A practical two-step procedure for the preparation of enantiopure pyridines: Multicomponent reactions of alkoxyallenes, nitriles and carboxylic acids followed by a cyclocondensation reaction

Article abstract of DOI:10.3762/bjoc.7.108

A practical approach to highly functionalized 4-hydroxypyridine derivatives with stereogenic side chains in the 2- and 6-positions is described. The presented two-step process utilizes a multicomponent reaction of alkoxyallenes, nitriles and carboxylic ac

Full text of DOI:10.3762/bjoc.7.108

A practical two-step procedure for the preparation of
enantiopure pyridines: Multicomponent reactions of
alkoxyallenes, nitriles and carboxylic acids followed
by a cyclocondensation reaction
Christian Eidamshaus, Roopender Kumar, Mrinal K. Bera
and Hans-Ulrich Reissig*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 962–975.
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3,
D-14195 Berlin, Germany
doi:10.3762/bjoc.7.108
Received: 07 March 2011
Accepted: 06 June 2011
Published: 13 July 2011
Email:
Hans-Ulrich Reissig* - hreissig@chemie.fu-berlin.de
* Corresponding author
This article is part of the Thematic Series "Multicomponent reactions".
Guest Editor: T. J. J. Müller
Keywords:
allenes; enantiopure pyridines; ketoenamides; multicomponent
reactions; nonaflates
© 2011 Eidamshaus et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A practical approach to highly functionalized 4-hydroxypyridine derivatives with stereogenic side chains in the 2- and 6-positions is
described. The presented two-step process utilizes a multicomponent reaction of alkoxyallenes, nitriles and carboxylic acids to
provide β-methoxy-β-ketoenamides which are transformed into 4-hydroxypyridines in a subsequent cyclocondensation. The process
shows broad substrate scope and leads to differentially substituted enantiopure pyridines in good to moderate yields. The prepar-
ation of diverse substituted lactic acid derived pyrid-4-yl nonaflates is described. Additional evidence for the postulated mechanism
of the multicomponent reaction is presented.
Introduction
The pyridine core is ubiquitous in pharmacologically active tion compounds makes pyridines ideal ligands for transition
agents, agrochemicals and natural products [1-5]. The HMG- metal-catalyzed processes and for the construction of supra-
CoA reductase inhibitors Glenvastatin and Cerivastatin are molecular architectures [13]. Pyridines with chiral side chains
exemplarily mentioned as pharmaceuticals that feature the pyri- are widely employed as ligands in asymmetric transformations,
dine nucleus [6-10]. Natural products that contain a pyridine for instance, in the asymmetric hydrogenation of olefins, in
ring include the 3-alkylpyridine alkaloid niphatesine C and the enantioselective additions of metal organyls to aldehydes and
fuzanin family [11,12]. Moreover, the ability to form coordina- enones, as well as in palladium-catalyzed allylic substitution
962

Beilstein J. Org. Chem. 2011, 7, 962–975.
Scheme 1: Preparation of β-ketoenamides and subsequent cyclocondensation to 4-hydroxypyridines. a) Et2O, −40 °C to r.t. 16 h, b) TMSOTf, NEt3,
CH2Cl2 or ClCH2CH2Cl reflux.
reactions [14-20]. Thus, the synthesis of specifically functional- Results and Discussion
ized pyridines is of considerable interest, and many approaches In continuation of our previous work, we addressed the ques-
toward this heterocyclic structure have been disclosed in the tion whether chiral starting materials react in the above
literature [21]. In addition to classical pyridine syntheses such sequence without loss of enantiopurity [40]. Chiral carboxylic
as the Kröhnke reaction, many new approaches have recently acids are readily available and their use would allow for a rapid
been developed [22-26]. Despite the wide range of conceptu- access to pyridines with side chains bearing stereogenic centers.
ally different syntheses, only few methods for introducing In recent years we studied intensively the multicomponent reac-
chirality into pyridine side chains have been described: Enantio- tions of lithiated alkoxyallenes with nitriles and carboxylic
selective reduction of pyridine carbonyl compounds, the add- acids and could demonstrate that precursor compounds with
ition of lithiated pyridine derivatives to chiral ketones or the alkyl, alkenyl or aryl substituents are smoothly converted into
resolution of racemates being the most common approaches. β-ketoenamides and subsequently transformed into the desired
The preparation of chiral pyridine derivatives starting from 4-hydroxypyridines. The mechanism of the multicomponent
simple enantiopure precursors is less common [27,28].
reaction is depicted in Scheme 2. In the first step, a lithiated
Recently, we reported a new synthesis of pyridines based on the
trimethylsilyl trifluoromethanesulfonate (TMSOTf) induced
cyclocondensation reaction of β-ketoenamides [29-34]. This
cyclocondensation step can be rationalized as a 6π-electrocy-
clization of the disilylated intermediate 5 to provide dihydropy-
ridine 6. Elimination of trimethylsilanol and subsequent O-desi-
lylation affords the 4-hydroxypyridine 7 (Scheme 1). The
desired β-ketoenamides 4 are either accessible by acylation of
enaminoketones or by a multicomponent reaction of lithiated
alkoxyallenes, nitriles and carboxylic acids [35,36].
In the past, we devoted considerable interest to the synthesis of
substituted pyridine derivatives by this route and investigated
their use in subsequent transformations [37-39]. Broadening the
scope of the process to functionalized, chiral starting materials
is the subject of this report. Additionally, herein we disclose the
full experimental data for compounds reported in a preliminary
communication [40].
Scheme 2: Mechanistic rational for the formation of β-ketoenamides
16.
963

