Syntheses of three new pyridyl thienopyridine ligands via the hurtley reaction

Article abstract of DOI:10.1002/jhet.903

The tridentate pyridyl thienopyridines 5-phenyl-7-(pyridin-2-yl)thieno[2,3- c]pyridine (L1), 7-(pyridin-2-yl)-5-(thiophen-2-yl)-thieno[2,3-c]pyridine (L2) and 5,7-di(pyridin-2-yl)thieno[2,3-c]pyridine (L3) have been synthesized via the Hurtley reaction. L

Full text of DOI:10.1002/jhet.903

1290
Syntheses of Three New Pyridyl Thienopyridine Ligands via the
Vol 49
Hurtley Reaction
*
Robert O. Steen, Lasse J. Nurkkala, and Simon J. Dunne
School of Sustainable Development of Society and Technology, Mälardalen University,
Drottninggatan 12, 631 05 Eskilstuna, Sweden
*
E-mail: robert.ove.steen@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received December 21, 2010
DOI 10.1002/jhet.903
View this article online at wileyonlinelibrary.com.
The tridentate pyridyl thienopyridines 5‐phenyl‐7‐(pyridin‐2‐yl)thieno[2,3‐c]pyridine (L1), 7‐(pyridin‐2‐yl)‐
5‐(thiophen‐2‐yl)‐thieno[2,3‐c]pyridine (L2) and 5,7‐di(pyridin‐2‐yl)thieno[2,3‐c]pyridine (L3) have been syn-
thesized via the Hurtley reaction. L1 and L2 were synthesized by condensing 3‐bromothiophene‐2‐carboxylic
acid with phenyl‐1,3‐butanedione and 1‐thienyl‐1,3‐butanedione respectively. L3 was synthesized by con-
densing 3‐bromothiophene‐2‐carboxylic acid with benzoylacetonitrile. Ring closure and a subsequent
Negishi or Stille cross‐coupling afforded L1, L2, and L3 in an overall yield of 20, 3, and 6%, respectively.
J. Heterocyclic Chem., 49, 1290 (2012).
INTRODUCTION
several novel bidentate pyridyl thienopyridines [6], it was
of interest to synthesize a range of tridentate ligands with
a thiophene fused onto the c face of the central pyridine
ring. We now report synthetic pathways to the compounds
5‐phenyl‐7‐(pyridin‐2‐yl)thieno[2,3‐c]pyridine (L1), 7‐(pyri-
din‐2‐yl)‐5‐(thiophen‐2‐yl)thieno[2,3‐c]pyridine (L2) and
5,7‐di(pyridin‐2‐yl) thieno[2,3‐c]pyridine (L3) (Fig. 1).
L1 can act as a cyclometallating ligand while L2 has two pos-
sible binding modes, S‐coordinated or cyclometallated [7].
Structural studies, together with electrochemical and photo-
physical measurements on the ruthenium(II)terpyridine com-
plexes of these ligands are currently under investigation.
In our studies into the use of oligothiophene substituted [Ru
(bpy)3]2+ complexes as electron sources within molecular
electronic devices, we have recently reported the effects of
various modes of attachment of a thiophene unit onto a 2,2′‐
bipyridine ligand (L) and examined the electrochemical and
photophysical properties of the resulting [Ru(bpy)2L]2+ com-
plexes [1,2]. Pendant attachment in the 4‐position led to the
longest luminescence lifetimes (3000 ns), whilst fusion
of a thiophene ring onto the b or c face of a bipyridine lead
to complexes with lifetimes in the range 275–1510 ns and
quantum yields ranging between 0.0047 and 0.014 [2].
[Ru(tpy)2]2+ complexes offer significant geometrical advan-
tages over their tris‐bipyridine analogs as linear arrays can be
easily generated. However the photophysical properties of
[Ru(tpy)2]2+ are vastly inferior to those of [Ru(bpy)3]2+. Results
by the groups of Constable [3], Ferraudi [4], and Zeissel [5]
have shown that introduction of thiophenyl and 2‐ethynyl‐
thiophenyl substituents at the 4′‐position of tpy greatly increases
the lifetimes of the [Ru(tpy)L]2+ complexes, from 0.25 ns for
[Ru(tpy)2]2+ into the vicinity of 80–150 ns (depending upon
the [Ru(tpy)L]2+ complex) [3–5]. In light of these results
and our recently reported photophysical and cyclic vol-
tammetry studies upon [Ru(bpy)2L]2+ complexes [2] of
RESULTS AND DISCUSSION
The key step in the synthesis of L1–L3 was the copper‐
catalysed condensation between 3‐bromothiophene‐2‐
carboxylic acid and a carbanion. This reaction is known
as the Hurtley reaction. In 1929, Hurtley [8a] demon-
strated that o‐bromobenzoic acid could be condensed
with carbanions under basic conditions through catalysis
by Cu powder or Cu(OAc)2. The reaction has been inves-
tigated several times, but quite a few details are still un-
clear. In its original incarnation the Hurtley reaction was
© 2012 HeteroCorporation

November 2012 Syntheses of Three New Pyridyl Thienopyridine Ligands via the Hurtley Reaction
1291
was recovered. The reaction was attempted again, this
time using 10 mol% Cu(OAc)2 as catalyst. After reflux
overnight and subsequent workup the desired product
3‐(2‐oxo‐2‐phenylethyl)‐2‐thiophenecarboxylic acid [8f]
(2) was obtained in moderate yield (64%).
