column chromatography
(silica gel, n-hexane–EtOAc, 5:1, with 5% Et3N, Rf = 0.8); yield:
683 mg (91%); mp 172 °C.
4,6¢-Bis(2,5-dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine (10); Typ-
ical Procedure for the Negishi Cross-Coupling Reaction
A 1.55 M soln of t-BuLi in pentane (5.0 mL, 7.78 mmol, 2.15 equiv)
was added to anhyd THF (10 mL) at –78 °C. Subsequently, a soln
of 3b (1 g, 3.98 mmol, 1.1 equiv) in anhyd THF (5 mL) was added
dropwise. The mixture was stirred at –78 °C for 30–45 min and then
Synthesis 2007, No. 17, 2711–2719 © Thieme Stuttgart · New York

2716
M. Hapke et al.
PAPER
a soln of anhyd ZnCl2 (1.36 g, 9.96 mmol, 2.75 equiv) in anhyd THF
(10 mL) was added slowly and the mixture was stirred at r.t. for 2–
3 h. After that time a soln of Pd(Pt-Bu3)2 (61 mg, 0.119 mmol, 3
mol% Pd) and 1a (746 mg, 3.62 mmol) in anhyd THF (5 mL) was
added and the mixture was heated at reflux until no further con-
sumption was observed by TLC monitoring.
(C8, C8¢), 136.0 (C5¢), 136.3 (C4¢), 147.8 (C4), 148.5 (C6¢), 150.3
(C6), 154.3 (C2¢), 157.0 (C2).
MS (EI): m/z (%) = 342.3 ([C22H22N4]+, 100).
HRMS (EI): m/z [M]+ calcd for [C22H22N4]+: 342.1844; found:
342.1838.
Anal. Calcd for C22H22N4·0.25 CH2Cl2: C, 73.48; H, 6.24; N, 15.41.
Found: C, 74.12; H, 6.39; N, 15.46.
After cooling to r.t., a suspension of EDTA (8.67 g, 29.87 mmol,
8.75 equiv) in H2O (100 mL) was added and the resulting mixture
was stirred for 15 min. After adjusting the pH to 8 with sat. aq
Na2CO3, the mixture was extracted several times with CH2Cl2. The
combined organic extracts were dried (Na2SO4) and the solvents
were removed in vacuo. The pure product was obtained after col-
umn chromatography (silica gel, n-hexane–EtOAc, 10:1, with 5%
Et3N, Rf = 0.5) as a pale yellow solid; yield: 866 mg (70%); mp 199
°C.
4,5¢-Diamino-2,2¢-bipyridine (13) (as the Dihydrochloride)
Following the typical procedure for 7 using 12 (730 mg, 2.13 mmol)
gave diamine 13. For further purification, the diamine was dis-
solved in EtOH. Et2O (20 mL) was added and the mixture was fil-
tered. A 2 M soln of HCl in Et2O (2.13 mL, 4.26 mmol) was added
to the filtrate and pure 13·2 HCl precipitated, which was collected
and dried under vacuum; yield: 179 mg (30%); mp >250 °C.
1H NMR (500.1 MHz, CDCl3): d = 2.11 (s, 6 H, H10), 2.19 (s, 6 H,
1H NMR (400.1 MHz, D2O, as dihydrochloride): d = 6.77 (dd,
3
H10¢), 5.92 (s, 2 H, H9), 5.93 (s, 2 H, H9¢), 7.19 (dd, J = 5.3 Hz,
4
3J = 7.0 Hz, J = 2.4 Hz, 1 H, H5), 7.07 (d, 4J = 2.4 Hz, 1 H, H3),
3
4J = 1.9 Hz, 1 H, H5), 7.26 (d, J = 7.5 Hz, 1 H, H5¢), 7.97 (dd,
7.46 (dd, 3J = 8.7 Hz, 4J = 2.7 Hz, 1 H, H4¢), 7.79 (dd, 3J = 8.7 Hz,
3J = 7.5 Hz, 3J = 7.5 Hz, 1 H, H4¢), 8.33 (d, 4J = 1.9 Hz, 1 H, H3),
3
5J = 0.4 Hz, 1 H, H3¢), 7.95 (d, J = 7.0 Hz, 1 H, H6), 8.21 (dd,
8.50 (d, 3J = 7.5 Hz, 1 H, H3¢), 8.77 (d, 3J = 5.3 Hz, 1 H, H6).
4J = 2.7 Hz, 5J = 0.4 Hz, 1 H, H6¢).
13C NMR (125.8 MHz, CDCl3): d = 13.2, 13.5 (C10, C10¢), 107.2,
107.5 (C9, C9¢), 119.3 (C3¢), 120.3 (C3), 121.9 (C5¢), 122.8 (C5),
128.3 (C8), 128.6 (C8¢), 138.9 (C4¢), 147.7 (C4), 150.2 (C6), 151.4
(C6¢), 155.0 (C2¢), 157.0 (C2).
MS (EI): m/z (%) = 342.3 ([C22H22N4]+, 100).
