TBAF-Catalysed silver oxide-mediated cross-coupling of functional trimethysilylpyridines: Access to arylpyridines and bihetaryl compounds

Article abstract of DOI:10.1039/c0ob00710b

The concomitant use of silver oxide and catalytic amount of TBAF allowed the efficient and chemoselective coupling of readily available 4-chloro- and 4-methyl-2-trimethyl-silyl-pyridines with heteroaromatic and aromatic halides. Based on control experiments, a mechanism involving the formation of a pyridylsilver intermediate and TBAF recycling is postulated.

Full text of DOI:10.1039/c0ob00710b

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PAPER
TBAF-Catalysed silver oxide-mediated cross-coupling of functional
trimethysilylpyridines: access to arylpyridines and bihetaryl compounds†‡
Fre´de´ric Loue¨rat,a Heather Tye,b Spencer Napier,b Michael Garrigou,b Mark Whittakerb and Philippe C. Gros*a
Received 13th September 2010, Accepted 9th December 2010
DOI: 10.1039/c0ob00710b
The concomitant use of silver oxide and catalytic amount of TBAF allowed the efficient and
chemoselective coupling of readily available 4-chloro- and 4-methyl-2-trimethyl-silyl-pyridines with
heteroaromatic and aromatic halides. Based on control experiments, a mechanism involving the
formation of a pyridylsilver intermediate and TBAF recycling is postulated.
DeShong reported the coupling of aryltriflates with a biscatechol
Introduction
silicate derivative introduced only at C-3 of 2-methoxypyridine.23
The metal-catalyzed cross-coupling of aromatic and heteroaro-
Thus the lack of stable and easily handled pyridylsilanes seriously
matic derivatives1,2 is a very important process because of the
limited the general applicability of the Hiyama cross-coupling
increasing demand for sophisticated functionalised biaryl com-
in pyridine series. Methodologies using trimethylsilylpyridines or
pounds involved in the development of functional materials and
analogs emerged only recently.
biologically active agents. The most popular methodologies for the
The first palladium-catalyzed cross-coupling of 2-trimethylsilyl
preparation of biaryl compounds are the Stille3–5 and the Suzuki6–8
reactions that, while efficient, display some drawbacks especially
in terms of toxicity of released tin halides and accessibility and
stability of starting boron derivatives respectively.
halogenopyridines has been reported five years ago24 using CuI
and an excess of TBAF as activating agents. Bi(het)aryl and
more recently, bipyridines,25 were obtained in excellent yields
at room temperature. Since an excess of TBAF could result in
purification and functional tolerance issues, methodologies have
been developed to omit this salt or decrease its amount. Yoshida
reported the cross-coupling of allyl(dimethyl)silyl pyridine in the
presence of silver oxide. The coordination of silver by both the
pyridine nitrogen and the allyl group was postulated.26 While
efficient, this process suffers from the cost of allyl(dimethyl)silyl
chloride used for the preparation of starting silanes. Such Ag2O-
mediated coupling could be applied to 2-trimethylsilylpyridine
provided that a catalytic amount of TBAF was used.27 This
promising reaction is still underdeveloped and really deserves
deeper synthetic and mechanistic investigations. Especially the
coupling of functional pyridine units and substituent tolerance
has not been studied yet. The cross-coupling of the synthetically
useful 4-chloro-2-trimethylsilylpyridines 128 with (het)aryl halides
was studied. The substrate has been chosen for several reasons. At
first, it can be easily prepared by selective lithiation-silylation of the
parent pyridine using the BuLi-LiDMAE superbasic reagent,29,30
secondly the C–Cl bond is a useful reactive site for further
functionalization of the bi(het)aryl product implying its retention
along the coupling process.