2 and NH4OAc were refluxed in acetic acid overnight to
yield 5‐phenylthieno[2,3‐c]pyridin‐7(6H)‐one [8f] (4) in
good yield (81%).
4 was added to fresh POCl3 and refluxed for 22 h.
After flash chromatography the product 7‐chloro‐5‐
phenylthieno[2,3‐c]pyridine (6) was recovered in moderate
yield (56%).
For the final step a Negishi cross‐coupling [9] was uti-
lized. Under a nitrogen atmosphere, 6 was treated with 2‐
pyridylzinc bromide in refluxing dry THF with 3 mol%
[Pd(PPh3)4] to give L1 as pale needles (68%). The overall
yield of this four‐step synthesis was 20%.
Figure 1. Three new tridentate thienopyridines, 5‐phenyl‐7‐(pyridin‐2‐
yl)thieno[2,3‐c]pyridine (L1), 7‐(pyridin‐2‐yl)‐5‐(thiophen‐2‐yl)thieno
[2,3‐c]pyridine (L2), and 5,7‐di(pyridin‐2‐yl)thieno[2,3‐c]pyridine (L3).
L2 was planned to be synthesized analogously to L1
(Scheme 1). 1 and 1‐thienyl‐1,3‐butanedione [10] were
treated with NaOEt and 10 mol% Cu(OAc)2 in EtOH in
the same manner as in the synthesis of 2. However, after
reflux overnight and workup, only small amounts of 3 were
found. The yield was only ∼10% (calculated from
1H‐NMR). Different catalysts and catalyst loadings were
conducted in ethanol/NaOEt with copper powder as cata-
lyst. Under these conditions the condensation between
o‐bromobenzoic acid and a β‐dicarbonyl compound was
usually followed by deacetylation through ethanolysis,
which may be a complication or an advantage depending
on the desired product. Bruggink and McKillop [8b]
showed that it is possible to avoid the deacetylation and
improve the yield by using the system toluene/NaH/CuBr
instead. Bruggink and McKillop [8b] also showed that
Cu(I) is almost certainly the catalytic species and
proposed a mechanism for the reaction. Several other
copper compounds have been used as catalysts in
the Hurtley reaction, for example CuO [8c], CuCl
[8c], and Cu(I)OAc [8b]. The necessity for a substituent
ortho to the halogen capable of coordinating the inter-
mediate copper species has been a limiting factor for
the Hurtley reaction, but recently Ma et al. performed
the condensation using arylbromides (both electron‐
rich and electron‐deficient) and the catalytic system
Cu(I)I/L‐proline [8d]. o‐Bromobenzoic acid and its
derivatives are not the only bromo‐acids that can be
used in the Hurtley reaction, Ames and Dodds [8e] ex-
tended the scope of the Hurtley reaction and showed,
using the ethanol/NaOEt system with Cu or Cu(OAc)2,
that the Hurtley reaction was applicable to bromopyri-
dine carboxylic acids and bromothiophene carboxylic
acids [8f].
Scheme 1. General outline for the synthesis of L1 and L2. Reagents and
conditions: (i) 10 mol% Cu(OAc)2 × H2O, 2.1 equiv. NaOEt, EtOH, 18 h,
Δ; (ii) 10 mol% Cu(I)OAc, 2.1 equiv. NaOEt, EtOH, N2‐atmosphere, 72 h, Δ;
(iii) NH4OAc, AcOH, 16 h, Δ; (iv) POCl3, 22 h, Δ; (v) 2‐pyridylzinc bromide,
3 mol% [Pd(PPh3)4], THF, N2‐atmosphere, 24 h, Δ; (vi) 2‐(tributylstannyl)
pyridine, 2 mol% [Pd2(dba)3], 4 mol% [(t‐Bu)3PH]BF4, 2.2 equiv. cesium
fluoride, dioxane, N2‐atmosphere, 48 h, Δ.
