One-pot synthesis of 2-ferrocenyl-substituted pyridines

Article abstract of DOI:10.1016/j.tetlet.2016.09.080

A facile, one-pot method for the synthesis of 2-ferrocenylpyridines is described. When reacted with propargylamine, α,β-alkynic ketones produced N-propargylic β-enaminones in situ, which, in the presence of copper(I) chloride, underwent electrophilic cyclization to afford 2-ferrocenylpyridine derivatives in good to high yields. This cyclization was found to be general for a variety of α,β-alkynic ketones and tolerated the presence of aryl groups with electron-withdrawing and electron-donating substituents. The enrichment of the pyridine core with a ferrocenyl moiety, in addition to benzoyl groups, may offer potential for the synthesis of molecules of pharmacological interest.

Full text of DOI:10.1016/j.tetlet.2016.09.080

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of 2-ferrocenyl-substituted pyridines
⇑
Eda Karadeniz, Metin Zora
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile, one-pot method for the synthesis of 2-ferrocenylpyridines is described. When reacted with
Received 19 August 2016
Revised 20 September 2016
Accepted 23 September 2016
Available online xxxx
propargylamine,
ence of copper(I) chloride, underwent electrophilic cyclization to afford 2-ferrocenylpyridine derivatives
in good to high yields. This cyclization was found to be general for a variety of ,b-alkynic ketones and
tolerated the presence of aryl groups with electron-withdrawing and electron-donating substituents.
The enrichment of the pyridine core with a ferrocenyl moiety, in addition to benzoyl groups, may offer
potential for the synthesis of molecules of pharmacological interest.
a,b-alkynic ketones produced N-propargylic b-enaminones in situ, which, in the pres-
a
Keywords:
Pyridine
Ferrocene
Ó 2016 Elsevier Ltd. All rights reserved.
Propargylamine
a,b-Alkynic ketone
N-Propargylic b-enaminone
Electrophilic cyclization
Pyridines form one of the most important classes of heterocyclic
compounds and their prevalence in natural products and pharma-
ceuticals as well as their potent bioactivities have created signifi-
cant interest in academia and the pharmaceutical industry.1
Indeed, pyridines have been studied for over a century as a result
of their range of applications in many branches of chemistry, such
as catalysis, drug design, molecular recognition, and material
science.2 Notably, many pyridine derivatives exhibit remarkable
medicinal properties, including hypnotic and sedative,3 HIV antivi-
ral,4 bone calcium regulator,5 cholesterol and triglyceride regula-
tor,6 antidiabetic,7 antihistaminic,8 antiulcerant,9 antineoplastic,
and anticancer activities.10 Pyridines also form integral parts of
structurally diverse natural products, such as diploclidine and
nakinadine A.11 Most pyridine-based alkaloid natural products
are derivatives of nicotinic acid, also known as vitamin B3 and
niacin.12 Moreover, pyridines are utilized in the preparation of con-
jugated polymers and functional materials which are employed in
light-emitting devices (LEDs).13 Although many methods for the
synthesis of the pyridine ring have been reported, they are gener-
ally constructed by two approaches that rely on the condensation
of carbonyl compounds with amines, and the cycloaddition of aza-
dienes and nitriles with alkenes and alkynes, respectively.14 In fact,
a wide range of methods have been developed for the preparation
of pyridines, and new ones continue to emerge due to their use as
crucial building blocks for the synthesis of many drugs and natural
products.15
Recently, ferrocene, the first sandwich-type metallocene
discovered, has gained considerable importance in medicinal
chemistry since it is neutral, chemically stable, non-toxic, and able
to cross cell membranes. Indeed, it is well established that the inte-
gration of a ferrocene unit into potentially bioactive organic com-
pounds can introduce significant, new and/or novel properties in
these molecules.16 Many ferrocene derivatives have been reported
to exhibit antimalarial17 and antitumor18 activities. For instance,
ferrocifen, a ferrocenyl analog of tamoxifen, displays antiprolifera-
tive activity on both hormone-dependent and hormone-indepen-
dent breast cancer cells with good efficacies, while tamoxifen
only shows antiestrogenic activity on hormone-dependent breast
cancer cells.18 The dual effect of ferrocifen has initiated the synthe-
sis and biological investigation of further ferrocifen-like com-
plexes. Accordingly, functionally substituted ferrocene derivatives
may have great potential for biological studies; therefore, it is cru-
cial to develop new methodologies for their formation.
