Highly functionalised enantiopure 4-hydroxypyridine derivatives by a versatile three-component synthesis

Article abstract of DOI:10.1002/adsc.200800789

The scope of a novel alkoxyallene-based pyridine synthesis was expanded to enantiopure carboxylic acids and nitriles as starting materials. The enantiomeric purity of the chiral α-secondary carboxylic acids and nitriles was completely preserved during thi

Full text of DOI:10.1002/adsc.200800789

UPDATES
DOI: 10.1002/adsc.200800789
Highly Functionalised Enantiopure 4-Hydroxypyridine
Derivatives by a Versatile Three-Component Synthesis
Christian Eidamshausa and Hans-Ulrich Reissiga,*
a
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin, Takustr. 3, 14195 Berlin, Germany
Fax : (+49)-30-838-55367; e-mail: hans.reissig@chemie.fu-berlin.de
Received: December 18, 2008; Published online: May 5, 2009
Dedicated to Professor Armin de Meijere on the occasion of his 70th birthday.
Abstract: The scope of a novel alkoxyallene-based
pyridine synthesis was expanded to enantiopure car-
boxylic acids and nitriles as starting materials. The
enantiomeric purity of the chiral a-secondary car-
boxylic acids and nitriles was completely preserved
during this reaction sequence thus allowing the
one-pot preparation of a whole range of 4-hydroxy-
pyridines or their 4-pyridinone tautomers in good
Scheme 1. A new three-component synthesis of highly func-
tionalised pyridines.
yields.
Keywords: alkoxyallenes; carboxylic acids; chiral li-
gands; nitriles; pyridines
ethylamine induces an intramolecular Mukaiyama-
type aldol reaction to convert the remaining enamide
intermediates into the corresponding 4-hydroxypyri-
dines.
The proposed mechanism of this reaction cascade
Pyridine derivatives are ubiquitous in the realms of leading to 4-hydroxypyridines is outlined in Scheme 2.
pharmacologically active compounds, agrochemicals In the first step the lithiated alkoxyallene adds to the
and natural products.[1] Moreover, ligands containing
the pyridine core such as pyridine-2,6-bis(oxazolines)
(pybox),[2] 1,10-phenanthrolines, 2,2’-bipyridines[3] and
2,2’:6’,2’’-terpyridines[4] are of great importance in
(asymmetric) catalysis. This background explains why
new and efficient approaches towards enantiopure,
highly functionalised pyridines are of considerable in-
terest.[5,6] Most syntheses rely on classical condensa-
tion reactions of carbonyl compounds or thermal and
metal-catalysed cycloadditions[7] but they are often re-
stricted in terms of functional group tolerability.[8]
Chirality is commonly introduced in a subsequent
enantioselective transformation or by any type of
chiral resolution. Incorporation of non-racemic chiral
starting materials provides another convenient route
for the synthesis of pyridines with stereogenic centres.
Recently, we reported a modular 4-hydroxypyridine
synthesis based on the reaction of lithiated alkoxyal-
lenes, nitriles and carboxylic acids.[9] As shown in
Scheme 1, a mixture of enamides and the desired 4-
hydroxypyridines is formed in this process. Subse-
quent treatment of the crude product with trimethyl-
silyl trifluoromethanesulfonate (TMSOTf) and tri- ide C, 4-hydoxypyridine E and 4-pyridinone F.
Scheme 2. Proposed mechanism for the formation of enam-
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Highly Functionalised Enantiopure 4-Hydroxypyridine Derivatives
UPDATES
Table 1. Scope of carboxylic acids in the synthesis of chiral
4-hydroxypyridines.
nitrile to furnish the expected primary adduct. Proto-
nation of the intermediate iminoallene by the carbox-
ylic acid furnishes the resonance-stabilised cation A,
which is attacked in the b-position by the carboxylate
to give intermediate B. Enamide C is formed via an
acyl transfer reaction and undergoes an intramolecu-
lar aldol-type condensation to afford 4-hydroxypyri-
dine E. In general, E is in equilibrium with the corre-
sponding 4-pyridinone F. In the subsequent illustra-
tions all pyridine derivatives are depicted in their pre-
dominating tautomeric form (in CDCl3 at room tem-
perature).
