A three-component synthesis of β-alkoxy-β-keto-enamides - Flexible precursors for 4-hydroxypyridine derivatives and their palladium-catalysed reactions

Article abstract of DOI:10.1039/b925468d

The flexible three-component reaction of lithiated alkoxyallenes with nitriles and carboxylic acids provided a series of highly functionalised β-alkoxy-β-ketoenamide derivatives. Upon base induced cyclisation and conversion to 4-pyridyl nonaflates various palladium-catalysed coupling reactions could be employed. The efficacy of this approach to functionalised pyridine derivatives was demonstrated by a fairly short route to a key intermediate suitable for a Glenvastatin synthesis. After Sonogashira couplings of alkynes with 4-pyridyl nonaflates subsequent cyclisations led to highly fluorescent [2,3c]furopyridine derivatives, whereas Suzuki reactions afforded 4-pyridyl stilbenes and by photocyclisation a highly substituted benzoisoquinoline derivative.

Full text of DOI:10.1039/b925468d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A three-component synthesis of b-alkoxy-b-keto-enamides—flexible
precursors for 4-hydroxypyridine derivatives and their palladium-catalysed
reactions†
Tilman Lechel,a Jyotirmayee Dash,a,b Christian Eidamshaus,a Irene Bru¨dgam,‡a Dieter Lentz‡a and
Hans-Ulrich Reissig*a
Received 3rd December 2009, Accepted 6th April 2010
First published as an Advance Article on the web 17th May 2010
DOI: 10.1039/b925468d
The flexible three-component reaction of lithiated alkoxyallenes with nitriles and carboxylic acids
provided a series of highly functionalised b-alkoxy-b-ketoenamide derivatives. Upon base induced
cyclisation and conversion to 4-pyridyl nonaflates various palladium-catalysed coupling reactions could
be employed. The efficacy of this approach to functionalised pyridine derivatives was demonstrated by
a fairly short route to a key intermediate suitable for a Glenvastatin synthesis. After Sonogashira
couplings of alkynes with 4-pyridyl nonaflates subsequent cyclisations led to highly fluorescent
[2,3c]furopyridine derivatives, whereas Suzuki reactions afforded 4-pyridyl stilbenes and by
photocyclisation a highly substituted benzoisoquinoline derivative.
Introduction
Lithiated alkoxyallenes 1 have proved to be remarkably versa-
tile C3-building blocks in the synthesis of a broad range of
heterocycles.1 The addition of 1 to nitriles, followed by quenching
with carboxylic acids led to a novel three-component reaction
which provides highly substituted b-alkoxy-b-ketoenamides 2
(Scheme 1). The mechanism of this reaction has been previously
described in more detail.2 The enamide moieties can be found
as substructures in natural products3 and they have been used
for the asymmetric synthesis of amides and amino acids.3,4 In
particular, the specifically substituted b-alkoxy-b-ketoenamides
2 were found to be ideal precursors for the cyclisation to
heteroaromatic compounds such as pyrimidines,5a,5b oxazoles,5c or
4-hydroxypyridine derivatives like 3.2 In addition, we reported on
the high utility of nonafluorobutanesulfonyl fluoride (NfF)6,7 for
Scheme 1 Approach to 4-pyridinyl nonaflates 4 via 3 by cyclisation of
the conversion of 4-hydroxypyridines into 4-pyridyl nonaflates 4
b-alkoxy-b-ketoenamides 2 starting from lithiated alkoxyallenes 1.
and their subsequent application in diverse palladium-catalysed
coupling reactions.2,3
b-alkoxy-b-ketoenamide intermediates using different alkoxyal-
Owing to their incontestable importance in material sci-
lenes, a broad range of mono carboxylic acids and of nitriles.
ence, and their diverse applications such as agrochemicals and
Moreover, their subsequent transformation into 4-pyridyl nona-
pharmaceuticals,8 we devoted considerable attention to the syn-
flates and further conversion to annulated pyridine derivatives via
thesis of highly substituted pyridine derivatives.9,10 Recently, we
palladium-catalysed coupling reactions are presented.
described the scope of this intriguing three-component reaction
for the synthesis of perfluorinated pyridines via the corresponding
carboxylic acids in full detail.2g In this article we want to
disclose the scope and limitation of the synthesis of the crucial
Results and discussion
Synthesis of b-alkoxy-b-ketoenamides
aInstitut fu¨r Chemie und Biochemie, Freie Universita¨t Berlin, Takustr.
In general, enamides 2a–q were prepared by following the reported
3, 14195, Berlin, Germany. E-mail: hans.reissig@chemie.fu-berlin.de;
procedure2 using 2.7 equivalents of lithiated alkoxyallene 1, which
Fax: +49-30-838-55367; Tel: +49-30-838-55366
bIndian Institute of Science, Education and Research Kolkata, Mohanpur
Campus, Mohanpur, 741252, Nadia, West Bengal, India
is generated in situ by deprotonation of the alkoxyallene with
n-butyllithium, 1.0 equivalent of the corresponding nitrile and
an excess of the carboxylic acid (method A, Table 1). A slightly
modified procedure (method B, Table 1) differs from method A in
the stoichiometry of the reagents: lithiated alkoxyallene (1.0 equiv.)
is the limiting component and the nitrile (1.5–3.0 equiv.)