In particular, ferrocenylpyridines (or pyridylferrocenes) have
attracted considerable interest due to their applications in cataly-
sis,19,20 self-assembly devices,21 electrochemical sensing,22 molecu-
lar electronics and machines,23 non-linear optics,24 and as
antitumor agents.25 In particular, ferrocenylpyridines have
emerged as important ligands for the synthesis of heterobimetallic
complexes via the metal-binding ability of the pyridine nitrogen
atom. In this way, many metal complexes of ferrocenylpyridines
have been prepared in order to facilitate electronic communication
between metal centers.26 In fact, changing the oxidation state of the
pendant ferrocenyl unit could allow the tuning of electron density,
and hence reactivity, at the second metal center without changing
⇑
Corresponding author. Tel.: +90 312 2103213; fax: +90 312 2103200.
E-mail address: zora@metu.edu.tr (M. Zora).
http://dx.doi.org/10.1016/j.tetlet.2016.09.080
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Karadeniz, E.; Zora, M. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.09.080

2
E. Karadeniz, M. Zora / Tetrahedron Letters xxx (2016) xxx–xxx
its immediate coordination sphere. N-Heterocyclic carbene adducts
of cyclopalladated ferrocenylpyridines have been reported as cata-
lysts in Heck and Suzuki coupling reactions.19 Ferrocenylpyridines
and/or their heterobimetallic complexes have also been evaluated
for their anticancer activities against human tumor cell lines.25
Notably, some have exhibited even higher activity than cisplatin,25b
a widely used chemotherapeutic and reference agent. In brief,
ferrocenylpyridines are valuable compounds that have wide
usage and application range. Therefore, the development of new
methods for ferrocenylpyridines continues to attract the interest
of researchers from synthetic, material, and biological points of
view.
formed b-enaminone 8a via a 6-endo-dig cyclization. In order to
improve the yield of 9a using DMF, the reaction was carried out
in the presence of various catalysts. First, the reaction was con-
ducted in the presence of 0.2 equiv of AuCl and AuCl3 in DMF
and/or THF (Entries 3–5), which afforded a mixture of N-propar-
gylic b-enaminone 8a and 2-ferrocenylpyridine 9a, with the former
as the major product. Subsequently, the reaction was tested in the
presence of 0.2 equiv of InCl3 and AlCl3 (Entries 6 and 7). These
reactions also produced a mixture of b-enaminone 8a and 2-ferro-
cenylpyridine 9a, but with the latter as the major product. The
reactions conducted in the presence of 0.2 equiv of CuI, CuBr, and
CuCl (Entries 8–10) all yielded 2-ferrocenylpyridine 9a as the sole
product, where the highest yield (49%) was obtained with CuCl.
Next, the reaction with CuCl was carried out in methanol, THF,
and acetonitrile (Entries 11–13), however, in these solvents, 9a
was isolated in lower yields (16–35%). When the reaction was per-
formed with 1.0 equiv of CuCl, 2-ferrocenylpyridine 9a was formed
in 60% yield (Entry 14). The reaction was also carried out with
2.0 equiv of CuCl (Entry 15), however, this reaction provided 9a
in the same yield (60%), indicating that higher equivalents of CuCl
did not improve the yield. The reaction was conducted under air
and in the presence of p-benzoquinone, since, during the reaction,
oxidation may be required for aromatization. When the reaction
with 1.0 equiv of CuCl was conducted open to air, 2-ferro-
cenylpyridine 9a was produced in 77% yield (Entry 16). The reac-
tion in the presence of 1.1 and 3.0 molar equivalents of
p-benzoquinone produced 9a in 72% and 61% yields, respectively
(Entries 17 and 18). Notably, excess p-benzoquinone was found
to interfere with the reaction to some extent and slightly decreased
the yield of 9a. In summary, the optimal conditions were 1.0 equiv
of CuCl in DMF at 110 °C and open to air (Entry 16).
