Iterative and regioselective cross-couplings of 2-chloro-3,4-diiodopyridine leading to 2,3,4-triheteroarylpyridines

Article abstract of DOI:10.1016/j.tet.2009.11.066

A one-pot synthesis of 2-chloro-3,4-diiodopyridine from 2-chloropyridine is described via a Directed ortho Metallation (DoM)/Halogen Dance (HD) mechanism in 26-28% yields. By performing sequential, iterative Suzuki-Miyaura cross-couplings using a variety of functionalised heteroaryl and arylboronic acids, a series of novel 2,3,4-triheteroarylpyridine scaffolds have been accessed in synthetically viable yields, including sterically hindered derivatives. 2-Chloro-4-heteroaryl-3-iodopyridines and 2-chloro-3,4-diheteroarylpyridines are also reported. The synthesis of 5-[3,4-bis(2-phenylethynyl)pyridin-2-yl]-2-fluoropyridine via a two-step Sonogashira/Suzuki-Miyaura reaction sequence from 2-chloro-3,4-diiodopyridine, phenylacetylene and 6-fluoropyridin-3-yl-3-boronic acid has been achieved in 48% overall yield.

Full text of DOI:10.1016/j.tet.2009.11.066

Tetrahedron 66 (2010) 668–675
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iterative and regioselective cross-couplings of 2-chloro-3,4-diiodopyridine
leading to 2,3,4-triheteroarylpyridines
*
Laura M. Daykin, Jamie S. Siddle, Adrian L. Ankers, Andrei S. Batsanov, Martin R. Bryce
Department of Chemistry, Durham University, Durham DH1 3LE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot synthesis of 2-chloro-3,4-diiodopyridine from 2-chloropyridine is described via a Directed
ortho Metallation (DoM)/Halogen Dance (HD) mechanism in 26–28% yields. By performing sequential,
iterative Suzuki–Miyaura cross-couplings using a variety of functionalised heteroaryl and arylboronic
acids, a series of novel 2,3,4-triheteroarylpyridine scaffolds have been accessed in synthetically viable
yields, including sterically hindered derivatives. 2-Chloro-4-heteroaryl-3-iodopyridines and 2-chloro-
3,4-diheteroarylpyridines are also reported. The synthesis of 5-[3,4-bis(2-phenylethynyl)pyridin-2-yl]-2-
fluoropyridine via a two-step Sonogashira/Suzuki–Miyaura reaction sequence from 2-chloro-3,4-diio-
dopyridine, phenylacetylene and 6-fluoropyridin-3-yl-3-boronic acid has been achieved in 48% overall
yield.
Received 14 September 2009
Accepted 12 November 2009
Available online 17 November 2009
Keywords:
Palladium catalysis
Cross-coupling
Halogen dance
Suzuki–Miyaura reaction
Arylation
Ó 2009 Elsevier Ltd. All rights reserved.
Arylpyridine
2-Chloro-3,4-diiodopyridine
1. Introduction
reactions are amenable to the regioselective synthesis of multi-
halogenated pyridines.11 For example, Rocca et al.12 reported that 2-
Highly-substituted pyridine scaffolds are of contemporary in-
terest due to their prevalence in bioactive compounds,1 as ligands
for organometallics2 and in materials chemistry applications.3 In
recent years, metal-catalysed cross-coupling methodologies have
expanded the scope of substitutions on heteroaryls by giving access
to aryl–aryl, aryl–alkyl, aryl–alkenyl, aryl–alkynyl and aryl–hetero-
atom bond formations.4 These substitutions have also been ach-
ieved via rhodium catalysed CH activation5 and iridium catalysed
borylations,6 as well as palladium catalysed direct arylations.7
The more commonly used coupling reactions, require pre-acti-
vation in the form of a halide or other leaving group on the elec-
trophilic substrate. Many such halogenated heteroaryl compounds
are commercially available; however, the 2,3,4-trihalopyridine
substitution pattern is not well exploited. 4-Bromo-2-chloro-3-
iodopyridine has recently been employed in the preparation of
naphthyridone p38 MAP kinase inhibitors8 and 2-chloro-3-fluoro-
4-iodo-5,6-dimethylpyridine has been used in the synthesis of
Streptonigrin analogues.9 Organometallic bases regioselectively
deprotonate aryl rings by Directed ortho Metallation (DoM) allow-
ing electrophilic halogenation and access to a range of halogenated
products.10 It has been well documented that ‘halogen dance’ (HD)
chloro-3-iodopyridine 1 can be selectively deprotonated ortho to
iodine with LDA leading to the 4-lithio species 2. Subsequent
isomerism (HD) gave the 3-lithio species 3 (with stability imparted
by a strongly inductive electron withdrawing effect of chlorine and
chelation of the lithium to chlorine in the intermediate 3).11d,11e,12
Electrophilic attack by molecular iodine on 3 then leads to 2-chloro-
3,4-diiodopyridine 4 in 71% yield (Scheme 1).12
I
I
Li
isomerisation
(HD)
I2
LDA
I
Li
I
I
-78 o
C
THF
N
Cl
N
Cl
N
Cl
N
2
Cl
-78 oC
71% yield
1
3
4
Scheme 1. The halogen dance (HD) mechanism for the synthesis of 4 from 1.12
We now report the synthesis of 4 in a one-pot reaction from
cheap and readily available13 2-chloropyridine using combined
DoM and HD methodology. We also demonstrate the first uti-
lisation of 4 in metal-catalysed cross-couplings leading to the
regioselective synthesis of novel 2,3,4-triheteroarylpyridines.
2. Results and discussion
The overview of our synthetic strategy is shown in Scheme 2.
Lithiation of 2-chloropyridine 5 at ꢀ78 ꢁC or ꢀ100 ꢁC using 2 equiv
* Corresponding author. Tel.: þ44 191 3342018.
E-mail address: m.r.bryce@durham.ac.uk (M.R. Bryce).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.066

L.M. Daykin et al. / Tetrahedron 66 (2010) 668–675
669
Table 1
of LDA (prepared in situ from n-butyllithium or n-hexyllithium and
Suzuki–Miyaura cross-couplings of 2-chloro-3,4-diiodopyridine
arylboronic acids to yield mono-coupled products
4
with hetero-
Yielda (%)
diisopropylamine) followed by addition of iodine (2.9 equiv) and
aqueous workup reproducibly afforded 2-chloro-3,4-diiodopyr-
idine 4 in 26–28% yields for ca. 4–5 g batches of product. Lower
yields of 4 were obtained under the following conditions: (i) scale-
up of the reaction; (ii) use of 2,2,6,6-tetramethylpiperidine as base
at ꢀ100 to ꢀ85 ꢁC. It is presumed that initial directed ortho lith-
iation of 2-chloropyridine 5 gives the 3-lithio intermediate 6 and
electrophilic attack by I2 then gives 2-chloro-3-iodopyridine 1.14
Subsequent directed lithiation and HD as reported previously12 and
a final electrophilic attack affords product 4 (Scheme 3).
Entry
R-X
Boronic acid
Product
N
N
44b
22c
MeO
MeO
1
4
I
B(OH)2
11
7
(0.9 equiv.)