Beilstein J. Org. Chem. 2011, 7, 962–975.
alkoxyallene such as 10 adds to a nitrile to yield an imino- Scope and limitations
allenyl anion 11. Protonation of 11 then gives a resonance stabi- Following the protocol mentioned before, we successfully
lized cation 12 which can be attacked in β-position by a prepared a series of 4-hydroxypyridines with chiral functional
carboxylate to afford an enol ester 14. The β-ketoenamide 16 is groups present in a side chain. As can be seen in Table 1 not
then formed by transfer of the acyl group to the amino group merely chiral aliphatic carboxylic acids and nitriles such as 17
and subsequent tautomerization.
and 31 can be transformed into 4-hydroxypyridines, but rather
complex substrates with appropriately protected functional
In some cases we observed the formation of minor amounts of groups. For instance, when lithiated methoxyallene was added
4-hydroxypyridines along with the β-ketoenamides. Depending to pivalonitrile and reacted with O-silylated mandelic acid 21,
on the substitution pattern of the β-ketoenamide, a conden- pyridine derivative 22 was obtained in good yield over two
sation to the corresponding pyridine can spontaneously occur. steps. Furthermore, readily available N,N-dibenzylated amino
In most cases a second step is necessary and the cyclocondensa- acids, such as those derived from valine and phenylalanine, 23
tion must be induced or completed by treatment with TMSOTf and 25 gave the respective pyridines 24 and 26 in 45% and 50%
and an amine base in a suitable solvents at elevated tempera- yield, respectively. Carboxylic acids featuring aromatic units
tures. In order to minimize the operational effort, the process and branched side chains including quaternary α-carbon atoms
can be performed as quasi-one-pot procedure without purifica- were also tolerated. Besides chiral carboxylic acids, enan-
tion of the intermediary β-ketoenamide.
tiopure nitriles were also successfully converted into pyridine
Table 1: Scope of the synthesis of 4-hydroxypyridine derivatives from lithiated methoxyallene, nitriles and carboxylic acids.
Carboxylic Acid
R2CO2H
Nitrile
R1-CN
Producta
Yieldb
24%
30%
50%
964

Beilstein J. Org. Chem. 2011, 7, 962–975.
Table 1: Scope of the synthesis of 4-hydroxypyridine derivatives from lithiated methoxyallene, nitriles and carboxylic acids. (continued)
45%
50%
45%
24%
85%
26%
(as a separable 1:1 mixture of
diastereomers)
965

Beilstein J. Org. Chem. 2011, 7, 962–975.
Table 1: Scope of the synthesis of 4-hydroxypyridine derivatives from lithiated methoxyallene, nitriles and carboxylic acids. (continued)
CF3CO2H
CF3CO2H
CF3CO2H
37%
28%
56%
–
CF3CO2H
–
aOnly the predominant tautomer in CDCl3 is depicted; bAll yields are based on the nitrile.
derivatives in comparable yields. As an example, (S)-2-methyl- very good yields, however, it should be noted that in only a few
butyronitrile (31) could be converted into compound 40 in good cases attempts to optimize the conditions have been undertaken.
yield. The use of carboxylic acids and nitriles with structurally Hence, there may be room for improvement of yields in cases
identical substituents allows a rapid access to pyridine deriva- where the standard conditions led only to moderate yields.
tives such as 32 which almost has C2-symmetry. Compound 32
is derived from nitrile 31 and carboxylic acid 17 and was Unfortunately, all attempts to incorporate proline-derived
obtained in high yield after two steps. Products 34 and 35 were moieties failed. N-Benzylproline (41) turned out to be almost
prepared from enantiopure acid 29 and racemic O-TBS-mande- insoluble in ethereal solvents, which might explain why the
lonitrile 33. The diastereomeric pyridines obtained from this desired β-ketoenamide was not formed [43]. To increase the
reaction are easily separable by column chromatography to give solubility of the proline component, we changed the protective
34 and 35 in moderate yields. If not commercially available, the group from benzyl to the more lipophilic trityl group [44].
desired nitriles were prepared from the corresponding acids by Surprisingly, the use of trityl-protected proline did not give the
an amide formation/dehydration sequence according to litera- β-ketoenamide 47 as main product (Scheme 3). Instead, a
ture procedures [41,42]. Not all transformations proceeded in diastereomeric 1:1 mixture of the β-keto-enolester 48 was
966