Recently, N-propargylic b-enaminones have been reported as
intermediates for the synthesis of a range of privileged heterocy-
cles,27 including pyrroles, pyridines, and dihydropyridines.28 In this
respect, we have recently prepared N-propargylic b-enaminones 3
from
a,b-alkynic ketones 1 and explored their cyclizations
(Scheme 1).29 Upon treatment with molecular iodine in the pres-
ence of sodium bicarbonate, N-propargylic b-enaminones 3 under-
went electrophilic cyclization to afford iodopyridines 4 in good to
high yields. Iodo-substituted pyridines 4 were further functional-
ized with aryl and alkynyl moieties via the Suzuki–Miyaura and
Sonogashira coupling reactions, respectively (Scheme 1).30
According to the strategy presented in Scheme 1, it was antici-
pated that ferrocenyl-substituted
a,b-alkynic ketones, such as 1
(R1 = Fc), would provide ferrocenylpyridine derivatives, such as 4,
through the intermediacy of N-propargylic b-enaminones 2 and
3. Interestingly, in initial studies, we observed that the reaction
of propargylamine with ferrocenyl-substituted
a,b-alkynic
ketones, particularly in the presence of a metal Lewis acid, afforded
2-ferrocenylpyridines in a one-pot manner, along with, or without,
the expected conjugate addition products. Our growing interest31
in the synthesis of novel ferrocenyl, carbocyclic, and heterocyclic
molecules as potential pharmaceuticals and scaffolds therefore
encouraged us to explore this new reaction, and herein, we report
the preliminary results of this study.
A range of substituted a,b-alkynic ketones 7 were employed to
synthesize a variety of 2-ferrocenylpyridine derivatives 9 (Table 2).
In general, the reactions proceeded smoothly and afforded the cor-
responding ferrocenylpyridines 9 in good to high yields (69–90%).
The reactions demonstrated good tolerance for both electron-
Initially, we prepared the requisite ferrocenyl-substituted
donating and electron-withdrawing groups. Notably, a,b-alkynic
a
,b-alkynic ketones 7 (i.e. 3-ferrocenylprop-2-yn-1-ones) via the
ketones with electron-withdrawing substituents provided the
corresponding ferrocenylpyridines 9 in relatively higher yields
(71–90%) (Entries 4–6) than did those with electron-donating
substituents (69–70%) (Entries 2–3).
A possible mechanism for the formation of 2-ferrocenylpyridi-
nes 9 is outlined in Scheme 2. First, conjugate addition of propar-
coupling of ethynylferrocene with acyl chlorides (ESI). Next, we
examined the model reaction of 3-ferrocenyl-1-phenylprop-2-yn-
1-one (7a) with propargylamine under different conditions in
order to find the optimal reaction conditions (Table 1). Initially,
we performed the reaction in methanol and DMF at 65 °C and
110 °C, respectively, under an argon atmosphere (Entries 1 and
2). Interestingly, the reaction in methanol produced the conjugate
addition product b-enaminone 8a while in DMF 2-ferro-
cenylpyridine 9a was formed, but both in low yields. In fact, as
shown later in the proposed mechanism, ferrocenylpyridine 9a is
a secondary product of the reaction and results from initially
gylamine to
a
,b-alkynic ketones
7
gives N-propargylic
b-enaminones 8. Although not isolated, b-enaminones 8 presum-
ably form as the (Z)-isomers on the basis of NOESY experiments
of our and the Cacchi research groups using similar com-
pounds.28,29 Moreover, as a result of their geometry, the presence
of an intramolecular hydrogen bond between the amine hydrogen
R2
R2
R3I
R3
O
O
O
NH2
PdCl2(PPh3)2
I2, NaHCO3
O
I
R2
R2
R1 NH
R1 NH
R1
N
R1
°
CuI, Et3N
DMF, r.t.