N
Cl
OMe
OMe
N
N
1
Het
B(OH)2 B(OH)2 B(OH)2
One-pot DoM/
halogen dance/
iodination
I
2
Het
Het
3
4
38b
1
3
2
I
Het
Het
Het
I
12
B(OH)2
8
N
Cl
N
F
Cl
N
Cl
N
3
3-steps
(2.5 equiv.)
Suzuki-Miyaura
Scheme 2. Reaction scheme for the four-step synthesis of 2,3,4-triheteroarylpyridines
from 2-chloropyridine.
F
N
N
4
4
50b
I
isomerisation
I2
LDA
THF
LDA
Li
I2
13
B(OH)2
[1]
[3]
4
[2]
9
THF
-78 o
N
Cl
-78 o
C
N
5
Cl
N
6
Cl
(2.5 equiv)
-78 o
C
-78 o
C
C
26-28%
yields
Scheme 3. Proposed mechanism for the one-pot synthesis of 4 from 5.
N
N
Suzuki–Miyaura15 cross-coupling reactions were performed on
5
4
13c
4 using a variety of heteroarylboronic acids16 to give a range of
functional mono-heteroarylated products 7–10 (Scheme 4 and
Table 1).
I
14
B(OH)2
(0.75 equiv.)
10
N
Cl
a
Isolated yields after purification via chromatography and/or recrystallisation.
Reagents and conditions: Pd(PPh3)4, Na2CO3, 1,4-dioxane, reflux, 20–24 h.
Reagents and conditions: Pd(PPh3)2Cl2, Na2CO3, 1,4-dioxane, reflux, 19–70 h.
Het 1
b
c
I
Het 1
I
I
"Pd/L"
+
Base
B(OH)2
N
7-10
Cl
N
Cl
1,4-dioxane
case. This was achieved by further reaction of 7–9 with a selection
of pyridylboronic acids under the standard conditions furnishing
compounds 18–20 in variable yields. The inherent regioselectivity,
vide supra, led to the second coupling occurring exclusively at the
3-position giving excellent control over the substitution pattern on
the pyridine core. When using boronic acid 11 the resulting product
19 was obtained in only 23% yield (Table 2, entry 5) presumably due
to the added steric hindrance of the ortho-methoxy group on 11.
The X-ray molecular structure of 19 is shown in Figure 1. Compound
18 does not suffer this steric interference and furthermore, the
electron withdrawing fluoropyridine substituent at C4 of 9 would
be expected to enhance reactivity at C3, thus explaining the high
yield in this case (Table 2, entry 4). In attempts to mitigate antici-
pated low yields for the coupling of the sterically encumbered 7
with boronic acid 12, Fu’s conditions (which have been reported to
provide excellent yields for sterically crowded substrates)19 were
employed. Using 12 (1.1 equiv) we were gratified to obtain 20 in
74% yield (Table 2, entry 6).
As stated above, on no occasion was a tris-coupled product ob-
served in the reactions shown in Schemes 4–6 (Tables 1 and 2). This
provided the opportunity to introduce regioselectively a third heter-
oaryl substituent into the pyridine core by reactions of the remaining
2-chloro functionality.20 For this purpose a selection of the bis-cou-
pled products (18, 19 and 20) were reacted with a range of aryl and
heteroarylboronic acids to gain access to 2,3,4-tri(hetero)arylpyr-
idines 22–25 in 23–51% yields (Scheme 7 and Table 3). The reactions
were performed using the conditions designed for coupling hetero-
aryl chlorides with nitrogen-containing heteroarylboronic acids21
4
11-14
Scheme 4. General reaction scheme for the mono-couplings of 4.
When using less than 1 equiv of the boronic acid a mixture of
unreacted 4, mono- and bis-coupled products was obtained. In
attempts to optimise the conversion of 4 (Table 1, entries 3 and 4)
by using 2.5 equiv of boronic acids 12 and 13, products 8 and 9 were
obtained in 38% and 50% yields, respectively, along with bis-cou-
pled side-products observed via GC–MS. Performing the Suzuki–
Miyaura reaction on 4 using 2.5 equiv of 11 yielded the bis-coupled
product 15 in 47% (see Table 2, entry 1) with 7 also observed via
GC–MS. The increased yield for the more electron deficient fluo-
ropyridylboronic acid 13 compared to the methoxypyridylboronic
acid 12 is consistent with the SE2 (coordination) mechanism for the
transmetalation to palladium.15a The activated 4-position of 4 re-
acts first, followed by reaction at the less electronically active and
more sterically hindered 3-position.17 X-ray diffraction studies
confirmed the regioselectivity for mono- and bis-coupled products
7 and 19 (see Fig. 1). A higher isolated yield of 7 was obtained for
the reaction of 4 when using Pd(PPh3)4 as catalyst rather than the
air stable Pd(PPh3)2Cl2 (Table 1, entry 1).18
Twofold cross-coupling of the boronic acids 11, 12 or 21 at both
the 4- and 3-positions of 4 gave 15–17 in optimised yields of 47–
64% (Scheme 5 and Table 2, entries 1–3). Tris-coupled products
were not observed in any of the reactions shown in Schemes 4–6.
Entries 4–6 in Table 2 show the products of stepwise reactions
where the pyridyl substituents at C3 and C4 are different in each

670
L.M. Daykin et al. / Tetrahedron 66 (2010) 668–675
Table 2
Het 1
Suzuki–Miyaura cross-couplings with pyridylboronic acids to yield bis-coupled
products
I
Het 1
Het 1
I
"Pd/L"
Yielda (%)
+
Entry
R-X
Boronic acid
Product
Base
B(OH)2
N
Cl
N
Cl
1,4-dioxane
N
N
4
11, 12, 21
15-17
MeO
MeO
47b
Scheme 5. General reaction scheme for bis-couplings of 4.
1
4
N
B(OH)2
11
[viz. Pd2(dba)3, PCy3, K3PO4, 1,4-dioxane, H2O, reflux]. However,
a similar yield of 25 was obtained on the one occasion when
Pd(PPh3)4/Na2CO3 was used (Table 3, entry 4).
OMe
15
(2.5 equiv.)
N
Cl
OMe
OMe
N
N
Het 1
Het 1
OMe
Het 2
2
3
4
5
4
4
9
64b
50b
90c
N
I
"Pd/L"
Het 2
+
12
B(OH)2
Base
16
N
Cl
Cl
Cl
N
Cl
N
Cl
B(OH)2
11, 12
1,4-dioxane
(2.5 equiv.)
OMe
7-9
18-20
OMe
Scheme 6. General reaction scheme for mono-couplings of 7–9.
OMe
OMe
Het 1
Het 1
21
B(OH)2
Het 2
+
17
Het 2
N
F
Ar/Het 3
(2.5 equiv.)
"Pd/L"
Base
OMe
N
N
Ar/Het 3
N
Cl
B(OH)2
13, 21, 26
1,4-dioxane
N
18-20
22-25
Scheme 7. General reaction scheme for the mono-couplings of 18–20.
N
12
B(OH)2
18
N
Suzuki–Miyaura reactions are known to be tolerant to un-
protected amine functionality,22 and accordingly, coupling of 2-
aminopyrimidin-5-yl-5-boronic acid 26 with 18 gave 23 in 23%
yield. With all of these third couplings (Scheme 7) a varying
amount of dechlorinated side-product was observed via GC–MS
thus accounting for the modest yields of 22–25. This can be
explained by the steric crowding in the bis-coupled substrate 18–
20 inhibiting transmetalation of the boronic acid in the transition
state leading to competing protodechlorination.