† Electronic supplementary information (ESI) available: Additional ex-
perimental procedures, analytical data, 1H and 13C NMR spectra. CCDC
reference numbers 756788 and 756789. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b925468d
‡ Responsible for X-ray crystal structure analyses.
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Table 1 Synthesis of b-alkoxy-b-ketoenamides 2 using method A or B
Scheme 2 Equilibrium of enamide 5 with 5¢.
Entry
R1
R2
R3
2, Yield (%), (methoda)
Constitution and E-configuration of enamide 5 were un-
ambiguously proved by NOESY-spectra and an X-ray crystal
structure analysis (Fig. 1). Currently, no definite explanation for
the formation of 5 can be offered. Formally, hydrogen cyanide
has served as electrophile, which seems fairly unlikely. A control
experiment with lithiated methoxyallene, DMF and picolinic acid
did not give defined products.
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Me
Me
Phb
2a, 13 (A)
2b, 22 (A)d
2c, 33 (A)e
2d, 53 (B)
2e, 79 (A)
2f, 63 (A)
2g, 76 (A)
2h, 72 (B)
2i, 45 (B)
2j, 43 (A)
2k, 72 (A)
2l, 47 (A)
2m, 56 (A)
2n, 54 (A)
2o, 27 (B)
2p, 32 (B)
2q, 71 (A)
2-Pyc
2-Pyc
Phb
CH2OMe
i-Pr
c-Pr
c-Pr
CH2OPh
Ph
t-Bu
t-Bu
≡
t-Bu
C
CH
9
Ph
Ph
Phb
10
11
12
13
14
15
16
17
2-Thienylb
Me
2-Thienyl
2-Thienyl
c-Pr
Ph
Ph
CH2OMe
c-Pr
Bn
Bn
Bn
Phb
2-Pyc
2-Thienyl
2-Thienylb
Phb
TMSE 2-Thienyl
a Method A: 2.7 equiv. lithiated alkoxyallene, 1.0 equiv. nitrile, 5.4 equiv.
carboxylic acid; method B: 1.0 equiv. lithiated alkoxyallene, 1.5–3.0 equiv.
nitrile, 6.0 equiv. carboxylic acid. b Dissolved in Et2O or THF. c Dissolved
in DMF. d 5% of enamide 5 (R2 = H) was isolated. e 10% of enamide 5
(R2 = H) was isolated.
Fig. 1 X-Ray crystal structure of enamide 5.11
Cyclisation to 4-hydroxypyridine derivatives
Enamides 2e and 2n have been cyclised under standard conditions2
employing an excess of trimethylsilyltrifluoromethane sulfonate in
the presence of triethylamine. After acidic workup the desired
pyridine derivatives 6a and 7b were obtained in very good yields
(90–97%) (Scheme 3). The NMR spectra recorded in CDCl3 show
the corresponding 4-hydroxypyridines 6, which are generally in
equilibrium with their tautomeric pyridinones 7. The ratio of
tautomers strongly depends on the substitution pattern at C-2
and C-6. In the case of R2 = R3 = Ph only pyridinone 7b was
observed. In polar protic solvents such as TFA-d1 or CD3OD the
NMR spectra show only one set of signals that has been assigned
and the carboxylic acid (ca. 5.0 equiv.) are used in excess.
Table 1 reveals that poor to good yields (13–79%) were obtained.
Aliphatic, aromatic and heteroaromatic substituents could suc-
cessfully be introduced into the desired enamides 2. Functional
groups such as ether or alkynyl units were tolerated without
problems (Table 1, entries 3, 8, 12). The synthesis of enamides 2
is not restricted to methoxyallene as precursor. Benzyloxyallene
or (2-trimethylsilyl)ethoxyallene are also feasible, which allow
subsequent reactions under modified conditions.
In the case of solid (hetero)aromatic carboxylic acids, these
precursors were dissolved in suitable solvents prior addition to the
reaction mixture at -78 ◦C. Whereas benzoic acid and thiophene
carboxylic acid are soluble in diethyl ether or THF, picolinic acid
has to be dissolved in DMF. A partial precipitation could not be
avoided, which might be the reason for lower yields in these cases
(Table 1, entries 2, 3, 15) demonstrating a limitation of the current
protocol. The relatively high a-acidity of the corresponding nitriles
employed in entries 1–3 might also lead to an additional decrease
of efficacy due to side-product formation.2g Thus, we obtained
the best yields with aliphatic carboxylic acids such as cyclopropyl
carboxylic acid, propiolic or acetic acid and nitriles without acidic
a-protons (entries 5, 8, 11).
The reactions of a-acidic nitriles with picolinic acid dissolved in
DMF (entries 2, 3) afforded an unexpected side product in 5% and
10% yield, which could be identified as enamide 5. Upon storage 5
provided a 10 : 1 mixture with its stereoisomer 5¢ (Scheme 2). This
behaviour was only observed for 5/5¢, whereas for other enamides
2 substituents R2 = aryl or alkyl apparently strongly stabilise the
E-configuration.