HRMS (EI): m/z [M]+ calcd for [C22H22N4]+: 342.1844; found:
13C NMR (100.6 MHz, D2O, as dihydrochloride): d = 105.5 (C3),
108.5 (C5), 123.8 (C3¢), 125.8 (C4), 136.4 (C6), 136.6 (C5¢), 139.6
(C6¢), 144.0 (C2¢), 145.6 (C2), 160.3 (C4).
MS (EI): m/z (%) = 186.1 ([C10H10N4]+, 100).
HRMS (EI): m/z [M]+ calcd for [C10H10N4]+: 186.0905; found:
186.0905.
342.1848.
Anal. Calcd for C22H22N4: C, 77.16; H, 6.48; N, 16.36. Found: C,
77.09; H, 6.74; N; 16.00.
5,6¢-Bis(2,5-dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine (14)
Following the typical procedure for 10 using 2b (500 mg, 1.99
mmol, 1.1 equiv) and 3a (373 mg, 1.81 mmol) gave 14 after column
chromatography (n-hexane–EtOAc, 10:1, with 5% Et3N, Rf = 0.8)
as a pale yellow solid; yield: 234 mg (38%); mp 143 °C.
4,6¢-Diamino-2,2¢-bipyridine (11)
Following the typical procedure for 7 using 10 (1.06 g, 3.10 mmol)
gave 11 after column chromatography (silica gel, CH2Cl2–MeOH,
2:1, Rf = 0.1) as an amorphous solid; yield: 486 mg (84%).
The desired product could also be obtained from 3b (500 mg, 1.99
mmol, 1.1 equiv) and 2a (373 mg, 1.81 mmol); yield: 419 mg
(68%).
1H NMR (400.1 MHz, CDCl3): d = 5.81 (br s, 2 H, C6¢-NH2), 6.00
(br s, 2 H, C4-NH2), 6.42–6.45 (m, 2 H, H5, H5¢), 7.41–7.45 (m, 3
H, H3, H3¢, H4¢), 8.01 (d, 3J = 5.4 Hz, 1 H, H6).
13C NMR (100.6 MHz, CDCl3): d = 105.7 (C3), 108.7, 109.0 (2 C,
C5,C5¢), 109.4 (C3¢), 138.0 (C4¢), 148.9 (C6), 154.4 (C2), 155.6
(C4), 156.1 (C2¢), 159.5 (C6¢).
1H NMR (500.1 MHz, CDCl3): d = 2.09 (s, 6 H, H10), 2.23 (s, 6 H,
H10¢), 5.95 (s, 2 H, H9), 5.96 (s, 2 H, H9¢), 7.26 (d, 3J = 7.7 Hz, 1
3
4
H, H5¢), 7.66 (dd, J = 8.3 Hz, J = 2.7 Hz, 1 H, H4), 7.98 (dd,
3J = 7.7 Hz, 3J = 7.7 Hz, 1 H, H4¢), 8.49 (d, 3J = 7.7 Hz, 1 H, H3¢),
8.56 (d, 3J = 8.3 Hz, 1 H, H3), 8.57 (s, 1 H, H6).
MS (EI): m/z (%) = 186.0 ([C10H10N4]+, 100).
HRMS (EI): m/z [M]+ calcd for [C10H10N4]+: 186.0905; found:
13C NMR (125.8 MHz, CDCl3): d = 13.0 (C10), 13.4 (C10¢), 106.9
(C9), 107.1 (C9¢), 119.4 (C3¢), 121.6 (C3), 121.9 (C5¢), 128.6 (C5),
128.9 (C8), 135.9 (C8¢), 136.5 (C4), 139.0 (C4¢), 148.2 (C6), 151.5
(C6¢), 154.2 (C2), 154.8 (C2¢).
186.0909.
Anal. Calcd for C10H10N4·0.5 MeOH·0.25 CH2Cl2: C, 57.38; H,
5.64; N, 25.07. Found: C, 57.64; H, 6.04; N, 25.03.
MS (EI): m/z (%) = 172.0 ([C10H9N3]+, 100), 342.1 ([C22H22N4]+,
10).
4,5¢-Bis(2,5-dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine (12)
Following the typical procedure for 10 using 1b (500 mg, 1.99
mmol, 1.1 equiv) and 2a (373 mg, 1.81 mmol) gave 12 after column
chromatography (n-hexane–EtOAc, 10:1, with 5% Et3N, Rf = 0.7)
as a pale yellow solid; yield: 376 mg (61%); mp 125 °C.
HRMS (EI): m/z [M]+ calcd for [C22H22N4]+: 342.1844; found:
342.1849.
Anal. Calcd for C22H22N4: C, 77.16; H, 6.48; N, 16.36. Found: C,
76.15; H, 6.06; N, 15.98.
The desired product could also be obtained from 2b (500 mg, 1.99
mmol, 1.1 equiv) and 1a (373 mg, 1.81 mmol); yield: 466 mg
(75%).
5,6¢-Diamino-2,2¢-bipyridine (15)
Following the typical procedure for 7 using 12 (700 mg, 2.04 mmol)
gave 15 after column chromatography (silica gel, CH2Cl2–MeOH,
2:1, Rf = 0.1) as an amorphous solid; yield: 233 mg (61%).