It is noteworthy that to our knowledge compounds 23–25 rep-
resent the first reported 2,3,4-triheteroarylpyridine derivatives.
2,3,4-Triphenylpyridine has been synthesised by the nickel catalysed
annulation of 2-iodobenzaldimine,23 3-[2-(pyridin-2-yl)-3-(pyridin-
3-yl)phenyl]pyridine and 5-[2-(pyridin-2-yl)-3-(pyrimidin-5-yl)-
phenyl]pyrimidine were synthesised via the ruthenium catalysed
ortho-arylation of 2-phenylpyridine.24 The phenyl core analogue 3-
[2,3-di(pyridin-3-yl)phenyl]pyridine has been used as an electron
(1.5 equiv.)
OMe
N
N
MeO
8
7
23c
N
B(OH)2
11
OMe
(1.5 equiv.)
N
Cl
19
OMe
N
N
OMe
MeO
6
74d
N
12
B(OH)2
N
Cl
20
(1.1 equiv.)
a
Isolated yields after purification via chromatography and/or recrystallisation.
Reagents and conditions: Pd(PPh3)4, Na2CO3, 1,4-dioxane, reflux, 20 h.
Reagents and conditions: Pd(PPh3)2Cl2, Na2CO3, 1,4-dioxane, reflux, 18–70 h.
Reagents and conditions: Pd2(dba)3, P(t-Bu)3.HBF4, 1,4-dioxane, KF, 80 ꢁC, 7 h.
b
c
d
Figure 1. X-raymolecular structures of 7 (left) and 19, showing thermal ellipsoids at 50% probabilitylevel. Dihedral angles betweenpyridyl rings: 72.4ꢁ in 7, i/ii 85.3ꢁ and i/iii 52.8ꢁ in 19.

L.M. Daykin et al. / Tetrahedron 66 (2010) 668–675
671
Table 3
the reaction of the same boronic acid 13 with the chloro substituent
of 20 (Table 3, entry 4) can be attributed to the reduced steric hin-
drance in 27 compared to 20. We note that (arylethynyl)pyridines
have been synthesised for pharmacological applications28 and
bis(arylethynyl)pyridines are of interest for their optoelectronic
properties.29
Suzuki–Miyaura cross-couplings of (hetero)arylboronic acids with compounds 18,
19 and 20
Entry
R-X
Boronic acid
Product
Yielda (%)
F
N
OMe
OMe
3. Conclusion
N
1
18
30b
We have described a new one-pot synthesis of 2-chloro-3,4-
21
diiodopyridine 4 in 4–5 g batches from 2-chloropyridine via
B(OH)2
N
a Directed ortho Metallation–Halogen Dance–iodination sequence.
Utilising 4 as a starting material has led to a versatile range of mono-,
bis- and triheteroarylpyridine derivatives in a series of iterative and
regioselective Suzuki–Miyaura cross-coupling reactions. These pro-
cedures have provided the first examples of pyridine derivatives
bearing heteroaryl units in the 2, 3 and 4 positions. The yields of the
products are synthetically viable, even for the more sterically hin-
dered derivatives, especially in view of the known challenges of
cross-coupling heteroaryl halides with heteroarylboronic acids/es-
ters.20,21 We have also established that compound 4 is a suitable re-
agentforSonogashira reactions. These protocols are versatile andcan
be further exploited in the synthesis of libraries of small molecules
derived from 4 for drug discovery and for materials chemistry
applications.
22
(1.2 equiv.)
OMe
OMe
F
N
NH2
N
N
N
N
2
18
23b
26
B(OH)2
N
23
(1.2 equiv.)
N
NH2
OMe
N
F
N
N
OMe
4. Experimental
4.1. General
3
19
45b
13
B(OH)2
N
24
(1.2 equiv.)
N
F
All reactions were performed under an argon atmosphere, which
was dried by passage through a column of phosphorus pentoxide.
Glassware was flame dried prior to use for moisture sensitive re-
actions. All reagents used were of standard reagent grade, used as
supplied unless otherwise stated and purchased from Sigma–Aldrich
or Alfa Aesar, except for methoxypyridylboronic acid derivatives
1122,30 and 12,22,30 which were supplied by Vertellus Specialities UK
Ltd., 2-fluoro-5-pyridylboronic acid 13,31 2-amino-5-pyrimidylbor-
onic acid 26,32 Pd(PPh3)4 and Pd(PPh3)2Cl2,33 which were prepared
in-house. Anhydrous THF was dried through a HPLC column on an
Innovative Technology Inc. solvent purification system. Anhydrous
triethylamine was dried over calcium hydride, distilled and stored
under dry nitrogen prior to use. All other solvents were used without
prior purification. Solvents were degassed by bubbling dry argon at
a steady rate through the solvent for ca. 20 min. Column chroma-
F
N
OMe
F
N
MeO
51b
50c
4
20
N
13
B(OH)2
N
(1.2 equiv.)
25
N
a
Isolated yields after purification via chromatography and/or recrystallisation.
Reagents and conditions: Pd2(dba)3, PCy3, 1,4-dioxane, K3PO4, 100 ꢁC, 2–20 h.
Reagents and conditions: Pd(PPh3)4, Na2CO3, 1,4-dioxane, reflux, 24 h.
b
c
transport material in electroluminescent devices.25 Related
bis(pyridyl)pyridines and linear quaterpyridines have recently been
synthesised via Suzuki–Miyaura reactions by Burzicki et al. starting
from dihalopyridines.26
To extend further the scope of 4 in cross-coupling reactions
a Sonogashira reaction27 was performed (Scheme 8). Compound 4
reacted with phenylacetylene (2.05 equiv) under standard condi-
tions [5 mol % Pd(PPh3)2Cl2, 5 mol % CuI, Et3N] togive 27 in 72% yield.
No dehalogenation was observed in this case. A subsequent Suzuki–
Miyaura reaction of 13 on the remaining 2-chloro substituent of 27
gave 28 in 66% yield. The higher yield in this case when comparing to
tography was carried out using 40–63 mm mesh silica. Thin-layer
chromatography (TLC) was performed on 20 mm pre-coated plates
of silica gel (Merck, silica gel 60F254), visualisation was made using
ultraviolet light (254 nm). NMR spectra were recorded on: a Bruker
Avance-400 spectrometer [1H NMR (400 MHz),13C NMR (100 MHz)],
a Varian Inova-500 spectrometer [1H NMR (500 MHz), 13C NMR
(125 MHz)] and a Varian NMR system 700 spectrometer using deu-
terated solvent as a lock. Chemical shifts are quoted in ppm, relative
to the residual solvent as internal reference for 1H and 13C. The
phenylacetylene
(2.05 equiv.)
5 mol% Pd(PPh3)2Cl2
5 mol% CuI
I
13 (1.2 equiv.)
5 mol% Pd(PPh3)4
I
1M Na2CO3
Et3N, 50 oC, 18 h
72%
N
Cl
Dioxane, reflux, 18 h
66%
N
N
27
Cl
28
4
N
F
Scheme 8. Synthesis of 28 via sequential twofold Sonogashira and Suzuki–Miyaura reactions.