Beilstein J. Org. Chem. 2011, 7, 962–975.
Scheme 3: Reaction of proline derivative 45 and formation of β-ketoenamide 47 and enolester 48.
isolated in 49% yield together with minor amounts of the
Table 2: Esterification of different pyridinol derivatives with the 3,3,3-
expected product 47. The formation of 48 is additional evi-
dence for our previously suggested mechanism (Scheme 2). We
assume that the bulkiness of the trityl group hampers the
transfer of the acyl group from intermediate 46 to 47. Upon the
addition of water, the enamine moiety of 46 was hydrolyzed to
furnish enol ester 48.
trifluoro-2-methoxy-2-phenylpropanoic acid.
The pyridines in Table 1 are depicted in their predominant
tautomeric form as found in CDCl3 at ambient temperature.
Interestingly, the pyridone/pyridinol equilibrium seems to
depend on the substituents at the C-2 or C-6 side chains. In
general, a hydrogen bond-acceptor seems to stabilize the pyri-
done tautomer, whereas the pyridinol tautomer is favored when
a hydrogen bond-donor is present. Compound 37 exists exclu-
sively as pyridone tautomer, but after desilylation the resulting
product, with a free hydroxy group in the side chain, strongly
prefers the pyridinol tautomer. It seems reasonable to assume
that the pyridone tautomer is stabilized through an internal
hydrogen bond between a silyl ether or a tertiary amine moiety
of the side chain as observed for compounds 22 and 24. More-
over, we found that the equilibrium is strongly influenced by
the solvent. In CDCl3 pyridine 40 exclusively exists in its pyri-
done form, but in methanol-d4 the equilibrium shifts completely
to the pyridinol tautomer.
Pyridine
Product
Yield
68%
dr >95:5a
22
55%
dr >95:5a
18
Subsequent transformations of the
prepared pyridine derivatives
To prove the enantiopurity of the pyridines derived from
carboxylic acids and nitriles, which are prone to racemization,
i.e., substrates with tertiary stereogenic centers in α-position,
compounds 18, 22 and 40 were transformed into esters 50, 49
and 51, respectively (Table 2). Treatment of the pyridones with
Mosher acid chloride in a mixture of pyridine and
dichloromethane as solvent afforded the desired esters in good
yields. Comparison with the diastereomeric compounds
67%
dr >95:5a
40
aDetermined by 1H NMR spectroscopic analysis of the crude products.
967

Beilstein J. Org. Chem. 2011, 7, 962–975.
Figure 1: 1H NMR spectra of 49 and the mixture of diastereoisomers 49 and 49’.
obtained from racemic starting materials unambiguously shows catalyzed transformations such as Suzuki, Stille, Heck and
that the sequence proceeds without noticeable racemization, Sonogashira reactions [45].
since 49, 50 and 51 were obtained in diastereomeric pure form
(Table 2) as judged by 1H NMR analysis (estimated error However, in contrast to the smooth nonaflation, the selective
3–5%). For instance, the signal of the methoxy group at C-3 of O-alkylation of the synthesized pyridines turned out to be more
diastereomeric 49’ (obtained by starting with racemic mandelic challenging (Scheme 5). Whereas pyridone 22 could be
acid) appears at 3.43 ppm in the 1H NMR-spectrum, whereas
this signal for 49 occurs at 3.49 ppm (Figure 1). In addition, the
tert-butyl group of the OTBS groups of the two diastereoiso-
mers 49 and 49’ show signals at different frequencies.
To explore the chemistry of the synthesized pyridine deriva-
tives, we investigated the selective functionalization of the
4-hydroxy group. Pyridone 20 was nonaflated according to
previously established conditions to provide 52 in 56% yield
(Scheme 4). As we have already demonstrated, pyrid-4-yl
nonaflates are excellent coupling partners in palladium-
Scheme 5: O-Methylation of pyridine derivatives 22 and 30 followed
Scheme 4: Synthesis of pyrid-4-yl nonaflate 52.
by desilylation.
968

Beilstein J. Org. Chem. 2011, 7, 962–975.
O-methylated in good yield with methyl iodide in THF, the at the stage of the β-alkoxy-β-ketoenamides 58 obtained by the
same conditions converted 30 into 55 in a disappointing 30% three-component reaction. Recently we demonstrated that
yield. Desilylation of 53 and 55 with HF in pyridine gave the β-alkoxy-β-ketoenamides are not only valuable intermediates in
desired deprotected pyridine derivatives 54 and 56 in high the synthesis of 4-hydroxypyridines 57, but that they can also
yields. This type of enantiopure hydroxymethyl-substituted serve as precursors in the synthesis of 5-alkoxypyrimidines 59
pyridine derivatives is of particular interest as they are known to (Scheme 6). When β-alkoxy-β-ketoenamides 58 were treated
be efficient catalysts for the asymmetric addition of zinc with an ammonia source such as NH4OAc in MeOH,
organyls to aldehydes [14,46].
5-alkoxypyrimidines with the general structure of 59 were
formed in high yields [37,38,47]. By this simple change in the
reaction conditions not only pyridine but also pyrimidine
derivatives with lactic acid based side chains should be acces-
sible.
Preparation of lactic acid derived pyrid-
4-yl nonaflates
In the course of our investigations on the scope of the present
procedure, we also discovered that easily available O-TBS-
protected lactic acid and O-TBS-protected lactic nitrile are
excellent reaction partners. We became interested in exploring
the scope of this reaction with respect to lactic acid derived
starting materials in more detail. In contrast to the previously
described procedures, we decided to purify the reaction mixture
O-TBS-protected lactic nitrile 63 was prepared following a
literature procedure in four steps starting from enantiopure
methyl lactate [48]. The scope of the multicomponent reaction
with respect to lactic acid derived precursors is summarized in
Table 3.
Scheme 6: Formation of 5-alkoxypyrimidines from β-alkoxy-β-ketoenamides.
Table 3: Scope of the synthesis of β-alkoxy-β-ketoenamides derived from lactic acid based precursors.
Carboxylic Acid
R2CO2H
Nitrile
R1-CN
Product
Yield
58%
58%
969