1H NMR (500.1 MHz, CDCl3): d = 2.09 (s, 6 H, H10), 2.15 (s, 6 H,
H10¢), 5.96 (s, 4 H, H9, H9¢), 7.21 (dd, 3J = 5.5 Hz, 4J = 1.1 Hz, 1
1H NMR (500.1 MHz, CDCl3): d = 5.49 (br s, 2 H, C5-NH2), 5.77
3
4
H, H5), 7.70 (dd, J = 8.2 Hz, J = 2.2 Hz, 1 H, H4¢), 8.37 (d,
3
(br s, 2 H, C6¢-NH2), 6.34 (d, J = 7.7 Hz, 1 H, H5¢), 6.96 (dd,
4J = 1.1 Hz, 1 H, H3), 8.55 (d, J = 2.2 Hz, 1 H, H6¢), 8.60 (d,
4
3J = 8.2 Hz, 4J = 2.8 Hz, 1 H, H4), 7.33 (d, 3J = 7.7 Hz, 1 H, H3¢),
7.38 (dd, 3J = 7.7 Hz, 3J = 7.7 Hz, 1 H, H4¢), 7.93 (d, 3J = 8.2 Hz, 1
H, H3), 7.95 (d, 4J = 2.8 Hz, 1 H, H6).
3J = 8.2 Hz, 1 H, H3¢), 8.79 (d, 3J = 5.5 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 13.0, 13.2 (C10, C10¢), 106.9,
107.4 (C9, C9¢), 120.4 (C3), 121.4 (C3¢), 122.8 (C5), 128.4, 128.9
Synthesis 2007, No. 17, 2711–2719 © Thieme Stuttgart · New York

PAPER
Synthesis of Diamino-2,2¢-bipyridines from 2-Bromo- and 2-Chloropyridines
2717
13C NMR (125.8 MHz, CDCl3): d = 106.4 (C5¢), 107.1 (C3¢), 119.9
(C4), 120.6 (C3), 135.3 (C6), 137.5 (C4¢), 144.1 (C2), 144.8 (C5),
154.4 (C2¢), 158.9 (C6¢).
MS (EI): m/z (%) = 186.0 ([C10H10N4]+, 100).
HRMS (EI): m/z [M]+ calcd for [C10H10N4]+: 186.0905; found:
perature below –5 °C. The mixture was stirred at r.t. for 0.5 h, then
cooled to 0 °C and a soln of NaOH (2.4 g) in H2O (5 mL) was added.
The mixture was extracted with CH2Cl2 (5 × 20 mL). The organic
phases were dried (Na2SO4) and the solvents were removed in vac-
uo. The pure product was obtained after column chromatography
(silica gel, CH2Cl2, Rf = 0.6) as a colorless solid; yield: 163 mg
(49%); mp 108 °C.
186.0906.
3
4
1H NMR (400.1 MHz, CDCl3): d = 7.48 (dd, J = 5.2 Hz, J = 1.9
Anal. Calcd for C10H10N4: C, 64.50; H, 5.41; N, 30.09. Found: C,
63.44; H, 5.65; N, 29.14.
Hz, 1 H, H5), 7.51 (dd, 3J = 7.8 Hz, 4J = 0.9 Hz, 1 H, H5¢), 7.66 (dd,
3
3
4
3J = 7.8 Hz, J = 7.8 Hz, 1 H, H4¢), 8.35 (dd, J = 7.8 Hz, J = 0.9
Hz, 1 H, H3¢), 8.45 (d, 4J = 5.2 Hz, 1 H, H6), 8.58 (d, 3J = 1.9 Hz, 1
H, H3).
2-Chloro-3-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (16)
3-Amino-2-chloropyridine (5.00 g, 38.89 mmol), hexane-2,5-dione
(4.68 mL, 46.67 mmol, 1.2 equiv), and PTSA (67 mg, 0.39 mmol,
1 mol%) were dissolved in toluene (20 mL) and heated in a Dean–
Stark apparatus for 2 h. After cooling, the dark brown mixture was
washed with sat. aq NaHCO3 (25 mL), H2O (5 × 20 mL), and brine
(20 mL). After drying (MgSO4) the solvent was removed in vacuo.
The dark residue was subjected to column chromatography (silica
gel, n-hexane–EtOAc, 3:1, with 5% Et3N, Rf = 0.7) to give the prod-
uct as a pale yellow solid; yield: 7.48 g (93%); mp 65 °C.
13C NMR (100.6 MHz, CDCl3): d = 120.1 (C3¢), 124.8 (C3), 127.5
(C5¢), 128.7 (C5), 134.1 (C4), 139.3 (C4¢), 141.7 (C6¢), 149.9 (C6),
155.8 (C2), 156.0 (C2¢).
MS (EI): m/z (%) = 313.9 ([C10H6N279Br81Br]+, 100), 232.9
([C10H6N279Br]+, 56), 234.9 ([C10H6N281Br]+, 53), 311.9
([C10H6N279Br2]+, 53), 315.9 ([C10H6N281Br2]+, 50).
HRMS (EI): m/z [M]+ calcd for [C10H6N279Br2]+ 311.8898; found:
:
1H NMR (500.1 MHz, CDCl3): d = 1.96 (s, 6 H, H10), 5.95 (s, 2 H,
311.8900.