Scheme 3 Cyclisation of enamides 2e and 2n to pyridine derivatives 6a,
6b and 7a, 7b.
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Table 2 Three-step/one-pot procedure to 4-pyridyl nonaflates 9 and 4-
methoxypyridines 10
Entry
R1
R2
9 or 10, Yield (%)a
1
2
3
4
5
6
7
8
9
i-Pr
Ph
c-Pr
Me
Ph
≡
9a, 52b
9b, 42
9c, 57
9d, 38
9e, 22
9f, 55
9g, 23
10a, 53b
10b, 58b
c-Pr
t-Bu
t-Bu
t-Bu
Ph
c
C
C-TMS
2-Py
2-Thienyl
2-Py
Me
Ph
Me
2-Thienyl
Scheme 4 Approach to Glenvastatin building block 13 starting from 9a.
a Overall yields for three steps. b Overall yield for two steps starting from
the corresponding enamide 2. c Starting material propiolic acid.
Cyclisation of 4-hydroxypyridines to furo[2,3c]pyridines and
investigation of their photophysical properties
to the 4-hydroxypyridine structure 6 (e.g. compound 6a with R2 =
R3 = c-Pr, measured in TFA-d1).
Smooth coupling reactions of pyridyl nonaflates with alkynes
proceeded under Sonogashira conditions. In contrast to earlier
results with similar 4-pyridyl nonaflates,2d the coupling of 9g with
phenylacetylene gave a relatively low yield of 58%, even under
optimised conditions (Scheme 5). Possibly, the 6-thienylpyridine
moiety is a competing ligand for the palladium making the desired
coupling less efficient in this specific case.
Owing to the problematic purification and characterisation of 4-
hydroxypyridines at this stage, we developed a three-step/one-pot
procedure starting from methoxyallene 8 (Table 2). After lithiated
methoxyallene was subjected to the standard conditions, the crude
enamides were cyclised without purification and the resulting
pyridine derivatives were either directly converted into 4-pyridyl
nonaflates 9 or into O-methylated compounds 10. The yields
mainly depend on the first step (enamide formation, see above) and
vary between 22% and 57% (entries 1–7) after three steps. Since an
excess of trimethylsilyltrifluoromethane sulfonate has been used
the alkynyl-substituted derivative 9e was exclusively obtained as
TMS-protected compound (entry 5). Although the procedures
have not been optimised in these cases, and therefore several
transformations occur only in fairly moderate overall yields, the
simplicity and flexibility of this synthesis of highly functionalised
pyridine derivatives compensates for these disadvantages. There is
certainly room for improvement in individual experiments.
Scheme 5 Sonogashira coupling of 9g with phenylacetylene to 14.
The previously developed cyclisation2d of compounds such as 14
and 15a–b to furo[2,3c]pyridines13 16a–c as depicted in Scheme 6
occurred after cleavage of the methoxy group with either sodium
ethanethiolate (method a) or BBr3 (method b). In the case of
method a the furan ring was immediately generated after cleavage,
whereas in method b a base had to be added to achieve ring
closure.14 In most cases method a was only applied when method
b did not succeed in complete deprotection. Method b generally
gives higher yields than method a.
Furopyridines such as 16 have interesting photophysical
properties2d that might be attractive for material science e.g. or-
ganic electronics and optoelectronic devices.15 Due to their similar
substitution pattern, compounds 16a–c were suitable candidates
to start a systematic investigation. In Fig. 2 the absorption and
emission data of compounds 16a–c have been displayed. While
Access to a Glenvastatin building block
Pyridyl nonaflates have already been proven as useful precursors
in palladium-catalysed reactions.2 In this report, nonaflate 9a
has been employed as starting material for a rapid access to
Glenvastatin building block 1312a using standard Suzuki condi-
tions (Scheme 4). Coupling of 9a with p-fluorophenylboronic acid
to intermediate 11 was achieved in 92% yield. Cleavage of the
methyl ether moiety with BBr3 led to 3-hydroxypyridine derivative
12 which could easily be transformed into 3-pyridyl nonaflate 13.
The overall yield after six steps starting from methoxyallene 8 is
19%. For a completion of the synthesis of the potent HMG-CoA
inhibitor Glenvastatin 13 has to be coupled to literature known12b–d
lactone A building blocks.
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Fig. 3 X-Ray crystal structure of 4-pyridyl stilbene derivative 17a.11
Scheme 6 Cyclisation to furo[2,3c]pyridines 16a–c.
the maxima of absorption are all in the same range of 290–
310 nm, the Stokes shifts increase parallel to the extension of
the corresponding p-system. The largest value was determined
for 16a with a maximum of emission at 410 nm and a Stokes
shift of 110 nm. Investigation of other derivatives is required for
understanding these effects.