Beilstein J. Org. Chem. 2011, 7, 962–975.
Table 3: Scope of the synthesis of β-alkoxy-β-ketoenamides derived from lactic acid based precursors. (continued)
73%
73%
51%
25%
Table 3 shows that O-TBS-protected lactic acid 60 and O-TBS- ture of the original ketoenamide. Even the configuration of the
protected lactic nitrile 63 gave the desired ketoenamides in enamide double bond seems to have no influence on the
moderate to high yields. When lithiated methoxyallene was cyclization, since the (E/Z)-mixture of enamide 66 also gave the
reacted with pivalonitrile or benzonitrile followed by the add- corresponding pyridine in good yield. Obviously, the diastere-
ition of O-TBS-protected lactic acid, the corresponding keto- omers are in equilibrium under the cyclization conditions. Of
enamides 61 and 62 were isolated in 58% yield. Reaction of particular interest are the pyrid-4-yl nonaflates 71 and 72,
lithiated methoxyallene with O-TBS-protected lactic nitrile and possessing a chiral side chain as well as heteroaromatic units.
benzoic acid furnished 64 in high yield. Heterocyclic moieties 2,2’-Bipyridines with structures similar to 72 might show
were also well tolerated as demonstrated by the efficient reac- interesting properties when used as ligands in asymmetric trans-
tion of 2-thiophene carboxylic acid. The relatively low yield in formations. The nonaflate moiety should allow electronic fine
the formation of 66 might be explained by the poor solubility of tuning of the ligand properties in palladium-catalyzed or nucle-
2-picolinic acid in ethereal solvents rather than for reactivity ophilic substitution reactions.
reasons. In contrast to the other examples, enamide 66 was
obtained as a 1:1 mixture of (E)- and (Z)-isomers. This may be Conclusion
due to alternative hydrogen bond formation with the NH unit to We have demonstrated that enantiopure functionalized
the pyridine nitrogen rather than to the carbonyl group. Subse- carboxylic acids and nitriles can be used without problems in
quent cyclocondensation with TMSOTf and NEt3 in 1,2- our previously reported pyridine synthesis. The starting ma-
dichloroethane gave the expected pyridine derivatives, which terials were successfully transformed into the corresponding
were directly converted into pyrid-4-yl nonaflates in a second pyridines without loss of enantiopurity to yield enantiopure
step. The results are depicted in Table 4.
4-hydroxypyridine derivatives with stereogenic side chains at
C-2 and C-6. The 4-hydroxy group allows further variations.
In all examples the cyclization/nonaflation sequence provided Applications of the prepared pyridines as ligands or catalysts in
the pyrid-4-yl nonaflates in good yields. Apparently, the re- asymmetric transformations will be studied and will be the
activity in this sequence is not strongly governed by the struc- subject of future reports.
970

Beilstein J. Org. Chem. 2011, 7, 962–975.
Table 4: Cyclization and nonaflation of lactic acid derived β-alkoxy-β-ketoenamides.
β-Alkoxy-β-ketoenamide
Product
Yielda
56%
61%
63%
52%
72%
39%
aYields over two steps based on the ketoenamide.
971