The cross-coupling of silicon-containing aromatics has to be
considered as a valuable alternative9–11 due to a relatively easy
access to silylated derivatives and the low environmental impact of
silicon. The most important issue to be addressed with this process
is the very weak polarity of the carbon–silicon bond. An efficient
activation mode, first disclosed by Hiyama,12 is the addition of
a nucleophilic compound to the aromatic silane to turn it into
a more polarized pentacoordinate silicate able to transmetallate
with the Pd(II) complex formed by reaction with an aromatic
halide. The efficiency of silicon activation and subsequent cross-
coupling has been found critically dependent on the silicon group
substitution pattern. Halosilanes,13–15 silanols,16,17 siloxanes,18–20 or
silacyclobutanes21,22 have been used with success in cross-couplings
of aromatic compounds. In contrast, essentially due to synthetic
and stability issues, these species have been scarcely used in
heterocyclic chemistry especially in the important pyridine series
for which efficient coupling methodologies are still needed. To
our knowledge, only two examples of activated pyridylsilanes have
been reported. Hiyama10 introduced the instable dichloroethylsilyl
group at C-2 of picoline which had to be in situ reacted and
aGroupe SOR, SRSMC, CNRS, Nancy Universite´, Boulevard des Aigu-
illettes, 54506, Vandoeuvre-Le`s-Nancy, France. E-mail: philippe.gros@
srsmc.uhp-nancy.fr; Fax: +33 38368 4785; Tel: +33 38368 4979
Results and discussion
bEvotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire, UK OX14 4SA
Reaction parameters were screened with
1 and using 3-
† This publication is part of the web themed issue on fluorine chemistry.
bromopyridine as the coupling partner (Table 1). As a general
trend, reactions containing Ag2O produced the expected product
1a indicating the activation of the C–Si bond of 1 using this salt
‡ Electronic supplementary information (ESI) available: Characterization
data and copies of 1H, 13C spectra for new compounds. See DOI:
10.1039/c0ob00710b
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Table 1 Conditions screening for cross-coupling of 1a
the presence of Ag2O (run 9), the yield was comparable to those
obtained with Ag2O alone (run 4) but homocoupling product 4,4¢-
dichlorobipyridine 3 was formed in notable amount. The other
fluoride salts KF (run 10) and CsF (run 11) gave the cross-coupling
product in 13 and 17% respectively with 3 as the main product
besides 3,3¢-bipyridine 4. The coupling was found very efficient
within a short reaction time (3 h) with 5% of TBAF and switching
from Pd(PPh3)4 to other sources of Pd0 such as PdCl2(PPh3)2 or
PdCl2dppf (runs 12–16). Finally, an additional decrease of TBAF
amount to 2% still gave 1a in 80% yield (run 13) but homocoupling
of 1 into 3 (20%) was obtained. Thus very efficient conditions have
been found for the cross-coupling of 1 using a minimal amount of
TBAF.
BrPy
Run (equiv.) Pd source
“Ag”
F- source (%) Conv.%b 1a%b
1
2
3
4
5
6
7
8
9
1
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Ag2O
Ag2O
Ag2O
Ag2O
—
TBAF (100) 50
TBAF (100) 65
TBAF (100) >98
10d
37d
55d
50
0e
0.8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
From the mechanistic angle, the increase in efficiency of the
coupling in the presence of catalytic TBAF was intriguing. Indeed
the Hiyama coupling typically involves at least 1 equiv. of TBAF
to generate a pentacoordinate fluorosilicate,10 that further releases
a fluorosilane (Me3SiF) upon the coupling step. The regeneration
of fluoride ions then could be due to the reaction of Me3SiF with
Ag2O to give AgF. Since Me3SiF is a volatile compound (16.4 ◦C),
—
50
TBAF (100) <5
TBAF (100) <5
TBAF (10)
Ag2Oc
Ag2O
0e
>98
94
AgF (100) <5
0e
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
AgF (10)
KF(10)
CsF(10)
TBAF (5)
TBAF (5)
TBAF (5)
TBAF (5)
TBAF (2)
>98
>98