672
L.M. Daykin et al. / Tetrahedron 66 (2010) 668–675
following abbreviations are used in listing NMR spectra: s¼singlet,
d¼doublet, dd¼doublet of doublets, t¼triplet, m¼multiplet,
br¼broad. J values are quoted in Hz. Melting points were determined
on a Stuart Scientific SMP3 melting point apparatus and are un-
corrected. Electron Impact (EI) mass spectra were recorded on
a Thermo-FinniganTrace mass spectrometer with positive ionisation
mode. Electrospray (ESþ) mass spectra were recorded on a Thermo-
Finnigan LTQ FT mass spectrometer or a Micromass Autospec LCT
mass spectrometer. High resolution ESþ mass spectra were recorded
on a Thermo-Finnigan LTQ FT mass spectrometer. High resolution
APCIþ mass spectra were obtained courtesy of Mr Liam Brady of
Waters Ltd on a Waters LCT Premier XE using atmospheric pressure
chemical ionisation with an ASAP probe or on a Waters Xevo QToF
equipped with Atmospheric Pressure Gas Chromatography (APGC).
Elemental analyses were obtained on an Exeter analytical Inc. CE-
440 elemental analyser.
temperature and the solvent was removed in vacuo. The residue
was extracted into ethyl acetate and washed with brine. The or-
ganic layers were dried over Na2SO4, filtered and then concentrated
in vacuo. Purification was achieved by flash chromatography on
a silica gel column followed in some cases by recrystallisation.
4.2.1. 3-(2-Chloro-3-iodopyridin-4-yl)-2-methoxypyridine 7.
4.2.1.1. Method A. Compound 4 (2.0 g, 5.5 mmol), 11 (0.754 g,
4.9 mmol), Pd(PPh3)4 (5 mol %, 0.316 g, 0.27 mmol), 1,4-dioxane
(20 mL), Na2CO3 (1 M, 10.94 mL, 10.94 mmol) reflux for 24 h.
Chromatography (SiO2, hexane/ethyl acetate, 4:1 v/v) yielded 7 as
a white solid (0.75 g, 44%) used in subsequent reactions without
further purification. A sample was recrystallised from hexane and
ethyl acetate; mp: 169.5–171.0 ꢁC; dH (500 MHz, CDCl3) 8.32 (1H,
d, J 4.8), 8.26 (1H, dd, J 5.1, 1.9), 7.37 (1H, dd, J 7.3, 1.9), 7.04 (1H, d, J
4.8), 6.99 (1H, dd, J 7.3, 5.1), 3.91 (3H, s); dC (126 MHz, CDCl3)
159.8, 156.0, 154.9, 148.5, 148.1, 138.4, 125.9, 123.7, 116.8, 101.6,
53.9; m/z (EI) 346 (Mþ, 45%), 219 (100, MþꢀI). Anal. Calcd for
C11H8ClIN2O: C, 38.12; H, 2.33; N, 8.08. Found: C, 38.14; H, 2.34; N,
7.97; vmax (film)/cmꢀ1 3032, 2993, 2949, 1581, 1463, 1402, 1342,
1017, 840, 783.
4.1.1. 2-Chloro-3,4-diiodopyridine 4.
4.1.1.1. Method A. A solution of diisopropylamine (12.33 mL,
88 mmol) and anhydrous THF (100 mL) was cooled to ꢀ10 ꢁC under
an argon atmosphere. To this n-hexyllithium (2.3 M in hexane,
35.2 mL, 88 mmol) was added dropwise over 10 min. Following the
addition, the reaction was stirred at 0 ꢁC for 0.5 h, yielding a clear
yellow solution. The solution was cooled to ꢀ78 ꢁC and treated
dropwise over 0.5 h with 2-chloropyridine 1 (4.2 mL, 44 mmol) in
THF (50 mL). The solution was stirred for 1 h and became clear
orange. To this solution iodine (32.4 g, 128 mmol) in THF (100 mL)
was added over 45 min after which the reaction was stirred at
ꢀ78 ꢁC for further 30 min. The solution was allowed to warm to
0 ꢁC before quenching with water (200 mL), followed by addition of
saturated solution of sodium sulfite (100 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate.
The combined organic extracts were dried over MgSO4, filtered and
then concentrated to yield a dark brown crude solid (10.4 g). This
product was dried and precipitated from acetonitrile yielding 2-
chloro-3,6-diiodopyridine 4 as a white solid (4.42 g, 28%); mp:
161.1–162.5 ꢁC; dH (700 MHz, CDCl3) 7.96 (1H, d, J 5.0), 7.67 (1H, d, J
5.0); dC (176 MHz, CDCl3) 155.0, 148.4, 133.2, 122.5, 110.5; m/z (EI)
365 (Mþ), 238 (62%, MþꢀI). Anal. Calcd for C5H2ClI2N: C, 16.44; H,
0.55; N, 3.83. Found: C, 16.32; H, 0.56; N, 3.68; vmax (film)/cmꢀ1
2359, 2337, 1535, 1408, 1331, 1180, 1141, 1001, 828.
4.2.1.2. Method B. Compound 4 (5.80 g, 16 mmol), 11 (2.20 g,
14 mmol), Pd(PPh3)2Cl2 (5 mol %, 0.557 g, 0.79 mmol), 1,4-dioxane
(30 mL), Na2CO3 (1 M, 29.0 mL, 29 mmol) reflux for 19 h. Chroma-
tography (SiO2, hexane/ethyl acetate, 4:1 v/v) yielded 7 (1.05 g, 22%).
Crystal data: C11H8ClIN2O, M¼346.54, T¼120 K, monoclinic, space
group P21/c (no. 14), a¼10.3846(7), b¼8.0785(6), c¼13.6228(9) Å,
b
¼99.452(3)ꢁ, V¼1127.3(1) Å3, Z¼4, Dx¼2.042 g cmꢀ3
, m(Mo
K
a
)¼3.06 mmꢀ1, 20,013 reflections (3291 unique), absorption cor-
rection by numerical integration, Rint¼0.066, R[Iꢂ2 (I)]¼0.022.
s
CCDC-745858.
4.2.2. 5-(2-Chloro-3-iodopyridin-4-yl)-2-methoxypyridine 8. Com-
pound 4 (3.0 g, 8.0 mmol), 12 (3.10 g, 21 mmol), Pd(PPh3)4 (5 mol %,
0.474 g, 0.41 mmol), 1,4-dioxane (30 mL), Na2CO3 (1 M, 41 mL,
41 mmol) reflux for 20 h. Chromatography (SiO2, hexane/ethyl ace-
tate, 3:1 v/v) yielded 8 as a cream solid (1.05 g, 38%), used in sub-
sequent reactions without further purification. A sample was
recrystallised from hexane and ethyl acetate; mp: 130.1–130.6 ꢁC; dH
(700 MHz, CDCl3) 8.31 (1H, d, J 4.8), 8.13 (1H, dd, J 2.5, 0.6), 7.57 (1H,
dd, J 8.6, 2.5), 7.07 (1H, d, J 4.8), 6.82 (1H, dd, J 8.5, 0.6), 3.98 (3H, s); dC
(176 MHz, CDCl3) 164.5, 156.6, 155.6, 148.7, 146.5, 139.1, 131.6, 123.3,
110.7, 100.8, 54.0; m/z (EI) 346 (Mþ). Anal. Calcd for C11H8ClIN2O: C,
38.12; H, 2.33; N, 8.08. Found: C, 38.07; H, 2.32; N, 7.90; vmax (film)/
cmꢀ1 3038, 3012, 2950, 1599, 1490, 1372, 1061, 1002, 828.