H9), 7.39 (dd, 3J = 7.7 Hz, 3J = 4.9 Hz, 1 H, H5), 7.65 (dd, 3J = 7.7
Anal. Calcd for C10H6N2Br2: C, 38.25; H, 1.93; N, 8.92. Found: C,
38.77; N, 8.76; H, 2.10.
3
Hz, 4J = 2.2 Hz, 1 H, H4), 8.48 (dd, J = 4.9 Hz, 4J = 2.2 Hz, 1 H,
H6).
13C NMR (125.8 MHz, CDCl3): d = 12.5 (C10), 106.6 (C9), 122.9
4,6¢-Bis(acetylamino)-2,2¢-bipyridine (19)
(C5), 128.7 (C8), 133.8 (C3), 139.1 (C4), 149.3 (C6), 151.4 (C2).
4,6¢-Diamino-2,2¢-bipyridine (11, 200 mg, 1.07 mmol) was dis-
solved in anhyd pyridine (10 mL). AcCl (0.17 mL, 2.36 mmol, 2.2
equiv) was added dropwise and the mixture was stirred at r.t. for 12
h. The reaction was quenched with H2O and extracted with CH2Cl2
(2 × 20 mL). The combined organic extracts were dried (Na2SO4)
and the solvents were removed in vacuo. The pure product was ob-
tained after column chromatography (silica gel, EtOAc with 5%
Et3N, Rf = 0.1) as a colorless solid; yield: 199 mg (69%); mp >250
°C.
MS (EI): m/z (%) = 205.1 ([C11H1035ClN2]+, 100), 206.1
([C11H1135ClN2]+, 84), 207.1 ([C11H1037ClN2]+, 41), 208.1
([C11H1137ClN2]+, 29).
HRMS (EI): m/z [M – H]+ calcd for [C11H1035ClN2]+: 205.0527;
found: 205.0536.
Anal. Calcd for C11H11ClN2·0.2 C6H14: C, 65.44; H, 6.21; N. 12.51.
Found: C, 65.57; H, 6.85; N, 13.31.
1H NMR (500.1 MHz, CDCl3): d = 2.12, 2.15 (s, 6 H, C4-CH3, C6¢-
CH3), 7.55 (dd, 3J = 5.4 Hz, 4J = 2.1 Hz, 1 H, H5), 7.88 (dd, 3J = 7.8
Hz, 3J = 7.8 Hz, 1 H, H4¢), 8.02 (dd, 3J = 7.8 Hz, 4J = 0.9 Hz, 1 H,
H5¢), 8.08 (dd, 3J = 7.8 Hz, 4J = 0.9 Hz, 1 H, H3¢), 8.51 (d, 3J = 5.4
Hz, 1 H, H6), 8.52 (d, 4J = 2.1 Hz, 1 H, H3), 10.47 (br s, 2 H, NH).
13C NMR (125.8 MHz, CDCl3): d = 24.4, 24.6 (2 CH3), 110.5 (C3),
113.8 (C5), 114.5 (C3¢), 116.6 (C5¢), 139.4 (C4¢), 147.2 (C4), 150.4
(C6), 152.0 (C6¢), 154.5 (C2¢), 156.4 (C2), 169.9 (CONH).
4,6¢-Diiodo-2,2¢-bipyridine (17)
A soln of 4,6¢-diamino-2,2¢-bipyridine (11, 250 mg, 1.34 mmol) in
2 M H2SO4 (10 mL) was stirred at –10 °C. A soln of NaNO2 (241
mg, 3.49 mmol, 2.6 equiv) in H2O (5 mL) was added dropwise at
this temperature. The mixture was stirred at 0 °C for 0.5 h. After that
time a soln of KI (4.01 g, 24.17 mmol, 18 equiv) in H2O (5 mL) was
added and the mixture stirred at r.t. for 45 min and then heated to 80
°C for 1 h. The mixture was neutralized with sat. aq Na2CO3 and ex-
tracted with CH2Cl2 (5 × 20 mL). The combined organic extracts
were washed with sat. aq Na2S2O3 and dried (Na2SO4). The pure
product was obtained after column chromatography (silica gel,
CHCl3–MeOH, 9:1, Rf = 0.6) as a pale yellow solid; yield: 192 mg
(33%); mp 184 °C.
MS (EI): m/z (%) = 228.1 ([C12H12N4O]+, 100), 270.1
([C14H14N4O2]+, 62), 186.1 ([C10H10N4]+, 58).
HRMS (EI): m/z [M]+ calcd for [C14H14N4O2]+: 270.1117; found:
270.1117.
Anal. Calcd for C14H14N4O2·0.25 CH2Cl2·0.25 H2O: C, 57.82; H,
5.11; N, 18.93. Found: C, 57.02; H, 5.79; N, 18.64.
1H NMR (400.1 MHz, CDCl3): d = 6.64 (dd, J = 9.2 Hz, J = 0.8
3
4
Hz, 1 H, H5), 6.76 (dd, 3J = 6.9 Hz, 4J = 0.8 Hz, 1 H, H3), 7.46 (dd,
3
3
4
3J = 9.2 Hz, J = 6.9 Hz, 1 H, H4), 7.70 (dd, J = 5.2 Hz, J = 2.5
Hz, 1 H, H5¢), 8.16 (dd, 4J = 2.5 Hz, 5J = 0.7 Hz, 1 H, H3¢), 8.28 (dd,
3J = 5.2 Hz, 5J = 0.7 Hz, 1 H, H6¢).