So far, it could be demonstrated that a variety of
substituted nitriles and carboxylic acids can success-
fully be converted into the corresponding 4-hydroxy-
pyridines E. Besides methoxyallene, other alkoxyal-
lenes are also suitable.[9] We were now interested to
expand the scope of this unique transformation by in-
corporation of chiral acids and nitriles.
The scope of this reaction is presented in Table 1.
As can be seen the protocol allows for the synthesis
of a wide range of substrates. Branched alkyl- and
aryl-substituted carboxylic acids (Table 1, entries 1
and 2), acids with quaternary a-carbon atoms
(Table 1, entry 3), tert-butyldimethylsilyl (TBS)-pro-
tected mandelic acid (Table 1, entry 4) and N,N-di-
benzylated amino acids (Table 1, entry 5) were suita-
ble precursors.
Entries 6 and 7 show limitations of the current pro-
tocol: TBS-protected b-hydroxy carboxylic acids
(Table 1, entry 6) and Cbz-protected amino acids such
as isoleucine (Table 1, entry 7) were not tolerated. In
general, the yields obtained over both steps (without
separation and purification of the enamide intermedi-
ate C) were fair to good.
To prove that not only chiral carboxylic acids can
be successfully incorporated but also chiral nitriles,
(S)-2-methylbutyronitrile (13) was treated with lithiat-
ed methoxyallene and trifluoroacetic acid to give the
corresponding 4-hydroxypyridine 14 in 56% yield
(Scheme 3). Unfortunately, (S)-tetrahydrofuran-2-car-
bonitrile did not afford the desired pyridine. Competi-
[a]
All yields refer to the converted nitrile.
tive elimination processes in the TMSOTf-promoted
cyclisation step might be responsible for the failure of
more sensitive compounds such as tetrahydrofuran-2-
carbonitrile or compound 11 (Table 1, entry 5).
Syntheses of pyridine derivatives containing neither
a tert-butyl group in position 2 nor bearing a trifluoro-
methyl group in position 6 are collected in Table 2.
The 4-pyridinone 15, which has close to C2-symmetry,
was prepared in 85% yield demonstrating that pyri-
dines with two stereogenic centres can smoothly be
prepared by our approach. The formation of diaste-
reomers due to (partial) racemisation was not ob-
served. Reaction between TBS-protected mandelic
acid (ent-7, Table 2, entry 2) and benzonitrile afforded
Scheme 3. Conversion of (S)-2-methylbutyronitrile into the
the desired 4-pyridinone, however, compared to the 4-hydroxypyridine derivative 14.
Adv. Synth. Catal. 2009, 351, 1162 – 1166
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Christian Eidamshaus and Hans-Ulrich Reissig
UPDATES
Table 2. Chiral pyridines with other substituents.
In conclusion, the scope of a new alkoxyallene-
based[12] three-component pyridine synthesis could
successfully be expanded to more complex starting
materials. We could demonstrate that enantiopure
carboxylic acids or nitriles can smoothly be converted
into the corresponding pyridine derivatives without
detectable loss of enantiomeric purity. On the basis of
three representative compounds, it was possible to
show that carboxylic acids and nitriles with a-secon-
dary stereogenic centres do not undergo racemisation
under the employed conditions. The coordination
chemistry of these compounds – which should be
prone to fine tuning of their properties by employing
the two oxy functionalities[9] – and their application as
ligands in asymmetric transition metal-catalysed pro-
cesses are under investigation.
Experimental Section
[a]
All yields refer to the converted nitrile.[a] All yields refer
to the converted nitrile.
General Methods
Reactions involving moisture- or oxygen-sensitive reagents
were performed under an atmosphere of dry argon in oven-
or flame-dried glassware. Solvents and reagents were han-
dled and added by standard Schlenk techniques. The reac-
tion temperatures stated were those of the external bath.
reaction of 7 and pivalonitrile (Table 1, entry 4) the
yield dropped significantly in this case.