>98
>98
>98
>98
>98
>98
48 (26)d,f
13 (60)d,f
17 (52)d,f
96
10 0.5
11 0.5
12 0.5
13 0.5
14 0.5
16 0.5
17 0.5
◦
its persistence in the medium under refluxing conditions (90 C)
95g
is highly improbable. Additionally, the Si–F bond is highly stable
(561 kJ/mole)31 thus making its cleavage by a nucleophilic species
unlikely in the medium. Furthermore even if AgF was formed,
we have shown that this salt was unable to promote the coupling
efficiently. On the other hand, 1 did not couple in the presence of
TBAF alone (Table 1, run 5) while Ag2O promoted the reaction
in 50% yield (run 4). Thus, it was reasonable to propose an initial
activation of the C–Si bond by Ag2O favoured by both pyridine
nitrogen coordination and silicon oxophilicity26,32 as reported by
Yoshida for allyldimethylsilylpyridine (Scheme 1). However in the
case of 1, the allyl group was not available to ensure additional
coordination of the second silver and subsequent cleavage into the
reactive silyloxysilver intermediate.33 Thus the intermediate could
remain as such or be turned into a pyridylsilver by cleavage of the
pyridyl carbon–silicon bond.
PdCl2(PPh3)2 Ag2O
PdCl2dppf Ag2O
PdCl2(PPh3)2 Ag2O
94g
92g
80 (20)f,g
a Reactions performed on 1 mmole of 1. b Yield and conversion of 3-
bromopyridine determined by GC. c 10% of Ag2O were used. d Formation
of 4. e Product not detected, only degradation of 1. f 3% in brackets.
g Reaction time was 3 h.
and subsequent transmetallation with the palladium complex.
The bromopyridine stoichiometry was found to be critical. The
coupling product was detected in only 10% amount using 1 equiv.
of BrPy (50% conversion) besides bipyridine 4. In contrast 0.8
equiv. of bromopyridine led to 1a in 37% yield with incomplete
conversion of bromopyridine (run 2) that was totally consumed
using 0.5 equiv. affording 1a in 55% yield (run 3). 0.5 equiv.
of BrPy was then used in next experiments. When TBAF was
omitted, Ag2O allowed the cross-coupling to occur in 50% yield
with 50% of unreacted BrPy and 1 was not recovered (run 4). An
extended reaction time up to 72 h did not improve the yield. This
result clearly illustrated the activating effect of the chlorine moiety
since a separate experiment (unreported here) performed with the
unsubstituted analogue did not give any coupling product under
the same conditions. Yoshida also reported such an inertness in
refluxing THF.26
Scheme 1 Yoshida’s activation of ally(dimethyl)silyl pyridine.
When stoichiometric TBAF was used in the absence (run 5) or
with a catalytic amount of Ag2O (run 6), only degradation of 1 was
observed in both cases indicating that the formed pyridylsilicate
was unable to be coupled in the absence of stoichiometric
Ag2O. We were pleased to observe that the use of a catalytic
amount of TBAF (10%) in association with Ag2O dramatically
improved the cross-coupling giving exclusively bipyridine 1a in
almost quantitative yield (run 7). Other fluoride sources were
also used to investigate the influence of the fluoride counterion.
Since AgF was suspected to be formed upon contact between
Ag2O and TBAF, its effect was also examined (runs 8 and 9). As
shown, no coupling was observed using 1 eq. of this salt but only
degradation of 1 (run 7). When TBAF was replaced by AgF in
To check this latter hypothesis, 1 was placed in DMF in
the presence of silver oxide (1 equiv.). After 24 h at 90 ◦C, 1
was recovered quantitatively indicating the absence of cleavage
of the C–Si bond and making unlikely the formation of a
pyridylsilver (Scheme 2). In contrast, when catalytic TBAF was
added, 1 was fully consumed and converted into degradation
products indicating the formation of an instable species in the
medium. When the reaction was repeated at room temperature, 4-
chloropyridine was isolated almost quantitatively besides a small
amount of 3. Thus TBAF was able to catalyse the desilylation of
1 in the presence of Ag2O.