2-Chloro-4-[(pyrrolidin-1-yl)diazenyl)pyridine (20); Typical
Procedure
4-Amino-2-chloropyridine (1.00 g, 7.78 mmol) was dissolved in 1
M H2SO4 (45 mL) and cooled to –5 °C. A soln of NaNO2 (1.82 g,
26.45 mmol, 3.4 equiv) in H2O (10 mL) was added dropwise. After
stirring at 0 °C for 1.5 h, the mixture was added to a cold soln of pyr-
rolidine (3.25 mL, 38.89 mmol, 5 equiv) and K2CO3 (5.38 g, 38.89
mmol, 5 equiv) in H2O (80 mL) and stirred again at r.t. for 1.5 h. The
mixture was extracted with Et2O (2 × 40 mL) and the combined or-
ganic extracts were washed with brine, dried (MgSO4), and concen-
trated in vacuo. The expected product was obtained after column
chromatography (silica gel, n-hexane–EtOAc, 3:1, with 0.5% Et3N,
Rf = 0.6) as a colorless solid; yield: 1.47 g (89%); mp 122 °C.
13C NMR (100.6 MHz, CDCl3): d = 103.4 (C3), 106.4 (C4¢), 122.9
(C5), 129.1 (C3¢), 133.6 (C5¢), 140.3 (C6), 140.4 (C4, C6), 148.8
(C2¢), 149.4 (C6¢), 162.7 (C2).
MS (EI): m/z (%) = 407.9 ([C10H6N2I2]+, 100).
HRMS (EI): m/z [M]+ calcd for [C10H6N2I2]+: 407.8620; found:
407.8630.
4,6¢-Dibromo-2,2¢-bipyridine (18)
4,6¢-Diamino-2,2¢-bipyridine (11, 200 mg, 1.07 mmol) was dis-
solved in aq HBr (62%, 5 mL) and cooled to –10 °C. Br2 (858 mg,
0.3 mL, 5.37 mmol, 5 equiv) was added. A soln of NaNO2 (371 mg,
5.37 mmol, 5 equiv) in H2O (2 mL) was added dropwise at a tem-
1H NMR (500.1 MHz, CDCl3): d = 2.07 (dt, 3J = 6.4 Hz, 4 H, CH2),
3.68 (t, 3J = 6.4 Hz, 2 H, NCH2), 3.97 (t, 3J = 6.4 Hz, 2 H, NCH2),
Synthesis 2007, No. 17, 2711–2719 © Thieme Stuttgart · New York

2718
M. Hapke et al.
PAPER
7.19 (dd, 3J = 5.5 Hz, 4J = 1.7 Hz, 1 H, H5), 7.30 (d, 4J = 1.7 Hz, 1
H, H3), 8.23 (d, 3J = 5.5 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 23.0, 23.4 (2 CH2), 46.6, 51.5
(2 NCH2), 114.0 (C3), 114.4 (C5), 149.5 (C6), 151.7 (C2), 159.3
(C4).
MS (EI): m/z (%) = 112.0 ([C5H335ClN]+, 100), 210.1
([C9H1135ClN4]+, 33), 114.0 ([C5H337ClN]+, 32), 212.1
([C9H1137ClN4]+, 11).
H9), 7.20 (d, 3J = 7.68 Hz, 1 H, H3), 7.31 (dd, 3J = 5.49 Hz,
4J = 1.64 Hz, 1 H, H5¢), 7.93 (dd, 3J = 7.68 Hz, 3J = 7.68 Hz, 1 H,
4
3
H4), 8.42 (d, J = 1.65 Hz, 1 H, H3¢), 8.47 (d, J = 7.68 Hz, 1 H,
H5), 8.56 (d, 3J = 5.49 Hz, 1 H, H6¢).
13C NMR (125.8 MHz, CDCl3): d = 13.4 (C10), 23.8, 23.9
(2 NCH2CH2), 47.0, 51.7 (2 NCH2CH2), 106.7 (C9), 113.0 (C3¢),
115.6 (C5¢), 119.4 (C5), 121.4 (C3), 128.8 (C8), 138.7 (C4), 149.5
(C6¢), 151.2 (C6), 156.1 (C2, C2¢), 158.7 (C4¢).
MS (EI): m/z (%) = 346.2 ([C20H22N6]+, 100).
HRMS (EI): m/z [M]+ calcd for [C20H22N6]+: 346.1905; found:
HRMS (EI): m/z [M]+ calcd for [C9H1135ClN4]+: 210.0672; found:
210.0672.
346.1906.
Anal. Calcd for C9H11ClN4: C, 51.31; H, 5.26; N, 26.60. Found: C,
51.25; H, 5.38; N, 26.08.