To prove whether enantiopure starting materials,
intermediates and products would racemise under the
employed conditions, 4-hydroxypyridines 2, 8, and 14 THF, Et2O, CH2Cl2 and acetonitrile were purified using the
were converted with Mosherꢃs acid chloride[10,11] into
solvent purification system SPS 800 by M. Braun. Anhy-
drous DMF was purchased from Aldrich and stored under
an argon atmosphere in sure sealꢄ bottles. Pyridine was dis-
the corresponding esters 17, 18 and 19 (Scheme 4). In
all cases the dr of the obtained products was found to
1
tilled from calcium hydride and stored over molecular sieves
4 ꢅ. Triethylamine was heated with calcium hydride, dis-
tilled and stored over KOH pellets. Hexane and ethyl ace-
tate were distilled from calcium hydride. All other reagents
were used as purchased without further purification unless
otherwise stated.
be higher than 95:5 by means of H NMR spectrosco-
py. Thus, the enantiomeric excess of the 4-hydroxy-
pyridines 2, 8 and 14 has to be higher than 90%. It
can be assumed that substrates with comparable pKa
values for the protons adjacent to the cyano and car-
boxylate group do not lead to racemisation during
this three-component synthesis of pyridines.
All proton, carbon and fluorine nuclear magnetic reso-
nance spectra (1H NMR, 13C NMR and 19F NMR spectra)
were recorded using Bruker AC 250 (250 MHz), Bruker AC
500 (500 MHz), Bruker ECP 400 (400 MHz) or Joel Eclipse
500 (500 MHz) instruments at ambient temperature. Chemi-
cal shifts (d) for all compounds are listed in parts per million
(ppm) and refer to solvent residual peaks (1H NMR: CDCl3
7.26 ppm, CD3OD 3.34 ppm; 13C NMR: CDCl3 77.0 ppm,
CD3OD 49.0) as internal standards. Integrals are in accord-
ance with assignments; coupling constants are given in Hz.
All 13C NMR spectra were proton-decoupled. For detailed
peak assignments 2D spectra were measured (COSY,
HMQC). Mass spectra and HR-MS analyses were recorded
with Agilent 6210 (ESI-ToF, 4 kV), Varian Ionspec QFT-7
(ESI-FT ICR-MS) or Finnigan MAT 711 (EI, 80 eV, 8 kV)
instruments. IR spectra were recorded as KBr pellets for
solid samples or as film between KBr plates for liquid sam-
ples on a Nicolet 5 SXC FT-IR Interferometer equipped
with a DTGS detector or on a Nicolet Avator 320 FT-IR
spectrometer. Elemental analyses were recorded with a
CHN analyzer 2400 from Perkin–Elmer. Optical rotations
were recorded using a Perkin–Elmer 241 polarimeter. Melt-
ing points were measured with a melting point microscopy
apparatus (Reichert Thermovar) and are uncorrected.
Scheme 4. Esterification of 4-hydroxpyridines (or their pyri-
dinone tautomers) with Mosherꢃs acid chloride.