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been unable to characterize pyridylsilver intermediates by NMR
or mass spectroscopy due to their too high instability on standing.
Such an instability is known for organosilver.40 As shown, TBAF
exhibited a unique behaviour compared with AgF, KF or CsF
that, while giving the expected cross-coupling, also promoted the
formation of homocoupling product 3 in notable amount (runs 9–
11, Table 1). Besides possible difference of solubility, cation effect
and ion-pairing could be responsible for the observed selectivities.
Indeed, the organic tetrabutylammonium cation (TBA+) is known
to greatly enhance the nucleophilicity of associated anion by
formation of a weak ion pair. In contrast, inorganic salts rather
lead to tighter ion pairs and thus to less reactive counterions.
The consequence should be a less efficient formation of 1-SiF and
then of 1-Ag that is implied in the subsequent transmetallation
process. The homocoupling product 3 then probably resulted of
the competitive formation of dipyridylargentate. Alternatively,
a reaction of TBAF with the palladium catalyst leading to a
more electrophilic PdII fluoride complex and further fluoride
release could be envisioned. However, PdII fluoride complex has
been reported to be far less reactive than its iodide or bromide
counterparts precluding an efficient transmetallation.41–43
The scope of the reaction was next examined. The best
conditions determined in Table 1 were applied to a set of
heteroaromatic and aromatic partners (Table 2). As shown, 4-
chloropyridine was generally efficiently reacted. The C–Cl bond
was tolerated in all reactions. Good yields were obtained with
heterocyclic compounds such as bromo-pyrimidine, quinoline or
thiophene (runs 1–3 and 5) giving access to a range of useful
bihetarylcompounds. Unfortunately we were unable to couple
2-bromopyridine and the reaction only gave reduction of the
C–Br bond and silane degradation (run 4). A deactivation of
the intermediate oxidative addition complex by coordination
with Ag2O could be involved in this case. Functional aromatic
compounds bearing methyl, cyano acetyl and trifluoromethyl or
nitro groups were coupled in moderate to excellent yields with full
retention of the sensitive substituents. The reaction was found to
be sensitive to steric effects since 2-iodotoluene was coupled in only
25% yield (run 6). In this case, the homocoupling product 3 was
formed in 40% yield in agreement with a sluggish transmetallation
of the pyridylsilver.
Scheme 2 Reaction of 1 with Ag2O.
Fluoride release probably occurred from nucleophilic attack
of the Ag2O oxygen at the pentacoordinate fluorosilicate 1-SiF
generated in catalytic amount (Scheme 3).34 The coordination of
silver atoms by pyridine nitrogen probably favoured the process
via proximity effects. This led us to postulate the formation of a
4-chloropyridylsilver intermediate 1-Ag35 giving 4-chloropyridine
upon hydrolysis and able to homocouple into 3 in the presence of
oxygen upon work-up. This pyridylsilver was then involved in the
palladium catalytic loop. The strong affinity of silver for halides36,37
then favoured the silver to palladium transmetallation step with
the PdII complex formed after oxidative addition of Pd0 into the C–
X bond of thearomatichalide partner. The target couplingproduct
was finally obtained after reductive elimination and regeneration
of Pd0 (Scheme 2). The need for 2 equiv. of pyridylsilane to
achieve complete reaction could be result of coordination of 1
equiv of the substrate by silver or to the alternative formation of a
dipyridylargentate.38,39 At this stage despite all our efforts we have
The effect of substitution on the reaction outcome was then
examined. When chlorine was moved from C-4 to C-3, 2 was
degradated and only traces of the expected product were detected
◦
(GC-MS) after reaction at 90 C with 4-iodo-nitrobenzene or 5-
bromopyrimidine which were excellent partners for coupling with
1 (Scheme 4). The same result was obtained when the reaction
was conducted at room temperature. It is worthy of note that 2
was previously coupled in excellent yield at room temperature in
copper mediated reaction.24
This showed the instability of the putative intermediate pyridyl
silver in the presence of a leaving group at the ortho position.