4-(3,3-Diethyltriaz-1-en-1-yl)-6¢-(2,5-dimethyl-1H-pyrrol-1-yl)-
2,2¢-bipyridine (24)
Following the typical procedure for 10 using 3b (500 mg, 1.99
mmol, 1.1 equiv) and 21 (385 mg, 1.81 mmol) gave the pure product
after column chromatography (silica gel, n-hexane–EtOAc, 5:1,
with 5% Et3N, Rf = 0.4) as a pale yellow oil; yield: 438 mg (70%).
1H NMR (500.1 MHz, CDCl3): d = 1.23, 1.35 (m, 6 H,
2 NCH2CH3), 2.22 (s, 6 H, H10), 3.82 (m, 4 H, 2 NCH2CH3), 5.94
(s, 2 H, H9), 7.20 (d, 3J = 7.7 Hz, 1 H, H5¢), 7.31 (dd, 3J = 5.5 Hz,
4J = 2.2 Hz, 1 H, H5), 7.92 (dd, 3J = 7.7 Hz, 3J = 7.7 Hz, 1 H, H4¢),
8.40 (d, 4J = 2.2 Hz, 1 H, H3), 8.43 (d, 3J = 7.7 Hz, 1 H, H3¢), 8.56
(d, 3J = 5.5 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 11.1, 14.3 (2 NCH2CH3), 13.4
(C10), 41.6, 49.4 (2 NCH2CH3), 106.8 (C9), 113.3 (C3), 115.3 (C5),
119.3 (C3¢), 121.3 (C5¢), 128.8 (C8), 138.6 (C4¢), 149.8 (C6), 151.2
(C6¢), 156.4 (C2, C2¢), 158.3 (C4).
2-Chloro-4-(3,3-diethyltriaz-1-en-1-yl)pyridine (21)
Following the typical procedure for 20 using 4-amino-2-chloropy-
ridine (1.00 g, 7.78 mmol) with Et2NH (4 mL, 38.89 mmol, 5 equiv)
gave 21 after column chromatography (silica gel, n-hexane–EtOAc,
1:1, with 0.5% Et3N, Rf = 0.6) as a pale yellow oil; yield: 1.40 g
(85%).
1H NMR (500.1 MHz, CDCl3): d = 1.21, 1.35 (t, 3J = 7.1 Hz, 6 H,
3
2 NCH2CH3), 3.77–3.83 (m, 4 H, 2 NCH2CH3), 7.18 (dd, J = 5.5
Hz, 4J = 1.7 Hz, 1 H, H5), 7.29 (d, 4J = 1.7 Hz, 1 H, H3), 8.22 (d,
3J = 5.5 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 11.0, 14.3 (2 NCH2CH3), 42.0,
49.7 (2 NCH2CH3), 114.6 (C5), 114.9 (C3), 149.7 (C6), 151.9 (C2),
159.7 (C4).
MS (EI): m/z (%) = 140.0 ([C5H3N335Cl]+, 100).
HRMS (EI): m/z [M]+ calcd for [C9H1335ClN4]+: 212.0828; found:
MS (EI): m/z (%) = 348.2 ([C20H24N6]+, 100).
HRMS (EI): m/z [M]+ calcd for [C20H24N6]+: 348.2062; found:
212.0820.
Anal. Calcd for C9H13ClN4: C, 50.83; H, 6.16; N, 26.34. Found: C,
50.46; H, 6.24; N, 26.11.
348.2060.
Anal. Calcd for C20H24N6: C, 68.94; H, 6.94; N, 24.12. Found: C,
68.63; H, 7.00; N, 23.45.
6-Methoxy-4¢-[(pyrrolidin-1-yl)diazenyl]-2,2¢-bipyridine (22)
Following the typical procedure for 10 using 2-bromo-6-methoxy-
pyridine (500 mg, 2.67 mmol, 1.1 equiv) and 20 (512 mg, 2.43
mmol) gave the pure product after column chromatography (silica
gel, EtOAc with 5% Et3N, Rf = 0.6) as a pale yellow solid; yield:
500 mg (73%); mp 88 °C.
1H NMR (500.1 MHz, CDCl3): d = 1.97–2.15 (m, 4 H, 2 CH2),
3.67–4.02 (m, 4 H, 2 NCH2), 4.05 (s, 3 H, OCH3), 6.75 (d, 3J = 7.7
Hz, 1 H, H5), 7.29 (dd, 3J = 5.5 Hz, 4J = 1.6 Hz, 1 H, H5¢), 7.67 (dd,
3J = 7.7 Hz, 3J = 7.7 Hz, 1 H, H4), 8.0 (d, 3J = 7.7 Hz, 1 H, H3), 8.34
(d, 4J = 1.6 Hz, 1 H, H3¢), 8.53 (d, 3J = 5.5 Hz, 1 H, H6¢).
6-Amino-4-(3,3-diethyltriaz-1-en-1-yl)-2,2¢-bipyridine (25)
Following the typical procedure for 7 using 24 (300 mg, 0.86 mmol)
with NH2OH·HCl (598 mg, 8.61 mmol, 10 equiv) and Et3N (0.36
mL, 2.58 mmol, 6 equiv) gave 25 after column chromatography
(silica gel, CH2Cl2–MeOH, 2:1, Rf = 0.1) as a yellow oil; yield: 223
mg (96%).