4.1.1.2. Method B. The experimental procedure of Method A was
followed using n-butyllithium (2.5 M in hexane, 35.2 mL, 88 mmol)
instead of n-hexyllithium. The crude solid (13.1 g) was recrystallised
from acetonitrile yielding 4 as a white solid (4.18 g, 26%). Scale-up
using diisopropylamine (24.67 mL, 180 mmol), n-butyllithium
(70.50 mL, 176 mmol), 2-chloropyridine 1 (8.30 mL, 88 mmol), io-
dine (65.0 g, 260 mmol), THF (350 mL) gave 4 (5.50 g, 17%). Analyt-
ical data were consistent with those obtained by Method A.
4.2.3. 5-(2-Chloro-3-iodopyridin-4-yl)-2-fluoropyridine 9. Compound
4 (1.61 g, 4.4 mmol), 13 (1.60 g,11 mmol), Pd(PPh3)4 (5 mol %, 0.255 g,
0.22 mmol), 1,4-dioxane (20 mL), Na2CO3 (1 M, 22 mL, 22 mmol)
reflux for 24 h. Chromatography (SiO2, 0–50% ethyl acetate in hexane)
yielded 9 as a white solid (0.740 g, 50%), used in subsequent reactions
without further purification. A sample was recrystallised from hexane
and DCM; mp: 152.9–153.9 ꢁC; dH (700 MHz, CDCl3) 8.36 (1H, d, J 4.8),
8.19 (1H, d, J 2.5), 7.78 (1H, ddd, J 8.4, 7.5, 2.6), 7.09 (1H, d, J 4.8), 7.04
(1H, dd, J 8.4, 2.5); dC (176 MHz, CDCl3) 163.7 (d, JCF 242.5),156.8,154.2,
148.9, 147.3 (d, JCF 15.4), 141.6 (d, JCF 8.3), 136.2 (d, JCF 4.8), 123.2, 109.6
(d, JCF 37.6), 100.6; m/z (EI) 334 (Mþ, 32%), 207 (15, MþꢀI), 127 (100,
MþꢀC10H5ClFN2). Anal. Calcd for C10H5ClFIN2: C, 35.90; H,1.51; N, 8.37.
Found: C, 35.73; H, 1.50; N, 8.31; vmax (film)/cmꢀ1 3048, 1588, 1485,
1376, 1260, 850, 828.
4.1.1.3. Method C. Method B was followed but with the tem-
perature maintained between ꢀ100 and ꢀ85 ꢁC during the addi-
tion of 2-chloropyridine and iodine. Iodine was added over 1.25 h.
This gave 4 as a white solid (4.16 g, 26%). Analysis was consistent
with that obtained by Method A.
4.2. General method for Suzuki–Miyaura cross-coupling
reactions
To an argon purged flask was added the halopyridine, boronic
acid, palladium source and additional ligand (when applicable).
Degassed 1,4-dioxane and aqueous base were added and the mix-
ture was heated to reflux, with stirring. The reaction was monitored
by TLC and on completion (2–70 h) the reaction was cooled to room
4.2.4. 3-(2-Chloro-3-iodopyridin-4-yl)quinoline 10. Compound
4
(2.80 g, 7.7 mmol), 14 (0.994 g, 5.75 mol), Pd(PPh3)2Cl2 (5 mol %,
0.269 g, 0.383 mmol), 1,4-dioxane (30 mL), Na2CO3 (1 M, 11 mL,

L.M. Daykin et al. / Tetrahedron 66 (2010) 668–675
673
11 mmol) reflux for 67 h. Chromatography (SiO2, ethyl acetate/
hexane, 4:1 v/v) and recrystallisation from hexane and DCM yielded
10 as a white solid (0.277 g, 13%); mp: 199.1–199.9 ꢁC; dH (700 MHz,
CDCl3) 8.90 (1H, d, J 2.3), 8.40 (1H, d, J 4.7), 8.17 (1H, d, J 8.5), 8.11 (1H,
d, J 2.2), 7.88 (1H, d, J 8.1), 7.81 (1H, ddd, J 8.4, 6.9,1.4), 7.63 (1H, ddd, J
8.1, 6.9,1.1), 7.19 (1H, d, J 4.7); dC (176 MHz, CDCl3) 156.7,155.5,149.7,
148.9,148.0,135.7,135.5,130.8,129.8,128.4,127.8,127.2,123.5,100.6;
m/z (ESþ) 366.94959 (MþþH, C14H935Cl127IN2 requires 366.94935);
vmax (film)/cmꢀ1 3060, 3036, 1565, 1329, 850, 786.
requires 315.05692); vmax (film)/cmꢀ1 2950, 1594, 1498, 1362, 1286,
1250, 1017, 830.
4.2.9. 5-[2-Chloro-3-(2-methoxypyridin-3-yl)pyridin-4-yl]-2-
methoxypyridine 19. Compound 8 (0.680 g, 1.96 mmol), 11 (0.450 g,
2.9 mmol), Pd(PPh3)2Cl2 (5 mol %, 0.0689 g, 0.0981 mmol), 1,4-di-
oxane (20 mL), Na2CO3 (1 M, 6.0 mL, 6.0 mmol) reflux for 70 h.
Chromatography (SiO2, diethyl ether/petroleum ether, 2:1 v/v) yiel-
ded19 asawhitesolid(0.146 g,23%). Asamplewasrecrystallisedfrom
hexane and ethyl acetate; mp: 149.6–150.2 ꢁC; dH (500 MHz, CDCl3)
8.42(1H, d,J5.0), 8.13(1H, dd, J5.0,1.9),7.93(1H, d,J2.4), 7.30(1H, dd, J
7.3,1.9), 7.25(1H, d,J5.1), 7.20(1H, dd, J8.6,2.5), 6.84(1H,dd, J7.3, 5.0),
6.55 (1H, d, J 8.6), 3.86 (3H, s), 3.78 (3H, s); dC (126 MHz, CDCl3) 164.0,
161.0, 152.3, 149.4, 148.9, 147.6, 146.6, 140.2, 138.7, 130.9, 127.3, 123.5,
119.7, 116.8, 110.5, 53.8, 53.8; m/z (EI) 327 (Mþ), 292 (100, MþꢀCl).