SYNTHESIS OF L1–L3
In the first step of the synthesis of L1 (Scheme 1) 3‐
bromothiophene‐2‐carboxylic acid (1) was condensed
with 1‐phenyl‐1,3‐butanedione using standard conditions
for the Hurtley reaction, i.e. ethanol and NaOEt. Accord-
ing to Cirigottis and Taylor [8c], CuO would be a more ef-
ficient catalyst than Cu(OAc)2. However, after reflux
overnight with EtOH/NaOEt/CuO only starting material
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R. O. Steen, L. J. Nurkkala, and S. J. Dunne
Vol 49
Scheme 2. General outline for the synthesis of L3. Reagents and condi-
tions: (i) 10 mol% Cu(OAc)2 × H2O, 2.1 equiv. NaOEt, EtOH, 18 h, Δ;
(ii) PBr3, 175°C, N2‐atmosphere, 5 h; (iii) 2.05 equiv. 2‐(tributylstannyl)-
pyridine, 5 mol% [Pd(PPh3)4], toluene, N2‐atmosphere, 24 h, Δ.
tested (10–20 mol% CuBr, 10–20 mol% Cu) but no im-
provement was achieved. A slight increase in the yield
(∼15%) was however achieved by using 10 mol% Cu(I)
OAc. In an attempt to increase the yield the reaction
mixture was refluxed for 72 h under N2 with Cu(I)
1
OAc as catalyst. According to H‐NMR this increased
the yield of 3 to 65%. However, it proved to be difficult
to isolate 3 from starting materials and byproducts.
Separation could not be achieved by either recrystalliza-
tion or chromatography with a range of different mobile
phases. In an attempt to investigate if separation
actually was necessary the product mixture was
dissolved in AcOH and refluxed with NH4OAc for
#16 h. After workup pure 5‐(thiophen‐2‐yl)thieno
[2,3‐c]pyridin‐7(6H)‐one (5) was recovered in 26%
yield (calculated from 1).
The pyridyl chloride (7) 7‐chloro‐5‐(thiophen‐2‐yl)
thieno[2,3‐c]pyridine was synthesized in the same manner
as 6, albeit in a lower yield (29%).
In the final step L2 was planned to be synthesized by
a Negishi cross‐coupling with 2‐pyridylzinc bromide
[6]. However, after refluxing for 24 h in THF only start-
ing materials were recovered in nearly quantitative
yield.
The final ligand L3 was also to be synthesized accord-
ing to the general pathway outlined in Scheme 1. How-
ever, even though Ames and Dodds [8e] showed that
2‐bromopyridine‐3‐carboxylic acid can be used as a start-
ing material in the Hurtley reaction it would appear that
the same is not true for the β‐dicarbonyl compound
1‐pyridyl‐1,3‐butanedione [13]. When 1 was reacted
with 1‐pyridyl‐1,3‐butanedione under the same reaction
conditions as in the synthesis of 2 and with the workup
as detailed by Ames and Dodds [8e] only starting mate-
rials were recovered in nearly quantitative yield. Differ-
ent reaction times (24, 48, and 72 h) were tested as well
as different catalysts (CuBr, CuO, Cu, Cu(I)OAc), and
catalyst loadings, but in all cases only starting materials
were recovered. A possible explanation is that the
copper ions forms a complex with to 1‐pyridyl‐1,3‐butane-
dione, removing them from the catalytic cycle. It would
appear that L3 is not accessible via the pathway shown
in Scheme 1. A new pathway was devised (Scheme 2).
3‐(Cyanomethyl)thiophene‐2‐carboxylic acid (8) had
previously been synthesized by Ames and Dodds [8f]
by the same general method used to synthesize 2. By
reacting 1 with benzoylacetonitrile in EtOH with NaOEt
and 10 mol% Cu(OAc)2, 8 was generated in moderate
yield (69%).
A Negishi cross‐coupling requires expensive arylzinc
reagents and rigorously dry conditions. Since stannyl
reagents are readily available and due to the general
robustness of the reaction, a Stille cross‐coupling [11]
was preferable for the final step in the synthesis of
L2. Previously it has not been feasible to conduct Stille
cross‐couplings with aryl chlorides, but thanks to the
work by Fu [12] this limitation has now been removed.
Fu showed that by utilizing a catalytic mixture of
[Pd2(dba)3] and P(t‐Bu)3 with 2–3 equiv. of potassium
fluoride or cesium fluoride it is possible to perform
Stille cross‐couplings with aryl chlorides in good yields
and also allows Stille, Suzuki, and Heck reactions with
aryl bromides and iodides to be performed at ambient
temperature. As P(t‐Bu)3 is a fairly sensitive chemical
to work with. Fu investigated the possibility of using
stable phosphonium salts as replacements and showed
that indeed, phosphonium tetrafluoroborate salts serve
as direct replacement for P(tBu)3 [12]. Mixtures of
[Pd2(dba)3]/[(t‐Bu)3PH]BF4 are now commercially
available.