1H NMR (500.1 MHz, CDCl3): d = 1.18–1.39 (m,
6 H,
2 NCH2CH3), 3.79–3.83 (m, 4 H, 2 NCH2CH3), 4.56 (br s, 2 H,
NH2), 6.50 (dd, 3J = 8.1 Hz, 4J = 0.8 Hz, 1 H, H5), 7.26 (dd, 3J = 5.4
Hz, 4J = 2.0 Hz, 1 H, H5¢), 7.53 (dd, 3J = 8.1 Hz, 3J = 8.1 Hz, 1 H,
H4), 7.68 (dd, 3J = 8.1 Hz, 4J = 0.8 Hz, 1 H, H3), 8.21 (dd, 4J = 2.0
Hz, 5J = 0.6 Hz, 1 H, H3¢), 8.53 (dd, 3J = 5.4 Hz, 5J = 0.6 Hz, 1 H,
H6¢).
13C NMR (125.8 MHz, CDCl3): d = 23.5, 23.8 (2 CH2), 47.0, 51.7
(2 NCH2), 53.3 (OCH3), 110.8 (C5), 113.3 (C3¢), 113.9 (C3), 114.1
(C5¢), 139.2 (C4), 149.5 (C6¢), 153.6 (C2), 156.9 (C2¢), 158.5 (C4¢),
163.5 (C6).
13C NMR (125.8 MHz, CDCl3): d = 11.1, 14.4 (2 NCH2CH3), 41.6,
49.5 (2 NCH2CH3), 108.7 (C5), 111.8 (C3), 112.9 (C3¢), 114.8
(C5¢), 138.5 (C4), 149.9 (C6¢), 155.1 (C2), 157.4 (C2¢), 158.1 (C4¢,
C6).
MS (EI): m/z (%) = 185.1 ([C11H9N2O]+, 100), 283.1
([C15H17N5O]+, 19).
HRMS (EI): m/z [M]+ calcd for [C15H17N5O]+: 283.1433; found:
283.1433.
MS (EI): m/z (%) = 170.1 ([C10H8N3]+, 100), 270.2 ([C14H18N6]+,
28).
Anal. Calcd for C15H17N5O·0.25 EtOAc: C, 62.93; H, 6.27; N,
22.94. Found: C, 62.85; H, 6.11; N, 24.65.
HRMS (EI): m/z [M]+ calcd for [C14H18N6]+: 270.1593; found:
270.1594.
6-(2,5-Dimethyl-1H-pyrrol-1-yl)-4¢-[(pyrrolidin-1-yl)diazenyl]-
2,2¢-bipyridine (23)
Following the typical procedure for 10 using 3b (500 mg, 1.99
mmol, 1.1 equiv) and 20 (381 mg, 1.81 mmol) gave the pure product
after column chromatography (silica gel, n-hexane–EtOAc, 1:1,
with 5% Et3N, Rf = 0.6) as a pale yellow oil; yield: 465 mg (74%).
Anal. Calcd for C14H18N6·0.5 EtOAc: C, 61.13; H, 7.05; N, 26.73.
Found: C, 61.07; H, 7.00; N, 26.57.
4-(3,3-Diethyltriaz-1-en-1-yl)-6¢-hydroxy-2,2¢-bipyridine (26)
A soln of 25 (150 mg, 0.55 mmol) in 2 M H2SO4 (10 mL) was stirred
at –10 °C. A soln of NaNO2 (49 mg, 0.79 mmol, 1.3 equiv) in H2O
(5 mL) was added at this temperature. The mixture was stirred at r.t.
1H NMR (500.1 MHz, CDCl3): d = 1.99–2.13 (m, 4 H, 2 NCH2CH2)
3.66–3.99 (m, 4 H, 2 NCH2CH3), 2.21 (s, 6 H, H10), 5.93 (s, 2 H,
Synthesis 2007, No. 17, 2711–2719 © Thieme Stuttgart · New York

PAPER
Synthesis of Diamino-2,2¢-bipyridines from 2-Bromo- and 2-Chloropyridines
2719
for 45 min and then heated to 80 °C for 1 h. The mixture was neu-
tralized with sat. aq Na2CO3 and extracted with CH2Cl2 (5 × 15
mL). The combined organic extracts were dried (Na2SO4). The pure
product was obtained after column chromatography (silica gel,
CHCl3–MeOH, 9:1, Rf = 0.4) as a yellow oil; yield: 127 mg (85%).
(5) Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH:
Weinheim, 2000.
(6) Examples: (a) Whittle, C. P. J. Heterocycl. Chem. 1977, 14,
191. (b) Newkome, G. R.; Gross, J.; Patri, A. K. J. Org.
Chem. 1997, 62, 3013. (c) Zhang, B.; Breslow, R. J. Am.
Chem. Soc. 1997, 119, 1676. (d) Thibault, M. E.; Luska, K.
L.; Schlaf, M. Synthesis 2007, 791.
(7) Albrecht, M.; Janser, I.; Lützen, A.; Hapke, M.; Fröhlich, R.;
Weis, P. Chem. Eur. J. 2005, 11, 5742.
(8) Some recent examples for the use of LiCl as an additive in
organometallic mediated reactions: (a) Krasovskiy, A.;
Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333; Angew.