Anal. Calcd for C17H14ClN3O2: C, 62.30; H, 4.31; N, 12.82. Found: C,
62.32;H, 4.37;N,12.73;vmax (film)/cmꢀ1 2978, 2939,1574,1492,1464,
1376, 1287, 1016, 784. Crystal data: C17H14ClN3O2, M¼327.76, T¼120 K,
triclinic, space group P1 (no. 2), a¼8.3074(11), b¼10.0536(14),
4.2.5. 3-[2-Chloro-3-(2-methoxypyridin-3-yl)pyridin-4-yl]-2-methoxy-
pyridine 15. Compound 4 (2.00 g, 5.5 mmol),11 (2.09 g,13.69 mmol),
Pd(PPh3)4 (5 mol %, 0.316 g, 0.274 mmol), 1,4-dioxane (20 mL),
Na2CO3 (1 M,10.95 mL,10.95 mmol)reflux for 20 h. Chromatography
(SiO2, hexane/ethyl acetate, 2:1 v/v) yielded 15 as a pale yellow waxy
solid (0.897 g, 47%), used in subsequent reactions without further
purification. A sample was recrystallised from hexane/ethyl acetate;
mp: 111.5–112.2 ꢁC; dH (500 MHz, CDCl3) 8.42 (1H, d, J 5.0), 8.05 (1H,
dd, J 5.0, 1.9), 8.03 (1H, dd, J 5.0, 1.9), 7.29–7.25 (2H, m), 7.23 (1H, d, J
5.0), 6.78–6.75 (2H, m), 3.77 (3H, s), 3.69 (3H, s); dC (126 MHz, CDCl3)
160.9, 160.0, 151.8, 148.6, 148.5, 147.5, 147.3, 139.7, 138.8, 131.7, 124.3,
121.4, 119.7, 116.5, 116.3, 53.6, 53.5; m/z (EI) 327 (Mþ, 60%), 292 (100,
MþꢀCl). Anal. Calcd for C17H14ClN3O2: C, 62.30; H, 4.31; N, 12.82.
Found: C, 62.19; H, 4.32; N,12.78; vmax (film)/cmꢀ1 2989, 2952,1578,
1468, 1400, 1366, 1300, 1188, 1017.
c¼10.0793(14) Å,
a
¼68.25(2),
b
¼78.16(2),
g
¼79.04(2)ꢁ, V¼759.2(2)
Å3, Z¼2, Dx¼1.434 g cmꢀ3
,
m
(Mo K
a
)¼0.27 mmꢀ1, 9263 reflections
(4187 unique), Rint¼0.015, R[Iꢂ2 (I)]¼0.032. CCDC-745859.
s
4.2.10. 3-[2-Chloro-3-(6-methoxypyridin-3-yl)pyridin-4-yl]-2-me-
thoxypyridine 20. Compound 7 (2.00 g, 5.77 mmol), 12 (0.970 g,
6.3 mmol), Pd2(dba)3 (3 mol %, 0.159 g, 0.173 mol), P(t-Bu)3$HBF4
(6 mol %, 0.100 g, 0.346 mmol) 1,4-dioxane (20 mL), KF (1.10 g,
19 mmol) reflux for 6 h. Chromatography (SiO2, hexane/ethyl ace-
tate, 4:1 v/v) yielded 20 as a white solid (1.40 g, 74%); mp: 102.7–
105.3 ꢁC; dH (700 MHz, CDCl3) 8.41 (1H, d, J 4.9), 8.06 (1H, dd, J 5.0,
1.8), 7.83 (1H, s), 7.35 (1H, d, J 7.3), 7.30 (1H, dd, J 7.2,1.7), 7.22 (1H, d,
J 4.9), 6.82 (1H, dd, J 7.2, 5.0), 6.62 (1H, d, J 8.5), 3.86 (3H, s), 3.68
(3H, s); dC (176 MHz, CDCl3) 163.6, 159.8, 151.8, 148.6, 148.4, 147.7
(2C), 140.4, 139.1, 133.3, 125.3, 124.6, 121.5, 116.8, 110.1, 53.7, 53.5;
m/z (ESþ) 328.08494 (MþþH, C17H1535ClN3O2 requires 328.08473);
vmax (film)/cmꢀ1 2952, 1469, 1400, 1375, 1284, 1016, 839, 788.
4.2.6. 2-Chloro-3,4-bis(6-methoxypyridin-3-yl)pyridine 16. Compound
4 (0.500 g, 1.37 mmol), 12 (0.419 g, 2.74 mmol), Pd(PPh3)4 (5 mol %,
0.081 g, 0.07 mmol), 1,4-dioxane (20 mL) and Na2CO3 (1 M, 5.5 mL,
5.5 mmol) reflux for 20 h. Chromatography (SiO2, petroleum ether/
ethyl acetate, 1:1 v/v) yielded 16 as a white powder (0.255 g, 50%);
mp: 145.6–147.9 ꢁC; dH (400 MHz, CDCl3) 8.44 (1H, d, J 5.0), 7.97 (1H,
d, J 2.7), 7.91 (1H, d, J 2.5), 7.39(1H, dd, J 2.5, 8.6), 7.29 (1H, d, J 5.1), 7.20
(1H, dd, J 2.6, 8.7), 6.73 (1H, d, J 8.0), 6.60 (1H, d, J 8.0), 3.93 (3H, s) 3.90
(3H, s); dC (100 MHz, CDCl3) 163.8, 163.5, 152.3, 149.0, 148.7, 148.2,
147.0,140.6,139.1,131.9,127.7,126.9,124.8,123.7,110.6, 53.6, 53.5;m/z
(ESþ) 328.08469 (Mþ, C17H1435ClN3O2 requires 328.08473); vmax
(film)/cmꢀ1 3039, 3010, 2945, 1602, 1560, 1498, 1456, 1359, 1302,
1289, 1257, 1188, 1012, 830, 776.
4.2.11. 2-Fluoro-5-[2-(4-methoxyphenyl)-3-(6-methoxypyridin-
3-yl)pyridin-4-yl]pyridine 22. Compound 18 (0.175 g, 0.554 mmol),
21 (0.100 g, 0.67 mmol), Pd2(dba)3 (2 mol %, 0.010 g, 0.011 mmol),
PCy3 (4.8 mol %, 0.008 g, 0.027 mmol) 1,4-dioxane (7 mL), K3PO4
(1.27 M, 0.74 mL, 0.94 mmol) reflux for 20 h. Chromatography (SiO2,
ethyl acetate/hexane, 3:1 v/v) yielded 22 as a pale yellow solid
(0.0640 g, 30%); mp: 139.2–140.2 ꢁC; dH (700 MHz, CDCl3) 8.72 (1H, d,
J 5.0), 7.98 (1H, d, J 1.9), 7.63 (1H, d, J 2.3), 7.40 (1H, td, J 8.0, 2.4), 7.25
(1H, d, J5.0), 7.17 (2H, d,J 8.7), 7.04 (1H, dd, J 8.5, 2.4), 6.79(1H, dd, J8.4,
2.6), 6.73 (2H, d, J 8.8), 6.50 (1H, d, J 8.5), 3.83 (3H, s), 3.74 (3H, s); dC
(176 MHz, CDCl3) 163.1, 163.0 (d, JCF 241.2), 159.6, 159.2, 149.0, 148.8,
147.9 (d, JCF 15.0), 145.8, 142.0 (d, JCF 8.0),141.3,133.1 (d, JCF 4.7),132.3,
131.4 (2C),130.9,126.1,123.3,113.7 (2C),110.8,109.4 (d, JCF 37.5), 55.4,
53.6; m/z (EI) 387 (Mþ, 85%), 386 (100, MþꢀH). Anal. Calcd for
C23H18FN3O2: C, 71.31; H, 4.68; N, 10.85. Found: C, 70.88; H, 4.74; N,
10.67; vmax (film)/cmꢀ1 3030, 2940,1604,1499,1252,1178,1016, 836.