Using [Pd2(dba)3]/[(t‐Bu)3PH]BF4 (Pd:P = 1:2) as cata-
lyst 7 was refluxed with 2‐(tributylstannyl)pyridine and
2.2 equivalents cesium fluoride in 1,4‐dioxane. L2 was
obtained in acceptable yield (44%). It should be noted that
the actual yield of L2 was higher (calculated from
1H‐NMR the yield was ∼75%) but after flash chromatography
only the fractions that contained pure L2 were kept, resulting
in a lower final yield. The overall yield of this four‐step
synthesis was 3%.
Under a nitrogen atmosphere 8 was then refluxed with
fresh PBr3 at 175°C with vigorous stirring. Despite the in-
tense stirring, black aggregates were formed during the re-
action. These were carefully broken up by removing the
condenser and crushing them with a glass rod. After
workup 5,7‐dibromothieno[2,3‐c]pyridine [14] (9) was
obtained in poor yield (11%). Even though the yield was
poor, enough material was produced to proceed with the fi-
nal step in the synthesis of L3.
In the final step of the synthesis of L3 a Stille cross‐
coupling was used. Dibromopyridine 9 was reacted with
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November 2012 Syntheses of Three New Pyridyl Thienopyridine Ligands via the Hurtley Reaction
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The mixture was heated to reflux overnight, after which the
solution was allowed to cool to r.t. and was poured into H2O
(100 mL), resulting in the formation of a precipitate. The
precipitate was recovered by suction filtration and washed with
water until it was free of acetic acid. The precipitate was dried
by suction after which it was subsequently recrystallized from
EtOH/H2O.
2‐(tributylstannyl)pyridine in refluxing toluene with 5 mol%
[Pd(PPh3)4] as catalyst. After flash chromatography and
recrystallization from MeOH, L3 was collected in good
yield (80%). The overall yield of this three‐step synthesis
was 6%.
EXPERIMENTAL
Yield: 0.26 g (81%); off‐white crystals. mp. 197.5–199.5°C
(lit. 195–197.5°C).[7] H‐NMR (DMSO‐d6, 300 MHz) δ: 11.70
1
All moisture and air sensitive reactions were performed in
oven‐dried (120°C, 12 h) glassware under nitrogen. Analyti-
cal TLC was performed on commercially prepared plates
coated with 0.20 mm of Macherey‐Nagel silica gel 60. The
compounds were visualized by illumination with UV light
(254 nm). Column chromatography was performed using
Matrex Normal Phase Silica 60 (particle size 35–70 μm).
All melting points were determined using an Electrothermal
9200 melting point apparatus and are uncorrected. Mass spec-
tra (MS) were obtained with a Fisions Instrument Trio 1000
spectrometer equipped with a Hewlett Packard 5MS gas
chromatography column. NMR spectra were recorded with a
Bruker DPX Avance 300 MHz spectrometer and the chemical
shifts are expressed in ppm from tetramethylsilane as internal
standard. Abbreviations for signal coupling are as follows: s,
singlet; d, doublet; tr, triplet; q, quartet; dd, doublet of doub-
lets; ddd, doublet of doublets of doublets; dtr, doublet of triplets;
m, multiplet; br, broad. The catalyst tris(dibenzylideneacetone)
dipalladium(0)/tri‐t‐butylphosphonium tetrafluoroborate admix-
ture (molar Pd:P = 1:2, Prod. No. 46‐3020) was purchased from
Strem Chemicals Inc. All commercially available chemicals were
used as received unless otherwise noted. THF and 1,4‐dioxane
were distilled from sodium/benzophenone ketal directly prior
to use.
3‐(2‐Oxo‐2‐phenylethyl)‐2‐thiophene‐carboxylic acid
(2). EtOH (99.7%, 30 mL) and NaOEt (0.78 g, 11.5 mmol)
were added to a dry round‐bottomed flask. The mixture was
stirred until all NaOEt was dissolved. 1‐Phenyl‐1,3‐butanedione
(1.0 g, 6 mmol), 3‐bromothiophene‐2‐carboxylic acid (1) (0.93 g,
4.5 mmol) and Cu(II)OAc × H2O (10 mol%, 0.12 g, 0.6 mmol)
were then added in that order. A spiral condenser and a drying
tube filled with CaCl2 were fitted and the mixture was refluxed
over 18 h. The solution was then poured into H2O (200 mL)
and the resulting solution was acidified with HCl (aq, 2 M).
The solution was extracted with Et2O (2 × 75 mL). The
organic phases were combined and extracted with Na2CO3 (aq,
1 M, 2 × 75 mL). The aqueous phases were combined and
washed with Et2O (50 mL) and subsequently acidified with
HCl (aq, 2 M). The acidified solution was extracted with
CHCl3 (2 × 50 mL). The organic phases were combined and
dried over MgSO4. After evaporation under reduced pressure 2
was obtained as a pale brown powder which was subsequently
recrystallized from EtOH/H2O.