Beilstein J. Org. Chem. 2011, 7, 962–975.
Experimental
layers were washed with brine, dried with Na2SO4, filtered and
General methods: Reactions were generally performed under the solvent was evaporated under reduced pressure. The residue
an argon atmosphere in flame-dried flasks, and the components was re-dissolved in CH2Cl2 (14 mL) and TMSOTf (0.41 mL,
were added by syringe. Methanol was purchased in p.a. quality 2.1 mmol) and NEt3 (0.30 mL, 2.1 mmol) were added. The mix-
and stored under an argon atmosphere over molecular sieves ture was heated under reflux under an atmosphere of argon for
(4 Å). Triethylamine was distilled from CaH2 and stored over 2 d. After complete consumption of the starting material (by
KOH under an atmosphere of argon. Pyridine was used as TLC), the reaction was quenched by the addition of aq. sat.
purchased and stored over KOH under an atmosphere of argon. NH4Cl solution (20 mL) and the aqueous layer extracted with
1,2-Dichloroethane was purchased in p.a. quality and stored CH2Cl2 (2 × 30 mL). The combined organic layers were dried
over molecular sieves (4 Å) under an atmosphere of argon. with Na2SO4, filtered and evaporated. The residue was purified
Tetrahydrofuran, diethyl ether, toluene and dichloromethane by flash column chromatography on silica gel (eluent: hexane/
were obtained from the solvent purification system MB-SPS- ethyl acetate 1:9) to afford 18 (41 mg, 24%) as colorless crys-
800 (M. Braun). Products were purified by flash chromatog- tals.
raphy on silica gel (230–400 mesh, Merck). Unless otherwise
stated, yields refer to analytically pure samples. Internal (S)-6-sec-Butyl-2-tert-butyl-3-methoxypyridin-4-one (18):
standards: for 1H NMR CDCl3 (δ = 7.26 ppm), TMS mp 109–110 °C; [α]D22 +20.9 (c 2.3, CHCl3); 1H NMR (500
(δ = 0.00 ppm), CD3OD (δ = 3.31 ppm), C6D6 (δ = 7.16 ppm), MHz, CDCl3) δ 0.90 (t, J ≈ 7 Hz, 3H, 4’-H), 1.24 (d, J = 6.9
for 13C NMR CDCl3 (δ = 77.0 ppm), CD3OD (δ = 49.0 ppm), Hz, 3H, 1’-H), 1.43 (s, 9H, t-Bu), 1.59 (quint, J ≈ 7 Hz, 2H,
C6D6 (δ = 128.1 ppm). NMR spectra were recorded on Bruker 3’-H), 2.47 (sext, J ≈ 7 Hz, 1H, 2’-H), 3.94 (s, 3H, OMe), 6.26
AC 250, ECP 400, AC 500, AVIII 700, or Jeol Eclipse 500 (s, 1H, 5-H), 7.74 (s, 1H, NH) ppm; 13C NMR (101 MHz,
instruments in CDCl3, CD3OD, or C6D6 solution. Integrals are CDCl3) δ 11.8 (q, C-4’), 19.5 (q, C-1’), 28.4, 29.5 (2, s, t-Bu),
in accord with assignments; coupling constants are given in Hz. 35.1 (t, C-3’), 39.9 (d, C-2’), 58.9 (q, OMe), 114.2 (d, C-5),
IR spectra were measured with a FT-IR spectrometer Nicolet 5 146.0, 146.4, 150.7 (3 s, C-2, C-3, C-6), 176.1 (s, C-4) ppm; IR
SXC or with a Nexus FT-IR equipped with a Nicolet Smart (KBr) : 3250 (N-H), 2965–2910 (=C-H, C-H), 1620 (C=O),
DuraSamplIR ATR. MS and HRMS analyses were obtained 1580, 1540 (C=C) cm−1; HRMS–ESI (m/z): [M + H]+ calcd for
with Finnigan Varian Ionspec QFT-7 (ESI-FT-ICR) and Agilent C14H24NO2, 238.1807; found, 238.1803; Anal. calcd for
ESI-TOF 6210 (4 μL/min, 1 bar, 4000 V) instruments. C14H23NO2: C, 70.85; H, 9.77; N, 5.90; found: C, 70.81; H,
Elemental analyses were obtained with “Elemental-Analyzers“ 9.79; N, 5.38.
(Perkin–Elmer or Carlo Erba). Melting points were measured
Typical procedure for the preparation of
with a Reichert apparatus (Thermovar) and are uncorrected.
Optical rotations ([α]D) were determined with a Perkin–Elmer β-alkoxy-β-ketoenamides (Procedure 2)
241 polarimeter at the temperatures given. Commercially avail- A solution of n-BuLi (1.30 mL, 3.28 mmol, 2.5 M in hexanes)
able chemicals were used without further purification unless was added to a solution of methoxyallene (0.30 mL, 3.28 mmol)
otherwise stated.
in diethyl ether (20 mL) at −50 °C. After stirring for 30 min at
−50 °C, the reaction mixture was cooled to −78 °C and (S)-
TBS-lactic nitrile (200 mg, 1.14 mmol) in anhydrous diethyl
ether (5 mL) was added to the mixture. After stirring for 4 h, a
solution of benzoic acid (0.84 g, 6.88 mmol) in anhydrous DMF
(10 mL) was added. The mixture was stirred overnight and
slowly allowed to reach r.t. The reaction was quenched with sat.
Typical procedure for the preparation of
3-methoxy-4-hydroxypyridines without isola-
tion of the intermediate β-alkoxy-β-keto-
enamide (Procedure 1)
A solution of n-BuLi (2.5 M in hexanes, 0.31 mL, 0.79 mmol) aq. NaHCO3 solution (15 mL) and the product extracted with
was added dropwise to a solution of methoxyallene (59 µL, diethyl ether (3 × 40 mL). The combined organic layers were
0.71 mmol) in diethyl ether (5 mL) at −40 °C. After stirring at washed with brine, dried with Na2SO4, filtered and the solvent
that temperature for 15 min, pivalonitrile was added (59 mg, was removed under reduced pressure. The crude product was
0.71 mmol) and the resulting yellow solution stirred for 4 h at purified by column chromatography on silica gel
−40 °C. The solution was then cooled to −78 °C and (S)-2- (eluent:hexane/EtOAc 3:1) to give 64 as a pale yellow oil (300
methylbutyric acid (0.23 mL, 2.14 mmol) added. Stirring was mg, 73%).
continued overnight during which time the mixture was slowly
allowed to reach r.t. The reaction was quenched by the addition (S)-N-{1-[1-(tert-Butyldimethylsiloxy)ethyl]-2-methoxy-3-
of sat. aq. NaHCO3 solution (10 mL) and the aqueous phase oxo-but-1-enyl}benzamide (64) 1H NMR (500 MHz, CDCl3) δ
extracted with diethyl ether (2 × 20 mL). The combined organic 0.07, 0.11, 0.88 (3 s, 3H, 3H, 9H, OTBS), 1.46 (d, J = 6.4 Hz,
972