4.2.7. 2-Chloro-3,4-bis(4-methoxyphenyl)pyridine 17. Compound 4
(0.500 g, 1.37 mmol), 21 (0.416 g, 2.74 mmol), Pd(PPh3)4 (5 mol %,
0.081 g, 0.07 mmol), 1,4-dioxane (20 mL) and Na2CO3 (1 M, 5.5 mL,
5.5 mL) reflux for 20 h. Chromatography (SiO2, petroleum ether/
ethyl acetate, 3:2 v/v) yielded 17 as a white crystalline powder
(0.288 g, 64%); mp: 126.4–129.9 ꢁC; dH (400 MHz, (CD3)2CO) 8.37
(1H, d, J 4.9), 7.39 (1H, d, J 5.2), 6.80 (2H, d, J 8.8), 7.10 (4H, d, J 9.1),
6.88 (2H, d, J 8.8), 6.80 (2H, d, J 8.8), 3.78 (3H, s), 3.75 (3H, s); dC
(100 MHz, (CD3)2CO) 160.4, 160.1, 152.6, 152.4, 148.8, 135.6, 132.5,
131.6, 131.4, 129.8, 125.0, 114.4, 114.3, 55.53, 55.48; m/z (APCIþ)
326.0938 (MþþH, C19H1735ClNO2 requires 326.0948); vmax (film)/
cmꢀ1 2963, 2838,1606, 1577,1511, 1454, 1371,1289,1246, 1173,1110,
1060, 1027, 998, 812, 767.
4.2.8. 5-[2-Chloro-3-(6-methoxypyridin-3-yl)pyridin-4-yl]-2-fluoropyr-
idine 18. Compound 9 (0.480 g, 1.43 mmol), 12 (0.330 g, 2.2 mmol),
Pd(PPh3)2Cl2 (5 mol %, 0.0504 g, 0.072 mmol), 1,4-dioxane (20 mL),
Na2CO3 (1 M, 4.0 mL, 4.0 mmol) reflux for 18 h. Chromatography
(SiO2, hexane/ethyl acetate, 2:1 v/v) yielded 18 as a yellow oil (0.410 g,
90%) used in subsequent reactions without further purification; dH
(700 MHz, CDCl3) 8.45 (1H, d, J 5.0), 7.97 (1H, d, J 2.2), 7.84 (1H, d, J 1.8),
7.42 (1H, td, J 8.4, 2.5), 7.33 (1H, dd, J 8.5, 2.4), 7.27 (1H, d, J 5.0), 6.79
(1H, dd, J 8.5, 2.6), 6.68 (1H, dd, J 8.5, 0.5), 3.88 (3H, s); dC (176 MHz,
CDCl3) 163.8, 163.2 (d, JCF 242.3), 152.7, 149.1, 148.3, 147.8 (d, JCF 15.2),
147.8, 141.8 (d, JCF 8.2), 140.6, 132.4, 131.9 (d, JCF 4.8), 124.4, 123.8, 111.0,
109.6 (d, JCF 37.6), 53.8; m/z (APCIþ) 315.05770 (Mþ, C16H1135ClFN3O
4.2.12. 5-[4-(6-Fluoropyridin-3-yl)-3-(6-methoxypyridin-3-yl)pyridin-
2-yl]pyrimidin-2-amine 23. Compound 18 (0.175 g, 0.5543 mmol), 26
(0.0920 g, 0.67 mmol), Pd2(dba)3 (2 mol %, 0.0102 g, 0.011 mmol),
PCy3 (4.8 mol %, 0.00750 g, 0.027 mmol) 1,4-dioxane (7 mL), K3PO4
(1.27 M, 0.742 mL, 0.942 mmol) reflux for 2 h. Chromatography (SiO2,
ethyl acetate/methanol, 4:1 v/v) yielded 23 as a white solid (0.0470 g,
23%); mp: 200.2–202.5 ꢁC; vmax (film)/cmꢀ1 3454 and 3305 (NH2),
3184,1638,1585,1487,1410,1285,1251, 828;dH (700 MHz, CDCl3) 8.76
(1H, d, J 4.9), 8.24 (2H, s), 7.99 (1H, d, J 1.6), 7.72 (1H, d, J 1.8), 7.40 (1H,
td, J8.4,2.4), 7.30(1H, d,J 4.9), 7.12 (1H, dd, J 8.5,2.5), 6.81(1H, dd, J 8.4,
2.6), 6.60 (1H, d, J 8.5), 5.20 (2H, br s), 3.86 (3H, s); dC (176 MHz, CDCl3)
163.6, 163.2 (d, JCF 242.0),161.5,159.2 (2C),154.1,149.7,148.8,147.9 (d,

674
L.M. Daykin et al. / Tetrahedron 66 (2010) 668–675
JCF 15.1), 146.3, 141.9 (d, JCF 8.0), 141.0, 132.6 (d, JCF 5.0), 131.1, 125.1,
124.2, 123.9, 111.5, 109.5 (d, JCF 37.5), 53.8; m/z (ESþ) 375.13660
(MþþH), C20H16 FN6O requires 375.13641.
followed. Compound 27 (0.400 g, 1.38 mmol), 13 (0.216 g,
1.53 mmol), Pd(PPh3)4 (5 mol %, 0.074 g, 0.06 mmol), 1,4-dioxane
(20 mL), Na2CO3 (1 M, 2.55 mL, 2.55 mmol) heated at reflux for
18 h. Chromatography (SiO2, ethyl acetate/hexane, 1:2 v/v) fol-
lowed by recrystallisation from hexane and DCM yielded 28 as
white needles (0.314 g, 66%); mp: 124.3–124.9 ꢁC; dH (700 MHz,
CDCl3) 8.95 (1H, d, J 2.4), 8.58 (1H, d, J 5.0), 8.50–8.37 (1H, m), 7.65–
7.51 (2H, m), 7.50–7.28 (9H, m), 7.04 (1H, dd, J 8.5, 2.7); dC (176 MHz,
CDCl3) 163.9 (d, JCF 241.2), 156.1, 148.8 (d, JCF 15.4), 148.2, 142.3,
135.6, 133.4 (d, JCF 4.6), 132.2, 131.7, 129.8, 129.4, 128.80, 128.77,
124.4, 122.6, 122.3, 119.8, 108.9 (d, JCF 37.4), 99.8, 98.9, 86.4, 85.9;
m/z (APCIþ) 375.1294 (MþþH, C26H16N2F requires 375.1298); vmax
(film)/cmꢀ1 3056, 2360, 2339, 2212, 1590, 1552, 1491, 1442, 1408,
1367, 1256, 1130, 1023, 899, 831, 740, 684.