Elimination of chlorine and formation of a pyridyne intermediate
probably occurred here. The reaction was also attempted with 2-
chloro-6-trimethylsilylpyridine 3 (Scheme 5). In this case, traces of
the expected product were obtained with recovery of the starting
silane. This indicated the critical effect of the pyridine nitrogen
environment. stereoelectronic effects generated by chlorine at C-
2 probably impeded efficient silver coordination and subsequent
coupling reaction.
Scheme 3 Proposed catalytic loop for cross-coupling.
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Table 2 Cross-coupling of 1 with various (het)aryl halidesa
Run
1
(Het)ArX (equiv.)
Product
Yield%b
1a, 70
2
3
1b, 85
1c, 62
Scheme 4 Attempted cross-coupling of 2.
4
5
1d, 0c
1e, 52
Scheme 5 Attempted cross-coupling of 3.
6
1f, 25d
7
8
9
1g, 80
1h, 59
1i, 60
Scheme 6 Cross-coupling of 4.
clearly showed the influence of electronic effects on the reaction.
Indeed the electron-withdrawing chlorine group gave better yields
in agreement with an increased polarization of the C–Si bond
making silicon more electrophilic and thus more prone to interact
with fluoride and subsquently with the oxygen of Ag2O. As another
contrast with 1, in this case the use of Ag2O alone did not give any
coupling product.
Conclusions
10
11
1j, 27(62)e
1k, 86
In summary, an efficient cross-coupling methodology of functional
2-trimethylsilylpyridylsilane has been developed using silver oxide
and a catalytic amount of TBAF. The formation of a reactive
pyridylsilver intermediate is postulated to explain the regeneration
of fluoride ions in the reaction medium. Heteroaromatic and
aromatic halides were reacted in acceptable to excellent yields
leading to a range of synthetically useful poly(hetero)aromatic
compounds. The best results were obtained using an electron-
withdrawing group on the pyridylsilane at C-4 while a leaving
group ortho to the silyl group must be avoided.
a Reactions performed on 1 mmole of 1. b Isolated yields after column
chromatography. c Reduction of 2-bromopyridine and degradation of 1.
d 3 was formed in 40% yield. e LC-MS yield in brackets, 1j was difficult to
separate from 3 (16%).
Experimental section
Then the chlorine at C-4 was changed into a methyl group to
examine the influence of an electron donating group (Scheme 6).
The 4-picolyl silane 4 was successfully coupled with 3-
bromopyridine and 5-bromopyrimidine but in moderate 43 and
46% yields respectively. A comparison with runs 1 and 2 in Table 2
General methods
All solvents were distilled before use. 4-chloro-2-
trimethysilylpyridine
1,
3-chloro-2-trimethysilyl-pyridine
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2, 2-chloro-6-trimethysilyl-pyridine
3
and 4-methyl-2-
150.3 ppm. FTIR (KBr): 3073, 2924, 1568, 1538, 1383, 1089, 819,
trimethysilylpyridine 4 were prepared by lithiation-silylation of
4-chloro-, 3-chloro-, 2-chloro- and 4-methylpyridine respectively
using the BuLi-LiDMAE reagent. Ag2O was dried overnight
under vacuum before use. All other reagents and catalysts were
commercially available and used as such. 1H and 13C NMR spectra
were performed on Bruker spectrometers at 250 or 400 MHz (1H)
and 62.5 or 100 MHz (13C) in CDCl3 using TMS as reference. GC
experiments were performed on a Shimadzu chromatograph fitted
with a 15 m capillary column. GC-MS spectra with electronic
impact were performed on a Shimadzu QP 2010 apparatus. LCMS
were performed on a Shimadzu LCMS-2010EV. High resolution
mass spectra were performed on a Bruker microTOF-Q. Column
Chromatography was performed on silica gel (70–230 mesh).