(br s, 1H), 8.60 (d, 1H, J = 5.1 Hz), 7.70–7.89 (m, 2H),
7.54–7.43 (m, 3H), 7.41 (d, 1H, J = 5.1 Hz), 7.03 (s, 1H) ppm.
13C‐NMR (DMSO‐d6, 75 MHz) δ: 159.0, 146.4, 141.9, 134.2,
133.9, 129.2, 128.8, 127.9, 126.8, 125.2, and 100.9 ppm. MS
(m/z): 227 (M+).
5‐(Thiophen‐2‐yl)thieno[2,3‐c]pyridin‐7(6H)‐one (5). EtOH
(99.7%, 450 mL) was added to a dry round‐bottomed flask and
the system was flushed with N2. Sodium (2.77 g, 0.12 mol) was
then added over ca. 30 min. When all the sodium had dissolved
1‐thienyl‐1,3‐butanedione (10.4 g, 61.8 mmol), 1 (12.1 g,
58.7 mmol) and Cu(I)OAc (10 mol%, 0.75 g, 6 mmol) were
added in that order and the mixture was refluxed for 72 h under
nitrogen. The resulting dark solution was allowed to cool to r.t.
after which it was concentrated to ∼1/3 of the original volume.
The residue was poured into H2O (500 mL) and the resulting
solution was acidified with HCl (aq, 2 M). The acidified solution
was extracted with Et2O (3 × 150 mL) and the organic phases
were combined and extracted with Na2CO3 (aq, 1 M, 3 × 100).
The aqueous phases were combined and washed with Et2O
(100 mL). The aqueous phase was separated and acidified with HCl
(aq, 2 M) resulting in the formation of a brown precipitate which
was recovered by suction filtration and dried on the filter.
Compound 3 was not isolated from starting materials and
byproducts, instead the precipitate (14.5 g) was dissolved in AcOH
(300 mL) and NH4OAc (140 g) was added. The resulting mixture
was refluxed for 16 h, after which the solution was cooled to r.t.
and poured into H2O (500 mL), resulting in the formation of a
precipitate. The mixture was transferred to a separatory funnel and
was extracted with Et2O (3 × 100 mL). The organic phases were
combined and washed with Na2CO3 (aq, 1 M, 2 × 100 mL). The
organic phase was separated, dried over MgSO4 and evaporated
under reduced pressure, yielding 5 as a pale white powder, which
was subsequently recrystallized from EtOH/H2O.
Yield: 3.8 g (26%); pale white needles. mp. 243–244.5°C.
1H‐NMR (DMSO‐d6, 300 MHz) δ: 11.80 (br s, 1H, exchangable
with deuterium), 8.05 (d, 1H, J = 5.1 Hz), 7.82 (dd, 1H, J = 3.7,
1.1 Hz), 7.65 (dd, 1H, J = 5.1, 1.1 Hz), 7.41 (d, 1H, J = 5.1 Hz),
7.17 (dd, 1H, J = 5.1, 3.7 Hz), 7.03 (br s, 1H) ppm. 13C‐NMR
(DMSO‐d6, 75 MHz) δ: 158.7, 146.3, 136.4, 135.8, 134.5,
128.5, 127.8, 127.5, 126.5, 125.3, and 100.0 ppm. MS (m/z):
233 (M+). Anal. Calcd. (%) for C11H7NOS2: C, 56.63; H, 3.02;
N, 6.00. Found C, 56.84; H, 2.73; N, 6.27.
Yield: 0.71 g (64%); pale needles. mp. 198–200°C (lit.
199–201°C) [8f]. 1H‐NMR (DMSO‐d6, 300 MHz) δ: 7.97–
8.07 (m, 2H), 7.77 (d, 1H, J = 5.0 Hz), 7.65 (dd, 1H, J = 7.3,
1.3 Hz), 7.50–7.60 (m, 2H), 7.09 (d, 1H, J = 5.0 Hz), 4.75 (s,
2H) ppm. 13C‐NMR (DMSO‐d6, 75 MHz) δ: 196.3, 163.4, 142.4,
136.6, 133.3, 132.3, 130.7, 129.1, 128.8, 128.0, and 39.3 ppm.
MS (m/z): 246 (M+).
5‐Phenylthieno[2,3‐c]pyridin‐7(6H)‐one (4). 2 (0.38 g, 1.54
mmol) and NH4OAc (3.9 g, 51 mmol) were transferred to a
round‐bottomed flask after which AcOH (15 mL) was added.
7‐Chloro‐5‐phenylthieno[2,3‐c]pyridine (6). The pyridone
4 (1.8 g, 8 mmol) was transferred to a dry round‐bottomed
flask. Fresh POCl3 (40 mL) was then added in one portion.