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Highly Functionalised Enantiopure 4-Hydroxypyridine Derivatives
UPDATES
propanoate (18): 22 mg (0.06 mmol) of
8 and 17 mL
Typical Procedure for the Preparation of
4-Hydroxypyridine Derivatives
(0.09 mmol) of (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropa-
noyl chloride were dissolved in 0.3 mL of pyridine and
0.3 mL of CH2Cl2 and stirred at ambient temperature over-
night. After complete consumption of the starting material
(as indicated by TLC) H2O was added, the organic layer
was separated and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried with
Na2SO4, filtered and the solvents were removed under re-
duced pressure to give spectroscopically pure 18 as a colour-
less oil; yield: 25 mg (68%); [a]2D2: +14 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3): d=0.01, 0.02, 0.96 (s, 3H, 3H,
9H, TBS), 1.35 (s, 9H, t-Bu), 3.49, 3.68 (2 s, 3H each, OMe),
5.80 (s, 1H, 1’-H), 7.17 (s, 1H, 5-H), 7.19–7.22, 7.27–7.31,
7.48–7.53, 7.61–7.71 (4 m, 10H, Ph); 19F NMR (376 MHz,
(S)-2-tert-Butyl-6-[(tert-butyldimethylsiloxy)phenylmethyl]-
3-methoxypyridin-4-one (8): 250 mL (3.00 mmol) of
methoxyACHTUNGTRENNUNGallene were dissolved in 6.6 mL of dry Et2O at
À408C and 1.16 mL (2.90 mmol) of a 2.5M solution of n-
BuLi in hexanes were added dropwise. The resulting light
yellowish solution was stirred at À408C for 30 min before
83 mg (1.00 mmol) of pivalonitrile were added. The mixture
was stirred for additional 4 h at À408C and then 1.60 g
(6.00 mmol, dissolved in a minimum amount of Et2O) of
(S)-2-(tert-butyldimethylsiloxy)-2-phenylacetic acid were
added at À788C. The reaction mixture was stirred overnight
during which time the mixture was allowed to warm to
room temperature. The reaction was quenched by addition
of saturated aqueous NaHCO3 solution and then extracted
with Et2O (three times). The combined organic layers were
dried with anhydrous Na2SO4, filtered and the solvent was
removed under vacuum. Successful conversion to the de-
sired enamide intermediate was evaluated on the basis of
1H NMR analysis.
˜
CDCl3): d=À71.1 (s, CF3); IR (film): n=2955, 2930 (C-H),
À
1775 (C=O), 1570, 1450 (C=C), 1170, 1105 (=C H), 780, 700
(C F) cmÀ1; HR-MS (ESI-ToF): m/z=618.2896, calcd. for
À
C33H43F3NO5Si [M+H]+: 618.2857.
The obtained crude material was redissolved in 6.6 mL of
anhydrous CH2Cl2 and 1.88 mL (12.0 mmol) of NEt3 and
2.61 mL (12.0 mmol) of TMSOTf were added. The mixture
was refluxed for three days. After complete consumption of
the starting material (as indicated by TLC) saturated aque-
ous NH4Cl solution was added, the organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2
(three times). The solvent was removed under reduced pres-
sure and the residue was redissolved in acetic acid (~5 mL)
and stirred for 30 min at room temperature to ensure com-
plete cleavage of remaining TMS groups. The solution was
diluted with water, the organic layer was separated and the
aqueous phase was extracted with CH2Cl2 (three times). The
combined organic layers were washed with saturated aque-
ous NaHCO3 solution and brine and dried with anhydrous
Na2SO4, filtered followed by removal of the solvent under
reduced pressure. The crude material was purified by flash
column chromatography on silica gel (eluent: hexane/ethyl
acetate 50:50 to 30:70 as linear gradient) to afford 8 as a
yellow oil; yield: 201 mg (51%); [a]2D2: À7.1 (c 10.7, CHCl3);
1H NMR (500 MHz, CDCl3): d=À0.08, 0.07, 0.90 (3 s, 3H,
3H, 9H, TBS), 1.40 (s, 9H, t-Bu), 3.89 (s, 3H, OMe), 5.56
(s, 1H, 1’-H), 6.13 (s, 1H, 5-H), 7.26–7.35 (m, 5H, Ph), 8.83
(s, 1H, NH); 13C NMR (126 MHz, CDCl3): d=À4.9, À4.7,
18.2, 25.8 (2q, s, q, TBS), 28.5, 35.3 (q, s, t-Bu), 58.8 (q,
OMe), 73.4 (d, C-1’), 113.9 (d, C-5), 126.4, 128.7, 128.9,
140.9 (3d, s, Ph), 145.6, 146.7, 147.1 (3 s, C-2, C-3, C-6),
À
Acknowledgements
Support by the Deutsche Forschungsgemeinschaft (SFB 765),
the Fonds der Chemischen Industrie and the Bayer Schering
Pharma AG is most gratefully acknowledged.
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Typical Procedure for the Esterification of 4-
Hydroxypyridines with (S)-3,3,3-Trifluoro-2-methoxy-
2-phenylpropanoyl Chloride
ACHTUNGTRENNUNG
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Christian Eidamshaus and Hans-Ulrich Reissig
UPDATES
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