4.2.13. 5-[2-(6-Fluoropyridin-3-yl)-3-(2-methoxypyridin-3-yl)pyridin-
4-yl]-2-methoxypyridine 24. Compound 19 (0.100 g, 0.31 mmol), 13
(0.052 g, 0.37 mmol), Pd2(dba)3 (2 mol %, 0.0056 g, 0.0061 mmol),
PCy3 (4.8 mol %, 0.0041 g, 0.015 mmol) 1,4-dioxane (5 mL), K3PO4
(1.27 M, 0.4 mL, 0.052 mmol) reflux for 5 h. Chromatography (SiO2,
ethyl acetate/hexane, 3:1 v/v) yielded 24 as a clear colourless oil
(0.0540 g, 45%); dH (700 MHz, CDCl3) 8.73 (1H, d, J 5.0), 8.07 (1H, d, J
1.8), 8.01 (1H, dd, J 5.0, 1.7), 7.93 (1H, d, J 1.9), 7.66 (1H, td, J 8.3, 2.4),
7.33 (1H, d, J 5.0), 7.16 (1H, dd, J 8.6, 2.5), 7.09 (1H, dd, J 7.3, 1.7), 6.76
(1H, dd, J 8.4, 2.5), 6.70 (1H, dd, J 7.2, 5.0), 6.55 (1H, d, J 8.6), 3.87 (3H,
s), 3.56 (3H, s); dC (176 MHz, CDCl3) 163.9, 163.0 (d, JCF 240.4), 160.7,
155.3, 149.3, 148.2 (d, JCF 15.1), 147.8, 147.5, 146.6, 141.8 (d, JCF 8.0),
140.9, 138.8, 134.4 (d, JCF 4.6), 130.3, 127.7, 124.2, 120.3, 117.0, 110.4,
108.7 (d, JCF 37.4), 53.8, 53.5; m/z (ESþ) 389.14105 (MþþH,
C22H18FN4O2 requires 389.14083); vmax (film)/cmꢀ1 2963,1592,1488,
1462, 1397, 1369, 1286, 1257, 1097, 1015, 827, 797, 732.
Acknowledgements
We thank EPSRC for funding (J.S.S.), Dr. A.E. Smith and Dr. K.M.
Clapham for preliminary experiments and B. Tarbit (Vertellus Spe-
cialities UK Ltd.) for the gift of some of the reagentsused in this work.
4.2.14. 3-[2-(6-Fluoropyridin-3-yl)-3-(6-methoxypyridin-3-yl)pyr-
idin-4-yl]-2-methoxypyridine 25.
References and notes
4.2.14.1. Method A. Compound 20 (0.500 g, 1.5 mmol), 13
(0.260 g,1.8 mmol), Pd2(dba)3 (2 mol %, 0.0279 g, 0.0305 mmol), PCy3
(4.8 mol %, 0.0205 g, 0.073 mmol) 1,4-dioxane (15 mL), K3PO4
(1.27 M, 2.04 mL, 2.59 mmol) reflux for 17 h. Chromatography (SiO2,
ethyl acetate/hexane, 3:1 v/v) yielded 25 as a clear colourless oil
(0.302 g, 51%); dH (700 MHz, CDCl3) 8.69 (1H, d, J 4.9), 8.06 (1H, d, J
2.2), 8.04(1H, dd, J 5.0,1.8), 7.71(1H, td, J8.3,2.4), 7.61(1H, s), 7.32(1H,
dd, J 7.2, 1.6), 7.27 (1H, d, J 4.9), 7.02 (1H, d, J 7.5), 6.81 (1H, dd, J 7.2, 5.1),
6.77 (1H, dd, J 8.5, 2.5), 6.43 (1H, d, J 8.5), 3.76 (3H, s), 3.60 (3H, s); dC
(176 MHz, CDCl3)163.1,162.9(d, JCF 240.8),159.9,154.4,149.1,149.0 (d,
JCF 15.1), 148.1, 147.4, 146.8, 142.6 (d, JCF 8.0), 140.5, 139.1, 134.1 (d, JCF
4.4),132.5,125.9,124.8,121.9,116.8,110.3,108.9(d, JCF 37.4), 53.5, 53.3;
m/z (ESþ) 389.14105 (MþþH, C22H18FN4O2 requires 389.14083); vmax
(film)/cmꢀ1 2949, 1592, 1463, 1400, 1285, 1249, 1016, 830.
1. (a) Mitsuya, M.; Bamba, M.; Sakai, F.; Watanabe, H.; Sasaki, Y.; Nishimura, T.;
Eiki, J.- i. WIPO WO 2,004,081,001 A1, 2004; Chem. Abstr. 2004, 141, 296024; (b)
Ismail, M. A.; Brun, R.; Easterbrook, J. D.; Tanious, F. A.; Wilson, W. D.; Boykin,
D. W. J. Med. Chem. 2003, 46, 4761–4769; (c) Aicher, T. D.; Boyd, S. A.; Chicarelli,
M. J. Condroski, K. R.; Hinklin, R. J.; Singh, A.; Turner, T. M.; Rustam, F. G. WIPO
WO 2,007,089,512 A1, 2007; Chem. Abstr. 2007, 147, 257756; (d) Sainz, Y. F.;
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4.2.14.2. Method B. Compound 20 (0.250 g, 0.763 mmol), 13
(0.130 g, 0.92 mmol), Pd(PPh3)4 (5 mol %, 0.0441 g, 0.038 mmol),
1,4-dioxane (12 mL), Na2CO3 (1 M, 1.8 mL, 1.8 mmol), reflux for
24 h. Chromatography (SiO2, ethyl acetate/hexane, 3:1 v/v) yielded
25 as a clear colourless oil (0.150 g, 50%).
8. Chung, J. Y. L.; Cvetovich, R. J.; McLaughlin, M.; Amato, J.; Tsay, F.-R.; Jensen, M.;
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J. F.; Marsais, F.; Queguiner, G. J. Organomet. Chem. 1996, 517, 25–36.
4.2.15. 2-Chloro-3,4-bis(2-phenylethynyl)pyridine 27. To a flask fit-
ted with a septumwas added 2-chloro-3,4-diiodopyridine 4 (1.500 g,
4.11 mmol), Pd(PPh3)2Cl2 (0.144 g, 0.21 mmol) and CuI (0.039 g,
0.21 mmol). The flask was evacuated and backfilled with dry argon
three times. Dry, degassed triethylamine (40 mL) was added via
a cannula and phenylacetylene (0.860 g, 8.42 mmol) was added via
syringe. The reaction was heated to 50 ꢁC for 18 h by which time the
reaction was complete by TLC. The reaction was cooled to room
temperature, triethylamine was removed in vacuo and the residue
was passed through a silica plug eluting with ethyl acetate (300 mL).
After concentration, the residue was purified by flash chromatogra-
phy (SiO2, DCM/hexane, 1:1 v/v) followed by recrystallisation from
methanol yielding 27 as a white solid (1.01 g, 72%); mp: 100.5–
101.7 ꢁC; dH (400 MHz, CDCl3) 8.26 (1H, d, J 5.1), 7.63–7.53 (4H, m),
7.44–7.31 (7H, m); dC (176 MHz, CDCl3) 152.9, 147.3, 136.2, 132.3,
132.0,129.9,129.5,128.8,128.7,124.1,122.7,122.11,122.07,101.0, 99.5,
85.9, 84.1; m/z (ESþ) 314.07294 (MþþH, C21H1335ClN requires
314.07310); vmax (film)/cmꢀ1 3046, 2365, 2323, 2235, 2202, 1596,
1567, 1519, 1490, 1442, 1389, 1279, 1160, 901, 841, 754.
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available to us. The synthesis of 1 from 5, as reported by Marzi, E.; Bigi, A.;
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14. In the GC–MS analysis of the crude product mixture, along with the signal for 4,
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