Beilstein J. Org. Chem. 2011, 7, 962–975.
3H, 2’’-H), 2.32 (s, 3H, 4’-H), 3.51 (s, 3H, OMe), 5.33 (q, J = [M + H]+ calcd for C24H29F9NO5SSi, 642.1387; found,
6.4 Hz, 1H, 1’’-H), 7.43–7.53, 7.85–7.87 (2 m, 3H, 2H, Ph), 642.1403.
10.10 (br s, 1H, NH) ppm; 13C NMR (125 MHz, CDCl3) δ
Typical procedure for the esterification of
−4.8, −4.7 (2 q, OTBS), 18.2 (q, C-4’), 21.9 (q, C-2’’), 25.9,
4-pyridones with 3,3,3-trifluoro-2-methoxy-2-
phenylpropanoic acid (Procedure 4)
27.2 (2, q, OTBS), 60.9 (q, OMe), 65.6 (d, C-1’’), 127.5, 128.8,
132.2, 134.2, 139.6, 141.9 (3 d, 3 s, Ph, C-1’, C-2’), 165.0 (s,
C-1), 200.2 (s, C-3’) ppm; IR (ATR) : 3315 (NH), 2955–2855
(=CH, C-H), 1720–1515 (C=O, C=C) cm−1; HRMS–ESI (m/z):
[M + H]+ calcd for C20H31NNaO4Si, 400.1915; found,
400.1930.
Pyridone 22 (22 mg, 0.06 mmol) was dissolved in anhydrous
CH2Cl2 (0.3 mL) and anhydrous pyridine (0.3 mL), and (S)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (17 µL,
0.09 mmol) added. The mixture was stirred under an atmos-
phere of argon at r.t. for 16 h. After complete consumption of
the starting material (TLC), the mixture was diluted with
CH2Cl2 (10 mL) and the organic layer was successively washed
with sat. NaHCO3 solution, 1 M HCl and H2O (10 mL each).
The organic layer was dried with Na2SO4, filtered and the
solvent was removed under reduced pressure to afford 49
(25 mg, 68%) as a colorless oil.
Typical procedure for the cyclization of
β-alkoxy-β-ketoenamides to 4-hydrox-
ypyridines and subsequent nonaflation
(Procedure 3)
Enamide 64 (40 mg, 0.11 mmol) was dissolved in 1,2-
dichloroethane (2 mL) and placed in a sealable tube. Triethyl-
amine (48 µL, 0.32 mmol) and TMSOTf (58 µL, 0.32 mmol) (S,S)-2-tert-Butyl-6-[(tert-butyldimethylsiloxy)phenyl-
were added at r.t., and the resulting mixture was heated at 90 °C methyl]-3-methoxypyridin-4-yl 3,3,3-trifluoro-2-methoxy-2-
for 2 d. After complete consumption of the starting material phenylpropanoate (49): [α]D22 +14.0 (c 1.0, CHCl3); 1H NMR
(TLC), the reaction was quenched with sat. aq. NH4Cl solution (500 MHz, CDCl3) δ 0.01, 0.02, 0.96 (s, 3H, 3H, 9H, OTBS),
(2 mL). After extraction with dichloromethane (3 × 10 mL), the 1.35 (s, 9H, t-Bu), 3.49, 3.68 (2 s, 3H each, OMe), 5.80 (s, 1H,
combined organic layers were dried with Na2SO4 filtered and 1’-H), 7.17 (s, 1H, 5-H), 7.19–7.22, 7.27–7.31, 7.48–7.53,
the solvent was removed under reduced pressure. The crude 7.61–7.71 (4 m, 10H, Ph) ppm; 19F NMR (376 MHz, CDCl3) δ
product was purified by flash column chromatography (SiO2, −71.1 (s, CF3) ppm; IR (neat) : 2955–2930 (C-H), 1775
EtOAc/Methanol 10:1) to afford the respective pyridine deriva- (C=O), 1570–1450 (C=C), 1170–1105 (=C-H), 780–700 (C-F)
tive (36 mg, 94%) as a brown liquid.
cm−1; HRMS–ESI (m/z): [M + H]+ calcd for C33H43F3NO5Si,
618.2857; found, 618.2896.
The pyridine derivative (33 mg, 0.09 mmol) was dissolved in
THF (3 mL) and NaH (6.6 mg, 0.28 mmol) added under an
argon atmosphere. Nonafluorobutanesulfonyl fluoride (50 µL,
0.28 mmol) was added dropwise at room temperature. The mix-
ture was stirred at the same temperature for 12 h and quenched
by the slow addition of water. The resulting product was
extracted with diethyl ether (3 × 10 mL), dried with Na2SO4,
filtered and concentrated to dryness. The residue was purified
by column chromatography on silica gel (eluent: 2–5% EtOAc
in hexane) to afford 70 (39 mg, 67%) as a colorless oil.
Supporting Information
Supporting Information File 1
Experimental procedures and characterization data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-108-S1.pdf]
Supporting Information File 2
1H NMR and 13C NMR spectra of synthesized compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-108-S2.pdf]
(S)-2-[1-(tert-Butyldimethylsiloxy)ethyl]-3-methoxy-6-phe-
nyl-pyridin-4-yl nonaflate (70): [α]D22 −21.2 (c 0.3, CHCl3);
1H NMR (500 MHz, CDCl3) δ 0.00, 0.05, 0.87 (3 s, 3H, 3H,
9H, OTBS), 1.60 (d, J = 6.6 Hz, 3H, 2’-H), 3.95 (s, 3H, OMe), Acknowledgements
5.30 (q, J = 6.6 Hz, 1H, 1’-H), 7.42–7.48 (m, 3H, Ph), 7.51 (s, Generous support of this work by the Deutsche Forschungsge-
1H, 5-H), 7.97–7.98 (m, 2H, Ph) ppm; 13C NMR (125 MHz, meinschaft (SFB 765), the Studienstiftung des Deutschen
CDCl3) δ −4.6, −4.4 (2 q, OTBS), 18.3 (q, C-2’), 25.9, 30.3 (2, Volkes (PhD fellowship to CE) and the Bayer Schering Pharma
s, OTBS), 62.6 (q, OMe), 68.8 (d, C-1’), 112.3, 126.9, 128.8, AG is most gratefully acknowledged. We thank Dr. R. Zimmer
129.5, 137.7, 144.4, 150.1, 153.7, 160.0 (4 d, 5 s, Ph, C-2, C-3, for help during the preparation of the manuscript.
C-4, C-5, C-6) ppm; IR (ATR) : 3310 (NH), 3010–2835
(=CH, C-H), 1685–1510 (C=O, C=C) cm−1; HRMS–ESI (m/z):
973

Beilstein J. Org. Chem. 2011, 7, 962–975.
27.Rahm, F.; Stranne, R.; Bremberg, U.; Nordstrom, K.; Cernerud, M.;
Macedo, E.; Moberg, C. J. Chem. Soc., Perkin Trans. 1 2000,
1983–1990. doi:10.1039/b000269k
References
1. Newkome, G. R. In Chemistry of Heterocyclic Compounds;
Newkome, G. R., Ed.; Wiley: New York, 1984; Vol. 15.
2. McKillop, A.; Boulton, A. J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;
Vol. 2, pp 67 ff.
28.Rahm, F.; Fischer, A.; Moberg, C. Eur. J. Org. Chem. 2003,
4205–4215. doi:10.1002/ejoc.200300368
29.Flögel, O.; Dash, J.; Brüdgam, I.; Hartl, H.; Reissig, H.-U.
Chem.–Eur. J. 2004, 10, 4283–4290. doi:10.1002/chem.200400322
30.Dash, J.; Lechel, T.; Reissig, H.-U. Org. Lett. 2007, 9, 5541–5544.
doi:10.1021/ol702468s
3. Kleemann, A.; Engel, J.; Kutscher, B. Pharmaceutical Substances;
Thieme: Stuttgart, 2000.
4. Spitzner, D. Science of Synthesis; Thieme: Stuttgart, 2004; Vol. 15.
5. Jones, G. In Comprehensive Heterocyclic Chemistry II; McKillop, A.,
Ed.; Pergamon Press: Oxford, 1996; Vol. 5, pp 167 ff.
6. Wess, G.; Kesseler, K.; Baader, E.; Bartmann, W.; Beck, G.;
Bergmann, A.; Jendralla, H.; Bock, K.; Holzstein, O.; Kleine, H.;
Schnierer, M. Tetrahedron Lett. 1990, 31, 2545–2548.
doi:10.1016/0040-4039(90)80121-2
31.Lechel, T.; Dash, J.; Hommes, P.; Lentz, D.; Reissig, H.-U.
J. Org. Chem. 2009, 75, 726–732. doi:10.1021/jo9022183
32.Lechel, T.; Reissig, H.-U. Pure Appl. Chem. 2010, 82, 1835–1845.
doi:10.1351/PAC-CON-09-09-06
33.Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc. Chem. Res. 2009, 42,
45–56. doi:10.1021/ar800011h
34.Lechel, T.; Dash, J.; Brüdgam, I.; Reissig, H.-U. Eur. J. Org. Chem.
2008, 3647–3655. doi:10.1002/ejoc.200800398
7. Miyachi, N.; Yanagawa, Y.; Iwasaki, H.; Ohara, Y.; Hiyama, T.
Tetrahedron Lett. 1993, 34, 8267–8270.
35.Zimmer, R.; Reissig, H.-U. Donor-Substituted Allenes. In Modern
Allene Chemistry; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004; pp 425–492.
doi:10.1016/S0040-4039(00)61407-7
8. Beck, G. Synlett 2002, 837–850. doi:10.1055/s-2002-31890
9. Beck, G.; Kesseler, K.; Baader, E.; Bartmann, W.; Bergmann, A.;
Granzer, E.; Jendralla, H.; Von Kerekjarto, B.; Krause, R.
J. Med. Chem. 1990, 33, 52–60. doi:10.1021/jm00163a010
10.Cattaneo, D.; Baldelli, S.; Merlini, S.; Zenoni, S.; Perico, N.;
Remuzzi, G. Expert Opin. Ther. Pat. 2004, 14, 1553–1566.
doi:10.1517/13543776.14.11.1553
36.Reissig, H.-U.; Zimmer, R. Cumulenes and Allenes: Synthesis from
Other Allenes. In Science of Synthesis; Krause, N., Ed.; Thieme:
Stuttgart, 2007; Vol. 44, pp 301–352.
37.Bera, M. K.; Reissig, H.-U. Synthesis 2010, 2129–2138.
doi:10.1055/s-0029-1218787
38.Zimmer, R.; Lechel, T.; Rancan, G.; Bera, M. K.; Reissig, H.-U. Synlett
2010, 1793–1796. doi:10.1055/s-0030-1258088
11.O'Hagan, D. Nat. Prod. Rep. 1997, 14, 637–651.
doi:10.1039/NP9971400637
39.Lechel, T.; Dash, J.; Eidamshaus, C.; Brüdgam, I.; Lentz, D.;
Reissig, H.-U. Org. Biomol. Chem. 2010, 8, 3007–3014.
doi:10.1039/B925468D
12.Aida, W.; Ohtsuki, T.; Li, X.; Ishibashi, M. Tetrahedron 2009, 65,
369–373. doi:10.1016/j.tet.2008.10.040
13.Lehn, J.-M. Supramolecular Chemistry - Concepts and Perspectives;
VCH: Weinheim, 1995.
40.Eidamshaus, C.; Reissig, H.-U. Adv. Synth. Catal. 2009, 351,
1162–1166. doi:10.1002/adsc.200800789
14.Bolm, C.; Schlingloff, G.; Harms, K. Chem. Ber. 1992, 125, 1191–1203.
doi:10.1002/cber.19921250529
41.Couty, F.; David, O.; Larmanjat, B.; Marrot, J. J. Org. Chem. 2007, 72,
1058–1061. doi:10.1021/jo062221e
15.Kwong, H.-L.; Yeung, H.-L.; Yeung, C.-T.; Lee, W.-S.; Lee, C.-S.;
Wong, W.-L. Coord. Chem. Rev. 2007, 251, 2188–2222.
doi:10.1016/j.ccr.2007.03.010
42.Aureggi, V.; Frankevicius, V.; Kitching, M. O.; Ley, S. V.;
Longbottom, D. A.; Oelke, A. J.; Sedelmeier, G. Org. Synth. 2008, 85,
72–87.
16.Bolm, C.; Ewald, M.; Felder, M. Chem. Ber. 1992, 125, 1205–1215.
doi:10.1002/cber.19921250530
43.Traverse, J. F.; Zhao, Y.; Hoveyda, A. H.; Snapper, M. L. Org. Lett.
2005, 7, 3151–3154. doi:10.1021/ol050814q
17.Bolm, C.; Ewald, M.; Zehnder, M.; Neuburger, M. A. Chem. Ber. 1992,
125, 453–458. doi:10.1002/cber.19921250224
44.Barlos, K.; Papaioannou, D.; Theodoropoulos, D. J. Org. Chem. 1982,
47, 1324–1326. doi:10.1021/jo00346a031
18.Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963–983.
doi:10.1002/adsc.200800776
45.Högermeier, J.; Reissig, H.-U. Adv. Synth. Catal. 2009, 351,
2747–2763. doi:10.1002/adsc.200900566
19.Drury, W. J.; Zimmermann, N.; Keenan, M.; Hayashi, M.; Kaiser, S.;
Goddard, R.; Pfaltz, A. Angew. Chem., Int. Ed. 2003, 116, 72–76.
doi:10.1002/anie.200352755
46.Liebehentschel, S.; Cvengroš, J.; Jacobi von Wangelin, A. Synlett
2007, 2574–2578. doi:10.1055/s-2007-986630
47.Lechel, T.; Möhl, S.; Reissig, H.-U. Synlett 2009, 1059–1062.
doi:10.1055/s-0028-1088220
20.Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402–1411.
doi:10.1021/ar700113g
48.Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983, 48,
5180–5182. doi:10.1021/jo00174a006
21.Henry, G. D. Tetrahedron 2004, 60, 6043–6061.
doi:10.1016/j.tet.2004.04.043
22.Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007,
129, 10096–10097. doi:10.1021/ja073912a
23.Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918–6919.
doi:10.1021/ja8013743
24.Manning, J. R.; Davies, H. M. L. J. Am. Chem. Soc. 2008, 130,
8602–8603. doi:10.1021/ja803139k
25.Xin, X.; Wang, Y.; Kumar, S.; Liu, X.; Lin, Y.; Dong, D.
Org. Biomol. Chem. 2010, 8, 3078–3082. doi:10.1039/C001117G
26.Hill, M. D. Chem.–Eur. J. 2010, 16, 12052–12062.
doi:10.1002/chem.201001100
974

Beilstein J. Org. Chem. 2011, 7, 962–975.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.7.108
975