699. MS (EI); m/z (%): 195 [M+] (100), 160 (25).
4-Chloro-2-(2-methylphenyl)-pyridine (1f). Yield, 25%. NMR
(250 MHz, CD3OD) dH = 2.30 (s, 3 H), 7.27–7.37 (m, 4 H), 7.48
(dd, J = 5.48, 1.98 Hz, 1H), 7.57 (d, J = 1.98 Hz, 1 H), 8.55 (d, J =
5.48 Hz, 1 H). NMR (62.5 MHz, CD3OD) dC = 23.3, 122.0, 124.4,
126.0, 129.0, 129.5, 130.9, 135.8, 139.1, 144.1, 150.0, 161.45 ppm.
FTIR (KBr): 3050, 1567, 1540, 1149, 1353, 1114, 1087, 824, 723.
LCMS (ESI): 206 (60), 204 (M+H+) (100), 157 (15). HRMS (ESI
(M+H+)): calcd. for C12H10ClN 204.0502, found 204.0497.
4-Chloro-2-(3-cyanophenyl)-pyridine (1g). Yield, 80%. NMR
(250 MHz, CDCl3) dH = 7.34 (dd, J = 5.33, 1.98 Hz, 1 H), 7.56–7.66
(m, 1 H), 7.68–7.78 (m, 2 H), 8.22 (dt, J = 7.92, 1.60 Hz, 1 H), 8.33
(t, J = 1.45 Hz, 1 H), 8.57–8.68 (m, 1 H). NMR (62.5 MHz, CDCl3)
dC = 113.2, 118.5, 121.0, 123.4, 129.7, 130.8, 131.0, 132.9, 139.2,
145.3, 150.8, 156.4 ppm. FTIR (KBr): 3050, 2227, 1573, 1549,
1458, 1367, 1058, 910, 873. LCMS (ESI): 217 (40), 215 (M+H+)
(100). HRMS (ESI (M+H+)): calcd. for C12H7ClN2 215.0376,
found 215.0371.
General procedure for cross-coupling reactions
To a suspension of the aryl halide (0.5 mmol) and Ag2O
(1 mmol) in degassed DMF (5 mL) under argon were added the
trimethylsilylpyridine (1 mmol), PdCl2(PPh3)2 (0.025 mmol) and
TBAF (0.05 mmol, 0.05 mL of a 1 M solution in THF). The
resulting suspension was stirred at 90 ◦C for 3h. After cooling,
the reaction medium was diluted with EtOAc (5 mL), filtered,
and concentrated. Column chromatography using Cyclohexane-
AcOEt as eluent afforded products.
4-Chloro-2-(3-acetylphenyl)-pyridine (1h). Yield, 59%. NMR
(250 MHz, CDCl3) dH = 2.70 (s, 3 H), 7.31 (dd, J = 5.33, 1.98 Hz,
1 H), 7.61 (t, J = 7.77 Hz, 1 H), 7.82 (d, J = 1.37 Hz, 1 H), 8.05
(dt, J = 7.77, 1.45 Hz, 1 H), 8.21 (ddd, J = 7.80, 1.87, 1.14 Hz,
1 H), 8.57 (t, J = 1.52 Hz, 1 H), 8.62 (d, J = 5.33 Hz, 1 H).
NMR (62.5 MHz, CDCl3) dC = 26.8, 121.1, 122.9, 126.8, 129.2,
131.5, 137.7, 138.5, 145.1, 150.5, 157.8, 197.9 ppm. FTIR (KBr):
3100, 1674, 1571, 1554, 1458, 1360, 1300, 1245, 802. LCMS (ESI):
234 (60), 232 (M+H+) (100). HRMS (ESI (M+H+)): calcd. for
C13H10ClNO 232.0529, found 232.0530.