The mixture was refluxed for 22 h. The reaction mixture was
then cooled to r.t., after which it was carefully poured into a
H2O/ice‐slurry with vigorous stirring. After the exothermic
reaction had subsided, the pH of the solution was adjusted to
10 with NaOH (aq, 1 M). The solution was extracted with
CH2Cl2 (3 × 100 mL), the organic phase were combined, dried
over MgSO4 and evaporated under reduced pressure, yielding
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R. O. Steen, L. J. Nurkkala, and S. J. Dunne
Vol 49
a dark oil. The oil was purified by flash chromatography (silica,
hexane:EtOAc 3:2). The fractions containing product (Rf = 0.95)
were combined and the solvent was removed under reduced
pressure, yielding a yellow oil that solidified upon standing
into a pale powder, which was recrystallized from MeOH.
The fractions containing pure product were combined and
evaporated under reduced pressure, yielding L2 as a pale solid.
An analytical sample was acquired by recrystallization from
MeOH/H2O.
Yield: 0.21 g (44%); off‐white needles. mp: 131–133°C. UV
(EtOH): λmax/nm (log ε/dm3 mol−1 cm−1) = 255 (4.47), 280
(4.53), 286 (4.56), 308 (4.37), 320 (4.36), and 354 (4.16).
1H‐NMR (CDCl3, 300 MHz) δ: 8.8–8.89 (m, 2H), 8.10 (s, 1H),
7.92 (dtr, 1H, J = 7.6, 1.6 Hz), 7.82 (d, 1H, J = 5.5 Hz), 7.72,
(dd, 1H, J = 3.7, 1.1 Hz) 7.43 (d, 1H, J = 5.5 Hz), 7.35–7.43
(m, 2H), 7.17 (dd, 1H, J = 3.7 Hz) ppm. 13C‐NMR (CDCl3, 75
MHz) δ: 155.6, 149.2, 148.1 (2 signals overlapping), 146.4, 145.8,
137.0, 136.8, 131.3, 128.3, 126.9, 124.0, 123.8, 122.6, 122.1, and
113.0 ppm. MS (m/z): 294 (M+). Anal. Calcd. (%) for C16H10N2S2:
C, 65.28; H, 3.42; N, 9.52. Found C, 65.41; H, 3.67; N, 9.17.
3‐(Cyanomethyl)thiophene‐2‐carboxylic acid [8f] (8). This
compound was synthesized analogously to 2, using benzoylacetonitrile
instead of 1‐phenyl‐1,3‐butanedione as starting material.
Yield: 1.1 g (56%); pale white crystals.mp. 72–75°C 1H‐NMR
(DMSO‐d6, 300 MHz) δ: 8.46 (s, 1H), 8.23 (d, 1H, J = 5.4 Hz),
8.06–8.13 (m, 2H), 7.66 (d, 1H, J = 5.4 Hz), 7.40–7.44 (m, 3H) ppm.
13C‐NMR (DMSO‐d6, 75 MHz) δ: 151.2, 148.6, 143.3, 137.4,
135.3, 133.3, 129.1, 128.9,126.6, 124.9, and 114.0 ppm. MS
(m/z): 245 (M+). Anal. Calcd. (%) for C13H8ClNS: C, 63.54; H,
3.28; N, 5.70. Found C, 63.85; H, 3.43; N, 6.0.
7‐Chloro‐5‐(thiophen‐2‐yl)thieno[2,3‐c]pyridine (7). This
compound was synthesized analogously to 6 [8e].
Yield: 29%; colourless crystals. mp. 81–84°C. 1H‐NMR
(DMSO‐d6, 300 MHz) δ: 8.40 (br s, 1H), 8.24 (d, 1H, J = 5.4
Hz), 7.83 (dd, 1H, J = 3.7, 1.1 Hz), 7.66 (dd, 1H, J = 5.1, 1.1
Hz), 7.63 (d, 1H, J = 5.4 Hz), 7.18 (dd, 1H, J = 5.1 Hz) ppm.
13C‐NMR (DMSO‐d6, 75 MHz) δ: 148.4, 147.0, 142.9, 142.8,
135.8, 132.8, 128.6, 128.3, 125.3, 124.7, and 112.3 ppm. MS
(m/z): 251 (M+). Anal. Calcd. (%) for C11H6ClNS2: C, 52.48;
H, 2.40; N, 5.56. Found C, 52.31; H, 2.23; N, 5.71.
5‐Phenyl‐7‐(pyridin‐2‐yl)thieno[2,3‐c]pyridine (L1). The
chloropyridine 6 (0.49 g, 2 mmol) and [Pd(PPh3)4] (3 mol%,
0.066 g, 0.06 mmol) were transferred to a three‐necked round‐
bottomed flask. The system was flushed with N2, after which dry
THF (20 mL) was added via a syringe. 2‐Pyridylzinc bromide
(0.5 M in THF, 6 mL, 3 mmol) was then added via a syringe.