Chem. 2004, 116, 3396. (b) Krasovskiy, A.; Straub, B.;
Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 159; Angew.
Chem. 2006, 118, 165. (c) Krasovskiy, A.; Krasovskaya, V.;
Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 2958; Angew.
Chem. 2006, 118, 3024. (d) Krasovskiy, A.; Tishkov, A.;
del Amo, V.; Mayr, H.; Knochel, P. Angew. Chem. Int. Ed.
2006, 45, 5010; Angew. Chem. 2006, 118, 5132.
(e) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel,
P. Angew. Chem. Int. Ed. 2006, 45, 6040; Angew. Chem.
2006, 118, 6186. (f) del Amo, V.; Dubbaka, S. R.;
Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45,
7838; Angew. Chem. 2006, 118, 8002. (g) Korn, T. B.;
Scahde, M. A.; Cheemala, M. N.; Wirth, S.; Guevara, S. A.;
Cahiez, G.; Knochel, P. Synthesis 2006, 3547.
1H NMR (400.1 MHz, CDCl3): d = 1.37, 1.24 (t, 6 H, 2 NCH2CH3),
3.79–3.87 (m, 4 H, 2 NCH2CH3), 6.59 (dd, 3J = 9.1 Hz, 4J = 0.8 Hz,
1 H, H5¢), 6.81 (dd, 3J = 6.9 Hz, 4J = 0.8 Hz, 1 H, H3¢), 7.31 (dd,
4
3
3
3J = 5.4 Hz, J = 1.8 Hz, 1 H, H5), 7.45 (dd, J = 9.1 Hz, J = 6.9
Hz, 1 H, H4¢), 7.75 (dd, 4J = 1.8 Hz, 5J = 0.5 Hz, 1 H, H3), 8.46 (dd,
3J = 5.4 Hz, 5J = 0.5 Hz, 1 H, H6), 10.73 (s, 1 H, OH).
13C NMR (100.6 MHz, CDCl3): d = 11.1, 14.4 (2 NCH2CH3), 42.0,
49.8 (2 NCH2CH3), 102.5 (C3¢), 111.5 (C3), 115.9 (C5), 121.6
(C5¢), 140.7 (C4¢), 142.5 (C2¢), 148.6 (C2), 149.8 (C6), 158.5 (C4),
162.9 (C6¢).
MS (EI): m/z (%) = 271.1 ([C14H17N5O]+, 100), 171.0
([C10H7N2O]+, 99).
HRMS (EI): m/z [M]+ calcd for [C14H17N5O]+: 271.1433; found:
271.1436.
Anal. Calcd for C14H17N5O·0.125 CH2Cl2: C, 60.17; H, 6.17; N,
24.84. Found: C, 60.24; H, 6.52; N, 24.44.
Acknowledgment
(h) Kloetzing, R. J.; Krasovskiy, A.; Knochel, P. Chem. Eur.
J. 2007, 13, 215.
(9) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Bull.
Chem. Soc. Jpn. 1990, 63, 80.
Financial support from the DFG (SFB 624 and SPP 1118) is grate-
fully acknowledged. We would like to thank Prof. Peter Köll for his
support and his steady interest in our work.
(10) Examples: (a) Janiak, C.; Deblon, S.; Wu, H.-P.; Kolm, M.
J.; Klufers, P.; Piotrowski, H.; Mayer, P. Eur. J. Inorg.
Chem. 1999, 1507. (b) Devic, T.; Avarvari, N.; Batail, P.
Chem. Eur. J. 2004, 10, 3697. (c) Ishida, H.; Kyakuno, M.;
Oishi, S. Biopolymers 2004, 76, 69.
(11) General overview: Schelhaas, M.; Waldmann, H. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2056; Angew. Chem. 1996,
108, 2192.
(12) Bräse, S. Acc. Chem. Res. 2004, 37, 805.
(13) Conditions: Barbero, M.; Degani, I.; Diulgheroff, N.;
Dughera, S.; Fochi, R. Synthesis 2001, 2180.
(14) Suffert, J. J. Org. Chem. 1989, 54, 509.
References
(1) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100,
3553.
(2) For the synthetic introduction of the bipyridine core in the
synthesis of caerulomycin C, see: Sammakia, T.;
Stangeland, E. L.; Whitcomb, M. C. In Strategies and
Tactics in Organic Synthesis, Vol. 6; Harmata, M., Ed.;
Elsevier: New York, 2005, 415.
(3) Newkome, G. R.; Petri, A. K.; Holder, E.; Schubert, U. S.
Eur. J. Org. Chem. 2004, 235.
(4) (a) Lützen, A.; Hapke, M. Eur. J. Org. Chem. 2002, 2292.
(b) Lützen, A.; Hapke, M.; Staats, H.; Bunzen, J. Eur. J. Org.
Chem. 2003, 3948. (c) Kiehne, U.; Bunzen, J.; Staats, H.;
Lützen, A. Synthesis 2007, 1061.
(15) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.
(16) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D.
Application of Transition Metal Catalysts in Organic
Synthesis; Springer Verlag: Berlin, 1999, 2.
Synthesis 2007, No. 17, 2711–2719 © Thieme Stuttgart · New York