4-Chloro-2,3¢-bipyridine (1a)44. Yield, 70%. NMR (400 MHz,
CDCl3): dH = 7.29 (dd, J = 5.3, 1.9 Hz, 1H), 7.40 (ddd, J = 8.8,
5.0, 0.9 Hz, 1H), 7.74 (dd, J = 1.9, 0.6 Hz, 1H), 8.28 (dt, J = 7.9,
1.9 Hz, 1H), 8.59 (s, 1H), 8.61 (d, J = 0.6 Hz, 1H), 8.67 (dd, J =
5.0, 1.9 Hz, 1H), 9,13 (d, J = 5.0, 1.9 Hz, 1H). NMR (100 MHz,
CDCl3): dC = 120.8, 123.0, 123.6, 133.6, 134.3, 145.0, 148.2, 150.5,
150.8, 156.3 ppm. FTIR (KBr): 3043, 2923, 1724, 1572, 1542,
1413, 1102, 1023, 804. MS (EI): m/z (%): 190[M+] (100), 164 (22).
4-Chloro-2-(4-acetylphenyl)-pyridine (1i)3. Yield, 60%. NMR
(250 MHz, CDCl3) dH = 2.67 (s, 3 H), 7.32 (dd, J = 5.33, 1.83 Hz, 1
H), 7.80 (d, J = 1.37 Hz, 1 H), 8.09 (brs, 4 H), 8.63 (d, J = 5.33 Hz,
1 H). NMR (62.5 MHz, CDCl3) dC = 26.8, 121.4, 123.1, 127.2,
128.9, 137.6, 142.2, 145.0, 150.7, 157.6, 197.7 ppm. FTIR (KBr):
3060, 1672, 1567, 1548, 1355, 1266, 967, 822. LCMS (ESI): 234
(60), 232 (M+H+) (100), 157 (14).
5-(4-Chloropyridin-2-yl)-pyrimidine (1b). Yield, 85%. NMR
(400 MHz, CDCl3): dH = 7.36 (dd, J = 5.3, 1.9 Hz, 1H), 7.76 (d,
J = 1.9 Hz, 1H), 8.64 (d, J = 5.4 Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H),
9.30 (s, 2H). NMR (100 MHz, CDCl3): dC = 120.8, 123.8, 131.3,
145.3, 151.2, 153.5, 155.1, 159.1 ppm. FTIR (KBr): 3045, 2923,
1564, 1376, 1185, 1056, 821. MS (EI): m/z (%): 191 [M+] (85),
113 (100). HRMS(ESI (M+H+)): calcd. for C9H6ClN3 192.0323,
found 192.0330.
4-Chloro-2-(4-(trifluoromethyl)phenyl)-pyridine
(1j). Yield,
27%. NMR (250 MHz, CDCl3) dH = 7.29–7.36 (m, 1 H), 7.67–7.84
(m, 3 H), 8.11 (d, J = 8.07 Hz, 2 H), 8.63 (dd, J = 5.25, 0.53 Hz,
1 H). NMR (62.5 MHz, CDCl3) dC = 121.2, 123.1, 124.5, 124.7
1
3
(d, JC–F, 272 Hz), 125.8, 126.5 (d, JC–F, 5 Hz), 127.3, 131.5 (q,
2JC–F, 33 Hz), 141.4, 145.1, 150.7, 157.3 ppm. NMR (235 MHz,
CDCl3) dF = -62.65 ppm. FTIR (KBr): 2985, 1674, 1549, 1329,
1167, 1104, 1245, 849, 827. LCMS (ESI): 260 (50), 258 (M+H+)
(100). HRMS(ESI (M+H+)): calcd. for C12H7ClF3N 258.0219,
found 258.0215.
3-(4-Chloropyridin-2-yl)-quinoline (1c). Yield, 62%. NMR
(400 MHz, CDCl3): dH = 7.30 (dd, J = 5.3, 1.9 Hz, 1H), 7.57
(td, J = 7.6, 1.2 Hz, 1H), 7.74 (td, J = 8.2, 1.6 Hz, 1H), 7.86 (dd,
J = 1.9, 0.6 Hz, 1H), 7.90 (dd, J = 8.2, 1.6 Hz, 1H), 8.14 (d, J =
8.5 Hz, 1H), 8.64 (d, J = 5.7 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H).
NMR (100 MHz, CDCl3): dC = 121.1, 123.0, 127.3, 127.7, 128.6,
129.4, 130.4, 130.7, 134.2, 145.1, 148.5, 149.0, 151.0, 156.4 ppm.
FTIR (KBr): 3039, 1573, 1329, 1121, 966, 753. MS (EI): m/z
(%): 240 [M+] (100), 205 (20). HRMS(ESI (M+H+)): calcd. for
C14H9ClN2 241.0527; found 241.0530.
4-Chloro-2-(4-nitrophenyl)-pyridine (1k). Yield, 86%. NMR
(250 MHz, CDCl3) dH = 7.37 (dd, J = 5.25, 1.90 Hz, 1 H), 7.78–7.87
(m, 1H), 8.14–8.24 (m, 2H), 8.30–8.43 (m, 2H), 8.61–8.71(m, 1H).
NMR (62.5 MHz, CDCl3) dC = 121.6, 123.8, 124.1, 127.8, 143.9,
145.2, 148.5, 150.9, 156.3. LCMS (ESI): 237 (55), 235 (M+H+)
(100). HRMS(ESI (M+H+)): calcd. for C11H7ClN2O2 235.0274,
found 235.0266.
4-Chloro-2-(2-thienyl)-pyridine (1e)24. Yield, 52%. NMR
(400 MHz, CDCl3): dH = 7.10-7.16 (m, 2H), 7.43 (dd, J = 5.0,
0.9 Hz, 1H), 7.59 (dd, J = 3.5, 1.0 Hz, 1H), 7.65 (dd, J = 1.9,
0.6 Hz, 1H), 8.45 (dd, J = 5.3, 0.6 Hz, 1H). NMR (100 MHz,
CDCl3): dC = 118.5, 118.9, 122.0, 124.4, 125.0, 125.3, 128.1, 128.4,
4-Methyl-2,3-pyridine (4a)45. Yield, 43%. NMR (250 MHz,
CDCl3) dH = 9.18 (m, 1H), 8.65 (m, 1H), 8.58 (d, J = 5.0, Hz,
1772 | Org. Biomol. Chem., 2011, 9, 1768–1773
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1H), 8.31 (ddd, J = 8.2, 4.1, 1.9 Hz, 1H), 7.57 (m, 1H), 7.40 (dd,
J = 4.9, 3.7 Hz, 1H), 7.12 (d, J = 5.1 Hz, 1H), 2.44 (s, 3H). NMR
(62.5 MHz, CDCl3) dC = 21.2, 121.6, 123.5, 123.8, 134.4, 148.1,
148.2, 149.3, 149.7, 150.0, 154.7. FTIR (KBr): 2918, 1602, 1545,
1379, 1207, 988, 829. MS (EI): m/z (%): 170 [M+] (100), 144 (29).
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5-(4-Methylpyridin-2-yl)-pyrimidine (4b)46. Yield, 46%. NMR
(250 MHz, CDCl3) dH = 9.31 (s, 2H), 9.25 (s, 1H), 8.60 (d, J =
5.0, Hz, 1H), 7.57 (m, 1H), 7.17 (d, J = 5.0, Hz, 1H), 2.46 (s, 3H).
NMR (62.5 MHz, CDCl3) dC = 21.2, 121.5, 124.5, 132.5, 148.4,
150.1, 151.8, 155.0, 158.5. FTIR (KBr): 2924, 2854, 1725, 1605,
1464, 14136, 1190, 1023, 869, 807. MS (EI): m/z (%): 171 [M+]
(97), 93 (100).
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