The reaction mixture was refluxed for 24 h with stirring,
resulting in the formation of a grey precipitate. The reaction
was quenched by pouring into a solution of Na2CO3/EDTA
(150 mL H2O, 150 mmol Na2CO3, 20 mmol EDTA). The
aqueous phase was extracted with Et2O (2 × 50 mL). The
organic extracts were washed with brine, dried over MgSO4 and
evaporated. After recrystallisation from MeOH L1 was obtained
as pale needles.
Yield: 69%; off‐white crystals. mp. 133–135°C (lit. 134–136°C).
1
[8f] H‐NMR (DMSO‐d6, 300 MHz) δ: 13.45 (br s, 1H), 7.89 (d,
1H, J = 5.1 Hz), 7.24 (d, 1H, J = 5.1 Hz), 4.25 (s, 2H) ppm. 13C‐
NMR (DMSO‐d6, 75 MHz) δ: 162.9, 136.8, 132.2, 130.4, 129.5,
118.4, and 17.5 ppm. MS (m/z): 167 (M+).
5,7‐Dibromothieno[2,3‐c]pyridine [14] (9). The carboxylic
acid 8 (6.5 g, 39 mmol) was transferred to a dry round‐
bottomed flask. Fresh PBr3 (100 g, 0.37 mol) was then
added in one portion and the system was flushed with N2.
With vigorous stirring the mixture was heated to 175°C
under N2. After 6 h the reaction mixture was allowed to
cool to r.t. Residual PBr3 was hydrolyzed by slow dropwise
addition of ice‐water (200 mL) through the condenser with
the round‐bottomed flask submerged in an ice‐bath. When
the addition was complete the resulting solution was made
alkaline with NaOH (aq, 1 M). The resulting solution was
divided into five portions and each portion was extracted
with EtOAc (2 × 100 mL). The organic phase were, washed
with brine and dried over MgSO4. Evaporation under
reduced pressure yielded a brown powder (1.59 g). The
product was purified by column chromatography (silica,
EtOAc:hexane 9:1). The fractions containing product
(Rf = 0.95) were evaporated under reduced pressure, yielding
9, which was recrystallized from MeOH.
Yield: 0.39 g (68%); pale needles. mp. 98–101°C. UV (EtOH):
λ
max/nm (log ε/dm3 mol−1 cm−1) = 255 (4.51), 265 (4.53), 288
(4.19), 298 (4.13), 309 (4.05), and 342 (4.14). 1H‐NMR (CDCl3,
300 MHz) δ: 8.92 (dd, 1H, J = 8.0, 1.0 Hz), 8.85 (m, 1H), 8.23–8.3
(m, 2H), 8.21 (s, 1H) 7.92 (dd, 1H, J = 7.9, 1.8 Hz), 7.84 (d,
1H, J = 5.6 Hz), 7.52–7.6 (m, 2H), 7.58 (d, 1H, J = 5.5 Hz),
7.57 (d, 1H, J = 6.1 Hz), 7.39 (dd, 1H, J = 4.8, 1.2 Hz) ppm.
13C‐NMR (CDCl3, 75 MHz) δ: 156.0, 150.9, 149.4, 148.3,
148.1, 139.8, 136.9, 136.4, 131.6, 128.9, 128.7, 127.2,
123.8, 122.8, 121.9, and 114.9 ppm. MS (m/z): 288 (M+).
Anal. Calcd. (%) for C18H12N2S: C, 74.97; H, 4.19; N, 9.71.
Found C, 75.15; H, 4.37; N, 9.56.
Yield: 1.59 g (11%); pale yellow needles. mp. 125–127.5°C.
1H‐NMR (DMSO‐d6, 300 MHz) δ: 8.29 (d, 1H, J = 5.4 Hz),
8.22 (s, 1H), 7.65 (d, 1H, J = 5.4 Hz) ppm. 13C‐NMR (DMSO‐d6,
75 MHz) δ: 148.6, 138.0, 137.1, 133.3, 132.8, 124.2, and 121.7 ppm.
MS (m/z): 293 (M+). Anal. Calcd. (%) for C7H3Br2NS: C, 28.70; H,
1.03; N, 4.78. Found C, 28.96; H, 1.22; N, 4.61.
7‐(Pyridin‐2‐yl)‐5‐(thiophen‐2‐yl)thieno[2,3‐c]pyridine (L2).