CH3CN, 82 °C
CH3OH, 65
C
1
4
R3
2
3
R4−B(OH)2
R5
H
R3
R3
R3
O
O
O
R5
PdCl2(PPh3)2
R4
I
PdCl2(PPh3)2
R2
R2
R2
R1
KHCO3, 110 °C
DMF/H O (4:1)
2
CuI, Et3N
DMF, 65 °C
R1
N
R1
N
N
5
4
6
Scheme 1. Synthesis of iodopyridines from a,b-alkynic ketones and their further functionalization via coupling reactions.
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E. Karadeniz, M. Zora / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 1
Optimization studies for the formation of 2-ferrocenylpyridine 9aa
O
O
NH2
O
N
+
NH
catalyst,oxidant
solvent
temperature
Fe
Fe
Fe
7a
8a
9a
Entry
Catalyst or additive (equiv)
Atmosphere (atm) or oxidant (equiv)
Solvent
Temp. (°C)
Product yieldb (%)
1
2
3
4
5
6
7
8
—
—
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
Ar (1 atm)
MeOH
DMF
DMF
DMF
THF
DMF
DMF
DMF
DMF
DMF
MeOH
THF
65
8a (40)
9a (25)
110
110
110
66
110
110
110
110
110
65
AuCl (0.2)
AuCl3 (0.2)
AuCl3 (0.2)
InCl3 (0.2)
AlCl3 (0.2)
CuI (0.2)
CuBr (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (1.0)
CuCl (2.0)
CuCl (1.0)
CuCl (1.0)
CuCl (1.0)
8a (28) + 9a (7)
8a (34) + 9a (16)
8a (30) + 9a (18)
8a (7) + 9a (16)
8a (14) + 9a (20)
9a (40)
9a (43)
9a (49)
8a (50) + 9a (16)
9a (30)
9a (35)
9
10
11
12
13
14
15
16
17
18
66
81
ACN
DMF
DMF
DMF
DMF
DMF
110
110
110
110
110
9a (60)
9a (60)
9a (77)
9a (72)
Air (1 atm)
p-Benzoquinone (1.1)
p-Benzoquinone (3.0)
9a (61)
a
Reactions were carried out using
a,b-alkynic ketone 7a (0.25 mmol), propargylamine (0.30 mmol), solvent (3 mL) under the indicated conditions. For work-up and
purification, see ‘‘General Procedure for the synthesis of 2-ferrocenyl-substituted pyridines 9” (ESI).
b
Isolated yield.
Table 2
One-pot synthesis of 2-ferrocenylpyridines 9a
O
O
4
R
R
NH2
6
2
N
Fe
CuCl
DMF, 110 °C
Fe
7
9
Entry
a,b-Alkynic ketone 7
2-Ferrocenylpyridine 9
Time (h)
Yieldb (%)
O
O
N
1
2.0
77
Fe
Fe
7a
9a
O
O
H3C
CH3
N
2
2.0
69
Fe
Fe
Fe
7b
9b
O
O
H3CO
N
OCH3
3
2.0
70
Fe
7c
9c
(continued on next page)
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4
E. Karadeniz, M. Zora / Tetrahedron Letters xxx (2016) xxx–xxx
Table 2 (continued)
Entry
a,b-Alkynic ketone 7
2-Ferrocenylpyridine 9
Time (h)
Yieldb (%)
O
O
Cl
N
Cl
4
5
6
1.5
81
Fe
Fe
Fe
7d
9d
O
Br
Br
O
N
1.5
90
Fe
7e
9e
O
O
O2N
N
NO2
2.0
71
Fe
Fe
7f
9f
a
Reagents and conditions: a,b-alkynic ketone 7 (0.25 mmol), propargylamine (0.30 mmol), CuCl (0.25 mmol), DMF (3 mL), 110 °C. For the full procedure, including work-
up and purification, see ‘‘General Procedure for the synthesis of 2-ferrocenyl-substituted pyridines 9” (ESI).
b
Isolated yield.
pyridine ring resonate at approximately 7.49–7.65, 7.17–7.28,
R
O
NH2
O
and 8.67–8.78 ppm, respectively. Each resonance typically appears
as a doublet of doublet where there is no overlap with other
aromatic hydrogens (see Table 2 for atom numbering). In the
13C NMR spectra, the peaks of C4, C5, and C6 were observed at
approximately 135.4–136.9, 119.6–120.2, and 150.0–150.8 ppm,
respectively. On the other hand, the C2 atom, connected to the
ferrocenyl group, resonated nearly at 156.2–158.3 ppm while the
C3 atom, attached to benzoyl group, appeared around 132.1–
134.5 ppm. In brief, the combined NMR data clearly support the
indicated regiochemistry of pyridine ring formation.
R
O
CuCl
+
Cu
Cu
Fc
NH
Cl
R
Fc
N
H
Fc
10
7
8
O
O
O
H
1/2 O2
-H2O
~H+
R
R
R
Fc
+
N
H
-
Cl
Fc
In conclusion, we have developed a one-pot method for the syn-
-CuCl
N
N
Fc
thesis of 2-ferrocenyl-substituted pyridines from
a,b-alkynic
9
12
11
ketones 7 and propargylamine, via in situ formation of N-propar-
gylic b-enaminones 8, followed by subsequent cyclization upon
treatment with CuCl. Notably, this cyclization has proven to be a
powerful and versatile tool for the generation of 2-ferrocenyl-sub-
stituted pyridines. It is anticipated that the efficiency and opera-
tional simplicity of the method could make it potentially
attractive for the library construction of ferrocenylpyrazoles, par-
ticularly in the area of pharmaceuticals.
O
1/2 O2
-H2O
~H+
R
N
H
Fc
13
Scheme 2. Proposed mechanism for the formation of 2-ferrocenylpyridines 9.
Acknowledgments
and carbonyl oxygen (N–HÁ Á ÁO) governs their tautomeric equilibria
and stability.32 Subsequently, coordination of the alkyne moiety to
copper produces complex 10, which initiates electrophilic cycliza-
tion to afford intermediate 11. Hydrogen atom transfer into copper
and concomitant regeneration of CuCl, possibly via reductive elim-
ination, gives 2,5-dihydropyridines 12. Finally, aerobic oxidation
yields the corresponding pyridines 9.33 It is also possible that
2,5-dihydropyridines 12 are first converted into 1,2-dihydropyridi-
nes 13 via a hydrogen shift; then aerobic oxidation affords pyridi-
nes 9 (Scheme 2).
We thank the Scientific and Technological Research Council of
Turkey (TUBITAK, Grant No. 110T113) and the Research Fund of
Middle East Technical University (METU, Grant No. BAP-2011-07-
02-00-01) for financial support of this research, and Research
Assistant Yılmaz Kelgökmen for technical support.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data and copies of 1H and 13C NMR spectra for all
a,b-alkynic
The synthesized pyridine derivatives show characteristic peaks
in their 1H and 13C NMR spectra which relate to the regiochemistry
of pyridine ring formation. In the 1H NMR spectra, owing to conju-
gation and electron density, H atoms at C4, C5, and C6 of the
ketones and 2-ferrocenylpyridines) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2016.09.080.
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E. Karadeniz, M. Zora / Tetrahedron Letters xxx (2016) xxx–xxx
5
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Please cite this article in press as: Karadeniz, E.; Zora, M. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.09.080