The photoirradiation of 4-styryl pyridine derivative 17b in the
presence of I2 and an excess of propylene oxide16b in toluene as
solvent using a 150 W medium pressure lamp (l = 254 nm)
furnished benzoisoquinoline 18 in good yield of 82% (Scheme 8)
demonstrating the synthetic potential of 4-pyridyl nonaflates
such as 9f for further elaboration to more complex heterocyclic
compounds.
Scheme 8 Photocyclisation of 4-pyridyl styrene derivative 17b to ben-
zoisoquinoline 18.
Fig. 2 UV and fluorescence spectra of furo[2,3c]pyridine derivatives
16a–c.
Conclusions
In conclusion, we demonstrated that the three-component reaction
of lithiated alkoxyallenes with different nitriles and carboxylic
acids constitutes a simple and very flexible synthesis of highly
substituted b-alkoxy-b-ketoenamides 2. These enamides have
been proven to be suitable precursors for the preparation of
4-hydroxypyridine derivatives 6. The corresponding nonaflates 9
derived thereof allow a variety of palladium-catalysed coupling
reactions leading to specifically substituted pyridine derivatives.
As an example a short and fairly efficient route to the pyridine
core of Glenvastatin has been developed. Whereas Sonogashira
reactions canbe combined withasubsequent cyclisation to provide
highly fluorescent furo[2,3c]pyridine derivatives 16, an alternative
reaction sequence via 4-pyridyl stilbenes 17 allows the preparation
of other complex heterocycles such as benzoisoquinoline 18. All
these transformations impressively show the high versatility and
synthetic value of alkoxyallene-based b-alkoxy-b-ketoenamides as
crucial intermediates.
Photocyclisation of pyridyl styrenes to benzoisoquinoline
derivatives
The photocyclisation of stilbenes leading to phenanthrenes is a
common reaction. However, there are limited literature reports
on their aza analogues16 and particularly the photocyclisation of
pyridyl styrenes are less explored. The Suzuki coupling reactions
of nonaflates 9c and 9f with trans-2-styryl boronic acid was
carried out using optimised conditions to afford 92% of 4-pyridyl
styrene derivative 17a and 89% of 17b, respectively (Scheme 7).
Constitution and configuration of compound 17a were confirmed
by an X-ray crystal structure analysis (Fig. 3).
Experimental
General
Reactions were generally performed under argon in flame-dried
flasks. Solvents and reagents were added by syringes. Solvents were
Scheme 7 Suzuki couplings of nonaflates 9c and 9f with trans-2-styryl
boronic acid to 4-pyridyl stilbene derivatives 17a–b.
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-1
=
=
dried using standard procedures. Reagents were purchased and
were used as received without further purification unless otherwise
stated. Unless otherwise stated, products were purified by flash
chromatography on silica gel (230–400 mesh, Merck or Fluka) or
HPLC (Nucleosil 50-5). Unless otherwise stated, yields refer to
analytical pure samples. NMR spectra were recorded on Bruker
(AC 500) and JOEL (Eclipse 500 and ECX 400) instruments.
Chemical shifts are reported relative to TMS (1H: d = 0.00 ppm),
CDCl3 (1H: d = 7.25 ppm, 13C: d = 77.0 ppm) or CF3CO2D
(d = 11.50 ppm, 13C: d = 116.6 ppm). Integrals are in accor-
dance with assignments; coupling constants are given in Hz. All
13C NMR spectra are proton-decoupled. Multiplicity is indicated
as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), mc (centered multiplet), dd (doublet of doublet), sbr (broad
singlet). For detailed peak assignments 2D spectra were measured
(COSY, HMBC and HMQC). IR spectra were measured with
an FT-IRD spectrometer Nicolet 5 SXC. UV/Vis spectra were
measured with a UV-Vis spectrophotometer Scinco S-3150 PDA.
Fluorescence spectra were measured with a spectrofluorometer
(C O, C C) cm . Calcd. for C12H17NO3 (223.3): C 64.55, H 7.67,
N 6.27%; found: C 64.79, H 7.52, N 5.94%.
Preparation of 3-(benzyloxy)-2,6-diphenylpyridin-4(1H)-one
(7b). Enamide 2n (338 mg, 0.910 mmol) was dissolved in
dichloromethane (5 mL) and treated at 0 ◦C with triethylamine
(0.38 mL, 2.73 mmol) and trimethylsilyl triflate (0.53 mL,
2.73 mmol). The mixture was heated under reflux for 3 d and then
quenched at room temperature with satd. aq. NH4Cl solution
(8 mL), extracted with dichloromethane (3 ¥ 10 mL) and the
combined organic phases were dried with Na2SO4 and evaporated
to provide the crude product. The resulting crude product was
dissolved again in dichloromethane (8 mL) and treated first with
acetic acid (1 mL) and then with water (10 mL). It was extracted
with dichloromethane (3 ¥ 8 mL) and the combined organic
extracts were dried with Na2SO4 and concentrated to dryness. The
residue was purified by chromatography on silica gel (hexane–
ethyl acetate, 4 : 1) to afford 289 mg (90%) of 7b as a light yellow
◦
1
solid. Mp: 47–50 C. H NMR (CDCl3, 500 MHz): d = 4.80 (s,
2 H, CH2Ph), 6.77 (s, 1 H, 5-H), 6.97–7.68, 8.08–8.10 (2 m, 15
H, Ph), 10.43 (sbr, 1 H, NH) ppm. 13C NMR (CDCl3, 126 MHz):
d = 73.3, 113.2, 127.1, 128.1, 128.32, 128.34, 128.6, 129.0, 129.28,
129.35, 129.8, 130.2, 131.0, 132.9, 136.9, 142.5, 148.9, 170.3 ppm.
Jasco FP-6500. For both techniques a concentration of 10-6
M
in degassed CH3CN (1 cm cuvette) at 25 ◦C was used. MS
and HRMS analyses were performed with Finnigan MAT 711
(EI, 80 eV, 8 kV), MAT CH7A (EI, 80 eV, 3 kV), CH5DF
(FAB, 3 kV), Varian Ionspec QFT-7 (ESI-FT ICRMS) and Agilent
6210 (ESI-TOF) instruments. Elemental analyses were carried out
with Perkin Elmer CHN-Analyzer 2400 and Vario EL Elemental
Analyzer. Melting points were measured with a Reichert apparatus
Thermovar and are uncorrected. Single-crystal X-ray data were
collected on a Bruker-XPS diffractometer (CCD area detector,
=
IR (KBr): n = 3250 (N–H), 3060–2865 ( C–H, C–H), 1700–
-1
=
=
1570 (C O, C C) cm . HRMS (ESI-TOF): calcd for C24H20NO2
[M+H]+: 534.0239; found: 534.0248.
Preparation of 2-tert-butyl-3-methoxy-6-methyl-4-pyridinyl nona-
flate (9c). Methoxyallene 8 (1.65 mL, 19.8 mmol) was dissolved
in diethyl ether (40 mL) and n-butyllithium (6.60 mL, 16.5 mmol,
2.5 M in hexanes), was added at -40 ◦C. After 25 min at -50
to -40 ◦C the solution was cooled to -78 ◦C and pivalonitrile
(0.66 mL, 5.97 mmol) was added. After stirring for 4 h at this
temperature acetic acid (2.23 mL, 39.0 mmol) was added and
the mixture was warmed up over night to room temperature.
The reaction mixture was then quenched with satd. aq. NaHCO3
solution (40 mL) and extracted with diethyl ether (3 ¥ 35 mL).
The combined organic phases were dried with Na2SO4 and
then evaporated. The residue was dissolved in dichloromethane
(35 mL) and treated at 0 ◦C with triethylamine (2.51 mL,
17.9 mmol) and trimethylsilyl triflate (3.46 mL, 17.9 mmol). The
mixture was heated under reflux for 3 d and then quenched
at room temperature with satd. aq. NH4Cl solution (40 mL),
extracted with dichloromethane (3 ¥ 35 mL), dried with Na2SO4
and evaporated to provide the crude product. The resulting crude
product was dissolved in THF (35 mL) and NaH (1.44 g, 60% in
mineral oil, 36.0 mmol) was added under an argon atmosphere.
Nonafluorobutanesulfonyl fluoride (6.48 mL, 36.0 mmol) was
added dropwise at room temperature. The mixture was stirred
at room temperature over night and quenched by slow addition
of methanol and water. It was extracted with ethyl acetate (3 ¥
35 mL), dried with Na2SO4 and concentrated to dryness. The
residue was purified by chromatography on silica gel (hexane–
ethyl acetate, 40 : 1) to afford 1.62 g (57%) of 9c as a light yellow
oil. 1H NMR (CDCl3, 500 MHz): d = 1.40 (s, 9 H, t-Bu), 2.50 (s,
3 H, CH3), 3.88 (s, 3 H, OMe), 6.92 (s, 1 H, 5-H) ppm. 13C NMR
(CDCl3, 126 MHz): d = 24.2, 29.3, 38.5, 61.7, 114.1, 144.9, 149.8,
˚
Mo-Ka radiation, l = 0.71073 A, graphite monochromator),
empirical absorption correction using symmetry-equivalent reflec-
tions (SADABS), structure solution and refinement by SHELXS-
97 and SHELXL-97 in the WINGX System.17 The hydrogen
atoms were located by difference Fourier syntheses. The pyridine
derivatives 15a2d and 15b2b were prepared using our previously
reported procedure.
Representative experimental procedures
Preparation of (E)-N-(1-cyclopropyl-2-methoxy-3-oxobut-1-
enyl)cyclopropanecarboxamide (2e). Methoxyallene 8 (1.00 g,
14.3 mmol) was dissolved in diethyl ether (28 mL) and n-
butyllithium (5.15 mL, 12.8 mmol, 2.5 M in hexanes) was added
at -40 ◦C. After 25 min at -50 to -40 ◦C the solution was cooled
to -78 ◦C and cyclopropylnitrile (0.35 mL, 4.77 mmol) was added.
After stirring for 4 h at this temperature cyclopropane carboxylic
acid (2.26 mL, 28.6 mmol) was added and the mixture was warmed
up over night to room temperature. Then the reaction mixture was
quenched with satd. aq. NaHCO3 solution (25 mL) and extracted
with diethyl ether (3 ¥ 25 mL). The combined organic phases
were dried with Na2SO4 and then evaporated. The residue was
purified by chromatography on silica gel (hexane–ethyl acetate,
10 : 1) to afford 844 mg (79%) of 2e as a colourless solid. Mp: 71 ◦C.
1H NMR (CDCl3, 500 MHz): d = 0.79–0.85, 0.96–1.02 (2 m, 4 H,
4 H, c-Pr), 1.54 (mc, 1 H, 1¢-H), 2.14 (mc, 1 H, 1¢¢-H), 3.65 (s, 3 H,
OMe), 11.76 (sbr, 1 H, NH) ppm. 13C NMR (CDCl3, 101 MHz):
d = 8.4, 8.8, 11.6, 16.6, 27.1, 61.6, 140.3, 146.8, 172.7, 201.1 ppm.
IR (KBr): n = 3380–3250 (N–H), 3095–2835 (C–H), 1700–1570
=
153.1, 163.8 ppm. IR (film): n = 2960–2930 ( C–H), 2870 (C–H),
-1
+
=
1590 (C C) cm . MS (EI): m/z (%) = 477 (18) [M] , 462 (13),
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194 (100), 69 (25). HRMS (EI): Calcd. for C15H16F9NO4S [M]+:
477.06564; found: 477.06638.
concentrated to dryness. Column chromatography on silica gel
(hexane–ethyl acetate, 10 : 1) afforded 46 mg (41%) of 16a as a
◦
1
colourless solid. Mp 181–183 C. H NMR (CDCl3, 500 MHz):
d = 7.07 (s, 1 H, 3-H), 7.13 (dd, 1 H, J = 5.0, 3.7 Hz, 4¢-H), 7.37 (dd,
1 H, J = 5.0, 1.1 Hz, 3¢-H), 7.43–7.61, 7.93–7.96, 8.57–8.59 (3 m,
6 H, 2 H, 2 H, Ph), 7.62 (dd, 1 H, J = 3.7, 1.1 Hz, 5¢-H), 7.80 (s, 1 H,
4-H) ppm. 13C NMR (CDCl3, 101 MHz): d = 100.7, 109.4, 123.3,
125.7, 126.6, 127.9, 128.60, 128.63, 129.0, 129.35, 129.39, 129.9,
Preparation of 3,4-dimethoxy-6-methyl-2-thiophen-2-yl-pyridine
(10b). Enamide 2k (478 mg, 2.00 mmol) was dissolved in 1,2-
dichloroethane (10 mL) followed by the addition of triethylamine
(1.12 mL, 8.00 mmol) and trimethylsilyl triflate (1.82 mL,
10.0 mmol). The reaction mixture was heated under reflux for
3 d and then quenched with satd. aq. NH4Cl solution (10 mL).
After extraction with dichloromethane (3 ¥ 10 mL) the combined
organic phases were dried with Na2SO4 and evaporated. The crude
product was dissolved in acetone (15 mL) and K2CO3 (405 mg,
3.00 mmol) and methyl iodide (0.25 mL, 4.00 mmol) were added
under an argon atmosphere. The mixture was refluxed for 7 h,
monitored by tlc, and diluted with water (15 mL). It was extracted
with ethyl acetate (3 ¥ 10 mL), dried with Na2SO4 and concentrated
to dryness. The residue was purified by chromatography on silica
gel (hexane–ethyl acetate, ◦1 : 1) to afford 273 mg (58%) of 10b as
136.0, 137.9, 140.5, 145.9, 146.1, 148.8, 159.2 ppm. IR (KBr): n =
-1
=
=
3105–2855 ( C–H, C–H), 1620–1575 (C C) cm . HRMS (ESI-
TOF): Calcd. for C23H15NOS [M+H]+: 354.0947; found 354.0940.
Preparation of 7-tert-butyl-2-phenyl-5-(trifluoromethyl)furo[2,3-
c]pyridine (16c) (method b). To a solution of pyridine 15b
(200 mg, 0.60 mmol) in dichloromethane (6 mL) under argon
atmosphere was added BBr3 (0.90 mL, 1 M in CH2Cl2, 0.90 mmol)
dropwise at 0 ◦C and warmed up to room temperature. The
reaction mixture was monitored by tlc; upon completion, ice water
was added and the mixture was extracted with dichloromethane
(3 ¥ 5 mL). The combined organic layers were washed with water
and brine, dried with Na2SO4 and evaporated under reduced
pressure. The residue was dissolved in DMF (5 mL) and K2CO3
(243 mg, 1.80 mmol) and water (1 mL) were added. After stirring
at 80 ◦C for 12 h, the mixture was diluted with water (12 mL) and
extracted with diethyl ether (3 ¥ 10 mL). The combined organic
phases were dried with Na2SO4 and concentrated to dryness.
Column chromatography on silica gel (hexane–ethyl acetate, 10 : 1)
afforded 139 mg (73%) of 16c as a colourless solid.
1
a brown solid. Mp 64–65 C. H NMR (CDCl3, 500 MHz): d =
2.50 (s, 3 H, CH3), 3.84 (s, 3 H, OMe), 3.88 (s, 3 H, OMe), 6.57
(s, 1 H, 5-H), 7.09 (dd, 1 H, J = 5.1, 3.7 Hz, 2¢-H), 7.35 (dd, 1
H, J = 5.1, 1.2 Hz, 3¢-H), 7.95 (dd, 1 H, J = 3.7, 1.2 Hz, 5¢-H)
ppm. 13C NMR (CDCl3, 126 MHz): d = 24.8, 55.7, 60.0, 105.6,
127.53, 127.56, 127.59, 139.9, 141.2, 144.8, 154.7, 159.4 ppm. IR
=
(KBr): n = 3100–3070 ( C–H), 2950–2850 (C–H), 1570–1520
-1
+
=
(C C) cm . MS (EI): m/z (%) = 235 (100) [M] , 220 (82), 83
(27). HRMS (EI): Calcd. for C12H13NO2S [M]+: 235.06670; found:
235.06722.
Characterisation of 16c has been previously reported.2d
Sonogashira coupling reaction of 9e to 3-methoxy-2-phenyl-
4-(phenylethynyl)-6-(thiophen-2-yl)pyridine (14). A mixture of
pyridyl nonaflate 9e (350 mg, 0.991 mmol), Pd(OAc)2 (11 mg,
0.050 mmol), PPh3 (52 mg, 0.198 mmol), CuI (9.4 mg,
0.050 mmol), phenylacetylene (122 mg, 1.19 mmol) in DMF (4.6
mL) and diisopropylamine (2.3 mL) was heated to 70 ◦C for 3 h
under an argon atmosphere. The mixture was allowed to cool to
room temperature, diluted with brine (8 mL) and extracted with
diethyl ether (3 ¥ 10 mL). The combined organic phases were
dried with Na2SO4 and concentrated to dryness. The residue was
purified by column chromatography on silica gel (hexane–ethyl
acetate, 40 : 1) to afford 211 mg (58%) of 14 as a colourless solid.
1H NMR (CDCl3, 500 MHz): d = 3.83 (s, 3 H, OMe), 7.11 (dd, 1 H,
J = 5.0, 3.7 Hz, 4¢-H), 7.38 (dd, 1 H, J = 5.0, 1.1 Hz, 3¢-H), 7.39–
7.51, 7.60–7.63, 8.08–8.12 (3 m, 6 H, 2 H, 2 H, Ph), 7.58 (dd, 1 H,
J = 3.7, 1.1 Hz, 5¢-H), 7.71 (s, 1 H, 5-H) ppm. 13C NMR (CDCl3,
101 MHz): d = 61.0, 83.8, 97.5, 120.8, 122.3, 124.3, 126.7, 127.4,
128.0, 128.2, 128.5, 128.8, 129.2, 129.3, 131.8, 137.1, 144.3, 147.6,
Suzuki coupling reaction of 9f to 5-methoxy-6-phenyl-4-styryl-
[2,2¢]bipyridinyl (17b). A mixture of 4-pyridyl nonaflate 9f
(530 mg, 1.00 mmol), trans-2-phenyl vinyl boronic acid (178 mg,
1.20 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), PPh3 (52 mg,
0.20 mmol) and K2CO3 (135 mg, 1.00 mmol) in DMF (5 mL)
was heated to 70 ◦C for 7 h under an argon atmosphere. The
mixture was allowed to cool to room temperature and diluted
with water (5 mL) and extracted with diethyl ether (3 ¥ 5 mL). The
combined organic phase was dried with Na2SO4 and concentrated
to dryness. The residue was purified by chromatography on silica
gel (hexane–ethyl acetate, 7 : 1) to give 324 mg (89%) of 17b as a
◦
1
colourless solid. Mp 121–122 C. H NMR (CDCl3, 500 MHz):
d = 3.59 (s, 3 H, OMe), 7.29 (ddd, 1 H, J = 7.4, 4.7, 1.2 Hz,
5¢-H), 7.33–7.36 (m, 1 H, Ph), 7.41–7.44 (m, 2 H, Ph), 7.45–7.48
(m, 1 H, Ph), 7.51–7.54 (m, 2 H, Ph), 7.54 (d, 1 H, J = 16.4 Hz,
=
=
HC C), 7.60 (d, 1 H, J = 16.5 Hz, HC C), 7.64–7.66 (m, 2 H,
Ph), 7.81 (td, 1 H, J = 7.4, 1.6 Hz, 4¢-H), 8.14–8.16 (m, 2 H,
Ph), 8.58 (dt, 1 H, J = 7.9, 1.0 Hz, 3¢-H), 8.70 (s, 1 H, 3-H), 8.74
(ddd, 1 H, J = 4.7, 1.8, 0.8 Hz, 6¢-H) ppm. 13C NMR (CDCl3, 126
MHz): d = 61.3, 116.3, 121.0, 121.3, 123.5, 127.3, 128.4, 128.71,
128.74, 128.9, 129.3, 134.1, 136.92, 136.95, 138.2, 139.8, 149.0,
=
151.1, 153.3 ppm. IR (KBr): n = 3105–3030 ( C–H), 3005–2850
-1
≡
=
(C–H), 2215 (C C), 1600–1570 (C C) cm . HRMS (ESI-TOF):
Calcd. for C24H18NOS [M+H]+: 368.1104; found: 368.1108. Calcd.
for C24H17NOS (367.5): C 78.45, H 4.66, N 3.81%; found: C 78.15,
H 4.21, N 3.87%.
=
151.2, 151.6, 152.5, 156.2 ppm. IR (KBr): n = 3080–3000 ( C–
-1
=
H), 2950–2830 (C–H), 1630, 1540–1500 (C C) cm . MS (EI):
Preparation of 2,7-diphenyl-5-(thiophen-2-yl)furo[2,3-c]pyridine
(16a) (method a). A mixture of pyridine 14 (118 mg, 0.321 mmol),
sodium thioethanolate (216 mg, 2.57 mmol) in DMF (2 mL) was
heated in an ACE-sealed tube to 80 ◦C for 1 h. The reaction
mixture was allowed to cool to room temperature, quenched
with brine (4 mL) and extracted with diethyl ether (3 ¥ 5 mL).
The combined organic phases were dried with Na2SO4 and
m/z (%) = 364 (100) [M]+, 349 (82), 287 (24). HRMS (EI): Calcd.
for C25H20N2O [M]+: 364.15756; found 364.15756.
Photocyclisation to 4-methoxy-3-phenyl-1-pyridin-2-yl-benzo-
[h]isoquinoline (18). A solution of pyridyl styrene derivative 17b
(50 mg, 0.137 mmol) in toluene (60 mL) in the presence of I2
(42 mg, 0.165 mmol) and propylene oxide (1.9 mL, 27.4 mmol)
3012 | Org. Biomol. Chem., 2010, 8, 3007–3014
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in a double-walled Pyrex tube cooled by water was irradiated
(l = 254 nm) with a 150 W medium pressure lamp for 10 h.
The photoirradiation was monitored by tlc. The reaction mixture
was washed with aqueous sodium thiosulfate solution and brine,
dried with Na2SO4 and concentrated to dryness. The residue was
purified by chromatography on silica gel (hexane–ethyl acetate,
5 : 1) to afford 41 mg (82%) of 18 as a colourless solid. Mp 73–
74 ◦C. 1H NMR (CDCl3, 500 MHz): d = 3.74 (s, 3 H, OMe), 7.21
(td, 1 H, J = 8.6, 1.4 Hz, 8-H), 7.31 (dd, 1 H, J = 8.6, 0.8 Hz,
7-H), 7.40 (td, 1 H, J = 7.4, 2.0 Hz, Ph), 7.42 (ddd, 1 H, J = 7.7,
4.9, 1.1 Hz, 4¢-H), 7.49 (dt, 1 H, J = 8.0, 1.2 Hz, 9-H), 7.47–7.50
(m, 2 H, Ph), 7.88 (dd, 1 H, J = 8.0, 1.4 Hz, 10-H), 7.91 (td, 1 H,
J = 7.7, 1.0 Hz, 5¢-H), 7.95 (dt, 1 H, J = 7.7, 1.7 Hz, 6¢-H), 7.98
(d, 1 H, J = 9.2 Hz, 6-H), 8.19 (d, 1 H, J = 9.2 Hz, 5-H), 8.20–8.21
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(m, 2 H, Ph), 8.67 (ddd, 1 H, J = 4.8, 1.8, 0.9 Hz, 3¢-H) ppm. 13
C
NMR (CDCl3, 126 MHz): d = 61.5, 119.4, 123.2, 124.4, 126.3,
127.0, 127.5, 128.5, 128.8, 129.3, 129.4, 132.1, 133.4, 133.7, 137.6,
137.8, 143.6, 149.1, 149.5, 152.5, 161.6 ppm. IR (KBr): n = 3050
-1
=
=
( C–H), 2930–2850 (C–H), 1620–1580, 1550–1475 (C C) cm .
MS (EI): m/z (%) = 362 (65) [M]+, 346 (31), 43 (100). HRMS (EI):
Calcd. for C25H18N2O [M]+: 362.14191; found 362.14277.
Acknowledgements
Generous support of this work by the Alexander von
Humboldt foundation (research fellowship for J.D.), the Fonds
der Chemischen Industrie, the Studienstiftung des Deutschen
Volkes (fellowship for C.E.) and the Bayer Schering Pharma AG
is most gratefully acknowledged. We also thank Dr R. Zimmer
(Freie Universita¨t Berlin) for his help during preparation of this
manuscript, C. Ehms and S. Mo¨hl (Freie Universita¨t Berlin) for
their experimental contributions.
7 For palladium-catalysed cross coupling reactions of aryl and alkenyl
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as ESI†.
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3014 | Org. Biomol. Chem., 2010, 8, 3007–3014
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