7 (0.40 g, 1.6 mmol), 2‐(tributylstannyl)pyridine (0.70 g, 1.9 mmol)
and cesium fluoride (0.53 g, 3.5 mmol) were added to dry 1,4‐dioxane
(20 mL) in a round‐bottomed flask. The resulting mixture was
purged with N2 for 15 min. The catalyst [Pd2(dba)3]/[(t‐Bu)3PH]
BF4 admixture (Pd:P 1:2, 50 mg, 2 mol% Pd, 4 mol% P) was
then added and the resulting solution was heated to 100°C
under N2. The reaction was monitored by TLC (silica, hexane:
EtOAc 7:3). After 48 h the reaction was deemed complete and
the reaction mixture was cooled to r.t. after which it was
diluted with Et2O (100 mL) and filtered through celite. The
filtrate was concentrated yielding an oily residue which was
purified by flash chromatography (silica, hexane:EtOAc 7:3).
5,7‐Di(pyridin‐2‐yl)thieno[2,3‐c]pyridine (L3). The dibromo
compound 9 (0.58 g, 2 mmol), 2‐(tributylstannyl)pyridine (80%,
1.89 g, 4.1 mmol) and [Pd(PPh3)4] (5 mol%, 0.11 g) were
added to toluene (25 mL) in a round‐bottomed flask and the
system was flushed with N2. The mixture was refluxed under
N2 and monitored by TLC (hexane:EtOAc 7:3). After 24 h, no
additional product appeared to have formed and the reaction
mixture was allowed to cool to r.t. The solution was washed
with potassium fluoride (aq, 1 M, 2 × 50 mL) and brine
(50 mL). The organic phase was separated, dried over MgSO4
and evaporated under reduced pressure, yielding a brown oily
substance which was purified by flash chromatography
(silica, hexane:EtOAc 7:3). The fractions containing product
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2012 Syntheses of Three New Pyridyl Thienopyridine Ligands via the Hurtley Reaction
1295
REFERENCES AND NOTES
(Rf = 0.55) were combined and evaporated under reduced
pressure, yielding L3 as an off‐white powder which was
recrystallized from MeOH.
[1] Steen, R. O.; Nurkkala, L. J.; Angus‐Dunne, S. J.; Schmitt, C.
X.; Constable, E. C.; Riley, M. J.; Bernhardt, P. V.; Dunne, S. J. Eur J
Inorg Chem 2008, 11, 1784.
[2] Nurkkala, L. J.; Steen, R. O.; Friberg, H. K. J.; Häggström, J.
A.; Bernhardt, P. V.; Riley, M. J.; Dunne, S. J. Eur J Inorg Chem 2008,
26, 4101.
Yield: 0.46 g (80%); white needles. mp. 134–136°C. UV
(EtOH): λmax /nm (log ε/dm3 mol−1 cm−1) = 254 (4.53), 277
(4.45), 286 (4.44), 301 (4.25), 313 (4.24), 334 (4.22), and 346
1
(4.20). H‐NMR (CDCl3, 300 MHz) δ: 8.92 (s, 1H), 8.90 (dd,
1H, J = 8.0, 1.1 Hz), 8.85 (m, 1H), 8.71–8.76 (m, 2H), 7.86–
7.97 (m, 2H), 7.84 (d, 1H, J = 5.6 Hz), 7.54 (d, 1H, J = 5.6
Hz), 7.39 (dd, 1H, J =4.8, 1.2 Hz), 7.33 (dd, 1H, J = 2.7, 1.0
Hz) ppm. 13C‐NMR (CDCl3, 75 MHz) δ: 156.6, 155.9, 149.4,
149.2, 149.1, 148.3, 148.2, 137.4, 136.9, 136.5, 133.1, 123.9,
123.5, 123.4, 121.8, 121.5, and 115.8 ppm. MS (m/z): 289
(M+). Anal. Calcd. (%) for C17H11N3S: C, 70.56; H, 3.83; N,
14.52. Found C, 70.79; H, 4.15; N, 14.27.
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[8] (a) Hurtley, W. R. H. J Chem Soc 1929, 1870.; (b) Bruggink, A.;
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SUPPORTING INFORMATION
1H-NMR of compounds 2, 4–9 and L1–L3 and UV
spectra of L1–L3 is provided as Supporting Information
in the online version of this article.
[11] Espinet, P.; Echavarren, A. M. Angew Chem Int Ed 2004, 44, 4704.
[12] Fu, G. C. Acc Chem Res 2008, 41, 1555.
[13] Levine, R.; Sneed, J. K. J Am Chem Soc 1951, 73, 5614.
[14] Ueno, K.; Sasaki, A.; Kawano, K.; Okabem, T.; Kitazawa, N.;
Takahashi, K.; Yamamoto, N.; Suzuki, Y.; Matsunaga, M.; Kubota, A.
Fused pyridine derivatives, US Patent 6,340,759, 2002.
Acknowledgments. The authors would like to thank the Faculty
Board (Science and Technology), Mälardalen University, for their
support of this project. R. O. Steen would like to thank the Dentist
Gustav Dahl Memorial Fund for generous support.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet